tiotropium bromide hydrate : A hydrate that is the monohydrate form of tiotropium bromide. Used for maintenance treatment of airflow obstruction in patients with chronic obstructive pulmonary disease. [Chemical Entities of Biological Interest (ChEBI), Hastings J, Owen G, Dekker A, Ennis M, Kale N, Muthukrishnan V, Turner S, Swainston N, Mendes P, Steinbeck C. (2016). ChEBI in 2016: Improved services and an expanding collection of metabolites. Nucleic Acids Res]
Tiotropium Bromide: A scopolamine derivative and CHOLINERGIC ANTAGONIST that functions as a BRONCHODILATOR AGENT. It is used in the treatment of CHRONIC OBSTRUCTIVE PULMONARY DISEASE. [Medical Subject Headings (MeSH), National Library of Medicine, extracted Dec-2023]
tiotropium bromide : An organic bromide salt having (1alpha,2beta,4beta,5alpha,7beta)-7-[(hydroxydi-2-thienylacetyl)oxy]-9,9-dimethyl-3-oxa-9-azoniatricyclo[3.3.1.0(2,4)]nonane as the counterion. Used (in the form of the hydrate) for maintenance treatment of airflow obstruction in patients with chronic obstructive pulmonary disease. [Chemical Entities of Biological Interest (ChEBI), Hastings J, Owen G, Dekker A, Ennis M, Kale N, Muthukrishnan V, Turner S, Swainston N, Mendes P, Steinbeck C. (2016). ChEBI in 2016: Improved services and an expanding collection of metabolites. Nucleic Acids Res]
| ID Source | ID |
|---|---|
| PubMed CID | 11431811 |
| CHEMBL ID | 3545181 |
| CHEBI ID | 32230 |
| SCHEMBL ID | 155760 |
| SCHEMBL ID | 1405692 |
| MeSH ID | M0458357 |
| PubMed CID | 5487426 |
| CHEMBL ID | 3189058 |
| CHEMBL ID | 4440620 |
| CHEMBL ID | 4638964 |
| CHEBI ID | 90959 |
| SCHEMBL ID | 440873 |
| SCHEMBL ID | 8625 |
| SCHEMBL ID | 7607795 |
| MeSH ID | M0458357 |
| Synonym |
|---|
| 139404-48-1 |
| ba-679 br |
| ba 679 br |
| spiriva |
| ba-679-br |
| 411207-31-3 |
| tiotropium bromide monohydrate |
| tiotropium bromide hydrate |
| 3-oxa-9-azoniatricyclo(3.3.1.02,4)nonane, 7-((hydroxydi-2-thienylacetyl)oxy)-9,9-dimethyl-, bromide, hydrate, (1alpha,2beta,4beta,5alpha,7beta)- |
| 6beta,7beta-epoxy-3beta-hydroxy-8-methyl-1alphah,5alphah-tropanium bromide, di-2-thienylglycolate |
| unii-l64sxo195n |
| l64sxo195n , |
| 3-oxa-9-azoniatricyclo(3.3.1.02,4)nonane, 7-((hydroxydi-2-thienylacetyl)oxy)-9,9-dimethyl-, bromide, monohydrate, (1alpha,2beta,4beta,5alpha,7beta)- |
| tiotropium bromide [mart.] |
| tiotropium bromide monohydrate [orange book] |
| 6.beta.,7.beta.-epoxy-3.beta.-hydroxy-8-methyl-1.alpha.h,5.alpha.h-tropanium bromide, di-2-thienylglycolate monohydrate |
| tiotropium bromide hydrate [jan] |
| tiotropium bromide monohydrate [mi] |
| tiotropium bromide monohydrate [ep monograph] |
| tiotropium bromide monohydrate [who-dd] |
| 1.alpha., 2.beta., 4.beta, 5.alpha, 7.beta-7-((hydroxydi-2-thienylacetyl)oxy)-9,9-dimethyl-3-oxa-9-azoniatricyclo(3.3.1.0 sup(2,4))nonane bromide monohydrate |
| AKOS015900631 |
| S2547 |
| tiotropium bromide anhydrous |
| ba-679br |
| HY-B0460 |
| tiotropium (bromide hydrate) |
| SCHEMBL155760 |
| (1alpha,2beta,4beta,5alpha,7beta)-7-[(hydroxydi-2-thienylacetyl)oxy]-9,9-dimethyl-3-oxa-9-azoniatricyclo[3.3.1.0(2,4)]nonane bromide--water (1/1) |
| CHEBI:32230 , |
| tiotropium bromide xhydrate |
| SCHEMBL1405692 |
| AB01568260_01 |
| CHEMBL3545181 |
| (1r,2r,4s,5s,7s)-7-(2-hydroxy-2,2-di(thiophen-2-yl)acetoxy)-9,9-dimethyl-3-oxa-9-azatricyclo[3.3.1.02,4]nonan-9-ium bromide hydrate |
| ba-679 br hydrate |
| tiotropium bromide monohydrate; 3-oxa-9-azatricyclo[3.3.1.02,4]nonane, 3-oxa-9-azoniatricyclo[3.3.1.02,4]nonane deriv.; tiotropium bromide hydrate; (1alpha,2beta,4beta,5alpha,7beta)-7-[(hydroxydi-2-thienylacetyl)oxy]-9,9-dimethyl-3-oxa-9-azoniatricyclo[3. |
| tiotropium bromide hydrate (ba679br) |
| tiotropium bromide monohydrate, pharmaceutical secondary standard; certified reference material |
| tiotropium bromide monohydrate, >=98% (hplc) |
| tiotropium for system suitability 1, european pharmacopoeia (ep) reference standard |
| tiotropium bromide monohydrate, european pharmacopoeia (ep) reference standard |
| SW219041-1 |
| DTXSID30904820 , |
| [(1r,2r,4s,5s)-9,9-dimethyl-3-oxa-9-azoniatricyclo[3.3.1.02,4]nonan-7-yl] 2-hydroxy-2,2-dithiophen-2-ylacetate;bromide;hydrate |
| MQLXPRBEAHBZTK-SEINRUQRSA-M |
| Q27114833 |
| BCP02924 |
| HMS3884F08 |
| CCG-269614 |
| A886014 |
| (1r,2r,4s,7r)-7-[2-hydroxy(di-2-thienyl)acetoxy]-9,9-dimethyl-3-oxa-9-azoniatricyclo[3.3.1.02,4]nonane bromide monohydrate |
| (1r,2r,4s,5s,7r)-7-{[2-hydroxy-2,2-bis(thiophen-2-yl)acetyl]oxy}-9,9-dimethyl-3-oxa-9-azatricyclo[3.3.1.0,nonan-9-ium hydrate bromide |
| AC-37192 |
| 136310-93-5 |
| AC-1300 |
| tiotropium bromide [usan:inn:ban] |
| unii-xx112xzp0j |
| xx112xzp0j , |
| tiotropium (bromide) |
| HY-17360 |
| tiotropium bromide |
| ba 679br |
| spiriva handihaler |
| 7-((hydroxybis(2-thienyl)acetyl)oxy)-9,9-dimethyl-3-oxa-9-azoniatricyclo(3.3.1.0(2,4))nonane bromide |
| spiriva respimat |
| 3-oxa-9-azoniatricyclo(3,3.1.0(2,4))nonane, 7-((hydroxydi-2-thienylacetyl)oxy)-9,9-dimethyl-, bromide, (1alpha,2beta,4beta,5alpha,7beta)- |
| NCGC00167971-01 |
| HMS2090H20 |
| cas-136310-93-5 |
| dtxcid20820565 |
| dtxsid2044214 , |
| tox21_112598 |
| (1r,2r,4s,5s,7s)-7-(2-hydroxy-2,2-di(thiophen-2-yl)acetoxy)-9,9-dimethyl-3-oxa-9-azatricyclo[3.3.1.0 |
| AKOS015920264 |
| tiopropium |
| (1r,2r,4s,5s,7r)-7-{[2-hydroxy-2,2-bis(thiophen-2-yl)acetyl]oxy}-9,9-dimethyl-3-oxa-9-azatricyclo[3.3.1.0^{2,4}]nonan-9-ium bromide |
| tiotropium bromide(spiriva, ba 679br) |
| BCP0726000293 |
| (1a,2b,4b,5a,7b)-7-[(hydroxydi-2-thienylacetyl)oxy]-9,9-dimethyl-3-oxa-9-azoniatricyclo[3.3.1.02,4]nonane bromide |
| CS-0903 |
| tiotropium bromide [orange book] |
| tiotropium bromide [usan] |
| 3-oxa-9-azoniatricyclo(3.3.1.02,4)nonane, 7-((hydroxydi-2-thienacetyl)oxy)-9,9-dimethyl-, bromide, (1.alpha.,2.beta.,4.beta.,5.alpha.,7.beta.)- |
| tiotropium bromide [mi] |
| 1.alpha., 2.beta., 4.beta, 5.alpha, 7.beta-7-((hydroxydi-2-thienylacetyl)oxy)-9,9-dimethyl-3-oxa-9-azoniatricyclo(3.3.1.0 sup(2,4))nonane bromide |
| tiotropium bromide [who-dd] |
| tiotropium bromide [inn] |
| SCHEMBL440873 |
| SCHEMBL8625 |
| KS-1402 |
| SCHEMBL7607795 |
| T3032 |
| (1r,2r,4s,5s,7s)-7-(2-hydroxy-2,2-di(thiophen-2-yl)acetoxy)-9,9-dimethyl-3-oxa-9-azatricyclo[3.3.1.02,4]nonan-9-ium bromide |
| CHEBI:90959 |
| (1alpha,2beta,4beta,5alpha,7beta)-7-[(hydroxydi-2-thienylacetyl)oxy]-9,9-dimethyl-3-oxa-9-azoniatricyclo[3.3.1.0(2,4)]nonane bromide |
| CHEMBL3189058 |
| ba679 br |
| mfcd00867027 |
| (1?,2?,4?,5?,7?)-7-[(2-hydroxy-2,2-di-2-thienylacetyl)oxy]-9,9-dimethyl-3-oxa-9-azoniatricyclo[3.3.1.02,4]nonane bromide |
| (1r,2r,4s,5s,7r)-7-{[2-hydroxy-2,2-bis(thiophen-2-yl)acetyl]oxy}-9,9-dimethyl-3-oxa-9-azatricyclo[3.3.1.0?,?]nonan-9-ium bromide |
| (1r,2r,4s,5s,7s)-7-[2-hydroxy-2,2-di(2-thienyl)acetoxy]-9,9-dimethyl-3-oxa-9-azatricyclo[3.3.1.02,4]nonan-9-ium bromide |
| olodaterol/tiotropium bromide |
| AKOS025400979 |
| Q27162952 |
| (1r,2r,4s,5s)-7-{[2-hydroxy-2,2-bis(thiophen-2-yl)acetyl]oxy}-9,9-dimethyl-3-oxa-9-azatricyclo[3.3.1.0(2),?]nonan-9-ium bromide |
| AS-75172 |
| BCP02925 |
| AMY23428 |
| [(1r,2r,4s,5s)-9,9-dimethyl-3-oxa-9-azoniatricyclo[3.3.1.02,4]nonan-7-yl] 2-hydroxy-2,2-dithiophen-2-ylacetate;bromide |
| 3-oxa-9-azoniatricyclo[3.3.1.02,4]nonane, 7-[(2-hydroxy-2,2-di-2-thienylacetyl)oxy]-9,9-dimethyl-, bromide (1:1), (1alpha,2beta,4beta,5alpha,7beta)- |
| rel-(1r,2r,4s,5s,7s)-7-(2-hydroxy-2,2-di(thiophen-2-yl)acetoxy)-9,9-dimethyl-3-oxa-9-azatricyclo[3.3.1.02,4]nonan-9-ium bromide |
| A846824 |
| CHEMBL4440620 |
| rel-(1r,2r,4s,5s,7s)-7-(2-hydroxy-2,2-di(thiophen-2-yl)acetoxy)-9,9-dimethyl-3-oxa-9-azatricyclo[3.3.1.02,4]nonan-9-iumbromide |
| bdbm50538220 |
| CHEMBL4638964 , |
| tiotropium bromide- bio-x |
| BT164474 |
| [(1r,2r,4s,5s)-9,9-dimethyl-3-oxa-9-azoniatricyclo[3.3.1.02,4]nonan-7-yl]2-hydroxy-2,2-dithiophen-2-yl-acetate bromide |
| EN300-7375203 |
| (1r,2r,4s,5s,7r)-7-{[2-hydroxy-2,2-bis(thiophen-2-yl)acetyl]oxy}-9,9-dimethyl-3-oxa-9-azatricyclo[3.3.1.0,2,4]nonan-9-ium bromide |
Tiotropium bromide (TIO) is a long-acting bronchodilator used in the treatment of chronic obstructive pulmonary disease (COPD) and asthma. It has gained worldwide acceptance as a first-line, once daily maintenance therapy for patients with COPD.
| Excerpt | Reference | Relevance |
|---|---|---|
| "Tiotropium bromide (TIO) is a long-acting bronchodilator used in the treatment of chronic obstructive pulmonary disease (COPD) and asthma. " | ( A semi-covalent molecularly imprinted electrochemical sensor for rapid and selective detection of tiotropium bromide. Atici, EB; Cetinkaya, A; Çorman, ME; Kaya, SI; Ozkan, SA; Uzun, L, 2022) | 2.38 |
| "Tiotropium bromide is a long-acting muscarinic antagonist (LAMA) and is the only LAMA licensed for management for patients' ≥6 years old with severe asthma who have experienced one or more severe asthma exacerbations in the preceding year. " | ( Tiotropium in the management of paediatric and adolescent asthma: Systematic review. Gupta, A; Marchon, K; Sunther, M, 2021) | 2.06 |
| "Tiotropium bromide is an anticholinergic agent that has gained worldwide acceptance as a first-line, once daily maintenance therapy for patients with moderate-to-severe chronic obstructive pulmonary disease. " | ( Ten years of tiotropium: clinical impact and patient perspectives. Connolly, MJ; Hanania, NA; Yohannes, AM, 2013) | 1.83 |
| "Tiotropium bromide is an effective therapy for COPD patients. " | ( The Tiotropium Safety and Performance in Respimat Trial (TIOSPIR), a large scale, randomized, controlled, parallel-group trial-design and rationale. Anzueto, A; Calverley, P; Cotton, D; Dahl, R; Disse, B; Dusser, D; Joseph, E; Koenen-Bergmann, M; Pledger, G; Wise, RA, 2013) | 1.83 |
| "Tiotropium bromide is a long-acting anticholinergic medicine used for maintenance treatment of chronic obstructive pulmonary disease." | ( Impact of drug administration route on drug delivery and distribution into the lung: an imaging mass spectrometry approach. Amadei, F; Catinella, S; Manni, ME; Moneti, G; Pedretti, P; Pieraccini, G; Pioselli, B; Pittelli, M; Trevisani, M; Zecchi, R, 2013) | 1.11 |
| "Tiotropium bromide is an anticholinergic bronchodilator used in the management of chronic obstructive pulmonary disease. " | ( Crystal structures of tiotropium bromide and its monohydrate in view of combined solid-state nuclear magnetic resonance and gauge-including projector-augmented wave studies. Kolodziejski, W; Majka, Z; Pindelska, E; Pisklak, DM; Szeleszczuk, L, 2015) | 2.17 |
| "Tiotropium bromide is a long-acting inhaled anticholinergic drug for the treatment of COPD that can improve lung function, reduce symptoms and exacerbations, and improve quality of life with once-daily dosing." | ( Safety, tolerability and risk benefit analysis of tiotropium in COPD. Oba, Y; Thameem, DM; Zaza, T, 2008) | 1.07 |
| "Tiotropium bromide (Spiriva) is a well established muscarinic antagonist in the pharmacological management of COPD with a once-daily posology." | ( Preclinical evaluation of long-acting muscarinic antagonists: comparison of tiotropium and investigational drugs. Bouyssou, T; Casarosa, P; Gantner, F; Germeyer, S; Pieper, M; Schnapp, A, 2009) | 1.07 |
| "Tiotropium bromide is a long-acting bronchodilator that has demonstrated clinical efficacy in significantly improving the FEV(1) and health-related quality of life (HRQL) in patients with COPD." | ( Efficacy of tiotropium in the prevention of exacerbations of COPD. Anzueto, A; Miravitlles, M, 2009) | 1.07 |
| "Tiotropium bromide is a long acting muscarinic antagonist (LAMA), marketed under the brand name Spiriva, for the treatment of chronic obstructive pulmonary disease (COPD). " | ( Tiotropium bromide exerts anti-inflammatory activity in a cigarette smoke mouse model of COPD. Pieper, MP; Wollin, L, 2010) | 3.25 |
| "Tiotropium bromide is a long-acting anticholinergic suitable for once daily administration." | ( Tiotropium bromide: a long-acting anticholinergic bronchodilator for the treatment of patients with chronic obstructive pulmonary disease. Brusselle, G; Derom, E; Joos, GF; Pauwels, R, 2003) | 2.48 |
| "Tiotropium bromide is a quaternary ammonium compound structurally related to ipratropium and has recently been approved in the US for the long-term, once-daily, maintenance treatment of bronchospasm associated with chronic-obstructive pulmonary disease (COPD). " | ( Tiotropium bromide, a new, once-daily inhaled anticholinergic bronchodilator for chronic-obstructive pulmonary disease. ZuWallack, AR; ZuWallack, RL, 2004) | 3.21 |
| "Tiotropium bromide (Spiriva) is a long-acting anticholinergic bronchodilator that maintains bronchodilation for at least 24 hours, allowing once-daily administration. " | ( Tiotropium bromide. A review of its use as maintenance therapy in patients with COPD. Keam, SJ; Keating, GM, 2004) | 3.21 |
| "Tiotropium bromide is a novel, inhaled, once-daily anticholinergic bronchodilator that has recently been approved in the United States for use in patients with COPD. " | ( Tiotropium bromide. Gross, NJ, 2004) | 3.21 |
| "Tiotropium bromide is a new inhaled anticholinergic agent approved for once-daily, long-term maintenance treatment of bronchospasm associated with chronic obstructive pulmonary disease (COPD)." | ( Tiotropium bromide: a new long-acting bronchodilator for the treatment of chronic obstructive pulmonary disease. Koumis, T; Samuel, S, 2005) | 3.21 |
| "Tiotropium bromide is an effective bronchodilator for patients with COPD. " | ( Tiotropium: a bronchodilator for chronic obstructive pulmonary disease. Remington, TL; Somand, H, 2005) | 1.77 |
| "Tiotropium bromide is a new long-acting inhaled anticholinergic agent with superior pharmacodynamic properties compared with the short-acting anticholinergic, ipratropium bromide." | ( The role of tiotropium bromide, a long-acting anticholinergic bronchodilator, in the management of COPD. O'Donnell, DE; Saberi, F, 2005) | 1.43 |
| "Tiotropium bromide is an cholinolitic bronchodilatator that antagonises muscarinic receptors and dissociates more slowly from M1 and M3 than from M2 and subsequently has a long duration of action." | ( [Tiotropium as new quality medication in the COPD management]. Lubiński, W; Płusa, T, 2006) | 1.06 |
| "Tiotropium bromide is a recently introduced long-acting anticholinergic agent able to reduce dyspnoea and COPD exacerbations and to improve pulmonary function and quality of life." | ( Effects of replacing oxitropium with tiotropium on pulmonary function in patients with COPD: a randomized study. Dugnani, N; Fumagalli, M; Incorvaia, C; Paterniti, F; Pessina, L; Pravettoni, C; Riario-Sforza, GG, 2007) | 1.06 |
| "Tiotropium bromide is a once-a-day antimuscarinic drug, marketed under the brand name Spiriva, for the treatment of chronic obstructive pulmonary disease (COPD)." | ( Acetylcholine-induced proliferation of fibroblasts and myofibroblasts in vitro is inhibited by tiotropium bromide. Chaudhary, NI; Park, JE; Pieper, MP, 2007) | 1.28 |
| "Tiotropium bromide is a new inhaled bronchodilator for COPD patients with a sustained duration of action; it has superior efficacy compared to other bronchodilators." | ( Use of tiotropium bromide for pre-operative treatment in chronic obstructive pulmonary disease patients: comparison with oxitropium bromide. Arimura, K; Higashimoto, I; Koreeda, Y; Matsuyama, W; Mitsuyama, H; Osame, M, 2007) | 1.52 |
| "Tiotropium bromide (tiotropium) is a novel anticholinergic agent with a long duration of action and kinetic selectivity for M1- and M3-subtypes of muscarinic receptors." | ( Prolonged effect of tiotropium bromide on methacholine-induced bronchoconstriction in asthma. Barnes, PJ; O'Connor, BJ; Towse, LJ, 1996) | 1.34 |
| "Tiotropium bromide (Ba 679 BR) is a novel potent and long-lasting muscarinic antagonist that has been developed for the treatment of chronic obstructive airways disease (COPD). " | ( Tiotropium bromide (Ba 679 BR), a novel long-acting muscarinic antagonist for the treatment of obstructive airways disease. Barnes, PJ; Belvisi, MG; Haddad, EB; Mak, JC; O'Connor, B, 1995) | 3.18 |
| "Tiotropium bromide is a new long-lasting anticholinergic drug which, like ipratropium bromide, is a quaternary ammonium derivative. " | ( Tiotropium bromide. Barnes, PJ, 2001) | 3.2 |
| "Tiotropium bromide is an anticholinergic bronchodilator that antagonises muscarinic M(1), M(2) and M(3) receptors. " | ( Tiotropium bromide. Goa, KL; Hvizdos, KM, 2002) | 3.2 |
Tiotropium bromide has a quaternary ammonium structure and acts as an anticholinergic bronchodilat. Theophylline is another treatment option for chronic obstructive pulmonary disease (COPD)
| Excerpt | Reference | Relevance |
|---|---|---|
| "Tiotropium bromide has a quaternary ammonium structure and acts as an anticholinergic bronchodilat" | ( Tiotropium bromide. A review of its use as maintenance therapy in patients with COPD. Keam, SJ; Keating, GM, 2004) | 2.49 |
| "Tiotropium bromide has been widely used in clinical practice, while theophylline is another treatment option for chronic obstructive pulmonary disease (COPD). " | ( Effects of Tiotropium Combined with Theophylline on Stable COPD Patients of Group B, D and its Impact on Small Airway Function: A Randomized Controlled Trial. Cheng, DY; Fan, LL; Wu, HX; Xiong, XF; Zhu, M, 2018) | 1.92 |
| "Tiotropium bromide has a quaternary ammonium structure and acts as an anticholinergic bronchodilat" | ( Tiotropium bromide. A review of its use as maintenance therapy in patients with COPD. Keam, SJ; Keating, GM, 2004) | 2.49 |
| "Tiotropium bromide has been consistently shown to have a greater impact than ipratropium bromide on clinically important outcome measures such as health status." | ( The role of tiotropium bromide, a long-acting anticholinergic bronchodilator, in the management of COPD. O'Donnell, DE; Saberi, F, 2005) | 1.43 |
| Excerpt | Reference | Relevance |
|---|---|---|
| "Tiotropium bromide, because of its once-daily administration and its established efficacy and tolerability profile, has emerged as an attractive therapeutic option for this condition." | ( The role of tiotropium bromide, a long-acting anticholinergic bronchodilator, in the management of COPD. O'Donnell, DE; Saberi, F, 2005) | 1.43 |
Treatment with tiotropium bromide significantly reduced airway inflammation and the Th2 cytokine production in bronchoalveolar lavage fluid (BALF) in both acute and chronic models of asthma.
| Excerpt | Reference | Relevance |
|---|---|---|
| "Treatment with tiotropium bromide has generally improved patients' health-related quality of life, reduced the number of patients suffering from acute exacerbations, decreased the number of hospitalizations, improved dyspnea, and reduced adverse events compared to placebo." | ( Ten years of tiotropium: clinical impact and patient perspectives. Connolly, MJ; Hanania, NA; Yohannes, AM, 2013) | 0.73 |
| "Treatment with tiotropium bromide significantly reduced airway inflammation and the Th2 cytokine production in bronchoalveolar lavage fluid (BALF) in both acute and chronic models of asthma. " | ( Effect of tiotropium bromide on airway inflammation and remodelling in a mouse model of asthma. Adachi, M; Hirose, T; Minoguchi, K; Nagase, H; Oda, N; Ohnishi, T; Ohta, K; Ohta, S; Tanaka, A; Watanabe, Y; Yamamoto, Y; Yokoe, T, 2010) | 1.12 |
| "Pretreatment with tiotropium bromide significantly attenuated the increases in ventilatory pressures, pulmonary dysfunction, and upper airway obstruction that occur after combined smoke inhalation and burn injury. " | ( Muscarinic receptor antagonist therapy improves acute pulmonary dysfunction after smoke inhalation injury in sheep. Cox, RA; Enkhbaatar, P; Hamahata, A; Hawkins, HK; Herndon, DN; Jacob, S; Jonkam, C; Kraft, E; Nakano, Y; Rehberg, S; Traber, DL; Traber, LD; Zhu, Y, 2010) | 0.69 |
| "Treatment with Tiotropium bromide was started and her pulmonary function improved significantly." | ( [A case of bronchiolitis obliterans syndrome successfully treated by Tiotropium bromide]. Arimura, K; Higashimoto, I; Machida, K; Matsuyama, W; Oonakahara, K; Osame, M; Watanabe, M; Yamamoto, M, 2006) | 0.91 |
| Excerpt | Reference | Relevance |
|---|---|---|
| " The GLISTEN trial compared the efficacy of two long-acting anti-muscarinic antagonists (LAMA), when combined with an inhaled corticosteroid (ICS) and a long-acting β2 agonist (LABA)." | ( Glycopyrronium once-daily significantly improves lung function and health status when combined with salmeterol/fluticasone in patients with COPD: the GLISTEN study, a randomised controlled trial. Bremner, P; Chang, CL; Day, P; Frenzel, C; Frith, PA; Kurstjens, N; Ratnavadivel, R; Thompson, PJ, 2015) | 0.42 |
| "This randomised, blinded, placebo-controlled trial in moderate/severe COPD patients compared once-daily glycopyrronium (GLY) 50 µg, once-daily tiotropium (TIO) 18 µg or placebo (PLA), when combined with salmeterol/fluticasone propionate (SAL/FP) 50/500 µg twice daily." | ( Glycopyrronium once-daily significantly improves lung function and health status when combined with salmeterol/fluticasone in patients with COPD: the GLISTEN study, a randomised controlled trial. Bremner, P; Chang, CL; Day, P; Frenzel, C; Frith, PA; Kurstjens, N; Ratnavadivel, R; Thompson, PJ, 2015) | 0.42 |
| " Although no inhibitory effects on MMP-2 and MMP-9 was observed in rats pretreated with budesonide alone, the combination with the ineffective dose of tiotropium induced a significant reduction on these parameters." | ( Protective effects of tiotropium alone or combined with budesonide against cadmium inhalation induced acute neutrophilic pulmonary inflammation in rats. Gustin, P; Lv, Y; Yang, Q; Yu, Z; Zhang, W; Zhao, S; Zhi, J, 2018) | 0.48 |
| "Tiotropium combined with low-dose theophylline significantly improved the symptoms and general health of patients with stable COPD of groups B and D after 6 months of follow-up." | ( Effects of Tiotropium Combined with Theophylline on Stable COPD Patients of Group B, D and its Impact on Small Airway Function: A Randomized Controlled Trial. Cheng, DY; Fan, LL; Wu, HX; Xiong, XF; Zhu, M, 2018) | 0.48 |
| " The aims of this phase II dose-finding study were to confirm the lung function benefit of adding olodaterol to tiotropium, describe the dose-response relationship of olodaterol in combination with tiotropium 5 μg, and compare it with the dose response of olodaterol monotherapy." | ( Dose Determination for a Fixed-Dose Drug Combination: A Phase II Randomized Controlled Trial for Tiotropium/Olodaterol Versus Tiotropium in Patients with COPD. Hamilton, A; Maleki-Yazdi, MR; Maltais, F; Voß, F, 2019) | 0.51 |
| "The objective of this research was to explore the effect of the treatment regimen of Spiriva combined with Symbicort on the immune function of non-small-cell lung cancer (NSCLC) based on computed tomography (CT) imaging features." | ( Random Walk Algorithm-Based Computer Tomography (CT) Image Segmentation Analysis Effect of Spiriva Combined with Symbicort on Immunologic Function of Non-Small-Cell Lung Cancer. Li, X; Liang, M; Liu, W; Sun, Z, 2022) | 0.72 |
| "The data of 104 patients with AOCS admitted to our hospital from December 2019 to December 2020 were assessed, randomly and divided into an experimental group (comprising 52 patients, receiving drug combination therapy) and a conventional group (comprising 52 patients, receiving drug therapy alone)." | ( Effect of budesonide formoterol combined with tiotropium bromide on pulmonary function and inflammatory factors in patients with asthma-COPD overlap syndrome. Jiang, T; Li, P; Wang, Y, 2023) | 1.17 |
| Protein | Taxonomy | Measurement | Average (µ) | Min (ref.) | Avg (ref.) | Max (ref.) | Bioassay(s) |
|---|---|---|---|---|---|---|---|
| estrogen nuclear receptor alpha | Homo sapiens (human) | Potency | 0.0944 | 0.0002 | 29.3054 | 16,493.5996 | AID743079 |
| Cellular tumor antigen p53 | Homo sapiens (human) | Potency | 23.7101 | 0.0023 | 19.5956 | 74.0614 | AID651631 |
| [prepared from compound, protein, and bioassay information from National Library of Medicine (NLM), extracted Dec-2023] | |||||||
| Protein | Taxonomy | Measurement | Average | Min (ref.) | Avg (ref.) | Max (ref.) | Bioassay(s) |
|---|---|---|---|---|---|---|---|
| Testosterone 17-beta-dehydrogenase 3 | Rattus norvegicus (Norway rat) | IC50 (µMol) | 0.0001 | 0.0001 | 0.0015 | 0.0040 | AID1054736 |
| Muscarinic acetylcholine receptor M2 | Homo sapiens (human) | IC50 (µMol) | 0.0001 | 0.0000 | 1.2326 | 7.7930 | AID1194253; AID430617; AID539981; AID631742 |
| Muscarinic acetylcholine receptor M2 | Homo sapiens (human) | Ki | 0.0001 | 0.0000 | 0.6902 | 10.0000 | AID1056125; AID327966; AID430623; AID627016; AID627079 |
| Muscarinic acetylcholine receptor M4 | Homo sapiens (human) | IC50 (µMol) | 0.0000 | 0.0000 | 1.1546 | 7.5858 | AID539982 |
| Muscarinic acetylcholine receptor M4 | Homo sapiens (human) | Ki | 0.0000 | 0.0000 | 0.7951 | 9.1201 | AID627081 |
| Muscarinic acetylcholine receptor M1 | Rattus norvegicus (Norway rat) | Ki | 0.0002 | 0.0001 | 0.5797 | 10.0000 | AID1224068 |
| Muscarinic acetylcholine receptor M5 | Homo sapiens (human) | IC50 (µMol) | 0.0001 | 0.0001 | 0.9917 | 8.0000 | AID539983 |
| Muscarinic acetylcholine receptor M5 | Homo sapiens (human) | Ki | 0.0000 | 0.0000 | 0.7292 | 6.9183 | AID627083 |
| Muscarinic acetylcholine receptor M2 | Rattus norvegicus (Norway rat) | Ki | 0.0002 | 0.0001 | 0.5890 | 8.2600 | AID1224069 |
| Muscarinic acetylcholine receptor M1 | Homo sapiens (human) | IC50 (µMol) | 0.0001 | 0.0000 | 1.4039 | 10.0000 | AID1194252; AID430616; AID539980 |
| Muscarinic acetylcholine receptor M1 | Homo sapiens (human) | Ki | 0.0001 | 0.0000 | 0.5972 | 9.1201 | AID430624; AID627077 |
| 5-hydroxytryptamine receptor 1A | Rattus norvegicus (Norway rat) | Ki | 0.0002 | 0.0001 | 0.7396 | 10.0000 | AID327965 |
| Muscarinic acetylcholine receptor M3 | Homo sapiens (human) | IC50 (µMol) | 0.0002 | 0.0001 | 1.0104 | 9.9280 | AID1054736; AID1194254; AID430618; AID539979; AID631741 |
| Muscarinic acetylcholine receptor M3 | Homo sapiens (human) | Ki | 0.0000 | 0.0000 | 0.5405 | 7.7600 | AID1056114; AID1056115; AID1056116; AID1056117; AID1056118; AID1056119; AID1056120; AID1056121; AID1056122; AID1056123; AID1056124; AID327965; AID430622; AID578407; AID627014; AID627015; AID627018 |
| Muscarinic acetylcholine receptor | Cavia porcellus (domestic guinea pig) | IC50 (µMol) | 0.0004 | 0.0004 | 0.8121 | 3.8000 | AID627025 |
| Muscarinic acetylcholine receptor | Cavia porcellus (domestic guinea pig) | Ki | 0.0003 | 0.0001 | 0.6120 | 3.8019 | AID327966 |
| Muscarinic acetylcholine receptor M2 | Homo sapiens (human) | Ki | 0.0005 | 0.0000 | 0.6902 | 10.0000 | AID1591564 |
| Muscarinic acetylcholine receptor M3 | Homo sapiens (human) | Ki | 0.0002 | 0.0000 | 0.5405 | 7.7600 | AID1591563 |
| [prepared from compound, protein, and bioassay information from National Library of Medicine (NLM), extracted Dec-2023] | |||||||
| Protein | Taxonomy | Measurement | Average | Min (ref.) | Avg (ref.) | Max (ref.) | Bioassay(s) |
|---|---|---|---|---|---|---|---|
| Muscarinic acetylcholine receptor M3 | Homo sapiens (human) | EC50 (µMol) | 0.0031 | 0.0004 | 0.9935 | 5.9000 | AID1648382; AID1648385 |
| [prepared from compound, protein, and bioassay information from National Library of Medicine (NLM), extracted Dec-2023] | |||||||
| Assay ID | Title | Year | Journal | Article |
|---|---|---|---|---|
| AID430613 | Metabolic stability in human plasma assessed as compound disappearance at pH 7.4 up to 5 mins by ultra-performance liquid chromatography | 2009 | Journal of medicinal chemistry, Aug-27, Volume: 52, Issue:16 | Discovery of novel quaternary ammonium derivatives of (3R)-quinuclidinol esters as potent and long-acting muscarinic antagonists with potential for minimal systemic exposure after inhaled administration: identification of (3R)-3-{[hydroxy(di-2-thienyl)ace |
| AID430624 | Binding affinity to muscarinic M1 receptor | 2009 | Journal of medicinal chemistry, Aug-27, Volume: 52, Issue:16 | Discovery of novel quaternary ammonium derivatives of (3R)-quinuclidinol esters as potent and long-acting muscarinic antagonists with potential for minimal systemic exposure after inhaled administration: identification of (3R)-3-{[hydroxy(di-2-thienyl)ace |
| AID1194259 | Antibronchoconstrictor effect against acetylcholine-induced bronchospasm in Dunkin-Hartley guinea pig administered via nebulizer dosed 5 mins after last acetylcholine dosing | 2015 | Bioorganic & medicinal chemistry letters, Apr-15, Volume: 25, Issue:8 | Discovery of novel quaternary ammonium derivatives of (3R)-quinuclidinyl amides as potent and long acting muscarinic antagonists. |
| AID627016 | Displacement of [3H]-NMS from human recombinant M2 receptor expressed in CHO cells after 2 hrs by filter binding assay | 2011 | Journal of medicinal chemistry, Oct-13, Volume: 54, Issue:19 | Inhalation by design: novel tertiary amine muscarinic M₃ receptor antagonists with slow off-rate binding kinetics for inhaled once-daily treatment of chronic obstructive pulmonary disease. |
| AID627019 | Displacement of [3H]-NMS from human recombinant M3 receptor expressed in CHO cells assessed as dissociation half life at 100 fold human M1 receptor binding Ki concentration after 24 hrs by dilution-offset filter binding assay | 2011 | Journal of medicinal chemistry, Oct-13, Volume: 54, Issue:19 | Inhalation by design: novel tertiary amine muscarinic M₃ receptor antagonists with slow off-rate binding kinetics for inhaled once-daily treatment of chronic obstructive pulmonary disease. |
| AID1224075 | Bronchodilatory effect in it dosed Sprague-Dawley rat assessed as inhibition of CCh-induced bronchoconstriction after 24 hrs | 2014 | Bioorganic & medicinal chemistry, Jul-01, Volume: 22, Issue:13 | Novel quinuclidinyl heteroarylcarbamate derivatives as muscarinic receptor antagonists. |
| AID631747 | Half life in guinea pig lungs at 1 ug/kg administered intratracheally | 2011 | Bioorganic & medicinal chemistry letters, Dec-15, Volume: 21, Issue:24 | The discovery of AZD9164, a novel muscarinic M3 antagonist. |
| AID627086 | Bronchodilator activity in Beagle dog assessed as inhibition of methacholine-induced lung resistance after cumulative intratracheal administration in micelle solution at hourly intervals challenged each time 1 hr later with methacholine | 2011 | Journal of medicinal chemistry, Oct-13, Volume: 54, Issue:19 | Inhalation by design: novel tertiary amine muscarinic M₃ receptor antagonists with slow off-rate binding kinetics for inhaled once-daily treatment of chronic obstructive pulmonary disease. |
| AID631742 | Displacement of [3H]NMS from recombinant human M2 receptor expressed in CHO-K1 cells after 16 hrs | 2011 | Bioorganic & medicinal chemistry letters, Dec-15, Volume: 21, Issue:24 | The discovery of AZD9164, a novel muscarinic M3 antagonist. |
| AID627024 | Intrinsic clearance in human liver microsomes assessed per mg of protein by glucuronidation assay in presence of Brijj-58 and UDPGA | 2011 | Journal of medicinal chemistry, Oct-13, Volume: 54, Issue:19 | Inhalation by design: novel tertiary amine muscarinic M₃ receptor antagonists with slow off-rate binding kinetics for inhaled once-daily treatment of chronic obstructive pulmonary disease. |
| AID1056123 | Binding affinity to wild type human M3 receptor expressed in HEK293T cells up to 24 hrs by radioligand displacement assay | 2013 | Journal of medicinal chemistry, Nov-14, Volume: 56, Issue:21 | Molecular basis for the long duration of action and kinetic selectivity of tiotropium for the muscarinic M3 receptor. |
| AID598152 | Selectivity ratio of IC50 for human muscarinic M2 receptor to IC50 for human muscarinic M3 receptor | 2011 | Bioorganic & medicinal chemistry letters, Jun-01, Volume: 21, Issue:11 | Discovery of novel quaternary ammonium derivatives of (3R)-quinuclidinyl carbamates as potent and long acting muscarinic antagonists. |
| AID578407 | Displacement of [3H]-N-methyl-scopolamine from human muscarinic M3 receptor after 6 hrs by cell based assay | 2011 | Bioorganic & medicinal chemistry letters, Mar-01, Volume: 21, Issue:5 | Discovery of muscarinic acetylcholine receptor antagonist and beta 2 adrenoceptor agonist (MABA) dual pharmacology molecules. |
| AID598187 | Metabolic stability of the compound in human plasma assessed as degradation at 5 uM after 1 hr | 2011 | Bioorganic & medicinal chemistry letters, Jun-01, Volume: 21, Issue:11 | Discovery of novel quaternary ammonium derivatives of (3R)-quinuclidinyl carbamates as potent and long acting muscarinic antagonists. |
| AID598153 | Selectivity ratio of IC50 for human muscarinic M1 receptor to IC50 for human muscarinic M3 receptor | 2011 | Bioorganic & medicinal chemistry letters, Jun-01, Volume: 21, Issue:11 | Discovery of novel quaternary ammonium derivatives of (3R)-quinuclidinyl carbamates as potent and long acting muscarinic antagonists. |
| AID1224076 | Ratio of ID50 for effect on CCh-induced salivation in Sprague-Dawley rat to ID50 for inhibition of CCh-induced bronchoconstriction Sprague-Dawley rat | 2014 | Bioorganic & medicinal chemistry, Jul-01, Volume: 22, Issue:13 | Novel quinuclidinyl heteroarylcarbamate derivatives as muscarinic receptor antagonists. |
| AID1056106 | Binding affinity to human M3 E228A mutant expressed in HEK293T cells assessed as half life by radioligand displacement assay | 2013 | Journal of medicinal chemistry, Nov-14, Volume: 56, Issue:21 | Molecular basis for the long duration of action and kinetic selectivity of tiotropium for the muscarinic M3 receptor. |
| AID1054731 | Inhibition of methacholine-induced bronchoconstriction in Dunkin-Hartley guinea pig administered via intratracheal/intranasal after 24 hrs relative to control | 2013 | Bioorganic & medicinal chemistry letters, Dec-01, Volume: 23, Issue:23 | The design of a novel series of muscarinic receptor antagonists leading to AZD8683, a potential inhaled treatment for COPD. |
| AID539980 | Displacement of [3H]NMS from human muscarinic M1 receptor expressed in CHO-K1 cells after 16 hrs by scintillation proximity assay | 2010 | Bioorganic & medicinal chemistry letters, Dec-15, Volume: 20, Issue:24 | The discovery of new spirocyclic muscarinic M3 antagonists. |
| AID1056117 | Binding affinity to human M3 F225A mutant expressed in HEK293T cells up to 24 hrs by radioligand displacement assay | 2013 | Journal of medicinal chemistry, Nov-14, Volume: 56, Issue:21 | Molecular basis for the long duration of action and kinetic selectivity of tiotropium for the muscarinic M3 receptor. |
| AID1056115 | Binding affinity to human M3 D518A mutant expressed in HEK293T cells up to 24 hrs by radioligand displacement assay | 2013 | Journal of medicinal chemistry, Nov-14, Volume: 56, Issue:21 | Molecular basis for the long duration of action and kinetic selectivity of tiotropium for the muscarinic M3 receptor. |
| AID430626 | Inhibition of acetylcholine-induced bronchoconstriction in Dunkin-Hartley guinea pig assessed as time taken to recover 50% of maximum inhibitory effect at 1 mg/mL administered as nebulized solution | 2009 | Journal of medicinal chemistry, Aug-27, Volume: 52, Issue:16 | Discovery of novel quaternary ammonium derivatives of (3R)-quinuclidinol esters as potent and long-acting muscarinic antagonists with potential for minimal systemic exposure after inhaled administration: identification of (3R)-3-{[hydroxy(di-2-thienyl)ace |
| AID1224068 | Displacement of [3H]-NMS from Sprague-Dawley rat muscarinic M1 receptor in cortex membrane | 2014 | Bioorganic & medicinal chemistry, Jul-01, Volume: 22, Issue:13 | Novel quinuclidinyl heteroarylcarbamate derivatives as muscarinic receptor antagonists. |
| AID430622 | Binding affinity to muscarinic M3 receptor | 2009 | Journal of medicinal chemistry, Aug-27, Volume: 52, Issue:16 | Discovery of novel quaternary ammonium derivatives of (3R)-quinuclidinol esters as potent and long-acting muscarinic antagonists with potential for minimal systemic exposure after inhaled administration: identification of (3R)-3-{[hydroxy(di-2-thienyl)ace |
| AID1054733 | Half life in guinea pig lung administered via intratracheal instillation at 1 ug/kg by HPLC-MS analysis | 2013 | Bioorganic & medicinal chemistry letters, Dec-01, Volume: 23, Issue:23 | The design of a novel series of muscarinic receptor antagonists leading to AZD8683, a potential inhaled treatment for COPD. |
| AID430614 | Metabolic stability in human plasma assessed as compound disappearance at pH 7.4 up to 15 mins by ultra-performance liquid chromatography | 2009 | Journal of medicinal chemistry, Aug-27, Volume: 52, Issue:16 | Discovery of novel quaternary ammonium derivatives of (3R)-quinuclidinol esters as potent and long-acting muscarinic antagonists with potential for minimal systemic exposure after inhaled administration: identification of (3R)-3-{[hydroxy(di-2-thienyl)ace |
| AID1194261 | Drug metabolism in human microsomes assessed as compound transformation at 5 uM at 37 degC in presence of NADPH generating system after 30 mins by HPLC-UV and HPLC-MS detection method | 2015 | Bioorganic & medicinal chemistry letters, Apr-15, Volume: 25, Issue:8 | Discovery of novel quaternary ammonium derivatives of (3R)-quinuclidinyl amides as potent and long acting muscarinic antagonists. |
| AID1056108 | Binding affinity to human M3 Q224A mutant expressed in HEK293T cells assessed as half life by radioligand displacement assay | 2013 | Journal of medicinal chemistry, Nov-14, Volume: 56, Issue:21 | Molecular basis for the long duration of action and kinetic selectivity of tiotropium for the muscarinic M3 receptor. |
| AID1056120 | Binding affinity to human M3 E220A mutant expressed in HEK293T cells up to 24 hrs by radioligand displacement assay | 2013 | Journal of medicinal chemistry, Nov-14, Volume: 56, Issue:21 | Molecular basis for the long duration of action and kinetic selectivity of tiotropium for the muscarinic M3 receptor. |
| AID627080 | Displacement of [3H]-NMS from human recombinant M2 receptor expressed in CHO cells assessed as dissociation half life at 100 fold human M2 receptor binding Ki concentration after 24 hrs by dilution-offset filter binding assay | 2011 | Journal of medicinal chemistry, Oct-13, Volume: 54, Issue:19 | Inhalation by design: novel tertiary amine muscarinic M₃ receptor antagonists with slow off-rate binding kinetics for inhaled once-daily treatment of chronic obstructive pulmonary disease. |
| AID430628 | Toxicity in Swiss mouse assessed as occurrence of mydriasis at 30 mg/kg, ip up to 24 hrs | 2009 | Journal of medicinal chemistry, Aug-27, Volume: 52, Issue:16 | Discovery of novel quaternary ammonium derivatives of (3R)-quinuclidinol esters as potent and long-acting muscarinic antagonists with potential for minimal systemic exposure after inhaled administration: identification of (3R)-3-{[hydroxy(di-2-thienyl)ace |
| AID1054735 | Plasma protein binding in human | 2013 | Bioorganic & medicinal chemistry letters, Dec-01, Volume: 23, Issue:23 | The design of a novel series of muscarinic receptor antagonists leading to AZD8683, a potential inhaled treatment for COPD. |
| AID631749 | Bronchoprotection activity in Dunkin Hartley guinea pig assessed as inhibition of methacholine-induced bronchoconstriction at ED80 administered intratracheally measured at 24 hrs post treatment | 2011 | Bioorganic & medicinal chemistry letters, Dec-15, Volume: 21, Issue:24 | The discovery of AZD9164, a novel muscarinic M3 antagonist. |
| AID598188 | Metabolic stability of the compound in human liver microsomes assessed as transformation at 5 uM after 30 mins | 2011 | Bioorganic & medicinal chemistry letters, Jun-01, Volume: 21, Issue:11 | Discovery of novel quaternary ammonium derivatives of (3R)-quinuclidinyl carbamates as potent and long acting muscarinic antagonists. |
| AID1224069 | Displacement of [3H]-NMS from Sprague-Dawley rat muscarinic M2 receptor in heart | 2014 | Bioorganic & medicinal chemistry, Jul-01, Volume: 22, Issue:13 | Novel quinuclidinyl heteroarylcarbamate derivatives as muscarinic receptor antagonists. |
| AID627082 | Displacement of [3H]-NMS from human recombinant M4 receptor expressed in CHO cells assessed as dissociation half life at 100 fold human M4 receptor binding Ki concentration after 24 hrs by dilution-offset filter binding assay | 2011 | Journal of medicinal chemistry, Oct-13, Volume: 54, Issue:19 | Inhalation by design: novel tertiary amine muscarinic M₃ receptor antagonists with slow off-rate binding kinetics for inhaled once-daily treatment of chronic obstructive pulmonary disease. |
| AID1194253 | Displacement of [3H]NMS from human M2 receptor expressed in CHOK1 cell membranes after 4 hrs by scintillation counting method | 2015 | Bioorganic & medicinal chemistry letters, Apr-15, Volume: 25, Issue:8 | Discovery of novel quaternary ammonium derivatives of (3R)-quinuclidinyl amides as potent and long acting muscarinic antagonists. |
| AID1056101 | Ratio of 7-(2,2-Dithiophen-2-ylacetoxy)-9,9-dimethyl-3-oxa-9-azoniatricyclo-[3.3.1.0(2,4)]nonane, Bromide Koff to compound Koff for wild type human M3 receptor | 2013 | Journal of medicinal chemistry, Nov-14, Volume: 56, Issue:21 | Molecular basis for the long duration of action and kinetic selectivity of tiotropium for the muscarinic M3 receptor. |
| AID1194257 | Antibronchoconstrictor effect against acetylcholine-induced bronchospasm in Dunkin-Hartley guinea pig assessed as time duration taken to recover 50% of compound-induced maximum inhibitory effect at 1 mg/ml administered via nebulizer dosed 5 mins after las | 2015 | Bioorganic & medicinal chemistry letters, Apr-15, Volume: 25, Issue:8 | Discovery of novel quaternary ammonium derivatives of (3R)-quinuclidinyl amides as potent and long acting muscarinic antagonists. |
| AID1224071 | Bronchodilatory effect in Sprague-Dawley rat assessed as inhibition of CCh-induced bronchoconstriction at 0.5 ug/kg, it after 0.25 hrs | 2014 | Bioorganic & medicinal chemistry, Jul-01, Volume: 22, Issue:13 | Novel quinuclidinyl heteroarylcarbamate derivatives as muscarinic receptor antagonists. |
| AID1224080 | Drug uptake in it dosed Sprague-Dawley rat submandibular gland after 24 hrs | 2014 | Bioorganic & medicinal chemistry, Jul-01, Volume: 22, Issue:13 | Novel quinuclidinyl heteroarylcarbamate derivatives as muscarinic receptor antagonists. |
| AID1056121 | Binding affinity to human M3 K213A mutant expressed in HEK293T cells up to 24 hrs by radioligand displacement assay | 2013 | Journal of medicinal chemistry, Nov-14, Volume: 56, Issue:21 | Molecular basis for the long duration of action and kinetic selectivity of tiotropium for the muscarinic M3 receptor. |
| AID430623 | Binding affinity to muscarinic M2 receptor | 2009 | Journal of medicinal chemistry, Aug-27, Volume: 52, Issue:16 | Discovery of novel quaternary ammonium derivatives of (3R)-quinuclidinol esters as potent and long-acting muscarinic antagonists with potential for minimal systemic exposure after inhaled administration: identification of (3R)-3-{[hydroxy(di-2-thienyl)ace |
| AID627075 | Antagonist activity at M3 receptor in human bronchial ring assessed as inhibition of electrically field-stimulated contractile response after 4 hrs | 2011 | Journal of medicinal chemistry, Oct-13, Volume: 54, Issue:19 | Inhalation by design: novel tertiary amine muscarinic M₃ receptor antagonists with slow off-rate binding kinetics for inhaled once-daily treatment of chronic obstructive pulmonary disease. |
| AID1056124 | Antagonist activity at human M3 receptor expressed in CHO cells assessed as inhibition of carbachol-induced response after 30 mins by AP-1-driven luciferase reporter gene assay | 2013 | Journal of medicinal chemistry, Nov-14, Volume: 56, Issue:21 | Molecular basis for the long duration of action and kinetic selectivity of tiotropium for the muscarinic M3 receptor. |
| AID627083 | Displacement of [3H]-NMS from human recombinant M5 receptor expressed in CHO cells after 24 hrs by filter binding assay | 2011 | Journal of medicinal chemistry, Oct-13, Volume: 54, Issue:19 | Inhalation by design: novel tertiary amine muscarinic M₃ receptor antagonists with slow off-rate binding kinetics for inhaled once-daily treatment of chronic obstructive pulmonary disease. |
| AID627015 | Displacement of [3H]-NMS from human recombinant M3 receptor expressed in CHO cells after 2 hrs by filter binding assay | 2011 | Journal of medicinal chemistry, Oct-13, Volume: 54, Issue:19 | Inhalation by design: novel tertiary amine muscarinic M₃ receptor antagonists with slow off-rate binding kinetics for inhaled once-daily treatment of chronic obstructive pulmonary disease. |
| AID627078 | Displacement of [3H]-NMS from human recombinant M1 receptor expressed in CHO cells assessed as dissociation half life at 100 fold human M1 receptor binding Ki concentration after 24 hrs by dilution-offset filter binding assay | 2011 | Journal of medicinal chemistry, Oct-13, Volume: 54, Issue:19 | Inhalation by design: novel tertiary amine muscarinic M₃ receptor antagonists with slow off-rate binding kinetics for inhaled once-daily treatment of chronic obstructive pulmonary disease. |
| AID430616 | Displacement of [3H]NMS from human muscarinic M1 receptor expressed in CHOK1 cells by microplate scintillation counting | 2009 | Journal of medicinal chemistry, Aug-27, Volume: 52, Issue:16 | Discovery of novel quaternary ammonium derivatives of (3R)-quinuclidinol esters as potent and long-acting muscarinic antagonists with potential for minimal systemic exposure after inhaled administration: identification of (3R)-3-{[hydroxy(di-2-thienyl)ace |
| AID627077 | Displacement of [3H]-NMS from human recombinant M1 receptor expressed in CHO cells after 24 hrs by filter binding assay | 2011 | Journal of medicinal chemistry, Oct-13, Volume: 54, Issue:19 | Inhalation by design: novel tertiary amine muscarinic M₃ receptor antagonists with slow off-rate binding kinetics for inhaled once-daily treatment of chronic obstructive pulmonary disease. |
| AID1056111 | Binding affinity to human M3 K213A mutant expressed in HEK293T cells assessed as half life by radioligand displacement assay | 2013 | Journal of medicinal chemistry, Nov-14, Volume: 56, Issue:21 | Molecular basis for the long duration of action and kinetic selectivity of tiotropium for the muscarinic M3 receptor. |
| AID627022 | Intrinsic clearance in human liver microsomes assessed per mg of protein in presence of NADPH | 2011 | Journal of medicinal chemistry, Oct-13, Volume: 54, Issue:19 | Inhalation by design: novel tertiary amine muscarinic M₃ receptor antagonists with slow off-rate binding kinetics for inhaled once-daily treatment of chronic obstructive pulmonary disease. |
| AID539983 | Displacement of [3H]NMS from human muscarinic M5 receptor expressed in CHO-K1 cells after 16 hrs by scintillation proximity assay | 2010 | Bioorganic & medicinal chemistry letters, Dec-15, Volume: 20, Issue:24 | The discovery of new spirocyclic muscarinic M3 antagonists. |
| AID1224074 | Bronchodilatory effect in Sprague-Dawley rat assessed as inhibition of CCh-induced bronchoconstriction at 0.5 ug/kg, it after 24 hrs | 2014 | Bioorganic & medicinal chemistry, Jul-01, Volume: 22, Issue:13 | Novel quinuclidinyl heteroarylcarbamate derivatives as muscarinic receptor antagonists. |
| AID1056103 | Ratio of 7-(2,2-Dithiophen-2-ylacetoxy)-9,9-dimethyl-3-oxa-9-azoniatricyclo-[3.3.1.0(2,4)]nonane, Bromide Koff to compound Koff for human M3 N508'6.52A mutant | 2013 | Journal of medicinal chemistry, Nov-14, Volume: 56, Issue:21 | Molecular basis for the long duration of action and kinetic selectivity of tiotropium for the muscarinic M3 receptor. |
| AID627074 | Antagonist activity at M3 receptor in Dunkin-Hartley guinea pig tracheal strips assessed as time taken for electrically field-stimulated contractile response to recover by 25 percent of inhibition at Emax after 2 hrs | 2011 | Journal of medicinal chemistry, Oct-13, Volume: 54, Issue:19 | Inhalation by design: novel tertiary amine muscarinic M₃ receptor antagonists with slow off-rate binding kinetics for inhaled once-daily treatment of chronic obstructive pulmonary disease. |
| AID627017 | Displacement of [3H]-NMS from human recombinant M3 receptor expressed in CHO cells assessed as dissociation half life at 100 fold human M1 receptor binding Ki concentration after 2 hrs by dilution-offset filter binding assay | 2011 | Journal of medicinal chemistry, Oct-13, Volume: 54, Issue:19 | Inhalation by design: novel tertiary amine muscarinic M₃ receptor antagonists with slow off-rate binding kinetics for inhaled once-daily treatment of chronic obstructive pulmonary disease. |
| AID631751 | Inhibition of pilocarpine-induced salivation in intranasally dosed guinea pig after 4 hrs measured for a period of 15 mins | 2011 | Bioorganic & medicinal chemistry letters, Dec-15, Volume: 21, Issue:24 | The discovery of AZD9164, a novel muscarinic M3 antagonist. |
| AID1056112 | Binding affinity to human M3 R133A mutant expressed in HEK293T cells assessed as half life by radioligand displacement assay | 2013 | Journal of medicinal chemistry, Nov-14, Volume: 56, Issue:21 | Molecular basis for the long duration of action and kinetic selectivity of tiotropium for the muscarinic M3 receptor. |
| AID631741 | Displacement of [3H]NMS from recombinant human M3 receptor expressed in CHO-K1 cells after 16 hrs | 2011 | Bioorganic & medicinal chemistry letters, Dec-15, Volume: 21, Issue:24 | The discovery of AZD9164, a novel muscarinic M3 antagonist. |
| AID627076 | Bronchodilator activity in Dunkin-Hartley guinea pig assessed as inhibition of acetylcholine-induced lung resistance after cumulative intratracheal administration in micelle solution at hourly intervals challenged each time 1 hr later with methacholine | 2011 | Journal of medicinal chemistry, Oct-13, Volume: 54, Issue:19 | Inhalation by design: novel tertiary amine muscarinic M₃ receptor antagonists with slow off-rate binding kinetics for inhaled once-daily treatment of chronic obstructive pulmonary disease. |
| AID430611 | Metabolic stability in human plasma assessed as compound disappearance at pH 7.4 up to 60 mins by ultra-performance liquid chromatography | 2009 | Journal of medicinal chemistry, Aug-27, Volume: 52, Issue:16 | Discovery of novel quaternary ammonium derivatives of (3R)-quinuclidinol esters as potent and long-acting muscarinic antagonists with potential for minimal systemic exposure after inhaled administration: identification of (3R)-3-{[hydroxy(di-2-thienyl)ace |
| AID631752 | Therapeutic index, ratio of EC50 for inhibition of pilocarpine-induced salivation in intranasally dosed guinea pig to ED80 for bronchoprotection activity in intratracheally dosed Dunkin Hartley guinea pig | 2011 | Bioorganic & medicinal chemistry letters, Dec-15, Volume: 21, Issue:24 | The discovery of AZD9164, a novel muscarinic M3 antagonist. |
| AID627084 | Displacement of [3H]-NMS from human recombinant M5 receptor expressed in CHO cells assessed as dissociation half life at 100 fold human M5 receptor binding Ki concentration after 24 hrs by dilution-offset filter binding assay | 2011 | Journal of medicinal chemistry, Oct-13, Volume: 54, Issue:19 | Inhalation by design: novel tertiary amine muscarinic M₃ receptor antagonists with slow off-rate binding kinetics for inhaled once-daily treatment of chronic obstructive pulmonary disease. |
| AID627079 | Displacement of [3H]-NMS from human recombinant M2 receptor expressed in CHO cells after 24 hrs by filter binding assay | 2011 | Journal of medicinal chemistry, Oct-13, Volume: 54, Issue:19 | Inhalation by design: novel tertiary amine muscarinic M₃ receptor antagonists with slow off-rate binding kinetics for inhaled once-daily treatment of chronic obstructive pulmonary disease. |
| AID1224073 | Bronchodilatory effect in Sprague-Dawley rat assessed as inhibition of CCh-induced bronchoconstriction at 0.5 ug/kg, it after 2 hrs | 2014 | Bioorganic & medicinal chemistry, Jul-01, Volume: 22, Issue:13 | Novel quinuclidinyl heteroarylcarbamate derivatives as muscarinic receptor antagonists. |
| AID1056104 | Binding affinity to human M3 K523A mutant expressed in HEK293T cells assessed as half life by radioligand displacement assay | 2013 | Journal of medicinal chemistry, Nov-14, Volume: 56, Issue:21 | Molecular basis for the long duration of action and kinetic selectivity of tiotropium for the muscarinic M3 receptor. |
| AID1056109 | Binding affinity to human M3 F222A mutant expressed in HEK293T cells assessed as half life by radioligand displacement assay | 2013 | Journal of medicinal chemistry, Nov-14, Volume: 56, Issue:21 | Molecular basis for the long duration of action and kinetic selectivity of tiotropium for the muscarinic M3 receptor. |
| AID1056110 | Binding affinity to human M3 E220A mutant expressed in HEK293T cells assessed as half life by radioligand displacement assay | 2013 | Journal of medicinal chemistry, Nov-14, Volume: 56, Issue:21 | Molecular basis for the long duration of action and kinetic selectivity of tiotropium for the muscarinic M3 receptor. |
| AID1056122 | Binding affinity to human M3 R133A mutant expressed in HEK293T cells up to 24 hrs by radioligand displacement assay | 2013 | Journal of medicinal chemistry, Nov-14, Volume: 56, Issue:21 | Molecular basis for the long duration of action and kinetic selectivity of tiotropium for the muscarinic M3 receptor. |
| AID327965 | Displacement of [3H]N-methylscopolamine from human recombinant muscarinic M3 receptor expressed in CHO cells | 2008 | Bioorganic & medicinal chemistry letters, Apr-15, Volume: 18, Issue:8 | Alkyne-quinuclidine derivatives as potent and selective muscarinic antagonists for the treatment of COPD. |
| AID1224078 | Displacement of [3H]-NMS from Sprague-Dawley rat muscarinic M3 receptor in submandibular gland measured after single/double washout | 2014 | Bioorganic & medicinal chemistry, Jul-01, Volume: 22, Issue:13 | Novel quinuclidinyl heteroarylcarbamate derivatives as muscarinic receptor antagonists. |
| AID1054730 | Inhibition of methacholine-induced bronchoconstriction in Dunkin-Hartley guinea pig administered via intratracheal/intranasal after 48 hrs relative to control | 2013 | Bioorganic & medicinal chemistry letters, Dec-01, Volume: 23, Issue:23 | The design of a novel series of muscarinic receptor antagonists leading to AZD8683, a potential inhaled treatment for COPD. |
| AID627023 | Intrinsic clearance in human hepatocytes assessed per million cells | 2011 | Journal of medicinal chemistry, Oct-13, Volume: 54, Issue:19 | Inhalation by design: novel tertiary amine muscarinic M₃ receptor antagonists with slow off-rate binding kinetics for inhaled once-daily treatment of chronic obstructive pulmonary disease. |
| AID430615 | Metabolic stability in human plasma assessed as elimination half life at pH 7.4 | 2009 | Journal of medicinal chemistry, Aug-27, Volume: 52, Issue:16 | Discovery of novel quaternary ammonium derivatives of (3R)-quinuclidinol esters as potent and long-acting muscarinic antagonists with potential for minimal systemic exposure after inhaled administration: identification of (3R)-3-{[hydroxy(di-2-thienyl)ace |
| AID430618 | Displacement of [3H]NMS from human muscarinic M3 receptor expressed in CHOK1 cells by microplate scintillation counting | 2009 | Journal of medicinal chemistry, Aug-27, Volume: 52, Issue:16 | Discovery of novel quaternary ammonium derivatives of (3R)-quinuclidinol esters as potent and long-acting muscarinic antagonists with potential for minimal systemic exposure after inhaled administration: identification of (3R)-3-{[hydroxy(di-2-thienyl)ace |
| AID627085 | Displacement of radioligand from M3 receptor assessed as dissociation half life | 2011 | Journal of medicinal chemistry, Oct-13, Volume: 54, Issue:19 | Inhalation by design: novel tertiary amine muscarinic M₃ receptor antagonists with slow off-rate binding kinetics for inhaled once-daily treatment of chronic obstructive pulmonary disease. |
| AID327968 | Antagonist activity at muscarinic M2 receptor in carbachol-stimulated guinea pig left atrium | 2008 | Bioorganic & medicinal chemistry letters, Apr-15, Volume: 18, Issue:8 | Alkyne-quinuclidine derivatives as potent and selective muscarinic antagonists for the treatment of COPD. |
| AID1056116 | Binding affinity to human M3 E228A mutant expressed in HEK293T cells up to 24 hrs by radioligand displacement assay | 2013 | Journal of medicinal chemistry, Nov-14, Volume: 56, Issue:21 | Molecular basis for the long duration of action and kinetic selectivity of tiotropium for the muscarinic M3 receptor. |
| AID327966 | Displacement of [3H]N-methylscopolamine from human recombinant muscarinic M2 receptor expressed in CHO cells | 2008 | Bioorganic & medicinal chemistry letters, Apr-15, Volume: 18, Issue:8 | Alkyne-quinuclidine derivatives as potent and selective muscarinic antagonists for the treatment of COPD. |
| AID1224077 | Effect on CCh-induced salivation in Sprague-Dawley rat after 24 hrs | 2014 | Bioorganic & medicinal chemistry, Jul-01, Volume: 22, Issue:13 | Novel quinuclidinyl heteroarylcarbamate derivatives as muscarinic receptor antagonists. |
| AID1054737 | Intrinsic clearance in human liver microsomes | 2013 | Bioorganic & medicinal chemistry letters, Dec-01, Volume: 23, Issue:23 | The design of a novel series of muscarinic receptor antagonists leading to AZD8683, a potential inhaled treatment for COPD. |
| AID627014 | Antagonist activity at human recombinant M3 receptor expressed in CHO-K1 cells assessed as inhibition of carbamoyl choline-induced calcium currents after 4 hrs by fluorimetry | 2011 | Journal of medicinal chemistry, Oct-13, Volume: 54, Issue:19 | Inhalation by design: novel tertiary amine muscarinic M₃ receptor antagonists with slow off-rate binding kinetics for inhaled once-daily treatment of chronic obstructive pulmonary disease. |
| AID1194252 | Displacement of [3H]NMS from human M1 receptor expressed in CHOK1 cell membranes after 4 hrs by scintillation counting method | 2015 | Bioorganic & medicinal chemistry letters, Apr-15, Volume: 25, Issue:8 | Discovery of novel quaternary ammonium derivatives of (3R)-quinuclidinyl amides as potent and long acting muscarinic antagonists. |
| AID430625 | Inhibition of acetylcholine-induced bronchoconstriction in Dunkin-Hartley guinea pig administered as nebulized solution | 2009 | Journal of medicinal chemistry, Aug-27, Volume: 52, Issue:16 | Discovery of novel quaternary ammonium derivatives of (3R)-quinuclidinol esters as potent and long-acting muscarinic antagonists with potential for minimal systemic exposure after inhaled administration: identification of (3R)-3-{[hydroxy(di-2-thienyl)ace |
| AID430617 | Displacement of [3H]NMS from human muscarinic M2 receptor expressed in CHOK1 cells by microplate scintillation counting | 2009 | Journal of medicinal chemistry, Aug-27, Volume: 52, Issue:16 | Discovery of novel quaternary ammonium derivatives of (3R)-quinuclidinol esters as potent and long-acting muscarinic antagonists with potential for minimal systemic exposure after inhaled administration: identification of (3R)-3-{[hydroxy(di-2-thienyl)ace |
| AID1056126 | Ratio of 7-(2,2-Dithiophen-2-ylacetoxy)-9,9-dimethyl-3-oxa-9-azoniatricyclo-[3.3.1.0(2,4)]nonane, Bromide Ki to compound Ki for human M3 N508'6.52A mutant | 2013 | Journal of medicinal chemistry, Nov-14, Volume: 56, Issue:21 | Molecular basis for the long duration of action and kinetic selectivity of tiotropium for the muscarinic M3 receptor. |
| AID627088 | Bronchodilator activity in methacholine challenged Beagle dog assessed as intrinsic duration of action at 10 ug intratracheally administered as single dose in micelle solution | 2011 | Journal of medicinal chemistry, Oct-13, Volume: 54, Issue:19 | Inhalation by design: novel tertiary amine muscarinic M₃ receptor antagonists with slow off-rate binding kinetics for inhaled once-daily treatment of chronic obstructive pulmonary disease. |
| AID1194260 | Stability in human plasma assessed as compound degradation at 5 uM at 37 degC after 15 and 60 mins by HPLC-UV and HPLC-MS detection method | 2015 | Bioorganic & medicinal chemistry letters, Apr-15, Volume: 25, Issue:8 | Discovery of novel quaternary ammonium derivatives of (3R)-quinuclidinyl amides as potent and long acting muscarinic antagonists. |
| AID627025 | Antagonist activity at M3 receptor in Dunkin-Hartley guinea pig tracheal strips assessed as inhibition of electrically field-stimulated contractile response after 8 hrs | 2011 | Journal of medicinal chemistry, Oct-13, Volume: 54, Issue:19 | Inhalation by design: novel tertiary amine muscarinic M₃ receptor antagonists with slow off-rate binding kinetics for inhaled once-daily treatment of chronic obstructive pulmonary disease. |
| AID627018 | Displacement of [3H]-NMS from human recombinant M3 receptor expressed in CHO cells after 24 hrs by filter binding assay | 2011 | Journal of medicinal chemistry, Oct-13, Volume: 54, Issue:19 | Inhalation by design: novel tertiary amine muscarinic M₃ receptor antagonists with slow off-rate binding kinetics for inhaled once-daily treatment of chronic obstructive pulmonary disease. |
| AID1056107 | Binding affinity to human M3 F225A mutant expressed in HEK293T cells assessed as half life by radioligand displacement assay | 2013 | Journal of medicinal chemistry, Nov-14, Volume: 56, Issue:21 | Molecular basis for the long duration of action and kinetic selectivity of tiotropium for the muscarinic M3 receptor. |
| AID1224079 | Drug uptake in it dosed Sprague-Dawley rat lung after 24 hrs | 2014 | Bioorganic & medicinal chemistry, Jul-01, Volume: 22, Issue:13 | Novel quinuclidinyl heteroarylcarbamate derivatives as muscarinic receptor antagonists. |
| AID1054736 | Displacement of [3H]NMS from recombinant human M3 receptor expressed in CHO-K1 cells after 16 hrs by SPA method | 2013 | Bioorganic & medicinal chemistry letters, Dec-01, Volume: 23, Issue:23 | The design of a novel series of muscarinic receptor antagonists leading to AZD8683, a potential inhaled treatment for COPD. |
| AID631744 | Plasma protein binding in human | 2011 | Bioorganic & medicinal chemistry letters, Dec-15, Volume: 21, Issue:24 | The discovery of AZD9164, a novel muscarinic M3 antagonist. |
| AID1056125 | Binding affinity to human M2 receptor | 2013 | Journal of medicinal chemistry, Nov-14, Volume: 56, Issue:21 | Molecular basis for the long duration of action and kinetic selectivity of tiotropium for the muscarinic M3 receptor. |
| AID1194255 | Selectivity index, ratio of IC50 for human M2 receptor to IC50 for human M3 rceeptor | 2015 | Bioorganic & medicinal chemistry letters, Apr-15, Volume: 25, Issue:8 | Discovery of novel quaternary ammonium derivatives of (3R)-quinuclidinyl amides as potent and long acting muscarinic antagonists. |
| AID1056114 | Binding affinity to human M3 K523A mutant expressed in HEK293T cells up to 24 hrs by radioligand displacement assay | 2013 | Journal of medicinal chemistry, Nov-14, Volume: 56, Issue:21 | Molecular basis for the long duration of action and kinetic selectivity of tiotropium for the muscarinic M3 receptor. |
| AID539982 | Displacement of [3H]NMS from human muscarinic M4 receptor expressed in CHO-K1 cells after 16 hrs by scintillation proximity assay | 2010 | Bioorganic & medicinal chemistry letters, Dec-15, Volume: 20, Issue:24 | The discovery of new spirocyclic muscarinic M3 antagonists. |
| AID1056119 | Binding affinity to human M3 F222A mutant expressed in HEK293T cells up to 24 hrs by radioligand displacement assay | 2013 | Journal of medicinal chemistry, Nov-14, Volume: 56, Issue:21 | Molecular basis for the long duration of action and kinetic selectivity of tiotropium for the muscarinic M3 receptor. |
| AID1056105 | Binding affinity to human M3 D518A mutant expressed in HEK293T cells assessed as half life by radioligand displacement assay | 2013 | Journal of medicinal chemistry, Nov-14, Volume: 56, Issue:21 | Molecular basis for the long duration of action and kinetic selectivity of tiotropium for the muscarinic M3 receptor. |
| AID1056113 | Binding affinity to wild type human M3 receptor expressed in HEK293T cells assessed as half life by radioligand displacement assay | 2013 | Journal of medicinal chemistry, Nov-14, Volume: 56, Issue:21 | Molecular basis for the long duration of action and kinetic selectivity of tiotropium for the muscarinic M3 receptor. |
| AID1056102 | Ratio of 7-(2,2-Dithiophen-2-ylacetoxy)-9,9-dimethyl-3-oxa-9-azoniatricyclo-[3.3.1.0(2,4)]nonane, Bromide Ki to compound Ki for human M3 receptor | 2013 | Journal of medicinal chemistry, Nov-14, Volume: 56, Issue:21 | Molecular basis for the long duration of action and kinetic selectivity of tiotropium for the muscarinic M3 receptor. |
| AID1054732 | Inhibition of methacholine-induced bronchoconstriction in Dunkin-Hartley guinea pig administered via intratracheal/intranasal after 2 to 4 hrs relative to control | 2013 | Bioorganic & medicinal chemistry letters, Dec-01, Volume: 23, Issue:23 | The design of a novel series of muscarinic receptor antagonists leading to AZD8683, a potential inhaled treatment for COPD. |
| AID1224072 | Bronchodilatory effect in Sprague-Dawley rat assessed as inhibition of CCh-induced bronchoconstriction at 0.5 ug/kg, it after 0.5 hrs | 2014 | Bioorganic & medicinal chemistry, Jul-01, Volume: 22, Issue:13 | Novel quinuclidinyl heteroarylcarbamate derivatives as muscarinic receptor antagonists. |
| AID1194254 | Displacement of [3H]NMS from human M3 receptor expressed in CHOK1 cell membranes after 4 hrs by scintillation counting method | 2015 | Bioorganic & medicinal chemistry letters, Apr-15, Volume: 25, Issue:8 | Discovery of novel quaternary ammonium derivatives of (3R)-quinuclidinyl amides as potent and long acting muscarinic antagonists. |
| AID1056118 | Binding affinity to human M3 Q224A mutant expressed in HEK293T cells up to 24 hrs by radioligand displacement assay | 2013 | Journal of medicinal chemistry, Nov-14, Volume: 56, Issue:21 | Molecular basis for the long duration of action and kinetic selectivity of tiotropium for the muscarinic M3 receptor. |
| AID430621 | Inhibition of acetylcholine-induced bronchoconstriction in Dunkin-Hartley guinea pig assessed as time taken to recover 50% of maximum inhibitory effect at 3 mg/mL administered as nebulized solution | 2009 | Journal of medicinal chemistry, Aug-27, Volume: 52, Issue:16 | Discovery of novel quaternary ammonium derivatives of (3R)-quinuclidinol esters as potent and long-acting muscarinic antagonists with potential for minimal systemic exposure after inhaled administration: identification of (3R)-3-{[hydroxy(di-2-thienyl)ace |
| AID631746 | Antagonist potency at M3 receptor in Dunkin Hartley guinea pig trachea assessed as inhibition of methacholine-induced airway smooth muscle contraction after 1 hr by organ-bath technique | 2011 | Bioorganic & medicinal chemistry letters, Dec-15, Volume: 21, Issue:24 | The discovery of AZD9164, a novel muscarinic M3 antagonist. |
| AID631743 | Intrinsic clearance in human liver microsomes | 2011 | Bioorganic & medicinal chemistry letters, Dec-15, Volume: 21, Issue:24 | The discovery of AZD9164, a novel muscarinic M3 antagonist. |
| AID539979 | Displacement of [3H]NMS from human muscarinic M3 receptor expressed in CHO-K1 cells after 16 hrs by scintillation proximity assay | 2010 | Bioorganic & medicinal chemistry letters, Dec-15, Volume: 20, Issue:24 | The discovery of new spirocyclic muscarinic M3 antagonists. |
| AID1054729 | Toxicity in guinea pig assessed as reduction of pilocarpine-induced salivation administered via intranasal administered for 4 hrs followed by pilocarpine challenge measured every 5 mins for 15 mins | 2013 | Bioorganic & medicinal chemistry letters, Dec-01, Volume: 23, Issue:23 | The design of a novel series of muscarinic receptor antagonists leading to AZD8683, a potential inhaled treatment for COPD. |
| AID430612 | Chemical stability assessed as half life at pH 7.4 by UV-HPLC analysis | 2009 | Journal of medicinal chemistry, Aug-27, Volume: 52, Issue:16 | Discovery of novel quaternary ammonium derivatives of (3R)-quinuclidinol esters as potent and long-acting muscarinic antagonists with potential for minimal systemic exposure after inhaled administration: identification of (3R)-3-{[hydroxy(di-2-thienyl)ace |
| AID1194256 | Selectivity index, ratio of IC50 for human M1 receptor to IC50 for human M3 rceeptor | 2015 | Bioorganic & medicinal chemistry letters, Apr-15, Volume: 25, Issue:8 | Discovery of novel quaternary ammonium derivatives of (3R)-quinuclidinyl amides as potent and long acting muscarinic antagonists. |
| AID1224070 | Displacement of [3H]-NMS from Sprague-Dawley rat muscarinic M3 receptor in submandibular gland | 2014 | Bioorganic & medicinal chemistry, Jul-01, Volume: 22, Issue:13 | Novel quinuclidinyl heteroarylcarbamate derivatives as muscarinic receptor antagonists. |
| AID631748 | Bronchoprotection activity in intratracheally dosed Dunkin Hartley guinea pig assessed as inhibition of methacholine-induced bronchoconstriction measured at 2 hrs post treatment | 2011 | Bioorganic & medicinal chemistry letters, Dec-15, Volume: 21, Issue:24 | The discovery of AZD9164, a novel muscarinic M3 antagonist. |
| AID327967 | Antagonist activity at muscarinic M3 receptor in carbachol-stimulated guinea pig trachea | 2008 | Bioorganic & medicinal chemistry letters, Apr-15, Volume: 18, Issue:8 | Alkyne-quinuclidine derivatives as potent and selective muscarinic antagonists for the treatment of COPD. |
| AID1054728 | Therapeutic index, ratio of ED80 for methacholine-induced bronchoconstriction in Dunkin-Hartley guinea pig to EC50 for reduction of pilocarpine-induced salivation in guinea pig | 2013 | Bioorganic & medicinal chemistry letters, Dec-01, Volume: 23, Issue:23 | The design of a novel series of muscarinic receptor antagonists leading to AZD8683, a potential inhaled treatment for COPD. |
| AID539981 | Displacement of [3H]NMS from human muscarinic M2 receptor expressed in CHO-K1 cells after 16 hrs by scintillation proximity assay | 2010 | Bioorganic & medicinal chemistry letters, Dec-15, Volume: 20, Issue:24 | The discovery of new spirocyclic muscarinic M3 antagonists. |
| AID627081 | Displacement of [3H]-NMS from human recombinant M4 receptor expressed in CHO cells after 24 hrs by filter binding assay | 2011 | Journal of medicinal chemistry, Oct-13, Volume: 54, Issue:19 | Inhalation by design: novel tertiary amine muscarinic M₃ receptor antagonists with slow off-rate binding kinetics for inhaled once-daily treatment of chronic obstructive pulmonary disease. |
| AID1296008 | Cytotoxic Profiling of Annotated Libraries Using Quantitative High-Throughput Screening | 2020 | SLAS discovery : advancing life sciences R & D, 01, Volume: 25, Issue:1 | Cytotoxic Profiling of Annotated and Diverse Chemical Libraries Using Quantitative High-Throughput Screening. |
| AID1346986 | P-glycoprotein substrates identified in KB-3-1 adenocarcinoma cell line, qHTS therapeutic library screen | 2019 | Molecular pharmacology, 11, Volume: 96, Issue:5 | A High-Throughput Screen of a Library of Therapeutics Identifies Cytotoxic Substrates of P-glycoprotein. |
| AID1346987 | P-glycoprotein substrates identified in KB-8-5-11 adenocarcinoma cell line, qHTS therapeutic library screen | 2019 | Molecular pharmacology, 11, Volume: 96, Issue:5 | A High-Throughput Screen of a Library of Therapeutics Identifies Cytotoxic Substrates of P-glycoprotein. |
| AID1591565 | Bronchodilatory activity in tracheotomized ICR mouse assessed as suppression of methacholine-induced increase in airway resistance at 4.2 ug/kg administered intratracheally 1 hr before by methacholine challenge | 2019 | Bioorganic & medicinal chemistry, 08-01, Volume: 27, Issue:15 | Chemical modification-mediated optimisation of bronchodilatory activity of mepenzolate, a muscarinic receptor antagonist with anti-inflammatory activity. |
| AID1591564 | Displacement of [3H]NMS from human M2R expressed in CHOK1 cell membranes incubated for 2 hrs by microbeta scintillation counting method | 2019 | Bioorganic & medicinal chemistry, 08-01, Volume: 27, Issue:15 | Chemical modification-mediated optimisation of bronchodilatory activity of mepenzolate, a muscarinic receptor antagonist with anti-inflammatory activity. |
| AID1591598 | Antiinflammatory activity in ICR mouse assessed as suppression of PPE-induced increase in the mean linear intercept at 42 ug/kg administered intratracheally once daily for 14 days measured at post last dose by hematoxylin and eosin staining based histopat | 2019 | Bioorganic & medicinal chemistry, 08-01, Volume: 27, Issue:15 | Chemical modification-mediated optimisation of bronchodilatory activity of mepenzolate, a muscarinic receptor antagonist with anti-inflammatory activity. |
| AID1591563 | Displacement of [3H]NMS from human M3R expressed in CHOK1 cell membranes incubated for 2 hrs by microbeta scintillation counting method | 2019 | Bioorganic & medicinal chemistry, 08-01, Volume: 27, Issue:15 | Chemical modification-mediated optimisation of bronchodilatory activity of mepenzolate, a muscarinic receptor antagonist with anti-inflammatory activity. |
| AID1591581 | Bronchodilatory activity in tracheotomized ICR mouse at 4.2 ug/kg administered intratracheally measured after 120 hrs | 2019 | Bioorganic & medicinal chemistry, 08-01, Volume: 27, Issue:15 | Chemical modification-mediated optimisation of bronchodilatory activity of mepenzolate, a muscarinic receptor antagonist with anti-inflammatory activity. |
| AID1591594 | Antiinflammatory activity in ICR mouse assessed as restoration of PPE-induced decrease in in FEV(0.1)/FVC ratio at 42 ug/kg administered intratracheally once daily for 14 days measured at post last dose | 2019 | Bioorganic & medicinal chemistry, 08-01, Volume: 27, Issue:15 | Chemical modification-mediated optimisation of bronchodilatory activity of mepenzolate, a muscarinic receptor antagonist with anti-inflammatory activity. |
| AID1591595 | Plasma concentration in ICR mouse at 10 mg/kg administered intratracheally measured after 1 min by RP-HPLC analysis | 2019 | Bioorganic & medicinal chemistry, 08-01, Volume: 27, Issue:15 | Chemical modification-mediated optimisation of bronchodilatory activity of mepenzolate, a muscarinic receptor antagonist with anti-inflammatory activity. |
| AID1591596 | Plasma concentration in ICR mouse at 7.5 mg/kg, iv measured after 1 min by RP-HPLC analysis | 2019 | Bioorganic & medicinal chemistry, 08-01, Volume: 27, Issue:15 | Chemical modification-mediated optimisation of bronchodilatory activity of mepenzolate, a muscarinic receptor antagonist with anti-inflammatory activity. |
| AID1591592 | Antiinflammatory activity in ICR mouse assessed as suppression of PPE-induced damage to the alveolar walls in lungs at 42 ug/kg administered intratracheally once daily for 14 days and measured at post last dose by hematoxylin and eosin staining based hist | 2019 | Bioorganic & medicinal chemistry, 08-01, Volume: 27, Issue:15 | Chemical modification-mediated optimisation of bronchodilatory activity of mepenzolate, a muscarinic receptor antagonist with anti-inflammatory activity. |
| AID1648387 | Antagonist activity at muscarinic M3 receptor (unknown origin) expressed in HEK293 cells coexpressing EA tagged beta-arrestin2 assessed as inhibition of carbachol-induced beta-arrestin2 recruitment preincubated for 30 mins followed by carbachol addition a | 2020 | Journal of medicinal chemistry, 04-23, Volume: 63, Issue:8 | Regiospecific Introduction of Halogens on the 2-Aminobiphenyl Subunit Leading to Highly Potent and Selective M3 Muscarinic Acetylcholine Receptor Antagonists and Weak Inverse Agonists. |
| AID1648382 | Antagonist activity at human muscarinic M3 receptor expressed in HEK293 assessed as inhibition of carbachol-induced IP1 accumulation preincubated for 30 mins followed by carbachol addition and measured after 90 mins by TR-HTRF assay | 2020 | Journal of medicinal chemistry, 04-23, Volume: 63, Issue:8 | Regiospecific Introduction of Halogens on the 2-Aminobiphenyl Subunit Leading to Highly Potent and Selective M3 Muscarinic Acetylcholine Receptor Antagonists and Weak Inverse Agonists. |
| AID1648385 | Antagonist activity at muscarinic M3 receptor (unknown origin) expressed in HEK293 cells coexpressing EA tagged beta-arrestin2 assessed as inhibition of carbachol-induced beta-arrestin2 recruitment preincubated for 30 mins followed by carbachol addition a | 2020 | Journal of medicinal chemistry, 04-23, Volume: 63, Issue:8 | Regiospecific Introduction of Halogens on the 2-Aminobiphenyl Subunit Leading to Highly Potent and Selective M3 Muscarinic Acetylcholine Receptor Antagonists and Weak Inverse Agonists. |
| AID1648386 | Agonist activity at muscarinic M3 receptor (unknown origin) expressed in HEK293 cells coexpressing EA tagged beta-arrestin2 assessed as beta-arrestin2 recruitment incubated for 90 mins by PathHunter assay relative to quinpirole | 2020 | Journal of medicinal chemistry, 04-23, Volume: 63, Issue:8 | Regiospecific Introduction of Halogens on the 2-Aminobiphenyl Subunit Leading to Highly Potent and Selective M3 Muscarinic Acetylcholine Receptor Antagonists and Weak Inverse Agonists. |
| AID1648381 | Agonist activity at human muscarinic M3 receptor expressed in HEK293 cells assessed as increase in IP1 accumulation incubated for 90 min by TR-HTRF assay relative to quinpirole | 2020 | Journal of medicinal chemistry, 04-23, Volume: 63, Issue:8 | Regiospecific Introduction of Halogens on the 2-Aminobiphenyl Subunit Leading to Highly Potent and Selective M3 Muscarinic Acetylcholine Receptor Antagonists and Weak Inverse Agonists. |
| AID1648383 | Antagonist activity at human muscarinic M3 receptor expressed in HEK293 assessed as inhibition of carbachol-induced IP1 accumulation preincubated for 30 mins followed by carbachol addition and measured after 90 mins by TR-HTRF assay relative to quinpirole | 2020 | Journal of medicinal chemistry, 04-23, Volume: 63, Issue:8 | Regiospecific Introduction of Halogens on the 2-Aminobiphenyl Subunit Leading to Highly Potent and Selective M3 Muscarinic Acetylcholine Receptor Antagonists and Weak Inverse Agonists. |
| [information is prepared from bioassay data collected from National Library of Medicine (NLM), extracted Dec-2023] | ||||
| Timeframe | Studies, This Drug (%) | All Drugs % |
|---|---|---|
| pre-1990 | 0 (0.00) | 18.7374 |
| 1990's | 10 (0.84) | 18.2507 |
| 2000's | 346 (29.17) | 29.6817 |
| 2010's | 718 (60.54) | 24.3611 |
| 2020's | 112 (9.44) | 2.80 |
| [information is prepared from research data collected from National Library of Medicine (NLM), extracted Dec-2023] | ||
According to the monthly volume, diversity, and competition of internet searches for this compound, as well the volume and growth of publications, there is estimated to be very strong demand-to-supply ratio for research on this compound.
| This Compound (68.70) All Compounds (24.57) |
| Publication Type | This drug (%) | All Drugs (%) |
|---|---|---|
| Trials | 1 (9.09%) | 5.53% |
| Trials | 393 (31.77%) | 5.53% |
| Reviews | 0 (0.00%) | 6.00% |
| Reviews | 283 (22.88%) | 6.00% |
| Case Studies | 0 (0.00%) | 4.05% |
| Case Studies | 25 (2.02%) | 4.05% |
| Observational | 0 (0.00%) | 0.25% |
| Observational | 21 (1.70%) | 0.25% |
| Other | 10 (90.91%) | 84.16% |
| Other | 515 (41.63%) | 84.16% |
| [information is prepared from research data collected from National Library of Medicine (NLM), extracted Dec-2023] | ||
| Trial | Phase | Enrollment | Study Type | Start Date | Status | ||
|---|---|---|---|---|---|---|---|
| A 16-week Randomised, Placebo-controlled, Double-blind, Double-dummy, Parallel-group Study Comparing the Efficacy and Safety of Tiotropium Inhalation Solution Delivered by the Respimat Inhaler (2 Actuations of 2.5 Mcg Once Daily) With That of Salmeterol F [NCT00350207] | Phase 2 | 388 participants (Actual) | Interventional | 2006-07-31 | Completed | ||
| Effect of Charcoal on Gastrointestinal Absorption of Tiotropium; A Randomised, Open, Single Centre, Single Dose, Crossover Study in Healthy Subjects [NCT03945344] | Phase 1 | 20 participants (Actual) | Interventional | 2019-05-27 | Completed | ||
| A Randomized, Double-Blind, Double-Dummy, Placebo-Controlled, Crossover, Multicenter Clinical Study to Assess the Efficacy and Safety of Once Daily Administration of Lupin Tiotropium Bromide Inhalation Powder Compared to SPIRIVA® HANDIHALER® and Placebo i [NCT03137992] | Phase 3 | 377 participants (Actual) | Interventional | 2017-11-21 | Completed | ||
| A 6-week, Multicenter, Randomized, Double-blind, Placebo and Active-controlled, Parallel Group, Dose-ranging Study to Evaluate the Efficacy and Safety of 4 Doses of CHF 5259 pMDI (HFA Glycopyrronium Bromide Via Pressurized Metered Dose Inhaler) in Subject [NCT03084796] | Phase 2 | 733 participants (Actual) | Interventional | 2017-07-28 | Completed | ||
| A Phase III, Randomised, Double-blind, Placebo-controlled, Parallel-group Trial to Evaluate Efficacy and Safety of Tiotropium Inhalation Solution Delivered Via Respimat® Inhaler (2.5 ug and 5 ug Once Daily) Compared to Placebo Over 12 Weeks in Mild Persis [NCT01316380] | Phase 3 | 465 participants (Actual) | Interventional | 2011-03-31 | Completed | ||
| Characteristics of Patients Initiating Spiriva Respimat in Asthma in the UK: a Cross-sectional Study Based on the Clinical Practice Research Datalink [NCT03692676] | 116,133 participants (Actual) | Observational | 2019-03-05 | Completed | |||
| A Phase II, Randomized, Double Blind, Placebo Controlled, Three-way Crossover Study to Assess the Bronchodilator Effect of RPL554 Administered in Addition to Open Label Tiotropium/Olodaterol in Patients With COPD [NCT03673670] | Phase 2 | 79 participants (Actual) | Interventional | 2018-07-16 | Completed | ||
| Randomized Phase II Crossover Study of Tiotropium For Dyspnea in Advanced Non-Small Cell Lung Cancer [NCT01172925] | Phase 2 | 34 participants (Anticipated) | Interventional | 2010-11-30 | Recruiting | ||
| A Randomised, Double-blind, Placebo-controlled (Within Dose Groups) Study to Assess Safety, Tolerability and Pharmacokinetics of Single Rising Inhaled Doses (2.5 μg, 5 μg, 10 μg, 20 μg and 40 μg) of BI 1744 CL (Administered With the Respimat®) in Free Dos [NCT02259946] | Phase 1 | 48 participants (Actual) | Interventional | 2006-04-30 | Completed | ||
| Randomized, Double-blind, Placebo-controlled, Cross-over Study to Investigate the Bronchodilator Efficacy and Safety After Single and Repeated Administrations of Different Doses of Glycopyrrolate Via pMDI in Moderate to Severe COPD Patients. [NCT01176903] | Phase 1/Phase 2 | 65 participants (Actual) | Interventional | 2010-08-31 | Completed | ||
| 1-yr Study Comparing TioSal Combo Regimens Versus Single Agent Therapies (Spiriva HandiHaler and Salmeterol PE Capsule) [NCT00662740] | Phase 3 | 220 participants (Actual) | Interventional | 2008-04-15 | Terminated | ||
| Personalized Treatment Algorithms for Difficult-to-treat Asthma: Bench to Community [NCT04179461] | Phase 2 | 21 participants (Actual) | Interventional | 2018-03-16 | Completed | ||
| [NCT03028142] | Phase 2 | 30 participants (Actual) | Interventional | 2017-01-31 | Completed | ||
| Acute and Chronic Effects of an Anticholinergic Agent or a Long-Acting Beta 2 Agonist on Levels of Exhaled Nitric Oxide and Pulmonary Function in Persons With Tetraplegia [NCT01355991] | Phase 1 | 40 participants (Anticipated) | Interventional | 2011-08-31 | Active, not recruiting | ||
| Effect of Acupuncture on Patients With Chronic Obstructive Pulmonary Disease: a Multi-center, Randomized, Controlled Trial [NCT03169504] | Phase 3 | 150 participants (Anticipated) | Interventional | 2017-05-31 | Not yet recruiting | ||
| A Randomized, Double-Blind, Parallel Group, Multi-Center 24-Week Study Comparing the Efficacy and Safety of Three Doses of PT001 to Placebo and Open-label Spiriva® Respimat® in Subjects With Persistent Asthma [NCT03358147] | Phase 2/Phase 3 | 1,077 participants (Actual) | Interventional | 2017-12-13 | Completed | ||
| A Multicenter, Non-interventional, Observational Clinical Trial to Assess the Quality of Life in Patients With ChRonic ObstructIve Pulmonary Disease Who Require Tiotropium as additiOnal treatmeNt. [NCT06170125] | 500 participants (Anticipated) | Observational | 2024-01-31 | Not yet recruiting | |||
| Proof of Concept Evaluation of Drug-Device Interaction With Aclidinium Bromide Via Genuair® and Tiotropium Bromide Via HandiHaler® in COPD Using Impulse Oscillometry [NCT02039050] | Phase 4 | 15 participants (Actual) | Interventional | 2014-02-28 | Completed | ||
| An Open-label, Low Interventional Clinical Study Investigating Error Rates (Critical and Overall) Prior to Any Retraining in Correct Use of the ELLIPTA Dry Powder Inhaler (DPI) Compared to Other DPIs Including; DISKUS, Turbuhaler, HandiHaler and Breezhale [NCT03114969] | 450 participants (Actual) | Observational | 2017-06-08 | Completed | |||
| A Randomized, Double-blind, Double-dummy, Active-controlled, Multi-center, Parallel Group Study to Show the Superiority in Lung Function of 12 Weeks Once Daily Treatment With Orally Inhaled Tiotropium+Olodaterol Fixed Dose Combination Delivered by the Res [NCT03240575] | Phase 4 | 302 participants (Actual) | Interventional | 2017-08-14 | Completed | ||
| A Real-world Non-interventional Study to Assess Patient Satisfaction With and Preference for Re-usable Respimat Soft Mist Inhaler in Patients With Chronic Obstructive Pulmonary Disease. [NCT04011735] | 262 participants (Actual) | Observational | 2019-09-30 | Completed | |||
| Quality of Life and Preference of COPD Patients After Switching From Tiotropium Monotherapy (Spiriva® Handihaler®) to Dual Therapy With Tiotropium Bromide Plus Olodaterol (Spiolto® Respimat®) Under Real Life Conditions in Greece (ELLACTO II Study) [NCT04672941] | 1,396 participants (Actual) | Observational | 2021-02-16 | Completed | |||
| A Multicenter, Partially-Blinded, Randomized, 24-Week, Parallel-Group, Non-Inferiority, Open-Label Active Controlled Study to Compare the Efficacy and Safety of QVM149 With a Free Triple Combination of Salmeterol/Fluticasone + Tiotropium in Patients With [NCT03158311] | Phase 3 | 1,426 participants (Actual) | Interventional | 2018-02-05 | Completed | ||
| A Dose Ranging, Parallel Group, Active (Spiriva® Respimat®) And Placebo Controlled Study To Assess Relative Bioavailability, Pharmacodynamics And Safety Of Three Doses Of Tiotropium Bromide Inhalation Solution In Subjects With Mild To Moderate Chronic Obs [NCT03118765] | Phase 2 | 155 participants (Actual) | Interventional | 2017-03-24 | Completed | ||
| A Multi-center Trial Comparing the Efficacy and Safety of GSK573719/GW642444 With GSK573719 and With Tiotropium Over 24 Weeks in Subjects With COPD [NCT01316913] | Phase 3 | 872 participants (Actual) | Interventional | 2011-03-31 | Completed | ||
| Taiwan Outcomes and Real-world Treatment Options for Chronic Obstructive Pulmonary Disease [NCT04011475] | 1,617 participants (Actual) | Observational | 2019-12-29 | Completed | |||
| The Pharmacokinetics, Safety and Tolerability of Tiotropium in Elderly COPD Patients (Open Label, Monocenter Study). [NCT02172326] | Phase 3 | 29 participants | Interventional | 1998-02-28 | Completed | ||
| Tolerability and Efficacy of Spiriva® 18 Micrograms in Patients With COPD in Daily Practice [NCT02172482] | 63,127 participants (Actual) | Observational | 2002-06-30 | Completed | |||
| A Retrospective Collection of Vital Status and Pulmonary Medication Usage Data for Patients With Chronic Obstructive Pulmonary Disease (COPD) Who Withdrew Prematurely From Either of Two One-Year Trials (205.254, 205.255) of Tiotropium Inhalation Solution [NCT02172560] | 441 participants (Actual) | Observational | 2007-03-31 | Completed | |||
| A Randomised, Double-Blind, Double-Dummy, Placebo-Controlled, Crossover Comparison of the Effect of 6-Week Treatment Periods of Tiotropium Inhalation Capsules (18 μg) and Salmeterol Inhalation Aerosol on Muscular Efficiency and Resting Energy Expenditure [NCT02172794] | Phase 3 | 48 participants (Actual) | Interventional | 2002-05-31 | Completed | ||
| Drug Use Results Survey of Tiotropium Bromide [NCT02177318] | 3,588 participants (Actual) | Observational | 2005-04-30 | Completed | |||
| A Phase IV, 12-week, Randomised, Double-blind, Triple Dummy Study to Compare Single Inhaler Triple Therapy, Fluticasone Furoate/Umeclidinium/Vilanterol (FF/UMEC/VI) With Multiple Inhaler Therapy (Budesonide/Formoterol Plus Tiotropium) Based on Lung Functi [NCT03478696] | Phase 4 | 732 participants (Actual) | Interventional | 2018-06-25 | Completed | ||
| The Pharmacokinetic, Safety and Tolerability of Tiotropium (4.8 mcg, Single i.v. Dose) in Outpatients With Renal Impairment in Comparison to Healthy Subjects (Open Label, Group Comparison, Two-center Study) [NCT02172339] | Phase 1 | 24 participants (Actual) | Interventional | 1998-04-30 | Completed | ||
| The Effect of Concomitant Cimetidine p.o. 400 mg t.i.d. and p.o. Ranitidine 300 mg Once Daily on Single Dose Pharmacokinetics of Tiotropium (14.4 µg) Given Intravenously Over 15 Minutes in Healthy Male and Female Subjects of 50-65 Years (Randomized, Open [NCT02172417] | Phase 1 | 18 participants (Actual) | Interventional | 2000-07-31 | Completed | ||
| Tolerability and Efficacy of Spiriva® 18 Micrograms in Patients With COPD in Daily Practice [NCT02172495] | 4,700 participants (Actual) | Observational | 2002-06-30 | Completed | |||
| A Multiple Dose Comparison of 18 µg, 36 µg of Ba679BR (Tiotropium) Inhalation Capsules and Oxitropium Metered Dose Inhaler (2 Puffs of 100µg) in a 4-week, Double-Blind, Double-Dummy, Safety and Efficacy Study in Patients With Chronic Obstructive Pulmonary [NCT02172807] | Phase 3 | 201 participants (Actual) | Interventional | 2000-12-31 | Completed | ||
| Tiotropium vs. Inhaled Corticosteroids in Children With Nonatopic Asthma Pilot Study [NCT04990167] | Phase 2 | 26 participants (Anticipated) | Interventional | 2022-01-01 | Recruiting | ||
| Efficacy of Intermittent Tiotropium in Early Childhood Wheezing [NCT03199976] | Phase 4 | 80 participants (Actual) | Interventional | 2016-04-20 | Completed | ||
| A Randomized, Double-blind, Double-dummy, Three Period Incomplete Cross-over Study to Evaluate the Safety and Efficacy of Multiple Daily Doses of QAX028 as Compared to Tiotropium Bromide (Positive Control) and Placebo in COPD Patients [NCT01068613] | Phase 2 | 62 participants (Actual) | Interventional | 2010-01-31 | Completed | ||
| A Regulatory Required Non Interventional Study to Monitor the Safety and Effectiveness of Once Daily Treatment of Orally Inhaled Vahelva Respimat (Tiotropium + Olodaterol Fixed Dose Combination 2.5µg/2.5µg Per Puff (2 Puffs Comprise One Medicinal Dose)) f [NCT02864407] | 3,223 participants (Actual) | Observational | 2016-12-19 | Completed | |||
| A Phase 3b, Randomized, Double-Blind, Double-Dummy, Parallel-Group, Study to Compare Once Daily Nebulized Revefenacin With Spiriva Once Daily Delivered Via the HandiHaler® on Lung Function in Subjects With COPD and a Low PIFR [NCT03095456] | Phase 3 | 207 participants (Actual) | Interventional | 2017-03-27 | Completed | ||
| A Prescription-Event Monitoring (PEM) Study of Tiotropium Based on Prescription Data Collected by the Prescription Pricing Authority (PPA) in England for Tiotropium (Spiriva®) [NCT02196194] | 13,891 participants (Actual) | Observational | 2002-09-30 | Completed | |||
| Safety, Tolerability, Pharmacodynamics and Pharmacokinetics of Single Rising Inhaled BEA 2180 BR Doses (2.5 μg to 1600 μg Cation Administered With the Respimat®) in Healthy Male Subjects, Alone and Followed by Methacholine Challenge. A Randomised, Double- [NCT02263976] | Phase 1 | 101 participants (Actual) | Interventional | 2003-08-31 | Completed | ||
| Comparison of Exacerbation Risk and Health Outcomes in Maintenance Treatment naïve Chronic Obstructive Pulmonary Disease (COPD) Patients Using Stiolto Versus Trelegy, a Real-World Study [NCT05169424] | 9,117 participants (Actual) | Observational | 2021-12-17 | Completed | |||
| A Randomised, Open-label, 4-way Crossover Study to Characterize the Pharmacokinetics, Safety and Efficacy of FDC Tiotropium/Salmeterol, Tiotropium, Salmeterol and a Free Combination of Tiotropium Plus Salmeterol Following 4-week Treatment Periods in Patie [NCT00673478] | Phase 3 | 50 participants (Actual) | Interventional | 2008-05-31 | Completed | ||
| A Randomized, Double-Blind, Double-Dummy, Parallel Group, Dose-Ranging Study of 3 Doses of Tiotropium Hydrofluoralkane (HFA) Breath Actuated Inhaler (BAI), Placebo HFA BAI, and Open-Label SPIRIVA® HandiHaler® (18 mcg) in Patients With Chronic Obstructive [NCT02203474] | Phase 2 | 0 participants (Actual) | Interventional | 2014-08-31 | Withdrawn | ||
| Comparison of Clinical Efficacy and Patient's Satisfaction of Tiotropium Respimat Administration With and Without Aerochamber in Patient With Chronic Obstructive Pulmonary Disease (COPD) [NCT04999930] | 100 participants (Actual) | Interventional | 2020-01-10 | Completed | |||
| A Randomised, Double-blind, Cross-over Study to Evaluate the Effect of 6 Weeks Treatment of Orally Inhaled Tiotropium + Olodaterol Fixed Dose Combination (5/5 µg) Compared With Tiotropium (5 µg), Both Delivered by the Respimat® Inhaler, on Breathlessness [NCT02853123] | Phase 4 | 106 participants (Actual) | Interventional | 2016-09-22 | Completed | ||
| Pharmacodynamic and Pharmacokinetic Dose Ranging Study of Tiotropium Bromide Administered Via Respimat Device in Patients With Chronic Obstructive Pulmonary Disease (COPD): a Randomized, 3-week Multiple-dose, Placebo Controlled, Intraformulation Double-bl [NCT02175342] | Phase 2 | 202 participants (Actual) | Interventional | 1998-03-31 | Completed | ||
| Effect of Tiotropium on Exercise Tolerance and Static and Dynamic Lung Volumes in COPD Patients (A Randomized Double-Blind, Placebo Controlled, Parallel Group Study) [NCT02172300] | Phase 3 | 198 participants (Actual) | Interventional | 1999-06-30 | Completed | ||
| Effect of a 12-week Treatment With Inhaled Tiotropium (18 mcg Once Daily) on Lung Function and Static Lung Volumes in Stable, Moderate to Severe COPD Patients. Correlation to Dyspnoea Scales. A Double-blind, Placebo-controlled, Randomized, Parallel Group [NCT02172378] | Phase 3 | 116 participants (Actual) | Interventional | 2000-05-31 | Completed | ||
| γ-Scintigraphic Evaluation of the Lung Deposition Rate and Distribution Pattern of a 99mTc-Labelled Tiotropium Powder Formulation Following Multiple Dose Inhalation of Tiotropium Via HandiHalerTM in Healthy Subjects and Patients With COPD [NCT02172456] | Phase 3 | 22 participants (Actual) | Interventional | 2002-05-31 | Completed | ||
| A Randomized, Double-blind Within Dose, Placebo-controlled Study to Investigate the Safety, Tolerability and Pharmacokinetics of Increasing Single and Multiple Doses (28-day Dosing) of Tiotropium Bromide Administered Once Daily Via the Respimat® Device in [NCT02172534] | Phase 1 | 113 participants (Actual) | Interventional | 2006-09-30 | Completed | ||
| A Randomized, Double-blind, Single Dose, Four-period, Six-treatment, Placebo-controlled, Balanced, Incomplete Block, Cross-over, Study of Four Doses of Inhaled PT001 in Patients With Mild to Moderate COPD, Compared to Open Label Tiotropium [NCT00871182] | Phase 1/Phase 2 | 33 participants (Actual) | Interventional | 2009-03-31 | Completed | ||
| Dose Ranging Study of Ba 679 BR Inhalation Powder Following Single Inhalation in COPD Patients - Double-blind, Placebo-controlled, 4 Treatment, 4 Period Crossover Study- [NCT02172352] | Phase 2 | 28 participants (Actual) | Interventional | 1998-07-31 | Completed | ||
| A Multiple Dose Comparison of Tiotropium 18 μg Inhalation Capsules and Oxitropium MDI (2 Puffs of 100 μg) in a One-year, Open-Label, Safety and Efficacy Study in Patients With COPD [NCT02172430] | Phase 3 | 161 participants (Actual) | Interventional | 2000-09-30 | Completed | ||
| A Randomised, Double-blind, Placebo-controlled 7-week Trial to Investigate the Effects of Tiotropium Inhalation Capsules (18 μg) Once Daily on Exercise Tolerance, Daily Activity and Dyspnoea in Patients With Chronic Obstructive Pulmonary Disease (COPD) Pa [NCT02172508] | Phase 4 | 15 participants (Actual) | Interventional | 2004-01-31 | Terminated | ||
| A Randomised, Phase II, Double-Blind, Double-Dummy, Four-period Crossover Efficacy and Safety Comparison of 4-Week Treatment Periods of Blinded Fluticasone (500 mcg Bid, MDI), Ciclesonide (400 mcg qd, MDI), Ciclesonide (800 mcg qd, MDI) or Placebo in Free [NCT00535366] | Phase 2 | 103 participants (Actual) | Interventional | 2007-10-31 | Completed | ||
| Health Care Resource Utilization, Cost and Other Outcomes of Patients Diagnosed With COPD Initiating Tiotropium Bromide/Olodaterol Versus Fluticasone Furoate/Umeclidinium/Vilanterol [NCT05127304] | 11,316 participants (Actual) | Observational | 2021-02-26 | Completed | |||
| A Phase IV, 12-week, Randomised, Double-blind, Triple Dummy Study to Compare Single Inhaler Triple Therapy, Fluticasone Furoate/Umeclidinium/Vilanterol (FF/UMEC/VI) With Multiple Inhaler Therapy (Budesonide/Formoterol Plus Tiotropium) Based on Lung Functi [NCT03478683] | Phase 4 | 729 participants (Actual) | Interventional | 2018-06-25 | Completed | ||
| A Phase IV, 12 Week, Randomised, Double-blind, Double-dummy Study to Compare Single Inhaler Triple Therapy, Fluticasone Furoate/Umeclidinium/Vilanterol (FF/UMEC/VI), With Tiotropium Monotherapy Based on Lung Function and Symptoms in Participants With Chro [NCT03474081] | Phase 4 | 800 participants (Actual) | Interventional | 2018-03-29 | Completed | ||
| Early Intervention Effectiveness of Tiotropium / Olodaterol Compared to Tiotropium in COPD [NCT04249310] | 6,788 participants (Actual) | Observational | 2020-03-27 | Completed | |||
| Comparison of Bronchodilator Efficacy of Tiotropium/Salmeterol/Fluticasone 9/50/500 mcg Combination Treatment Administered Via Discair® With Original Products Seretide Diskus 500 mcg Inhalation Powder Plus Spiriva 18 mcg Inhalation Powder Treatment in Pat [NCT03395002] | Phase 4 | 58 participants (Actual) | Interventional | 2018-03-22 | Completed | ||
| Safety Profile of Tiotropium + Olodaterol Used as Maintenance Treatment in COPD Patients in Taiwan: a Non-interventional Study Based on the Taiwan National Health Insurance (NHI) Data [NCT05393245] | 19,467 participants (Actual) | Observational | 2022-09-30 | Completed | |||
| [NCT02813200] | Phase 4 | 24 participants (Actual) | Interventional | 2017-01-10 | Completed | ||
| A Multi-center, Open-label, Randomized, Controlled Study to Evaluate the Effectiveness of Yong Chong Cao Capsule on Outcomes in Patients With Mild to Severe COPD [NCT03745261] | Phase 3 | 240 participants (Anticipated) | Interventional | 2018-06-20 | Recruiting | ||
| Comparative Study Between Three Therapeutic Options for Treatment of Chronic Obstructive Pulmonary Disease Patients [NCT04520230] | Phase 4 | 45 participants (Actual) | Interventional | 2014-10-31 | Completed | ||
| An Exploratory, Randomised, Double-blind, Double-dummy, Active-controlled, Two Period Cross-over Study to Investigate the Effect of 6 Weeks Treatment of Orally Inhaled Tiotropium + Olodaterol Fixed Dose Combination (FDC) Delivered by the Respimat® Inhaler [NCT03055988] | Phase 4 | 76 participants (Actual) | Interventional | 2017-03-29 | Completed | ||
| A Multicenter Trial Comparing the Efficacy and Safety of GSK573719/GW642444 With GW642444 and With Tiotropium Over 24 Weeks in Subjects With COPD [NCT01316900] | Phase 3 | 846 participants (Actual) | Interventional | 2011-03-01 | Completed | ||
| Effects of Tiotropium on Walking Capacity in Patients With COPD [NCT01307189] | Phase 4 | 33 participants (Actual) | Interventional | 2005-04-30 | Completed | ||
| An Open Label, Randomised, Two-way Crossover Phase I Study to Assess Safety, Tolerability and Pharmacokinetics of the Fixed Dose Combination of Tiotropium Plus BI 54903 Via Respimat® B Versus the Combination of the Monoproducts of Tiotropium Via Respimat® [NCT01309139] | Phase 1 | 36 participants (Actual) | Interventional | 2011-03-31 | Completed | ||
| A Randomised, Double-blind, Placebo-controlled, Parallel-group Trial to Evaluate Efficacy and Safety of Tiotropium Inhalation Solution Delivered Via Respimat® Inhaler (2.5 mcg and 5 mcg Once Daily) Over 12 Weeks as add-on Controller Therapy on Top of Usua [NCT01277523] | Phase 3 | 392 participants (Actual) | Interventional | 2011-01-31 | Completed | ||
| A Randomized, Double-blind, Placebo Controlled, Multicenter, 3-period Crossover Study to Compare the Effect of Indacaterol (150μg o.d.) on Inspiratory Capacity to Placebo in Patients With Moderate COPD, Using Open Label Tiotropium (18μg o.d.) as Active Co [NCT01012765] | Phase 3 | 173 participants (Actual) | Interventional | 2009-11-30 | Completed | ||
| A Randomized, Double-blind, Placebo-controlled, 6-week, Crossover Study to Examine the Effects of Tiotropium (Spiriva® HandiHaler®, 18 µg Once Daily) on Dynamic Hyperinflation and Physical Exercise Capacity in Patients With Early Stage Chronic Obstructive [NCT01072396] | Phase 4 | 126 participants (Actual) | Interventional | 2010-02-28 | Completed | ||
| A Multicenter, Randomised, Placebo- and Active-controlled, 5 Way, Crossover Trial to Characterise the Pharmacokinetics and Evaluate the Bronchodilator Efficacy and Safety of Once-daily Tiotropium Delivered (Double-blind) From the Respimat Inhaler as Solut [NCT01222533] | Phase 2 | 154 participants (Actual) | Interventional | 2010-10-31 | Completed | ||
| Effects of Long Acting Bronchodilators on CARDiac Autonomic Nervous System Control in Patients With COPD [NCT02872090] | Phase 4 | 42 participants (Actual) | Interventional | 2016-03-31 | Completed | ||
| Multicenter, Randomized, Blinded, Placebo-controlled, Crossover, Single-dose Study to Assess the Effect of Indacaterol (150 μg) Versus Tiotropium (18 μg) on Inspiratory Capacity in Moderate Chronic Obstructive Pulmonary Disease (COPD) Patients [NCT00999908] | Phase 3 | 54 participants (Actual) | Interventional | 2009-10-31 | Completed | ||
| A Randomized, Double-blind, Controlled, Parallel-group, 12-week Study to Compare the Efficacy and Safety of the Combination of Indacaterol 150 µg Once Daily With Open Label Tiotropium 18 µg Once Daily Versus Open Label Tiotropium 18 µg Once Daily in Patie [NCT00877383] | Phase 3 | 1,142 participants (Actual) | Interventional | 2009-04-30 | Completed | ||
| Phase I Randomised, Five-period Cross-over Study in Healthy Male and Female Volunteers to Compare the Pharmacokinetics of Tiotropium Delivered From Three Test Products With Two Reference Products [NCT02627625] | Phase 1 | 31 participants (Actual) | Interventional | 2015-11-30 | Completed | ||
| Duration of Bronchoprotection of the Long Acting Muscarinic Antagonists Tiotropium and Glycopyrronium Against Methacholine Induced Bronchoconstriction [NCT02622243] | Phase 4 | 13 participants (Actual) | Interventional | 2015-11-30 | Completed | ||
| A Randomized, Placebo-controlled, Double-blind, Parallel Group, Multi Center Study to Assess the Safety and Efficacy of Tiotropium Bromide (18 µg) Delivered Via the HandiHaler® in Chronic Obstructive Pulmonary Disease (COPD) Subjects Recovering From Hospi [NCT01662986] | Phase 4 | 79 participants (Actual) | Interventional | 2012-08-01 | Completed | ||
| A Multiple Dose Comparison of Tiotropium Inhalation Capsules, Salmeterol Inhalation Aerosol and Placebo in a Six-Month, Double-Blind, Double-Dummy, Safety and Efficacy Study in Patients With Chronic Obstructive Pulmonary Disease (COPD) [NCT02172287] | Phase 3 | 623 participants (Actual) | Interventional | 1999-02-28 | Completed | ||
| Comparison of 18 mcg of Tiotropium Inhalation Capsules and Atrovent Metered Dose Inhaler (2 Puffs of 20 mcg) in a Double Blind, Double Dummy, Efficacy and Safety Study in Adults With Chronic Obstructive Pulmonary Disease (COPD) [NCT02172443] | Phase 3 | 50 participants (Actual) | Interventional | 2001-06-30 | Completed | ||
| Effect of Spiriva® 18 Microgram on Health-related Quality of Life and Physical Functioning in Patients With COPD and Proven Hyperinflation [NCT02172521] | 1,536 participants (Actual) | Observational | 2006-01-31 | Completed | |||
| A Multiple Dose Comparison of Tiotropium Inhalation Capsules, Salmeterol Inhalation Aerosol and Placebo in a Six-Month, Double-Blind, Double-Dummy, Safety and Efficacy Study in Patients With Chronic Obstructive Pulmonary Disease (COPD) [NCT02173691] | Phase 3 | 584 participants (Actual) | Interventional | 1999-02-28 | Completed | ||
| A Randomised, Double-blind, Double-dummy, Crossover Efficacy and Safety Comparison of 6-week Treatment Periods of the Free Combination of Tiotropium Inhalation Powder Capsule (18 μg) + Formoterol Inhalation Powder Capsule (12 μg) QD, Tiotropium Inhalation [NCT02238119] | Phase 2 | 74 participants (Actual) | Interventional | 2002-02-28 | Completed | ||
| Comparison of Tiotropium Pharmacokinetics After Inhalation From Tiotropium Easyhaler® Product Variants and After Spiriva® Capsules Administered Via HandiHaler®; Study in Healthy Volunteers [NCT04850144] | Phase 1 | 43 participants (Actual) | Interventional | 2021-04-26 | Completed | ||
| Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of Multiple Rising Inhalative Doses (2 μg/5 μg, 10 μg/5 μg, and 40 μg/10 μg) of BI 1744 CL in Fixed Dose Combination With Tiotropium Bromide for 14 Days in Healthy Male Volunteers (Double-blind, [NCT02259959] | Phase 1 | 36 participants (Actual) | Interventional | 2007-04-30 | Completed | ||
| A 24 Week Treatment, Multicenter, Randomized, Double Blinded, Double Dummy, Parallel-group, Clinical Trial Evaluating the Efficacy and Safety of Aclidinium Bromide 400 μg/Formoterol Fumarate 12 μg Fixed-dose Combination BID Compared With Each Monotherapy [NCT02796677] | Phase 3 | 1,595 participants (Actual) | Interventional | 2016-07-05 | Completed | ||
| A Randomized, Phase IIIb, Three-period, Three-treatment, Double-blind, Multi-center, Crossover Study to Evaluate the 24-hour Lung Function Profile in Subjects With Moderate to Very Severe COPD After 4 Weeks of Treatment With PT003, Open-Label Spiriva® Res [NCT02347072] | Phase 3 | 80 participants (Actual) | Interventional | 2015-02-01 | Completed | ||
| The Effects of Tiotropium Therapy on Airway Diameter in Patients With COPD (a Randomized, Double-blind, Placebo-controlled, Parallel-group Study) [NCT02172391] | Phase 3 | 81 participants | Interventional | 2000-11-30 | Completed | ||
| A Comparison of 18 µg of Tiotropium Inhalation Capsules and Atrovent® Metered Dose Inhaler (2 Puffs of 20 µg, 4 Times Daily) in a Double-Blind, Double-Dummy, Efficacy and Safety Study in Adults With Chronic Obstructive Pulmonary Disease (COPD) [NCT02172469] | Phase 3 | 215 participants (Actual) | Interventional | 2001-05-31 | Completed | ||
| Effect of Spiriva® 18 Microgram on Health-related Quality of Life in COPD Patients Who Stopped Smoking During Treatment. [NCT02172547] | 10,821 participants (Actual) | Observational | 2006-04-30 | Completed | |||
| A Double-blind, Randomised, Two-way Cross-over Study to Investigate the Pharmacokinetic and Pharmacodynamic Effects of a Single Additional Dose of 500 µg Ipratropium Bromide Unit Dose Vial Inhaled Via Nebuliser Versus Placebo After 19 Days of Treatment Wi [NCT02172781] | Phase 1 | 36 participants (Actual) | Interventional | 2001-01-31 | Completed | ||
| A Single Increasing Dose Tolerance Study After Ocular Administration of Tiotropium (Single Doses: 0.02 - 0.4 mcg) in Healthy Male Volunteers (Randomised, Placebo-controlled, Double-blind, Parallel Groups). [NCT02177305] | Phase 1 | 48 participants (Actual) | Interventional | 1998-10-31 | Completed | ||
| A Two-Week, Randomized, Modified-Blind, Double-Dummy, Parallel-Group Efficacy and Safety Study of Arformoterol Tartrate Inhalation Solution Twice-Daily, Tiotropium Once-Daily, and Arformoterol Tartrate Inhalation Solution Twice-Daily and Tiotropium Once D [NCT00424528] | Phase 4 | 235 participants (Actual) | Interventional | 2006-12-31 | Completed | ||
| Efficacy {FEV1, COPD Exacerbations & HRQoL} & Safety of 5mcg Tiotropium Respimat in COPD [NCT00387088] | Phase 3 | 3,991 participants (Actual) | Interventional | 2006-09-30 | Completed | ||
| A Randomized, Double-blind, Placebo-controlled, Parallel Group Trial Assessing the Rate of Decline of Lung Function With Tiotropium 18 mcg Inhalation Capsule Once Daily in Patients With Chronic Obstructive Pulmonary Disease (COPD). [NCT00144339] | Phase 3 | 5,993 participants (Actual) | Interventional | 2002-12-31 | Completed | ||
| A Randomised, Double-blind, Active-controlled Parallel Group Study to Evaluate the Effect of 52 Weeks of Once Daily Treatment of Orally Inhaled Tiotropium + Olodaterol Fixed Dose Combination Compared With Tiotropium on Chronic Obstructive Pulmonary Diseas [NCT02296138] | Phase 3 | 7,903 participants (Actual) | Interventional | 2015-01-13 | Completed | ||
| A Randomized, Double-Blind, Placebo-Controlled, 3-Way Cross-Over Study to Evaluate the Safety, Efficacy, and Pharmacokinetics of GSK573719 Administered Once- and Twice-Daily in Subjects With COPD [NCT00950807] | Phase 2 | 176 participants (Actual) | Interventional | 2009-09-01 | Completed | ||
| Comparing the Acute Effects of Tiotropium Handihaler With Tiotropium Respimat on the Ventilation Distribution in COPD Patients [NCT05838703] | Phase 2 | 0 participants (Actual) | Interventional | 2023-05-01 | Withdrawn(stopped due to Study halted prematurely due to funding, prior to enrollment of first participant) | ||
| Phase I Randomised, Three-period Cross-over Study in Healthy Male and Female Volunteers to Compare the Pharmacokinetics of Tiotropium Delivered From Two Test Products With Spiriva Respimat Comparator Product [NCT02676297] | Phase 1 | 26 participants (Actual) | Interventional | 2016-01-31 | Completed | ||
| A 12-week Treatment, Multicenter, Randomized, Parallel-group, Blinded, Double-dummy Study to Compare the Efficacy and Safety of Indacaterol (150 µg Once Daily [od]) Delivered Via a Single Dose Dry Powder Inhaler (SDDPI) With Tiotropium (18 µg od) Delivere [NCT00900731] | Phase 3 | 1,598 participants (Actual) | Interventional | 2009-06-30 | Completed | ||
| Effect of Tiotropium Bromide Combined With Odaterol on Small Airway Remodeling in Patients With Mild to Moderate Chronic Obstructive Pulmonary Disease [NCT05295355] | 72 participants (Anticipated) | Interventional | 2021-01-25 | Recruiting | |||
| Safety and Effectiveness of Spiriva® in COPD (Chronic Obstructive Pulmonary Disease) Patients Under the Real Condition of Usual Practice [NCT00624377] | 2,031 participants (Actual) | Observational | 2007-12-31 | Completed | |||
| A Multinational, Randomised, Double-blind, Placebo- and Active-controlled, Parallel Group Efficacy and Safety Comparison Over 24 Weeks of Three Doses (50µg, 100µg, 200µg) of BEA 2180 BR to Tiotropium 5µg, Delivered by the Respimat Inhaler and Placebo in P [NCT00528996] | Phase 2 | 2,080 participants (Actual) | Interventional | 2007-09-06 | Completed | ||
| A Randomized, Double-blind, Parallel Group Trial Comparing 12 Weeks Treatment With Tiotropium 18 mcg Daily to Combivent MDI 2 Actuations Qid in COPD Patients Previously Prescribed Combivent MDI [NCT00359788] | Phase 4 | 349 participants (Actual) | Interventional | 2006-07-31 | Completed | ||
| The Comparisons of the Efficacy and Safety of Inhaled LAMA or LAMA+LABA or ICS+LABA for Patients in COPD C Group With Bronchiectasis [NCT02546297] | Phase 4 | 90 participants (Anticipated) | Interventional | 2017-09-15 | Enrolling by invitation | ||
| A Randomized, Double-blind, Placebo-controlled Two-year Trial to Examine the Changes in Exercise Endurance and COPD Treated With Tiotropium Once Daily (EXACTT) [NCT00525512] | Phase 4 | 519 participants (Actual) | Interventional | 2007-08-31 | Completed | ||
| A Randomized, Open-label, Two-way Crossover Study to Compare Patient Acceptability/Preference of Tiotropium Respimat® With Tiotropium Handihaler® in Patients With Moderate to Very Severe Chronic Obstructive Pulmonary Disease (COPD) [NCT03964207] | Phase 4 | 72 participants (Actual) | Interventional | 2019-11-25 | Completed | ||
| A Randomised, Double Blind, Placebo-controlled, Double Dummy, 4-way Cross-over, Dose Ascending Study to Assess the Safety, Tolerability, Pharmacodynamics and Pharmacokinetics of Single Inhaled Doses of GSK573719 (250, 500 and 1000 μg) and Tiotropium Bromi [NCT00515502] | Phase 2 | 24 participants (Actual) | Interventional | 2007-06-21 | Completed | ||
| Effect of Inhalation of Tiotropium Once Daily 18 Mcg Versus Salmeterol Twice Daily 50 Mcg on Time to First Exacerbation in COPD Patients (a Randomised, Double-blind, Double-dummy, Parallel Group, One-year Study). [NCT00563381] | Phase 4 | 7,376 participants (Actual) | Interventional | 2008-01-31 | Completed | ||
| A Randomized, Double-blind, Placebo-controlled, 4 Period Incomplete Block Cross-over, Multi-center, Multiple Dose (7 Days) Dose-ranging Study to Assess the Efficacy and Safety of 4 Doses of NVA237 in Patients With Stable COPD, Compared to Seven Days Treat [NCT00501852] | Phase 2 | 83 participants (Actual) | Interventional | 2007-07-31 | Completed | ||
| A 12-week, Double-blind, Randomised, Parallel Group, Multi-centre, Study to Evaluate Efficacy and Safety of Budesonide/Formoterol (Symbicort Turbuhaler®) 320/9 µg One Inhalation Twice Daily on Top of Tiotropium (Spiriva®) 18 µg One Inhalation Once Daily [NCT00496470] | Phase 4 | 660 participants (Actual) | Interventional | 2007-05-31 | Completed | ||
| A Hazardous Combination of Cigarette Smoking and Bronchodilation in Chronic Obstructive Pulmonary Disease [NCT00981851] | 40 participants (Anticipated) | Interventional | 2009-09-30 | Completed | |||
| A Randomised, Open-label Four-way Crossover Study to Evaluate Relative Bioavailability of Tiotropium and Salmeterol After Inhalation of a Fixed Combined Single Dose (7.5 μg Tiotropium, 25 μg Salmeterol, Inhalation Powder, Hard Capsule, HandiHaler®2), a Fr [NCT02254174] | Phase 1 | 36 participants (Actual) | Interventional | 2006-03-31 | Completed | ||
| Specific Use-Result Surveillance of Spiriva Respimat in Asthmatics (Patients With Mild and Moderate Persistent Asthma) [NCT03188120] | 193 participants (Actual) | Observational | 2017-07-04 | Completed | |||
| A 12-week Double-blind, Randomised, Parallel-group, Multi-centre Study Evaluating the Efficacy of Tiotropium Versus Placebo in Patients With Mild COPD, According to Swedish Guidelines (SPIRIMILD) [NCT00144196] | Phase 4 | 224 participants | Interventional | 2004-03-11 | Completed | ||
| A 52 WEEK, RANDOMIZED, DOUBLE BLIND, MULTINATIONAL, MULTICENTRE, ACTIVE CONTROLLED, 3-ARM PARALLEL GROUP TRIAL COMPARING CHF 5993 200/6/12.5 µg pMDI (FIXED COMBINATION OF EXTRAFINE BECLOMETASONE DIPROPIONATE PLUS FORMOTEROL FUMARATE PLUS GLYCOPYRRONIUM BR [NCT02676089] | Phase 3 | 1,433 participants (Actual) | Interventional | 2016-04-06 | Completed | ||
| A 26-week Treatment, Multicenter, Randomized, Double Blind, Double Dummy, Placebo-controlled, Adaptive, Seamless, Parallel-group Study to Assess the Efficacy, Safety and Tolerability of Two Doses of Indacaterol (Selected From 75, 150, 300 & 600 µg o.d.) i [NCT00463567] | Phase 2/Phase 3 | 2,059 participants (Actual) | Interventional | 2007-04-30 | Completed | ||
| Randomised Cross-over Study to Compare the Effect of Formoterol Plus Tiotropium Versus Formoterol Monotherapy on Breathlessness, Dynamic Hyperinflation and Exercise Tolerance in Moderate-to-severe Stable COPD Patients [NCT00680056] | Phase 4 | 33 participants (Actual) | Interventional | 2007-11-30 | Completed | ||
| A Randomized, Double-blind, Placebo-controlled Parallel Group Study to Investigate the Safety and Efficacy of Two Doses of Tiotropium Bromide (2.5 mcg and 5 mcg) Administered Once Daily Via the Respimat Device for 12 Weeks in Patients With Cystic Fibrosis [NCT00737100] | Phase 2 | 510 participants (Actual) | Interventional | 2008-09-30 | Completed | ||
| A Phase III Randomised, Double-blind, Placebo-controlled, Parallel-group Trial to Evaluate Efficacy and Safety of Tiotropium Inhalation Solution Delivered Via Respimat® Inhaler (5 mcg/Day) Over 48 Weeks as add-on Controller Therapy on Top of Usual Care in [NCT00776984] | Phase 3 | 453 participants (Actual) | Interventional | 2008-10-31 | Completed | ||
| A Randomized, Double-Blind, Parallel-Group, 24-Week Study to Evaluate the Efficacy and Safety of ADVAIR DISKUS (Fluticasone Propionate/Salmeterol Combination Product 250/50mcg Inhalation Powder) BID Plus Spiriva HandiHaler (Tiotropium Bromide Inhalation P [NCT00784550] | Phase 4 | 342 participants (Actual) | Interventional | 2008-12-31 | Completed | ||
| Effect of Bronchodilators on Respiratory Mechanics in COPD Patients With Poor Reversibility [NCT00783250] | Phase 4 | 20 participants (Actual) | Interventional | 2008-09-30 | Terminated(stopped due to Problems with data collection) | ||
| A Phase III Randomised, Double-blind, Placebo-controlled, Parallel-group Trial to Evaluate Efficacy and Safety of Tiotropium Inhalation Solution Delivered Via Respimat® Inhaler (5 mcg/Day) Over 48 Weeks as add-on Controller Therapy on Top of Usual Care in [NCT00772538] | Phase 3 | 459 participants (Actual) | Interventional | 2008-10-31 | Completed | ||
| Effect of Methacholine, Long-acting M-cholinolytic and beta2-agonist on the Binding Activity of Beta-receptors in Healthy Volunteers [NCT04137029] | 20 participants (Anticipated) | Interventional | 2019-04-24 | Recruiting | |||
| Yiqi Huoxue Huatan Granule for Reducing Mortality in COPD With Chronic Respiratory Failure: A Randomized, Double-blind, Placebo Controlled Trial [NCT04208581] | Phase 3 | 372 participants (Anticipated) | Interventional | 2019-10-08 | Enrolling by invitation | ||
| A 52-week Treatment, Randomized, Double-blind, Placebo-controlled, With Open-label Tiotropium, Parallel-group Study to Assess the Efficacy, Safety, and Tolerability of Glycopyrronium Bromide (NVA237) in Patients With Chronic Obstructive Pulmonary Disease [NCT00929110] | Phase 3 | 1,066 participants (Actual) | Interventional | 2009-06-30 | Completed | ||
| A Randomised, Double-blind, Placebo-controlled Parallel-group Trial to Confirm the Efficacy After 12 Weeks and the Safety of Tiotropium 5 Mcg Administered Once Daily Via the Respimat® Device in Patients With Cystic Fibrosis. [NCT01179347] | Phase 3 | 464 participants (Actual) | Interventional | 2010-09-30 | Completed | ||
| A Randomised, Double-blind, Active-controlled Study to Evaluate the Impact of Stepwise Withdrawal of Inhaled Corticosteroid Treatment in Patients With Severe to Very Severe Chronic Obstructive Pulmonary Disease (COPD) on Optimized Bronchodilator Therapy [NCT00975195] | Phase 4 | 2,488 participants (Actual) | Interventional | 2009-02-28 | Completed | ||
| Indacaterol 110µg/ Glycopyrronium 50µg (Ultibro®) Versus Tiotropium (Spiriva®) Alone to Reduce Exertional Dyspnea in Patients With Moderate to Severe COPD [NCT02567214] | Phase 4 | 50 participants (Actual) | Interventional | 2016-06-30 | Completed | ||
| The Treatment Effect of Inhaled Corticosteroid and Long-acting beta2 Agonist Combination Versus Long-acting Anti-cholinergic Agent on Stratified COPD Patients Based on the Levels of Exhaled Nitric Oxide [NCT02546349] | Phase 4 | 143 participants (Anticipated) | Interventional | 2014-07-31 | Active, not recruiting | ||
| Randomised, Double-Blind, Parallel Group Study to Assess the Efficacy and Safety of 4 Weeks of Once Daily Treatment of 3 Doses of Orally Inhaled BI 1744 CL, Each in Fixed Dose Combination With 5 Microgram Tiotropium Bromide (Delivered by the Respimat Inha [NCT00696020] | Phase 2 | 360 participants (Actual) | Interventional | 2008-06-30 | Completed | ||
| Study to Investigate the Effect of Inhaled Tiotropium Bromide on Neurokinin-A Induced Bronchoconstriction in Patients With Mild-to-moderate Asthma [NCT00557700] | Phase 2 | 15 participants (Anticipated) | Interventional | 2008-01-31 | Completed | ||
| A Phase III, Randomized, Double-blind, Double-dummy, Placebo-controlled, Multicenter, 3-period Incomplete Block, Multidose Crossover Study to Determine the Effect on Lung Function of Indacaterol (150 and 300 μg o.d.) in Patients With Moderate to Severe CO [NCT00615459] | Phase 3 | 169 participants (Actual) | Interventional | 2008-02-29 | Completed | ||
| [NCT01465906] | Phase 4 | 160 participants (Anticipated) | Interventional | 2010-11-30 | Active, not recruiting | ||
| A Randomized, Open Label, Multicenter, Phase 4 Study for the Comparison of Efficacy of Tiotropium Plus Salmeterol/ Fluticasone Propionate Compared With Tiotropium Alone in COPD Patients [NCT00864812] | Phase 4 | 509 participants (Actual) | Interventional | 2009-03-31 | Completed | ||
| Effect of Spiriva on the Activities of Daily Living Score Recommended in Austrian COPD Guidelines [NCT00615992] | 754 participants (Actual) | Observational | 2007-04-30 | Completed | |||
| RUSSE / Russian Spiriva® Safety & Efficacy Study [NCT00613574] | 407 participants (Actual) | Observational | Completed | ||||
| The Effect of Twice Daily Aclidinium Bromide/Formoterol Fumarate 340/12 mcg vs. Once Daily Tiotropium 'Respimat' 5mcg on Static and Dynamic Hyperinflation in Patients With COPD During 24 Hours [NCT03275116] | Phase 4 | 49 participants (Anticipated) | Interventional | 2017-07-07 | Recruiting | ||
| A Randomized, Double-blind, Controlled, Parallel-group, 12-week Study to Compare the Efficacy and Safety of the Combination of Indacaterol 150 µg Once Daily With Open Label Tiotropium 18 µg Once Daily Versus Open Label Tiotropium 18 µg Once Daily in Patie [NCT00846586] | Phase 3 | 1,134 participants (Actual) | Interventional | 2009-03-31 | Completed | ||
| A Phase IIIb Multicenter, 52 Week Treatment, Randomized, Blinded, Double Dummy, Parallel Group Efficacy Study Comparing the Effect of Inhaled Indacaterol 150 µg o.d. vs Inhaled Tiotropium 18 µg o.d. on Lung Function, Rate of Exacerbations and Related Outc [NCT00845728] | Phase 3 | 3,439 participants (Actual) | Interventional | 2009-03-31 | Completed | ||
| Effect of Inhalation of a Free Combination of Tiotropium Once Daily 18 Mcg and Salmeterol Twice Daily 50 Mcg Versus a Fixed Combination of Fluticasone and Salmeterol Twice Daily (500/50 Mcg) on Static Lung Volumes and Exercise Tolerance in COPD Patients ( [NCT00530842] | Phase 4 | 344 participants (Actual) | Interventional | 2007-09-30 | Completed | ||
| Randomised, Double-blind, Cross-over Study to Assess the Efficacy and Safety of 4 Weeks of Once Daily Treatment of 2 Doses of Orally Inhaled BI 1744 CL, Each in Fixed Dose Combination (FDC) With 5 Microgram Tiotropium Bromide (Delivered by the Respimat® I [NCT00720499] | Phase 2 | 141 participants (Actual) | Interventional | 2008-07-31 | Completed | ||
| A Randomized, Double-blind, Placebo-controlled Trial to Determine the Effects and Duration of Action of Tiotropium Bromide on Pulmonary Function in Persons With SCI [NCT02586649] | Phase 2 | 10 participants (Actual) | Interventional | 2014-07-31 | Completed | ||
| A Phase II, Randomized, Double-Blind, Placebo Controlled Dose Ranging Study to Assess the Effect of RPL554 Added on to Tiotropium in Patients With Chronic Obstructive Pulmonary Disease [NCT03937479] | Phase 2 | 416 participants (Actual) | Interventional | 2019-05-01 | Completed | ||
| A Randomised, Double-blind Clinical Efficacy and Safety Comparison of Tiotropium/Salmeterol 7.5/25 Inhalation Powder in the Morning Via Tiotropium/Salmeterol HandiHaler, Tiotropium 18 Mcg Inhalation Powder in the Morning Via Spiriva HandiHaler, Salmeterol [NCT00662792] | Phase 3 | 147 participants (Actual) | Interventional | 2008-04-15 | Completed | ||
| A 12-week Randomised, Double Blind, Placebo Controlled, Parallel Group Trial Evaluating the Efficacy and Safety of Inhaled Tiotropium 18μg q.d. in Patients With COPD and a Concomitant Diagnosis of Asthma [NCT00152984] | Phase 4 | 472 participants | Interventional | 2004-12-31 | Completed | ||
| A Randomized, Parallel-group, Phase IV Study to Compare the Bronchodilator Efficacy of Tiotropium (18 µg Once Daily [od]) Delivered Via a DISCAIR With Tiotropium (18 µg od) Delivered Via a HandiHaler®, in Patients With Moderate-to-severe COPD [NCT02541006] | Phase 4 | 58 participants (Actual) | Interventional | 2014-11-30 | Completed | ||
| A Randomized, Double Blind , Placebo Controlled Trial to Compare the Effect of Tiotropium Inhalation Capsules on Exercise Tolerance in Patients With COPD Participating in 8 Weeks of Pulmonary Rehabilitation [NCT00157235] | Phase 3 | 234 participants | Interventional | 2002-09-30 | Completed | ||
| Anti-inflammatory Effects of Tiotropium in Patients With Stable COPD- A Multicenter Randomized Controlled Double-blind Study [NCT04061161] | Phase 4 | 50 participants (Anticipated) | Interventional | 2019-08-19 | Recruiting | ||
| Bufei Yishen Granule for Reducing Acute Exacerbation in GOLD Stage 3 or 4 COPD: A Randomized, Double-blind, Placebo Controlled Trial [NCT03976713] | Phase 3 | 348 participants (Anticipated) | Interventional | 2019-06-30 | Not yet recruiting | ||
| A Randomised, Double-Blind, Placebo-Controlled, Parallel-Group Efficacy and Safety Comparison of One-Year Treatment of Two Doses (5mg and 10mg) of Tiotropium Inhalation Solution Delivered by the Respimat Device in Patients With Chronic Obstructive Pulmona [NCT00168844] | Phase 3 | 983 participants (Actual) | Interventional | 2003-01-31 | Completed | ||
| A 24 Week, Randomized, Double-blind, Placebo Controlled, Multicenter Study to Evaluate the Efficacy and Safety of 18 MCG of Tiotropium Inhalation Capsules Administered by HandiHaler Once-daily Plus PRN Albuterol (Salbutamol) vs. Placebo Plus PRN Albuterol [NCT00523991] | Phase 4 | 457 participants (Actual) | Interventional | 2007-04-30 | Completed | ||
| A Randomised, Double-Blind, Placebo-Controlled, Parallel-Group Efficacy and Safety Comparison of One-Year Treatment of Two Doses (5mg and 10mg) of Tiotropium Inhalation Solution Delivered by the Respimat Device in Patients With Chronic Obstructive Pulmona [NCT00168831] | Phase 3 | 1,007 participants (Actual) | Interventional | 2003-02-28 | Completed | ||
| A 52-wk Randomized Double Blind Parallel Trial: Combination of Beclometasone+Formoterol+Glycopyrrolate vs Tiotropium and vs Combination of Beclometasone+Formoterol and Tiotropium in Patients With Chronic Obstructive Pulmonary Disease [NCT01911364] | Phase 3 | 3,686 participants (Actual) | Interventional | 2014-01-31 | Completed | ||
| A Six-Week, Randomized, Double-Blind, Quadruple-Dummy Parallel Group Multiple Dose Study Comparing the Efficacy and Safety of Tiotropium Inhalation Capsules Plus Formoterol Inhalation Capsules to Salmeterol Inhalation Aerosol Plus Fluticasone Inhalation A [NCT00239421] | Phase 4 | 605 participants | Interventional | 2003-11-30 | Completed | ||
| Tiotropium Efficacy Against Allergen Induced Early Asthmatic Responses [NCT04648813] | Phase 4 | 15 participants (Actual) | Interventional | 2020-11-13 | Completed | ||
| Effectiveness of Tiotropium to Maintain Inspiratory Capacity Against Metronome Paced Hyperventilation Induced Dynamic Hyperinflation in COPD Patients With Lung CT Scored Emphysema [NCT00570544] | 29 participants (Actual) | Observational | 2004-08-31 | Completed | |||
| Comparison of Bronchodilation and Oxygenation Patterns Induced by Long-acting β2-agonists and Muscarinic Antagonists in Chronic Obstructive Pulmonary Disease (COPD) [NCT05927155] | Phase 3 | 30 participants (Actual) | Interventional | 2021-06-15 | Completed | ||
| Response to Bronchodilation With Tiotropium Plus Salbutamol Correlates With Radiologic Morphology of the Lung in COPD of the Emphysematous Phenotype [NCT02008162] | 60 participants (Anticipated) | Observational | 2009-11-30 | Recruiting | |||
| A Randomized, Blinded, Double Dummy, Multi-center, Placebo Controlled, 3 Period, Crossover Study to Assess the Effect of QVA149 (110/50 µg o.d.) on Exercise Endurance in Patients With Moderate to Severe Chronic Obstructive Pulmonary Disease (COPD), Using [NCT01294787] | Phase 3 | 85 participants (Actual) | Interventional | 2011-02-28 | Completed | ||
| A Partially Blinded, Single-dose, Cross-over Proof of Concept Study to Assess the Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of QAX028 Compared to Open-label Tiotropium Bromide (Positive Control) and Placebo in Mild-to-moderate COPD Patie [NCT00568503] | Phase 1 | 29 participants (Actual) | Interventional | 2007-10-31 | Completed | ||
| A Randomized, Double-Blind (Test Products and Placebo), Chronic Dosing (7 Days), Four-Period, Eight-Treatment, Placebo-Controlled, Incomplete Block, Cross-Over, Multi-Center Study to Assess Efficacy and Safety of Two Doses of PT003, Two Doses of PT005 and [NCT01085045] | Phase 2 | 118 participants (Actual) | Interventional | 2010-03-31 | Completed | ||
| A Randomized, Double-blind, Double-dummy, Placebo- and Active-controlled, Parallel Group Efficacy and Safety Comparison of 12-week Treatment of Two Doses (5 Mcg and 10 Mcg) of Tiotropium Inhalation Solution Delivered by the Respimat Inhaler, Placebo and I [NCT00240435] | Phase 3 | 491 participants | Interventional | 2002-11-30 | Completed | ||
| A Study of Fluticasone Propionate/Salmeterol DISKUS Combination Product 250/50 mcg Twice Daily Plus Tiotropium 18 mcg Daily Versus Placebo DISKUS Twice Daily Plus Tiotropium 18 mcg Daily on Exercise Time and Physiological Parameters in Subjects With Chron [NCT01124422] | Phase 4 | 255 participants (Actual) | Interventional | 2010-07-19 | Completed | ||
| A 52-week Treatment, Multi-center, Randomized, Open Label, Parallel Group Study to Assess the Long Term Safety and Tolerability of NVA237 (50µg o.d.) Using Tiotropium (18µg o.d.) as an Active Control in Japanese Patients With Moderate to Severe Chronic Ob [NCT01119937] | Phase 3 | 211 participants (Actual) | Interventional | 2010-05-31 | Completed | ||
| A 26-week Treatment Multi-center, Randomized, Double-blind, Parallel-group, Placebo and Active Controlled (Open Label) Study to Assess the Efficacy, Safety and Tolerability of QVA149 (110/50 μg q.d.) in Patients With Moderate to Severe Chronic Obstructive [NCT01202188] | Phase 3 | 2,144 participants (Actual) | Interventional | 2010-09-30 | Completed | ||
| A Phase III Randomised, Double-blind, Placebo-controlled, Parallel-group Trial to Evaluate Efficacy and Safety of Tiotropium Inhalation Solution Delivered Via Respimat® Inhaler (2.5 and 5 µg Once Daily) Compared With Placebo and Salmeterol HFA MDI (50 µg [NCT01172821] | Phase 3 | 1,032 participants (Actual) | Interventional | 2010-08-31 | Completed | ||
| A Proof Of Concept Study To Evaluate Tiotropium as Add-on Therapy to Inhaled Budesonide/Formoterol Combination in COPD [NCT00996697] | Phase 4 | 23 participants (Actual) | Interventional | 2006-10-31 | Completed | ||
| A Phase II, Randomised, Double- Blind, Placebo Controlled, Cross-over Efficacy and Safety Comparison of Tiotropium 5 µg Administered Once Daily (in the Evening) and Tiotropium 2.5 µg Administered Twice Daily Delivered by the Respimat® Inhaler for Four Wee [NCT01152450] | Phase 2 | 94 participants (Actual) | Interventional | 2010-07-31 | Completed | ||
| A Phase III Randomised, Double-blind, Placebo-controlled, Parallel-group Trial to Evaluate Efficacy and Safety of Tiotropium Inhalation Solution Delivered Via Respimat® Inhaler (2.5 and 5 µg Once Daily) Compared With Placebo and Salmeterol HFA MDI (50 µg [NCT01172808] | Phase 3 | 1,071 participants (Actual) | Interventional | 2010-08-31 | Completed | ||
| [NCT00868231] | Phase 2 | 30 participants (Actual) | Interventional | 2009-03-31 | Completed | ||
| A 64-week Treatment, Multi-center, Randomized, Double-blind, Parallel-group, Active Controlled Study to Evaluate the Effect of QVA149 (110/50 μg o.d.) vs NVA237 (50 μg o.d.) and Open-label Tiotropium (18 μg o.d.) on COPD Exacerbations in Patients With Sev [NCT01120691] | Phase 3 | 2,224 participants (Actual) | Interventional | 2010-04-30 | Completed | ||
| Effects of Ultra-long Acting Bronchodilator Therapy Assessed by Impulse Oscillometry in Smoking Asthmatics Taking Inhaled Corticosteroids [NCT02682862] | Phase 4 | 17 participants (Actual) | Interventional | 2016-07-11 | Completed | ||
| A Phase III, Randomised, Double Blind, Placebo-controlled, Parallel Group Study to Assess the Efficacy and Safety Over 48 Weeks of Orally Inhaled Tiotropium Bromide (2.5 and 5 µg Once Daily ) Delivered by the Respimat® Inhaler in Adolescents (12 to 17 Yea [NCT01257230] | Phase 3 | 398 participants (Actual) | Interventional | 2010-12-31 | Completed | ||
| A Phase II Randomised, Double-blind, Placebo-controlled, Incomplete Crossover Trial With 4-week Treatment Periods to Evaluate Efficacy and Safety of Tiotropium Inhalation Solution (Doses of 1.25 µg, 2.5 µg and 5 µg) Delivered Via Respimat® Inhaler Once Da [NCT01122680] | Phase 2 | 105 participants (Actual) | Interventional | 2010-05-31 | Completed | ||
| A Phase II Randomised, Double-blind, Placebo Controlled, Cross-over Efficacy and Safety Comparison of Three Doses of Tiotropium Inhalation Solution Delivered Via Respimat Inhaler (1.25, 2.5 and 5.0 Mcg Once Daily) Versus Placebo in Patients With Moderate [NCT01233284] | Phase 2 | 149 participants (Actual) | Interventional | 2010-11-30 | Completed | ||
| A Randomised, Double-blind, 8 Treatments, 4 Periods, Incomplete Crossover Study to Determine the Optimal Free Dose Combination of BI 1744 CL and Tiotropium Bromide (Both Delivered by the Respimat® Inhaler) After 4 Weeks Once Daily Treatment in Patients Wi [NCT01040403] | Phase 2 | 233 participants (Actual) | Interventional | 2010-01-31 | Completed | ||
| A Multi-Center, Randomized, Double-Blind, Placebo-Controlled, Multiple Ascending Dose, Two-Way Cross-Over, Phase 2a Study to Evaluate the Safety and Bronchodilator Activity of TRN-157 in Stable Mild and Moderate Asthmatics [NCT02382510] | Phase 2 | 59 participants (Actual) | Interventional | 2015-04-30 | Completed | ||
| Daily Dosing of Tiotropium and Tolerance to Bronchoprotection Against Methacholine Challenge [NCT05113615] | Phase 4 | 12 participants (Actual) | Interventional | 2021-12-13 | Completed | ||
| Small Airways Evaluation and Peripherical Effect of Two Bronchodilators in Healthy Subjects and Stable COPD Patients [NCT01437748] | Phase 4 | 40 participants (Actual) | Interventional | 2011-08-31 | Completed | ||
| A Randomized Double-blind, Placebo-controlled, Crossover, Dose Escalation Study to Examine the Safety, Tolerability, Pharmacodynamics and Pharmacokinetics of Single Inhaled Doses of GSK1160724 and Tiotropium Bromide [NCT00555022] | Phase 1 | 21 participants (Actual) | Interventional | 2007-12-12 | Completed | ||
| A Randomized, Open-Label, Repeat Dosing, Four-Period Crossover Study to Compare the Pharmacokinetics, Efficacy and Safety of Tiotropium Bromide Delivered Via Breath Actuated Inhaler (BAI), SPIRIVA® HandiHaler® and Respimat® Soft Mist™ Inhaler (SMI) in Sub [NCT01785433] | Phase 1/Phase 2 | 36 participants (Actual) | Interventional | 2013-01-31 | Completed | ||
| A Randomised, Double-Blind, Parallel-Group, Placebo-Controlled Study to Evaluate the Changes in Inflammatory Markers in Induced Sputum Following Treatment With Tiotropium Inhalation Capsules 18mcg Once Daily in Patients With Chronic Obstructive Pulmonary [NCT00405236] | Phase 4 | 220 participants | Interventional | 2002-10-31 | Completed | ||
| Assessing Treatment Options for Smokers With Asthma. [NCT00546234] | Phase 4 | 0 participants (Actual) | Interventional | 2007-11-30 | Withdrawn(stopped due to No subjects enrolled and no ongoing funding.) | ||
| Effectiveness and Safety of Maintenance Treatment With Combination of Tiotropium and Olodaterol in Comparison to Maintenance Treatment With a Combination of Inhaled Corticosteroids and Long-acting β2 Agonists in COPD Patients [NCT04138758] | 42,953 participants (Actual) | Observational | 2019-11-01 | Completed | |||
| A Multicentre, Randomised, Partially Blinded, Placebo-controlled, Three-way Crossover, Incomplete Block Design Study to Investigate the Safety, Tolerability, Pharmacodynamics/ Efficacy and Pharmacokinetics of Dual Bronchodilator Therapy With Salmeterol 50 [NCT00422604] | Phase 2 | 60 participants (Actual) | Interventional | 2006-10-31 | Completed | ||
| INvestigating COPD Outcomes, Genomics and Neutrophilic Inflammation With Tiotropium and Olodaterol [NCT03152149] | Phase 4 | 80 participants (Actual) | Interventional | 2017-06-01 | Completed | ||
| A Phase III Randomised, Double-blind, Placebo-controlled, Parallel-group Trial to Evaluate Safety and Efficacy of Tiotropium Inhalation Solution Delivered Via Respimat Inhaler (2.5 and 5 µg Once Daily) Compared With Placebo Over 52 Weeks in Patients With [NCT01340209] | Phase 3 | 285 participants (Actual) | Interventional | 2011-04-30 | Completed | ||
| A 52-week Treatment, Multi-center, Randomized, Open Label, Parallel Group Study to Assess the Long Term Safety and Tolerability of QVA149 (110 Mcg Indacaterol / 50 Mcg Glycopyrrolate o.d.) Using Tiotropium (18 Mcg o.d.) as an Active Control in Japanese Pa [NCT01285492] | Phase 3 | 160 participants (Actual) | Interventional | 2011-01-31 | Completed | ||
| A Randomized, Double-blind, Placebo-controlled Study to Assess the Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of an Efficacious Dose of QAT370 Compared to Open-label Tiotropium Bromide Following Once Daily Dosing for 7 Days in COPD Patien [NCT00532350] | Phase 1 | 22 participants (Actual) | Interventional | 2007-07-31 | Completed | ||
| Obesity, Inflammation and Response to Therapy in Asthma - Ancillary to Asthma Clinical Research Network (ACRN) Trials [NCT00557180] | 33 participants (Actual) | Observational | 2007-10-31 | Completed | |||
| An Open-label Positron Emission Tomography Phase I Study to Determine Muscarinic Receptor Occupancy in the Lungs in Healthy Volunteers After Inhalation of Single Dose of Tiotropium or AZD2115. [NCT03097380] | Phase 1 | 19 participants (Actual) | Interventional | 2017-04-26 | Completed | ||
| Effects of Tiotropium/Olodaterol on Cardio-pulmonary Exercise Capacity in Patients With Hyperinflated Chronic Obstructive Pulmonary Disease [ACHIEVE] [NCT04994574] | 44 participants (Anticipated) | Interventional | 2021-08-31 | Not yet recruiting | |||
| A Randomized, Crossover, Placebo Controlled, Double-blind Trial of the Effect of STIOLTO™ RESPIMAT® on Central and Peripheral Components of Fatigue During Exercise in Chronic Obstructive Pulmonary Disease [NCT02845752] | Phase 4 | 14 participants (Actual) | Interventional | 2017-03-01 | Completed | ||
| Comparison of 18 mg of Tiotropium Inhalation Capsules Once Daily and Atrovent Metered Dose Inhaler (2 Puffs of 20 mg, Four Times Daily) in a Double-Blind, Double-dummy, Efficacy and Safety Study in Adults With Chronic Obstructive Pulmonary Disease (COPD). [NCT00239434] | Phase 3 | 200 participants | Interventional | 2003-06-30 | Completed | ||
| A Randomised, Double-Blind, Double-Dummy, Placebo- and Active-Controlled, Parallel Group Efficacy and Safety Comparison of 12-Week Treatment of Two Doses [5 μg (2 Actuations of 2.5 μg) and 10 μg (2 Actuations of 5 μg)] of Tiotropium Inhalation Solution De [NCT00239473] | Phase 3 | 429 participants | Interventional | 2002-11-30 | Completed | ||
| A Double-blind, Randomised, Placebo Controlled, Three-way Cross-over Study With an Open Label Positive Control (Moxifloxacin) to Assess the Influence of Inhaled Tiotropium Once Daily Over Twelve Days on the QTC Interval of the ECG in Healthy Male and Fema [NCT00257452] | Phase 1 | 56 participants | Interventional | 2004-10-31 | Completed | ||
| An 8 Week Randomized, Placebo Controlled, Double-blind Study to Assess the Efficacy of Tiotropium Inhalation Capsules in Patients of African Descent With Chronic Obstructive Pulmonary Disease [NCT00106821] | Phase 4 | 166 participants (Actual) | Interventional | 2004-06-30 | Completed | ||
| Randomised, Double-Blind, Placebo-Controlled, Cross-Over Study to Examine the Effects of Tiotropium on Lung Hyperinflation, Respiratory Mechanics and Dyspnea During Exercise in Patients With COPD [NCT00274027] | Phase 3 | 19 participants (Actual) | Interventional | 2001-01-31 | Completed | ||
| The Acute Bronchodilator Effects of a Single Dose (2 Puffs) of the Shortacting Anticholinergic Ipratropium Bromide (40μg) and the Short-acting Beta-adrenergic Fenoterol (200μg) in Comparison to Placebo on Top of Pharmacodynamic Steady State of Once Daily [NCT00274066] | Phase 3 | 65 participants | Interventional | 2002-10-31 | Completed | ||
| A Comparison of the Effects of Tiotropium (18 Mcg) Inhalation Capsule q.d. and Salmeterol (50 Mcg) Inhalation Aerosol b.i.d. on Arterial Blood Gases in a Double-blind, Double-dummy, 4-week Crossover Study in Patients With Chronic Obstructive Pulmonary Dis [NCT00274534] | Phase 3 | 36 participants | Interventional | 2000-12-31 | Completed | ||
| Acute and Long-term Effects of Once Daily Oral Inhalation of Tiotropium 18 Mcg Dry Powder Inhalation Capsules in a Placebo Controlled Parallel Group Design Study in Patients With Chronic Obstructive Pulmonary Disease (COPD) of Different Severity [NCT00274573] | Phase 3 | 1,639 participants (Actual) | Interventional | 2002-03-31 | Completed | ||
| Spiriva® Assessment of FEV1 (SAFE). The Effect of Inhaled Tiotropium Bromide (18 Mcg Once Daily) on the Change in FEV1 During Long-term Treatment in Patients With COPD. A One-year Parallel Group, Double-blind, Randomised, Placebo-controlled Study [NCT00277264] | Phase 3 | 914 participants | Interventional | 2002-01-31 | Completed | ||
| A Randomised, Double Blind, Placebo-controlled, Double Dummy, 4-way Cross-over, Dose Ascending Study to Assess the Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of Single Inhaled Doses of GSK233705 and Tiotropium Bromide (18µg) Via DPI in CO [NCT00279019] | Phase 1 | 31 participants (Actual) | Interventional | 2005-12-12 | Completed | ||
| A 6-Week Double-Blind, Parallel-Group, Active-Controlled Trial to Compare the Efficacy and Safety of Concomitant Treatment of Formoterol Fumarate Inhalation Solution 20 Mcg Twice Daily and Tiotropium 18 Mcg Once Daily to Tiotropium 18 Mcg Once Daily Alone [NCT00308191] | Phase 3 | 128 participants | Interventional | 2006-04-30 | Completed | ||
| Acute and Two-week Effects of Spiolto® Respimat® (Tiotropium/Olodaterol) on Cardiac Function, the Autonomic Nervous System and Small Airway Function in Hyperinflated COPD Subjects [NCT04231214] | Phase 4 | 32 participants (Actual) | Interventional | 2020-01-28 | Completed | ||
| Single Dose, Double-blind, Double-dummy, 3 Period Cross-over, Placebo Controlled Clinical Trial to Assess the Reate of Onset of Action of Inhaled Aclidinium Bromide 200µg Compared to Placebo and Tiotropium 18µg in Patients With Chronic Obstructive Pulmona [NCT00435760] | Phase 3 | 115 participants (Actual) | Interventional | 2007-02-28 | Completed | ||
| A Randomised, Double-blind, Placebo-controlled, 12 Week Trial to Evaluate the Effect, of Tiotropium Inhalation Capsules on the Magnitude of Exercise, Measured Using an Accelerometer, in Patients With Chronic Obstructive Pulmonary Disease (COPD). [NCT00144326] | Phase 3 | 250 participants (Actual) | Interventional | 2003-07-31 | Completed | ||
| Asthma Clinical Research Network (ACRN) Trial - Tiotropium Bromide as an Alternative to Increased Inhaled Corticosteroid in Patients Inadequately Controlled on a Lower Dose of Inhaled Corticosteroid (TALC) [NCT00565266] | Phase 3 | 210 participants (Actual) | Interventional | 2008-05-31 | Completed | ||
| Genotype Stratified Treatment With Anticholinergic vs. Beta-agonist (Long Acting) and Exacerbations (GABLE) [NCT00706446] | 255 participants (Actual) | Interventional | 2008-06-30 | Terminated(stopped due to Funding was terminated) | |||
| Outcomes and Costs Associated With Initiating Maintenance Treatment With Fluticasone Propionate 250mcg/Salmeterol Xinafoate 50mcg Combination (FSC) Versus Anticholinergics Including Tiotropium (TIO) in Patients With Chronic Obstructive Pulmonary Disease ( [NCT01331694] | 76,130 participants (Actual) | Observational | 2009-07-31 | Completed | |||
| Efficacy and Safety (Including 24-hour Holter Monitoring) of Tiotropium Inhalation Capsules in Patients With Chronic Obstructive Pulmonary Disease (a 12-week, Parallel Group, Randomized, Placebo-cotrolled, Double-blind Study). [NCT00239460] | Phase 3 | 196 participants | Interventional | 2003-07-31 | Completed | ||
| A Six-Week, Randomised, Double-Blind, Triple-Dummy, Parallel Group, Multiple Dose, Pilot Study Comparing Tiotropium Inhalation Capsules to Salmeterol Inhalation Aerosol Combined With Fluticasone Inhalation Aerosol in Patients With Chronic Obstructive Pulm [NCT00239499] | Phase 4 | 107 participants | Interventional | 2003-09-30 | Completed | ||
| A Randomized, Active-controlled, Double-blind, Double-dummy, Parallel Group Design, Multi-center Trial to Compare the Efficacy and Safety of 2.5 µg and 5 µg Tiotropium Inhalation Solution Delivered by the Respimat Inhaler With Tiotropium Inhalation Capsul [NCT01126437] | Phase 3 | 17,183 participants (Actual) | Interventional | 2010-05-31 | Completed | ||
| Replacement of Nebulised Ipratropium With Inhaled Tiotropium in Stable COPD [NCT00335621] | Phase 4 | 45 participants (Anticipated) | Interventional | 2006-06-30 | Withdrawn(stopped due to Study terminated prior to recruitment - recruitment proved impossible) | ||
| A Randomized, Multiple-dose, Double-blind, Placebo- and Active-controlled, Parallel Group Efficacy and Safety Study to Determine the Optimum Dose of BEA 2180 BR Delivered by the Respimat® Inhaler in Patients With Chronic Obstructive Pulmonary Disease (COP [NCT00122434] | Phase 2 | 389 participants (Actual) | Interventional | 2005-07-31 | Completed | ||
| A Randomized, Multiple-dose, Double-Blind, Crossover Study to Compare the Efficacy and Safety of 200 μg and 400 μg of BEA 2180 BR to Tiotropium 5 μg and Placebo When Each is Delivered by the Respimat® Inhaler in Patients With Chronic Obstructive Pulmonary [NCT00128440] | Phase 2 | 78 participants (Actual) | Interventional | 2005-08-31 | Completed | ||
| Comparative Effectiveness of Combination Therapies in COPD [NCT03376295] | 3,954 participants (Actual) | Observational | 2017-12-01 | Completed | |||
| A Randomized Crossover Trial Comparing the Efficacy and Safety of Tiotropium + Procaterol vs. Tiotropium + Placebo in Moderate COPD Patients [NCT00394485] | Phase 4 | 50 participants (Anticipated) | Interventional | 2006-05-31 | Terminated(stopped due to Difficulty in recruting patients) | ||
| A Double-blind, Placebo-controlled, Crossover Study to Evaluate the Effects of Tiotropium Bromide on Gas Exchange in Subjects With COPD During Exercise [NCT00412204] | Phase 4 | 20 participants (Actual) | Interventional | 2006-06-30 | Completed | ||
| Proof of Concept Study to Evaluate Single and Chronic Dosing Effects of Ultra-long Acting Bronchodilator Therapy on Mannitol Challenge in Asthmatic Patients Taking Inhaled Corticosteroids [NCT02039011] | Phase 4 | 14 participants (Actual) | Interventional | 2014-02-28 | Completed | ||
| Effect of Tiotropium on Airway Remodeling in Patients With Early Stage COPD Accessed by Optical Coherence Tomography [NCT03842839] | 100 participants (Anticipated) | Interventional | 2018-10-01 | Recruiting | |||
| Phase I Randomised, Five-period Cross-over Study in Healthy Male and Female Volunteers to Compare the Pharmacokinetics of Tiotropium Delivered From Four Test pMDI Products With Spiriva Respimat [NCT03155204] | Early Phase 1 | 46 participants (Actual) | Interventional | 2017-04-25 | Completed | ||
| A 52-week Treatment, Multi-center, Randomized, Open Label, Parallel Group Study to Assess the Efficacy of NVA237 (50 μg o.d.) Using Tiotropium (5 μg o.d.) as an Active Control in Brazilian Patients With Moderate to Severe Chronic Obstructive Pulmonary Dis [NCT01837927] | Phase 3 | 0 participants (Actual) | Interventional | 2014-04-30 | Withdrawn | ||
| Cross-sectional Study to Assess the Handling , Patient Satisfaction, and Preference for Inhalation Devices in Patients With Chronic Obstructive Pulmonary Disease (COPD). [NCT01810692] | 150 participants (Actual) | Observational | 2013-03-31 | Completed | |||
| Spiriva Assessment of FEV1 - (SAFE-Portugal). The Effect of Inhaled Tiotropium Bromide (18 Mcg Once Daily) on the Change in FEV1 During Treatment in Patients With COPD. A Three-month Parallel Group, Double-blind, Randomised, Placebo-controlled Study. [NCT00239408] | Phase 4 | 311 participants | Interventional | 2002-12-31 | Completed | ||
| Effects of Inhaled Tiotropium Bromide on Severity of Airflow Obstruction During Long-term Treatment in Patients With Moderately Severe Copd. Impact on Severity and Incidence of Exacerbations. [NCT00274014] | Phase 3 | 1,000 participants | Interventional | 2000-10-31 | Completed | ||
| Effect of a 9-month Treatment of SPIRIVA® on Health Related Quality of Life in Patients With Chronic Obstructive Pulmonary Disease. Validation of a New HRQoL Questionnaire Appropriate to Common Daily Practice. (TIPHON Study) [NCT00274053] | Phase 3 | 555 participants (Actual) | Interventional | 2002-04-30 | Completed | ||
| A Comparison of 18 Mcg of Tiotropium Inhalation Capsules and Atrovent Metered Dose Inhaler (2 Puffs of 20 Mcg) in a Double-Blind, Double-Dummy, Efficacy and Safety Study in Adults With Chronic Obstructive Pulmonary Disease (COPD) [NCT00274092] | Phase 3 | 132 participants (Actual) | Interventional | 2002-09-30 | Completed | ||
| A Randomized, Double-blind, Placebo Controlled 25-week Trial to Compare the Effect of Tiotropium Inhalation Capsuled (18 Mcg) Once Daily on Exercise Tolerance in Patients With Chronic Obstructive Pulmonary Disease (COPD) Participating in 8 Weeks of Pulmon [NCT00274521] | Phase 3 | 108 participants | Interventional | 2001-05-31 | Completed | ||
| A Comparison of 18 μg of Tiotropium Inhalation Capsules and Atrovent Metered Dose Inhaler (2 Puffs of 20 μg, 4 Times Daily) in a Double-Blind, Double-Dummy, Efficacy and Safety Study in Adults With Chronic Obstructive Pulmonary Disease (COPD). [NCT00274040] | Phase 3 | 141 participants | Interventional | 2002-07-31 | Completed | ||
| A Randomised, Double-blind, Parallel Group, 12 Week Study, Comparing the Effect of Once Daily Tiotropium Lactose Capsule With Placebo in Patients With Chronic Obstructive Pulmonary Disease (COPD), naïve to Anticholinergic Agents in Addition to Receiving T [NCT00274079] | Phase 4 | 395 participants | Interventional | 2002-10-31 | Completed | ||
| A Randomized, Double-blind, Placebo-controlled, Parallel Group Trial Assessing the Proportion of Patients Experiencing an Exacerbation and Proportion of Patients Hospitalized for an Exacerbation Over 6 Months During Treatment With Tiotropium 18 Mcg Capsul [NCT00274547] | Phase 3 | 1,829 participants (Actual) | Interventional | 2001-09-30 | Completed | ||
| A Randomised, Double-blind, Double-dummy, Placebo-controlled, Crossover Efficacy and Safety Comparison of 4-week Treatment Periods of Two Doses [5 μg (2 Actuations of 2.5 μg) and 10 μg (2 Actuations of 5 μg)] of Tiotropium Inhalation Solution Delivered by [NCT00281567] | Phase 3 | 76 participants (Actual) | Interventional | 2002-08-31 | Completed | ||
| A Randomised, Double-blind, Double-dummy, Crossover Efficacy and Safety Comparison of 4-week Treatment Periods of Ba 679 BR Respimat® 5 μg and Tiotropium Inhalation Capsule 18 μg in Patients With COPD [NCT00292448] | Phase 2 | 157 participants | Interventional | 2006-02-28 | Completed | ||
| A Randomised, Double-blind, Placebo and Active Controlled, Multi-centre, 6 Way Cross-over, Single-dose Phase IIa Study to Investigate the Local and Systemic Effects of 3 Different Doses of Inhaled AZD2115 in Patients With Chronic Obstructive Pulmonary Dis [NCT01498081] | Phase 2 | 39 participants (Actual) | Interventional | 2012-03-31 | Completed | ||
| Evaluation of Effects of Chronic Dose Exposure to Cardioselective and Non-cardioselective Beta Blockers on Measures of Cardiopulmonary Function in Moderate to Severe COPD. [NCT01656005] | Phase 4 | 18 participants (Actual) | Interventional | 2012-08-31 | Completed | ||
| Pharmacokinetic Study to Compare Tiotropium Easyhaler® Product Variants and Spiriva® 18 µg Capsules Administered Via HandiHaler® in Healthy Volunteers. [NCT05246046] | Phase 1 | 88 participants (Actual) | Interventional | 2022-02-16 | Completed | ||
| Cardiac Effects of Spiolto®/Respimat® in Patients With Congestive Heart Failure and COPD [NCT02812862] | Phase 4 | 0 participants (Actual) | Interventional | 2016-08-31 | Withdrawn(stopped due to Rationale obsolete) | ||
| Randomized, Open-label, Crossover Clinical Trial to Assess the Effects of Indacaterol 150 µg d.o. Compared to Tiotropium Bromide 5 µg d.o. on Dyspnea, Dynamic Pulmonary Hyperinflation and Exercise Tolerance in Patients With Moderate COPD [NCT01693003] | Phase 4 | 20 participants (Actual) | Interventional | 2013-03-31 | Completed | ||
| A Randomized, Double-blind Placebo-controlled Study to Compare the Efficacy of Indacaterol With That of Placebo in Patients With COPD Who Have Not Previously Received Maintenance COPD Medication, Using Blinded Tiotropium as Active Control [NCT01715311] | Phase 4 | 0 participants (Actual) | Interventional | 2012-11-30 | Withdrawn(stopped due to withdrawn prior to patient recruitment) | ||
| A Randomised, Double-blind, Parallel Group Study to Assess the Efficacy and Safety of 52 Weeks of Once Daily Treatment of Orally Inhaled Tiotropium + Olodaterol Fixed Dose Combination (2.5 µg / 5 µg; 5 µg / 5 µg) (Delivered by the Respimat® Inhaler) Compa [NCT01431274] | Phase 3 | 2,624 participants (Actual) | Interventional | 2011-09-30 | Completed | ||
| A Phase 4, Randomized, Double-Blind, Double-Dummy, Parallel-Group, Study Comparing Improvements in Lung Function in Adults With Severe to Very Severe Chronic Obstructive Pulmonary Disease and Suboptimal Inspiratory Flow Rate Following Once-Daily Treatment [NCT05165485] | Phase 4 | 404 participants (Actual) | Interventional | 2022-01-07 | Completed | ||
| Randomised, Double-blind, Double-dummy, Placebo-controlled, 4-way Cross-over Study to Characterise the 24-hour FEV1-time Profiles of BI 1744 CL 5μg and 10μg (Oral Inhalation, Delivered by the Respimat® Inhaler) and Tiotropium Bromide 18μg (Oral Inhalation [NCT01040728] | Phase 3 | 122 participants (Actual) | Interventional | 2010-01-31 | Completed | ||
| Chronic Obstructive Pulmonary Disease (COPD)-Related Outcomes and Costs for Patients on Combination Fluticasone Propionate-Salmeterol Xinafoate 250/50mcg Versus Anticholinergics in a Comorbid COPD-Depression/Anxiety Population [NCT01337336] | 1 participants (Actual) | Observational | 2010-10-31 | Completed | |||
| Impact of Initiating Tiotropium Alone Versus Initiating Tiotropium in Combination With Fluticasone Propionate/Salmeterol Xinafoate Combination (FSC) on Chronic Obstructive Pulmonary Disease-related Outcomes in Patients With Pre-existing Exacerbations [NCT01381406] | 3,333 participants (Actual) | Observational | 2008-07-31 | Completed | |||
| Outcomes From Initial Maintenance Therapy With Fluticasone Propionate 250/Salmeterol 50 (FSC) or Tiotropium in Chronic Obstructive Pulmonary Disease [NCT01387178] | 22,223 participants (Actual) | Observational | 2008-07-31 | Completed | |||
| Comparison of Bronchodilator Efficacy of Tiotropium/Formoterol Combination Treatment Administered (qd) Via Discair® With Tiotropium (qd) Monotherapy or Tiotropium (qd) + Formoterol (Bid) Free Combination Treatment in Patients With Chronic Obstructive Pulm [NCT02988869] | Phase 4 | 84 participants (Actual) | Interventional | 2016-08-31 | Completed | ||
| A Randomised, Double Blind, Parallel Group Study to Assess the Efficacy and Safety of 12 Weeks of Once Daily, Orally Inhaled, Co-administration of Olodaterol 5µg (Delivered by the Respimat® Inhaler) and Tiotropium 18µg (Delivered by the HandiHaler®) Compa [NCT01696058] | Phase 3 | 1,137 participants (Actual) | Interventional | 2012-09-30 | Completed | ||
| Switching COPD Patients From Spiriva® HandiHaler® Maintenance Therapy to Spiriva® Respimat®: a Non-Interventional Real-world clinicAl ouTcome assEssment: NIS PIRATE [NCT05362487] | 7 participants (Actual) | Observational | 2022-08-05 | Terminated(stopped due to Insufficient recruitment) | |||
| Multicentre,Randomized,Double-Blind,Double-Dummy,3period,6Seq,Crossover,Active&Placebo,SD PD Study to Evaluate Therapeutic Equivalence of Test Tiotropium Bromide Inh. Powder to Reference SPIRIVA® HANDIHALER in Subjects w/COPD* [NCT05161156] | Phase 3 | 306 participants (Actual) | Interventional | 2022-03-24 | Completed | ||
| A 12 Week Study to Evaluate the Effect of Fluticasone Furoate (FF, GW685698)/Vilanterol (VI, GW642444) 100/25 mcg Inhalation Powder Delivered Once Daily Via a Novel Dry Powder Inhaler (NDPI) on Arterial Stiffness Compared With Tiotropium Bromide 18 mcg De [NCT01395888] | Phase 3 | 260 participants (Actual) | Interventional | 2011-06-30 | Completed | ||
| AKTIV: Changes in Physical Functioning in Patients With COPD During Therapy With a Combination of Spiriva® Respimat® + Striverdi® Respimat® or Spiriva® 18 Mikrogramm + Striverdi® Respimat® [NCT02173769] | 1,845 participants (Actual) | Observational | 2014-06-30 | Completed | |||
| Replication of the INSPIRE Trial in Healthcare Claims Data [NCT05179512] | 98,278 participants (Actual) | Observational | 2020-09-22 | Completed | |||
| Replication of the POET-COPD Trial in Healthcare Claims Data [NCT05083429] | 8,716 participants (Actual) | Observational | 2020-09-22 | Completed | |||
| Randomized Double-blind Placebo-controlled Crossover Study to Evaluate the Effects of Formoterol and Beclomethasone Dipropionate Combination Therapy on Small Airways Function in COPD Patients. [NCT01466712] | Phase 4 | 20 participants (Anticipated) | Interventional | 2011-11-30 | Enrolling by invitation | ||
| A Randomised, Double-blind, Double-dummy, Crossover Efficacy and Safety Comparison of 6-week Treatment Periods of the Free Combinations of Tiotropium Inhalation Powder Capsule (18 μg) QD + Salmeterol Metered Dose Inhaler (2 Puffs of 25 μg) QD or BID, Tiot [NCT02242253] | Phase 2 | 97 participants (Actual) | Interventional | 2003-09-30 | Completed | ||
| Multicentre, Randomised, Double-Blind, Double Dummy, Parallel Group, 104-week Study to Compare the Effect of the Salmeterol/Fluticasone Propionate Combination Product (SERETIDE*) 50/500mcg Delivered Twice Daily Via the DISKUS*/ACCUHALER* Inhaler With Tiot [NCT00361959] | Phase 4 | 1,270 participants (Actual) | Interventional | 2003-06-30 | Completed | ||
| A Pilot Study to Investigate Pharmacokinetic Characteristics After Co-administration of HCP0910 and HGP1011 [NCT02441114] | Phase 1 | 10 participants (Actual) | Interventional | 2015-07-31 | Completed | ||
| An Exploratory, 12 Week, Randomised, Partially Double-blinded, Placebo-controlled Parallel Group Trial to Explore the Effects of Once Daily Treatments of Orally Inhaled Tiotropium + Olodaterol Fixed Dose Combination or Tiotropium (Both Delivered by Respim [NCT02085161] | Phase 3 | 304 participants (Actual) | Interventional | 2014-03-31 | Completed | ||
| Acute Bronchodilator Responsiveness in Obliterative Bronchiolitis (OB) Following Hematopoietic Stem Cell Transplantation [NCT01112241] | Phase 4 | 17 participants (Actual) | Interventional | 2010-04-30 | Completed | ||
| A Randomized, Double Blind, Placebo Controlled, Incomplete Block, Crossover, Dose Ranging Study to Evaluate the Dose Response of GSK573719 Administered Once or Twice Daily Over 7 Days in Patients With Chronic Obstructive Pulmonary Disease (COPD) [NCT01372410] | Phase 2 | 163 participants (Actual) | Interventional | 2011-07-01 | Completed | ||
| A Randomised, Double-Blind, Placebo-Controlled, Crossover Efficacy and Safety Evaluation of 8-Week Treatment Periods of Two Doses [5 Mcg (2 Actuations of 2.5 Mcg) and 10 Mcg (2 Actuations of 5 Mcg)] of Tiotropium Inhalation Solution Delivered by the Respi [NCT00365560] | Phase 2 | 115 participants | Interventional | 2006-08-31 | Completed | ||
| A Randomised, Double Blind, Parallel Group Study to Assess the Efficacy and Safety of 12 Weeks of Once Daily, Orally Inhaled, Co-administration of Olodaterol 5µg (Delivered by the Respimat® Inhaler) and Tiotropium 18µg (Delivered by the HandiHaler®) Compa [NCT01694771] | Phase 3 | 1,134 participants (Actual) | Interventional | 2012-09-30 | Completed | ||
| A Randomized, Double Blind (Test Products and Placebo), Chronic Dosing (14 Days), Four Period, Eight Treatment, Placebo-Controlled, Incomplete Block, Cross Over, Multi Center Study to Assess Efficacy and Safety of Six Doses of PT001 in Patients With Moder [NCT01566773] | Phase 2 | 140 participants (Actual) | Interventional | 2012-03-31 | Completed | ||
| Targeting of the Small Airways in Patients With COPD: Airway Effects of Tiotropium - Respimat vs Handihaler [NCT02683668] | Phase 3 | 44 participants (Actual) | Interventional | 2016-02-01 | Completed | ||
| A Randomized, Multicenter, Open-label, Parallel-group, 12-week Study to Assess the Efficacy and Safety of Switching From Tiotropium to QVA149 (Indacaterol Maleate/Glycopyrronium Bromide) in Symptomatic Mild to Moderate COPD Patients [NCT02566031] | Phase 4 | 379 participants (Actual) | Interventional | 2013-03-23 | Completed | ||
| Efficacy and Safety of Indacaterol vs tiotropiuM on walkEd Distance From Baseline to 24 Weeks, in Women With modeRAte-severe COPD Secondary to Biomass Exposure: Randomized, Non Inferior, Open Label, Parallel Groups Clinical Trial [NCT05506865] | Phase 4 | 97 participants (Actual) | Interventional | 2012-09-30 | Completed | ||
| A Randomized, Placebo-controlled, Double-blind, Parallel Group, Multi Center Study to Assess the Safety and Efficacy of Tiotropium Bromide (18 µg) Delivered Via the HandiHaler® in Chronic Obstructive Pulmonary Disease (COPD) Subjects Recovering From Hospi [NCT01663987] | Phase 4 | 79 participants (Actual) | Interventional | 2012-08-01 | Completed | ||
| Exacerbation Risk and Health Care Resource Use Among Patients With Asthma Using ICS+Tiotropium Versus ICS/LABA [NCT05501639] | 1,899 participants (Actual) | Observational | 2021-05-14 | Completed | |||
| Randomised, Double-blind, Double-dummy, Placebo-controlled, 4-way Cross-over Study to Characterise the 24-hour Forced, Expiratory Volume After 1 Second (FEV1) Time Profiles of BI 1744 CL 5µg and 10µg (Oral Inhalation, Delivered by the Respimat® Inhaler) a [NCT01040689] | Phase 3 | 108 participants (Actual) | Interventional | 2010-01-31 | Completed | ||
| Randomised, Double-Blind, Placebo-Controlled, 4-Way Cross-Over Study to Assess the Efficacy and Safety of a Single Dose of Orally Inhaled BEA 2180 BR (Doses 80, 200 and 800 μg) in COPD Patients Followed by an Open-Label, Active-Control (Tiotropium 72 μg) [NCT02242279] | Phase 2 | 37 participants (Actual) | Interventional | 2004-06-30 | Completed | ||
| A Double-blind, Double-dummy, Placebo-controlled, Randomised, Multi-centre, 5-way Cross-over, Single-dose Study to Investigate the Local and Systemic Effects of Inhaled AZD9164 Compared to Tiotropium in Subjects With Chronic Obstructive Pulmonary Disease [NCT00939211] | Phase 2 | 25 participants (Actual) | Interventional | 2009-06-30 | Completed | ||
| Pharmacokinetic Pilot Study Comparing Absorption of Inhaled Tiotropium Between Tiotropium Easyhaler® Products and Spiriva® Capsules Delivered Via HandiHaler® [NCT03400241] | Phase 1 | 24 participants (Actual) | Interventional | 2018-02-19 | Completed | ||
| A Randomised, Double-blind, Double Dummy, 3 Way Crossover Study Evaluating the Effects of a Combination of Seretide 50/500mcg Twice Daily Plus Tiotropium Bromide 18mcg Once Daily Compared With the Individual Agents (Tiotropium Bromide 18mcg Alone and Sere [NCT00325169] | Phase 2 | 41 participants (Actual) | Interventional | 2005-12-31 | Completed | ||
| A Single Dose, Placebo-controlled, Randomized, Double-blind, Double-dummy, Crossover Efficacy, Pharmacokinetics and Safety Comparison of Tiotropium Inhalation Powder (5 μg and 10 μg), Administered as the Bromide Salt From Hard Polyethylene Capsule Via the [NCT02242266] | Phase 2 | 121 participants (Actual) | Interventional | 2005-07-28 | Completed | ||
| A Randomized, Double-blind, Double-dummy, Parallel Group Trial Comparing 12 Weeks Treatment With Tiotropium Inhalation Capsules 18 mcg Via the HandiHaler® Once Daily to Combivent® Inhalation Aerosol CFC MDI 2 Actuations q.i.d. in COPD Patients Currently P [NCT00388882] | Phase 4 | 327 participants (Actual) | Interventional | 2006-10-04 | Completed | ||
| A Multiple Dose Comparison of Tiotropium Inhalation Capsules and Salmeterol Inhalation Aerosol in a 12 Week, Randomized, Double-Blind, Double-Dummy Parallel Group Study in Patients With Chronic Obstructive Pulmonary Disease (COPD). [NCT00274560] | Phase 3 | 653 participants (Actual) | Interventional | 2002-05-01 | Completed | ||
| Effect of Tiotropium on Exercise Tolerance and Static and Dynamic Lung Volumes in COPD Patients (A Randomized, Double-Blind, Placebo-Controlled, Parallel Group Study) [NCT00274508] | Phase 3 | 261 participants (Actual) | Interventional | 2000-10-10 | Completed | ||
| Efficacy and Safety Comparison of 4-week Treatment Periods of Two Doses [5 μg (2 Actuations of 2.5 μg) and 10 μg (2 Actuations of 5 μg)] of Tiotropium Inhalation Solution Delivered by the Respimat Inhaler, Tiotropium Inhalation Powder Capsule (18μg) Deliv [NCT00239447] | Phase 3 | 131 participants | Interventional | 2002-11-26 | Completed | ||
| A Randomized, Blinded, Double-dummy, Parallel-group Study to Evaluate the Efficacy and Safety of Umeclidinium (UMEC) 62.5 mcg Compared With Tiotropium 18 mcg in Subjects With Chronic Obstructive Pulmonary Disease (COPD) [NCT02207829] | Phase 3 | 1,017 participants (Actual) | Interventional | 2014-09-01 | Completed | ||
| The Role of Inhaler Device in the Treatment Persistence With Dual Bronchodilators in Patients With COPD [NCT03979807] | 11,296 participants (Actual) | Observational | 2019-06-10 | Completed | |||
| A Randomised, Double-blind, Placebo-controlled, Parallel-group Trial to Evaluate Efficacy and Safety of Tiotropium Inhalation Solution (2.5 mcg and 5 mcg) Delivered Via Respimat® Inhaler Once Daily in the Evening Over 48 Weeks in Children (6 to 11 Years O [NCT01634139] | Phase 3 | 403 participants (Actual) | Interventional | 2012-07-31 | Completed | ||
| A Randomized, Multicenter, Open-label, Cross-over Study to Assess Lung Function and Patient Preference After a 4 Week Treatment Each With QVA149 vs. Tiotropium in Patients With Stable Chronic Obstructive Pulmonary Disease (COPD) and Moderate to Severe Air [NCT02125734] | Phase 4 | 88 participants (Actual) | Interventional | 2014-04-30 | Completed | ||
| Steroids In Eosinophil Negative Asthma [NCT02066298] | Phase 3 | 295 participants (Actual) | Interventional | 2014-07-31 | Completed | ||
| A 2-Part, Randomised, Placebo-Controlled, Safety, Tolerability, Pharmacokinetic And Pharmacodynamic Study Of LAS190792 Delivered By Inhalation In Asthmatic And Chronic Obstructive Pulmonary Disease (COPD) Subjects [NCT02059434] | Phase 1 | 55 participants (Actual) | Interventional | 2013-09-01 | Completed | ||
| Specific Use-result Surveillance of Spiriva Respimat in Asthmatics (Patients With Severe Persistent Asthma) [NCT02489981] | 359 participants (Actual) | Observational | 2015-06-01 | Completed | |||
| A Randomised, Double-blind, Placebo- and Active-controlled Parallel Group Study to Assess the Efficacy of 12 Weeks of Once Daily Treatment of Two Doses of Orally Inhaled Tiotropium + Olodaterol Fixed Dose Combination (Delivered by the Respimat Inhaler) in [NCT01964352] | Phase 3 | 813 participants (Actual) | Interventional | 2013-11-30 | Completed | ||
| Multicenter, Randomized, Blinded, Two-period Cross-over Study to Assess the Effect of Glycopyrronium (44 Micrograms QD) Versus Tiotropium (18 Micrograms QD) on Morning Symptoms and Pulmonary Function in Patients With Moderate to Severe COPD [NCT01959516] | Phase 4 | 124 participants (Actual) | Interventional | 2014-02-28 | Completed | ||
| A Randomised, Placebo-controlled, Double-blind, Single Dose, Cross-over Study to Evaluate the Efficacy and Safety of Orally Inhaled Tiotropium + Olodaterol as Both a Fixed Dose Combination and a Free Combination (Both Delivered by the Respimat® Inhaler) i [NCT02030535] | Phase 2 | 53 participants (Actual) | Interventional | 2014-01-31 | Completed | ||
| Blacks and Exacerbations on LABA vs. Tiotropium (BELT) [NCT01290874] | Phase 3 | 1,070 participants (Actual) | Interventional | 2011-03-30 | Completed | ||
| A Phase II/III, Randomised, Double-blind, Placebo-controlled, Parallel Group Trial to Evaluate Safety and Efficacy of Tiotropium Inhalation Solution (2.5 µg and 5 µg) Administered Once Daily in the Afternoon Via Respimat® Inhaler for 12 Weeks in Patients [NCT01634113] | Phase 2 | 102 participants (Actual) | Interventional | 2012-07-31 | Completed | ||
| A Randomised, Double-blind, Parallel-group Study to Assess the Safety and Efficacy of 52 Weeks of Once Daily Treatment of Orally Inhaled Tiotropium + Olodaterol Fixed-dose Combination (2.5µg / 5µg, 5µg / 5µg ) and Olodaterol (5 µg) Delivered by the RESPIM [NCT01536262] | Phase 3 | 122 participants (Actual) | Interventional | 2012-02-29 | Completed | ||
| A Randomised, Double-blind, 5 Treatment Arms, 4-period, Incomplete Cross-over Study to Determine the Effect of 6 Weeks Treatment of Orally Inhaled Tiotropium + Olodaterol Fixed Dose Combination (FDC) (2.5 / 5 µg; and 5 / 5 µg) (Delivered by the Respimat® [NCT01533922] | Phase 3 | 295 participants (Actual) | Interventional | 2012-03-31 | Completed | ||
| A Multicenter, Randomized, Placebo-Controlled, Crossover, Single Dose Study To Demonstrate Clinical Pharmacodynamic Bioequivalence of Tiotropium 18 μg Inhalation Powder, Hard Capsule With Spiriva®Handihaler® 18 μg Inhalation Powder, Hard Capsule in Patien [NCT05986591] | Phase 3 | 335 participants (Anticipated) | Interventional | 2022-08-17 | Active, not recruiting | ||
| Characteristics and Treatment Patterns of Patients With Chronic Obstructive Pulmonary Disease (COPD), Initiating Tio+Olo or Other Maintenance Therapies in the US and the UK: A Retrospective Claims Database Study [NCT04926233] | 1,371,146 participants (Actual) | Observational | 2019-11-15 | Completed | |||
| Effectiveness and Safety of Maintenance Treatment With Combination of Tiotropium and Olodaterol in Comparison to Maintenance Treatment With a Combination of Inhaled Corticosteroids, Long-acting β2 Agonists and Long-acting Muscarinic Antagonists in COPD Pa [NCT04184297] | 27,190 participants (Actual) | Observational | 2019-11-01 | Completed | |||
| A Randomized, Double-blind, Placebo-controlled, Multi-center, Parallel Group Study to Compare the Efficacy of Inhaled Tiotropium + Olodaterol, Fixed Dose Combination (5 mcg/5mcg) vs. Placebo Delivered by Respimat Inhaler in Patients With Moderate to Sever [NCT04223843] | Phase 4 | 213 participants (Actual) | Interventional | 2020-01-08 | Completed | ||
| An Open-label Trial to Assess Pharmacokinetics and Safety of Tiotropium + Olodaterol Fixed-dose Combination (5 µg/ 5 µg) Delivered by the RESPIMAT Inhaler After Single and Multiple Dose Treatment in Chinese Patients With Chronic Obstructive Pulmonary Dise [NCT02969317] | Phase 1 | 12 participants (Actual) | Interventional | 2017-02-24 | Completed | ||
| Preliminary Study for Comparison of Triple Therapy Nebulizer Versus Dry Powdered Inhaler for Care Transitions in COPD [NCT03219866] | Phase 4 | 40 participants (Actual) | Interventional | 2017-10-03 | Terminated(stopped due to Lower enrollment than Sponsor expected - Sponsor stopped study) | ||
| The Effectiveness of Tiotropium Add-on Therapy Using a Real-world Cohort of Patients With Asthma [NCT03964220] | 7,857 participants (Actual) | Observational | 2019-03-15 | Completed | |||
| A Randomised, Double-blind, 5 Treatment Arms, 4-period, Incomplete Cross-over Study to Determine the Effect of 6 Weeks Treatment of Orally Inhaled Tiotropium + Olodaterol Fixed Dose Combination (FDC) (2.5 / 5 µg; and 5 / 5 µg) (Delivered by the Respimat® [NCT01533935] | Phase 3 | 291 participants (Actual) | Interventional | 2012-02-29 | Completed | ||
| A Randomised, Double-blind, Placebo-controlled, Parallel Group Study to Determine the Effect of 12 Weeks Treatment of Orally Inhaled Tiotropium + Olodaterol Fixed Dose Combination (2.5/5 µg and 5/5 µg) Delivered by the Respimat® Inhaler, on Exercise Endur [NCT01525615] | Phase 3 | 404 participants (Actual) | Interventional | 2012-02-29 | Completed | ||
| A 12-week, Randomised, Placebo-controlled, Double-blind, Parallel Group, Multi-center Trial to Assess the Efficacy and Safety of Tiotropium Bromide (18 µg) Delivered Via the HandiHaler® in Patients With Newly Diagnosed and/or Maintenance Treatment naïve C [NCT01483625] | Phase 4 | 140 participants (Actual) | Interventional | 2011-11-30 | Completed | ||
| A Randomised, Double-blinded, Active-controlled 2-way Cross Over Trial to Assess the Effects of 6 Weeks Treatment of Once Daily Orally Inhaled Tiotropium + Olodaterol Fixed Dose Combination Delivered by RESPIMAT Inhaler Compared With Tiotropium Delivered [NCT02629965] | Phase 3 | 184 participants (Actual) | Interventional | 2016-02-12 | Completed | ||
| Efficiency of Twice Daily Formoterol Versus Once Daily Tiotropium in Patients With GOLD A/B COPD: a Randomised, Open-label, Multicentre Trial [NCT03258749] | 120 participants (Anticipated) | Interventional | 2017-11-01 | Not yet recruiting | |||
| Protocol With Amendments 1 and 2: Phase I Randomised, Two-period 21 Day Crossover Study in Healthy Male and Female Volunteers to Compare the Steadystate Pharmacokinetics of Tiotropium Delivered From a Test pMDI Product With Spiriva Respimat [NCT03246581] | Phase 1 | 40 participants (Actual) | Interventional | 2017-07-13 | Completed | ||
| A 2-part, Randomised, Placebo-controlled, Safety, Tolerability, Pharmacokinetic and Pharmacodynamic Study of AZD8871 Delivered by Inhalation in Asthmatic and Chronic Obstructive Pulmonary Disease (COPD) Subjects [NCT02573155] | Phase 1 | 134 participants (Actual) | Interventional | 2015-10-31 | Completed | ||
| A 4-week, Randomised, Double-blind, Parallel Group Study to Evaluate the Efficacy and Safety of Tiotropium + Olodaterol Fixed Dose Combination (5/5 µg) Delivered by the Respimat® Inhaler Versus the Free Combination of Tiotropium 5 µg and Olodaterol 5 µg D [NCT02683109] | Phase 4 | 221 participants (Actual) | Interventional | 2016-03-08 | Completed | ||
| A Phase 3, 52-week, Randomized, Active-Controlled Parallel Group Study to Evaluate the Safety and Tolerability of Nebulized TD-4208 in Subjects With Chronic Obstructive Pulmonary Disease [NCT02518139] | Phase 3 | 1,060 participants (Actual) | Interventional | 2015-09-30 | Completed | ||
| 1-yr Study Comparing TioSal Combo Regimens Versus Single Agent Therapies (Spiriva HandiHaler and Salmeterol PE Capsule) [NCT00668772] | Phase 3 | 207 participants (Actual) | Interventional | 2008-04-15 | Terminated | ||
| A 28-Week, Multi-Center, Randomized, Double Blind, Parallel-Group, Active-Controlled Safety Extension Study to Evaluate the Safety and Efficacy of PT003, PT001, and PT005 in Subjects With Moderate to Very Severe COPD, With Spiriva® Handihaler® as an Activ [NCT01970878] | Phase 3 | 892 participants (Actual) | Interventional | 2013-11-30 | Completed | ||
| A Multicenter, Randomized, Blinded, Double-dummy, Placebo-controlled, 3-period Cross-over Study to Evaluate the Effect of QVA149 on Patient Reported Dyspnea in Moderate to Severe Chronic Obstructive Pulmonary Disease (COPD), Using Tiotropium as an Active [NCT01490125] | Phase 3 | 247 participants (Actual) | Interventional | 2011-10-31 | Completed | ||
| A 26-week Treatment, Multicenter, Randomized, Parallel Group, Blinded Study to Assess the Efficacy and Safety of QVA149 in Patients With Moderate to Severe Chronic Obstructive Pulmonary Disease Using Tiotropium Plus Formoterol as Control [NCT01574651] | Phase 3 | 934 participants (Actual) | Interventional | 2012-05-31 | Completed | ||
| A Multicenter, Randomized, Blinded, Active-controlled, Parallel-group Study to Compare the Efficacy, Tolerability and Safety of NVA237 Compared to Tiotropium Added on to Fluticasone/Salmeterol in Patients With Chronic Obstructive Pulmonary Disease [NCT01513460] | Phase 3 | 773 participants (Actual) | Interventional | 2012-04-30 | Completed | ||
| A Randomized, Double-Blind, Placebo-Controlled, Multi-Center, Seven Arm, Four-Period Cross-over, Incomplete Block Design, 7-Day Dosing Study to Assess the Dose-Response, Safety, and Efficacy of EP-101 (SUN101) in Subjects With Moderate to Severe COPD [NCT01426009] | Phase 2 | 140 participants (Actual) | Interventional | 2011-08-31 | Completed | ||
| A Phase II Randomised, Double-blind, Placebo-controlled Incomplete Crossover Trial With 4-week Treatment Periods to Evaluate Efficacy and Safety of Tiotropium Inhalation Solution (Doses of 1.25 µg, 2.5 µg and 5 µg) Delivered Via Respimat® Inhaler Once Dai [NCT01383499] | Phase 2 | 101 participants (Actual) | Interventional | 2011-08-31 | Completed | ||
| A Randomised, Double-blind, 3-way Crossover Study to Compare Pharmacokinetics and Safety of 10 μg BI 1744 CL Plus 5 μg Tiotropium Bromide Given as Fixed Dose Combination Via the Respimat® Inhaler With the Pharmacokinetics and the Safety of the Single Agen [NCT02231177] | Phase 1 | 47 participants (Actual) | Interventional | 2008-06-30 | Completed | ||
| A Randomised, Double- Blind, 2 Way Cross-over Study to Determine 24-hour FEV1-time Profile of Inhaled Tiotropium, Delivered Via the Respimat Inhaler, After 4 Weeks of Once Daily [5 mcg in the Evening (2 Actuations of 2.5 mcg)] or Twice Daily [2.5 mcg in t [NCT01696071] | Phase 2 | 98 participants (Actual) | Interventional | 2012-09-30 | Completed | ||
| A Phase 2, Randomized, Partially-blinded, Parallel Group, Dose-ranging Study to Assess the Pharmacodynamics, Relative Bioavailability, and Safety of of Tiotropium Bromide Inhalation Solution in Subjects With COPD [NCT04780984] | Phase 2 | 116 participants (Actual) | Interventional | 2020-11-01 | Completed | ||
| A Multiple Dose, Double-blind, Double-dummy, Placebo Controlled, Parallel Clinical Trial to Assess the Efficacy and Safety of Twice Daily Inhaled Aclidinium Bromide 400 µg Compared to Placebo and to Tiotropium Bromide in Patients With Stable Moderate to S [NCT01462929] | Phase 3 | 414 participants (Actual) | Interventional | 2011-11-30 | Completed | ||
| Study to Evaluate the Preference, Satisfaction and Correct Use of Inhalers in Patients With Chronic Obstructive Pulmonary Disease [NCT01727024] | Phase 4 | 140 participants (Actual) | Interventional | 2013-04-30 | Completed | ||
| A Multicenter, Trial Comparing the Efficacy and Safety of Umeclidinium/Vilanterol 62.5/25 mcg Once Daily With Tiotropium 18 mcg Once Daily Over 24 Weeks in Subjects With Chronic Obstructive Pulmonary Disease (COPD) [NCT01777334] | Phase 3 | 905 participants (Actual) | Interventional | 2013-01-23 | Completed | ||
| Cardiac Limitations in Chronic Obstructive Pulmonary Disease: Benefits of Bronchodilation [NCT00578968] | Phase 4 | 36 participants (Actual) | Interventional | 2006-10-31 | Completed | ||
| A Randomised, Double-blind, Double Dummy, 3 Way Cross-over Study Evaluating the Effects of ADOAIR 50/250mcg Twice Daily Plus Tiotropium Bromide 18mcg Once Daily Compared With the Individual Treatments (Tiotropium Bromide 18mcg Alone and ADOAIR 50/250mcg A [NCT01751113] | Phase 4 | 53 participants (Actual) | Interventional | 2013-02-28 | Completed | ||
| A Randomised, Double-blind Placebo- and Active-controlled, Multi-centre, 6-way Cross-over, Single-dose Phase IIa Study to Investigate the Bronchodilatory and Systemic Effects of 4 Different Doses of Inhaled AZD8683 in Patients With Chronic Obstructive Pul [NCT01708057] | Phase 2 | 3 participants (Actual) | Interventional | 2012-10-31 | Terminated | ||
| Randomized, Double-blind, Double-dummy, Active-controlled, 4 Period Complete Cross-over Study to Compare the Effect on Lung Function of 6 Weeks Once Daily Treatment With Orally Inhaled Tiotropium+Olodaterol Fixed Dose Combination Delivered by the Respimat [NCT01969721] | Phase 3 | 229 participants (Actual) | Interventional | 2013-10-31 | Completed | ||
| A Randomised, Open-label, Parallel-group Trial to Assess Pharmacokinetics and Safety of Tiotropium + Olodaterol Fixed-dose Combination (2.5 µg/ 5 µg, 5 µg/ 5 µg) Delivered by the RESPIMAT Inhaler After 3 Weeks Once Daily Treatment in Japanese Patients Wit [NCT01703845] | Phase 1 | 32 participants (Actual) | Interventional | 2012-10-31 | Completed | ||
| Lung Function Changes Following the Addition of Formoterol Inhalation Capsules (12 µ Once or Twice Daily) to Pharmacodynamic Steady State of Once Daily Tiotropium (18 µg) Inhalation Capsule in Patients With COPD [NCT02242240] | Phase 2 | 95 participants (Actual) | Interventional | 2001-03-31 | Completed | ||
| A 26-week, Randomized, Double Blind, Parallel-group Multicenter Study to Assess the Efficacy and Safety of QVA149 (110/50 μg o.d.) vs Tiotropium (18 µg o.d.) + Salmeterol/Fluticasone Propionate FDC (50/500 µg b.i.d.) in Patients With Moderate to Severe CO [NCT02603393] | Phase 4 | 1,053 participants (Actual) | Interventional | 2015-11-20 | Completed | ||
| Evaluating the Control of COPD Symptoms in Patients Treated With Tiotropium Bromide 18mcg Once Daily Alone, ADOAIR 50/250mcg Twice Daily Alone or ADOAIR 50/250mcg Plus Tiotropium Bromide 18mcg [NCT01762800] | Phase 4 | 407 participants (Actual) | Interventional | 2013-02-28 | Completed | ||
| The Effects of Tiotropium on the Cough Reflex in Patients With COPD [NCT00870896] | Early Phase 1 | 5 participants (Actual) | Interventional | 2008-02-29 | Completed | ||
| Post-Marketing Observational Study of the Impact of Adherence to Treatment With Once-Daily Administered Long-Acting Bronchodilators (LABAs / LAMAs) on Patients Health Related Quality of Life in COPD Patients [NCT01937390] | 645 participants (Actual) | Observational | 2011-11-06 | Completed | |||
| A Randomised, Parallel-group, Open-label, Multicentre, 3-month Phase IV, Efficacy and Tolerability Study of Budesonide/Formoterol (Symbicort® Turbuhaler® 160/4.5μg/Inhalation, 2 Inhalations Twice Daily) Added to Tiotropium (SpirivaTM 18 μg/Inhalation, 1 I [NCT01397890] | Phase 4 | 793 participants (Actual) | Interventional | 2011-07-31 | Completed | ||
| A Randomised Open-label Study to Compare the Effectiveness of the Fixed Dose Combination of FF/UMEC/VI (Using the Connected Inhaler System) With the Combination of FP/SAL Plus Tiotropium (Without the Connected Inhaler System) in Participants With Inadequa [NCT03376932] | Phase 3 | 0 participants (Actual) | Interventional | 2019-01-18 | Withdrawn(stopped due to withdrawn due to internal reasons) | ||
| Early Intervention With Tiotropium （Spiriva） in Chinese Patients With Chronic Obstructive Pulmonary Disease (COPD): a Randomized, Double-blind, Placebo-controlled, Parallel, Multicentre Trial [NCT01455129] | Phase 4 | 841 participants (Actual) | Interventional | 2011-11-30 | Completed | ||
| Effectiveness of Maintenance Treatment With Tiotropium + Olodaterol in Comparison to Inhaled Corticosteroids + Long-acting β2 Agonists in COPD Patients in Taiwan: a Non-interventional Study Based on the Taiwan National Health Insurance (NHI) Data [NCT05402020] | 20,775 participants (Actual) | Observational | 2022-09-30 | Completed | |||
| Tiotropium Respimat Soft Mist Inhaler Versus HandiHaler to Improve Sleeping Oxygen Saturation and Sleep Quality in COPD. [NCT02331940] | 200 participants (Actual) | Interventional | 2010-03-31 | Completed | |||
| A 1-year Multi-center, Prospective, Cohort Study in Patients With Chronic Obstructive Pulmonary Disease Treated With Long-acting Bronchodilator [NCT01794780] | Phase 4 | 2,229 participants (Actual) | Interventional | 2013-02-05 | Completed | ||
| Inspiratory Flow Parameters With Placebo Tiotropium Easyhaler® and Placebo Spiriva® Capsule Via HandiHaler® in Patients With COPD and in Healthy Volunteers. Substudy: Easyhaler® and HandiHaler® Usability Study in Patients With COPD [NCT04147572] | 200 participants (Actual) | Interventional | 2019-11-01 | Completed | |||
| Effeciency of Budesonide Combined With Formoterol and Tiotropium in the Treatment of Acute Exacerbation of Asthma-chronic Obstructive Pulmonary Overlap: A Randomized Controlled Clinical Study [NCT03504527] | 120 participants (Anticipated) | Interventional | 2018-05-01 | Not yet recruiting | |||
| A Randomised, Double-blind, Placebo-controlled, Parallel-group Trial to Evaluate Efficacy and Safety of Tiotropium Inhalation Solution (2.5 mcg and 5 mcg) Delivered Via Respimat® Inhaler Once Daily in the Evening Over 12 Weeks as add-on Controller Therapy [NCT01634152] | Phase 3 | 401 participants (Actual) | Interventional | 2012-07-31 | Completed | ||
| Effects of Dual Bronchodilator Treatment (Tiotropium + Olodaterol Respimat) on Cardiopulmonary Interactions in Hyperinflated Patients With COPD [NCT03425617] | Phase 4 | 25 participants (Actual) | Interventional | 2017-01-01 | Completed | ||
| A Randomised, Double-blind, Parallel Group Study to Assess the Efficacy and Safety of 52 Weeks of Once Daily Treatment of Orally Inhaled Tiotropium + Olodaterol Fixed Dose Combination (2.5 µg / 5 µg; 5 µg / 5 µg) (Delivered by the Respimat® Inhaler) Compa [NCT01431287] | Phase 3 | 2,539 participants (Actual) | Interventional | 2011-09-30 | Completed | ||
| A Multinational, Multicentre, Randomised, Open-Label, Active-Controlled, 26-Week, 2-Arm, Parallel Group Study to Evaluate the Non-Inferiority of Fixed Combination of Beclomethasone Dipropionate Plus Formoterol Fumarate Plus Glycopyrronium Bromide (CHF 599 [NCT02467452] | Phase 3 | 1,479 participants (Actual) | Interventional | 2015-05-31 | Completed | ||
| A Randomized, Double Blind, Chronic Dosing, Placebo-Controlled, Parallel Group, Multi Center Study to Assess the Efficacy and Safety of PT003, PT005, and PT001 in Subjects With Moderate to Very Severe COPD, Compared With Placebo and Spiriva® Handihaler® ( [NCT01854645] | Phase 3 | 2,103 participants (Actual) | Interventional | 2013-05-31 | Completed | ||
| A Placebo and Active Controlled Study to Assess the Long-term Safety of Once Daily QVA149 for 52 Weeks in Chronic Obstructive Pulmonary Disease (COPD) Patients With Moderate to Severe Airflow Limitation [NCT01610037] | Phase 3 | 1,215 participants (Actual) | Interventional | 2012-10-31 | Completed | ||
| A Randomised, Double-blind, Placebo- and Active-controlled Parallel Group Study to Assess the Efficacy of 12 Weeks of Once Daily Treatment of Two Doses of Orally Inhaled Tiotropium+ Olodaterol Fixed Dose Combination (Delivered by the Respimat Inhaler) in [NCT02006732] | Phase 3 | 809 participants (Actual) | Interventional | 2013-11-30 | Completed | ||
| A Prospective Study of Salvational Intervention With ICS/LABA for Reducing Chronic Obstructive Pulmonary Disease Exacerbation Under Severe Air Pollution (SIRCAP) in Beijing [NCT03083067] | 402 participants (Actual) | Interventional | 2017-03-20 | Completed | |||
| Efficacy and Acute Effects on Walked Distance froM basEline and Post Dose of indacateRol vs Tiotropium in Women With modeRAte to Severe COPD Secondary to Biomass Exposure: Open Label Crossover Clinical Trial [NCT02473237] | Phase 4 | 40 participants (Anticipated) | Interventional | 2013-04-30 | Completed | ||
| Phase I Randomised, Four-period Balanced Incomplete Block Design Cross-over Study in Healthy Male and Female Volunteers to Compare the Pharmacokinetics of Tiotropium Delivered From Four Test pMDI Products With One Reference Product [NCT03302065] | Phase 1 | 38 participants (Actual) | Interventional | 2016-05-31 | Completed | ||
| DB2116960: A Randomized, Double-Dummy, Parallel Group, Multicenter Trial Comparing the Efficacy and Safety of UMEC/VI (a Fixed Combination of Umeclidinium and Vilanterol) With Tiotropium In Subjects With COPD Who Continue To Have Symptoms on Tiotropium [NCT01899742] | Phase 3 | 497 participants (Actual) | Interventional | 2014-09-15 | Completed | ||
| A Randomized, Open-Label, Active-Controlled, Parallel-Group, Multicenter, Long-Term Safety Trial of Treatment With Nebulized SUN-101 in Patients With COPD: GOLDEN-5 (Glycopyrrolate for Obstructive Lung Disease Via Electronic Nebulizer) [NCT02276222] | Phase 3 | 1,087 participants (Actual) | Interventional | 2014-10-31 | Completed | ||
| A Randomized, Double Blind, (Test Products), Chronic Dosing (7 Days), Four Period, Eight Treatment , Incomplete Block, Cross Over, Multi Center Study to Assess Efficacy and Safety of Five Doses of PT003, One Dose of PT001 and One Dose of PT005 in Patients [NCT01587079] | Phase 2 | 159 participants (Actual) | Interventional | 2012-04-30 | Completed | ||
| A 12-week Treatment, Randomized, Blinded, Double-dummy, Parallel-group Study to Assess the Efficacy, Safety, and Tolerability of NVA237 (50 µg o.d.) Compared to Tiotropium (18 µg o.d.) in Patients With Chronic Obstructive Pulmonary Disease (COPD) [NCT01613326] | Phase 3 | 657 participants (Actual) | Interventional | 2012-06-30 | Completed | ||
| A Comparative Effectiveness and Safety Study of Arformoterol Tartrate Inhalation Solution and Tiotropium Bromide on Re-hospitalization in Chronic Obstructive Pulmonary Disease (COPD) Subjects [NCT02275481] | Phase 4 | 66 participants (Actual) | Interventional | 2014-11-30 | Terminated(stopped due to lack of enrollment) | ||
| Study DB2116961, A Multicentre, Randomised, Blinded, Parallel Group Study to Compare UMEC/VI (Umeclidinium/Vilanterol) in a Fixed Dose Combination With Indacaterol Plus Tiotropium in Symptomatic Subjects With Moderate to Very Severe COPD [NCT02257385] | Phase 3 | 967 participants (Actual) | Interventional | 2014-10-15 | Completed | ||
| MATHS: Assessment of Health-status of Patients With COPD on MAintenance THerapy With Spiriva® HH Measured by CAT Test [NCT01644734] | Phase 4 | 1,328 participants (Actual) | Interventional | 2011-11-30 | Completed | ||
| A 12-Week Study to Evaluate the 24-Hour Pulmonary Function Profile of Fluticasone Furoate /Vilanterol (FF/VI) Inhalation Powder 100/25mcg Once-Daily Via a Novel Dry Powder Inhaler Compared With Tiotropium Bromide Inhalation Powder 18mcg Delivered Once-Dai [NCT01627327] | Phase 3 | 623 participants (Actual) | Interventional | 2012-04-01 | Completed | ||
| A Randomized, Double-blind, Multicenter, 2-period Single-dose Cross-over Study to Assess the Early Bronchodilation of Glycopyrronium Bromide (44 μg o.d.) Compared to Tiotropium (18 µg. o.d.) in Patients With Moderate to Severe COPD (FAST Study) [NCT01922271] | Phase 4 | 152 participants (Actual) | Interventional | 2013-08-31 | Completed | ||
| Randomised, Double-blind, Placebo-controlled, 6 Treatment, 4 Period, Incomplete Cross-over Trial to Characterise the 24-hour Lung Function Profiles of Tiotropium + Olodaterol Fixed Dose Combination (2.5/5 µg, 5/5 µg), Tiotropium (2.5 µg, 5 µg) and Olodate [NCT01559116] | Phase 3 | 219 participants (Actual) | Interventional | 2012-03-31 | Completed | ||
| [information is prepared from clinicaltrials.gov, extracted Sep-2024] | |||||||
"SGRQ total score summarizes the impact of COPD on overall patient's health status.~Total scores are expressed as a percentage of overall impairment where 100 represents worst possible health status and 0 indicates best possible health status.~The scale is continuous.~Rate of decline shows the yearly change of SGRQ total score." (NCT00144339)
Timeframe: Month 12
| Intervention | Units on a scale (Mean) |
|---|---|
| Placebo | 42.501 |
| Tiotropium Bromide Inhalation Capsules 18 mcg | 39.730 |
Number of exacerbation days normalized by treatment exposure (NCT00144339)
Timeframe: Day 1 to 4 years
| Intervention | days/patient year (Mean) |
|---|---|
| Placebo | 13.64 |
| Tiotropium Bromide Inhalation Capsules 18 mcg | 12.11 |
Estimated number of exacerbations leading to hospitalizations per patient year (NCT00144339)
Timeframe: From Day 1 to 4 years
| Intervention | Number per patient year (Number) |
|---|---|
| Placebo | 0.16 |
| Tiotropium Bromide Inhalation Capsules 18 mcg | 0.15 |
Rate of decline of forced expiratory volume in one second (FEV1) measured after the use of bronchodilators. A negative rate of decline indicates decreasing FEV1 over time, while a positive value indicates increasing FEV1 (NCT00144339)
Timeframe: Day 1 to 30 days after completion of double blinded treatment between Day 1 and 4 years plus 30 days
| Intervention | ml/year (Median) |
|---|---|
| Placebo | -32 |
| Tiotropium Bromide Inhalation Capsules 18 mcg | -27 |
Rate of decline of forced expiratory volume in one second (FEV1) measured after bronchodilation. A negative rate of decline indicates decreasing FEV1 over time, while a positive value indicates increasing FEV1. (NCT00144339)
Timeframe: From day 30 to 4 years
| Intervention | ml/year (Mean) |
|---|---|
| Placebo | -42 |
| Tiotropium Bromide Inhalation Capsules 18 mcg | -40 |
Rate of decline of forced vital capacity (FVC) after bronchodilation. A negative rate of decline indicates decreasing FVC over time, while a positive value indicates increasing FVC (NCT00144339)
Timeframe: Day 1 to 30 days after completion of double blinded treatment between Day 1 and 4 years plus 30 days
| Intervention | ml/year (Median) |
|---|---|
| Placebo | -40 |
| Tiotropium Bromide Inhalation Capsules 18 mcg | -40 |
Rate of decline of forced vital capacity (FVC) measured after bronchodilation. A negative rate of decline indicates decreasing FVC over time, while a positive value indicates increasing FVC (NCT00144339)
Timeframe: From day 30 to 4 years
| Intervention | ml/year (Mean) |
|---|---|
| Placebo | -61 |
| Tiotropium Bromide Inhalation Capsules 18 mcg | -61 |
Rate of decline of slow vital capacity (SVC) after bronchodilation. A negative rate of decline indicates decreasing SVC over time, while a positive value indicates increasing SVC (NCT00144339)
Timeframe: Day 1 to 30 days after completion of double blinded treatment between Day 1 and 4 years plus 30 days
| Intervention | ml/year (Median) |
|---|---|
| Placebo | -46 |
| Tiotropium Bromide Inhalation Capsules 18 mcg | -42 |
Rate of decline of slow vital capacity (SVC) measured after bronchodilation. A negative rate of decline indicates decreasing SVC over time, while a positive value indicates increasing SVC (NCT00144339)
Timeframe: From day 30 to 4 years
| Intervention | ml/year (Mean) |
|---|---|
| Placebo | -65 |
| Tiotropium Bromide Inhalation Capsules 18 mcg | -66 |
Rate of decline of forced expiratory volume in one second (FEV1) measured before the use of bronchodilators. A negative rate of decline indicates decreasing FEV1 over time, while a positive value indicates increasing FEV1 (NCT00144339)
Timeframe: Day 1 to 30 days after completion of double blinded treatment between Day 1 and 4 years plus 30 days.
| Intervention | ml/year (Median) |
|---|---|
| Placebo | -17 |
| Tiotropium Bromide Inhalation Capsules 18 mcg | -15 |
(NCT00144339)
Timeframe: Month 36
| Intervention | L (Mean) |
|---|---|
| Placebo | 2.731 |
| Tiotropium Bromide Inhalation Capsules 18 mcg | 2.897 |
Rate of decline of forced expiratory volume in one second (FEV1) measured before the use of bronchodilators. A negative rate of decline indicates decreasing FEV1 over time, while a positive value indicates increasing FEV1. (NCT00144339)
Timeframe: From day 30 to 4 years
| Intervention | ml/year (Mean) |
|---|---|
| Placebo | -30 |
| Tiotropium Bromide Inhalation Capsules 18 mcg | -30 |
Rate of decline of forced vital capacity (FVC) before bronchodilation. A negative rate of decline indicates decreasing FVC over time, while a positive value indicates increasing FVC (NCT00144339)
Timeframe: Day 1 to 30 days after completion of double blinded treatment between Day 1 and 4 years plus 30 days.
| Intervention | ml/year (Median) |
|---|---|
| Placebo | -12 |
| Tiotropium Bromide Inhalation Capsules 18 mcg | -10 |
Rate of decline of forced vital capacity (FVC) measured before the use of bronchodilators. A negative rate of decline indicates decreasing FVC over time, while a positive value indicates increasing FVC (NCT00144339)
Timeframe: From day 30 to 4 years
| Intervention | ml/year (Mean) |
|---|---|
| Placebo | -39 |
| Tiotropium Bromide Inhalation Capsules 18 mcg | -43 |
Rate of decline slow vital capacity (SVC) before bronchodilation. A negative rate of decline indicates decreasing SVC over time, while a positive value indicates increasing SVC (NCT00144339)
Timeframe: Day 1 to 30 days after completion of double blinded treatment between Day 1 and 4 years plus 30 days
| Intervention | ml/year (Median) |
|---|---|
| Placebo | -17 |
| Tiotropium Bromide Inhalation Capsules 18 mcg | -17 |
Rate of decline of slow vital capacity (SVC) measured before the use of bronchodilators. A negative rate of decline indicates decreasing SVC over time, while a positive value indicates increasing SVC (NCT00144339)
Timeframe: From day 30 to 4 years
| Intervention | ml/year (Mean) |
|---|---|
| Placebo | -41 |
| Tiotropium Bromide Inhalation Capsules 18 mcg | -47 |
SGRQ total score shows the impact of COPD on patient's health status, and expressed as a percentage of impairment with scale from 0 (best health status) to 100 (worst possible status). A negative rate of decline shows decreasing SGRQ total score (or improved health) over time, while a positive value shows increasing score (or worsen health). (NCT00144339)
Timeframe: From month 6 to 4 years
| Intervention | Score on scale per year (Mean) |
|---|---|
| Placebo | 1.21 |
| Tiotropium Bromide Inhalation Capsules 18 mcg | 1.25 |
(NCT00144339)
Timeframe: Day 1 to 4 years
| Intervention | months (Median) |
|---|---|
| Placebo | 28.64 |
| Tiotropium Bromide Inhalation Capsules 18 mcg | 35.89 |
Descriptive statistics show the number of patients with event, central tendency shows incidence rate. Incidence rate calculated as number of patients with event divided by at-risk years * 100. (NCT00144339)
Timeframe: Day 1 to completion of double blinded treatment plus 30 days
| Intervention | Number of patients with event (Number) | |
|---|---|---|
| Number of patients with event | Incidence rate (number events/100-patient years) | |
| Placebo | 67 | 0.77 |
| Tiotropium Bromide Inhalation Capsules 18 mcg | 69 | 0.74 |
(NCT00144339)
Timeframe: Month 18
| Intervention | L (Mean) |
|---|---|
| Placebo | 1.326 |
| Tiotropium Bromide Inhalation Capsules 18 mcg | 1.379 |
Chronic obstructive pulmonary disease (COPD) exacerbation (NCT00144339)
Timeframe: From Day 1 to 4 years
| Intervention | months (Median) |
|---|---|
| Placebo | 12.51 |
| Tiotropium Bromide Inhalation Capsules 18 mcg | 16.65 |
Descriptive statistics show the number of patients with event, central tendency shows incidence rate. Incidence rate calculated as number of patients with event divided by at-risk years * 100. (NCT00144339)
Timeframe: Day 1 to completion of double blinded treatment plus 30 days
| Intervention | Number of patients with event (Number) | |
|---|---|---|
| Number of patients with event | Incidence rate (number events/100-patient years) | |
| Placebo | 31 | 0.36 |
| Tiotropium Bromide Inhalation Capsules 18 mcg | 48 | 0.51 |
Descriptive statistics show the number of patients with event, central tendency shows incidence rate. Incidence rate calculated as number of patients with event divided by at-risk years * 100. (NCT00144339)
Timeframe: Day 1 to completion of double blinded treatment plus 30 days
| Intervention | Number of patients with event (Number) | |
|---|---|---|
| Number of patients with event | Incidence rate (number events/100-patient years) | |
| Placebo | 27 | 0.31 |
| Tiotropium Bromide Inhalation Capsules 18 mcg | 35 | 0.37 |
Descriptive statistics show the number of patients with event, central tendency shows incidence rate. Incidence rate calculated as number of patients with event divided by at-risk years * 100. (NCT00144339)
Timeframe: Day 1 to completion of double blinded treatment plus 30 days
| Intervention | Number of patients with event (Number) | |
|---|---|---|
| Number of patients with event | Incidence rate (number events/100-patient years) | |
| Placebo | 42 | 0.48 |
| Tiotropium Bromide Inhalation Capsules 18 mcg | 27 | 0.29 |
Descriptive statistics show the number of patients with event, central tendency shows incidence rate. Incidence rate calculated as number of patients with event divided by at-risk years * 100. (NCT00144339)
Timeframe: Day 1 to completion of double blinded treatment plus 30 days
| Intervention | Number of patients with event (Number) | |
|---|---|---|
| Number of patients with event | Incidence rate (number events/100-patient years) | |
| Placebo | 42 | 0.48 |
| Tiotropium Bromide Inhalation Capsules 18 mcg | 57 | 0.61 |
Descriptive statistics show the number of patients with event, central tendency shows incidence rate. Incidence rate calculated as number of patients with event divided by at-risk years * 100. (NCT00144339)
Timeframe: Day 1 to completion of double blinded treatment plus 30 days
| Intervention | Number of patients with event (Number) | |
|---|---|---|
| Number of patients with event | Incidence rate (number events/100-patient years) | |
| Placebo | 742 | 9.70 |
| Tiotropium Bromide Inhalation Capsules 18 mcg | 688 | 8.19 |
Descriptive statistics show the number of patients with event, central tendency shows incidence rate. Incidence rate calculated as number of patients with event divided by at-risk years * 100. (NCT00144339)
Timeframe: Day 1 to completion of double blinded treatment plus 30 days
| Intervention | Number of patients with event (Number) | |
|---|---|---|
| Number of patients with event | Incidence rate (number events/100-patient years) | |
| Placebo | 32 | 0.37 |
| Tiotropium Bromide Inhalation Capsules 18 mcg | 20 | 0.21 |
Descriptive statistics show the number of patients with event, central tendency shows incidence rate. Incidence rate calculated as number of patients with event divided by at-risk years * 100. (NCT00144339)
Timeframe: Day 1 to completion of double blinded treatment plus 30 days
| Intervention | Number of patients with event (Number) | |
|---|---|---|
| Number of patients with event | Incidence rate (number events/100-patient years) | |
| Placebo | 54 | 0.62 |
| Tiotropium Bromide Inhalation Capsules 18 mcg | 36 | 0.38 |
Descriptive statistics show the number of patients with event, central tendency shows incidence rate. Incidence rate calculated as number of patients with event divided by at-risk years * 100. (NCT00144339)
Timeframe: Day 1 to completion of double blinded treatment plus 30 days
| Intervention | Number of patients with event (Number) | |
|---|---|---|
| Number of patients with event | Incidence rate (number events/100-patient years) | |
| Placebo | 84 | 0.97 |
| Tiotropium Bromide Inhalation Capsules 18 mcg | 65 | 0.69 |
Descriptive statistics show the number of patients with event, central tendency shows incidence rate. Incidence rate calculated as number of patients with event divided by at-risk years * 100. (NCT00144339)
Timeframe: Day 1 to completion of double blinded treatment plus 30 days
| Intervention | Number of patients with event (Number) | |
|---|---|---|
| Number of patients with event | Incidence rate (number events/100-patient years) | |
| Placebo | 290 | 3.46 |
| Tiotropium Bromide Inhalation Capsules 18 mcg | 296 | 3.28 |
Descriptive statistics show the number of patients with event, central tendency shows incidence rate. Incidence rate calculated as number of patients with event divided by at-risk years * 100. (NCT00144339)
Timeframe: Day 1 to completion of double blinded treatment plus 30 days
| Intervention | Number of patients with event (Number) | |
|---|---|---|
| Number of patients with event | Incidence rate (number events/100-patient years) | |
| Placebo | 113 | 1.31 |
| Tiotropium Bromide Inhalation Capsules 18 mcg | 85 | 0.90 |
(NCT00144339)
Timeframe: Month 18
| Intervention | L (Mean) |
|---|---|
| Placebo | 2.811 |
| Tiotropium Bromide Inhalation Capsules 18 mcg | 2.965 |
Descriptive statistics show the number of patients with event, central tendency shows incidence rate. Incidence rate calculated as number of patients with event divided by at-risk years * 100. (NCT00144339)
Timeframe: Day 1 to completion of double blinded treatment plus 30 days
| Intervention | Number of patients with event (Number) | |
|---|---|---|
| Number of patients with event | Incidence rate (number of events/100 patient year) | |
| Placebo | 350 | 4.21 |
| Tiotropium Bromide Inhalation Capsules 18 mcg | 322 | 3.56 |
Number of days with chronic obstructive pulmonary disease (COPD) exacerbation leading to hospitalization (normalized by treatment exposure) (NCT00144339)
Timeframe: From Day 1 to 4 years
| Intervention | days/patient year (Mean) |
|---|---|
| Placebo | 3.13 |
| Tiotropium Bromide Inhalation Capsules 18 mcg | 3.17 |
Estimated forced expiratory volume in one second (FEV1) after bronchodilator at month 1 (NCT00144339)
Timeframe: Month 1
| Intervention | L (Mean) |
|---|---|
| Placebo | 1.372 |
| Tiotropium Bromide Inhalation Capsules 18 mcg | 1.418 |
(NCT00144339)
Timeframe: Month 42
| Intervention | L (Mean) |
|---|---|
| Placebo | 2.713 |
| Tiotropium Bromide Inhalation Capsules 18 mcg | 2.875 |
(NCT00144339)
Timeframe: Month 48
| Intervention | L (Mean) |
|---|---|
| Placebo | 2.696 |
| Tiotropium Bromide Inhalation Capsules 18 mcg | 2.846 |
(NCT00144339)
Timeframe: Month 6
| Intervention | L (Mean) |
|---|---|
| Placebo | 2.841 |
| Tiotropium Bromide Inhalation Capsules 18 mcg | 3.027 |
(NCT00144339)
Timeframe: Month 12
| Intervention | L (Mean) |
|---|---|
| Placebo | 1.345 |
| Tiotropium Bromide Inhalation Capsules 18 mcg | 1.398 |
"SGRQ total score summarizes the impact of COPD on overall patient's health status.~Total scores are expressed as a percentage of overall impairment where 100 represents worst possible health status and 0 indicates best possible health status.~The scale is continuous.~Rate of decline shows the yearly change of SGRQ total score." (NCT00144339)
Timeframe: Month 18
| Intervention | Units on a scale (Mean) |
|---|---|
| Placebo | 43.067 |
| Tiotropium Bromide Inhalation Capsules 18 mcg | 40.474 |
"SGRQ total score summarizes the impact of COPD on overall patient's health status.~Total scores are expressed as a percentage of overall impairment where 100 represents worst possible health status and 0 indicates best possible health status.~The scale is continuous.~Rate of decline shows the yearly change of SGRQ total score." (NCT00144339)
Timeframe: Month 24
| Intervention | Units on a scale (Mean) |
|---|---|
| Placebo | 43.562 |
| Tiotropium Bromide Inhalation Capsules 18 mcg | 41.178 |
"SGRQ total score summarizes the impact of COPD on overall patient's health status.~Total scores are expressed as a percentage of overall impairment where 100 represents worst possible health status and 0 indicates best possible health status.~The scale is continuous.~Rate of decline shows the yearly change of SGRQ total score." (NCT00144339)
Timeframe: Month 30
| Intervention | Units on a scale (Mean) |
|---|---|
| Placebo | 44.342 |
| Tiotropium Bromide Inhalation Capsules 18 mcg | 41.919 |
"SGRQ total score summarizes the impact of COPD on overall patient's health status.~Total scores are expressed as a percentage of overall impairment where 100 represents worst possible health status and 0 indicates best possible health status.~The scale is continuous.~Rate of decline shows the yearly change of SGRQ total score." (NCT00144339)
Timeframe: Month 36
| Intervention | Units on a scale (Mean) |
|---|---|
| Placebo | 45.280 |
| Tiotropium Bromide Inhalation Capsules 18 mcg | 41.935 |
"SGRQ total score summarizes the impact of COPD on overall patient's health status.~Total scores are expressed as a percentage of overall impairment where 100 represents worst possible health status and 0 indicates best possible health status.~The scale is continuous.~Rate of decline shows the yearly change of SGRQ total score." (NCT00144339)
Timeframe: Month 42
| Intervention | Units on a scale (Mean) |
|---|---|
| Placebo | 45.722 |
| Tiotropium Bromide Inhalation Capsules 18 mcg | 42.905 |
"SGRQ total score summarizes the impact of COPD on overall patient's health status.~Total scores are expressed as a percentage of overall impairment where 100 represents worst possible health status and 0 indicates best possible health status.~The scale is continuous.~Rate of decline shows the yearly change of SGRQ total score." (NCT00144339)
Timeframe: Month 48
| Intervention | Units on a scale (Mean) |
|---|---|
| Placebo | 45.968 |
| Tiotropium Bromide Inhalation Capsules 18 mcg | 43.665 |
"SGRQ total score summarizes the impact of COPD on overall patient's health status.~Total scores are expressed as a percentage of overall impairment where 100 represents worst possible health status and 0 indicates best possible health status.~The scale is continuous.~Rate of decline shows the yearly change of SGRQ total score." (NCT00144339)
Timeframe: Month 6
| Intervention | Units on a scale (Mean) |
|---|---|
| Placebo | 42.289 |
| Tiotropium Bromide Inhalation Capsules 18 mcg | 39.409 |
(NCT00144339)
Timeframe: Day 1 to 4 years
| Intervention | number per patient year (Mean) |
|---|---|
| Placebo | 0.85 |
| Tiotropium Bromide Inhalation Capsules 18 mcg | 0.73 |
(NCT00144339)
Timeframe: Month 24
| Intervention | L (Mean) |
|---|---|
| Placebo | 1.294 |
| Tiotropium Bromide Inhalation Capsules 18 mcg | 1.356 |
(NCT00144339)
Timeframe: Month 30
| Intervention | L (Mean) |
|---|---|
| Placebo | 1.274 |
| Tiotropium Bromide Inhalation Capsules 18 mcg | 1.335 |
(NCT00144339)
Timeframe: Month 36
| Intervention | L (Mean) |
|---|---|
| Placebo | 1.250 |
| Tiotropium Bromide Inhalation Capsules 18 mcg | 1.315 |
Estimated FEV1 after bronchodilator at Month 42 (NCT00144339)
Timeframe: Month 42
| Intervention | L (Mean) |
|---|---|
| Placebo | 1.236 |
| Tiotropium Bromide Inhalation Capsules 18 mcg | 1.297 |
(NCT00144339)
Timeframe: Month 48
| Intervention | L (Mean) |
|---|---|
| Placebo | 1.219 |
| Tiotropium Bromide Inhalation Capsules 18 mcg | 1.268 |
(NCT00144339)
Timeframe: Month 6
| Intervention | L (Mean) |
|---|---|
| Placebo | 1.365 |
| Tiotropium Bromide Inhalation Capsules 18 mcg | 1.423 |
(NCT00144339)
Timeframe: Month 1
| Intervention | L (Mean) |
|---|---|
| Placebo | 3.149 |
| Tiotropium Bromide Inhalation Capsules 18 mcg | 3.204 |
(NCT00144339)
Timeframe: Month 12
| Intervention | L (Mean) |
|---|---|
| Placebo | 3.110 |
| Tiotropium Bromide Inhalation Capsules 18 mcg | 3.158 |
(NCT00144339)
Timeframe: Month 18
| Intervention | L (Mean) |
|---|---|
| Placebo | 3.075 |
| Tiotropium Bromide Inhalation Capsules 18 mcg | 3.126 |
(NCT00144339)
Timeframe: Month 24
| Intervention | L (Mean) |
|---|---|
| Placebo | 3.036 |
| Tiotropium Bromide Inhalation Capsules 18 mcg | 3.095 |
(NCT00144339)
Timeframe: Month 30
| Intervention | L (Mean) |
|---|---|
| Placebo | 3.010 |
| Tiotropium Bromide Inhalation Capsules 18 mcg | 3.057 |
(NCT00144339)
Timeframe: Month 36
| Intervention | L (Mean) |
|---|---|
| Placebo | 2.973 |
| Tiotropium Bromide Inhalation Capsules 18 mcg | 3.038 |
(NCT00144339)
Timeframe: Month 42
| Intervention | L (Mean) |
|---|---|
| Placebo | 2.959 |
| Tiotropium Bromide Inhalation Capsules 18 mcg | 3.005 |
(NCT00144339)
Timeframe: Month 48
| Intervention | L (Mean) |
|---|---|
| Placebo | 2.929 |
| Tiotropium Bromide Inhalation Capsules 18 mcg | 2.961 |
(NCT00144339)
Timeframe: Month 6
| Intervention | L (Mean) |
|---|---|
| Placebo | 3.137 |
| Tiotropium Bromide Inhalation Capsules 18 mcg | 3.193 |
(NCT00144339)
Timeframe: Month 1
| Intervention | L (Mean) |
|---|---|
| Placebo | 3.280 |
| Tiotropium Bromide Inhalation Capsules 18 mcg | 3.318 |
(NCT00144339)
Timeframe: Month 12
| Intervention | L (Mean) |
|---|---|
| Placebo | 3.228 |
| Tiotropium Bromide Inhalation Capsules 18 mcg | 3.260 |
(NCT00144339)
Timeframe: Month 18
| Intervention | L (Mean) |
|---|---|
| Placebo | 3.195 |
| Tiotropium Bromide Inhalation Capsules 18 mcg | 3.234 |
(NCT00144339)
Timeframe: Month 24
| Intervention | L (Mean) |
|---|---|
| Placebo | 3.157 |
| Tiotropium Bromide Inhalation Capsules 18 mcg | 3.189 |
(NCT00144339)
Timeframe: Month 30
| Intervention | L (Mean) |
|---|---|
| Placebo | 3.126 |
| Tiotropium Bromide Inhalation Capsules 18 mcg | 3.157 |
(NCT00144339)
Timeframe: Month 36
| Intervention | L (Mean) |
|---|---|
| Placebo | 3.086 |
| Tiotropium Bromide Inhalation Capsules 18 mcg | 3.136 |
(NCT00144339)
Timeframe: Month 42
| Intervention | L (Mean) |
|---|---|
| Placebo | 3.073 |
| Tiotropium Bromide Inhalation Capsules 18 mcg | 3.100 |
(NCT00144339)
Timeframe: Month 48
| Intervention | L (Mean) |
|---|---|
| Placebo | 3.041 |
| Tiotropium Bromide Inhalation Capsules 18 mcg | 3.067 |
(NCT00144339)
Timeframe: Month 6
| Intervention | L (Mean) |
|---|---|
| Placebo | 3.268 |
| Tiotropium Bromide Inhalation Capsules 18 mcg | 3.304 |
Estimated FEV1 before bronchodilator at Month 1 (NCT00144339)
Timeframe: Month 1
| Intervention | L (Mean) |
|---|---|
| Placebo | 1.134 |
| Tiotropium Bromide Inhalation Capsules 18 mcg | 1.221 |
(NCT00144339)
Timeframe: Month 12
| Intervention | L (Mean) |
|---|---|
| Placebo | 1.111 |
| Tiotropium Bromide Inhalation Capsules 18 mcg | 1.213 |
Descriptive statistics show the number of patients with event, central tendency shows incidence rate. Incidence rate calculated as number of patients with event divided by at-risk years * 100. (NCT00144339)
Timeframe: Day 1 to completion of double blinded treatment plus 30 days
| Intervention | Number of patients with event (Number) | |
|---|---|---|
| Number of patients with event | Incidence rate (number events/100-patient years) | |
| Placebo | 985 | 13.47 |
| Tiotropium Bromide Inhalation Capsules 18 mcg | 911 | 11.32 |
The primary cause of death was adjudicated by an external committee prior to unblinding; vital status was information followed-up after discontinuation; vital status information up to 1470 days after the start of treatment was used (NCT00144339)
Timeframe: Day 1 to day 1470
| Intervention | Participants (Number) | |
|---|---|---|
| Number of patients with lower respiratory death | Percentage patients with lower respiratory death | |
| Placebo | 173 | 5.8 |
| Tiotropium Bromide Inhalation Capsules 18 mcg | 153 | 5.1 |
(NCT00144339)
Timeframe: Day 1 to day 1440
| Intervention | Participants (Number) | |
|---|---|---|
| Number of patients died from day 1 to day 1440 | Percentage of patients died from day 1 to day 1440 | |
| Placebo | 491 | 16.3 |
| Tiotropium Bromide Inhalation Capsules 18 mcg | 430 | 14.4 |
All cause mortality vital status information was followed-up after discontinuation; vital status information up to 1470 days after the start of treatment was used. (NCT00144339)
Timeframe: Day 1 to day 1470
| Intervention | Participants (Number) | |
|---|---|---|
| Number of patients died from day 1 to day 1470 | Percentage of patients died from day 1 to day 1470 | |
| Placebo | 495 | 16.5 |
| Tiotropium Bromide Inhalation Capsules 18 mcg | 446 | 14.9 |
On-treatment defined as day 1 to completion of double blinded treatment plus 30 days (NCT00144339)
Timeframe: Day 1 to completion of double blinded treatment plus 30 days between Day 1 and 4 years plus 30 days
| Intervention | Participants (Number) | |
|---|---|---|
| Number of patients with on-treatment death | Percentage patients with on-treatment death | |
| Placebo | 402 | 13.4 |
| Tiotropium Bromide Inhalation Capsules 18 mcg | 374 | 12.5 |
The primary cause of death was adjudicated by an external committee prior to unblinding; on-treatment defined as day 1 to completion of double blinded treatment plus 30 days (NCT00144339)
Timeframe: Day 1 to completion of double blinded treatment plus 30 days between Day 1 and 4 years plus 30 days
| Intervention | Participants (Number) | |
|---|---|---|
| Number of patients with lower respiratory | Percentage of patients with lower respiratory | |
| Placebo | 140 | 4.7 |
| Tiotropium Bromide Inhalation Capsules 18 mcg | 131 | 4.4 |
(NCT00144339)
Timeframe: From Day 1 to 4 years
| Intervention | Participants (Number) | |
|---|---|---|
| Number of patients | Percentage of patients | |
| Placebo | 811 | 27 |
| Tiotropium Bromide Inhalation Capsules 18 mcg | 759 | 25.4 |
(NCT00144339)
Timeframe: Day 1 to 4 years
| Intervention | Participants (Number) | |
|---|---|---|
| Number of patients | Percentage of patients | |
| Placebo | 2049 | 68.2 |
| Tiotropium Bromide Inhalation Capsules 18 mcg | 2001 | 67 |
(NCT00144339)
Timeframe: Month 12
| Intervention | L (Mean) |
|---|---|
| Placebo | 2.640 |
| Tiotropium Bromide Inhalation Capsules 18 mcg | 2.838 |
(NCT00144339)
Timeframe: Month 18
| Intervention | L (Mean) |
|---|---|
| Placebo | 2.622 |
| Tiotropium Bromide Inhalation Capsules 18 mcg | 2.816 |
(NCT00144339)
Timeframe: Month 24
| Intervention | L (Mean) |
|---|---|
| Placebo | 2.597 |
| Tiotropium Bromide Inhalation Capsules 18 mcg | 2.785 |
(NCT00144339)
Timeframe: Month 30
| Intervention | L (Mean) |
|---|---|
| Placebo | 2.572 |
| Tiotropium Bromide Inhalation Capsules 18 mcg | 2.757 |
(NCT00144339)
Timeframe: Month 24
| Intervention | L (Mean) |
|---|---|
| Placebo | 2.775 |
| Tiotropium Bromide Inhalation Capsules 18 mcg | 2.942 |
(NCT00144339)
Timeframe: Month 36
| Intervention | L (Mean) |
|---|---|
| Placebo | 2.553 |
| Tiotropium Bromide Inhalation Capsules 18 mcg | 2.753 |
(NCT00144339)
Timeframe: Month 42
| Intervention | L (Mean) |
|---|---|
| Placebo | 2.540 |
| Tiotropium Bromide Inhalation Capsules 18 mcg | 2.724 |
(NCT00144339)
Timeframe: Month 48
| Intervention | L (Mean) |
|---|---|
| Placebo | 2.532 |
| Tiotropium Bromide Inhalation Capsules 18 mcg | 2.702 |
(NCT00144339)
Timeframe: Month 6
| Intervention | L (Mean) |
|---|---|
| Placebo | 2.658 |
| Tiotropium Bromide Inhalation Capsules 18 mcg | 2.862 |
(NCT00144339)
Timeframe: Month 1
| Intervention | L (Mean) |
|---|---|
| Placebo | 2.847 |
| Tiotropium Bromide Inhalation Capsules 18 mcg | 3.017 |
(NCT00144339)
Timeframe: Month 12
| Intervention | L (Mean) |
|---|---|
| Placebo | 2.820 |
| Tiotropium Bromide Inhalation Capsules 18 mcg | 2.996 |
(NCT00144339)
Timeframe: Month 30
| Intervention | L (Mean) |
|---|---|
| Placebo | 2.738 |
| Tiotropium Bromide Inhalation Capsules 18 mcg | 2.908 |
(NCT00144339)
Timeframe: Month 18
| Intervention | L (Mean) |
|---|---|
| Placebo | 1.101 |
| Tiotropium Bromide Inhalation Capsules 18 mcg | 1.192 |
(NCT00144339)
Timeframe: Month 24
| Intervention | L (Mean) |
|---|---|
| Placebo | 1.079 |
| Tiotropium Bromide Inhalation Capsules 18 mcg | 1.173 |
(NCT00144339)
Timeframe: Month 30
| Intervention | L (Mean) |
|---|---|
| Placebo | 1.061 |
| Tiotropium Bromide Inhalation Capsules 18 mcg | 1.156 |
(NCT00144339)
Timeframe: Month 36
| Intervention | L (Mean) |
|---|---|
| Placebo | 1.045 |
| Tiotropium Bromide Inhalation Capsules 18 mcg | 1.144 |
(NCT00144339)
Timeframe: Month 42
| Intervention | L (Mean) |
|---|---|
| Placebo | 1.034 |
| Tiotropium Bromide Inhalation Capsules 18 mcg | 1.129 |
(NCT00144339)
Timeframe: Month 48
| Intervention | L (Mean) |
|---|---|
| Placebo | 1.024 |
| Tiotropium Bromide Inhalation Capsules 18 mcg | 1.112 |
Estimated forced expiratory volume in one second (FEV1) before bronchodilator at month 6 (NCT00144339)
Timeframe: Month 6
| Intervention | L (Mean) |
|---|---|
| Placebo | 1.126 |
| Tiotropium Bromide Inhalation Capsules 18 mcg | 1.225 |
(NCT00144339)
Timeframe: Month 1
| Intervention | L (Mean) |
|---|---|
| Placebo | 2.667 |
| Tiotropium Bromide Inhalation Capsules 18 mcg | 2.856 |
FEV1 AUC0-3 represents the Area under Curve over the time interval from 0 to 3 hours after 2, 8, 16, 24, 32, 40 and 48 weeks. The means are adjusted for centre, smoking status at entry and baseline value. (NCT00168831)
Timeframe: 10 minutes prior to test-drug inhalation and at 5, 30 and 60 minutes and 2 and 3 hours after inhalation of study medication
| Intervention | Litres (Mean) | ||||||
|---|---|---|---|---|---|---|---|
| Week 2 | Week 8 | Week 16 | Week 24 | Week 32 | Week 40 | Week 48 | |
| Placebo | 0.044 | 0.037 | 0.026 | 0.024 | 0.018 | -0.000 | -0.002 |
| Tiotropium Respimat 10mcg | 0.257 | 0.258 | 0.242 | 0.245 | 0.241 | 0.206 | 0.210 |
| Tiotropium Respimat 5mcg | 0.246 | 0.234 | 0.235 | 0.222 | 0.198 | 0.197 | 0.181 |
FVC AUC0-3 represents the Area under Curve over the time interval from 0 to 3 hours after 2, 8, 16, 24, 32, 40 and 48 weeks. The means are adjusted for centre, smoking status at entry and baseline value. (NCT00168831)
Timeframe: 10 minutes prior to test-drug inhalation and at 5, 30 and 60 minutes and 2 and 3 hours after inhalation of study medication
| Intervention | Litres (Mean) | ||||||
|---|---|---|---|---|---|---|---|
| Week 2 | Week 8 | Week 16 | Week 24 | Week 32 | Week 40 | Week 48 | |
| Placebo | 0.140 | 0.117 | 0.108 | 0.092 | 0.075 | 0.029 | 0.018 |
| Tiotropium Respimat 10mcg | 0.522 | 0.521 | 0.488 | 0.498 | 0.477 | 0.406 | 0.411 |
| Tiotropium Respimat 5mcg | 0.513 | 0.463 | 0.466 | 0.468 | 0.438 | 0.417 | 0.387 |
Change From Baseline in Trough Forced Expiratory Volume in 1 second (FEV1) after 2, 8, 16, 24, 32 and 40 weeks. The means are adjusted for centre, smoking status at entry and baseline value. (NCT00168831)
Timeframe: 10 minutes prior to test-drug inhalation and at 5, 30 and 60 minutes and 2 and 3 hours after inhalation of study medication
| Intervention | Litres (Mean) | |||||
|---|---|---|---|---|---|---|
| Week 2 | Week 8 | Week 16 | Week 24 | Week 32 | Week 40 | |
| Placebo | -0.003 | -0.012 | -0.008 | -0.010 | -0.012 | -0.027 |
| Tiotropium Respimat 10mcg | 0.114 | 0.133 | 0.132 | 0.132 | 0.145 | 0.106 |
| Tiotropium Respimat 5mcg | 0.111 | 0.099 | 0.118 | 0.104 | 0.095 | 0.091 |
Change From Baseline in Trough Forced vital capacity (FVC) after 2, 8, 16, 24, 32, 40 and 48 weeks. The means are adjusted for centre, smoking status at entry and baseline value. (NCT00168831)
Timeframe: 10 minutes prior to test-drug inhalation and at 5, 30 and 60 minutes and 2 and 3 hours after inhalation of study medication
| Intervention | Litres (Mean) | ||||||
|---|---|---|---|---|---|---|---|
| Week 2 | Week 8 | Week 16 | Week 24 | Week 32 | Week 40 | Week 48 | |
| Placebo | 0.009 | -0.007 | -0.002 | 0.008 | -0.008 | -0.028 | -0.043 |
| Tiotropium Respimat 10mcg | 0.264 | 0.266 | 0.266 | 0.274 | 0.286 | 0.207 | 0.209 |
| Tiotropium Respimat 5mcg | 0.257 | 0.207 | 0.259 | 0.236 | 0.203 | 0.211 | 0.197 |
"COPD symptoms Scores - wheezing, shortness of breath, coughing and tightness of chest over the treatment period.~Scale: 0 = None, 1 = Mild, 2 = Moderate, 3 = Severe The means are adjusted for centre, smoking status at entry and baseline value." (NCT00168831)
Timeframe: Week 48
| Intervention | Points on a scale (Mean) | |||
|---|---|---|---|---|
| Wheezing | Shortness of Breath | Coughing | Tightness of Chest | |
| Placebo | 0.85 | 1.61 | 1.06 | 0.64 |
| Tiotropium Respimat 10mcg | 0.72 | 1.41 | 1.05 | 0.55 |
| Tiotropium Respimat 5mcg | 0.66 | 1.42 | 0.96 | 0.51 |
"Mahler Transitional Dyspnoea Index (TDI) scores measured as change in functional impairment, change in magnitude of tasks and change in magnitude of efforts over the treatment period. The means are adjusted for centre, smoking status at entry and baseline value.~Worst score = -3, best score = +3" (NCT00168831)
Timeframe: Week 48
| Intervention | Points on a scale (Mean) | ||
|---|---|---|---|
| Functional Impairment | Magnitude of Task | Magnitude of Effort | |
| Placebo | 0.318 | 0.275 | 0.264 |
| Tiotropium Respimat 10mcg | 0.577 | 0.621 | 0.594 |
| Tiotropium Respimat 5mcg | 0.630 | 0.654 | 0.604 |
"Saint George's Respiratory Questionnaire (SGRQ) Scores impacts, activities and symptoms. Worst score = 100, best score = 0.~The means are adjusted for centre, smoking status at entry and baseline value." (NCT00168831)
Timeframe: Week 48
| Intervention | Points on a scale (Mean) | ||
|---|---|---|---|
| Symptoms | Activities | Impacts | |
| Placebo | 48.244 | 60.921 | 32.239 |
| Tiotropium Respimat 10mcg | 42.108 | 57.045 | 29.532 |
| Tiotropium Respimat 5mcg | 40.680 | 58.529 | 28.858 |
Weekly mean evening peak expiratory flow rates (PEFRs). The means are adjusted for centre, smoking status at entry, and baseline value. (NCT00168831)
Timeframe: Weeks 2, 8, 16, 24, 32, 40, 48
| Intervention | Litres/minute (Mean) | ||||||
|---|---|---|---|---|---|---|---|
| Week 2 | Week 8 | Week 16 | Week 24 | Week 32 | Week 40 | Week 48 | |
| Placebo | 237.5 | 240.6 | 240.8 | 241.9 | 241.0 | 240.5 | 241.9 |
| Tiotropium Respimat 10mcg | 265.0 | 273.5 | 276.3 | 280.3 | 279.7 | 280.5 | 281.0 |
| Tiotropium Respimat 5mcg | 262.7 | 267.9 | 272.7 | 275.5 | 276.6 | 274.0 | 274.0 |
Weekly mean morning pre-dose peak expiratory flow rates (PEFRs). The means are adjusted for centre, smoking status at entry, and baseline value. (NCT00168831)
Timeframe: Weeks 2, 8, 16, 24, 32, 40, 48
| Intervention | Litres/minute (Mean) | ||||||
|---|---|---|---|---|---|---|---|
| Week 2 | Week 8 | Week 16 | Week 24 | Week 32 | Week 40 | Week 48 | |
| Placebo | 226.9 | 229.4 | 231.6 | 230.9 | 232.6 | 231.1 | 232.4 |
| Tiotropium Respimat 10mcg | 245.4 | 253.9 | 258.4 | 263.8 | 264.6 | 264.7 | 264.1 |
| Tiotropium Respimat 5mcg | 245.7 | 252.4 | 257.5 | 260.5 | 261.5 | 260.7 | 260.3 |
Weekly mean number of puffs of rescue medication used per day as required (PRN salbutamol). The means are adjusted for centre, smoking status at entry, and baseline value. (NCT00168831)
Timeframe: Weeks 2, 8, 16, 24, 32, 40, 48
| Intervention | Puffs (Mean) | ||||||
|---|---|---|---|---|---|---|---|
| Week 2 | Week 8 | Week 16 | Week 24 | Week 32 | Week 40 | Week 48 | |
| Placebo | 2.8 | 3.0 | 3.0 | 3.0 | 3.1 | 3.2 | 3.2 |
| Tiotropium Respimat 10mcg | 2.0 | 2.0 | 2.1 | 2.3 | 2.3 | 2.4 | 2.5 |
| Tiotropium Respimat 5mcg | 2.0 | 2.3 | 2.5 | 2.5 | 2.7 | 2.7 | 2.8 |
"Number of Chronic Obstructive Pulmonary Disease (COPD) exacerbations per patient year~For this endpoint data of the twin studies NCT00168844 and NCT00168831 was combined." (NCT00168831)
Timeframe: 48 weeks
| Intervention | Number of exacerbations per patient year (Mean) |
|---|---|
| Tiotropium Respimat 5mcg | 0.93 |
| Tiotropium Respimat 10mcg | 1.02 |
| Placebo | 1.91 |
Week 48 - baseline (NCT00168831)
Timeframe: Baseline to Week 48 or at premature discontinuation if before Week 48
| Intervention | mmol/L (Mean) |
|---|---|
| Tiotropium Respimat 5mcg | 0.01 |
| Tiotropium Respimat 10mcg | 0.00 |
| Placebo | 0.02 |
Week 48 - baseline (NCT00168831)
Timeframe: Baseline to Week 48 or at premature discontinuation if before Week 48
| Intervention | 10^9/L (Mean) |
|---|---|
| Tiotropium Respimat 5mcg | 5 |
| Tiotropium Respimat 10mcg | 3 |
| Placebo | 0 |
(NCT00168831)
Timeframe: Baseline to Week 40 pre-dose
| Intervention | milliseconds (msec) (Mean) |
|---|---|
| Tiotropium Respimat 5mcg | -0.8 |
| Tiotropium Respimat 10mcg | -2.5 |
| Placebo | -0.5 |
Week 48 - baseline (NCT00168831)
Timeframe: Baseline to Week 48 or at premature discontinuation if before Week 48
| Intervention | grams per litre (g/L) (Mean) |
|---|---|
| Tiotropium Respimat 5mcg | -1 |
| Tiotropium Respimat 10mcg | -1 |
| Placebo | -1 |
Week 40 pre-dose - baseline (NCT00168831)
Timeframe: Baseline to Week 40 pre-dose
| Intervention | msec (Mean) |
|---|---|
| Tiotropium Respimat 5mcg | 0.9 |
| Tiotropium Respimat 10mcg | 1.7 |
| Placebo | -1.1 |
Week 40 pre-dose - baseline (NCT00168831)
Timeframe: Baseline to Week 40 pre-dose
| Intervention | msec (Mean) |
|---|---|
| Tiotropium Respimat 5mcg | -4.6 |
| Tiotropium Respimat 10mcg | -3.5 |
| Placebo | -3.2 |
Week 40 pre-dose - baseline (NCT00168831)
Timeframe: Baseline to Week 40 pre-dose
| Intervention | msec (Mean) |
|---|---|
| Tiotropium Respimat 5mcg | -0.5 |
| Tiotropium Respimat 10mcg | 5.4 |
| Placebo | 2.5 |
Week 40 pre-dose - baseline (NCT00168831)
Timeframe: Baseline to Week 40 pre-dose
| Intervention | msec (Mean) |
|---|---|
| Tiotropium Respimat 5mcg | -2.0 |
| Tiotropium Respimat 10mcg | 2.2 |
| Placebo | 0.5 |
Week 48 - baseline (NCT00168831)
Timeframe: Baseline to Week 48 or at premature discontinuation if before Week 48
| Intervention | 10^12/Litre (L) (Mean) |
|---|---|
| Tiotropium Respimat 5mcg | 0.0 |
| Tiotropium Respimat 10mcg | 0.0 |
| Placebo | 0.0 |
Week 40 - baseline (NCT00168831)
Timeframe: Baseline to Week 40
| Intervention | premature beats per 24 hours (Mean) |
|---|---|
| Tiotropium Respimat 5mcg | -3.4 |
| Tiotropium Respimat 10mcg | 6.8 |
| Placebo | 20.9 |
Week 40 - baseline (NCT00168831)
Timeframe: Baseline to Week 40
| Intervention | events per 24 hours (Mean) |
|---|---|
| Tiotropium Respimat 5mcg | 0.0 |
| Tiotropium Respimat 10mcg | -0.1 |
| Placebo | -0.1 |
Week 40 - baseline (NCT00168831)
Timeframe: Baseline to Week 40
| Intervention | pairs per 24 hours (Mean) |
|---|---|
| Tiotropium Respimat 5mcg | -0.4 |
| Tiotropium Respimat 10mcg | -0.2 |
| Placebo | 2.0 |
Change From Baseline in Trough Forced Expiratory Volume in 1 second (FEV1) after 48 weeks (NCT00168831)
Timeframe: 10 minutes prior to test-drug inhalation and at 5, 30 and 60 minutes and 2 and 3 hours after inhalation of study medication
| Intervention | Litres (Mean) |
|---|---|
| Tiotropium Respimat 5mcg | 0.077 |
| Tiotropium Respimat 10mcg | 0.105 |
| Placebo | -0.036 |
Week 48 - baseline (NCT00168831)
Timeframe: Baseline to Week 48 or at premature discontinuation if before Week 48
| Intervention | mmol/L (Mean) |
|---|---|
| Tiotropium Respimat 5mcg | -0.2 |
| Tiotropium Respimat 10mcg | 0.0 |
| Placebo | 0.1 |
Week 48 - baseline (NCT00168831)
Timeframe: Baseline to Week 48 or at premature discontinuation if before Week 48
| Intervention | umol/L (Mean) |
|---|---|
| Tiotropium Respimat 5mcg | 16.41 |
| Tiotropium Respimat 10mcg | 9.39 |
| Placebo | 6.52 |
Week 48 - baseline (NCT00168831)
Timeframe: Baseline to Week 48 or at premature discontinuation if before Week 48
| Intervention | U/L (Mean) |
|---|---|
| Tiotropium Respimat 5mcg | -1 |
| Tiotropium Respimat 10mcg | -1 |
| Placebo | -1 |
Week 48 - baseline (NCT00168831)
Timeframe: Baseline to Week 48 or at premature discontinuation if before Week 48
| Intervention | g/L (Mean) |
|---|---|
| Tiotropium Respimat 5mcg | 1 |
| Tiotropium Respimat 10mcg | 1 |
| Placebo | 1 |
Week 48 - baseline (NCT00168831)
Timeframe: Baseline to Week 48 or at premature discontinuation if before Week 48
| Intervention | U/L (Mean) |
|---|---|
| Tiotropium Respimat 5mcg | -4 |
| Tiotropium Respimat 10mcg | -5 |
| Placebo | -3 |
Week 48 - baseline (NCT00168831)
Timeframe: Baseline to Week 48 or at premature discontinuation if before Week 48
| Intervention | Units per litre (U/L) (Mean) |
|---|---|
| Tiotropium Respimat 5mcg | -1 |
| Tiotropium Respimat 10mcg | -1 |
| Placebo | -2 |
Week 48 - baseline (NCT00168831)
Timeframe: Baseline to Week 48 or at premature discontinuation if before Week 48
| Intervention | percentage of white blood cell count (Mean) |
|---|---|
| Tiotropium Respimat 5mcg | 0 |
| Tiotropium Respimat 10mcg | 0 |
| Placebo | 0 |
Week 48 - baseline (NCT00168831)
Timeframe: Baseline to Week 48 or at premature discontinuation if before Week 48
| Intervention | 10^9/L (Mean) |
|---|---|
| Tiotropium Respimat 5mcg | 0.0 |
| Tiotropium Respimat 10mcg | 0.0 |
| Placebo | 0.0 |
Week 48 - baseline (NCT00168831)
Timeframe: Baseline to Week 48 or at premature discontinuation if before Week 48
| Intervention | umol/L (Mean) |
|---|---|
| Tiotropium Respimat 5mcg | -0.2 |
| Tiotropium Respimat 10mcg | 0.4 |
| Placebo | -0.1 |
Week 48 - baseline (NCT00168831)
Timeframe: Baseline to Week 48 or at premature discontinuation if before Week 48
| Intervention | milligrams per decilitre (mg/dL) (Mean) |
|---|---|
| Tiotropium Respimat 5mcg | -0.3 |
| Tiotropium Respimat 10mcg | 0.0 |
| Placebo | 0.2 |
Week 48 - baseline (NCT00168831)
Timeframe: Baseline to Week 48 or at premature discontinuation if before Week 48
| Intervention | millimoles per litre (mmol/L) (Mean) |
|---|---|
| Tiotropium Respimat 5mcg | 0.0 |
| Tiotropium Respimat 10mcg | 0.0 |
| Placebo | 0.0 |
Week 48 - baseline (NCT00168831)
Timeframe: Baseline to Week 48 or at premature discontinuation if before Week 48
| Intervention | micromoles per litre (umol/L) (Mean) |
|---|---|
| Tiotropium Respimat 5mcg | 2.2 |
| Tiotropium Respimat 10mcg | 1.5 |
| Placebo | 2.1 |
Week 48 - baseline (NCT00168831)
Timeframe: Baseline to Week 48 or at premature discontinuation if before Week 48
| Intervention | percentage of white blood cell count (Mean) |
|---|---|
| Tiotropium Respimat 5mcg | 0 |
| Tiotropium Respimat 10mcg | 0 |
| Placebo | 0 |
Week 48 - baseline (NCT00168831)
Timeframe: Baseline to Week 48 or at premature discontinuation if before Week 48
| Intervention | 10^9/L (Mean) |
|---|---|
| Tiotropium Respimat 5mcg | 0.0 |
| Tiotropium Respimat 10mcg | 0.0 |
| Placebo | 0.0 |
Week 48 - baseline (NCT00168831)
Timeframe: Baseline to Week 48 or at premature discontinuation if before Week 48
| Intervention | mmol/L (Mean) |
|---|---|
| Tiotropium Respimat 5mcg | 0.02 |
| Tiotropium Respimat 10mcg | 0.26 |
| Placebo | 0.10 |
(NCT00168831)
Timeframe: Baseline to Week 48 or at premature discontinuation if before Week 48
| Intervention | Percentage of erythrocytes (Mean) |
|---|---|
| Tiotropium Respimat 5mcg | 0 |
| Tiotropium Respimat 10mcg | 0 |
| Placebo | 0 |
Week 48 - baseline (NCT00168831)
Timeframe: Baseline to Week 48 or at premature discontinuation if before Week 48
| Intervention | grams per litre (g/L) (Mean) |
|---|---|
| Tiotropium Respimat 5mcg | 0 |
| Tiotropium Respimat 10mcg | -1 |
| Placebo | -1 |
Week 40 - baseline (NCT00168831)
Timeframe: Baseline to Week 40
| Intervention | bpm (Mean) |
|---|---|
| Tiotropium Respimat 5mcg | 0.3 |
| Tiotropium Respimat 10mcg | 1.2 |
| Placebo | 0.3 |
Week 40 pre-dose - baseline (NCT00168831)
Timeframe: Baseline to Week 40 pre-dose
| Intervention | beats per minute (bpm) (Mean) |
|---|---|
| Tiotropium Respimat 5mcg | 2.1 |
| Tiotropium Respimat 10mcg | 3.6 |
| Placebo | 1.8 |
Week 48 - baseline (NCT00168831)
Timeframe: Baseline to Week 48 or at premature discontinuation if before Week 48
| Intervention | U/L (Mean) |
|---|---|
| Tiotropium Respimat 5mcg | 1 |
| Tiotropium Respimat 10mcg | 3 |
| Placebo | 5 |
Week 48 - baseline (NCT00168831)
Timeframe: Baseline to Week 48 or at premature discontinuation if before Week 48
| Intervention | percentage of white blood cell count (Mean) |
|---|---|
| Tiotropium Respimat 5mcg | -1 |
| Tiotropium Respimat 10mcg | -1 |
| Placebo | 0 |
Week 48 - baseline (NCT00168831)
Timeframe: Baseline to Week 48 or at premature discontinuation if before Week 48
| Intervention | 10^9/L (Mean) |
|---|---|
| Tiotropium Respimat 5mcg | -0.1 |
| Tiotropium Respimat 10mcg | 0.0 |
| Placebo | 0.0 |
Week 40 - baseline (NCT00168831)
Timeframe: Baseline to Week 40
| Intervention | events per 24 hours (Mean) |
|---|---|
| Tiotropium Respimat 5mcg | 0.0 |
| Tiotropium Respimat 10mcg | 0.0 |
| Placebo | 0.0 |
Week 40 - baseline (NCT00168831)
Timeframe: Baseline to Week 40
| Intervention | premature beats per 24 hours (Mean) |
|---|---|
| Tiotropium Respimat 5mcg | -14.3 |
| Tiotropium Respimat 10mcg | 4.6 |
| Placebo | -24.1 |
Week 40 - baseline (NCT00168831)
Timeframe: Baseline to Week 40
| Intervention | pairs per 24 hours (Mean) |
|---|---|
| Tiotropium Respimat 5mcg | -0.2 |
| Tiotropium Respimat 10mcg | -0.1 |
| Placebo | -0.9 |
Week 48 - baseline (NCT00168831)
Timeframe: Baseline to Week 48 or at premature discontinuation if before Week 48
| Intervention | 10^9/Litre (L) (Mean) |
|---|---|
| Tiotropium Respimat 5mcg | 0.2 |
| Tiotropium Respimat 10mcg | 0.3 |
| Placebo | 0.2 |
Physician's Global evaluation (PGE) scores over the treatment period. Scale: 1-2 = Poor, 3-4 = Fair, 5-6 = Good, 7-8 = Excellent The means are adjusted for centre, smoking status at entry and baseline value. (NCT00168831)
Timeframe: Week 48
| Intervention | Points on a scale (Mean) |
|---|---|
| Tiotropium Respimat 5mcg | 4.90 |
| Tiotropium Respimat 10mcg | 4.84 |
| Placebo | 4.44 |
Patient's Global rating (PGR) scores over the treatment period. Scale: 1=much better to 7=much worse The means are adjusted for centre, smoking status at entry and baseline value. (NCT00168831)
Timeframe: Week 48
| Intervention | Points on a scale (Mean) |
|---|---|
| Tiotropium Respimat 5mcg | 2.88 |
| Tiotropium Respimat 10mcg | 2.94 |
| Placebo | 3.42 |
Rating scale of 3 domains - symptoms, activities and impact (weighted). Worst score = 100, best score = 0 (NCT00168831)
Timeframe: Week 48
| Intervention | Points on a scale (Mean) |
|---|---|
| Tiotropium Respimat 5mcg | 39.771 |
| Tiotropium Respimat 10mcg | 40.038 |
| Placebo | 43.484 |
"Rating scale of 3 components - change in functional impairment, change in magnitude of tasks, change in magnitude of efforts. Worst score = -9, best score = +9~For this endpoint data of twin studies NCT00168844 and NCT00168831 was combined." (NCT00168831)
Timeframe: Week 48
| Intervention | Points on a scale (Mean) |
|---|---|
| Tiotropium Respimat 5mcg | 1.890 |
| Tiotropium Respimat 10mcg | 1.913 |
| Placebo | 0.837 |
Week 48 - baseline (NCT00168831)
Timeframe: Baseline to Week 48 or at premature discontinuation if before Week 48
| Intervention | percentage of white blood cell count (Mean) |
|---|---|
| Tiotropium Respimat 5mcg | 0 |
| Tiotropium Respimat 10mcg | 0 |
| Placebo | 0 |
Week 48 - baseline (NCT00168831)
Timeframe: Baseline to Week 48 or at premature discontinuation if before Week 48
| Intervention | 10^9/L (Mean) |
|---|---|
| Tiotropium Respimat 5mcg | 0.0 |
| Tiotropium Respimat 10mcg | 0.0 |
| Placebo | 0.0 |
Week 48 - baseline (NCT00168831)
Timeframe: Baseline to Week 48 or at premature discontinuation if before Week 48
| Intervention | percentage of white blood cell count (Mean) |
|---|---|
| Tiotropium Respimat 5mcg | 1 |
| Tiotropium Respimat 10mcg | 1 |
| Placebo | 0 |
Week 48 - baseline (NCT00168831)
Timeframe: Baseline to Week 48 or at premature discontinuation if before Week 48
| Intervention | 10^9/L (Mean) |
|---|---|
| Tiotropium Respimat 5mcg | 0.2 |
| Tiotropium Respimat 10mcg | 0.3 |
| Placebo | 0.2 |
Week 48 - baseline (NCT00168844)
Timeframe: Baseline to Week 48 or at premature discontinuation if before Week 48
| Intervention | U/L (Mean) |
|---|---|
| Tiotropium Respimat 5mcg | 4 |
| Tiotropium Respimat 10mcg | 2 |
| Placebo | 0 |
Week 48 - baseline (NCT00168844)
Timeframe: Baseline to Week 48 or at premature discontinuation if before Week 48
| Intervention | percentage of white blood cell count (Mean) |
|---|---|
| Tiotropium Respimat 5mcg | -1 |
| Tiotropium Respimat 10mcg | -1 |
| Placebo | 0 |
Week 48 - baseline (NCT00168844)
Timeframe: Baseline to Week 48 or at premature discontinuation if before Week 48
| Intervention | 10^9/L (Mean) |
|---|---|
| Tiotropium Respimat 5mcg | 0.0 |
| Tiotropium Respimat 10mcg | -0.1 |
| Placebo | 0.1 |
Week 48 - baseline (NCT00168844)
Timeframe: Baseline to Week 48 or at premature discontinuation if before Week 48
| Intervention | percentage of white blood cell count (Mean) |
|---|---|
| Tiotropium Respimat 5mcg | 0 |
| Tiotropium Respimat 10mcg | 0 |
| Placebo | 0 |
Week 48 - baseline (NCT00168844)
Timeframe: Baseline to Week 48 or at premature discontinuation if before Week 48
| Intervention | 10^9/L (Mean) |
|---|---|
| Tiotropium Respimat 5mcg | 0.0 |
| Tiotropium Respimat 10mcg | 0.0 |
| Placebo | 0.0 |
Week 48 - baseline (NCT00168844)
Timeframe: Baseline to Week 48 or at premature discontinuation if before Week 48
| Intervention | percentage of white blood cell count (Mean) |
|---|---|
| Tiotropium Respimat 5mcg | 1 |
| Tiotropium Respimat 10mcg | 1 |
| Placebo | 1 |
Week 48 - baseline (NCT00168844)
Timeframe: Baseline to Week 48 or at premature discontinuation if before Week 48
| Intervention | 10^9/L (Mean) |
|---|---|
| Tiotropium Respimat 5mcg | 0.2 |
| Tiotropium Respimat 10mcg | 0.1 |
| Placebo | 0.2 |
Week 48 - baseline (NCT00168844)
Timeframe: Baseline to Week 48 or at premature discontinuation if before Week 48
| Intervention | mmol/L (Mean) |
|---|---|
| Tiotropium Respimat 5mcg | 0.02 |
| Tiotropium Respimat 10mcg | 0.00 |
| Placebo | 0.01 |
Week 48 - baseline (NCT00168844)
Timeframe: Baseline to Week 48 or at premature discontinuation if before Week 48
| Intervention | 10^9/L (Mean) |
|---|---|
| Tiotropium Respimat 5mcg | 4 |
| Tiotropium Respimat 10mcg | 1 |
| Placebo | 7 |
(NCT00168844)
Timeframe: Baseline to Week 40 pre-dose
| Intervention | milliseconds (msec) (Mean) |
|---|---|
| Tiotropium Respimat 5mcg | -0.8 |
| Tiotropium Respimat 10mcg | -2.5 |
| Placebo | -0.5 |
"Mahler Transitional Dyspnoea Index (TDI) scores measured as change in functional impairment, change in magnitude of tasks and change in magnitude of efforts over the treatment period. The means are adjusted for centre, smoking status at entry and baseline value.~Worst score = -3, best score = +3" (NCT00168844)
Timeframe: Week 48
| Intervention | Points on a scale (Mean) | ||
|---|---|---|---|
| Functional Impairment | Magnitude of Task | Magnitude of Effort | |
| Placebo | 0.255 | 0.291 | 0.240 |
| Tiotropium Respimat 10mcg | 0.679 | 0.673 | 0.706 |
| Tiotropium Respimat 5mcg | 0.606 | 0.650 | 0.633 |
Week 48 - baseline (NCT00168844)
Timeframe: Baseline to Week 48 or at premature discontinuation if before Week 48
| Intervention | grams per litre (g/L) (Mean) |
|---|---|
| Tiotropium Respimat 5mcg | -1 |
| Tiotropium Respimat 10mcg | -1 |
| Placebo | -1 |
Week 40 pre-dose - baseline (NCT00168844)
Timeframe: Baseline to Week 40 pre-dose
| Intervention | msec (Mean) |
|---|---|
| Tiotropium Respimat 5mcg | 0.9 |
| Tiotropium Respimat 10mcg | 1.7 |
| Placebo | -1.1 |
Week 40 pre-dose - baseline (NCT00168844)
Timeframe: Baseline to Week 40 pre-dose
| Intervention | msec (Mean) |
|---|---|
| Tiotropium Respimat 5mcg | -4.6 |
| Tiotropium Respimat 10mcg | -3.5 |
| Placebo | -3.2 |
Week 40 pre-dose - baseline (NCT00168844)
Timeframe: Baseline to Week 40 pre-dose
| Intervention | msec (Mean) |
|---|---|
| Tiotropium Respimat 5mcg | -0.5 |
| Tiotropium Respimat 10mcg | 5.4 |
| Placebo | 2.5 |
Week 40 pre-dose - baseline (NCT00168844)
Timeframe: Baseline to Week 40 pre-dose
| Intervention | msec (Mean) |
|---|---|
| Tiotropium Respimat 5mcg | -2.0 |
| Tiotropium Respimat 10mcg | 2.2 |
| Placebo | 0.5 |
Week 48 - baseline (NCT00168844)
Timeframe: Baseline to Week 48 or at premature discontinuation if before Week 48
| Intervention | 10^12/Litre (L) (Mean) |
|---|---|
| Tiotropium Respimat 5mcg | 0.0 |
| Tiotropium Respimat 10mcg | -0.1 |
| Placebo | 0.0 |
Week 40 - baseline (NCT00168844)
Timeframe: Baseline to Week 40
| Intervention | premature beats per 24 hours (Mean) |
|---|---|
| Tiotropium Respimat 5mcg | -3.4 |
| Tiotropium Respimat 10mcg | 6.8 |
| Placebo | 20.9 |
Week 40 - baseline (NCT00168844)
Timeframe: Baseline to Week 40
| Intervention | pairs per 24 hours (Mean) |
|---|---|
| Tiotropium Respimat 5mcg | -0.4 |
| Tiotropium Respimat 10mcg | -0.2 |
| Placebo | 2.0 |
Trough Forced Expiratory Volume in 1 second (FEV1) (NCT00168844)
Timeframe: 10 minutes prior to test-drug inhalation and at 5, 30 and 60 minutes and 2 and 3 hours after inhalation of study medication
| Intervention | Litres (Mean) |
|---|---|
| Tiotropium Respimat 5mcg | 0.097 |
| Tiotropium Respimat 10mcg | 0.116 |
| Placebo | -0.046 |
Week 48 - baseline (NCT00168844)
Timeframe: Baseline to Week 48 or at premature discontinuation if before Week 48
| Intervention | mmol/L (Mean) |
|---|---|
| Tiotropium Respimat 5mcg | 0.1 |
| Tiotropium Respimat 10mcg | 0.0 |
| Placebo | 0.0 |
Week 48 - baseline (NCT00168844)
Timeframe: Baseline to Week 48 or at premature discontinuation if before Week 48
| Intervention | umol/L (Mean) |
|---|---|
| Tiotropium Respimat 5mcg | 13.55 |
| Tiotropium Respimat 10mcg | 1.03 |
| Placebo | 7.83 |
Week 40 - baseline (NCT00168844)
Timeframe: Baseline to Week 40
| Intervention | premature beats per 24 hours (Mean) |
|---|---|
| Tiotropium Respimat 5mcg | -14.3 |
| Tiotropium Respimat 10mcg | 4.6 |
| Placebo | -24.1 |
Week 40 - baseline (NCT00168844)
Timeframe: Baseline to Week 40
| Intervention | pairs per 24 hours (Mean) |
|---|---|
| Tiotropium Respimat 5mcg | -0.2 |
| Tiotropium Respimat 10mcg | -0.1 |
| Placebo | -0.9 |
Week 40 - baseline (NCT00168844)
Timeframe: Baseline to Week 40
| Intervention | events per 24 hours (Mean) |
|---|---|
| Tiotropium Respimat 5mcg | 0.0 |
| Tiotropium Respimat 10mcg | 0.0 |
| Placebo | 0.0 |
Week 48 - baseline (NCT00168844)
Timeframe: Baseline to Week 48 or at premature discontinuation if before Week 48
| Intervention | 10^9/Litre (L) (Mean) |
|---|---|
| Tiotropium Respimat 5mcg | 0.1 |
| Tiotropium Respimat 10mcg | 0.0 |
| Placebo | 0.2 |
"Number of Chronic Obstructive Pulmonary Disease (COPD) exacerbations per patient year.~For this endpoint data of the twin studies NCT00168844 and NCT00168831 was combined." (NCT00168844)
Timeframe: 48 weeks
| Intervention | Number of exacerbations per patient year (Mean) |
|---|---|
| Tiotropium Respimat 5mcg | 0.93 |
| Tiotropium Respimat 10mcg | 1.02 |
| Placebo | 1.91 |
Week 40 - baseline (NCT00168844)
Timeframe: Baseline to Week 40
| Intervention | events per 24 hours (Mean) |
|---|---|
| Tiotropium Respimat 5mcg | 0.0 |
| Tiotropium Respimat 10mcg | -0.1 |
| Placebo | -0.1 |
"Physician's Global evaluation (PGE) scores over the treatment period. Scale: 1-2 = Poor, 3-4 = Fair, 5-6 = Good, 7-8 = Excellent~The means are adjusted for centre, smoking status at entry and baseline value." (NCT00168844)
Timeframe: Week 48
| Intervention | Points on a scale (Mean) |
|---|---|
| Tiotropium Respimat 5mcg | 5.18 |
| Tiotropium Respimat 10mcg | 5.18 |
| Placebo | 4.62 |
"Patient's Global rating (PGR) score over the treatment period. Scale: 1=much better to 7=much worse~The means are adjusted for centre, smoking status at entry and baseline value." (NCT00168844)
Timeframe: Week 48
| Intervention | Points on a scale (Mean) |
|---|---|
| Tiotropium Respimat 5mcg | 3.05 |
| Tiotropium Respimat 10mcg | 2.86 |
| Placebo | 3.52 |
Rating scale of 3 domains - symptoms, activities and impact (weighted). Worst score = 100, best score = 0 (NCT00168844)
Timeframe: Week 48
| Intervention | Points on a scale (Mean) |
|---|---|
| Tiotropium Respimat 5mcg | 39.648 |
| Tiotropium Respimat 10mcg | 38.675 |
| Placebo | 42.917 |
"Rating scale of 3 components - change in functional impairment, change in magnitude of tasks, change in magnitude of efforts. Worst score = -9, best score = +9~For this endpoint data of twin studies NCT00168844 and NCT00168831 was combined." (NCT00168844)
Timeframe: Week 48
| Intervention | Points on a scale (Mean) |
|---|---|
| Tiotropium Respimat 5mcg | 1.890 |
| Tiotropium Respimat 10mcg | 1.913 |
| Placebo | 0.837 |
FEV1 AUC0-3 represents the Area under Curve over the time interval from 0 to 3 hours after 2, 8, 16, 24, 32, 40 and 48 weeks. The means are adjusted for centre, smoking status at entry and baseline value. (NCT00168844)
Timeframe: 10 minutes prior to test-drug inhalation and at 5, 30 and 60 minutes and 2 and 3 hours after inhalation of study medication
| Intervention | Litres (Mean) | ||||||
|---|---|---|---|---|---|---|---|
| Week 2 | Week 8 | Week 16 | Week 24 | Week 32 | Week 40 | Week 48 | |
| Placebo | 0.045 | 0.041 | 0.024 | 0.026 | 0.019 | 0.003 | -0.008 |
| Tiotropium Respimat 10mcg | 0.258 | 0.274 | 0.248 | 0.241 | 0.240 | 0.233 | 0.226 |
| Tiotropium Respimat 5mcg | 0.256 | 0.246 | 0.241 | 0.242 | 0.239 | 0.225 | 0.212 |
FVC AUC0-3 represents the Area under Curve over the time interval from 0 to 3 hours after 2, 8, 16, 24, 32, 40 and 48 weeks. The means are adjusted for centre, smoking status at entry and baseline value. (NCT00168844)
Timeframe: 10 minutes prior to test-drug inhalation and at 5, 30 and 60 minutes and 2 and 3 hours after inhalation of study medication
| Intervention | Litres (Mean) | ||||||
|---|---|---|---|---|---|---|---|
| Week 2 | Week 8 | Week 16 | Week 24 | Week 32 | Week 40 | Week 48 | |
| Placebo | 0.130 | 0.126 | 0.076 | 0.067 | 0.049 | 0.034 | 0.003 |
| Tiotropium Respimat 10mcg | 0.492 | 0.538 | 0.487 | 0.465 | 0.465 | 0.453 | 0.422 |
| Tiotropium Respimat 5mcg | 0.421 | 0.397 | 0.376 | 0.364 | 0.357 | 0.328 | 0.312 |
Change From Baseline in Trough Forced Expiratory Volume in 1 second (FEV1) after 2, 8, 16, 24, 32 and 40 weeks. The means are adjusted for centre, smoking status at entry and baseline value. (NCT00168844)
Timeframe: 10 minutes prior to test-drug inhalation and at 5, 30 and 60 minutes and 2 and 3 hours after inhalation of study medication
| Intervention | Litres (Mean) | |||||
|---|---|---|---|---|---|---|
| Week 2 | Week 8 | Week 16 | Week 24 | Week 32 | Week 40 | |
| Placebo | 0.013 | -0.004 | -0.022 | -0.009 | -0.025 | -0.031 |
| Tiotropium Respimat 10mcg | 0.133 | 0.150 | 0.125 | 0.121 | 0.132 | 0.133 |
| Tiotropium Respimat 5mcg | 0.118 | 0.124 | 0.121 | 0.125 | 0.124 | 0.107 |
Change From Baseline in Trough Forced vital capacity (FVC) after 2, 8, 16, 24, 32, 40 and 48 weeks. The means are adjusted for centre, smoking status at entry and baseline value. (NCT00168844)
Timeframe: 10 minutes prior to test-drug inhalation and at 5, 30 and 60 minutes and 2 and 3 hours after inhalation of study medication
| Intervention | Litres (Mean) | ||||||
|---|---|---|---|---|---|---|---|
| Week 2 | Week 8 | Week 16 | Week 24 | Week 32 | Week 40 | Week 48 | |
| Placebo | 0.025 | 0.009 | -0.019 | -0.012 | -0.038 | -0.043 | -0.070 |
| Tiotropium Respimat 10mcg | 0.278 | 0.300 | 0.267 | 0.274 | 0.276 | 0.294 | 0.253 |
| Tiotropium Respimat 5mcg | 0.163 | 0.168 | 0.145 | 0.155 | 0.156 | 0.130 | 0.108 |
"COPD symptoms Scores - wheezing, shortness of breath, coughing and tightness of chest over the treatment period. Scale: 0 = None, 1 = Mild, 2 = Moderate, 3 = Severe~The means are adjusted for centre, smoking status at entry and baseline value." (NCT00168844)
Timeframe: Week 48
| Intervention | Points on a scale (Mean) | |||
|---|---|---|---|---|
| Wheezing | Shortness of Breath | Coughing | Tightness of Chest | |
| Placebo | 0.91 | 1.51 | 1.21 | 0.78 |
| Tiotropium Respimat 10mcg | 0.65 | 1.31 | 1.04 | 0.50 |
| Tiotropium Respimat 5mcg | 0.67 | 1.35 | 1.05 | 0.61 |
Weekly mean number of puffs of rescue medication used per day as required (PRN salbutamol). The means are adjusted for centre, smoking status at entry, and baseline value. (NCT00168844)
Timeframe: Weeks 2, 8, 16, 24, 32, 40, 48
| Intervention | Puffs (Mean) | ||||||
|---|---|---|---|---|---|---|---|
| Week 2 | Week 8 | Week 16 | Week 24 | Week 32 | Week 40 | Week 48 | |
| Placebo | 2.7 | 2.7 | 2.8 | 3.0 | 3.0 | 3.0 | 3.1 |
| Tiotropium Respimat 10mcg | 1.9 | 2.0 | 2.0 | 2.2 | 2.2 | 2.2 | 2.2 |
| Tiotropium Respimat 5mcg | 1.9 | 2.0 | 2.1 | 2.1 | 2.2 | 2.2 | 2.3 |
Weekly mean morning pre-dose peak expiratory flow rates (PEFRs). The means are adjusted for centre, smoking status at entry, and baseline value. (NCT00168844)
Timeframe: Weeks 2, 8, 16, 24, 32, 40, 48
| Intervention | Litres/minute (Mean) | ||||||
|---|---|---|---|---|---|---|---|
| Week 2 | Week 8 | Week 16 | Week 24 | Week 32 | Week 40 | Week 48 | |
| Placebo | 235.4 | 241.8 | 241.1 | 244.3 | 244.7 | 247.4 | 245.9 |
| Tiotropium Respimat 10mcg | 261.5 | 265.6 | 269.0 | 270.1 | 275.1 | 276.7 | 279.0 |
| Tiotropium Respimat 5mcg | 255.4 | 259.0 | 262.7 | 265.7 | 267.2 | 267.0 | 268.5 |
Weekly mean evening peak expiratory flow rates (PEFRs). The means are adjusted for centre, smoking status at entry, and baseline value. (NCT00168844)
Timeframe: Weeks 2, 8, 16, 24, 32, 40, 48
| Intervention | Litres/minute (Mean) | ||||||
|---|---|---|---|---|---|---|---|
| Week 2 | Week 8 | Week 16 | Week 24 | Week 32 | Week 40 | Week 48 | |
| Placebo | 249.3 | 253.4 | 252.7 | 254.7 | 255.0 | 257.1 | 257.0 |
| Tiotropium Respimat 10mcg | 279.2 | 282.1 | 284.1 | 287.0 | 290.6 | 292.2 | 292.5 |
| Tiotropium Respimat 5mcg | 270.6 | 274.5 | 278.0 | 280.0 | 281.8 | 283.1 | 282.5 |
"Saint George's Respiratory Questionnaire (SGRQ) Scores impacts, activities and symptoms. Worst score = 100, best score = 0.~The means are adjusted for centre, smoking status at entry and baseline value." (NCT00168844)
Timeframe: Week 48
| Intervention | Points on a scale (Mean) | ||
|---|---|---|---|
| Symptoms | Activities | Impacts | |
| Placebo | 47.835 | 58.629 | 32.466 |
| Tiotropium Respimat 10mcg | 41.798 | 55.180 | 28.054 |
| Tiotropium Respimat 5mcg | 42.323 | 56.317 | 29.413 |
Week 48 - baseline (NCT00168844)
Timeframe: Baseline to Week 48 or at premature discontinuation if before Week 48
| Intervention | U/L (Mean) |
|---|---|
| Tiotropium Respimat 5mcg | -2 |
| Tiotropium Respimat 10mcg | -1 |
| Placebo | -1 |
Week 48 - baseline (NCT00168844)
Timeframe: Baseline to Week 48 or at premature discontinuation if before Week 48
| Intervention | g/L (Mean) |
|---|---|
| Tiotropium Respimat 5mcg | 1 |
| Tiotropium Respimat 10mcg | 1 |
| Placebo | 1 |
Week 48 - baseline (NCT00168844)
Timeframe: Baseline to Week 48 or at premature discontinuation if before Week 48
| Intervention | U/L (Mean) |
|---|---|
| Tiotropium Respimat 5mcg | -3 |
| Tiotropium Respimat 10mcg | -6 |
| Placebo | -5 |
Week 48 - baseline (NCT00168844)
Timeframe: Baseline to Week 48 or at premature discontinuation if before Week 48
| Intervention | Units per litre (U/L) (Mean) |
|---|---|
| Tiotropium Respimat 5mcg | -3 |
| Tiotropium Respimat 10mcg | -1 |
| Placebo | 0 |
Week 48 - baseline (NCT00168844)
Timeframe: Baseline to Week 48 or at premature discontinuation if before Week 48
| Intervention | percentage of white blood cell count (Mean) |
|---|---|
| Tiotropium Respimat 5mcg | 0 |
| Tiotropium Respimat 10mcg | 0 |
| Placebo | 0 |
Week 48 - baseline (NCT00168844)
Timeframe: Baseline to Week 48 or at premature discontinuation if before Week 48
| Intervention | 10^9/L (Mean) |
|---|---|
| Tiotropium Respimat 5mcg | 0.0 |
| Tiotropium Respimat 10mcg | 0.0 |
| Placebo | 0.0 |
Week 48 - baseline (NCT00168844)
Timeframe: Baseline to Week 48 or at premature discontinuation if before Week 48
| Intervention | umol/L (Mean) |
|---|---|
| Tiotropium Respimat 5mcg | 0.0 |
| Tiotropium Respimat 10mcg | -0.1 |
| Placebo | 0.0 |
Week 48 - baseline (NCT00168844)
Timeframe: Baseline to Week 48 or at premature discontinuation if before Week 48
| Intervention | milligrams per decilitre (mg/dL) (Mean) |
|---|---|
| Tiotropium Respimat 5mcg | 0.1 |
| Tiotropium Respimat 10mcg | 0.0 |
| Placebo | -0.1 |
Week 48 - baseline (NCT00168844)
Timeframe: Baseline to Week 48 or at premature discontinuation if before Week 48
| Intervention | millimoles per litre (mmol/L) (Mean) |
|---|---|
| Tiotropium Respimat 5mcg | 0.0 |
| Tiotropium Respimat 10mcg | 0.0 |
| Placebo | 0.0 |
Week 48 - baseline (NCT00168844)
Timeframe: Baseline to Week 48 or at premature discontinuation if before Week 48
| Intervention | micromoles per litre (umol/L) (Mean) |
|---|---|
| Tiotropium Respimat 5mcg | 2.7 |
| Tiotropium Respimat 10mcg | 1.0 |
| Placebo | 1.7 |
Week 48 - baseline (NCT00168844)
Timeframe: Baseline to Week 48 or at premature discontinuation if before Week 48
| Intervention | percentage of white blood cell count (Mean) |
|---|---|
| Tiotropium Respimat 5mcg | 0 |
| Tiotropium Respimat 10mcg | 0 |
| Placebo | 0 |
Week 48 - baseline (NCT00168844)
Timeframe: Baseline to Week 48 or at premature discontinuation if before Week 48
| Intervention | 10^9/L (Mean) |
|---|---|
| Tiotropium Respimat 5mcg | 0.0 |
| Tiotropium Respimat 10mcg | 0.0 |
| Placebo | 0.0 |
Week 48 - baseline (NCT00168844)
Timeframe: Baseline to Week 48 or at premature discontinuation if before Week 48
| Intervention | mmol/L (Mean) |
|---|---|
| Tiotropium Respimat 5mcg | -0.09 |
| Tiotropium Respimat 10mcg | 0.07 |
| Placebo | 0.17 |
Volume of red cells (erythrocytes) in blood, expressed as a fraction (percentage) of the total volume of blood (NCT00168844)
Timeframe: Baseline to Week 48 or at premature discontinuation if before Week 48
| Intervention | Percentage of erythrocytes (Mean) |
|---|---|
| Tiotropium Respimat 5mcg | 0 |
| Tiotropium Respimat 10mcg | -1 |
| Placebo | 0 |
Week 48 - baseline (NCT00168844)
Timeframe: Baseline to Week 48 or at premature discontinuation if before Week 48
| Intervention | grams per litre (g/L) (Mean) |
|---|---|
| Tiotropium Respimat 5mcg | -1 |
| Tiotropium Respimat 10mcg | -2 |
| Placebo | 1 |
Week 40 - baseline (NCT00168844)
Timeframe: Baseline to Week 40
| Intervention | bpm (Mean) |
|---|---|
| Tiotropium Respimat 5mcg | 0.3 |
| Tiotropium Respimat 10mcg | 1.2 |
| Placebo | 0.3 |
Week 40 pre-dose - baseline (NCT00168844)
Timeframe: Baseline to Week 40 pre-dose
| Intervention | beats per minute (bpm) (Mean) |
|---|---|
| Tiotropium Respimat 5mcg | 2.1 |
| Tiotropium Respimat 10mcg | 3.6 |
| Placebo | 1.8 |
Unit on a scale 1-5. 1: Not at all, 2: A little of the time, 3: A moderate amount of the time, 4: Most of the time, 5: All the time. 1 is the best value (NCT00350207)
Timeframe: After 12 weeks of treatment
| Intervention | Unit on a scale (Least Squares Mean) |
|---|---|
| Tiotropium | 1.539 |
| Salmeterol | 1.505 |
| Placebo | 1.572 |
Unit on a scale 1-5. 1: Not at all, 2: A little of the time, 3: A moderate amount of the time, 4: Most of the time, 5: All the time. 1 is the best value (NCT00350207)
Timeframe: After 16 weeks of treatment
| Intervention | Unit on a scale (Least Squares Mean) |
|---|---|
| Tiotropium | 1.528 |
| Salmeterol | 1.515 |
| Placebo | 1.669 |
Unit on a scale 1-5. 1: Not at all, 2: A little of the time, 3: A moderate amount of the time, 4: Most of the time, 5: All the time. 1 is the best value (NCT00350207)
Timeframe: After 4 weeks of treatment
| Intervention | Unit on a scale (Least Squares Mean) |
|---|---|
| Tiotropium | 1.679 |
| Salmeterol | 1.605 |
| Placebo | 1.652 |
Unit on a scale 1-5. 1: Not at all, 2: A little of the time, 3: A moderate amount of the time, 4: Most of the time, 5: All the time. 1 is the best value (NCT00350207)
Timeframe: After 8 weeks of treatment
| Intervention | Unit on a scale (Least Squares Mean) |
|---|---|
| Tiotropium | 1.519 |
| Salmeterol | 1.56 |
| Placebo | 1.575 |
Unit on a scale 1-5. 1: Did not wake up, 2: Woke up once, 3: Woke up 2-5 times, 4: Woke up more than 5 times, 5: Was awake all night. 1 is the best value (NCT00350207)
Timeframe: After 12 weeks of treatment
| Intervention | Unit on a scale (Least Squares Mean) |
|---|---|
| Tiotropium | 1.203 |
| Salmeterol | 1.194 |
| Placebo | 1.224 |
Unit on a scale 1-5. 1: Did not wake up, 2: Woke up once, 3: Woke up 2-5 times, 4: Woke up more than 5 times, 5: Was awake all night. 1 is the best value (NCT00350207)
Timeframe: After 16 weeks of treatment
| Intervention | Unit on a scale (Least Squares Mean) |
|---|---|
| Tiotropium | 1.196 |
| Salmeterol | 1.135 |
| Placebo | 1.185 |
Unit on a scale 1-5. 1: Did not wake up, 2: Woke up once, 3: Woke up 2-5 times, 4: Woke up more than 5 times, 5: Was awake all night. 1 is the best value (NCT00350207)
Timeframe: After 4 weeks of treatment
| Intervention | Unit on a scale (Least Squares Mean) |
|---|---|
| Tiotropium | 1.267 |
| Salmeterol | 1.22 |
| Placebo | 1.232 |
Unit on a scale 1-5. 1: Did not wake up, 2: Woke up once, 3: Woke up 2-5 times, 4: Woke up more than 5 times, 5: Was awake all night. 1 is the best value (NCT00350207)
Timeframe: After 8 weeks of treatment
| Intervention | Unit on a scale (Least Squares Mean) |
|---|---|
| Tiotropium | 1.182 |
| Salmeterol | 1.176 |
| Placebo | 1.21 |
Unit on a scale 1-5. 1: Not limited at all, 2: A little limited, 3: Moderately limited, 4: Severely limited, 5: Totally limited. 1 is the best value (NCT00350207)
Timeframe: After 12 weeks of treatment
| Intervention | Unit on a scale (Least Squares Mean) |
|---|---|
| Tiotropium | 1.458 |
| Salmeterol | 1.436 |
| Placebo | 1.52 |
Unit on a scale 1-5. 1: Not limited at all, 2: A little limited, 3: Moderately limited, 4: Severely limited, 5: Totally limited. 1 is the best value (NCT00350207)
Timeframe: After 16 weeks of treatment
| Intervention | Unit on a scale (Least Squares Mean) |
|---|---|
| Tiotropium | 1.446 |
| Salmeterol | 1.415 |
| Placebo | 1.593 |
Unit on a scale 1-5. 1: Not limited at all, 2: A little limited, 3: Moderately limited, 4: Severely limited, 5: Totally limited. 1 is the best value (NCT00350207)
Timeframe: After 4 weeks of treatment
| Intervention | Unit on a scale (Least Squares Mean) |
|---|---|
| Tiotropium | 1.549 |
| Salmeterol | 1.514 |
| Placebo | 1.583 |
Unit on a scale 1-5. 1: Not limited at all, 2: A little limited, 3: Moderately limited, 4: Severely limited, 5: Totally limited. 1 is the best value (NCT00350207)
Timeframe: After 8 weeks of treatment
| Intervention | Unit on a scale (Least Squares Mean) |
|---|---|
| Tiotropium | 1.475 |
| Salmeterol | 1.478 |
| Placebo | 1.545 |
Unit on a scale 1-5. 1: None, 2: A very little, 3: A moderate amount, 4: Quite a lot, 5: A very great deal. 1 is the best value (NCT00350207)
Timeframe: After 12 weeks of treatment
| Intervention | Unit on a scale (Least Squares Mean) |
|---|---|
| Tiotropium | 1.57 |
| Salmeterol | 1.482 |
| Placebo | 1.62 |
Unit on a scale 1-5. 1: None, 2: A very little, 3: A moderate amount, 4: Quite a lot, 5: A very great deal. 1 is the best value (NCT00350207)
Timeframe: After 16 weeks of treatment
| Intervention | Unit on a scale (Least Squares Mean) |
|---|---|
| Tiotropium | 1.623 |
| Salmeterol | 1.482 |
| Placebo | 1.691 |
Unit on a scale 1-5. 1: None, 2: A very little, 3: A moderate amount, 4: Quite a lot, 5: A very great deal. 1 is the best value (NCT00350207)
Timeframe: After 4 weeks of treatment
| Intervention | Unit on a scale (Least Squares Mean) |
|---|---|
| Tiotropium | 1.699 |
| Salmeterol | 1.627 |
| Placebo | 1.735 |
Unit on a scale 1-5. 1: None, 2: A very little, 3: A moderate amount, 4: Quite a lot, 5: A very great deal. 1 is the best value (NCT00350207)
Timeframe: After 8 weeks of treatment
| Intervention | Unit on a scale (Least Squares Mean) |
|---|---|
| Tiotropium | 1.557 |
| Salmeterol | 1.571 |
| Placebo | 1.643 |
Unit on a scale 1-5. 1: No asthma symptoms, 2: Mild asthma symptoms, 3: Moderate asthma symptoms, 4: Severe asthma symptoms, 5: Very severe asthma symptoms. 1 is the best value (NCT00350207)
Timeframe: After 12 weeks of treatment
| Intervention | Unit on a scale (Least Squares Mean) |
|---|---|
| Tiotropium | 1.572 |
| Salmeterol | 1.495 |
| Placebo | 1.682 |
Unit on a scale 1-5. 1: No asthma symptoms, 2: Mild asthma symptoms, 3: Moderate asthma symptoms, 4: Severe asthma symptoms, 5: Very severe asthma symptoms. 1 is the best value (NCT00350207)
Timeframe: After 16 weeks of treatment
| Intervention | Unit on a scale (Least Squares Mean) |
|---|---|
| Tiotropium | 1.609 |
| Salmeterol | 1.476 |
| Placebo | 1.711 |
Unit on a scale 1-5. 1: No asthma symptoms, 2: Mild asthma symptoms, 3: Moderate asthma symptoms, 4: Severe asthma symptoms, 5: Very severe asthma symptoms. 1 is the best value (NCT00350207)
Timeframe: After 4 weeks of treatment
| Intervention | Unit on a scale (Least Squares Mean) |
|---|---|
| Tiotropium | 1.735 |
| Salmeterol | 1.637 |
| Placebo | 1.744 |
Unit on a scale 1-5. 1: No asthma symptoms, 2: Mild asthma symptoms, 3: Moderate asthma symptoms, 4: Severe asthma symptoms, 5: Very severe asthma symptoms. 1 is the best value (NCT00350207)
Timeframe: After 8 weeks of treatment
| Intervention | Unit on a scale (Least Squares Mean) |
|---|---|
| Tiotropium | 1.603 |
| Salmeterol | 1.569 |
| Placebo | 1.699 |
Unit on a scale 1-5. 1: No asthma symptoms, 2: Mild asthma symptoms, 3: Moderate asthma symptoms, 4: Severe asthma symptoms, 5: Very severe asthma symptoms. 1 is the best value (NCT00350207)
Timeframe: After 4 weeks of treatment
| Intervention | Unit on a scale (Least Squares Mean) |
|---|---|
| Tiotropium | 1.612 |
| Salmeterol | 1.486 |
| Placebo | 1.615 |
Unit on a scale 1-5. 1: No asthma symptoms, 2: Mild asthma symptoms, 3: Moderate asthma symptoms, 4: Severe asthma symptoms, 5: Very severe asthma symptoms. 1 is the best value (NCT00350207)
Timeframe: After 12 weeks of treatment
| Intervention | Unit on a scale (Least Squares Mean) |
|---|---|
| Tiotropium | 1.519 |
| Salmeterol | 1.436 |
| Placebo | 1.542 |
Unit on a scale 1-5. 1: No asthma symptoms, 2: Mild asthma symptoms, 3: Moderate asthma symptoms, 4: Severe asthma symptoms, 5: Very severe asthma symptoms. 1 is the best value (NCT00350207)
Timeframe: After 16 weeks of treatment
| Intervention | Unit on a scale (Least Squares Mean) |
|---|---|
| Tiotropium | 1.536 |
| Salmeterol | 1.461 |
| Placebo | 1.647 |
Unit on a scale 1-5. 1: No asthma symptoms, 2: Mild asthma symptoms, 3: Moderate asthma symptoms, 4: Severe asthma symptoms, 5: Very severe asthma symptoms. 1 is the best value (NCT00350207)
Timeframe: After 8 weeks of treatment
| Intervention | Unit on a scale (Least Squares Mean) |
|---|---|
| Tiotropium | 1.504 |
| Salmeterol | 1.481 |
| Placebo | 1.613 |
Change from baseline in mean weekly morning peak expiratory flow at 16 weeks. Baseline is defined as the last week prior to the randomisation visit (NCT00350207)
Timeframe: baseline and after 16 weeks of treatment
| Intervention | L/min (Least Squares Mean) |
|---|---|
| Tiotropium | -3.93 |
| Salmeterol | -3.15 |
| Placebo | -24.63 |
Diastolic blood pressure collected in conjunction with spirometry at 6 weeks (NCT00350207)
Timeframe: After 6 weeks of treatment
| Intervention | mmHg (Mean) |
|---|---|
| Tiotropium | 78.62 |
| Salmeterol | 77.62 |
| Placebo | 79.34 |
Diastolic blood pressure collected in conjunction with spirometry at 12 weeks (NCT00350207)
Timeframe: After 12 weeks of treatment
| Intervention | mmHg (Mean) |
|---|---|
| Tiotropium | 77.88 |
| Salmeterol | 77.22 |
| Placebo | 78.29 |
Diastolic blood pressure collected in conjunction with spirometry at 16 weeks (NCT00350207)
Timeframe: After 16 weeks of treatment
| Intervention | mmHg (Mean) |
|---|---|
| Tiotropium | 79.23 |
| Salmeterol | 77.61 |
| Placebo | 78.38 |
PEF (Peak expiratory flow) variability is defined as the difference between the highest morning PEF value and the highest evening PEF value of one day divided by the arithmetic mean of these two PEF values and multiplied by 100% (NCT00350207)
Timeframe: After 12 weeks of treatment
| Intervention | ratio expressed in percent (Least Squares Mean) |
|---|---|
| Tiotropium | 11.735 |
| Salmeterol | 11.320 |
| Placebo | 11.257 |
PEF (Peak expiratory flow) variability is defined as the difference between the highest morning PEF value and the highest evening PEF value of one day divided by the arithmetic mean of these two PEF values and multiplied by 100% (NCT00350207)
Timeframe: After 16 weeks of treatment
| Intervention | ratio expressed in percent (Least Squares Mean) |
|---|---|
| Tiotropium | 11.742 |
| Salmeterol | 10.793 |
| Placebo | 12.305 |
PEF (Peak expiratory flow) variability is defined as the difference between the highest morning PEF value and the highest evening PEF value of one day divided by the arithmetic mean of these two PEF values and multiplied by 100% (NCT00350207)
Timeframe: After 4 weeks of treatment
| Intervention | ratio expressed in percent (Least Squares Mean) |
|---|---|
| Tiotropium | 12.043 |
| Salmeterol | 10.547 |
| Placebo | 12.085 |
PEF (Peak expiratory flow) variability is defined as the difference between the highest morning PEF value and the highest evening PEF value of one day divided by the arithmetic mean of these two PEF values and multiplied by 100% (NCT00350207)
Timeframe: After 8 weeks of treatment
| Intervention | ratio expressed in percent (Least Squares Mean) |
|---|---|
| Tiotropium | 13.377 |
| Salmeterol | 11.252 |
| Placebo | 12.964 |
Mean weekly evening forced expiratory volume in 1 second at week 12, pre-dose (NCT00350207)
Timeframe: After 12 weeks of treatment
| Intervention | L (Least Squares Mean) |
|---|---|
| Tiotropium | 2.31 |
| Salmeterol | 2.299 |
| Placebo | 2.231 |
Mean weekly evening forced expiratory volume in 1 second at week 16, pre-dose (NCT00350207)
Timeframe: After 16 weeks of treatment
| Intervention | L (Least Squares Mean) |
|---|---|
| Tiotropium | 2.343 |
| Salmeterol | 2.291 |
| Placebo | 2.215 |
Mean weekly evening forced expiratory volume in 1 second at week 4, pre-dose (NCT00350207)
Timeframe: After 4 weeks of treatment
| Intervention | L (Least Squares Mean) |
|---|---|
| Tiotropium | 2.369 |
| Salmeterol | 2.318 |
| Placebo | 2.25 |
Mean weekly evening forced expiratory volume in 1 second at week 8, pre-dose (NCT00350207)
Timeframe: After 8 weeks of treatment
| Intervention | L (Least Squares Mean) |
|---|---|
| Tiotropium | 2.32 |
| Salmeterol | 2.301 |
| Placebo | 2.239 |
Mean weekly evening peak expiratory flow at week 12, pre-dose (NCT00350207)
Timeframe: After 12 weeks of treatment
| Intervention | L/min (Least Squares Mean) |
|---|---|
| Tiotropium | 366.282 |
| Salmeterol | 362.01 |
| Placebo | 344.291 |
Mean weekly evening peak expiratory flow at week 16, pre-dose (NCT00350207)
Timeframe: After 16 weeks of treatment
| Intervention | L/min (Least Squares Mean) |
|---|---|
| Tiotropium | 363.657 |
| Salmeterol | 360.304 |
| Placebo | 340.099 |
Mean weekly evening peak expiratory flow at week 4, pre-dose (NCT00350207)
Timeframe: After 4 weeks of treatment
| Intervention | L/min (Least Squares Mean) |
|---|---|
| Tiotropium | 374.496 |
| Salmeterol | 366.219 |
| Placebo | 348.344 |
Mean weekly evening peak expiratory flow at week 8, pre-dose (NCT00350207)
Timeframe: After 8 weeks of treatment
| Intervention | L/min (Least Squares Mean) |
|---|---|
| Tiotropium | 368.758 |
| Salmeterol | 359.586 |
| Placebo | 345.299 |
Mean weekly morning forced expiratory volume in 1 second at week 12, pre-dose (NCT00350207)
Timeframe: After 12 weeks of treatment
| Intervention | L (Least Squares Mean) |
|---|---|
| Tiotropium | 2.256 |
| Salmeterol | 2.254 |
| Placebo | 2.156 |
Mean weekly morning forced expiratory volume in 1 second at week 16, pre-dose (NCT00350207)
Timeframe: After 16 weeks of treatment
| Intervention | L (Least Squares Mean) |
|---|---|
| Tiotropium | 2.3 |
| Salmeterol | 2.278 |
| Placebo | 2.188 |
Mean weekly morning forced expiratory volume in 1 second at week 4, pre-dose (NCT00350207)
Timeframe: After 4 weeks of treatment
| Intervention | L (Least Squares Mean) |
|---|---|
| Tiotropium | 2.301 |
| Salmeterol | 2.316 |
| Placebo | 2.161 |
Mean weekly morning forced expiratory volume in 1 second at week 8, pre-dose (NCT00350207)
Timeframe: After 8 weeks of treatment
| Intervention | L (Least Squares Mean) |
|---|---|
| Tiotropium | 2.254 |
| Salmeterol | 2.287 |
| Placebo | 2.164 |
Mean weekly morning peak expiratory flow at week 12, pre-dose (NCT00350207)
Timeframe: After 12 weeks of treatment
| Intervention | L/min (Least Squares Mean) |
|---|---|
| Tiotropium | 359.05 |
| Salmeterol | 351.3 |
| Placebo | 332.808 |
Mean weekly morning peak expiratory flow at week 16, pre-dose (NCT00350207)
Timeframe: After 16 weeks of treatment
| Intervention | L/min (Least Squares Mean) |
|---|---|
| Tiotropium | 355.619 |
| Salmeterol | 355.799 |
| Placebo | 334.525 |
Mean weekly morning peak expiratory flow at week 4, pre-dose (NCT00350207)
Timeframe: After 4 weeks of treatment
| Intervention | L/min (Least Squares Mean) |
|---|---|
| Tiotropium | 360.695 |
| Salmeterol | 359.762 |
| Placebo | 335.515 |
Mean weekly morning peak expiratory flow at week 8, pre-dose (NCT00350207)
Timeframe: After 8 weeks of treatment
| Intervention | L/min (Least Squares Mean) |
|---|---|
| Tiotropium | 355.42 |
| Salmeterol | 350.53 |
| Placebo | 330.193 |
Mean of the responses to 15 questions from 4 domains: Symptoms (1), Activity Limitations (2), Emotional Function (3), Environmental Stimuli (4). Unit on a scale 1-7. For domain (2): 1: totally limited, 2: extremely limited, 3: very limited, 4: moderate limitation, 5: some limitation, 6: a little limitation, 7: not at all limited. For other domains: 1: all of the time, 2: most of the time, 3: a good bit of the time, 4: some of the time, 5: a little of the time, 6: hardly any of the time, 7: none of the time. 7 is the best value (NCT00350207)
Timeframe: After 12 weeks of treatment
| Intervention | Unit on a scale (Least Squares Mean) |
|---|---|
| Tiotropium | 5.233 |
| Salmeterol | 5.399 |
| Placebo | 5.078 |
Mean of the responses to 15 questions from 4 domains: Symptoms (1), Activity Limitations (2), Emotional Function (3), Environmental Stimuli (4). Unit on a scale 1-7. For domain (2): 1: totally limited, 2: extremely limited, 3: very limited, 4: moderate limitation, 5: some limitation, 6: a little limitation, 7: not at all limited. For other domains: 1: all of the time, 2: most of the time, 3: a good bit of the time, 4: some of the time, 5: a little of the time, 6: hardly any of the time, 7: none of the time. 7 is the best value (NCT00350207)
Timeframe: After 16 weeks of treatment
| Intervention | Unit on a scale (Least Squares Mean) |
|---|---|
| Tiotropium | 5.305 |
| Salmeterol | 5.454 |
| Placebo | 5.214 |
Mean of the responses to 15 questions from 4 domains: Symptoms (1), Activity Limitations (2), Emotional Function (3), Environmental Stimuli (4). Unit on a scale 1-7. For domain (2): 1: totally limited, 2: extremely limited, 3: very limited, 4: moderate limitation, 5: some limitation, 6: a little limitation, 7: not at all limited. For other domains: 1: all of the time, 2: most of the time, 3: a good bit of the time, 4: some of the time, 5: a little of the time, 6: hardly any of the time, 7: none of the time. 7 is the best value (NCT00350207)
Timeframe: After 6 weeks of treatment
| Intervention | Unit on a scale (Least Squares Mean) |
|---|---|
| Tiotropium | 5.050 |
| Salmeterol | 5.259 |
| Placebo | 5.097 |
Morning pre-dose forced expiratory volume in 1 second as measured by spirometry after 6 weeks of treatment (NCT00350207)
Timeframe: After 6 weeks of treatment
| Intervention | L (Least Squares Mean) |
|---|---|
| Tiotropium | 2.471 |
| Salmeterol | 2.401 |
| Placebo | 2.299 |
Morning pre-dose forced expiratory volume in 1 second as measured by spirometry after 12 weeks of treatment (NCT00350207)
Timeframe: After 12 weeks of treatment
| Intervention | L (Least Squares Mean) |
|---|---|
| Tiotropium | 2.467 |
| Salmeterol | 2.442 |
| Placebo | 2.266 |
Morning pre-dose forced expiratory volume in 1 second as measured by spirometry after 16 weeks od treatment (NCT00350207)
Timeframe: After 16 weeks of treatment
| Intervention | L (Least Squares Mean) |
|---|---|
| Tiotropium | 2.439 |
| Salmeterol | 2.457 |
| Placebo | 2.29 |
Morning pre-dose forced vital capacity as measured by spirometry after 6 weeks of treatment (NCT00350207)
Timeframe: After 6 weeks of treatment
| Intervention | L (Least Squares Mean) |
|---|---|
| Tiotropium | 3.531 |
| Salmeterol | 3.441 |
| Placebo | 3.367 |
Morning pre-dose forced vital capacity as measured by spirometry after 12 weeks of treatment (NCT00350207)
Timeframe: After 12 weeks of treatment
| Intervention | L (Least Squares Mean) |
|---|---|
| Tiotropium | 3.509 |
| Salmeterol | 3.495 |
| Placebo | 3.307 |
Morning pre-dose forced vital capacity as measured by spirometry after 16 weeks of treatment (NCT00350207)
Timeframe: After 16 weeks of treatment
| Intervention | L (Least Squares Mean) |
|---|---|
| Tiotropium | 3.488 |
| Salmeterol | 3.474 |
| Placebo | 3.353 |
Pulse rate collected in conjunction with spirometry at 6 weeks (NCT00350207)
Timeframe: After 6 weeks of treatment
| Intervention | bpm (Mean) |
|---|---|
| Tiotropium | 74.7 |
| Salmeterol | 74.9 |
| Placebo | 74.2 |
Pulse rate collected in conjunction with spirometry at 12 weeks (NCT00350207)
Timeframe: After 12 weeks of treatment
| Intervention | bpm (Mean) |
|---|---|
| Tiotropium | 74.8 |
| Salmeterol | 74.6 |
| Placebo | 74.2 |
Pulse rate collected in conjunction with spirometry at 16 weeks (NCT00350207)
Timeframe: After 16 weeks of treatment
| Intervention | bpm (Mean) |
|---|---|
| Tiotropium | 74.4 |
| Salmeterol | 75.3 |
| Placebo | 74.7 |
Systolic blood pressure collected in conjunction with spirometry at 6 weeks (NCT00350207)
Timeframe: After 6 weeks of treatment
| Intervention | mmHg (Mean) |
|---|---|
| Tiotropium | 124.68 |
| Salmeterol | 123.11 |
| Placebo | 126.41 |
Systolic blood pressure collected in conjunction with spirometry at 12 weeks (NCT00350207)
Timeframe: After 12 weeks of treatment
| Intervention | mmHg (Mean) |
|---|---|
| Tiotropium | 124.81 |
| Salmeterol | 123.92 |
| Placebo | 125.18 |
Systolic blood pressure collected in conjunction with spirometry at 16 weeks (NCT00350207)
Timeframe: After 16 weeks of treatment
| Intervention | mmHg (Mean) |
|---|---|
| Tiotropium | 124.23 |
| Salmeterol | 123.83 |
| Placebo | 124.47 |
The Physician Global Evaluation reflected the physician's opinion of the patients overall condition with respect to COPD. The scale responses were: Poor (1,2). Fair (3,4), Good (5,6) and Excellent (7,8). (NCT00359788)
Timeframe: Week 6
| Intervention | Units on a scale (Least Squares Mean) |
|---|---|
| Tiotropium | 4.867 |
| Combivent (Ipratropium/Albuterol) | 4.716 |
Puffs of rescue albuterol used during the day in week 5 (NCT00359788)
Timeframe: Week 5
| Intervention | Puffs per day (Least Squares Mean) |
|---|---|
| Tiotropium | 1.275 |
| Combivent (Ipratropium/Albuterol) | 1.345 |
Puffs of rescue albuterol used during the day in week 6 (NCT00359788)
Timeframe: Week 6
| Intervention | Puffs per day (Least Squares Mean) |
|---|---|
| Tiotropium | 1.259 |
| Combivent (Ipratropium/Albuterol) | 1.405 |
Puffs of rescue albuterol used during the day in week 7 (NCT00359788)
Timeframe: Week 7
| Intervention | Puffs per day (Least Squares Mean) |
|---|---|
| Tiotropium | 1.313 |
| Combivent (Ipratropium/Albuterol) | 1.398 |
Puffs of rescue albuterol used during the day in week 8 (NCT00359788)
Timeframe: Week 8
| Intervention | Puffs per day (Least Squares Mean) |
|---|---|
| Tiotropium | 1.301 |
| Combivent (Ipratropium/Albuterol) | 1.471 |
Puffs of rescue albuterol used during the day in week 9 (NCT00359788)
Timeframe: Week 9
| Intervention | Puffs per day (Least Squares Mean) |
|---|---|
| Tiotropium | 1.369 |
| Combivent (Ipratropium/Albuterol) | 1.43 |
Weekly means for evening PEFR (NCT00359788)
Timeframe: Week 1
| Intervention | Liters/minute (Least Squares Mean) |
|---|---|
| Tiotropium | 222.89 |
| Combivent (Ipratropium/Albuterol) | 222.64 |
Trough FVC is measured 10 minutes before drug administration (NCT00359788)
Timeframe: Baseline and 6 weeks
| Intervention | Liters (Least Squares Mean) |
|---|---|
| Tiotropium | 0.258 |
| Combivent (Ipratropium/Albuterol) | -0.02 |
Trough FVC is measured 10 minutes before drug administration (NCT00359788)
Timeframe: Baseline and 12 weeks
| Intervention | Liters (Least Squares Mean) |
|---|---|
| Tiotropium | 0.225 |
| Combivent (Ipratropium/Albuterol) | 0.051 |
Trough FEV1 is measured 10 minutes before drug administration (NCT00359788)
Timeframe: Baseline and 6 Weeks
| Intervention | Liters (Least Squares Mean) |
|---|---|
| Tiotropium | 0.11 |
| Combivent (Ipratropium/Albuterol) | -0.036 |
Trough FEV1 is measured 10 minutes before drug administration (NCT00359788)
Timeframe: Baseline and 12 Weeks
| Intervention | Liters (Least Squares Mean) |
|---|---|
| Tiotropium | 0.081 |
| Combivent (Ipratropium/Albuterol) | -0.025 |
Peak FVC is defined as the maximum FVC observed in the first three hours after dose of study medication (NCT00359788)
Timeframe: Day 1
| Intervention | Liters (Least Squares Mean) |
|---|---|
| Tiotropium | 0.542 |
| Combivent (Ipratropium/Albuterol) | 0.824 |
Peak FVC is defined as the maximum FVC observed in the first three hours after dose of study medication (NCT00359788)
Timeframe: baseline and 6 Weeks (after first dose)
| Intervention | Liters (Least Squares Mean) |
|---|---|
| Tiotropium | 0.43 |
| Combivent (Ipratropium/Albuterol) | 0.791 |
Peak FVC is defined as the maximum FVC observed in the first three hours after dose of study medication (NCT00359788)
Timeframe: Baseline and 12 Weeks
| Intervention | Liters (Least Squares Mean) |
|---|---|
| Tiotropium | 0.418 |
| Combivent (Ipratropium/Albuterol) | 0.703 |
Peak FEV1 is defined as the maximum FEV1 observed in the first three hours after dose of study medication (NCT00359788)
Timeframe: Day 1
| Intervention | Liters (Least Squares Mean) |
|---|---|
| Tiotropium | 0.232 |
| Combivent (Ipratropium/Albuterol) | 0.364 |
Peak FEV1 is defined as the maximum FEV1 observed in the first three hours after dose of study medication (NCT00359788)
Timeframe: Baseline and 6 weeks
| Intervention | Liters (Least Squares Mean) |
|---|---|
| Tiotropium | 0.204 |
| Combivent (Ipratropium/Albuterol) | 0.356 |
Peak FEV1 is defined as the maximum FEV1 observed in the first three hours after dose of study medication (NCT00359788)
Timeframe: Baseline and 12 weeks
| Intervention | Liters (Least Squares Mean) |
|---|---|
| Tiotropium | 0.209 |
| Combivent (Ipratropium/Albuterol) | 0.342 |
Average hourly FVC AUC0-6 minus baseline FVC (NCT00359788)
Timeframe: Day 1
| Intervention | Liters (Least Squares Mean) |
|---|---|
| Tiotropium | 0.327 |
| Combivent (Ipratropium/Albuterol) | 0.484 |
Average hourly FVC AUC0-6 minus baseline FVC (NCT00359788)
Timeframe: Baseline and 6 Weeks
| Intervention | Liters (Least Squares Mean) |
|---|---|
| Tiotropium | 0.464 |
| Combivent (Ipratropium/Albuterol) | 0.425 |
Average hourly FVC AUC0-6 minus baseline FVC (NCT00359788)
Timeframe: Baseline and 12 Weeks
| Intervention | Liters (Least Squares Mean) |
|---|---|
| Tiotropium | 0.443 |
| Combivent (Ipratropium/Albuterol) | 0.432 |
Average hourly FEV1 AUC0-6 minus baseline FEV1 (NCT00359788)
Timeframe: Day 1 (after first dose)
| Intervention | Liters (Least Squares Mean) |
|---|---|
| Tiotropium | 0.132 |
| Combivent (Ipratropium/Albuterol) | 0.211 |
Average hourly FEV1 AUC0-6 minus baseline FEV1 (NCT00359788)
Timeframe: Baseline and week 6
| Intervention | Liters (Least Squares Mean) |
|---|---|
| Tiotropium | 0.207 |
| Combivent (Ipratropium/Albuterol) | 0.153 |
Average hourly FEV1 AUC0-6 minus baseline FEV1 (NCT00359788)
Timeframe: Baseline and 12 Weeks
| Intervention | Liters (Least Squares Mean) |
|---|---|
| Tiotropium | 0.187 |
| Combivent (Ipratropium/Albuterol) | 0.167 |
Puffs of rescue albuterol used during the day in week 1 (NCT00359788)
Timeframe: Week 1
| Intervention | Puffs per day (Least Squares Mean) |
|---|---|
| Tiotropium | 1.175 |
| Combivent (Ipratropium/Albuterol) | 1.217 |
Puffs of rescue albuterol used during the day in week 10 (NCT00359788)
Timeframe: Week 10
| Intervention | Puffs per day (Least Squares Mean) |
|---|---|
| Tiotropium | 1.351 |
| Combivent (Ipratropium/Albuterol) | 1.394 |
Puffs of rescue albuterol used during the day in week 11 (NCT00359788)
Timeframe: Week 11
| Intervention | Puffs per day (Least Squares Mean) |
|---|---|
| Tiotropium | 1.352 |
| Combivent (Ipratropium/Albuterol) | 1.445 |
Puffs of rescue albuterol used during the day in week 12 (NCT00359788)
Timeframe: Week 12
| Intervention | Puffs per day (Least Squares Mean) |
|---|---|
| Tiotropium | 1.361 |
| Combivent (Ipratropium/Albuterol) | 1.409 |
Puffs of rescue albuterol used during the day in week 2 (NCT00359788)
Timeframe: Week 2
| Intervention | Puffs per day (Least Squares Mean) |
|---|---|
| Tiotropium | 1.24 |
| Combivent (Ipratropium/Albuterol) | 1.309 |
Puffs of rescue albuterol used during the day in week 3 (NCT00359788)
Timeframe: Week 3
| Intervention | Puffs per day (Least Squares Mean) |
|---|---|
| Tiotropium | 1.337 |
| Combivent (Ipratropium/Albuterol) | 1.41 |
Puffs of rescue albuterol used during the day in week 4 (NCT00359788)
Timeframe: Week 4
| Intervention | Puffs per day (Least Squares Mean) |
|---|---|
| Tiotropium | 1.287 |
| Combivent (Ipratropium/Albuterol) | 1.399 |
Weekly means for evening PEFR (NCT00359788)
Timeframe: Week 10
| Intervention | Liters/minute (Least Squares Mean) |
|---|---|
| Tiotropium | 220.46 |
| Combivent (Ipratropium/Albuterol) | 216.32 |
Weekly means for evening PEFR (NCT00359788)
Timeframe: Week 11
| Intervention | Liters/minute (Least Squares Mean) |
|---|---|
| Tiotropium | 218.35 |
| Combivent (Ipratropium/Albuterol) | 217.17 |
Weekly means for evening PEFR (NCT00359788)
Timeframe: Week 12
| Intervention | Liters/minute (Least Squares Mean) |
|---|---|
| Tiotropium | 219.66 |
| Combivent (Ipratropium/Albuterol) | 215.46 |
Weekly means for evening PEFR (NCT00359788)
Timeframe: Week 3
| Intervention | Liters/minute (Least Squares Mean) |
|---|---|
| Tiotropium | 221.23 |
| Combivent (Ipratropium/Albuterol) | 218.52 |
Weekly means for evening PEFR (NCT00359788)
Timeframe: Week 4
| Intervention | Liters/minute (Least Squares Mean) |
|---|---|
| Tiotropium | 221.96 |
| Combivent (Ipratropium/Albuterol) | 215.06 |
Weekly means for evening PEFR (NCT00359788)
Timeframe: Week 2
| Intervention | Liters/minute (Least Squares Mean) |
|---|---|
| Tiotropium | 221.97 |
| Combivent (Ipratropium/Albuterol) | 221.12 |
(NCT00359788)
Timeframe: 15 minutes
| Intervention | Liters (Least Squares Mean) |
|---|---|
| Tiotropium | 3.069 |
| Combivent (Ipratropium/Albuterol) | 3.263 |
Weekly means for evening PEFR (NCT00359788)
Timeframe: Week 5
| Intervention | Liters/minute (Least Squares Mean) |
|---|---|
| Tiotropium | 217.95 |
| Combivent (Ipratropium/Albuterol) | 214.53 |
Weekly means for evening PEFR (NCT00359788)
Timeframe: Week 6
| Intervention | Liters/minute (Least Squares Mean) |
|---|---|
| Tiotropium | 218.45 |
| Combivent (Ipratropium/Albuterol) | 219.42 |
Weekly means for evening PEFR (NCT00359788)
Timeframe: Week 7
| Intervention | Liters/minute (Least Squares Mean) |
|---|---|
| Tiotropium | 220.98 |
| Combivent (Ipratropium/Albuterol) | 220.79 |
Weekly means for evening PEFR (NCT00359788)
Timeframe: Week 8
| Intervention | Liters/minute (Least Squares Mean) |
|---|---|
| Tiotropium | 223.33 |
| Combivent (Ipratropium/Albuterol) | 218.2 |
Weekly means for evening PEFR (NCT00359788)
Timeframe: Week 9
| Intervention | Liters/minute (Least Squares Mean) |
|---|---|
| Tiotropium | 221.47 |
| Combivent (Ipratropium/Albuterol) | 217.41 |
(NCT00359788)
Timeframe: 10 minutes before dosing
| Intervention | Liters (Least Squares Mean) |
|---|---|
| Tiotropium | 1.225 |
| Combivent (Ipratropium/Albuterol) | 1.119 |
(NCT00359788)
Timeframe: 10 minutes before dosing
| Intervention | Liters (Least Squares Mean) |
|---|---|
| Tiotropium | 1.254 |
| Combivent (Ipratropium/Albuterol) | 1.108 |
(NCT00359788)
Timeframe: 1 hour
| Intervention | Liters (Least Squares Mean) |
|---|---|
| Tiotropium | 1.327 |
| Combivent (Ipratropium/Albuterol) | 1.41 |
(NCT00359788)
Timeframe: 1 hour
| Intervention | Liters (Least Squares Mean) |
|---|---|
| Tiotropium | 1.343 |
| Combivent (Ipratropium/Albuterol) | 1.405 |
(NCT00359788)
Timeframe: 1 hour
| Intervention | Liters (Least Squares Mean) |
|---|---|
| Tiotropium | 1.272 |
| Combivent (Ipratropium/Albuterol) | 1.455 |
(NCT00359788)
Timeframe: 15 minutes
| Intervention | Liters (Least Squares Mean) |
|---|---|
| Tiotropium | 1.268 |
| Combivent (Ipratropium/Albuterol) | 1.351 |
(NCT00359788)
Timeframe: 15 minutes
| Intervention | Liters (Least Squares Mean) |
|---|---|
| Tiotropium | 1.3 |
| Combivent (Ipratropium/Albuterol) | 1.355 |
(NCT00359788)
Timeframe: 15 minutes
| Intervention | Liters (Least Squares Mean) |
|---|---|
| Tiotropium | 1.214 |
| Combivent (Ipratropium/Albuterol) | 1.389 |
(NCT00359788)
Timeframe: 2 hour
| Intervention | Liters (Least Squares Mean) |
|---|---|
| Tiotropium | 1.353 |
| Combivent (Ipratropium/Albuterol) | 1.398 |
(NCT00359788)
Timeframe: 2 hour
| Intervention | Liters (Least Squares Mean) |
|---|---|
| Tiotropium | 1.364 |
| Combivent (Ipratropium/Albuterol) | 1.382 |
(NCT00359788)
Timeframe: 2 hour
| Intervention | Least Squares Mean (Least Squares Mean) |
|---|---|
| Tiotropium | 1.293 |
| Combivent (Ipratropium/Albuterol) | 1.43 |
(NCT00359788)
Timeframe: 3 hour
| Intervention | Liters (Least Squares Mean) |
|---|---|
| Tiotropium | 1.353 |
| Combivent (Ipratropium/Albuterol) | 1.333 |
(NCT00359788)
Timeframe: 3 hour
| Intervention | Liters (Least Squares Mean) |
|---|---|
| Tiotropium | 1.371 |
| Combivent (Ipratropium/Albuterol) | 1.31 |
(NCT00359788)
Timeframe: 3 hour
| Intervention | Liters (Least Squares Mean) |
|---|---|
| Tiotropium | 1.29 |
| Combivent (Ipratropium/Albuterol) | 1.375 |
(NCT00359788)
Timeframe: 30 minutes
| Intervention | Liters (Least Squares Mean) |
|---|---|
| Tiotropium | 1.306 |
| Combivent (Ipratropium/Albuterol) | 1.393 |
(NCT00359788)
Timeframe: 30 minutes
| Intervention | Liters (Least Squares Mean) |
|---|---|
| Tiotropium | 1.328 |
| Combivent (Ipratropium/Albuterol) | 1.388 |
(NCT00359788)
Timeframe: 30 minutes
| Intervention | Liters (Least Squares Mean) |
|---|---|
| Tiotropium | 1.261 |
| Combivent (Ipratropium/Albuterol) | 1.429 |
(NCT00359788)
Timeframe: 4 hour
| Intervention | Liters (Least Squares Mean) |
|---|---|
| Tiotropium | 1.337 |
| Combivent (Ipratropium/Albuterol) | 1.263 |
(NCT00359788)
Timeframe: 4 hour
| Intervention | Liters (Least Squares Mean) |
|---|---|
| Tiotropium | 1.369 |
| Combivent (Ipratropium/Albuterol) | 1.247 |
(NCT00359788)
Timeframe: 4 hour
| Intervention | Liters (Least Squares Mean) |
|---|---|
| Tiotropium | 1.284 |
| Combivent (Ipratropium/Albuterol) | 1.319 |
(NCT00359788)
Timeframe: 6 hour
| Intervention | Liters (Least Squares Mean) |
|---|---|
| Tiotropium | 1.318 |
| Combivent (Ipratropium/Albuterol) | 1.182 |
(NCT00359788)
Timeframe: 6 hour
| Intervention | Liters (Least Squares Mean) |
|---|---|
| Tiotropium | 1.33 |
| Combivent (Ipratropium/Albuterol) | 1.168 |
(NCT00359788)
Timeframe: 6 hours
| Intervention | Liters (Least Squares Mean) |
|---|---|
| Tiotropium | 1.269 |
| Combivent (Ipratropium/Albuterol) | 1.233 |
(NCT00359788)
Timeframe: 10 minutes before dosing
| Intervention | Liters (Least Squares Mean) |
|---|---|
| Tiotropium | 2.967 |
| Combivent (Ipratropium/Albuterol) | 2.792 |
(NCT00359788)
Timeframe: 10 minutes before dosing
| Intervention | Liters (Least Squares Mean) |
|---|---|
| Tiotropium | 3 |
| Combivent (Ipratropium/Albuterol) | 2.722 |
(NCT00359788)
Timeframe: 1 hour
| Intervention | Liters (Least Squares Mean) |
|---|---|
| Tiotropium | 3.177 |
| Combivent (Ipratropium/Albuterol) | 3.375 |
(NCT00359788)
Timeframe: 1 hour
| Intervention | Liters (Least Squares Mean) |
|---|---|
| Tiotropium | 3.206 |
| Combivent (Ipratropium/Albuterol) | 3.388 |
(NCT00359788)
Timeframe: 1 hour
| Intervention | Liters (Least Squares Mean) |
|---|---|
| Tiotropium | 3.087 |
| Combivent (Ipratropium/Albuterol) | 3.444 |
(NCT00359788)
Timeframe: 15 minutes
| Intervention | Liters (Least Squares Mean) |
|---|---|
| Tiotropium | 3.09 |
| Combivent (Ipratropium/Albuterol) | 3.279 |
(NCT00359788)
Timeframe: 15 minutes
| Intervention | Liters (Least Squares Mean) |
|---|---|
| Tiotropium | 2.938 |
| Combivent (Ipratropium/Albuterol) | 3.308 |
(NCT00359788)
Timeframe: 2 hour
| Intervention | Liters (Least Squares Mean) |
|---|---|
| Tiotropium | 3.231 |
| Combivent (Ipratropium/Albuterol) | 3.328 |
(NCT00359788)
Timeframe: 2 hour
| Intervention | Liters (Least Squares Mean) |
|---|---|
| Tiotropium | 3.227 |
| Combivent (Ipratropium/Albuterol) | 3.338 |
(NCT00359788)
Timeframe: 2 hour
| Intervention | Liters (Least Squares Mean) |
|---|---|
| Tiotropium | 3.103 |
| Combivent (Ipratropium/Albuterol) | 3.388 |
(NCT00359788)
Timeframe: 3 hour
| Intervention | Liters (Least Squares Mean) |
|---|---|
| Tiotropium | 3.226 |
| Combivent (Ipratropium/Albuterol) | 3.218 |
(NCT00359788)
Timeframe: 3 hour
| Intervention | Liters (Least Squares Mean) |
|---|---|
| Tiotropium | 3.235 |
| Combivent (Ipratropium/Albuterol) | 3.185 |
(NCT00359788)
Timeframe: 3 hour
| Intervention | Liters (Least Squares Mean) |
|---|---|
| Tiotropium | 3.091 |
| Combivent (Ipratropium/Albuterol) | 3.261 |
(NCT00359788)
Timeframe: 30 minutes
| Intervention | Liters (Least Squares Mean) |
|---|---|
| Tiotropium | 3.143 |
| Combivent (Ipratropium/Albuterol) | 3.358 |
(NCT00359788)
Timeframe: 30 minutes
| Intervention | Liters (Least Squares Mean) |
|---|---|
| Tiotropium | 3.158 |
| Combivent (Ipratropium/Albuterol) | 3.362 |
(NCT00359788)
Timeframe: 30 minutes
| Intervention | Liters (Least Squares Mean) |
|---|---|
| Tiotropium | 3.044 |
| Combivent (Ipratropium/Albuterol) | 3.4 |
(NCT00359788)
Timeframe: 4 hour
| Intervention | Liters (Least Squares Mean) |
|---|---|
| Tiotropium | 3.199 |
| Combivent (Ipratropium/Albuterol) | 3.074 |
(NCT00359788)
Timeframe: 4 hour
| Intervention | Liters (Least Squares Mean) |
|---|---|
| Tiotropium | 3.23 |
| Combivent (Ipratropium/Albuterol) | 3.068 |
(NCT00359788)
Timeframe: 4 hour
| Intervention | Liters (Least Squares Mean) |
|---|---|
| Tiotropium | 3.087 |
| Combivent (Ipratropium/Albuterol) | 3.136 |
(NCT00359788)
Timeframe: 6 hour
| Intervention | Liters (Least Squares Mean) |
|---|---|
| Tiotropium | 3.155 |
| Combivent (Ipratropium/Albuterol) | 2.932 |
(NCT00359788)
Timeframe: 6 hour
| Intervention | Liters (Least Squares Mean) |
|---|---|
| Tiotropium | 3.190 |
| Combivent (Ipratropium/Albuterol) | 2.914 |
(NCT00359788)
Timeframe: 6 hour
| Intervention | Liters (Least Squares Mean) |
|---|---|
| Tiotropium | 3.053 |
| Combivent (Ipratropium/Albuterol) | 2.972 |
(NCT00359788)
Timeframe: Week 1
| Intervention | Liters/minute (Least Squares Mean) |
|---|---|
| Tiotropium | 205.8 |
| Combivent (Ipratropium/Albuterol) | 195.1 |
Weekly means for morning PEFR (NCT00359788)
Timeframe: Week 10
| Intervention | Liters/minute (Least Squares Mean) |
|---|---|
| Tiotropium | 204.83 |
| Combivent (Ipratropium/Albuterol) | 193.23 |
Weekly means for morning PEFR (NCT00359788)
Timeframe: Week 11
| Intervention | Liters/minute (Least Squares Mean) |
|---|---|
| Tiotropium | 206.47 |
| Combivent (Ipratropium/Albuterol) | 195.47 |
Weekly means for morning PEFR (NCT00359788)
Timeframe: Week 12
| Intervention | Liters/minute (Least Squares Mean) |
|---|---|
| Tiotropium | 206.52 |
| Combivent (Ipratropium/Albuterol) | 192.44 |
Weekly means for morning PEFR (NCT00359788)
Timeframe: Week 2
| Intervention | Liters/minute (Least Squares Mean) |
|---|---|
| Tiotropium | 206.07 |
| Combivent (Ipratropium/Albuterol) | 194.81 |
Weekly means for morning PEFR (NCT00359788)
Timeframe: Week 3
| Intervention | Liters/minute (Least Squares Mean) |
|---|---|
| Tiotropium | 206.61 |
| Combivent (Ipratropium/Albuterol) | 193.83 |
Weekly means for morning PEFR (NCT00359788)
Timeframe: Week 4
| Intervention | Liters/minute (Least Squares Mean) |
|---|---|
| Tiotropium | 206.76 |
| Combivent (Ipratropium/Albuterol) | 193.19 |
Weekly means for morning PEFR (NCT00359788)
Timeframe: Week 5
| Intervention | Liters/minute (Least Squares Mean) |
|---|---|
| Tiotropium | 205.6 |
| Combivent (Ipratropium/Albuterol) | 193.55 |
Weekly means for morning PEFR (NCT00359788)
Timeframe: Week 6
| Intervention | Liters/minute (Least Squares Mean) |
|---|---|
| Tiotropium | 206.49 |
| Combivent (Ipratropium/Albuterol) | 195.38 |
Weekly means for morning PEFR (NCT00359788)
Timeframe: Week 7
| Intervention | Liters/minute (Least Squares Mean) |
|---|---|
| Tiotropium | 208.72 |
| Combivent (Ipratropium/Albuterol) | 197.66 |
Weekly means for morning PEFR (NCT00359788)
Timeframe: Week 8
| Intervention | Liters/minute (Least Squares Mean) |
|---|---|
| Tiotropium | 208.88 |
| Combivent (Ipratropium/Albuterol) | 195.22 |
Weekly means for morning PEFR (NCT00359788)
Timeframe: Week 9
| Intervention | Liters/minute (Least Squares Mean) |
|---|---|
| Tiotropium | 208.97 |
| Combivent (Ipratropium/Albuterol) | 194.74 |
(NCT00359788)
Timeframe: Week 1
| Intervention | Puffs per night (Least Squares Mean) |
|---|---|
| Tiotropium | 3.493 |
| Combivent (Ipratropium/Albuterol) | 2.966 |
Puffs of rescue albuterol used during the night in week 10 (NCT00359788)
Timeframe: Week 10
| Intervention | Puffs per night (Least Squares Mean) |
|---|---|
| Tiotropium | 3.199 |
| Combivent (Ipratropium/Albuterol) | 2.909 |
Puffs of rescue albuterol used during the night in week 11 (NCT00359788)
Timeframe: Week 11
| Intervention | Puffs per night (Least Squares Mean) |
|---|---|
| Tiotropium | 3.224 |
| Combivent (Ipratropium/Albuterol) | 2.907 |
Puffs of rescue albuterol used during the night in week 12 (NCT00359788)
Timeframe: Week 12
| Intervention | Puffs per night (Least Squares Mean) |
|---|---|
| Tiotropium | 3.178 |
| Combivent (Ipratropium/Albuterol) | 3.069 |
Puffs of rescue albuterol used during the night in week 2 (NCT00359788)
Timeframe: Week 2
| Intervention | Puffs per night (Least Squares Mean) |
|---|---|
| Tiotropium | 3.269 |
| Combivent (Ipratropium/Albuterol) | 3.004 |
Puffs of rescue albuterol used during the night in week 3 (NCT00359788)
Timeframe: Week 3
| Intervention | Puffs per night (Least Squares Mean) |
|---|---|
| Tiotropium | 3.282 |
| Combivent (Ipratropium/Albuterol) | 2.931 |
Puffs of rescue albuterol used during the night in week 4 (NCT00359788)
Timeframe: Week 4
| Intervention | Puffs per night (Least Squares Mean) |
|---|---|
| Tiotropium | 3.285 |
| Combivent (Ipratropium/Albuterol) | 2.921 |
Puffs of rescue albuterol used during the night in week 5 (NCT00359788)
Timeframe: Week 5
| Intervention | Puffs per night (Least Squares Mean) |
|---|---|
| Tiotropium | 3.152 |
| Combivent (Ipratropium/Albuterol) | 2.789 |
Puffs of rescue albuterol used during the night in week 6 (NCT00359788)
Timeframe: Week 6
| Intervention | Puffs per night (Least Squares Mean) |
|---|---|
| Tiotropium | 3.178 |
| Combivent (Ipratropium/Albuterol) | 2.806 |
Puffs of rescue albuterol used during the night in week 7 (NCT00359788)
Timeframe: Week 7
| Intervention | Puffs per night (Least Squares Mean) |
|---|---|
| Tiotropium | 3.156 |
| Combivent (Ipratropium/Albuterol) | 2.966 |
Puffs of rescue albuterol used during the night in week 8 (NCT00359788)
Timeframe: Week 8
| Intervention | Puffs per night (Least Squares Mean) |
|---|---|
| Tiotropium | 3.104 |
| Combivent (Ipratropium/Albuterol) | 2.983 |
Puffs of rescue albuterol used during the night in week 9 (NCT00359788)
Timeframe: Week 9
| Intervention | Puffs per night (Least Squares Mean) |
|---|---|
| Tiotropium | 3.254 |
| Combivent (Ipratropium/Albuterol) | 3.006 |
The Patient Global Evaluation reflected the patient's opinion of their overall condition with respect to chronic obstructive pulmonary disease (COPD). The scale responses were: Poor (1,2). Fair (3,4), Good (5,6) and Excellent (7,8) (NCT00359788)
Timeframe: Week 6
| Intervention | Units on a scale (Least Squares Mean) |
|---|---|
| Tiotropium | 4.273 |
| Combivent (Ipratropium/Albuterol) | 4.069 |
The Patient Global Evaluation reflected the patient's opinion of their overall condition with respect to COPD. The scale responses were: Poor (1,2). Fair (3,4), Good (5,6) and Excellent (7,8). (NCT00359788)
Timeframe: Week 12
| Intervention | Units on a scale (Least Squares Mean) |
|---|---|
| Tiotropium | 4.49 |
| Combivent (Ipratropium/Albuterol) | 4.239 |
The Physician Global Evaluation reflected the physician's opinion of the patients overall condition with respect to COPD. The scale responses were: Poor (1,2). Fair (3,4), Good (5,6) and Excellent (7,8). (NCT00359788)
Timeframe: Week 12
| Intervention | Units on a scale (Least Squares Mean) |
|---|---|
| Tiotropium | 5.057 |
| Combivent (Ipratropium/Albuterol) | 4.772 |
Number of COPD exacerbations (defined as a complex of respiratory events/symptoms (increase or new onset) with a duration of 3 days or more requiring a change in treatment) per patient adjusted by length of treatment exposure (i.e. number of exacerbations multiplied by 365.25 and then divided by days of treatment exposure) (NCT00387088)
Timeframe: During actual study treatment period (planned Day 1 to Day 337)
| Intervention | COPD exacerbations per year (Median) |
|---|---|
| Tiotropium | 0 |
| Placebo | 0 |
Number of COPD exacerbations (defined as a complex of respiratory events/symptoms (increase or new onset) with a duration of 3 days or more requiring a change in treatment) per patient not adjusted for treatment exposure (i.e. naïve estimate) (NCT00387088)
Timeframe: During actual study treatment period (planned Day 1 to Day 337)
| Intervention | COPD exacerbations (Median) |
|---|---|
| Tiotropium | 0 |
| Placebo | 0 |
Number of hospitalisations for COPD exacerbations (a complex of respiratory events/symptoms (increase or new onset) with a duration of 3 days or more requiring a change in treatment) per patient adjusted by length of treatment exposure (i.e. no. of exacerbations multiplied by 365.25 and then divided by days of treatment exposure) (NCT00387088)
Timeframe: During actual study treatment period (planned Day 1 to Day 337)
| Intervention | hospitalisations for COPD exacerbations (Median) |
|---|---|
| Tiotropium | 0 |
| Placebo | 0 |
Number of hospitalisations for COPD exacerbations (a complex of respiratory events/symptoms (increase or new onset) with a duration of 3 days or more requiring a change in treatment) per patient not adjusted for treatment exposure (i.e. naïve estimate) (NCT00387088)
Timeframe: During actual study treatment period (planned Day 1 to Day 337)
| Intervention | hospitalisations for COPD exacerbations (Median) |
|---|---|
| Tiotropium | 0 |
| Placebo | 0 |
Number of patients with at least one COPD exacerbation (defined as a complex of respiratory events/symptoms (increase or new onset) with a duration of 3 days or more requiring a change in treatment) (NCT00387088)
Timeframe: During actual study treatment period (planned Day 1 to Day 337)
| Intervention | participants (Number) |
|---|---|
| Tiotropium | 685 |
| Placebo | 842 |
Number of patients with at least one hospitalisation for a COPD exacerbation (a complex of respiratory events/symptoms (increase or new onset) with a duration of 3 days or more requiring a change in treatment) (NCT00387088)
Timeframe: During actual study treatment period (planned Day 1 to Day 337)
| Intervention | participants (Number) |
|---|---|
| Tiotropium | 161 |
| Placebo | 198 |
Time to first COPD exacerbation (defined as a complex of respiratory events/symptoms (increase or new onset) with a duration of 3 days or more requiring a change in treatment). Time is days from start of study treatment to onset of exacerbation. (NCT00387088)
Timeframe: During actual study treatment period (planned Day 1 to Day 337)
| Intervention | Days (Median) |
|---|---|
| Tiotropium | NA |
| Placebo | NA |
Time to first hospitalisation for COPD exacerbation (a complex of respiratory events/symptoms (increase or new onset) with a duration of 3 days or more requiring a change in treatment). Time is days from start of study treatment to onset of exacerbation (NCT00387088)
Timeframe: During actual study treatment period (planned Day 1 to Day 337)
| Intervention | Days (Median) |
|---|---|
| Tiotropium | NA |
| Placebo | NA |
The SGRQ domain score (symptom, activity and impact) measures quality of life on a continuous scale ranging from 0=best state to 100=worst state (NCT00387088)
Timeframe: Baseline and Day 169
| Intervention | Units on a scale (Least Squares Mean) | ||
|---|---|---|---|
| Symptoms (N=1704,1688) | Activities (N=1690,1668) | Impacts (N=1690,1668) | |
| Placebo | -3.268 | -1.218 | -2.935 |
| Tiotropium | -6.555 | -3.573 | -4.917 |
The SGRQ domain score (symptom, activity and impact) measures quality of life on a continuous scale ranging from 0=best state to 100=worst state (NCT00387088)
Timeframe: Baseline and Day 337
| Intervention | Units on a scale (Least Squares Mean) | ||
|---|---|---|---|
| Symptoms (N=1704,1688) | Activities (N=1690,1668) | Impacts (N=1690,1668) | |
| Placebo | -3.307 | -0.226 | -2.038 |
| Tiotropium | -7.260 | -3.196 | -4.873 |
Clinically relevant findings in Physical Examination and ECG at end of treatment (NCT00387088)
Timeframe: End of treatment
| Intervention | participants (Number) | |||||
|---|---|---|---|---|---|---|
| Phys. Exam - No new/worsened finding | Phys. Exam - new or worsened finding | Phys. Exam - Missing | ECG - No new/worsened finding | ECG - new or worsened finding | ECG - Missing | |
| Placebo | 1733 | 17 | 215 | 1677 | 39 | 249 |
| Tiotropium | 1723 | 22 | 207 | 1674 | 37 | 241 |
"Marked changes from baseline in vital signs (diastolic and systolic blood pressure (DBP and SBP) and pulse rate (PR)) at end of treatment.~SBP - Increase means SBP >150 mmHg and an increase above baseline of >25 mmHg. SBP - Decrease means SBP <100 mmHg and a decrease below baseline of >10 mmHg.~DBP - Increase means DBP >90 mmHg and an increase above baseline of >10 mmHg. DBP - Decrease means DBP <60 mmHg and a decrease below baseline of >10 mmHg.~PR - Increase means PR >100 bpm and an increase above baseline of >10 bpm. PR - Decrease means PR <60 bpm and a decrease below baseline of >10 bpm." (NCT00387088)
Timeframe: Baseline and end of treatment
| Intervention | participants (Number) | |||||
|---|---|---|---|---|---|---|
| SBP - Increase | SBP - Decrease | DBP - Increase | DBP - Decrease | PR - Increase | PR - Decrease | |
| Placebo | 31 | 12 | 39 | 14 | 43 | 26 |
| Tiotropium | 29 | 6 | 40 | 9 | 35 | 26 |
Trough FEV1 is the mean volume of air that can be forced out in one second after taking a deep breath approximately 24 hours after the last administration of study drug. (NCT00387088)
Timeframe: Baseline and Day 169
| Intervention | Litres (Least Squares Mean) |
|---|---|
| Tiotropium | 0.121 |
| Placebo | 0.018 |
Trough FVC is the mean maximum volume of air that can be forcibly expired from the lungs; measured approximately 24 hours after the last administration of study drug. (NCT00387088)
Timeframe: Baseline and Day 337
| Intervention | Litres (Least Squares Mean) |
|---|---|
| Tiotropium | 0.168 |
| Placebo | -0.001 |
The SGRQ total score measures quality of life on a continuous scale ranging from 0=best state to 100=worst state (NCT00387088)
Timeframe: Baseline and Day 337
| Intervention | Units on a scale (Least Squares Mean) |
|---|---|
| Tiotropium | -4.726 |
| Placebo | -1.787 |
Trough FEV1 is the mean volume of air that can be forced out in one second after taking a deep breath approximately 24 hours after the last administration of study drug. (NCT00387088)
Timeframe: Baseline and Day 29
| Intervention | Litres (Least Squares Mean) |
|---|---|
| Tiotropium | 0.11 |
| Placebo | 0.017 |
Trough FEV1 is defined as the FEV1 measured at the -10 min time point at the end of the dosing interval (24 h post drug administration). (NCT00387088)
Timeframe: Baseline and Day 337
| Intervention | Litres (Least Squares Mean) |
|---|---|
| Tiotropium | 0.119 |
| Placebo | 0.018 |
Trough FVC is the mean maximum volume of air that can be forcibly expired from the lungs; measured approximately 24 hours after the last administration of study drug. (NCT00387088)
Timeframe: Baseline and Day 169
| Intervention | Litres (Least Squares Mean) |
|---|---|
| Tiotropium | 0.179 |
| Placebo | 0.019 |
Trough FVC is the mean maximum volume of air that can be forcibly expired from the lungs; measured approximately 24 hours after the last administration of study drug. (NCT00387088)
Timeframe: Baseline and Day 29
| Intervention | Litres (Least Squares Mean) |
|---|---|
| Tiotropium | 0.176 |
| Placebo | 0.025 |
The SGRQ total score measures quality of life on a continuous scale ranging from 0=best state to 100=worst state (NCT00387088)
Timeframe: Baseline and Day 169
| Intervention | Units on a scale (Least Squares Mean) |
|---|---|
| Tiotropium | -4.764 |
| Placebo | -2.568 |
12 hour peak change in FEV1 is defined as maximum of the post dose changes through the nominal 12 hour assessment. (NCT00424528)
Timeframe: 2 weeks
| Intervention | Liters (Mean) | |
|---|---|---|
| Week 0; N=76, 79, 78 | Week 2; N=71, 75, 74 | |
| Arformoterol /Tiotropium | 0.311 | 0.379 |
| Arformoterol 15 Mcg Twice Daily | 0.264 | 0.273 |
| Tiotropium 18 Mcg Once Daily | 0.218 | 0.265 |
TDI Focal score (range -9 to 9) is defined as the sum of function impairment, magnitude of task, and magnitude of effort (each on a -3 to 3 scale). A score of -9 is maximum worsening and 9 is maximum improvement. (NCT00424528)
Timeframe: 2 weeks
| Intervention | Units on a scale (Mean) |
|---|---|
| Arformoterol 15 Mcg Twice Daily | 2.28 |
| Tiotropium 18 Mcg Once Daily | 1.79 |
| Arformoterol /Tiotropium | 3.13 |
Analyzed from end of dosing to 12 hours. (NCT00424528)
Timeframe: 2 weeks
| Intervention | Hours (Median) |
|---|---|
| Arformoterol 15 Mcg Twice Daily | 0.39 |
| Tiotropium 18 Mcg Once Daily | 0.72 |
| Arformoterol /Tiotropium | 0.17 |
Trough FEV1 is defined as the measurement collected approximately 24 hours after the first in-clinic double-blind dose at Week 0. Change is calculated as Week 2 24 hour post first dose FEV1 - Week 0 pre-first dose FEV1. (NCT00424528)
Timeframe: Following 2 weeks of dosing
| Intervention | Liters (Mean) |
|---|---|
| Arformoterol 15 Mcg Twice Daily | 0.086 |
| Tiotropium 18 Mcg Once Daily | 0.080 |
| Arformoterol /Tiotropium | 0.154 |
Trough Inspiratory Capacity is defined as the measurement collected approximately 24 hours after the first in clinic double-blind treatment dose at week 0. Change is calculated as Week 2 24 hr post dose IC - Week 0 pre first dose IC. (NCT00424528)
Timeframe: 2 weeks
| Intervention | Liters (Mean) |
|---|---|
| Arformoterol 15 Mcg Twice Daily | 0.074 |
| Tiotropium 18 Mcg Once Daily | 0.023 |
| Arformoterol /Tiotropium | 0.150 |
A Greater than or Equal to 1 unit of Improvement in the TDI Focal Score is considered to be clinically important. (NCT00424528)
Timeframe: 2 weeks
| Intervention | Participants (Number) |
|---|---|
| Arformoterol 15 Mcg Twice Daily | 50 |
| Tiotropium 18 Mcg Once Daily | 44 |
| Arformoterol /Tiotropium | 60 |
A Greater than or Equal to 1 unit of Improvement in the TDI Focal Score is considered to be clinically important. (NCT00424528)
Timeframe: 2 weeks
| Intervention | Percentage of participants (Number) |
|---|---|
| Arformoterol 15 Mcg Twice Daily | 66.67 |
| Tiotropium 18 Mcg Once Daily | 57.14 |
| Arformoterol /Tiotropium | 77.92 |
(NCT00424528)
Timeframe: Following 2 weeks of dosing
| Intervention | Liters (Mean) |
|---|---|
| Arformoterol 15 Mcg Twice Daily | 0.094 |
| Tiotropium 18 Mcg Once Daily | 0.054 |
| Arformoterol /Tiotropium | 0.217 |
Analyzed from end of dosing to 12 hours. (NCT00424528)
Timeframe: 2 weeks
| Intervention | Hours (Median) |
|---|---|
| Arformoterol 15 Mcg Twice Daily | 0.76 |
| Tiotropium 18 Mcg Once Daily | 1.29 |
| Arformoterol /Tiotropium | 0.39 |
(NCT00424528)
Timeframe: 0-12 hours following two weeks of dosing
| Intervention | Liters (Mean) |
|---|---|
| Arformoterol 15 Mcg Twice Daily | 0.118 |
| Tiotropium 18 Mcg Once Daily | 0.130 |
| Arformoterol /Tiotropium | 0.242 |
(NCT00424528)
Timeframe: 24 hours following two weeks of dosing.
| Intervention | Liters (Mean) |
|---|---|
| Arformoterol 15 Mcg Twice Daily | 0.104 |
| Tiotropium 18 Mcg Once Daily | 0.080 |
| Arformoterol /Tiotropium | 0.221 |
Baseline is FEV1 measurement collected prior to the first double-blind dose at week 0. Change defined as Week 0 FEV1 - Week 2 pre first dose FEV1. (NCT00424528)
Timeframe: 2 weeks
| Intervention | Liters (Mean) | ||||||||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Week 0: immediately post first dose; N=76, 78, 78 | Week 0: 30 minutes post first dose; N=75, 78, 76 | Week 0: 1 hour post first dose; N=75, 78, 77 | Week 0: 2 hours post first dose; N=76, 78, 77 | Week 0: 4 hours post first dose; N=75, 77, 77 | Week 0: 6 hours post first dose; N=72, 74, 77 | Week 0: 8 hours post first dose; N=70, 73, 77 | Week 0: 10 hours post first dose; N=69, 71, 76 | Week 0: 12 hours post first dose; N=69, 71, 75 | Week 2: immediately post first dose; N=71, 75, 74 | Week 2: 30 minutes post first dose; N=70, 74, 74 | Week 2: 1 hour post first dose; N=71, 75, 73 | Week 2: 2 hours post first dose; N=71, 73, 74 | Week 2: 4 hours post first dose; N=69, 72, 74 | Week 2: 6 hours post first dose; N=69, 72, 73 | Week 2: 8 hours post first dose; N=69, 70, 74 | Week 2: 10 hours post first dose; N=69, 71, 71 | Week 2: 12 hours post first dose; N=63, 67, 71 | Week 2: immediately post second dose; N=65, 67, 72 | Week 2: 12.5 hours post first dose; N=65, 66, 72 | Week 2: 13 hours post first dose; N=63, 68, 72 | Week 2: 14 hours post first dose; N=65, 71, 72 | Week 2: 16 hours post first dose; N=63, 70, 71 | Week 2: 23 hours post first dose; N=70, 74, 74 | Week 2: 24 hours post first dose; N=69, 73, 74 | |
| Arformoterol /Tiotropium | 0.139 | 0.183 | 0.189 | 0.239 | 0.223 | 0.214 | 0.194 | 0.190 | 0.199 | 0.240 | 0.280 | 0.308 | 0.330 | 0.279 | 0.266 | 0.220 | 0.205 | 0.189 | 0.235 | 0.270 | 0.272 | 0.292 | 0.240 | 0.145 | 0.154 |
| Arformoterol 15 Mcg Twice Daily | 0.132 | 0.163 | 0.182 | 0.193 | 0.155 | 0.128 | 0.102 | 0.101 | 0.044 | 0.154 | 0.188 | 0.185 | 0.213 | 0.154 | 0.123 | 0.067 | 0.054 | 0.035 | 0.115 | 0.143 | 0.159 | 0.182 | 0.114 | 0.040 | 0.086 |
| Tiotropium 18 Mcg Once Daily | -0.20 | 0.056 | 0.106 | 0.140 | 0.120 | 0.125 | 0.109 | 0.111 | 0.094 | 0.066 | 0.126 | 0.163 | 0.195 | 0.164 | 0.143 | 0.138 | 0.109 | 0.101 | 0.040 | 0.063 | 0.061 | 0.068 | 0.048 | -0.006 | 0.080 |
Baseline is FEV1 collected prior to first double-blind dose at week 0. Change is defined as Week 0 FEV1 percent predicted - Week 2 pre first dose FEV1 percent predicted. (NCT00424528)
Timeframe: 2 weeks
| Intervention | Percent of predicted FEV1 (Mean) | ||||||||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Week 0: Immediately post first dose; N=76, 78, 78 | Week 0: 30 minutes post first dose; N=75, 78, 76 | Week 0: 1 hour post first dose; N-75, 78, 77 | Week 0: 2 hours post first dose; N=76, 78, 77 | Week 0: 4 hours post first dose; N=75, 77, 77 | Week 0: 6 hours post first dose; N=72, 74, 77 | Week 0: 8 hours post first dose; N=70, 73, 77 | Week 0: 10 hours post first dose; N=69, 71, 76 | Week 0: 12 hours post first dose; N=69, 71, 75 | Week 2: Immediately post first dose; N=71, 75, 74 | Week 2: 30 minutes post first dose; N=70, 74, 74 | Week 2: 1 hour post first dose; N=71, 75, 73 | Week 2: 2 hours post first dose; N=71, 73, 74 | Week 2: 4 hours post first dose; N=69, 72, 74 | Week 2: 6 hours post first dose; N=69, 72, 73 | Week 2: 8 hours post first dose; N=69, 70, 74 | Week 2: 10 hours post first dose; N=69, 71, 71 | Week 2: 12 hours post first dose; N=63, 67, 71 | Week 2: Immediately post second dose; N=65, 67, 72 | Week 2: 12.5 hours post first dose; N=65, 66, 72 | Week 2: 13 hours post first dose; N=63, 68, 72 | Week 2: 14 hours post first dose; N=65, 71, 72 | Week 2: 16 hours post first dose; N=63, 70, 71 | Week 2: 23 hours post first dose; N=70, 74, 74 | Week 2: 24 hours post first dose; N=69, 73, 74 | |
| Arformoterol /Tiotropium | 4.7 | 6.1 | 6.3 | 8.1 | 7.5 | 7.3 | 6.6 | 6.5 | 6.7 | 8.0 | 9.3 | 10.2 | 11.0 | 9.2 | 8.8 | 7.4 | 6.8 | 6.3 | 7.8 | 9.0 | 9.1 | 9.8 | 8.0 | 4.8 | 5.2 |
| Arformoterol 15 Mcg Twice Daily | 4.3 | 5.5 | 6.1 | 6.6 | 5.3 | 4.4 | 3.5 | 3.3 | 1.6 | 5.1 | 6.2 | 6.2 | 7.1 | 5.1 | 4.0 | 2.0 | 1.8 | 1.3 | 3.8 | 4.9 | 5.4 | 6.0 | 3.9 | 1.3 | 2.8 |
| Tiotropium 18 Mcg Once Daily | -0.6 | 2.0 | 3.5 | 4.7 | 4.0 | 4.1 | 3.5 | 3.7 | 2.9 | 1.9 | 4.0 | 5.2 | 6.3 | 5.1 | 4.7 | 4.4 | 3.5 | 3.4 | 1.1 | 2.0 | 1.8 | 2.0 | 1.4 | -0.2 | 2.6 |
(NCT00424528)
Timeframe: 2 Weeks
| Intervention | Liters (Mean) | ||||||||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Week 0: Immediately post first dose; N=76, 78, 78 | Week 0: 30 minutes post first dose; N=75, 78, 76 | Week 0: 1 hour post first dose; N=75, 78, 77 | Week 0: 2 hours post first dose; N=76, 78, 77 | Week 0: 4 hours post first dose; N=75, 77, 77 | Week 0: 6 hours post first dose; N=72, 74, 77 | Week 0: 8 hours post first dose; N=70, 73, 77 | Week 0: 10 hours post first dose; N=69, 71, 76 | Week 0: 12 hours post first dose; N=69, 71, 75 | Week 2: Immediately post first dose; N=71, 75, 74 | Week 2: 30 minutes post first dose; N=70, 74, 74 | Week 2: 1 hour post first dose; N=71, 75, 73 | Week 2: 2 hours post first dose; N=71, 73, 74 | Week 2: 4 hours post first dose; N=69, 72, 74 | Week 2: 6 hours post first dose; N=69, 72, 73 | Week 2: 8 hours post first dose; N=69, 70, 74 | Week 2: 10 hours post first dose; N=69, 71, 71 | Week 2: 12 hours post first dose; N=63, 67, 71 | Week 2: Immediately post second dose; N=65, 67, 72 | Week 2: 12.5 hours post first dose; N=65, 66, 72 | Week 2: 13 hours post first dose; N=63, 68, 72 | Week 2: 14 hours post first dose; N=65, 71, 72 | Week 2: 16 hours post first dose; N=63, 70, 71 | Week 2: 23 hours post first dose; N=70, 74, 74 | Week 2: 24 hours post first dose; N=69, 73, 74 | |
| Arformoterol /Tiotropium | 0.259 | 0.323 | 0.351 | 0.429 | 0.392 | 0.371 | 0.338 | 0.346 | 0.344 | 0.389 | 0.461 | 0.487 | 0.526 | 0.461 | 0.413 | 0.349 | 0.323 | 0.301 | 0.360 | 0.399 | 0.424 | 0.459 | 0.374 | 0.226 | 0.250 |
| Arformoterol 15 Mcg Twice Daily | 0.276 | 0.312 | 0.344 | 0.376 | 0.291 | 0.242 | 0.207 | 0.209 | 0.131 | 0.293 | 0.343 | 0.350 | 0.380 | 0.265 | 0.202 | 0.136 | 0.098 | 0.087 | 0.210 | 0.262 | 0.307 | 0.343 | 0.215 | 0.082 | 0.138 |
| Tiotropium 18 Mcg Once Daily | -0.031 | 0.122 | 0.197 | 0.248 | 0.206 | 0.195 | 0.159 | 0.175 | 0.146 | 0.055 | 0.203 | 0.224 | 0.290 | 0.221 | 0.209 | 0.214 | 0.158 | 0.124 | 0.034 | 0.087 | 0.082 | 0.110 | 0.098 | -0.011 | 0.115 |
Overall: Average of the levalbuterol usage in days per week over the 2 week period. Mean number of days/week=number of days levalbuterol used during time period, divided by number of days in the period, multiplied by 7. An actuation is one puff of levalbuterol. (NCT00424528)
Timeframe: 2 weeks
| Intervention | Days per week (Mean) | |
|---|---|---|
| Baseline: Number of days used per week | Overall: Number of days used per week | |
| Arformoterol /Tiotropium | 4.57 | 1.38 |
| Arformoterol 15 Mcg Twice Daily | 4.44 | 2.16 |
| Tiotropium 18 Mcg Once Daily | 4.27 | 1.94 |
Overall: Average of the usage in number of actuations per day over the 2 week period. An actuation is one puff of levalbuterol. Mean number of actuations/day=number actuations used during time period, divided by number of days in time period. (NCT00424528)
Timeframe: 2 weeks
| Intervention | Actuations per day (Mean) | |
|---|---|---|
| Baseline: Number of actuations per day | Overall: Number of actuations per day | |
| Arformoterol /Tiotropium | 3.08 | 0.68 |
| Arformoterol 15 Mcg Twice Daily | 3.24 | 1.18 |
| Tiotropium 18 Mcg Once Daily | 2.77 | 1.00 |
"Interim Analysis: Stage 1.~Spirometry was conducted according to internationally accepted standards. Standardized with respect to time (AUC 1h-4h) for FEV1 measurements taken from 1 hour to 4 hour post morning dose on Day 14. Standardized FEV1 AUC was calculated by the trapezoidal rule. Mixed model used baseline FEV1, FEV1 prior to and 30 minutes post inhalation of salbutamol/albuterol, and FEV1 prior to and 1 hour post inhalation of ipratropium as covariates." (NCT00463567)
Timeframe: Day 14, After 2 Weeks of treatment in Stage 1
| Intervention | Liters (Least Squares Mean) |
|---|---|
| Indacaterol 150 µg | 1.53 |
| Indacaterol 300 µg | 1.58 |
| Tiotropium 18 µg | 1.49 |
| Placebo | 1.30 |
| Indacaterol 75 µg | 1.50 |
| Indacaterol 600 µg | 1.53 |
| Formoterol 12 µg | 1.52 |
"A Chronic Obstructive Pulmonary Disease (COPD) day of poor control was defined as any day in the participant's diary with a score ≥2 (moderate or severe) for at least 2 of 5 symptoms (cough, wheeze, production of sputum, color of sputum, breathlessness). Score for each symptom ranges from 0-3; a higher number indicates a more severe symptom. The model contained baseline percentage of days of poor control as well as FEV1 reversibility components as covariates." (NCT00463567)
Timeframe: up to 26 weeks
| Intervention | Percentage of days (Least Squares Mean) |
|---|---|
| Indacaterol 150 µg (Continued Into Stage 2) | 31.5 |
| Indacaterol 300 µg (Continued Into Stage 2) | 30.8 |
| Tiotropium (Continued Into Stage 2) | 31.0 |
| Placebo (Continued Into Stage 2) | 34.0 |
"Interim Analysis: Stage 1.~Spirometry was conducted according to internationally accepted standards. Trough FEV1 was defined as the average of the 23 h 10 min and the 23 h 45 min post dose values. Mixed model used baseline FEV1, FEV1 prior to and 30 minutes post inhalation of salbutamol/albuterol, and FEV1 prior to and 1 hour post inhalation of ipratropium as covariates." (NCT00463567)
Timeframe: Day 15, After 2 Weeks of treatment in Stage 1
| Intervention | Liters (Least Squares Mean) |
|---|---|
| Indacaterol 150 µg | 1.49 |
| Indacaterol 300 µg | 1.52 |
| Tiotropium 18 µg | 1.45 |
| Placebo | 1.31 |
| Indacaterol 75 µg | 1.46 |
| Indacaterol 600 µg | 1.51 |
| Formoterol 12 µg | 1.42 |
FEV1 was measured with spirometry conducted according to internationally accepted standards. Trough FEV1 was defined as the average of the 23 h 10 min and the 23 h 45 min post dose values. Mixed model used baseline FEV1, FEV1 prior to and 30 minutes post inhalation of salbutamol/albuterol, and FEV1 prior to and 1 hour post inhalation of ipratropium as covariates. (NCT00463567)
Timeframe: after 12 weeks of treatment
| Intervention | Liters (Least Squares Mean) |
|---|---|
| Indacaterol 150 µg (Continued Into Stage 2) | 1.46 |
| Indacaterol 300 µg (Continued Into Stage 2) | 1.46 |
| Tiotropium 18 µg (Continued Into Stage 2) | 1.42 |
| Placebo (Continued Into Stage 2) | 1.28 |
Change in the 60 min post-dose IC from baseline to week 12 (calculated as a mean using all available data of treatment period between week 1 and week 12) (NCT00496470)
Timeframe: Baseline to 12 weeks
| Intervention | Liters (Mean) |
|---|---|
| Symbicort+Tiotropium | 0.26 |
| Placebo+Tiotropium | 0.149 |
Daily diary record - Total, 24 hours, during the night, and during the day. Change in average values from run-in to the full treatment period (NCT00496470)
Timeframe: Baseline to 12 weeks
| Intervention | Inhalations (Mean) |
|---|---|
| Symbicort+Tiotropium | -1.024 |
| Placebo+Tiotropium | -0.347 |
Change in the 5 min post-dose FEV1from baseline to week 12 (calculated as a mean using all available data of treatment period between week 1 and week 12) (NCT00496470)
Timeframe: Baseline to 12 weeks
| Intervention | Liters (Mean) |
|---|---|
| Symbicort+Tiotropium | 0.165 |
| Placebo+Tiotropium | 0.042 |
Daily diary record - Morning, after morning measurement till midday. Change in average values from run-in to the full treatment period (NCT00496470)
Timeframe: Baseline to 12 weeks
| Intervention | Inhalations (Mean) |
|---|---|
| Symbicort+Tiotropium | -0.417 |
| Placebo+Tiotropium | -0.124 |
Daily diary record - Day, after morning measurement till evening. Change in average values from run-in to the full treatment period (NCT00496470)
Timeframe: Baseline to 12 weeks
| Intervention | Inhalations (Mean) |
|---|---|
| Symbicort+Tiotropium | -0.745 |
| Placebo+Tiotropium | -0.371 |
"Change in total score from baseline (Visit 3) to end of treatment (Visit 6, or last available visit).~SGRQ-C is a health related quality of life questionnaire consisting of 40 items divided into two components: 1) symptoms, 2) activity& impacts. The lowest possible value is zero and the highest 100. Higher values correspond to greater impairment in quality of life." (NCT00496470)
Timeframe: Baseline and 12 weeks
| Intervention | Score on a scale (Mean) |
|---|---|
| Symbicort+Tiotropium | -4.12 |
| Placebo+Tiotropium | -1.99 |
Patients with worsening of COPD leading to treatment with systemic steroids (oral or parenteral), emergency room treatment or hospitalisation (NCT00496470)
Timeframe: 12 weeks
| Intervention | Participants (Number) |
|---|---|
| Symbicort+Tiotropium | 25 |
| Placebo+Tiotropium | 61 |
Ratio of treatment period mean to run-in value (NCT00496470)
Timeframe: Baseline to 12 weeks
| Intervention | Ratio (Median) |
|---|---|
| Symbicort+Tiotropium | 0.96 |
| Placebo+Tiotropium | 0.99 |
Ratio of treatment period mean to run-in value (NCT00496470)
Timeframe: Baseline to 12 weeks
| Intervention | Ratio (Median) |
|---|---|
| Symbicort+Tiotropium | 1.0 |
| Placebo+Tiotropium | 1.0 |
Ratio of treatment period mean to run-in value (NCT00496470)
Timeframe: Baseline to 12 weeks
| Intervention | Ratio (Median) |
|---|---|
| Symbicort+Tiotropium | 0.97 |
| Placebo+Tiotropium | 0.98 |
Ratio of treatment period mean to run-in value (NCT00496470)
Timeframe: Baseline to 12 weeks
| Intervention | Ratio (Median) |
|---|---|
| Symbicort+Tiotropium | 0.95 |
| Placebo+Tiotropium | 0.95 |
Ratio of treatment period mean to run-in value (NCT00496470)
Timeframe: Baseline to 12 weeks
| Intervention | Ratio (Median) |
|---|---|
| Symbicort+Tiotropium | 1.0 |
| Placebo+Tiotropium | 1.0 |
Ratio of treatment period mean to run-in value (NCT00496470)
Timeframe: Baseline to 12 weeks
| Intervention | Ratio (Median) |
|---|---|
| Symbicort+Tiotropium | 1.0 |
| Placebo+Tiotropium | 1.0 |
Ratio of treatment period mean to run-in value (NCT00496470)
Timeframe: Baseline to 12 weeks
| Intervention | Ratio (Median) |
|---|---|
| Symbicort+Tiotropium | 0.91 |
| Placebo+Tiotropium | 0.97 |
Daily diary record. Change in average values from run-in to the full treatment period (NCT00496470)
Timeframe: Baseline to 12 weeks
| Intervention | Liters/minute (Mean) |
|---|---|
| Symbicort+Tiotropium | 5.12 |
| Placebo+Tiotropium | -3.52 |
Daily diary record. Change in average values from run-in to the full treatment period (NCT00496470)
Timeframe: Baseline to 12 weeks
| Intervention | Liters/minute (Mean) |
|---|---|
| Symbicort+Tiotropium | 16.71 |
| Placebo+Tiotropium | 1.1 |
"Daily diary record. Change in average values from run-in to the full treatment period.~The GCSQ consisted of two questions that required the patient to rate shortness of breath and feelings of chest tightness. The patients recorded their response on a five-point Likert-type scale ranging from 0 (not at all) to 4 (extremely), the total score being calculated as the average score of the two questions." (NCT00496470)
Timeframe: Baseline to 12 weeks
| Intervention | Scores on a scale (Mean) |
|---|---|
| Symbicort+Tiotropium | -0.404 |
| Placebo+Tiotropium | -0.28 |
"Daily diary record. Change in average values from run-in to the full treatment period.~The GCSQ consisted of two questions that required the patient to rate shortness of breath and feelings of chest tightness. The patients recorded their response on a five-point Likert-type scale ranging from 0 (not at all) to 4 (extremely), the total score being calculated as the average score of the two questions." (NCT00496470)
Timeframe: Baseline to 12 weeks
| Intervention | Scores on a scale (Mean) |
|---|---|
| Symbicort+Tiotropium | -0.325 |
| Placebo+Tiotropium | -0.202 |
Daily diary record. Change in average values from run-in to the full treatment period (NCT00496470)
Timeframe: Baseline to 12 weeks
| Intervention | Liters (Mean) |
|---|---|
| Symbicort+Tiotropium | 0.209 |
| Placebo+Tiotropium | 0.014 |
Daily diary record - Night, after evening measurement till morning. Change in average values from run-in to the full treatment period (NCT00496470)
Timeframe: Baseline to 12 weeks
| Intervention | Inhalations (Mean) |
|---|---|
| Symbicort+Tiotropium | -0.279 |
| Placebo+Tiotropium | 0.022 |
"Daily diary record. Change in average values from run-in to the full treatment period.~The GCSQ consisted of two questions that required the patient to rate shortness of breath and feelings of chest tightness. The patients recorded their response on a five-point Likert-type scale ranging from 0 (not at all) to 4 (extremely), the total score being calculated as the average score of the two questions." (NCT00496470)
Timeframe: Baseline to 12 weeks
| Intervention | Scores on a scale (Mean) |
|---|---|
| Symbicort+Tiotropium | -0.143 |
| Placebo+Tiotropium | -0.006 |
"Daily diary record. Change in average values from run-in to the full treatment period.~The CDLM questionnaire is as a questionnaire to report on patient's ability to carry out each of six different morning activities (score ranging from 0 not performed to 1performed) and rank the difficulty of performing each of those activities (score ranging from 0 so difficult that the activity could not be carried out by the patient on their own to 5 activity was not at all difficult to carry out. Total score for each morning activity range from 0-6. Total score for whole CDLM questionnaire range from 0-36." (NCT00496470)
Timeframe: Baseline to 12 weeks
| Intervention | Scores on a scale (Mean) |
|---|---|
| Symbicort+Tiotropium | 0.202 |
| Placebo+Tiotropium | 0.07 |
Daily diary record. Change in average values from run-in to the full treatment period. Symptom scale 0 - 4 (0) None (1) Mild (2) Moderate (3) Marked (4) Severe (NCT00496470)
Timeframe: Baseline to 12 weeks
| Intervention | Units on a Scale (Mean) |
|---|---|
| Symbicort+Tiotropium | -0.177 |
| Placebo+Tiotropium | -0.049 |
Daily diary record. Change in average values from run-in to the full treatment period. Symptom scale 0 - 4 (0) None (1) Mild (2) Moderate (3) Marked (4) Severe (NCT00496470)
Timeframe: Baseline to 12 weeks
| Intervention | Units on a Scale (Mean) |
|---|---|
| Symbicort+Tiotropium | -0.184 |
| Placebo+Tiotropium | -0.061 |
Daily diary record. Change in average values from run-in to the full treatment period. Symptom scale 0 - 4 (0) None (1) Mild (2) Moderate (3) Marked (4) Severe (NCT00496470)
Timeframe: Baseline to 12 weeks
| Intervention | Units on a Scale (Mean) |
|---|---|
| Symbicort+Tiotropium | -0.246 |
| Placebo+Tiotropium | -0.079 |
Daily diary record. Change in average values from run-in to the full treatment period. Symptom scale 0 - 4 (0) None (1) Mild (2) Moderate (3) Marked (4) Severe (NCT00496470)
Timeframe: Baseline to 12 weeks
| Intervention | Units on a Scale (Mean) |
|---|---|
| Symbicort+Tiotropium | -0.197 |
| Placebo+Tiotropium | -0.045 |
Daily diary record. Change in average values from run-in to the full treatment period (NCT00496470)
Timeframe: Baseline to 12 weeks
| Intervention | Liters (Mean) |
|---|---|
| Symbicort+Tiotropium | 0.012 |
| Placebo+Tiotropium | -0.065 |
Change in the pre-dose IC from baseline to week 12 (calculated as a mean using all available data of treatment period between week 1 and week 12) (NCT00496470)
Timeframe: Baseline to 12 weeks
| Intervention | Liters (Mean) |
|---|---|
| Symbicort+Tiotropium | 0.078 |
| Placebo+Tiotropium | 0.014 |
Daily diary record. Change in average values from run-in to the full treatment period (NCT00496470)
Timeframe: Baseline to 12 weeks
| Intervention | Liters/minute (Mean) |
|---|---|
| Symbicort+Tiotropium | 2.82 |
| Placebo+Tiotropium | -5.54 |
Daily diary record. Change in average values from run-in to the full treatment period (NCT00496470)
Timeframe: Baseline to 12 weeks
| Intervention | Liters (Mean) |
|---|---|
| Symbicort+Tiotropium | 0.054 |
| Placebo+Tiotropium | -0.046 |
Change in the 60 min post-dose FEV1from baseline to week 12 (calculated as a mean using all available data of treatment period between week 1 and week 12) (NCT00496470)
Timeframe: Baseline to 12 weeks
| Intervention | Liters (Mean) |
|---|---|
| Symbicort+Tiotropium | 0.214 |
| Placebo+Tiotropium | 0.083 |
Change in the pre-dose FEV1from baseline to week 12 (calculated as a mean using all available data of treatment period between week 1 and week 12) (NCT00496470)
Timeframe: Baseline to 12 weeks
| Intervention | Liters (Mean) |
|---|---|
| Symbicort+Tiotropium | 0.064 |
| Placebo+Tiotropium | -0.001 |
Change in the 5 min post-dose FVC from baseline to week 12 (calculated as a mean using all available data of treatment period between week 1 and week 12) (NCT00496470)
Timeframe: Baseline to 12 weeks
| Intervention | Liters (Mean) |
|---|---|
| Symbicort+Tiotropium | 0.266 |
| Placebo+Tiotropium | 0.106 |
Change in the 60 min post-dose FVC from baseline to week 12 (calculated as a mean using all available data of treatment period between week 1 and week 12 (NCT00496470)
Timeframe: Baseline to 12 weeks
| Intervention | Liters (Mean) |
|---|---|
| Symbicort+Tiotropium | 0.353 |
| Placebo+Tiotropium | 0.19 |
Daily diary record. Change in average values from run-in to the full treatment period (NCT00496470)
Timeframe: Baseline to 12 weeks
| Intervention | Liters (Mean) |
|---|---|
| Symbicort+Tiotropium | 0.169 |
| Placebo+Tiotropium | -0.018 |
Daily diary record. Change in average values from run-in to the full treatment period (NCT00496470)
Timeframe: Baseline to 12 weeks
| Intervention | Liters/minute (Mean) |
|---|---|
| Symbicort+Tiotropium | 20.4 |
| Placebo+Tiotropium | 5.2 |
Change in the pre-dose FVC from baseline to week 12 (calculated as a mean using all available data of treatment period between week 1 and week 12) (NCT00496470)
Timeframe: Baseline to 12 weeks
| Intervention | Liters (Mean) |
|---|---|
| Symbicort+Tiotropium | 0.07 |
| Placebo+Tiotropium | 0.014 |
FEV1 was measured at 5, 15, 30 minutes, 1, 2, 3, 4, 5, 23 hours and 15 minutes, and 23 hours and 45 minutes post dose. (NCT00501852)
Timeframe: Day 1
| Intervention | Liters (Least Squares Mean) | ||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Day 1: -45 minutes | Day 1: -15 minutes | Day 1: 5 minutes | Day 1: 15 minutes | Day 1: 30 minutes | Day 1: 1 hour | Day 1: 2 hours | Day 1: 3 hours | Day 1: 4 hours | Day 1: 5 hours | Day 1: 23 hours 15 minutes | Day 1: 23 hours 45 minutes | Trough | |
| NVA237 100 ug | 1.24 | 1.26 | 1.35 | 1.41 | 1.45 | 1.48 | 1.52 | 1.53 | 1.52 | 1.49 | 1.37 | 1.39 | 1.38 |
| NVA237 12.5 ug | 1.25 | 1.25 | 1.30 | 1.36 | 1.41 | 1.42 | 1.44 | 1.43 | 1.41 | 1.39 | 1.27 | 1.29 | 1.28 |
| NVA237 25 ug | 1.24 | 1.26 | 1.34 | 1.41 | 1.44 | 1.46 | 1.48 | 1.48 | 1.45 | 1.43 | 1.29 | 1.31 | 1.30 |
| NVA237 50 ug | 1.24 | 1.25 | 1.34 | 1.41 | 1.44 | 1.46 | 1.50 | 1.49 | 1.49 | 1.44 | 1.36 | 1.37 | 1.36 |
| Placebo | 1.24 | 1.26 | 1.26 | 1.27 | 1.28 | 1.28 | 1.31 | 1.30 | 1.30 | 1.28 | 1.24 | 1.25 | 1.24 |
| Tiotropium Bromide | 1.25 | 1.25 | 1.31 | 1.35 | 1.40 | 1.41 | 1.45 | 1.46 | 1.46 | 1.45 | 1.35 | 1.37 | 1.36 |
FEV1 is the amount of air which can be forcibly exhaled from the lungs in the first second of a forced exhalation, measured through spirometry testing. The trough in FEV1 was defined as the mean of two measurements at 23h 15min and 23h 45min post dosing. (NCT00501852)
Timeframe: Day 7
| Intervention | Liters (Least Squares Mean) |
|---|---|
| NVA237 12.5 ug | 1.317 |
| NVA237 25 ug | 1.333 |
| NVA237 50 ug | 1.374 |
| NVA237 100 ug | 1.385 |
| Placebo | 1.243 |
| Tiotropium Bromide | 1.370 |
Blood samples were collected for the measurement of total bilirubin, creatinine, and uric acid at pre-dose and 24 hour (h) post-dose of each treatment period. (NCT00515502)
Timeframe: Day 1 of each treatment period (up to Study Day 46)
| Intervention | Micromoles per liter (µmol/L) (Mean) | |||||
|---|---|---|---|---|---|---|
| Total bilirubin, Pre-dose | Total bilirubin, 24 h Post-dose | Creatinine, Pre-dose | Creatinine, 24 h Post-dose | Uric acid, Pre-dose | Uric acid, 24 h Post-dose | |
| Placebo | 7.92 | 8.70 | 78.55 | 78.02 | 295.86 | 285.55 |
| Tiotropium 18 µg | 7.69 | 6.83 | 79.79 | 76.29 | 281.19 | 268.64 |
| UMEC 1000 µg | 8.68 | 10.27 | 78.64 | 76.44 | 317.09 | 306.26 |
| UMEC 250 µg | 8.33 | 8.26 | 80.50 | 79.08 | 301.24 | 293.21 |
| UMEC 500 µg | 8.66 | 9.48 | 80.24 | 78.14 | 303.18 | 296.28 |
Blood samples were collected to determine the plasma concentrations of UMEC from pre-dose up to 24 hour post-dose of each treatment period to derive tmax, tlast and t1/2. Blood samples for PK analysis of UMEC were obtained on Day 1at pre-dose and 5 minutes (min), 15 min, 30 min, 1 hour (h), 2 h, 4 h, 6 h, 8 h, 12 h, 16 h, and 24 h post UMEC dose administration. (NCT00515502)
Timeframe: Day 1 of each treatment period (up to Study Day 46)
| Intervention | Hours (Median) | ||
|---|---|---|---|
| tmax, n=22, 21, 13 | tlast, n=22, 21, 13 | t1/2, n=22, 21, 13 | |
| UMEC 1000 µg | 0.250 | 6.000 | 1.19780 |
| UMEC 250 µg | 0.090 | 1.975 | NA |
| UMEC 500 µg | 0.100 | 4.030 | 1.24490 |
Blood samples were collected for the measurement of the red blood cells count at pre-dose and 24 hour (h) post-dose of each treatment period. (NCT00515502)
Timeframe: Day 1 of each treatment period (up to Study Day 46)
| Intervention | 10^12 cells per liter (TI/L) (Mean) | |
|---|---|---|
| Pre-dose | 24 h Post-dose | |
| Placebo | 4.493 | 4.539 |
| Tiotropium 18 µg | 4.625 | 4.543 |
| UMEC 1000 µg | 4.456 | 4.464 |
| UMEC 250 µg | 4.537 | 4.498 |
| UMEC 500 µg | 4.498 | 4.457 |
The terminal half-life (t1/2) of UMEC is defined as the time required for the urine concentration of UMEC to reach half of its original concentration. Urine samples for PK analysis of UMEC were obtained on Day 1; a single sample was collected at each of the following timepoints: 0-2 h, 2-8 h, 8-12 h, 12-24 h and 24-48 h post UMEC dose administration. (NCT00515502)
Timeframe: Day 1 of each treatment period (up to Study Day 46)
| Intervention | Hours (Geometric Mean) |
|---|---|
| UMEC 250 µg | 10.679 |
| UMEC 500 µg | 12.023 |
| UMEC 1000 µg | 10.821 |
Blood samples were collected for the measurement of platelets count and WBC count at pre-dose and 24 hour (h) post-dose of each treatment period. (NCT00515502)
Timeframe: Day 1 of each treatment period (up to Study Day 46)
| Intervention | 10^9 cells per liter (GI/L) (Mean) | |||
|---|---|---|---|---|
| Platelets count, Pre-dose | Platelets count, 24 h Post-dose | WBC count, Pre-dose | WBC count, 24 h Post-dose | |
| Placebo | 247.2 | 248.8 | 7.623 | 7.520 |
| Tiotropium 18 µg | 243.4 | 237.6 | 6.763 | 6.623 |
| UMEC 1000 µg | 235.9 | 237.9 | 7.121 | 7.999 |
| UMEC 250 µg | 245.0 | 245.4 | 7.130 | 7.385 |
| UMEC 500 µg | 250.7 | 250.3 | 7.560 | 7.218 |
Resting diastolic blood pressure was measured at pre-dose and 15 minutes (min), 45 min, 1.5 hours (h), 4 h, 8 h and 24 h post-dose of each treatment period and the maximum value for diastolic blood pressure (0-4 hours) was derived. Baseline is the mean of the 3 pre-dose measurements for each period. Participant level Baseline is the mean of the Baselines for each participant and period level Baseline is the difference between the Baseline and the participant level Baseline in each treatment period for each participant. Analysis was performed using a mixed model with participant level Baseline, period level Baseline, period and treatment group were fitted as fixed effects and participant as a random effect. (NCT00515502)
Timeframe: Day 1 of each treatment period (up to Study Day 46)
| Intervention | Millimeters of mercury (mmHg) (Least Squares Mean) |
|---|---|
| Placebo | 82.7 |
| UMEC 250 µg | 80.2 |
| UMEC 500 µg | 80.6 |
| UMEC 1000 µg | 86.0 |
| Tiotropium 18 µg | 80.3 |
Resting heart rate was measured at pre-dose and 15 minutes (min), 45min, 1.5 hour (h) 4 h, 8 h, and 24 h post-dose of each treatment period and the maximum value for heart rate (0-4hours) was derived at rest. Baseline is the mean of the 3 pre-dose measurements for each period. Participant level Baseline is the mean of the Baselines for each participant and period level Baseline is the difference between the Baseline and the participant level Baseline in each treatment period for each participant. Analysis was performed using a mixed model with participant level Baseline, period level Baseline, period and treatment group were fitted as fixed effects and participant as a random effect. (NCT00515502)
Timeframe: Day 1 of each treatment period (up to Study Day 46)
| Intervention | Beats per minute (bpm) (Least Squares Mean) |
|---|---|
| Placebo | 69.1 |
| UMEC 250 µg | 68.7 |
| UMEC 500 µg | 69.5 |
| UMEC 1000 µg | 71.2 |
| Tiotropium 18 µg | 66.4 |
Twelve-lead ECGs (electrocardiograms) were performed to measure QT interval corrected according to Bazzet's formula (QTcB) at pre-dose and 15 minutes (min), 45 min, 1.5 hours (h), 4 h, 8 h and 24 h post-dose of each treatment period and the maximum value for QTcB (0-4 hours) was derived. Baseline is the mean of the 3 pre-dose measurements for each period. Participant level Baseline is the mean of the Baselines for each participant and period level Baseline is the difference between the Baseline and the participant level Baseline in each treatment period for each participant. Analysis was performed using a mixed model with participant level Baseline, period level Baseline, period and treatment group were fitted as fixed effects and participant as a random effect. (NCT00515502)
Timeframe: Day 1 of each treatment period (up to Study Day 46)
| Intervention | Milliseconds (msec) (Least Squares Mean) |
|---|---|
| Placebo | 402.79 |
| UMEC 250 µg | 399.48 |
| UMEC 500 µg | 404.48 |
| UMEC 1000 µg | 401.25 |
| Tiotropium 18 µg | 397.62 |
Twelve-lead ECGs were performed to measure QT interval corrected according to Fredericia's formula (QTcF) at pre-dose and 15 minutes (min), 45 min, 1.5 hours (h), 4 h, 8 h and 24 h post-dose of each treatment period and the maximum value for QTcF (0-4 hours) was derived. Baseline is the mean of the 3 pre-dose measurements for each period. Participant level Baseline is the mean of the Baselines for each participant and period level Baseline is the difference between the Baseline and the participant level Baseline in each treatment period for each participant. Analysis was performed using a mixed model with participant level Baseline, period level Baseline, period and treatment group were fitted as fixed effects and participant as a random effect. (NCT00515502)
Timeframe: Day 1 of each treatment period (up to Study Day 46)
| Intervention | Milliseconds (msec) (Least Squares Mean) |
|---|---|
| Placebo | 394.25 |
| UMEC 250 µg | 394.34 |
| UMEC 500 µg | 395.60 |
| UMEC 1000 µg | 393.10 |
| Tiotropium 18 µg | 393.93 |
Resting systolic blood pressure was measured at pre-dose and 15 minutes (min), 45 min, 1.5 hours (h), 4 h, 8 h and 24 h post-dose of each treatment period and the maximum value for systolic blood pressure (0-4 hours) was derived. Baseline is the mean of the 3 pre-dose measurements for each period. Participant level Baseline is the mean of the Baselines for each participant and period level Baseline is the difference between the Baseline and the participant level Baseline in each treatment period for each participant. Analysis was performed using a mixed model with participant level Baseline, period level Baseline, period and treatment group were fitted as fixed effects and participant as a random effect. (NCT00515502)
Timeframe: Day 1 of each treatment period (up to Study Day 46)
| Intervention | Millimeters of mercury (mmHg) (Least Squares Mean) |
|---|---|
| Placebo | 129.7 |
| UMEC 250 µg | 129.0 |
| UMEC 500 µg | 126.2 |
| UMEC 1000 µg | 133.0 |
| Tiotropium 18 µg | 131.0 |
Blood samples were collected to determine the plasma concentrations of UMEC from pre-dose up to 24 hour post-dose of each treatment period to derive the Cmax. Blood samples for PK analysis of UMEC were obtained on Day 1at pre-dose and 5 minutes (min), 15 min, 30 min, 1 hour (h), 2 h, 4 h, 6 h, 8 h, 12 h, 16 h, and 24 h post UMEC dose administration. (NCT00515502)
Timeframe: Day 1 of each treatment period (up to Study Day 46)
| Intervention | ng/mL (Geometric Mean) |
|---|---|
| UMEC 250 µg | 0.12615 |
| UMEC 500 µg | 0.30389 |
| UMEC 1000 µg | 0.83228 |
Twenty-four-hour Holter monitoring was conducted to measure heart rate for the 24-h period following dosing of each treatment period and the mean value for heart rate (0-24 hours) was derived. Analysis was performed using a mixed model of period and treatment group fitted as fixed effects and participant as a random effect. (NCT00515502)
Timeframe: Day 1 of each treatment period (up to Study Day 46)
| Intervention | Beats per minute (bpm) (Least Squares Mean) |
|---|---|
| Placebo | 77.1 |
| UMEC 250 µg | 75.3 |
| UMEC 500 µg | 76.8 |
| UMEC 1000 µg | 75.5 |
| Tiotropium 18 µg | 76.1 |
The CLr is defined as the apparent total clearance of the drug from plasma after oral administration. Blood samples for PK analysis of UMEC were obtained on Day 1at pre-dose and 5 minutes (min), 15 min, 30 min, 1 hour (h), 2 h, 4 h, 6 h, 8 h, 12 h, 16 h, and 24 h post UMEC dose administration. (NCT00515502)
Timeframe: Day 1 of each treatment period (up to Study Day 46)
| Intervention | Liters per hour (L/hr) (Geometric Mean) |
|---|---|
| UMEC 250 µg | 5.317 |
| UMEC 500 µg | 6.395 |
| UMEC 1000 µg | 6.831 |
Resting diastolic blood pressure was measured at pre-dose and 15 minutes (min), 45 min, 1.5 hours (h), 4 h, 8 h and 24 h post-dose of each treatment period and the weighted mean value for diastolic blood pressure (0-4 hours) was derived. Baseline is the mean of the 3 pre-dose measurements for each period. Participant level Baseline is the mean of the Baselines for each participant and period level Baseline is the difference between the Baseline and the participant level Baseline in each treatment period for each participant. Analysis was performed using a mixed model with participant level Baseline, period level Baseline, period and treatment group were fitted as fixed effects and participant as a random effect. (NCT00515502)
Timeframe: Day 1 of each treatment period (up to Study Day 46)
| Intervention | Millimeters of mercury (mmHg) (Least Squares Mean) |
|---|---|
| Placebo | 79.21 |
| UMEC 250 µg | 76.23 |
| UMEC 500 µg | 77.69 |
| UMEC 1000 µg | 81.42 |
| Tiotropium 18 µg | 75.89 |
Resting heart rate was measured at pre-dose and 15 minutes (min), 45 min, 1.5 hours (h), 4 h, 8 h and 24 h post-dose of each treatment period and the weighted mean value for heart rate (0-4 hours) was derived. Baseline is the mean of the 3 pre-dose measurements for each period. Participant level Baseline is the mean of the Baselines for each participant and period level Baseline is the difference between the Baseline and the participant level Baseline in each treatment period for each participant. Analysis was performed using a mixed model with participant level Baseline, period level Baseline, period and treatment group were fitted as fixed effects and participant as a random effect. (NCT00515502)
Timeframe: Day 1 of each treatment period (up to Study Day 46)
| Intervention | Beats per minute (bpm) (Least Squares Mean) |
|---|---|
| Placebo | 64.66 |
| UMEC 250 µg | 63.88 |
| UMEC 500 µg | 65.69 |
| UMEC 1000 µg | 66.61 |
| Tiotropium 18 µg | 62.93 |
Twelve-lead ECGs were performed to measure QTcB at pre-dose and 15 minutes (min), 45 min, 1.5 hours (h), 4 h, 8 h and 24 h post-dose of each treatment period and the weighted mean value for QTcB (0-4 hours) was derived. Baseline is the mean of the 3 pre-dose measurements for each period. Participant level Baseline is the mean of the Baselines for each participant and period level Baseline is the difference between the Baseline and the participant level Baseline in each treatment period for each participant. Analysis was performed using a mixed model with participant level Baseline, period level Baseline, period and treatment group were fitted as fixed effects and participant as a random effect. (NCT00515502)
Timeframe: Day 1 of each treatment period (up to Study Day 46)
| Intervention | Milliseconds (msec) (Least Squares Mean) |
|---|---|
| Placebo | 391.266 |
| UMEC 250 µg | 390.968 |
| UMEC 500 µg | 392.332 |
| UMEC 1000 µg | 389.204 |
| Tiotropium 18 µg | 391.628 |
Twelve-lead ECGs were performed to measure QTcF at pre-dose and 15 minutes (min), 45 min, 1.5 hours (h), 4 h, 8 h and 24 h post-dose of each treatment period and the weighted mean value for QTcF (0-4 hours) was derived. Baseline is the mean of the 3 pre-dose measurements for each period. Participant level Baseline is the mean of the Baselines for each participant and period level Baseline is the difference between the Baseline and the participant level Baseline in each treatment period for each participant. Analysis was performed using a mixed model with participant level Baseline, period level Baseline, period and treatment group were fitted as fixed effects and participant as a random effect. (NCT00515502)
Timeframe: Day 1 of each treatment period (up to Study Day 46)
| Intervention | Milliseconds (msec) (Least Squares Mean) |
|---|---|
| Placebo | 386.501 |
| UMEC 250 µg | 387.965 |
| UMEC 500 µg | 386.750 |
| UMEC 1000 µg | 383.856 |
| Tiotropium 18 µg | 389.086 |
Resting systolic blood pressure was measured at pre-dose and 15 minutes (min), 45 min, 1.5 hours (h), 4 h, 8 h and 24 h post-dose of each treatment period and the weighted mean value for systolic blood pressure (0-4 hours) was derived. Baseline is the mean of the 3 pre-dose measurements for each period. Participant level Baseline is the mean of the Baselines for each participant and period level Baseline is the difference between the Baseline and the participant level Baseline in each treatment period for each participant. Analysis was performed using a mixed model with participant level Baseline, period level Baseline, period and treatment group were fitted as fixed effects and participant as a random effect. (NCT00515502)
Timeframe: Day 1 of each treatment period (up to Study Day 46)
| Intervention | Millimeters of mercury (mmHg) (Least Squares Mean) |
|---|---|
| Placebo | 124.49 |
| UMEC 250 µg | 122.07 |
| UMEC 500 µg | 122.61 |
| UMEC 1000 µg | 125.61 |
| Tiotropium 18 µg | 124.80 |
Serial spirometry assessments were conducted on Day 1 of each treatment period over the course of 24 hours and were taken at 1 hour (h), 2 h, 6 h, 9 h, 12 h and 24 h post-dose. The maximum of the 3 FEV1 measurements for each participant, treatment period and timepoint were used in the calculation of the mean for each treatment group at each timepoint. (NCT00515502)
Timeframe: Day 1 of each treatment period (up to Study Day 46)
| Intervention | Liters (Least Squares Mean) | |||||
|---|---|---|---|---|---|---|
| FEV1, 1 h, n= 21, 20, 21, 13, 8 | FEV1, 2h, n= 21, 20, 21, 13, 8 | FEV1, 6h, n=21, 22, 21, 13, 8 | FEV1, 9h, n=21, 19, 21, 13, 7 | FEV1, 12h, n=21, 22, 21, 13, 7 | FEV1, 24h, n=21, 22, 21, 13, 8 | |
| Placebo | 1.638 | 1.654 | 1.669 | 1.721 | 1.662 | 1.583 |
| Tiotropium 18 µg | 1.880 | 1.910 | 2.050 | 1.927 | 1.812 | 1.655 |
| UMEC 1000 µg | 1.834 | 1.992 | 2.070 | 2.024 | 1.988 | 1.856 |
| UMEC 250 µg | 1.861 | 1.951 | 1.991 | 1.938 | 1.917 | 1.818 |
| UMEC 500 µg | 1.915 | 2.027 | 2.083 | 2.021 | 1.996 | 1.827 |
Blood samples were collected for the measurement of ALP, ALT, AST, CPK, and GGT at pre-dose and 24 hour (h) post-dose of each treatment period. (NCT00515502)
Timeframe: Day 1 of each treatment period (up to Study Day 46)
| Intervention | International units per liter (IU/L) (Mean) | |||||||||
|---|---|---|---|---|---|---|---|---|---|---|
| ALP, Pre-dose, n=21, 22, 21, 13, 8 | ALP, 24 h Post-dose, n=21, 22, 21, 13, 8 | ALT, Pre-dose,n=21, 22, 21, 13, 8 | ALT, 24 h Post-dose,n=21, 22, 21, 13, 8 | AST, Pre-dose, n=21, 22, 20, 13, 8 | AST, 24 h Post-dose, n=21, 22, 21, 13, 8 | CPK, Pre-dose, n=21, 22, 21, 13, 8 | CPK, 24 h Post-dose, n=21, 22, 21, 13, 8 | GGT, Pre-dose, n=21, 22, 21, 13, 8 | GGT, 24 h Post-dose, n=21, 22, 21, 13, 8 | |
| Placebo | 67.04 | 67.20 | 23.6 | 23.3 | 21.98 | 21.68 | 124.33 | 99.97 | 27.81 | 27.14 |
| Tiotropium 18 µg | 71.06 | 71.84 | 19.1 | 17.8 | 22.09 | 19.23 | 117.08 | 109.36 | 19.94 | 19.59 |
| UMEC 1000 µg | 63.37 | 61.76 | 26.2 | 25.6 | 23.03 | 20.75 | 100.16 | 87.78 | 29.86 | 29.38 |
| UMEC 250 µg | 65.32 | 65.04 | 24.1 | 23.0 | 24.55 | 22.01 | 101.88 | 82.81 | 26.41 | 25.33 |
| UMEC 500 µg | 66.60 | 64.96 | 21.3 | 20.5 | 22.13 | 20.58 | 104.39 | 83.77 | 26.41 | 25.89 |
Urine samples were collected to determine the urine concentrations of UMEC from 0 min up to 48 hours post-dose of each treatment period to derive Ae(0-2), Ae(0-8), Ae(0-12), Ae(0-24), Ae(0-48), AUER(0-18) and AUER(0-36). Urine samples for PK analysis of UMEC were obtained on Day 1; a single sample was collected at each of the following timepoints: 0-2 h, 2-8 h, 8-12 h, 12-24 h and 24-48 h post UMEC dose administration. (NCT00515502)
Timeframe: Day 1 of each treatment period (up to Study Day 46)
| Intervention | ng (Geometric Mean) | ||||||
|---|---|---|---|---|---|---|---|
| Ae(0-2) | Ae(0-8) | Ae(0-12) | Ae(0-24) | Ae(0-48) | AUER(0-18) | AUER(0-36) | |
| UMEC 1000 µg | 4456.582 | 9935.792 | 10983.771 | 12401.722 | 13671.981 | 10919.838 | 12363.246 |
| UMEC 250 µg | 734.525 | 1676.101 | 1987.910 | 2352.662 | 2729.434 | 2119.916 | 2487.288 |
| UMEC 500 µg | 1793.951 | 4146.206 | 4712.376 | 5486.724 | 6361.233 | 4830.401 | 5752.880 |
Blood samples were collected to determine the plasma concentrations of UMEC from pre-dose up to 24 hour post-dose of each treatment period to derive the AUC(0-2) and AUC(0-t). Blood samples for PK analysis of UMEC were obtained on Day 1at pre-dose and 5 minutes (min), 15 min, 30 min, 1 hour (h), 2 h, 4 h, 6 h, 8 h, 12 h, 16 h, and 24 h post UMEC dose administration. (NCT00515502)
Timeframe: Day 1 of each treatment period (up to Study Day 46)
| Intervention | hr * nanograms per milliliter (ng/mL) (Geometric Mean) | |
|---|---|---|
| AUC(0-2) | AUC(0-t) | |
| UMEC 1000 µg | 0.71522 | 0.96100 |
| UMEC 250 µg | 0.10264 | 0.10271 |
| UMEC 500 µg | 0.27099 | 0.35491 |
Blood samples were collected for the measurement of basophils, eosinophils, lymphocytes, monocytes, and total neutrophils at pre-dose and 24 hour (h) post-dose of each treatment period. (NCT00515502)
Timeframe: Day 1 of each treatment period (up to Study Day 46)
| Intervention | Percentage (Mean) | |||||||||
|---|---|---|---|---|---|---|---|---|---|---|
| Basophils, Pre-dose | Basophils, 24 h Post-dose | Eosinophils, Pre-dose | Eosinophils, 24 h Post-dose | Lymphocytes, Pre-dose | Lymphocytes, 24 h Post-dose | Monocytes, Pre-dose | Monocytes, 24 h Post-dose | Total neutrophils, Pre-dose | Total neutrophils, 24 h Post-dose | |
| Placebo | 0.65 | 0.70 | 3.30 | 3.34 | 29.23 | 31.60 | 8.53 | 8.10 | 58.30 | 56.26 |
| Tiotropium 18 µg | 0.71 | 0.76 | 3.05 | 3.38 | 27.99 | 30.86 | 9.33 | 9.40 | 58.88 | 55.63 |
| UMEC 1000 µg | 0.87 | 0.58 | 4.03 | 3.49 | 33.70 | 31.72 | 8.10 | 7.45 | 53.32 | 56.78 |
| UMEC 250 µg | 0.73 | 0.65 | 3.46 | 3.25 | 30.66 | 30.86 | 8.50 | 7.62 | 56.64 | 57.62 |
| UMEC 500 µg | 0.74 | 0.56 | 3.67 | 3.30 | 28.91 | 30.99 | 8.60 | 8.23 | 58.10 | 56.94 |
Blood samples were collected for the measurement of the calcium, bicarbonate, chloride, glucose, IP, potassium, sodium, and urea at pre-dose and 24 hour (h) post-dose of each treatment period. (NCT00515502)
Timeframe: Day 1 of each treatment period (up to Study Day 46)
| Intervention | Millimoles per liter (mmol/L) (Mean) | |||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Calcium, Pre-dose, n=21, 22, 21, 13, 8 | Calcium, 24 h Post-dose, n=21, 22, 21, 13, 8 | Chloride, Pre-dose, n=21, 22, 21, 13, 8 | Chloride, 24 h Post-dose, n=21, 22, 21, 13, 8 | Glucose, Pre-dose, n=21, 22, 21, 13, 8 | Glucose, 24 h Post-dose, n=21, 22, 21, 13, 8 | Bicarbonate, Pre-dose, n=21, 22, 21, 13, 8 | Bicarbonate, 24 h Post-dose, n=21, 22, 21, 13, 7 | Potassium, Pre-dose, n=21, 22, 21, 13, 8 | Potassium, 24 h Post-dose, n=21, 22, 21, 13, 8 | Sodium, Pre-dose,n=21, 22, 21, 13, 8 | Sodium, 24 h Post-dose, n=21, 22, 21, 13, 8 | IP, Pre-dose, n=21, 22, 21, 13, 8 | IP, 24 h Post-dose, n=21, 22, 21, 13, 8 | Urea, Pre-dose, n=21, 22, 21, 13, 8 | Urea, 24 h Post-dose, n=21, 22, 21, 13, 8 | |
| Placebo | 2.283 | 2.270 | 106.88 | 107.18 | 5.225 | 5.278 | 22.41 | 22.98 | 4.283 | 4.270 | 140.45 | 140.90 | 1.153 | 1.131 | 4.905 | 4.700 |
| Tiotropium 18 µg | 2.278 | 2.280 | 106.49 | 106.59 | 5.326 | 5.291 | 22.98 | 25.14 | 4.193 | 4.359 | 140.86 | 140.56 | 1.161 | 1.158 | 4.820 | 4.764 |
| UMEC 1000 µg | 2.242 | 2.244 | 107.26 | 107.17 | 5.098 | 5.031 | 23.08 | 23.80 | 4.248 | 4.279 | 141.07 | 141.13 | 1.105 | 1.121 | 4.904 | 4.579 |
| UMEC 250 µg | 2.277 | 2.290 | 107.11 | 107.10 | 5.046 | 5.203 | 22.95 | 22.62 | 4.177 | 4.274 | 140.95 | 140.68 | 1.095 | 1.118 | 4.629 | 4.721 |
| UMEC 500 µg | 2.267 | 2.265 | 106.42 | 106.94 | 5.082 | 5.224 | 23.28 | 23.30 | 4.209 | 4.266 | 140.84 | 140.93 | 1.135 | 1.143 | 5.002 | 4.710 |
FEV1 and FVC are measures of lung function. FEV1 is defined as the maximal amount of air that can be forcefully exhaled in one second. FVC is defined as the amount of air that can be forcibly exhaled from the lungs after taking the deepest breath possible. FEV1 and FVC measurements were taken at pre-dose and 1 hour (h), 2 h, 6 h, 9 h, 12 h and 24 h post-dose of each treatment period. (NCT00515502)
Timeframe: Day 1 of each treatment period (up to Study Day 46)
| Intervention | Liters (Mean) | |||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| FEV1, Pre-dose, n= 21, 22, 21, 13, 8 | FEV1, 1h, n=21, 20, 21, 13, 8 | FEV1, 2h, n= 21, 20, 21, 13, 8 | FEV1, 6h, n=21, 22, 21, 13, 8 | FEV1, 9h, n=21, 19, 21, 13, 7 | FEV1, 12h, n=21, 22, 21, 13,8 | FEV1, 24h, =21, 22, 21, 13, 8 | FVC, Pre-dose, n=21, 22, 21, 13, 8 | FVC, 1h, n=21, 20, 21, 13, 8 | FVC, 2h, n=21, 20, 21, 13, 8 | FVC, 6h, n=21, 22, 21, 13, 8 | FVC, 9h, n=21, 19, 21, 13, 7 | FVC, 12h, n=21, 22, 21, 13, 8 | FVC, 24h, n=21, 22, 21, 13, 8 | |
| Placebo | 1.637 | 1.670 | 1.689 | 1.700 | 1.754 | 1.688 | 1.612 | 3.438 | 3.490 | 3.545 | 3.572 | 3.662 | 3.595 | 3.389 |
| Tiotropium 18 µg | 1.400 | 1.663 | 1.696 | 1.841 | 1.767 | 1.619 | 1.454 | 3.080 | 3.631 | 3.674 | 3.780 | 3.544 | 3.563 | 3.280 |
| UMEC 1000 µg | 1.732 | 1.966 | 2.123 | 2.198 | 2.135 | 2.103 | 1.978 | 3.640 | 4.006 | 4.205 | 4.257 | 4.184 | 4.130 | 3.993 |
| UMEC 250 µg | 1.559 | 1.874 | 1.969 | 2.000 | 1.984 | 1.933 | 1.830 | 3.247 | 3.751 | 3.877 | 3.940 | 4.015 | 3.841 | 3.712 |
| UMEC 500 µg | 1.589 | 1.905 | 2.015 | 2.073 | 2.010 | 1.988 | 1.817 | 3.337 | 3.845 | 3.976 | 4.064 | 3.969 | 3.923 | 3.705 |
Urine samples were collected to determine the urine concentrations of UMEC from 0 min up to 48 hours post-dose of each treatment period to derive Fe(0-24) and Fe(0-48). Urine samples for PK analysis of UMEC were obtained on Day 1; a single sample was collected at each of the following timepoints: 0-2 h, 2-8 h, 8-12 h, 12-24 h and 24-48 h post UMEC dose administration. (NCT00515502)
Timeframe: Day 1 of each treatment period (up to Study Day 46)
| Intervention | Percentage of total dose administered (Median) | |
|---|---|---|
| Fe(0-24) | Fe(0-48) | |
| UMEC 1000 µg | 1.360 | 1.512 |
| UMEC 250 µg | 0.993 | 1.142 |
| UMEC 500 µg | 1.253 | 1.413 |
Blood samples were collected for the measurement of hematocrit at pre-dose and 24 hour (h) post-dose of each treatment period. (NCT00515502)
Timeframe: Day 1 of each treatment period (up to Study Day 46)
| Intervention | Proportion of red blood cells in blood (Mean) | |
|---|---|---|
| Pre-dose | 24 h Post-dose | |
| Placebo | 0.421 | 0.427 |
| Tiotropium 18 µg | 0.445 | 0.434 |
| UMEC 1000 µg | 0.416 | 0.417 |
| UMEC 250 µg | 0.428 | 0.424 |
| UMEC 500 µg | 0.423 | 0.418 |
Blood samples were collected for the measurement of hemoglobin, MCHC, albumin and total protein at pre-dose and 24 hour (h) post-dose of each treatment period. (NCT00515502)
Timeframe: Day 1 of each treatment period (up to Study Day 46)
| Intervention | Grams per liter (G/L) (Mean) | |||||||
|---|---|---|---|---|---|---|---|---|
| Hemoglobin, Pre-dose | Hemoglobin, 24 h Post-dose | MCHC, Pre-dose | MCHC, 24 h Post-dose | Albumin, Pre-dose | Albumin, 24 h Post-dose | Total protein, Pre-dose | Total protein, 24 h Post-dose | |
| Placebo | 146.1 | 147.0 | 347.2 | 344.9 | 39.16 | 39.36 | 66.05 | 66.37 |
| Tiotropium 18 µg | 152.0 | 148.9 | 343.0 | 342.9 | 39.49 | 38.38 | 65.35 | 64.14 |
| UMEC 1000 µg | 143.8 | 143.5 | 346.8 | 345.2 | 39.10 | 39.30 | 66.15 | 66.44 |
| UMEC 250 µg | 146.6 | 145.5 | 343.3 | 344.0 | 39.24 | 38.75 | 66.04 | 65.40 |
| UMEC 500 µg | 145.4 | 144.1 | 344.1 | 344.9 | 39.33 | 38.76 | 66.19 | 65.62 |
Blood samples were collected for the measurement of the mean corpuscle hemoglobin at pre-dose and 24 hour (h) post-dose of each treatment period. (NCT00515502)
Timeframe: Day 1 of each treatment period (up to Study Day 46)
| Intervention | picograms/cell (pg) (Mean) | |
|---|---|---|
| Pre-dose | 24 Hour Post-dose | |
| Placebo | 32.56 | 32.41 |
| Tiotropium 18 µg | 32.86 | 32.79 |
| UMEC 1000 µg | 32.29 | 32.15 |
| UMEC 250 µg | 32.36 | 32.36 |
| UMEC 500 µg | 32.36 | 32.36 |
Blood samples were collected for the measurement of the mean corpuscle volume at pre-dose and 24 hour (h) post-dose of each treatment period. (NCT00515502)
Timeframe: Day 1 of each treatment period (up to Study Day 46)
| Intervention | Femtoliters (FL) (Mean) | |
|---|---|---|
| Pre-dose | 24 h Post-dose | |
| Placebo | 93.78 | 93.99 |
| Tiotropium 18 µg | 95.83 | 95.65 |
| UMEC 1000 µg | 93.11 | 93.15 |
| UMEC 250 µg | 94.23 | 94.09 |
| UMEC 500 µg | 94.04 | 93.85 |
sGaw is the specific airways resistance (mid) which was assessed by whole body plethysmography. Values used were the mean of the 3 readings recorded at each timepoint. sGaw measurements were taken at 2 hour (h), 6 h, 12 h and 24 h post-dose of each treatment period. 1/kPa.s=1(the inverses)/kPa (kilopascal).s (second) (NCT00515502)
Timeframe: Day 1 of each treatment period (up to Study Day 46)
| Intervention | 1/kPa*s (Geometric Mean) | |||
|---|---|---|---|---|
| sGaw, 2h, n= 21, 20, 21, 13, 8 | sGaw, 6h, n=21, 21, 21, 13, 8 | sGaw, 12h, n=21, 21, 21, 13, 8 | sGaw, 24h, n=21, 21, 21, 13, 8 | |
| Placebo | 0.400 | 0.426 | 0.403 | 0.379 |
| Tiotropium 18 µg | 0.648 | 0.711 | 0.550 | 0.440 |
| UMEC 1000 µg | 0.714 | 0.778 | 0.730 | 0.514 |
| UMEC 250 µg | 0.652 | 0.734 | 0.637 | 0.514 |
| UMEC 500 µg | 0.699 | 0.806 | 0.735 | 0.501 |
An AE is defined as any untoward medical occurrence in a clinical investigation participant, temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally associated with the use of a medicinal product. An SAE is defined as any untoward medical occurrence that, at any dose, results in death, is life threatening, requires hospitalization or prolongation of existing hospitalization, results in disability/incapacity, is a congenital anomaly/birth defect, may jeopardize the participant or may require medical or surgical intervention to prevent one of the other outcomes listed in this definition, or is an event of possible drug-induced liver injury. Refer to the general AE/SAE module for a list of AEs and SAEs. (NCT00515502)
Timeframe: From Day 1 of Treatment Period 1until Follow-up (up to 10 weeks)
| Intervention | Participants (Number) | |
|---|---|---|
| Any AE | Any SAE | |
| Placebo | 6 | 0 |
| Tiotropium 18 µg | 3 | 0 |
| UMEC 1000 µg | 4 | 0 |
| UMEC 250 µg | 9 | 0 |
| UMEC 500 µg | 8 | 0 |
Twenty-four hour Holter monitoring was conducted to measure heart rate for the 24-hour period following dosing at each treatment period and the maximum value for heart rate (0-24 hours) was derived. Analysis was performed using a mixed model of period and treatment group fitted as fixed effects and participant as a random effect. (NCT00515502)
Timeframe: Day 1 of each treatment period (up to Study Day 46)
| Intervention | Beats per minute (bpm) (Least Squares Mean) |
|---|---|
| Placebo | 116.7 |
| UMEC 250 µg | 111.5 |
| UMEC 500 µg | 112.1 |
| UMEC 1000 µg | 109.0 |
| Tiotropium 18 µg | 111.4 |
"WPAI: self-administered instrument used to measure effect of general health and symptom severity on work productivity and regular activities and yields 4 types of scores: Absenteeism (work time missed); Presenteeism (impairment at work/reduced on-the-job effectiveness); Work Productivity Loss (overall work impairment/absenteeism plus presenteeism); and Activity Impairment.~Absenteeism, Presenteeism, Work productivity loss, Activity Impairment Scores range from 0 to 100 for each of the above 4 types; higher scores indicate greater impairment." (NCT00523991)
Timeframe: baseline
| Intervention | units on a scale (Mean) |
|---|---|
| Placebo | 5.5 |
| Tiotropium | 2.7 |
"WPAI: self-administered instrument used to measure effect of general health and symptom severity on work productivity and regular activities and yields 4 types of scores: Absenteeism (work time missed); Presenteeism (impairment at work/reduced on-the-job effectiveness); Work Productivity Loss (overall work impairment/absenteeism plus presenteeism); and Activity Impairment.~Absenteeism, Presenteeism, Work productivity loss, Activity Impairment Scores range from 0 to 100 for each of the above 4 types; higher scores indicate greater impairment." (NCT00523991)
Timeframe: baseline
| Intervention | units on a scale (Mean) |
|---|---|
| Placebo | 19.3 |
| Tiotropium | 22.0 |
"WPAI: self-administered instrument used to measure effect of general health and symptom severity on work productivity and regular activities and yields 4 types of scores: Absenteeism (work time missed); Presenteeism (impairment at work/reduced on-the-job effectiveness); Work Productivity Loss (overall work impairment/absenteeism plus presenteeism); and Activity Impairment.~Absenteeism, Presenteeism, Work productivity loss, Activity Impairment Scores range from 0 to 100 for each of the above 4 types; higher scores indicate greater impairment." (NCT00523991)
Timeframe: baseline
| Intervention | units on a scale (Mean) |
|---|---|
| Placebo | 17.2 |
| Tiotropium | 21.1 |
"WPAI: self-administered instrument used to measure effect of general health and symptom severity on work productivity and regular activities and yields 4 types of scores: Absenteeism (work time missed); Presenteeism (impairment at work/reduced on-the-job effectiveness); Work Productivity Loss (overall work impairment/absenteeism plus presenteeism); and Activity Impairment.~Absenteeism, Presenteeism, Work productivity loss, Activity Impairment Scores range from 0 to 100 for each of the above 4 types; higher scores indicate greater impairment." (NCT00523991)
Timeframe: baseline
| Intervention | units on a scale (Mean) |
|---|---|
| Placebo | 25.4 |
| Tiotropium | 28 |
Trough FVC defined as the FVC measured at 10 minutes prior to the end of the dosing interval, approximately 24 hours post drug administration. Baseline FVC was the pre-treatment FVC measured at Week 0 in the morning 10 minutes prior to the administration of the first dose of the study medication. (NCT00523991)
Timeframe: baseline
| Intervention | litres (Mean) |
|---|---|
| Placebo | 3.17 |
| Tiotropium | 3.24 |
Trough FEV1 defined as the FEV1 measured at 10 minutes prior to the end of the dosing interval, approximately 24 hours post drug administration. Baseline FEV1 was the pre-treatment FEV1 measured at Week 0 in the morning 10 minutes prior to the administration of the first dose of the study medication. (NCT00523991)
Timeframe: Baseline
| Intervention | litres (Mean) |
|---|---|
| Placebo | 1.71 |
| Tiotropium | 1.74 |
"Moderate or higher intensity is greater than or equal to three metabolic equivalents~Metabolic equivalent threshold (MET): Unit used to estimate the metabolic cost of physical activity, in terms of multiples of the subject's resting metabolic rate. One metabolic equivalent is, by convention, 3.5 ml of O2 uptake per minute per kilogram body weight, and theoretically approximates the resting metabolic rate.~ln in measure value unit means natural logarithm" (NCT00523991)
Timeframe: baseline
| Intervention | ln(minutes) (Mean) |
|---|---|
| Placebo | 4.2 |
| Tiotropium | 4.3 |
"Light intensity is less than three metabolic equivalents.~Metabolic equivalent threshold (MET): Unit used to estimate the metabolic cost of physical activity, in terms of multiples of the subject's resting metabolic rate. One metabolic equivalent is, by convention, 3.5 ml of O2 uptake per minute per kilogram body weight, and theoretically approximates the resting metabolic rate.~ln in measure value unit means natural logarithm." (NCT00523991)
Timeframe: baseline
| Intervention | ln(minutes) (Mean) |
|---|---|
| Placebo | 6.9 |
| Tiotropium | 6.8 |
Peak FEV1 defined as the maximum of the observed values over 30, 60, 120, and 180 minutes post-dose for FEV1. (NCT00523991)
Timeframe: baseline
| Intervention | litres (Mean) |
|---|---|
| Placebo | 3.17 |
| Tiotropium | 3.24 |
Peak FEV1 defined as the maximum of the observed values over 30, 60, 120, and 180 minutes post-dose for FEV1. (NCT00523991)
Timeframe: Baseline
| Intervention | litres (Mean) |
|---|---|
| Placebo | 1.71 |
| Tiotropium | 1.74 |
"Moderate or higher intensity is greater than or equal to three metabolic equivalents~Metabolic equivalent threshold (MET): Unit used to estimate the metabolic cost of physical activity, in terms of multiples of the subject's resting metabolic rate. One metabolic equivalent is, by convention, 3.5 ml of O2 uptake per minute per kilogram body weight, and theoretically approximates the resting metabolic rate.~ln in measure value unit means natural logarithm" (NCT00523991)
Timeframe: baseline, week 12
| Intervention | ln(minutes) (Least Squares Mean) |
|---|---|
| Placebo | -0.14 |
| Tiotropium | -0.09 |
"Light intensity is less than three metabolic equivalents~Metabolic equivalent threshold (MET): Unit used to estimate the metabolic cost of physical activity, in terms of multiples of the subject's resting metabolic rate. One metabolic equivalent is, by convention, 3.5 ml of O2 uptake per minute per kilogram body weight, and theoretically approximates the resting metabolic rate.~ln in measure value unit means natural logarithm" (NCT00523991)
Timeframe: baseline, week 8
| Intervention | ln(minutes) (Least Squares Mean) |
|---|---|
| Placebo | 0.02 |
| Tiotropium | 0.03 |
"Light intensity is less than three metabolic equivalents~Metabolic equivalent threshold (MET): Unit used to estimate the metabolic cost of physical activity, in terms of multiples of the subject's resting metabolic rate. One metabolic equivalent is, by convention, 3.5 ml of O2 uptake per minute per kilogram body weight, and theoretically approximates the resting metabolic rate.~ln in measure value unit means natural logarithm" (NCT00523991)
Timeframe: baseline, week 4
| Intervention | ln(minutes) (Least Squares Mean) |
|---|---|
| Placebo | 0.03 |
| Tiotropium | 0.02 |
"Light intensity is less than three metabolic equivalents~Metabolic equivalent threshold (MET): Unit used to estimate the metabolic cost of physical activity, in terms of multiples of the subject's resting metabolic rate. One metabolic equivalent is, by convention, 3.5 ml of O2 uptake per minute per kilogram body weight, and theoretically approximates the resting metabolic rate.~ln in measure value unit means natural logarithm" (NCT00523991)
Timeframe: baseline, week 24
| Intervention | ln(minutes) (Least Squares Mean) |
|---|---|
| Placebo | 0.02 |
| Tiotropium | 0.03 |
"Light intensity is less than three metabolic equivalents~Metabolic equivalent threshold (MET): Unit used to estimate the metabolic cost of physical activity, in terms of multiples of the subject's resting metabolic rate. One metabolic equivalent is, by convention, 3.5 ml of O2 uptake per minute per kilogram body weight, and theoretically approximates the resting metabolic rate.~ln in measure value unit means natural logarithm" (NCT00523991)
Timeframe: baseline, week 20
| Intervention | ln(minutes) (Least Squares Mean) |
|---|---|
| Placebo | 0.03 |
| Tiotropium | 0.04 |
"Light intensity is less than three metabolic equivalents~Metabolic equivalent threshold (MET): Unit used to estimate the metabolic cost of physical activity, in terms of multiples of the subject's resting metabolic rate. One metabolic equivalent is, by convention, 3.5 ml of O2 uptake per minute per kilogram body weight, and theoretically approximates the resting metabolic rate.~ln in measure value unit means natural logarithm" (NCT00523991)
Timeframe: baseline, week 16
| Intervention | ln(minutes) (Least Squares Mean) |
|---|---|
| Placebo | 0.03 |
| Tiotropium | 0.04 |
"Light intensity defined as less than three metabolic equivalents.~Metabolic equivalent threshold (MET): Unit used to estimate the metabolic cost of physical activity, in terms of multiples of the subject's resting metabolic rate. One metabolic equivalent is, by convention, 3.5 ml of O2 uptake per minute per kilogram body weight, and theoretically approximates the resting metabolic rate.~ln in measure value unit means natural logarithm" (NCT00523991)
Timeframe: baseline, week 12
| Intervention | ln(minutes) (Least Squares Mean) |
|---|---|
| Placebo | 0.03 |
| Tiotropium | 0.02 |
Peak FEV1 defined as the maximum of the observed values over 30, 60, 120, and 180 minutes post-dose for FEV1. Peak response was defined as the change from baseline to the peak FEV1 value at the final visit. (NCT00523991)
Timeframe: baseline, week 8
| Intervention | litres (Mean) |
|---|---|
| Placebo | 0.13 |
| Tiotropium | 0.43 |
Peak FEV1 defined as the maximum of the observed values over 30, 60, 120, and 180 minutes post-dose for FEV1. Peak response was defined as the change from baseline to the peak FEV1 value at the final visit. (NCT00523991)
Timeframe: baseline, week 24
| Intervention | litres (Least Squares Mean) |
|---|---|
| Placebo | 0.06 |
| Tiotropium | 0.40 |
Peak FEV1 defined as the maximum of the observed values over 30, 60, 120, and 180 minutes post-dose for FEV1. Peak response was defined as the change from baseline to the peak FEV1 value at the final visit. (NCT00523991)
Timeframe: baseline, week 16
| Intervention | litres (Mean) |
|---|---|
| Placebo | 0.08 |
| Tiotropium | 0.38 |
Peak FEV1 defined as the maximum of the observed values over 30, 60, 120, and 180 minutes post-dose for FEV1. Peak response was defined as the change from baseline to the peak FEV1 value at the final visit. (NCT00523991)
Timeframe: Baseline, week 8
| Intervention | litres (Mean) |
|---|---|
| Placebo | 0.09 |
| Tiotropium | 0.31 |
Peak FEV1 defined as the maximum of the observed values over 30, 60, 120, and 180 minutes post-dose for FEV1. Peak response was defined as the change from baseline to the peak FEV1 value at the final visit. (NCT00523991)
Timeframe: Baseline, week 24
| Intervention | litres (Least Squares Mean) |
|---|---|
| Placebo | 0.02 |
| Tiotropium | 0.26 |
Change from baseline in peak forced expiratory volume in 1 second (at week 24, pre-dose) (NCT00523991)
Timeframe: baseline, week 24, pre-dose
| Intervention | litres (Least Squares Mean) |
|---|---|
| Placebo | -0.08 |
| Tiotropium | 0.06 |
Change from baseline in peak forced expiratory volume in 1 second (at week 24, 60 minutes) (NCT00523991)
Timeframe: baseline, week 24, 60 minutes
| Intervention | litres (Least Squares Mean) |
|---|---|
| Placebo | -0.05 |
| Tiotropium | 0.18 |
Change from baseline in peak forced expiratory volume in 1 second (at week 24, 30 minutes) (NCT00523991)
Timeframe: baseline, week 24, 30 minutes
| Intervention | litres (Least Squares Mean) |
|---|---|
| Placebo | -0.05 |
| Tiotropium | 0.15 |
Change from baseline in peak forced expiratory volume in 1 second (at week 24, 180 minutes) (NCT00523991)
Timeframe: baseline, week 24, 180 minutes
| Intervention | litres (Least Squares Mean) |
|---|---|
| Placebo | -0.05 |
| Tiotropium | 0.20 |
Change from baseline in peak forced expiratory volume in 1 second (at week 24, 120 minutes) (NCT00523991)
Timeframe: baseline, week 24, 120 minutes
| Intervention | litres (Least Squares Mean) |
|---|---|
| Placebo | -0.06 |
| Tiotropium | 0.18 |
Peak FEV1 defined as the maximum of the observed values over 30, 60, 120, and 180 minutes post-dose for FEV1. Peak response was defined as the change from baseline to the peak FEV1 value at the final visit. (NCT00523991)
Timeframe: Baseline, week 16
| Intervention | litres (Mean) |
|---|---|
| Placebo | 0.05 |
| Tiotropium | 0.29 |
Change from baseline in peak forced expiratory volume in 1 second (at week 16, 60 minutes) (NCT00523991)
Timeframe: baseline, week 16, 60 minutes
| Intervention | litres (Mean) |
|---|---|
| Placebo | -0.02 |
| Tiotropium | 0.21 |
Change from baseline in peak forced expiratory volume in 1 second (at week 16, 30 minutes) (NCT00523991)
Timeframe: Baseline, week 16, 30 minutes
| Intervention | litres (Mean) |
|---|---|
| Placebo | -0.02 |
| Tiotropium | 0.19 |
"Moderate or higher intensity is greater than or equal to three metabolic equivalents~Metabolic equivalent threshold (MET): Unit used to estimate the metabolic cost of physical activity, in terms of multiples of the subject's resting metabolic rate. One metabolic equivalent is, by convention, 3.5 ml of O2 uptake per minute per kilogram body weight, and theoretically approximates the resting metabolic rate.~ln in measure value unit means natural logarithm" (NCT00523991)
Timeframe: baseline, week 16
| Intervention | ln(minutes) (Least Squares Mean) |
|---|---|
| Placebo | -0.26 |
| Tiotropium | -0.20 |
Change from baseline in peak forced expiratory volume in 1 second (at week 16, 180 minutes) (NCT00523991)
Timeframe: baseline, week 16, 180 minutes
| Intervention | litres (Mean) |
|---|---|
| Placebo | -0.02 |
| Tiotropium | 0.22 |
Change from baseline in peak forced expiratory volume in 1 second (at week 16, 120 minutes) (NCT00523991)
Timeframe: baseline, week 16, 120 minutes
| Intervention | litres (Mean) |
|---|---|
| Placebo | -0.03 |
| Tiotropium | 0.22 |
Change from baseline in number of steps per day (week 8) (NCT00523991)
Timeframe: baseline, week 8
| Intervention | Steps (Least Squares Mean) |
|---|---|
| Placebo | -121.66 |
| Tiotropium | -153.09 |
Change from baseline in number of steps per day (week 4) (NCT00523991)
Timeframe: baseline, week 4
| Intervention | Steps (Least Squares Mean) |
|---|---|
| Placebo | -263.91 |
| Tiotropium | -287.45 |
Change from baseline in number of steps per day (week 24) (NCT00523991)
Timeframe: baseline, week 24
| Intervention | Steps (Least Squares Mean) |
|---|---|
| Placebo | -234.80 |
| Tiotropium | -183.34 |
Change from baseline in number of steps per day (week 20) (NCT00523991)
Timeframe: baseline, week 20
| Intervention | Steps (Least Squares Mean) |
|---|---|
| Placebo | -408.34 |
| Tiotropium | -197.17 |
Change from baseline in number of steps per day (week 16) (NCT00523991)
Timeframe: baseline, week 16
| Intervention | Steps (Least Squares Mean) |
|---|---|
| Placebo | -655.04 |
| Tiotropium | -396.21 |
Change from baseline in Number of steps per day (week 12) (NCT00523991)
Timeframe: baseline, week 12
| Intervention | Steps (Least Squares Mean) |
|---|---|
| Placebo | -351.30 |
| Tiotropium | -169.31 |
Change = Week 24 Value - Baseline Value (NCT00523991)
Timeframe: baseline, week 24
| Intervention | litres * hours (Least Squares Mean) |
|---|---|
| Placebo | -0.06 |
| Tiotropium | 0.16 |
Change from baseline in forced vital capacity (week 8, pre-dose) (NCT00523991)
Timeframe: baseline, week 8, pre-dose
| Intervention | litres (Mean) |
|---|---|
| Placebo | -0.06 |
| Tiotropium | 0.16 |
Change from baseline in forced vital capacity (week 8, 60 minutes) (NCT00523991)
Timeframe: baseline, week 8, 60 minutes
| Intervention | litres (Mean) |
|---|---|
| Placebo | 0.00 |
| Tiotropium | 0.29 |
Change from baseline in forced vital capacity (week 8, 30 minutes) (NCT00523991)
Timeframe: baseline, week 8, 30 minutes
| Intervention | litres (Mean) |
|---|---|
| Placebo | 0.00 |
| Tiotropium | 0.27 |
Change from baseline in forced vital capacity (week 8, 180 minutes) (NCT00523991)
Timeframe: baseline, week 8, 180 minutes
| Intervention | litres (Mean) |
|---|---|
| Placebo | 0.00 |
| Tiotropium | 0.30 |
Change from baseline in forced vital capacity (week 8, 120 minutes) (NCT00523991)
Timeframe: baseline, week 8, 120 minutes
| Intervention | litres (Mean) |
|---|---|
| Placebo | -0.02 |
| Tiotropium | 0.30 |
Change from baseline in forced vital capacity (week 24, pre-dose) (NCT00523991)
Timeframe: baseline, week 24, pre-dose
| Intervention | litres (Least Squares Mean) |
|---|---|
| Placebo | -0.14 |
| Tiotropium | 0.07 |
Change from baseline in forced vital capacity (week 24, 60 minutes) (NCT00523991)
Timeframe: baseline, week 24, 60 minutes
| Intervention | litres (Least Squares Mean) |
|---|---|
| Placebo | -0.07 |
| Tiotropium | 0.23 |
Change from baseline in forced vital capacity (week 24, 30 minutes) (NCT00523991)
Timeframe: baseline, week 24, 30 minutes
| Intervention | litres (Least Squares Mean) |
|---|---|
| Placebo | -0.10 |
| Tiotropium | 0.19 |
Change from baseline in forced vital capacity (week 24, 180 minutes) (NCT00523991)
Timeframe: baseline, week 24, 180 minutes
| Intervention | litres (Least Squares Mean) |
|---|---|
| Placebo | -0.07 |
| Tiotropium | 0.29 |
Change from baseline in forced vital capacity (week 24, 120 minutes) (NCT00523991)
Timeframe: baseline, week 24, 120 minutes
| Intervention | litres (Least Squares Mean) |
|---|---|
| Placebo | -0.11 |
| Tiotropium | 0.22 |
Change from baseline in forced vital capacity (week 16, pre-dose) (NCT00523991)
Timeframe: baseline, week 16, pre-dose
| Intervention | litres (Mean) |
|---|---|
| Placebo | -0.13 |
| Tiotropium | 0.10 |
Change from baseline in forced vital capacity (week 16, 60 minutes) (NCT00523991)
Timeframe: baseline, week 16, 60 minutes
| Intervention | litres (Mean) |
|---|---|
| Placebo | -0.05 |
| Tiotropium | 0.27 |
Change from baseline in forced vital capacity (week 16, 30 minutes) (NCT00523991)
Timeframe: baseline, week 16, 30 minutes
| Intervention | litres (Mean) |
|---|---|
| Placebo | -0.06 |
| Tiotropium | 0.24 |
Number of steps per day (baseline) (NCT00523991)
Timeframe: baseline
| Intervention | Steps (Mean) |
|---|---|
| Placebo | 7343.4 |
| Tiotropium | 7366.1 |
Change from baseline in Forced vital capacity (FVC) area under the curve from 0-3 hours (AUC0-3h) (week 8) (NCT00523991)
Timeframe: baseline, week 8
| Intervention | litres * hours (Mean) |
|---|---|
| Placebo | -0.01 |
| Tiotropium | 0.28 |
Change from baseline in forced vital capacity (week 16, 180 minutes) (NCT00523991)
Timeframe: baseline, week 16, 180 minutes
| Intervention | litres (Mean) |
|---|---|
| Placebo | -0.05 |
| Tiotropium | 0.26 |
Change from baseline in forced vital capacity (week 16, 120 minutes) (NCT00523991)
Timeframe: baseline, week 16, 120 minutes
| Intervention | litres (Mean) |
|---|---|
| Placebo | -0.05 |
| Tiotropium | 0.26 |
Change from baseline in forced expiratory volume in 1 second (at week 8, pre-dose) (NCT00523991)
Timeframe: baseline, week 8, pre-dose
| Intervention | litres (Mean) |
|---|---|
| Placebo | -0.03 |
| Tiotropium | 0.12 |
Change from baseline in forced expiratory volume in 1 second (at week 8, 60 minutes) (NCT00523991)
Timeframe: baseline, week 8, 60 minutes
| Intervention | litres (Mean) |
|---|---|
| Placebo | 0.01 |
| Tiotropium | 0.22 |
Change from baseline in Forced vital capacity (FVC) area under the curve from 0-3 hours (AUC0-3h) (week 24) (NCT00523991)
Timeframe: baseline, week 24
| Intervention | litres * hours (Least Squares Mean) |
|---|---|
| Placebo | -0.11 |
| Tiotropium | 0.19 |
Change from baseline in Forced vital capacity (FVC) area under the curve from 0-3 hours (AUC0-3h)(week 16) (NCT00523991)
Timeframe: baseline, week 16
| Intervention | litres * hours (Mean) |
|---|---|
| Placebo | -0.06 |
| Tiotropium | 0.24 |
Forced vital capacity (FVC) area under the curve from 0-3 hours (AUC0-3h) (NCT00523991)
Timeframe: baseline
| Intervention | litres * hours (Mean) |
|---|---|
| Placebo | 3.17 |
| Tiotropium | 3.24 |
Forced vital capacity (baseline, pre-dose) (NCT00523991)
Timeframe: baseline
| Intervention | litres (Mean) |
|---|---|
| Placebo | 3.17 |
| Tiotropium | 3.24 |
Forced vital capacity (baseline, 60 minutes) (NCT00523991)
Timeframe: baseline, 60 minutes
| Intervention | litres (Mean) |
|---|---|
| Placebo | 3.22 |
| Tiotropium | 3.48 |
Forced vital capacity (baseline, 30 minutes) (NCT00523991)
Timeframe: baseline, 30 minutes
| Intervention | litres (Mean) |
|---|---|
| Placebo | 3.20 |
| Tiotropium | 3.45 |
Forced vital capacity (baseline, 180 minutes) (NCT00523991)
Timeframe: baseline, 180 minutes
| Intervention | litres (Mean) |
|---|---|
| Placebo | 3.21 |
| Tiotropium | 3.50 |
Forced vital capacity (baseline, 120 minutes) (NCT00523991)
Timeframe: baseline, 120 minutes
| Intervention | litres (Mean) |
|---|---|
| Placebo | 3.21 |
| Tiotropium | 3.49 |
Forced expiratory volume in 1 second (baseline, pre-dose) (NCT00523991)
Timeframe: Baseline
| Intervention | litres (Mean) |
|---|---|
| Placebo | 1.71 |
| Tiotropium | 1.74 |
Forced expiratory volume in 1 second (baseline, 60 minutes) (NCT00523991)
Timeframe: baseline, 60 minutes
| Intervention | litres (Mean) |
|---|---|
| Placebo | 1.74 |
| Tiotropium | 1.90 |
Forced expiratory volume in 1 second (baseline, 30 minutes) (NCT00523991)
Timeframe: baseline, 30 minutes
| Intervention | litres (Mean) |
|---|---|
| Placebo | 1.73 |
| Tiotropium | 1.87 |
Forced expiratory volume in 1 second (baseline, 180 minutes) (NCT00523991)
Timeframe: Baseline, 180 minutes
| Intervention | litres (Mean) |
|---|---|
| Placebo | 1.76 |
| Tiotropium | 1.94 |
Forced expiratory volume in 1 second (baseline, 120 minutes) (NCT00523991)
Timeframe: Baseline, 120 minutes
| Intervention | litres (Mean) |
|---|---|
| Placebo | 1.75 |
| Tiotropium | 1.92 |
WPAI: self-administered instrument used to measure effect of general health and symptom severity on work productivity and regular activities and yields 4 types of scores: Absenteeism (work time missed); Presenteeism (impairment at work/reduced on-the-job effectiveness); Work Productivity Loss (overall work impairment/absenteeism plus presenteeism); and Activity Impairment. Scores range from 0 to 100 for each of the above 4 types; higher scores indicate greater impairment. Difference refers to change in scale between week 8 and baseline. (NCT00523991)
Timeframe: baseline, week 8
| Intervention | units on a scale (Least Squares Mean) |
|---|---|
| Placebo | -1.94 |
| Tiotropium | 3.85 |
WPAI: self-administered instrument used to measure effect of general health and symptom severity on work productivity and regular activities and yields 4 types of scores: Absenteeism (work time missed); Presenteeism (impairment at work/reduced on-the-job effectiveness); Work Productivity Loss (overall work impairment/absenteeism plus presenteeism); and Activity Impairment. Scores range from 0 to 100 for each of the above 4 types; higher scores indicate greater impairment. Difference refers to change in scale between week 4 and baseline. (NCT00523991)
Timeframe: baseline, week 4
| Intervention | units on a scale (Least Squares Mean) |
|---|---|
| Placebo | -1.89 |
| Tiotropium | -0.15 |
WPAI: self-administered instrument used to measure effect of general health and symptom severity on work productivity and regular activities and yields 4 types of scores: Absenteeism (work time missed); Presenteeism (impairment at work/reduced on-the-job effectiveness); Work Productivity Loss (overall work impairment/absenteeism plus presenteeism); and Activity Impairment. Scores range from 0 to 100 for each of the above 4 types; higher scores indicate greater impairment. Difference refers to change in scale between week 24 and baseline. (NCT00523991)
Timeframe: baseline, week 24
| Intervention | units on a scale (Least Squares Mean) |
|---|---|
| Placebo | 0.96 |
| Tiotropium | -1.37 |
WPAI: self-administered instrument used to measure effect of general health and symptom severity on work productivity and regular activities and yields 4 types of scores: Absenteeism (work time missed); Presenteeism (impairment at work/reduced on-the-job effectiveness); Work Productivity Loss (overall work impairment/absenteeism plus presenteeism); and Activity Impairment. Scores range from 0 to 100 for each of the above 4 types; higher scores indicate greater impairment. Difference refers to change in scale between week 20 and baseline. (NCT00523991)
Timeframe: baseline, week 20
| Intervention | units on a scale (Least Squares Mean) |
|---|---|
| Placebo | 0.51 |
| Tiotropium | 2.00 |
WPAI: self-administered instrument used to measure effect of general health and symptom severity on work productivity and regular activities and yields 4 types of scores: Absenteeism (work time missed); Presenteeism (impairment at work/reduced on-the-job effectiveness); Work Productivity Loss (overall work impairment/absenteeism plus presenteeism); and Activity Impairment. Scores range from 0 to 100 for each of the above 4 types; higher scores indicate greater impairment. Difference refers to change in scale between week 16 and baseline. (NCT00523991)
Timeframe: baseline, week 16
| Intervention | units on a scale (Least Squares Mean) |
|---|---|
| Placebo | -3.39 |
| Tiotropium | 0.04 |
WPAI: self-administered instrument used to measure effect of general health and symptom severity on work productivity and regular activities and yields 4 types of scores: Absenteeism (work time missed); Presenteeism (impairment at work/reduced on-the-job effectiveness); Work Productivity Loss (overall work impairment/absenteeism plus presenteeism); and Activity Impairment. Scores range from 0 to 100 for each of the above 4 types; higher scores indicate greater impairment. Difference refers to change in scale between week 12 and baseline. (NCT00523991)
Timeframe: baseline, week 12
| Intervention | units on a scale (Least Squares Mean) |
|---|---|
| Placebo | 0.12 |
| Tiotropium | 4.22 |
WPAI: self-administered instrument used to measure effect of general health and symptom severity on work productivity and regular activities and yields 4 types of scores: Absenteeism (work time missed); Presenteeism (impairment at work/reduced on-the-job effectiveness); Work Productivity Loss (overall work impairment/absenteeism plus presenteeism); and Activity Impairment. Scores range from 0 to 100 for each of the above 4 types; higher scores indicate greater impairment. Difference refers to change in scale between week 8 and baseline. (NCT00523991)
Timeframe: baseline, week 8
| Intervention | units on a scale (Least Squares Mean) |
|---|---|
| Placebo | -0.62 |
| Tiotropium | -1.04 |
WPAI: self-administered instrument used to measure effect of general health and symptom severity on work productivity and regular activities and yields 4 types of scores: Absenteeism (work time missed); Presenteeism (impairment at work/reduced on-the-job effectiveness); Work Productivity Loss (overall work impairment/absenteeism plus presenteeism); and Activity Impairment. Scores range from 0 to 100 for each of the above 4 types; higher scores indicate greater impairment. Difference refers to change in scale between week 4 and baseline. (NCT00523991)
Timeframe: baseline, week 4
| Intervention | units on a scale (Least Squares Mean) |
|---|---|
| Placebo | -2.39 |
| Tiotropium | -3.50 |
WPAI: self-administered instrument used to measure effect of general health and symptom severity on work productivity and regular activities and yields 4 types of scores: Absenteeism (work time missed); Presenteeism (impairment at work/reduced on-the-job effectiveness); Work Productivity Loss (overall work impairment/absenteeism plus presenteeism); and Activity Impairment. Scores range from 0 to 100 for each of the above 4 types; higher scores indicate greater impairment. Difference refers to change in scale between week 24 and baseline. (NCT00523991)
Timeframe: baseline, week 24
| Intervention | units on a scale (Least Squares Mean) |
|---|---|
| Placebo | 2.20 |
| Tiotropium | -2.70 |
WPAI: self-administered instrument used to measure effect of general health and symptom severity on work productivity and regular activities and yields 4 types of scores: Absenteeism (work time missed); Presenteeism (impairment at work/reduced on-the-job effectiveness); Work Productivity Loss (overall work impairment/absenteeism plus presenteeism); and Activity Impairment. Scores range from 0 to 100 for each of the above 4 types; higher scores indicate greater impairment. Difference refers to change in scale between week 20 and baseline. (NCT00523991)
Timeframe: baseline, week 20
| Intervention | units on a scale (Least Squares Mean) |
|---|---|
| Placebo | 3.93 |
| Tiotropium | 4.10 |
WPAI: self-administered instrument used to measure effect of general health and symptom severity on work productivity and regular activities and yields 4 types of scores: Absenteeism (work time missed); Presenteeism (impairment at work/reduced on-the-job effectiveness); Work Productivity Loss (overall work impairment/absenteeism plus presenteeism); and Activity Impairment. Scores range from 0 to 100 for each of the above 4 types; higher scores indicate greater impairment. Difference refers to change in scale between week 16 and baseline. (NCT00523991)
Timeframe: baseline, week 16
| Intervention | units on a scale (Least Squares Mean) |
|---|---|
| Placebo | 2.20 |
| Tiotropium | 4.79 |
WPAI: self-administered instrument used to measure effect of general health and symptom severity on work productivity and regular activities and yields 4 types of scores: Absenteeism (work time missed); Presenteeism (impairment at work/reduced on-the-job effectiveness); Work Productivity Loss (overall work impairment/absenteeism plus presenteeism); and Activity Impairment. Scores range from 0 to 100 for each of the above 4 types; higher scores indicate greater impairment. Difference refers to change in scale between week 12 and baseline. (NCT00523991)
Timeframe: baseline, week 12
| Intervention | units on a scale (Least Squares Mean) |
|---|---|
| Placebo | 0.32 |
| Tiotropium | 4.11 |
WPAI: self-administered instrument used to measure effect of general health and symptom severity on work productivity and regular activities and yields 4 types of scores: Absenteeism (work time missed); Presenteeism (impairment at work/reduced on-the-job effectiveness); Work Productivity Loss (overall work impairment/absenteeism plus presenteeism); and Activity Impairment. Scores range from 0 to 100 for each of the above 4 types; higher scores indicate greater impairment. Difference refers to change in scale between week 8 and baseline. (NCT00523991)
Timeframe: baseline, week 8
| Intervention | units on a scale (Least Squares Mean) |
|---|---|
| Placebo | 0.41 |
| Tiotropium | -0.61 |
WPAI: self-administered instrument used to measure effect of general health and symptom severity on work productivity and regular activities and yields 4 types of scores: Absenteeism (work time missed); Presenteeism (impairment at work/reduced on-the-job effectiveness); Work Productivity Loss (overall work impairment/absenteeism plus presenteeism); and Activity Impairment. Scores range from 0 to 100 for each of the above 4 types; higher scores indicate greater impairment. Difference refers to change in scale between week 4 and baseline. (NCT00523991)
Timeframe: baseline, week 4
| Intervention | units on a scale (Least Squares Mean) |
|---|---|
| Placebo | -2.03 |
| Tiotropium | -2.64 |
WPAI: self-administered instrument used to measure effect of general health and symptom severity on work productivity and regular activities and yields 4 types of scores: Absenteeism (work time missed); Presenteeism (impairment at work/reduced on-the-job effectiveness); Work Productivity Loss (overall work impairment/absenteeism plus presenteeism); and Activity Impairment. Scores range from 0 to 100 for each of the above 4 types; higher scores indicate greater impairment. Difference refers to change in scale between week 24 and baseline. (NCT00523991)
Timeframe: baseline, week 24
| Intervention | units on a scale (Least Squares Mean) |
|---|---|
| Placebo | 4.04 |
| Tiotropium | -1.84 |
WPAI: self-administered instrument used to measure effect of general health and symptom severity on work productivity and regular activities and yields 4 types of scores: Absenteeism (work time missed); Presenteeism (impairment at work/reduced on-the-job effectiveness); Work Productivity Loss (overall work impairment/absenteeism plus presenteeism); and Activity Impairment. Scores range from 0 to 100 for each of the above 4 types; higher scores indicate greater impairment. Difference refers to change in scale between week 20 and baseline. (NCT00523991)
Timeframe: baseline, week 20
| Intervention | units on a scale (Least Squares Mean) |
|---|---|
| Placebo | 4.27 |
| Tiotropium | 3.08 |
WPAI: self-administered instrument used to measure effect of general health and symptom severity on work productivity and regular activities and yields 4 types of scores: Absenteeism (work time missed); Presenteeism (impairment at work/reduced on-the-job effectiveness); Work Productivity Loss (overall work impairment/absenteeism plus presenteeism); and Activity Impairment. Scores range from 0 to 100 for each of the above 4 types; higher scores indicate greater impairment. Difference refers to change in scale between week 16 and baseline. (NCT00523991)
Timeframe: baseline, week 16
| Intervention | units on a scale (Least Squares Mean) |
|---|---|
| Placebo | 3.68 |
| Tiotropium | 3.66 |
WPAI: self-administered instrument used to measure effect of general health and symptom severity on work productivity and regular activities and yields 4 types of scores: Absenteeism (work time missed); Presenteeism (impairment at work/reduced on-the-job effectiveness); Work Productivity Loss (overall work impairment/absenteeism plus presenteeism); and Activity Impairment. Scores range from 0 to 100 for each of the above 4 types; higher scores indicate greater impairment. Difference refers to change in scale between week 12 and baseline. (NCT00523991)
Timeframe: baseline, week 12
| Intervention | units on a scale (Least Squares Mean) |
|---|---|
| Placebo | -0.32 |
| Tiotropium | 0.46 |
WPAI: self-administered instrument used to measure effect of general health and symptom severity on work productivity and regular activities and yields 4 types of scores: Absenteeism (work time missed); Presenteeism (impairment at work/reduced on-the-job effectiveness); Work Productivity Loss (overall work impairment/absenteeism plus presenteeism); and Activity Impairment. Scores range from 0 to 100 for each of the above 4 types; higher scores indicate greater impairment. Difference refers to change in scale between week 8 and baseline. (NCT00523991)
Timeframe: baseline, week 8
| Intervention | units on a scale (Least Squares Mean) |
|---|---|
| Placebo | 2.12 |
| Tiotropium | -0.38 |
WPAI: self-administered instrument used to measure effect of general health and symptom severity on work productivity and regular activities and yields 4 types of scores: Absenteeism (work time missed); Presenteeism (impairment at work/reduced on-the-job effectiveness); Work Productivity Loss (overall work impairment/absenteeism plus presenteeism); and Activity Impairment. Scores range from 0 to 100 for each of the above 4 types; higher scores indicate greater impairment. Difference refers to change in scale between week 4 and baseline. (NCT00523991)
Timeframe: baseline, week 4
| Intervention | units on a scale (Least Squares Mean) |
|---|---|
| Placebo | 0.34 |
| Tiotropium | 0.98 |
WPAI: self-administered instrument used to measure effect of general health and symptom severity on work productivity and regular activities and yields 4 types of scores: Absenteeism (work time missed); Presenteeism (impairment at work/reduced on-the-job effectiveness); Work Productivity Loss (overall work impairment/absenteeism plus presenteeism); and Activity Impairment. Scores range from 0 to 100 for each of the above 4 types; higher scores indicate greater impairment. Difference refers to change in scale between week 24 and baseline. (NCT00523991)
Timeframe: baseline, week 24
| Intervention | units on a scale (Least Squares Mean) |
|---|---|
| Placebo | 5.26 |
| Tiotropium | 1.51 |
WPAI: self-administered instrument used to measure effect of general health and symptom severity on work productivity and regular activities and yields 4 types of scores: Absenteeism (work time missed); Presenteeism (impairment at work/reduced on-the-job effectiveness); Work Productivity Loss (overall work impairment/absenteeism plus presenteeism); and Activity Impairment. Scores range from 0 to 100 for each of the above 4 types; higher scores indicate greater impairment. Difference refers to change in scale between week 20 and baseline. (NCT00523991)
Timeframe: baseline, week 20
| Intervention | units on a scale (Least Squares Mean) |
|---|---|
| Placebo | 4.32 |
| Tiotropium | 3.52 |
WPAI: self-administered instrument used to measure effect of general health and symptom severity on work productivity and regular activities and yields 4 types of scores: Absenteeism (work time missed); Presenteeism (impairment at work/reduced on-the-job effectiveness); Work Productivity Loss (overall work impairment/absenteeism plus presenteeism); and Activity Impairment. Scores range from 0 to 100 for each of the above 4 types; higher scores indicate greater impairment. Difference refers to change in scale between week 16 and baseline. (NCT00523991)
Timeframe: baseline, week 16
| Intervention | units on a scale (Least Squares Mean) |
|---|---|
| Placebo | 4.47 |
| Tiotropium | 2.62 |
WPAI: self-administered instrument used to measure effect of general health and symptom severity on work productivity and regular activities and yields 4 types of scores: Absenteeism (work time missed); Presenteeism (impairment at work/reduced on-the-job effectiveness); Work Productivity Loss (overall work impairment/absenteeism plus presenteeism); and Activity Impairment. Scores range from 0 to 100 for each of the above 4 types; higher scores indicate greater impairment. Difference refers to change in scale between week 12 and baseline. (NCT00523991)
Timeframe: baseline, week 12
| Intervention | units on a scale (Least Squares Mean) |
|---|---|
| Placebo | -0.54 |
| Tiotropium | -1.07 |
Change from baseline in forced expiratory volume in 1 second (at week 8, 30 minutes) (NCT00523991)
Timeframe: Baseline, week 8, 30 minutes
| Intervention | litres (Mean) |
|---|---|
| Placebo | 0.00 |
| Tiotropium | 0.20 |
Change from baseline in forced expiratory volume in 1 second (at week 8, 180 minutes) (NCT00523991)
Timeframe: baseline, week 8, 180 minutes
| Intervention | litres (Mean) |
|---|---|
| Placebo | 0.01 |
| Tiotropium | 0.24 |
Change from baseline in forced expiratory volume in 1 second (at week 8, 120 minutes) (NCT00523991)
Timeframe: baseline, week 8, 120 minutes
| Intervention | litres (Mean) |
|---|---|
| Placebo | 0.01 |
| Tiotropium | 0.24 |
Change from baseline in forced expiratory volume in 1 second (at week 16, pre-dose) (NCT00523991)
Timeframe: baseline, week 16, pre-dose
| Intervention | litres (Mean) |
|---|---|
| Placebo | -0.06 |
| Tiotropium | 0.09 |
Difference in number of days that participants used albuterol prn per week between week 20 and baseline (NCT00523991)
Timeframe: baseline, week 20
| Intervention | days (Mean) |
|---|---|
| Placebo | -0.4 |
| Tiotropium | -0.3 |
Difference in number of days that participants used albuterol prn per week between week 12 and baseline (NCT00523991)
Timeframe: baseline, week 12
| Intervention | days (Mean) |
|---|---|
| Placebo | -0.3 |
| Tiotropium | -0.3 |
Difference in number of days that participants used albuterol prn per week between week 8 and baseline (NCT00523991)
Timeframe: baseline, week 8
| Intervention | days (Mean) |
|---|---|
| Placebo | -0.3 |
| Tiotropium | -0.3 |
Difference in number of days that participants used albuterol prn per week between week 4 and baseline (NCT00523991)
Timeframe: baseline, week 4
| Intervention | days (Mean) |
|---|---|
| Placebo | -0.2 |
| Tiotropium | -0.2 |
Difference in number of days that participants used albuterol prn per week between week 24 and baseline (NCT00523991)
Timeframe: baseline, week 24
| Intervention | days (Least Squares Mean) |
|---|---|
| Placebo | -0.64 |
| Tiotropium | -0.62 |
The amount of energy (kcal/day) that a person uses while physically active. (NCT00523991)
Timeframe: baseline, week 8
| Intervention | kilo calories per day (Least Squares Mean) |
|---|---|
| Placebo | 0.01 |
| Tiotropium | -0.03 |
The amount of energy (kcal/day) that a person uses while physically active. (NCT00523991)
Timeframe: baseline, week 4
| Intervention | kilo calories per day (Least Squares Mean) |
|---|---|
| Placebo | -0.04 |
| Tiotropium | -0.03 |
The amount of energy (kcal/day) that a person uses while physically active. (NCT00523991)
Timeframe: baseline, week 24
| Intervention | kilo calories per day (Least Squares Mean) |
|---|---|
| Placebo | -0.08 |
| Tiotropium | -0.10 |
The amount of energy (kcal/day) that a person uses while physically active. (NCT00523991)
Timeframe: baseline, week 20
| Intervention | kilo calories per day (Least Squares Mean) |
|---|---|
| Placebo | -0.08 |
| Tiotropium | -0.09 |
The amount of energy (kcal/day) that a person uses while physically active. (NCT00523991)
Timeframe: baseline, week 16
| Intervention | kilo calories per day (Least Squares Mean) |
|---|---|
| Placebo | -0.07 |
| Tiotropium | -0.09 |
The amount of energy (kcal/day) that a person uses while physically active. (NCT00523991)
Timeframe: baseline, week 12
| Intervention | kilo calories per day (Least Squares Mean) |
|---|---|
| Placebo | -0.05 |
| Tiotropium | -0.06 |
Number of days that participants used albuterol prn per week (NCT00523991)
Timeframe: baseline
| Intervention | days (Mean) |
|---|---|
| Placebo | 2.1 |
| Tiotropium | 1.8 |
The amount of energy (kcal/day) that a person uses while physically active. (NCT00523991)
Timeframe: baseline
| Intervention | kilo calories per day (Mean) |
|---|---|
| Placebo | 0.87 |
| Tiotropium | 0.87 |
Healthy lifestyle defined as 30 minutes of activity > 3 metabolic equivalent levels for 70% of eligible days. Two categories: Yes, no (NCT00523991)
Timeframe: week 8
| Intervention | Participants (Number) | |
|---|---|---|
| Yes | No | |
| Placebo | 125 | 66 |
| Tiotropium | 137 | 60 |
Difference in number of days that participants used albuterol prn per week between week 16 and baseline (NCT00523991)
Timeframe: baseline, week 16
| Intervention | days (Mean) |
|---|---|
| Placebo | -0.4 |
| Tiotropium | -0.3 |
Healthy lifestyle defined as 30 minutes of activity > 3 metabolic equivalent levels for 70% of eligible days. Two categories: Yes, no (NCT00523991)
Timeframe: week 4
| Intervention | Participants (Number) | |
|---|---|---|
| Yes | No | |
| Placebo | 129 | 58 |
| Tiotropium | 154 | 50 |
Healthy lifestyle defined as 30 minutes of activity > 3 metabolic equivalent levels for 70% of eligible days. Two categories: Yes, no (NCT00523991)
Timeframe: week 24
| Intervention | Participants (Number) | |
|---|---|---|
| Yes | No | |
| Placebo | 118 | 64 |
| Tiotropium | 136 | 60 |
Healthy lifestyle defined as 30 minutes of activity > 3 metabolic equivalent levels for 70% of eligible days. Two categories: Yes, no (NCT00523991)
Timeframe: week 20
| Intervention | Participants (Number) | |
|---|---|---|
| Yes | No | |
| Placebo | 127 | 61 |
| Tiotropium | 134 | 56 |
Healthy lifestyle defined as 30 minutes of activity > 3 metabolic equivalent levels for 70% of eligible days. Two categories: Yes, no (NCT00523991)
Timeframe: week 16
| Intervention | Participants (Number) | |
|---|---|---|
| Yes | No | |
| Placebo | 116 | 71 |
| Tiotropium | 133 | 60 |
Healthy lifestyle defined as 30 minutes of activity > 3 metabolic equivalent levels for 70% of eligible days. Two categories: Yes, no (NCT00523991)
Timeframe: week 12
| Intervention | Participants (Number) | |
|---|---|---|
| Yes | No | |
| Placebo | 118 | 71 |
| Tiotropium | 139 | 60 |
Healthy lifestyle defined as 30 minutes of activity > 3 metabolic equivalent levels for 70% of eligible days. Two categories: Yes, no (NCT00523991)
Timeframe: baseline
| Intervention | Participants (Number) | |
|---|---|---|
| Yes | No | |
| Placebo | 126 | 58 |
| Tiotropium | 143 | 60 |
"The physician's global assessment reflected the physician's opinion of the participant's overall clinical condition with respect to COPD. The evaluation was based on the participant's use of concomitant medications, as well as the number and severity of COPD exacerbations and related emergency room visits and/or hospitalizations since the last visit. The frequency and severity of symptoms ( cough, dyspnea, wheezing) and the impact of these on the participant's ability to exercise were considered.~Range: 1-2 = Poor, 3-4 = Fair 5-6 = Good, 7-8 = Excellent." (NCT00523991)
Timeframe: week 24
| Intervention | Participants (Number) | ||
|---|---|---|---|
| Poor/Fair | Good | Excellent | |
| Placebo | 51 | 128 | 22 |
| Tiotropium | 41 | 136 | 39 |
"The physician's global assessment reflected the physician's opinion of the participant's overall clinical condition with respect to COPD. The evaluation was based on the participant's use of concomitant medications, as well as the number and severity of COPD exacerbations and related emergency room visits and/or hospitalizations since the last visit. The frequency and severity of symptoms ( cough, dyspnea, wheezing) and the impact of these on the participant's ability to exercise were considered.~Range: 1-2 = Poor, 3-4 = Fair 5-6 = Good, 7-8 = Excellent." (NCT00523991)
Timeframe: week 12
| Intervention | Participants (Number) | ||
|---|---|---|---|
| Poor/Fair | Good | Excellent | |
| Placebo | 49 | 135 | 20 |
| Tiotropium | 50 | 134 | 36 |
"The physician's global assessment reflected the physician's opinion of the participant's overall clinical condition with respect to COPD. The evaluation was based on the participant's use of concomitant medications, as well as the number and severity of COPD exacerbations and related emergency room visits and/or hospitalizations since the last visit. The frequency and severity of symptoms ( cough, dyspnea, wheezing) and the impact of these on the participant's ability to exercise were considered.~Range: 1-2 = Poor, 3-4 = Fair 5-6 = Good, 7-8 = Excellent." (NCT00523991)
Timeframe: baseline
| Intervention | Participants (Number) | ||
|---|---|---|---|
| Poor/Fair | Good | Excellent | |
| Placebo | 62 | 122 | 23 |
| Tiotropium | 78 | 132 | 17 |
"The patient's global assessment was based on the subject's need to take additional medications for breathing, their need for emergency room or hospital visits for COPD, and severity and amount of coughing, wheezing, and/or breathing discomfort experienced, and the impact of these symptoms on the subject's ability to exercise and perform daily activities.~Range: 1-2 = Poor, 3-4 = Fair 5-6 = Good, 7-8 = Excellent." (NCT00523991)
Timeframe: week 24
| Intervention | Participants (Number) | ||
|---|---|---|---|
| Poor/Fair | Good | Excellent | |
| Placebo | 66 | 116 | 19 |
| Tiotropium | 56 | 128 | 32 |
"The patient's global assessment was based on the subject's need to take additional medications for breathing, their need for emergency room or hospital visits for COPD, and severity and amount of coughing, wheezing, and/or breathing discomfort experienced, and the impact of these symptoms on the subject's ability to exercise and perform daily activities.~Range: 1-2 = Poor, 3-4 = Fair 5-6 = Good, 7-8 = Excellent." (NCT00523991)
Timeframe: week 12
| Intervention | Participants (Number) | ||
|---|---|---|---|
| Poor/Fair | Good | Excellent | |
| Placebo | 62 | 127 | 17 |
| Tiotropium | 53 | 132 | 35 |
"The patient's global assessment was based on the subject's need to take additional medications for breathing, their need for emergency room or hospital visits for COPD, and severity and amount of coughing, wheezing, and/or breathing discomfort experienced, and the impact of these symptoms on the subject's ability to exercise and perform daily activities.~Range: 1-2 = Poor, 3-4 = Fair 5-6 = Good, 7-8 = Excellent." (NCT00523991)
Timeframe: baseline
| Intervention | Participants (Number) | ||
|---|---|---|---|
| Poor/Fair | Good | Excellent | |
| Placebo | 72 | 111 | 23 |
| Tiotropium | 95 | 117 | 15 |
Trough FVC defined as the FVC measured at 10 minutes prior to the end of the dosing interval, approximately 24 hours post drug administration. Baseline FVC was the pre-treatment FVC measured at Week 0 in the morning 10 minutes prior to the administration of the first dose of the study medication. (NCT00523991)
Timeframe: baseline, week 8
| Intervention | litres (Mean) |
|---|---|
| Placebo | -0.06 |
| Tiotropium | 0.16 |
Trough FVC defined as the FVC measured at 10 minutes prior to the end of the dosing interval, approximately 24 hours post drug administration. Baseline FVC was the pre-treatment FVC measured at Week 0 in the morning 10 minutes prior to the administration of the first dose of the study medication. (NCT00523991)
Timeframe: baseline, week 24
| Intervention | litres (Least Squares Mean) |
|---|---|
| Placebo | -0.14 |
| Tiotropium | 0.07 |
Trough FVC defined as the FVC measured at 10 minutes prior to the end of the dosing interval, approximately 24 hours post drug administration. Baseline FVC was the pre-treatment FVC measured at Week 0 in the morning 10 minutes prior to the administration of the first dose of the study medication. (NCT00523991)
Timeframe: baseline, week 16
| Intervention | litres (Mean) |
|---|---|
| Placebo | -0.13 |
| Tiotropium | 0.10 |
Trough FEV1 defined as the FEV1 measured at 10 minutes prior to the end of the dosing interval, approximately 24 hours post drug administration. Baseline FEV1 was the pre-treatment FEV1 measured at Week 0 in the morning 10 minutes prior to the administration of the first dose of the study medication. (NCT00523991)
Timeframe: Baseline, week 8
| Intervention | litres (Mean) |
|---|---|
| Placebo | -0.03 |
| Tiotropium | 0.12 |
Trough FEV1 defined as the FEV1 measured at 10 minutes prior to the end of the dosing interval, approximately 24 hours post drug administration. Baseline FEV1 was the pre-treatment FEV1 measured at Week 0 in the morning 10 minutes prior to the administration of the first dose of the study medication. (NCT00523991)
Timeframe: Baseline, week 24
| Intervention | litres (Least Squares Mean) |
|---|---|
| Placebo | -0.08 |
| Tiotropium | 0.06 |
Trough FEV1 defined as the FEV1 measured at 10 minutes prior to the end of the dosing interval, approximately 24 hours post drug administration. Baseline FEV1 was the pre-treatment FEV1 measured at Week 0 in the morning 10 minutes prior to the administration of the first dose of the study medication. (NCT00523991)
Timeframe: Baseline, week 16
| Intervention | litres (Mean) |
|---|---|
| Placebo | -0.06 |
| Tiotropium | 0.09 |
"Moderate or higher intensity is greater than or equal to three metabolic equivalents~Metabolic equivalent threshold (MET): Unit used to estimate the metabolic cost of physical activity, in terms of multiples of the subject's resting metabolic rate. One metabolic equivalent is, by convention, 3.5 ml of O2 uptake per minute per kilogram body weight, and theoretically approximates the resting metabolic rate.~ln in measure value unit means natural logarithm" (NCT00523991)
Timeframe: baseline, week 8
| Intervention | ln(minutes) (Least Squares Mean) |
|---|---|
| Placebo | 0.01 |
| Tiotropium | -0.06 |
"Moderate or higher intensity is greater than or equal to three metabolic equivalents~Metabolic equivalent threshold (MET): Unit used to estimate the metabolic cost of physical activity, in terms of multiples of the subject's resting metabolic rate. One metabolic equivalent is, by convention, 3.5 ml of O2 uptake per minute per kilogram body weight, and theoretically approximates the resting metabolic rate.~ln in measure value unit means natural logarithm" (NCT00523991)
Timeframe: baseline, week 4
| Intervention | ln(minutes) (Least Squares Mean) |
|---|---|
| Placebo | -0.06 |
| Tiotropium | -0.12 |
"Moderate or higher intensity is greater than or equal to three metabolic equivalents~Metabolic equivalent threshold (MET): Unit used to estimate the metabolic cost of physical activity, in terms of multiples of the subject's resting metabolic rate. One metabolic equivalent is, by convention, 3.5 ml of O2 uptake per minute per kilogram body weight, and theoretically approximates the resting metabolic rate.~ln in measure value unit means natural logarithm" (NCT00523991)
Timeframe: baseline, week 24
| Intervention | ln(minutes) (Least Squares Mean) |
|---|---|
| Placebo | -0.19 |
| Tiotropium | -0.20 |
"Moderate or higher intensity is greater than or equal to three metabolic equivalents~Metabolic equivalent threshold (MET): Unit used to estimate the metabolic cost of physical activity, in terms of multiples of the subject's resting metabolic rate. One metabolic equivalent is, by convention, 3.5 ml of O2 uptake per minute per kilogram body weight, and theoretically approximates the resting metabolic rate.~ln in measure value unit means natural logarithm" (NCT00523991)
Timeframe: baseline, week 20
| Intervention | ln(minutes) (Least Squares Mean) |
|---|---|
| Placebo | -0.20 |
| Tiotropium | -0.20 |
The evaluation represented the global opinion of the overall clinical condition on a scale of: 1-2 (Poor), 3-4 (Fair), 5-6 (Good), 7-8 (Excellent) (NCT00525512)
Timeframe: baseline, 8 weeks
| Intervention | units on scale (Mean) |
|---|---|
| Placebo | -0.03 |
| Tiotropium | 0.34 |
FEV1 is the maximal amount of air you can forcefully exhale in one second. (NCT00525512)
Timeframe: baseline, 96 weeks
| Intervention | liters (Least Squares Mean) |
|---|---|
| Placebo | 1.072 |
| Tiotropium | 1.202 |
FEV1 is the maximal amount of air you can forcefully exhale in one second. (NCT00525512)
Timeframe: baseline, 80 weeks
| Intervention | liters (Least Squares Mean) |
|---|---|
| Placebo | 1.079 |
| Tiotropium | 1.228 |
FEV1 is the maximal amount of air you can forcefully exhale in one second. (NCT00525512)
Timeframe: baseline, 8 weeks
| Intervention | liters (Least Squares Mean) |
|---|---|
| Placebo | 1.126 |
| Tiotropium | 1.280 |
FEV1 is the maximal amount of air you can forcefully exhale in one second. (NCT00525512)
Timeframe: baseline, 64 weeks
| Intervention | liters (Least Squares Mean) |
|---|---|
| Placebo | 1.097 |
| Tiotropium | 1.230 |
Efficacy was assessed by measuring the exercise duration during a treadmill exercise test. (NCT00525512)
Timeframe: baseline, 100 weeks
| Intervention | seconds (Least Squares Mean) |
|---|---|
| Placebo / Open Tiotropium | 337.25 |
| Tiotropium / Open Tiotropium | 358.80 |
Efficacy was assessed by measuring the exercise duration during a treadmill exercise test. (NCT00525512)
Timeframe: baseline, 16 weeks
| Intervention | seconds (Least Squares Mean) |
|---|---|
| Placebo | 308.6 |
| Tiotropium | 338.6 |
Efficacy was assessed by measuring the exercise duration during a treadmill exercise test. (NCT00525512)
Timeframe: baseline, 32 weeks
| Intervention | seconds (Least Squares Mean) |
|---|---|
| Placebo | 311.8 |
| Tiotropium | 358.7 |
Efficacy was assessed by measuring the exercise duration during a treadmill exercise test. (NCT00525512)
Timeframe: baseline, 48 weeks
| Intervention | seconds (Least Squares Mean) |
|---|---|
| Placebo | 309.8 |
| Tiotropium | 365.7 |
Efficacy was assessed by measuring the exercise duration during a treadmill exercise test. (NCT00525512)
Timeframe: baseline, 64 weeks
| Intervention | seconds (Least Squares Mean) |
|---|---|
| Placebo | 313.4 |
| Tiotropium | 349.0 |
Efficacy was assessed by measuring the exercise duration during a treadmill exercise test. (NCT00525512)
Timeframe: baseline, 8 weeks
| Intervention | seconds (Least Squares Mean) |
|---|---|
| Placebo | 304.9 |
| Tiotropium | 343.0 |
Efficacy was assessed by measuring the exercise duration during a treadmill exercise test. (NCT00525512)
Timeframe: baseline, 80 weeks
| Intervention | seconds (Least Squares Mean) |
|---|---|
| Placebo | 302.8 |
| Tiotropium | 340.1 |
Efficacy was assessed by measuring the exercise duration during a treadmill exercise test. (NCT00525512)
Timeframe: baseline, 96 weeks
| Intervention | seconds (Least Squares Mean) |
|---|---|
| Placebo | 297.1 |
| Tiotropium | 336.6 |
Borg scale assessed degreee of discomfort on a scale from 0 (Nothing at all) to 10 (Maximal) (NCT00525512)
Timeframe: baseline, 96 weeks
| Intervention | units on scale (Least Squares Mean) |
|---|---|
| Placebo | 4.1 |
| Tiotropium | 3.8 |
Borg scale assessed degreee of discomfort on a scale from 0 (Nothing at all) to 10 (Maximal) (NCT00525512)
Timeframe: baseline, 96 weeks
| Intervention | unit on scale (Least Squares Mean) |
|---|---|
| Placebo | 5.6 |
| Tiotropium | 5.6 |
Borg scale assessed degreee of discomfort on a scale from 0 (Nothing at all) to 10 (Maximal) (NCT00525512)
Timeframe: baseline, 96 weeks
| Intervention | unit on scale (Least Squares Mean) |
|---|---|
| Placebo | 4.0 |
| Tiotropium | 4.1 |
The evaluation represented the global opinion of the overall clinical condition on a scale of: 1-2 (Poor), 3-4 (Fair), 5-6 (Good), 7-8 (Excellent) (NCT00525512)
Timeframe: baseline, 16 weeks
| Intervention | units on scale (Mean) |
|---|---|
| Placebo | 0.07 |
| Tiotropium | 0.30 |
The evaluation represented the global opinion of the overall clinical condition on a scale of: 1-2 (Poor), 3-4 (Fair), 5-6 (Good), 7-8 (Excellent) (NCT00525512)
Timeframe: baseline, 32 weeks
| Intervention | units on scale (Mean) |
|---|---|
| Placebo | 0.13 |
| Tiotropium | 0.20 |
The evaluation represented the global opinion of the overall clinical condition on a scale of: 1-2 (Poor), 3-4 (Fair), 5-6 (Good), 7-8 (Excellent) (NCT00525512)
Timeframe: baseline, 48 weeks
| Intervention | units on scale (Mean) |
|---|---|
| Placebo | 0.02 |
| Tiotropium | 0.18 |
The evaluation represented the global opinion of the overall clinical condition on a scale of: 1-2 (Poor), 3-4 (Fair), 5-6 (Good), 7-8 (Excellent) (NCT00525512)
Timeframe: baseline, 64 weeks
| Intervention | units on scale (Mean) |
|---|---|
| Placebo | -0.02 |
| Tiotropium | 0.16 |
FEV1 is the maximal amount of air you can forcefully exhale in one second. (NCT00525512)
Timeframe: baseline, 48 weeks
| Intervention | liters (Least Squares Mean) |
|---|---|
| Placebo | 1.105 |
| Tiotropium | 1.232 |
The evaluation represented the global opinion of the overall clinical condition on a scale of: 1-2 (Poor), 3-4 (Fair), 5-6 (Good), 7-8 (Excellent) (NCT00525512)
Timeframe: baseline, 80 weeks
| Intervention | units on scale (Mean) |
|---|---|
| Placebo | -0.08 |
| Tiotropium | 0.09 |
The evaluation represented the global opinion of the overall clinical condition on a scale of: 1-2 (Poor), 3-4 (Fair), 5-6 (Good), 7-8 (Excellent) (NCT00525512)
Timeframe: baseline, 96 weeks
| Intervention | units on scale (Mean) |
|---|---|
| Placebo | -0.04 |
| Tiotropium | 0.03 |
The evaluation represented the global opinion of the overall clinical condition on a scale of: 1-2 (Poor), 3-4 (Fair), 5-6 (Good), 7-8 (Excellent) (NCT00525512)
Timeframe: baseline, 16 weeks
| Intervention | units on scale (Mean) |
|---|---|
| Placebo | 0.02 |
| Tiotropium | 0.35 |
FVC is the volume of air that can be forcibly blown out after full inspiration. (NCT00525512)
Timeframe: baseline, 64 weeks
| Intervention | liters (Least Squares Mean) |
|---|---|
| Placebo | 2.423 |
| Tiotropium | 2.584 |
The evaluation represented the global opinion of the overall clinical condition on a scale of: 1-2 (Poor), 3-4 (Fair), 5-6 (Good), 7-8 (Excellent) (NCT00525512)
Timeframe: baseline, 32 weeks
| Intervention | units on scale (Mean) |
|---|---|
| Placebo | -0.04 |
| Tiotropium | 0.30 |
The evaluation represented the global opinion of the overall clinical condition on a scale of: 1-2 (Poor), 3-4 (Fair), 5-6 (Good), 7-8 (Excellent) (NCT00525512)
Timeframe: baseline, 48 weeks
| Intervention | units on scale (Mean) |
|---|---|
| Placebo | 0.03 |
| Tiotropium | 0.25 |
The evaluation represented the global opinion of the overall clinical condition on a scale of: 1-2 (Poor), 3-4 (Fair), 5-6 (Good), 7-8 (Excellent) (NCT00525512)
Timeframe: baseline, 64 weeks
| Intervention | units on scale (Mean) |
|---|---|
| Placebo | 0.03 |
| Tiotropium | 0.25 |
The evaluation represented the global opinion of the overall clinical condition on a scale of: 1-2 (Poor), 3-4 (Fair), 5-6 (Good), 7-8 (Excellent) (NCT00525512)
Timeframe: baseline, 8 weeks
| Intervention | unit on scale (Mean) |
|---|---|
| Placebo | -0.04 |
| Tiotropium | 0.32 |
The evaluation represented the global opinion of the overall clinical condition on a scale of: 1-2 (Poor), 3-4 (Fair), 5-6 (Good), 7-8 (Excellent) (NCT00525512)
Timeframe: baseline, 80 weeks
| Intervention | units on scale (Mean) |
|---|---|
| Placebo | -0.06 |
| Tiotropium | 0.10 |
The evaluation represented the global opinion of the overall clinical condition on a scale of: 1-2 (Poor), 3-4 (Fair), 5-6 (Good), 7-8 (Excellent) (NCT00525512)
Timeframe: baseline, 96 weeks
| Intervention | units on scale (Mean) |
|---|---|
| Placebo | -0.07 |
| Tiotropium | 0.10 |
FEV1 is the maximal amount of air you can forcefully exhale in one second. (NCT00525512)
Timeframe: baseline, 100 weeks
| Intervention | liters (Least Squares Mean) |
|---|---|
| Placebo / Open Tiotropium | 1.23 |
| Tiotropium / Open Tiotropium | 1.23 |
COPD exacerbation is a complex of symptoms related to COPD with a duration of three days or more requiring a change of treatment. (NCT00525512)
Timeframe: baseline, 96 weeks
| Intervention | participants (Number) | |
|---|---|---|
| Patients with exacerbations | Censored patients | |
| Placebo | 102 | 157 |
| Tiotropium | 112 | 148 |
Clinical Relevant Abnormalities for Vital Signs and Physical examination, including vital status. Any new or clinically relevant worsening of baseline conditions was reported as Adverse Events. (NCT00525512)
Timeframe: From first drug administration until 30 days after last drug administration
| Intervention | participants (Number) | ||||
|---|---|---|---|---|---|
| Blood pressure increased | Heart rate increased | Oxygen saturation decreased | Weight decreased | Fatal | |
| Placebo | 0 | 1 | 1 | 1 | 6 |
| Placebo / Open Tiotropium | 0 | 1 | 0 | 0 | 0 |
| Tiotropium | 2 | 1 | 0 | 2 | 6 |
| Tiotropium / Open Tiotropium | 0 | 0 | 0 | 0 | 0 |
Score summarises the impact of disease on overall health status with zero indicating best health status and 100 indicating worst possible health status. (NCT00525512)
Timeframe: baseline, 96 weeks
| Intervention | units on scale (Least Squares Mean) |
|---|---|
| Placebo | 44.5 |
| Tiotropium | 40.5 |
Score summarises the impact of disease on overall health status with zero indicating best health status and 100 indicating worst possible health status. (NCT00525512)
Timeframe: baseline, 100 weeks
| Intervention | units on scale (Least Squares Mean) |
|---|---|
| Placebo / Open Tiotropium | 39.82 |
| Tiotropium / Open Tiotropium | 39.21 |
Score summarises the impact of disease on overall health status with zero indicating best health status and 100 indicating worst possible health status. (NCT00525512)
Timeframe: baseline, 96 weeks
| Intervention | units on scale (Least Squares Mean) |
|---|---|
| Placebo | 54.4 |
| Tiotropium | 45.5 |
Score summarises the impact of disease on overall health status with zero indicating best health status and 100 indicating worst possible health status. (NCT00525512)
Timeframe: baseline, 100 weeks
| Intervention | units on scale (Least Squares Mean) |
|---|---|
| Placebo / Open Tiotropium | 45.47 |
| Tiotropium / Open Tiotropium | 41.14 |
Score summarises the impact of disease on overall health status with zero indicating best health status and 100 indicating worst possible health status. (NCT00525512)
Timeframe: baseline, 96 weeks
| Intervention | units on scale (Least Squares Mean) |
|---|---|
| Placebo | 34.0 |
| Tiotropium | 30.4 |
Score summarises the impact of disease on overall health status with zero indicating best health status and 100 indicating worst possible health status. (NCT00525512)
Timeframe: baseline, 100 weeks
| Intervention | units on scale (Least Squares Mean) |
|---|---|
| Placebo / Open Tiotropium | 29.65 |
| Tiotropium / Open Tiotropium | 29.67 |
Score summarises the impact of disease on overall health status with zero indicating best health status and 100 indicating worst possible health status. (NCT00525512)
Timeframe: baseline, 96 weeks
| Intervention | units on scale (Least Squares Mean) |
|---|---|
| Placebo | 56.9 |
| Tiotropium | 54.6 |
Score summarises the impact of disease on overall health status with zero indicating best health status and 100 indicating worst possible health status. (NCT00525512)
Timeframe: baseline, 100 weeks
| Intervention | units on scale (Least Squares Mean) |
|---|---|
| Placebo / Open Tiotropium | 53.57 |
| Tiotropium / Open Tiotropium | 54.46 |
FVC is the volume of air that can be forcibly blown out after full inspiration. (NCT00525512)
Timeframe: baseline, 96 weeks
| Intervention | liters (Least Squares Mean) |
|---|---|
| Placebo | 2.368 |
| Tiotropium | 2.609 |
FVC is the volume of air that can be forcibly blown out after full inspiration. (NCT00525512)
Timeframe: baseline, 80 weeks
| Intervention | liters (Least Squares Mean) |
|---|---|
| Placebo | 2.343 |
| Tiotropium | 2.555 |
FVC is the volume of air that can be forcibly blown out after full inspiration. (NCT00525512)
Timeframe: baseline, 8 weeks
| Intervention | liters (Least Squares Mean) |
|---|---|
| Placebo | 2.432 |
| Tiotropium | 2.649 |
FVC is the volume of air that can be forcibly blown out after full inspiration. (NCT00525512)
Timeframe: baseline, 48 weeks
| Intervention | liters (Least Squares Mean) |
|---|---|
| Placebo | 2.406 |
| Tiotropium | 2.640 |
FVC is the volume of air that can be forcibly blown out after full inspiration. (NCT00525512)
Timeframe: baseline, 32 weeks
| Intervention | liters (Least Squares Mean) |
|---|---|
| Placebo | 2.425 |
| Tiotropium | 2.607 |
FVC is the volume of air that can be forcibly blown out after full inspiration. (NCT00525512)
Timeframe: baseline, 16 weeks
| Intervention | liters (Least Squares Mean) |
|---|---|
| Placebo | 2.407 |
| Tiotropium | 2.564 |
FEV1 is the maximal amount of air you can forcefully exhale in one second. (NCT00525512)
Timeframe: baseline, 96 weeks
| Intervention | liters (Least Squares Mean) |
|---|---|
| Placebo | 1.050 |
| Tiotropium | 1.125 |
FEV1 is the maximal amount of air you can forcefully exhale in one second. (NCT00525512)
Timeframe: baseline, 80 weeks
| Intervention | liters (Least Squares Mean) |
|---|---|
| Placebo | 1.039 |
| Tiotropium | 1.134 |
FEV1 is the maximal amount of air you can forcefully exhale in one second. (NCT00525512)
Timeframe: baseline, 8 weeks
| Intervention | liters (Least Squares Mean) |
|---|---|
| Placebo | 1.082 |
| Tiotropium | 1.198 |
FEV1 is the maximal amount of air you can forcefully exhale in one second. (NCT00525512)
Timeframe: baseline, 64 weeks
| Intervention | liters (Least Squares Mean) |
|---|---|
| Placebo | 1.066 |
| Tiotropium | 1.157 |
FEV1 is the maximal amount of air you can forcefully exhale in one second. (NCT00525512)
Timeframe: baseline, 48 weeks
| Intervention | liters (Least Squares Mean) |
|---|---|
| Placebo | 1.066 |
| Tiotropium | 1.172 |
FEV1 is the maximal amount of air you can forcefully exhale in one second. (NCT00525512)
Timeframe: baseline, 32 weeks
| Intervention | liters (Least Squares Mean) |
|---|---|
| Placebo | 1.090 |
| Tiotropium | 1.179 |
FEV1 is the maximal amount of air you can forcefully exhale in one second. (NCT00525512)
Timeframe: baseline, 16 weeks
| Intervention | liters (Least Squares Mean) |
|---|---|
| Placebo | 1.082 |
| Tiotropium | 1.164 |
FVC is the volume of air that can be forcibly blown out after full inspiration. (NCT00525512)
Timeframe: baseline, 96 weeks
| Intervention | liters (Least Squares Mean) |
|---|---|
| Placebo | 2.420 |
| Tiotropium | 2.753 |
FVC is the volume of air that can be forcibly blown out after full inspiration. (NCT00525512)
Timeframe: baseline, 80 weeks
| Intervention | liters (Least Squares Mean) |
|---|---|
| Placebo | 2.479 |
| Tiotropium | 2.733 |
FVC is the volume of air that can be forcibly blown out after full inspiration. (NCT00525512)
Timeframe: baseline, 8 weeks
| Intervention | liters (Least Squares Mean) |
|---|---|
| Placebo | 2.529 |
| Tiotropium | 2.806 |
FVC is the volume of air that can be forcibly blown out after full inspiration. (NCT00525512)
Timeframe: baseline, 64 weeks
| Intervention | liters (Least Squares Mean) |
|---|---|
| Placebo | 2.466 |
| Tiotropium | 2.767 |
FEV1 is the maximal amount of air you can forcefully exhale in one second. (NCT00525512)
Timeframe: baseline, 16 weeks
| Intervention | liters (Least Squares Mean) |
|---|---|
| Placebo | 1.092 |
| Tiotropium | 1.254 |
FEV1 is the maximal amount of air you can forcefully exhale in one second. (NCT00525512)
Timeframe: baseline, 32 weeks
| Intervention | liters (Least Squares Mean) |
|---|---|
| Placebo | 1.113 |
| Tiotropium | 1.259 |
FVC is the volume of air that can be forcibly blown out after full inspiration. (NCT00525512)
Timeframe: baseline, 48 weeks
| Intervention | liters (Least Squares Mean) |
|---|---|
| Placebo | 2.499 |
| Tiotropium | 2.758 |
FVC is the volume of air that can be forcibly blown out after full inspiration. (NCT00525512)
Timeframe: baseline, 32 weeks
| Intervention | liters (Least Squares Mean) |
|---|---|
| Placebo | 2.462 |
| Tiotropium | 2.816 |
FVC is the volume of air that can be forcibly blown out after full inspiration. (NCT00525512)
Timeframe: baseline, 16 weeks
| Intervention | liters (Least Squares Mean) |
|---|---|
| Placebo | 2.442 |
| Tiotropium | 2.767 |
FVC is the volume of air that can be forcibly blown out after full inspiration. (NCT00525512)
Timeframe: baseline, 100 weeks
| Intervention | liters (Least Squares Mean) |
|---|---|
| Placebo / Open Tiotropium | 2.72 |
| Tiotropium / Open Tiotropium | 2.77 |
The patient recorded twice daily peak flow measurements with an electronic peak flow meter throughout the entire evaluation period. Morning measurements were performed immediately upon arising after the patient had cleared out mucus, prior to administration of trial and/or rescue medication. The evening measurements were performed at bedtime. The weekly mean morning peak expiratory flow rate (PEFR) is reported. (NCT00528996)
Timeframe: Assessed before drug administration per day during 24 weeks with weekly mean values reporting.
| Intervention | litres/minute (Mean) | |||||||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Week 1 | Week 2 | Week 3 | Week 4 | Week 5 | Week 6 | Week 7 | Week 8 | Week 9 | Week 10 | Week 11 | Week 12 | Week 13 | Week 14 | Week 15 | Week 16 | Week 17 | Week 18 | Week 19 | Week 20 | Week 21 | Week 22 | Week 23 | Week 24 | |
| BEA 2180 BR Inhalation Solution 100 Microgram (mcg) | 176.20 | 175.82 | 177.38 | 176.37 | 176.90 | 175.31 | 174.35 | 173.95 | 172.84 | 171.24 | 169.92 | 169.90 | 169.96 | 168.51 | 168.69 | 169.26 | 169.53 | 168.95 | 170.45 | 169.84 | 169.12 | 169.29 | 167.26 | 165.87 |
| BEA 2180 BR Inhalation Solution 200 Microgram (mcg) | 179.46 | 179.24 | 178.94 | 178.06 | 178.29 | 177.59 | 175.85 | 176.41 | 177.35 | 176.14 | 174.05 | 175.40 | 175.51 | 175.65 | 175.01 | 174.07 | 174.89 | 173.59 | 175.29 | 174.81 | 175.43 | 175.12 | 174.30 | 176.36 |
| BEA 2180 BR Inhalation Solution 50 Microgram (mcg) | 177.03 | 177.64 | 177.19 | 174.99 | 176.16 | 176.26 | 175.71 | 173.99 | 175.74 | 173.63 | 173.45 | 174.72 | 173.59 | 172.29 | 171.12 | 170.92 | 171.32 | 169.36 | 169.24 | 169.31 | 169.30 | 167.60 | 167.38 | 167.08 |
| Placebo | 163.41 | 164.34 | 164.53 | 163.82 | 163.00 | 162.31 | 160.30 | 159.83 | 159.89 | 158.74 | 157.98 | 156.91 | 156.22 | 156.66 | 156.78 | 155.76 | 154.59 | 154.04 | 154.37 | 154.77 | 153.47 | 153.85 | 153.41 | 153.15 |
| Tiotropium Bromide 5 Microgram (mcg) | 177.54 | 176.46 | 175.49 | 175.17 | 176.32 | 175.09 | 175.50 | 174.71 | 174.75 | 174.71 | 174.82 | 174.63 | 175.97 | 174.86 | 174.03 | 174.23 | 174.04 | 171.90 | 172.92 | 173.31 | 172.77 | 171.93 | 171.13 | 171.53 |
"The 36-item-health Survey (SF-36) is a multi-purpose, short-form health survey with 36 questions evaluating patient's physical and mental health. Among the 36 questions, 1 is on the health comparing to 1 year ago and the remaining 35 questions are divided into 8 domains: Physical function, role limitations physical, Bodily pain, General physical health, Vitality, Social functioning, role limitations emotional, and General mental health.~The domain score of physical function (based on 10 questions) is reported, which is the weighted sum of the questions in corresponding domain with the domain score ranging from 0 to 100. The higher the domain score, the better the physical function." (NCT00528996)
Timeframe: At Week 4, 12, and 24.
| Intervention | Score on a scale (Mean) | ||
|---|---|---|---|
| Week 4 | Week 12 | Week 24 | |
| BEA 2180 BR 100 Microgram (mcg) | 52.812 | 52.099 | 51.631 |
| BEA 2180 BR 200 Microgram (mcg) | 52.961 | 53.716 | 52.256 |
| BEA 2180 BR 50 Microgram (mcg) | 51.831 | 52.561 | 52.702 |
| Placebo | 50.201 | 50.541 | 50.624 |
| Tiotropium Bromide 5 Microgram (mcg) | 53.052 | 53.935 | 54.191 |
"Number of patients with at least one Chronic Obstructive Pulmonary Disease (COPD) exacerbation is reported. Incidence rate of Chronic Obstructive Pulmonary Disease (COPD) exacerbation is reported. A Chronic Obstructive Pulmonary Disease (COPD) exacerbation is defined as a complex of lower respiratory events / symptoms (increase or new onset) related to the underlying COPD, with a duration of three days or more, requiring a change in treatment, where a complex of lower respiratory events / symptoms means at least two of the following: Shortness of breath, Sputum production (volume), Occurrence of purulent sputum, Cough, Wheezing, Chest tightness." (NCT00528996)
Timeframe: From first does until 30 days after the end of treatment, up to 205 days.
| Intervention | Participants (Count of Participants) |
|---|---|
| Placebo | 85 |
| BEA 2180 BR 50 Microgram (mcg) | 60 |
| BEA 2180 BR 100 Microgram (mcg) | 77 |
| BEA 2180 BR 200 Microgram (mcg) | 57 |
| Tiotropium Bromide 5 Microgram (mcg) | 73 |
Trough Forced expiratory volume in one second (FEV1) response was defined as the change from baseline in trough FEV1. Trough FEV1 was defined as the mean of the two FEV1 measurements recorded at the pre-dose measurements (40 and 15 minutes before the drug administration) at the end of the dosing interval (24 hours post previous drug administration from the Respimat® Inhaler). Baseline FEV1 was pre-treatment FEV1 values measured at Day 1 of treatment period (baseline) prior to administration of the first dose of study medication, which was the mean of the measurements recorded from the pulmonary function tests taken at 40 and 15 minutes prior to drug administration at Day 1 of treatment period. (NCT00528996)
Timeframe: 40 minutes (min) and 15 min before drug administration at baseline (Day 1 of treatment period) and Week 24.
| Intervention | litre (Mean) |
|---|---|
| Placebo | -0.034 |
| BEA 2180 BR 50 Microgram (mcg) | 0.044 |
| BEA 2180 BR 100 Microgram (mcg) | 0.066 |
| BEA 2180 BR 200 Microgram (mcg) | 0.087 |
| Tiotropium Bromide 5 Microgram (mcg) | 0.092 |
"The 36-item-health Survey (SF-36) is a multi-purpose, short-form health survey with 36 questions evaluating patient's physical and mental health. Among the 36 questions, 1 is on the health comparing to 1 year ago and the remaining 35 questions are divided into 8 domains: Physical function, role limitations physical, Bodily pain, General physical health, Vitality, Social functioning, role limitations emotional, and General mental health.~The domain score of bodily pain (based on 2 questions) is reported, which is the weighted sum of the questions in the corresponding domain with the domain score ranging from 0 to 100. The higher the domain score, the less severer the bodily pain." (NCT00528996)
Timeframe: At Week 4, 12, and 24.
| Intervention | Score on a scale (Mean) | ||
|---|---|---|---|
| Week 4 | Week 12 | Week 24 | |
| BEA 2180 BR 100 Microgram (mcg) | 70.738 | 70.316 | 68.279 |
| BEA 2180 BR 200 Microgram (mcg) | 66.439 | 67.815 | 66.887 |
| BEA 2180 BR 50 Microgram (mcg) | 68.184 | 66.698 | 66.610 |
| Placebo | 66.828 | 66.749 | 64.964 |
| Tiotropium Bromide 5 Microgram (mcg) | 70.512 | 70.300 | 69.995 |
"The 36-item-health Survey (SF-36) is a multi-purpose, short-form health survey with 36 questions evaluating patient's physical and mental health. Among the 36 questions, 1 is on the health comparing to 1 year ago and the remaining 35 questions are divided into 8 domains: Physical function, role limitations physical, Bodily pain, General physical health, Vitality, Social functioning, role limitations emotional, and General mental health.~The domain score of general mental health (based on 5 questions) is reported, which is the weighted sum of the questions in the corresponding domain with the domain score ranging from 0 to 100. The higher the domain score, the better the mental health in general." (NCT00528996)
Timeframe: At Week 4, 12, and 24.
| Intervention | Score on a scale (Mean) | ||
|---|---|---|---|
| Week 4 | Week 12 | Week 24 | |
| BEA 2180 BR 100 Microgram (mcg) | 70.927 | 70.362 | 69.868 |
| BEA 2180 BR 200 Microgram (mcg) | 71.038 | 71.466 | 70.904 |
| BEA 2180 BR 50 Microgram (mcg) | 71.056 | 70.320 | 70.012 |
| Placebo | 69.585 | 69.201 | 68.144 |
| Tiotropium Bromide 5 Microgram (mcg) | 71.281 | 71.048 | 69.286 |
"The 36-item-health Survey (SF-36) is a multi-purpose, short-form health survey with 36 questions evaluating patient's physical and mental health. Among the 36 questions, 1 is on the health comparing to 1 year ago and the remaining 35 questions are divided into 8 domains: Physical function, role limitations physical, Bodily pain, General physical health, Vitality, Social functioning, role limitations emotional, and General mental health.~The domain score of general physical health (based on 5 questions) is reported, which is the weighted sum of the questions in the corresponding domain with the domain score ranging from 0 to 100. The higher the domain score, the better the physical health in general." (NCT00528996)
Timeframe: At Week 4, 12, and 24.
| Intervention | Score on a scale (Mean) | ||
|---|---|---|---|
| Week 4 | Week 12 | Week 24 | |
| BEA 2180 BR 100 Microgram (mcg) | 50.929 | 50.057 | 50.156 |
| BEA 2180 BR 200 Microgram (mcg) | 49.476 | 49.482 | 49.816 |
| BEA 2180 BR 50 Microgram (mcg) | 48.725 | 48.402 | 48.520 |
| Placebo | 47.187 | 46.709 | 45.913 |
| Tiotropium Bromide 5 Microgram (mcg) | 50.609 | 50.847 | 49.477 |
"The 36-item-health Survey (SF-36) is a multi-purpose, short-form health survey with 36 questions evaluating patient's physical and mental health. Among the 36 questions, 1 is on the health comparing to 1 year ago and the remaining 35 questions are divided into 8 domains: Physical function, role limitations physical, Bodily pain, General physical health, Vitality, Social functioning, role limitations emotional, and General mental health.~The domain score of role emotional (based on 4 questions) is reported, which is the weighted sum of the questions in the corresponding domain with the domain score ranging from 0 to 100. The higher the domain score, the less limitation in roles due to emotional problems." (NCT00528996)
Timeframe: At Week 4, 12, and 24.
| Intervention | Score on a scale (Mean) | ||
|---|---|---|---|
| Week 4 | Week 12 | Week 24 | |
| BEA 2180 BR 100 Microgram (mcg) | 70.473 | 71.035 | 68.756 |
| BEA 2180 BR 200 Microgram (mcg) | 71.646 | 69.505 | 70.454 |
| BEA 2180 BR 50 Microgram (mcg) | 70.509 | 70.213 | 70.884 |
| Placebo | 69.365 | 67.399 | 66.168 |
| Tiotropium Bromide 5 Microgram (mcg) | 71.313 | 70.081 | 69.259 |
"The 36-item-health Survey (SF-36) is a multi-purpose, short-form health survey with 36 questions evaluating patient's physical and mental health. Among the 36 questions, 1 is on the health comparing to 1 year ago and the remaining 35 questions are divided into 8 domains: Physical function, role limitations physical, Bodily pain, General physical health, Vitality, Social functioning, role limitations emotional, and General mental health.~The domain score of role limitations due to physical health problems (based on 4 questions) is reported, which is the weighted sum of the questions in the corresponding domain with the domain score ranging from 0 to 100. The higher the domain score, the less limitations in roles due to physical health problems." (NCT00528996)
Timeframe: At Week 4, 12, and 24.
| Intervention | Score on a scale (Mean) | ||
|---|---|---|---|
| Week 4 | Week 12 | Week 24 | |
| BEA 2180 BR 100 Microgram (mcg) | 57.469 | 57.186 | 54.934 |
| BEA 2180 BR 200 Microgram (mcg) | 56.898 | 56.938 | 55.871 |
| BEA 2180 BR 50 Microgram (mcg) | 57.326 | 57.271 | 57.095 |
| Placebo | 55.168 | 54.405 | 53.138 |
| Tiotropium Bromide 5 Microgram (mcg) | 57.950 | 57.417 | 57.020 |
"The 36-item-health Survey (SF-36) is a multi-purpose, short-form health survey with 36 questions evaluating patient's physical and mental health. Among the 36 questions, 1 is on the health comparing to 1 year ago and the remaining 35 questions are divided into 8 domains: Physical function, role limitations physical, Bodily pain, General physical health, Vitality, Social functioning, role limitations emotional, and General mental health.~The domain score of Social functioning (based on 2 questions) is reported, which is the weighted sum of the questions in the corresponding domain with the domain score ranging from 0 to 100. The higher the domain score, the better the social functioning." (NCT00528996)
Timeframe: At Week 4, 12, and 24.
| Intervention | Score on a scale (Mean) | ||
|---|---|---|---|
| Week 4 | Week 12 | Week 24 | |
| BEA 2180 BR 100 Microgram (mcg) | 76.418 | 75.108 | 74.295 |
| BEA 2180 BR 200 Microgram (mcg) | 77.177 | 75.798 | 75.520 |
| BEA 2180 BR 50 Microgram (mcg) | 76.235 | 76.801 | 75.157 |
| Placebo | 75.574 | 73.093 | 71.440 |
| Tiotropium Bromide 5 Microgram (mcg) | 77.053 | 76.992 | 73.993 |
"The 36-item-health Survey (SF-36) is a multi-purpose, short-form health survey with 36 questions evaluating patient's physical and mental health. Among the 36 questions, 1 is on the health comparing to 1 year ago and the remaining 35 questions are divided into 8 domains: Physical function, role limitations physical, Bodily pain, General physical health, Vitality, Social functioning, role limitations emotional, and General mental health.~The domain score of vitality (based on 4 questions) is reported, which is the weighted sum of the questions in the corresponding domain with the domain score ranging from 0 to 100. The higher the domain score, the more vitality and less fatigue one has." (NCT00528996)
Timeframe: At Week 4, 12, and 24.
| Intervention | Score on a scale (Mean) | ||
|---|---|---|---|
| Week 4 | Week 12 | Week 24 | |
| BEA 2180 BR 100 Microgram (mcg) | 54.084 | 53.947 | 54.080 |
| BEA 2180 BR 200 Microgram (mcg) | 53.630 | 53.935 | 54.211 |
| BEA 2180 BR 50 Microgram (mcg) | 53.516 | 53.670 | 52.892 |
| Placebo | 52.501 | 51.676 | 51.188 |
| Tiotropium Bromide 5 Microgram (mcg) | 54.881 | 55.317 | 54.542 |
The 36-item-health Survey (SF-36) is a multi-purpose, short-form health survey with 36 questions evaluating patient's physical and mental health. Among the 36 questions, 1 is on the health comparing to 1 year ago and the remaining 35 questions are divided into 8 domains: Physical function (10 questions), role physical (4 questions), Bodily pain (2 questions), General physical health (5 questions), Vitality (4 questions), Social functioning (2 questions), role emotional (3 questions), and General mental health (5 questions). Each domain score is the weighted sum of the questions in the corresponding domain with the domain score ranging from 0 to 100. The higher the score value, the better the health condition. (NCT00528996)
Timeframe: At baseline (Week 0, Day 1 of treatment period).
| Intervention | Score on a scale (Mean) | |||||||
|---|---|---|---|---|---|---|---|---|
| Physical function | Role physical | Bodily pain | General physical health | Vitality | Social functioning | Role emotional | General mental health | |
| BEA 2180 BR 100 Microgram (mcg) | 51.9 | 53.3 | 66.7 | 48.0 | 53.4 | 75.2 | 69.3 | 71.2 |
| BEA 2180 BR 200 Microgram (mcg) | 49.1 | 53.9 | 67.1 | 48.5 | 52.1 | 74.3 | 67.8 | 68.5 |
| BEA 2180 BR 50 Microgram (mcg) | 51.4 | 55.9 | 68.6 | 49.2 | 53.6 | 76.2 | 70.8 | 70.4 |
| Placebo | 50.2 | 53.9 | 68.9 | 48.5 | 53.9 | 75.3 | 70.0 | 72.0 |
| Tiotropium Bromide 5 Microgram (mcg) | 51.1 | 54.9 | 65.9 | 47.1 | 51.8 | 74.2 | 68.5 | 68.5 |
Forced expiratory volume in one second (FEV1) area under the curve from 0 to 3 hours (AUC0-3h) response after 0, 4, 12 and 24 weeks are reported. The FEV1 AUC0-3h response is the area under the curve from 0 to 3 hours post drug administration for change from baseline values of FEV1. The area under the curve (AUC) is calculated as the area under the curve from 0 to 3 hours at weeks 0, 4, 12 and 24 using the trapezoidal rule and using planned time, divided by the full duration (3 hours) to report in litres. The mean of the pre-dose values (at 40 minutes and 15 minutes before dosing) are used with a time value of zero for calculating the AUC values starting at zero. The baseline FEV1 is the mean of the two measurements taken at 40 and 15 minutes before drug administration at Day 1 of treatment period. (NCT00528996)
Timeframe: 40 minutes (min) and 15 min before drug administration and 15 min, 30 min, 60 min, 2 hours, 3 hours after drug administration at Week 0 (Day 1 of treatment period), 4, 12, 24.
| Intervention | litre (Mean) | |||
|---|---|---|---|---|
| Week 0 | Week 4 | Week 12 | Week 24 | |
| BEA 2180 BR Inhalation Solution 100 Microgram (mcg) | 0.186 | 0.175 | 0.166 | 0.150 |
| BEA 2180 BR Inhalation Solution 200 Microgram (mcg) | 0.177 | 0.165 | 0.166 | 0.146 |
| BEA 2180 BR Inhalation Solution 50 Microgram (mcg) | 0.172 | 0.166 | 0.164 | 0.140 |
| Placebo | 0.029 | 0.021 | 0.019 | -0.007 |
| Tiotropium Bromide 5 Microgram (mcg) | 0.165 | 0.203 | 0.203 | 0.177 |
Forced expiratory volume in one second (FEV1) values at 3 minutes and 10 minutes following drug administration at Week 0, 4, 12, and 24 are reported. (NCT00528996)
Timeframe: 3 minutes (min) and 10 after drug administration at Week 0 (Day 1 of treatment period), 4, 12, and 24.
| Intervention | litre (Mean) | |||||||
|---|---|---|---|---|---|---|---|---|
| Week 0 - 3 minutes (min) | Week 0 -10 min | Week 4 - 3 min | Week 4 - 10 min | Week 12 - 3 min | Week 12 - 10 min | Week 24 - 3 min | Week 24 - 10 min | |
| BEA 2180 BR Inhalation Solution 100 Microgram (mcg) | 1.185 | 1.268 | 1.259 | 1.312 | 1.251 | 1.304 | 1.230 | 1.278 |
| BEA 2180 BR Inhalation Solution 200 Microgram (mcg) | 1.147 | 1.224 | 1.227 | 1.252 | 1.258 | 1.279 | 1.211 | 1.244 |
| BEA 2180 BR Inhalation Solution 50 Microgram (mcg) | 1.195 | 1.253 | 1.208 | 1.252 | 1.233 | 1.258 | 1.196 | 1.240 |
| Placebo | 1.128 | 1.135 | 1.161 | 1.160 | 1.151 | 1.172 | 1.115 | 1.138 |
| Tiotropium Bromide 5 Microgram (mcg) | 1.206 | 1.247 | 1.260 | 1.301 | 1.310 | 1.336 | 1.301 | 1.329 |
Forced expiratory volume in one second (FEV1) peak response after 0, 4, 12, and 24 weeks were reported. Peak FEV1 response was the maximum change from baseline for the post-dose measurements of FEV1. Baseline FEV1 is the mean of the two measurements taken at 40 and 15 minutes before drug administration. (NCT00528996)
Timeframe: 40 minutes (min) and 15 min before drug administration and 15 min, 30 min, 60 min, 2 hours, 3 hours after drug administration at Week 0 (Day 1 of treatment period), 4, 12, 24.
| Intervention | litre (Mean) | |||
|---|---|---|---|---|
| Week 0 | Week 4 | Week 12 | Week 24 | |
| BEA 2180 BR Inhalation Solution 100 Microgram (mcg) | 0.260 | 0.250 | 0.236 | 0.216 |
| BEA 2180 BR Inhalation Solution 200 Microgram (mcg) | 0.266 | 0.243 | 0.241 | 0.216 |
| BEA 2180 BR Inhalation Solution 50 Microgram (mcg) | 0.246 | 0.237 | 0.236 | 0.207 |
| Placebo | 0.103 | 0.090 | 0.078 | 0.051 |
| Tiotropium Bromide 5 Microgram (mcg) | 0.246 | 0.274 | 0.273 | 0.242 |
Forced vital capacity (FVC) area under the curve from 0 to 3 hours (AUC0-3h) response after 0, 4, 12 and 24 weeks are reported. The FVC AUC0-3h response is the area under the curve from 0 to 3 hours post drug administration for change from baseline values of FVC. The area under the curve (AUC) is calculated as the area under the curve from 0 to 3 hours at weeks 0, 4, 12 and 24 using the trapezoidal rule and using planned time, divided by the full duration (3 hours) to report in litres. The mean of the pre-dose values (at 40 minutes and 15 minutes before dosing) are used with a time value of zero for calculating the AUC values starting at zero. The baseline FVC is the mean of the two measurements taken at 40 and 15 minutes before drug administration at Day 1 of treatment period. (NCT00528996)
Timeframe: 40 minutes (min) and 15 min before drug administration and 15 min, 30 min, 60 min, 2 hours, 3 hours after drug administration at Week 0 (Day 1 of treatment period), 4, 12, 24.
| Intervention | litre (Mean) | |||
|---|---|---|---|---|
| Week 0 | Week 4 | Week 12 | Week 24 | |
| BEA 2180 BR Inhalation Solution 100 Microgram (mcg) | 0.336 | 0.298 | 0.278 | 0.218 |
| BEA 2180 BR Inhalation Solution 200 Microgram (mcg) | 0.302 | 0.247 | 0.251 | 0.210 |
| BEA 2180 BR Inhalation Solution 50 Microgram (mcg) | 0.321 | 0.292 | 0.276 | 0.233 |
| Placebo | 0.067 | 0.050 | 0.053 | -0.002 |
| Tiotropium Bromide 5 Microgram (mcg) | 0.312 | 0.340 | 0.326 | 0.274 |
Forced Vital Capacity (FVC) values at 3 minutes and 10 minutes following drug administration at Week 0, 4, 12, and 24 are reported. (NCT00528996)
Timeframe: 3 minutes (min) and 10 min after drug administration at Week 0 (Day 1 of treatment period), 4, 12, and 24.
| Intervention | litre (Mean) | |||||||
|---|---|---|---|---|---|---|---|---|
| Week 0 - 3 minutes (min) | Week 0 - 10 min | Week 4 - 3 min | Week 4 - 10 min | Week 12 - 3 min | Week 12 - 10 min | Week 24 - 3 min | Week 24 - 10 min | |
| BEA 2180 BR Inhalation Solution 100 Microgram (mcg) | 2.535 | 2.658 | 2.638 | 2.697 | 2.604 | 2.637 | 2.556 | 2.599 |
| BEA 2180 BR Inhalation Solution 200 Microgram (mcg) | 2.455 | 2.557 | 2.523 | 2.540 | 2.549 | 2.579 | 2.513 | 2.545 |
| BEA 2180 BR Inhalation Solution 50 Microgram (mcg) | 2.530 | 2.624 | 2.623 | 2.693 | 2.594 | 2.648 | 2.566 | 2.635 |
| Placebo | 2.381 | 2.392 | 2.391 | 2.391 | 2.395 | 2.417 | 2.355 | 2.403 |
| Tiotropium Bromide 5 Microgram (mcg) | 2.500 | 2.593 | 2.601 | 2.634 | 2.631 | 2.646 | 2.624 | 2.664 |
Forced Vital Capacity (FVC) peak response after 0, 4, 12, and 24 weeks were reported. Peak FVC response was the maximum change from baseline for the post-dose measurements of FVC. Baseline FVC is the mean of the two measurements taken at 40 and 15 minutes before drug administration. (NCT00528996)
Timeframe: 40 minutes (min) and 15 min before drug administration and 15 min, 30 min, 60 min, 2 hours, 3 hours after drug administration at Week 0 (Day 1 of treatment period), 4, 12, 24.
| Intervention | litre (Mean) | |||
|---|---|---|---|---|
| Week 0 | Week 4 | Week 12 | Week 24 | |
| BEA 2180 BR Inhalation Solution 100 Microgram (mcg) | 0.478 | 0.449 | 0.412 | 0.345 |
| BEA 2180 BR Inhalation Solution 200 Microgram (mcg) | 0.463 | 0.386 | 0.384 | 0.335 |
| BEA 2180 BR Inhalation Solution 50 Microgram (mcg) | 0.474 | 0.434 | 0.417 | 0.369 |
| Placebo | 0.216 | 0.186 | 0.177 | 0.122 |
| Tiotropium Bromide 5 Microgram (mcg) | 0.463 | 0.479 | 0.463 | 0.393 |
Individual Forced expiratory volume in one second (FEV1) values measured at each time points at Week 0, 4, 12, and 24 were reported. (NCT00528996)
Timeframe: 15 minutes (min), 30 min, 1 hour (h), 2 h, 3 h after drug administration at Week 0 (Day 1 of treatment period), 4, 12, and 24. At 0 min (at drug administration) at Week 4, 12, and 24.
| Intervention | litre (Mean) | ||||||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Week 0 - 15 minutes (min) | Week 0 - 30 min | Week 0 - 1 hour (h) | Week 0 - 2 h | Week 0 - 3 h | Week 4 - 0 min | Week 4 - 15 min | Week 4 - 30 min | Week 4 - 1 h | Week 4 - 2 h | Week 4 - 3 h | Week 12 - 0 min | Week 12 - 15 min | Week 12 - 30 min | Week 12 - 1 h | Week 12 - 2 h | Week 12 - 3 h | Week 24 - 0 min | Week 24 0:15 min | Week 24 - 30 min | Week 24 - 1 h | Week 24 - 2 h | Week 24 - 3 h | |
| BEA 2180 BR Inhalation Solution 100 Microgram (mcg) | 1.310 | 1.357 | 1.390 | 1.388 | 1.389 | 1.274 | 1.321 | 1.346 | 1.366 | 1.372 | 1.368 | 1.267 | 1.313 | 1.335 | 1.356 | 1.365 | 1.363 | 1.250 | 1.298 | 1.320 | 1.342 | 1.345 | 1.344 |
| BEA 2180 BR Inhalation Solution 200 Microgram (mcg) | 1.263 | 1.318 | 1.369 | 1.395 | 1.403 | 1.284 | 1.279 | 1.308 | 1.350 | 1.372 | 1.380 | 1.291 | 1.292 | 1.313 | 1.345 | 1.372 | 1.384 | 1.270 | 1.278 | 1.296 | 1.331 | 1.346 | 1.357 |
| BEA 2180 BR Inhalation Solution 50 Microgram (mcg) | 1.309 | 1.347 | 1.375 | 1.373 | 1.363 | 1.249 | 1.319 | 1.346 | 1.360 | 1.360 | 1.355 | 1.249 | 1.321 | 1.348 | 1.358 | 1.357 | 1.352 | 1.227 | 1.297 | 1.318 | 1.338 | 1.332 | 1.326 |
| Placebo | 1.200 | 1.206 | 1.223 | 1.212 | 1.220 | 1.163 | 1.187 | 1.200 | 1.207 | 1.211 | 1.211 | 1.174 | 1.188 | 1.196 | 1.209 | 1.205 | 1.205 | 1.150 | 1.164 | 1.170 | 1.180 | 1.180 | 1.180 |
| Tiotropium Bromide 5 Microgram (mcg) | 1.276 | 1.311 | 1.353 | 1.378 | 1.388 | 1.283 | 1.348 | 1.374 | 1.397 | 1.401 | 1.401 | 1.293 | 1.354 | 1.371 | 1.391 | 1.401 | 1.401 | 1.276 | 1.326 | 1.355 | 1.368 | 1.373 | 1.370 |
Individual Forced Vital Capacity (FVC) values measured at each time point at Week 0, 4, 12, and 24 were reported. (NCT00528996)
Timeframe: 15 minutes (min), 30 min, 1 hour (h), 2 h, 3 h after drug administration at Week 0 (Day 1 of treatment period), 4, 12, and 24. At 0 min (at drug administration) at Week 4, 12, and 24.
| Intervention | litre (Mean) | ||||||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Week 0 - 15 minutes (min) | Week 0 - 30 min | Week 0 - 1 hour (h) | Week 0 - 2 h | Week 0 - 3 h | Week 4 - 0 minutes | Week 4 - 15 minutes | Week 4 - 30 min | Week 4 - 1 h | Week 4 - 2 h | Week 4 - 3 h | Week 12 - 0 min | Week 12 - 15 min | Week 12 - 30 minutes | Week 12 - 1 h | Week 12 - 2 h | Week 12 - 3 h | Week 24 - 0 min | Week 24 - 15 min | Week 24- 30 min | Week 24 - 1 h | Week 24 - 2 h | Week 24 - 3 h | |
| BEA 2180 BR Inhalation Solution 100 Microgram (mcg) | 2.778 | 2.852 | 2.907 | 2.896 | 2.896 | 2.689 | 2.776 | 2.803 | 2.848 | 2.851 | 2.849 | 2.687 | 2.751 | 2.788 | 2.821 | 2.829 | 2.836 | 2.637 | 2.705 | 2.724 | 2.763 | 2.770 | 2.766 |
| BEA 2180 BR Inhalation Solution 200 Microgram (mcg) | 2.691 | 2.776 | 2.853 | 2.886 | 2.896 | 2.688 | 2.670 | 2.711 | 2.779 | 2.815 | 2.837 | 2.703 | 2.688 | 2.720 | 2.773 | 2.820 | 2.840 | 2.664 | 2.667 | 2.690 | 2.739 | 2.771 | 2.789 |
| BEA 2180 BR Inhalation Solution 50 Microgram (mcg) | 2.787 | 2.854 | 2.885 | 2.881 | 2.867 | 2.665 | 2.770 | 2.812 | 2.842 | 2.842 | 2.842 | 2.654 | 2.764 | 2.796 | 2.823 | 2.828 | 2.819 | 2.614 | 2.725 | 2.753 | 2.793 | 2.778 | 2.769 |
| Placebo | 2.572 | 2.589 | 2.617 | 2.598 | 2.617 | 2.510 | 2.547 | 2.575 | 2.590 | 2.592 | 2.595 | 2.533 | 2.563 | 2.574 | 2.606 | 2.584 | 2.588 | 2.489 | 2.504 | 2.520 | 2.539 | 2.533 | 2.547 |
| Tiotropium Bromide 5 Microgram (mcg) | 2.729 | 2.802 | 2.864 | 2.885 | 2.901 | 2.702 | 2.822 | 2.852 | 2.891 | 2.893 | 2.891 | 2.711 | 2.803 | 2.844 | 2.866 | 2.878 | 2.886 | 2.678 | 2.761 | 2.803 | 2.823 | 2.822 | 2.806 |
"Physicians make a global evaluation reflecting the physician's global opinion of the overall clinical condition of the patient as poor (score 1 or 2), fair (score 3 or 4), good (score 5 or 6), or excellent (score 7 or 8). These assessments are made prior to pulmonary function testing and are summarized on pulmonary function test days. This evaluation was based on the need for concomitant medication, number and severity of exacerbations since the last visit, severity of cough, ability to exercise, amount of wheezing, and other relevant clinical observations. The score ranges from 1 to 8 with higher score indicating better overall clinical condition." (NCT00528996)
Timeframe: At Week 0, 4, 12, and 24.
| Intervention | Score on scale (Mean) | |||
|---|---|---|---|---|
| Week 0 | Week 4 | Week 12 | Week 24 | |
| BEA 2180 BR Inhalation Solution 100 Microgram (mcg) | 4.5 | 4.747 | 4.790 | 4.775 |
| BEA 2180 BR Inhalation Solution 200 Microgram (mcg) | 4.4 | 4.807 | 4.880 | 4.888 |
| BEA 2180 BR Inhalation Solution 50 Microgram (mcg) | 4.5 | 4.714 | 4.804 | 4.865 |
| Placebo | 4.4 | 4.541 | 4.582 | 4.613 |
| Tiotropium Bromide 5 Microgram (mcg) | 4.5 | 4.739 | 4.816 | 4.810 |
The St. George's Respiratory Questionnaire (SGRQ) is a well-established, self-completed tool measuring health-related quality of life in patients with diseases of airways obstruction on three aspects of symptoms, activity, and impacts. The total SGRQ score is reported, which ranges from 0 (the best score) to 100 (the worst score) with smaller score value indicating less limitations due to breathlessness and better quality of life. (NCT00528996)
Timeframe: At Week 0, 4, 12, and 24.
| Intervention | Score on a scale (Mean) | |||
|---|---|---|---|---|
| Week 0 | Week 4 | Week 12 | Week 24 | |
| BEA 2180 BR 100 Microgram (mcg) | 42.5 | 39.865 | 39.506 | 40.058 |
| BEA 2180 BR 200 Microgram (mcg) | 43.8 | 40.689 | 40.368 | 40.728 |
| BEA 2180 BR 50 Microgram (mcg) | 41.9 | 40.552 | 40.293 | 40.103 |
| Placebo | 43.2 | 41.969 | 42.744 | 42.993 |
| Tiotropium Bromide 5 Microgram (mcg) | 43.1 | 40.706 | 39.489 | 39.547 |
The transitional dyspnea index (TDI) evaluates the patient's condition related to breathlessness. The TDI includes three domains: functional impairment, magnitude of task, and magnitude of effort. The TDI domain score of functional impairment is reported, which domain score ranges from -3 (major deterioration in the ability of working and doing activities due to shortness of breath; the worst score) to 3 (major improvement in the ability of working and doing activities; mild restriction on full activities due to the improvement of shortness of breath; the best score). (NCT00528996)
Timeframe: At Week 0 (baseline), 4, 12 and 24.
| Intervention | Score on a scale (Mean) | |||
|---|---|---|---|---|
| Week 0 | Week 4 | Week 12 | Week 24 | |
| BEA 2180 BR Inhalation Solution 100 Microgram (mcg) | 2.3 | 0.480 | 0.519 | 0.445 |
| BEA 2180 BR Inhalation Solution 200 Microgram (mcg) | 2.2 | 0.518 | 0.454 | 0.465 |
| BEA 2180 BR Inhalation Solution 50 Microgram (mcg) | 2.3 | 0.379 | 0.474 | 0.465 |
| Placebo | 2.3 | 0.192 | 0.276 | 0.353 |
| Tiotropium Bromide 5 Microgram (mcg) | 2.3 | 0.462 | 0.492 | 0.488 |
The transitional dyspnea index (TDI) evaluates the patient's condition related to breathlessness. The TDI includes three domains: functional impairment, magnitude of task, and magnitude of effort. The TDI domain score of magnitude of effort is reported, which sub-score ranges from -3 (severe decrease in effort from baseline to avoid shortness of breath. Activities now take 50-100% longer to complete than required at baseline; the worst score) to 3 (Able to do things with much greater effort than previously with few pauses. Activities may be performed 50- 100% more rapidly than at baseline; the best score). (NCT00528996)
Timeframe: At Week 0 (baseline), 4, 12 and 24
| Intervention | Score on a scale (Mean) | |||
|---|---|---|---|---|
| Week 0 | Week 4 | Week 12 | Week 24 | |
| BEA 2180 BR Inhalation Solution 100 Microgram (mcg) | 2.0 | 0.497 | 0.486 | 0.472 |
| BEA 2180 BR Inhalation Solution 200 Microgram (mcg) | 2.0 | 0.478 | 0.460 | 0.502 |
| BEA 2180 BR Inhalation Solution 50 Microgram (mcg) | 2.0 | 0.437 | 0.423 | 0.458 |
| Placebo | 2.1 | 0.161 | 0.253 | 0.273 |
| Tiotropium Bromide 5 Microgram (mcg) | 2.0 | 0.449 | 0.478 | 0.474 |
The transitional dyspnea index (TDI) evaluates the patient's condition related to breathlessness. The TDI includes three domains: functional impairment, magnitude of task, and magnitude of effort. The TDI domain score of magnitude of task is reported, which domain score ranges from -3 (major deterioration from baseline status; the worst score) to 3 (major improvement from baseline status; the best score). (NCT00528996)
Timeframe: At week 0 (baseline), 4, 12 and 24
| Intervention | Score on a scale (Mean) | |||
|---|---|---|---|---|
| Week 0 | Week 4 | Week 12 | Week 24 | |
| BEA 2180 BR Inhalation Solution 100 Microgram (mcg) | 2.2 | 0.538 | 0.587 | 0.513 |
| BEA 2180 BR Inhalation Solution 200 Microgram (mcg) | 2.2 | 0.571 | 0.479 | 0.514 |
| BEA 2180 BR Inhalation Solution 50 Microgram (mcg) | 2.2 | 0.494 | 0.494 | 0.510 |
| Placebo | 2.2 | 0.245 | 0.282 | 0.322 |
| Tiotropium Bromide 5 Microgram (mcg) | 2.2 | 0.489 | 0.523 | 0.496 |
Trough Forced expiratory volume in one second (FEV1) response was defined as the change from baseline in trough FEV1. Trough FEV1 was defined as the mean of the two FEV1 measurements recorded at the pre-dose measurements (40 and 15 minutes before the drug administration) at the end of the dosing interval (24 hours post previous drug administration from the Respimat® Inhaler). Baseline FEV1 was pre-treatment FEV1 values measured at Day 1 of treatment period (baseline) prior to administration of the first dose of study medication, which was the mean of the measurements recorded from the pulmonary function tests taken at 40 and 15 minutes prior to drug administration at Day 1 of treatment period. (NCT00528996)
Timeframe: 40 minutes (min) and 15 min before drug administration at baseline (Day 1 of treatment period) and Week 1, 2, 4, 8, 12 and 18.
| Intervention | litre (Mean) | |||||
|---|---|---|---|---|---|---|
| Week 1 | Week 2 | Week 4 | Week 8 | Week 12 | Week 18 | |
| BEA 2180 BR Inhalation Solution 100 Microgram (mcg) | 0.090 | 0.094 | 0.090 | 0.086 | 0.083 | 0.072 |
| BEA 2180 BR Inhalation Solution 200 Microgram (mcg) | 0.106 | 0.110 | 0.100 | 0.101 | 0.107 | 0.096 |
| BEA 2180 BR Inhalation Solution 50 Microgram (mcg) | 0.070 | 0.080 | 0.066 | 0.078 | 0.066 | 0.063 |
| Placebo | -0.014 | -0.013 | -0.020 | -0.006 | -0.010 | -0.023 |
| Tiotropium Bromide 5 Microgram (mcg) | 0.097 | 0.105 | 0.099 | 0.104 | 0.109 | 0.096 |
Trough Forced expiratory volume in one second (FEV1) response on Day 3 and 5 are reported, for which the FEV1 response is the change from baseline in trough FEV1. Trough FEV1 for respective day (Day 3 or Day 5)was defined as the mean of the two FEV1 measurements recorded at the pre-dose measurements (40 and 15 minutes before the drug administration) at the end of the dosing interval (24 hours post previous drug administration from the Respimat® Inhaler) at that day. Baseline FEV1 was pre-treatment FEV1 values measured at Day 1 of treatment period (baseline) prior to administration of the first dose of study medication, which was the mean of the measurements recorded from the pulmonary function tests taken at 40 and 15 minutes prior to drug administration at Day 1 of treatment period. (NCT00528996)
Timeframe: 40 minutes (min) and 15 min before drug administration at Day 1 (baseline) and Day 3 and 5 of treatment period.
| Intervention | liter (Mean) | |
|---|---|---|
| Day 3 | Day 5 | |
| BEA 2180 BR Inhalation Solution 100 Microgram (mcg) | 0.101 | 0.095 |
| BEA 2180 BR Inhalation Solution 200 Microgram (mcg) | 0.124 | 0.115 |
| BEA 2180 BR Inhalation Solution 50 Microgram (mcg) | 0.060 | 0.041 |
| Placebo | 0.008 | 0.012 |
| Tiotropium Bromide 5 Microgram (mcg) | 0.103 | 0.118 |
Trough forced vital capacity (FVC) response was defined as the change from baseline in trough FVC. Trough FVC was defined as the mean of the two FVC measurements recorded at the pre-dose measurements (40 and 15 minutes before drug administration) at the end of the dosing interval (24 hours post previous drug administration from the Respimat® Inhaler), which were obtained through spirometry at the same time points as for forced expiratory volume in one second. Baseline FVC was the mean of the two measurements of FVC taken at 40 and 15 minutes before drug administration at Day 1 of treatment period. (NCT00528996)
Timeframe: 40 minutes (min) and 15 min before drug administration at baseline (Day 1 of treatment period) and Week 1, 2, 4, 8, 12, 18, and 24.
| Intervention | litre (Mean) | ||||||
|---|---|---|---|---|---|---|---|
| Week 1 | Week 2 | Week 4 | Week 8 | Week 12 | Week 18 | Week 24 | |
| BEA 2180 BR Inhalation Solution 100 Microgram (mcg) | 0.172 | 0.177 | 0.157 | 0.166 | 0.155 | 0.131 | 0.104 |
| BEA 2180 BR Inhalation Solution 200 Microgram (mcg) | 0.186 | 0.186 | 0.156 | 0.173 | 0.171 | 0.153 | 0.132 |
| BEA 2180 BR Inhalation Solution 50 Microgram (mcg) | 0.146 | 0.166 | 0.132 | 0.148 | 0.121 | 0.117 | 0.081 |
| Placebo | -0.002 | -0.002 | -0.022 | 0.006 | 0.001 | -0.023 | -0.044 |
| Tiotropium Bromide 5 Microgram (mcg) | 0.174 | 0.188 | 0.169 | 0.177 | 0.178 | 0.146 | 0.146 |
The patient recorded twice daily peak flow measurements with an electronic peak flow meter throughout the entire evaluation period. Morning measurements were performed immediately upon arising after the patient had cleared out mucus, prior to administration of trial and/or rescue medication. The evening measurements were performed at bedtime. The weekly mean of evening peak expiratory flow rate (PEFR) is reported. (NCT00528996)
Timeframe: Assessed at bed time per day during 24 weeks with weekly mean values reporting.
| Intervention | litres/minute (Mean) | |||||||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Week 1 | Week 2 | Week 3 | Week 4 | Week 5 | Week 6 | Week 7 | Week 8 | Week 9 | Week 10 | Week 11 | Week 12 | Week 13 | Week 14 | Week 15 | Week 16 | Week 17 | Week 18 | Week 19 | Week 20 | Week 21 | Week 22 | Week 23 | Week 24 | |
| BEA 2180 BR Inhalation Solution 100 Microgram (mcg) | 186.37 | 185.96 | 183.77 | 184.33 | 186.84 | 185.32 | 184.57 | 182.81 | 181.88 | 179.46 | 179.36 | 179.65 | 178.40 | 177.70 | 177.33 | 177.30 | 177.51 | 176.28 | 177.78 | 177.23 | 176.16 | 175.23 | 176.10 | 176.20 |
| BEA 2180 BR Inhalation Solution 200 Microgram (mcg) | 187.31 | 187.16 | 187.41 | 187.11 | 185.67 | 184.51 | 182.39 | 182.01 | 184.21 | 182.53 | 182.54 | 180.52 | 181.12 | 181.26 | 181.66 | 180.18 | 178.95 | 178.92 | 178.64 | 179.20 | 178.87 | 177.71 | 177.54 | 179.04 |
| BEA 2180 BR Inhalation Solution 50 Microgram (mcg) | 186.40 | 187.16 | 187.14 | 186.96 | 186.03 | 183.97 | 183.82 | 183.69 | 182.98 | 181.90 | 182.05 | 180.46 | 180.80 | 179.23 | 178.86 | 179.17 | 179.50 | 177.88 | 177.34 | 177.50 | 175.87 | 174.78 | 174.37 | 172.72 |
| Placebo | 173.64 | 173.18 | 171.85 | 170.91 | 172.33 | 169.29 | 168.10 | 166.98 | 165.67 | 164.15 | 163.02 | 163.84 | 163.95 | 162.72 | 162.77 | 161.50 | 161.12 | 161.66 | 161.70 | 160.54 | 161.13 | 160.32 | 160.75 | 159.69 |
| Tiotropium Bromide 5 Microgram (mcg) | 187.13 | 185.79 | 185.61 | 185.23 | 185.02 | 184.34 | 183.80 | 181.66 | 183.38 | 182.12 | 181.58 | 181.09 | 183.50 | 183.27 | 182.12 | 180.76 | 180.40 | 179.47 | 179.98 | 180.70 | 179.66 | 178.98 | 178.20 | 178.21 |
The patient recorded the number of occasions salbutamol (albuterol) Metered Dose Inhaler (MDI) was used each day and night during the entire evaluation period. The weekly mean number of occasions of rescue therapy used per day (PRN salbutamol [albuterol]) is reported. (NCT00528996)
Timeframe: Assessed once per day during 24 weeks with weekly mean values reporting.
| Intervention | Metered Dose Inhaler use per day (Mean) | |||||||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Week 1 | Week 2 | Week 3 | Week 4 | Week 5 | Week 6 | Week 7 | Week 8 | Week 9 | Week 10 | Week 11 | Week 12 | Week 13 | Week 14 | Week 15 | Week 16 | Week 17 | Week 18 | Week 19 | Week 20 | Week 21 | Week 22 | Week 23 | Week 24 | |
| BEA 2180 BR Inhalation Solution 100 Microgram (mcg) | 1.972 | 2.044 | 2.037 | 2.017 | 2.012 | 2.041 | 2.039 | 2.010 | 1.981 | 2.013 | 2.020 | 2.011 | 2.108 | 2.161 | 2.127 | 2.090 | 2.111 | 2.078 | 2.083 | 2.149 | 2.116 | 2.119 | 2.094 | 2.116 |
| BEA 2180 BR Inhalation Solution 200 Microgram (mcg) | 1.790 | 1.803 | 1.835 | 1.885 | 1.768 | 1.789 | 1.851 | 1.877 | 1.834 | 1.838 | 1.872 | 1.899 | 1.844 | 1.844 | 1.859 | 1.906 | 1.899 | 1.872 | 1.896 | 1.975 | 1.928 | 1.928 | 1.959 | 1.961 |
| BEA 2180 BR Inhalation Solution 50 Microgram (mcg) | 1.964 | 1.985 | 1.960 | 1.977 | 2.040 | 2.048 | 2.042 | 2.007 | 2.026 | 2.062 | 2.136 | 2.127 | 2.074 | 2.131 | 2.148 | 2.081 | 2.060 | 2.074 | 2.105 | 2.084 | 2.103 | 2.124 | 2.056 | 2.114 |
| Placebo | 2.514 | 2.524 | 2.509 | 2.498 | 2.548 | 2.629 | 2.656 | 2.612 | 2.617 | 2.623 | 2.693 | 2.678 | 2.645 | 2.655 | 2.712 | 2.732 | 2.738 | 2.756 | 2.706 | 2.670 | 2.706 | 2.704 | 2.675 | 2.672 |
| Tiotropium Bromide 5 Microgram (mcg) | 2.084 | 2.109 | 2.093 | 2.118 | 2.106 | 2.116 | 2.122 | 2.129 | 2.094 | 2.137 | 2.154 | 2.122 | 2.112 | 2.063 | 2.141 | 2.143 | 2.153 | 2.146 | 2.154 | 2.180 | 2.156 | 2.168 | 2.138 | 2.148 |
"Incidence rate of Chronic Obstructive Pulmonary Disease (COPD) exacerbation is reported. A Chronic Obstructive Pulmonary Disease (COPD) exacerbation is defined as a complex of lower respiratory events / symptoms (increase or new onset) related to the underlying COPD, with a duration of three days or more, requiring a change in treatment, where a complex of lower respiratory events / symptoms means at least two of the following: Shortness of breath, Sputum production (volume), Occurrence of purulent sputum, Cough, Wheezing, Chest tightness." (NCT00528996)
Timeframe: From first does until 30 days after the end of treatment, up to 205 days.
| Intervention | Events per patient-year (Number) |
|---|---|
| Placebo | 0.5797 |
| BEA 2180 BR 50 Microgram (mcg) | 0.4345 |
| BEA 2180 BR 100 Microgram (mcg) | 0.4898 |
| BEA 2180 BR 200 Microgram (mcg) | 0.4373 |
| Tiotropium Bromide 5 Microgram (mcg) | 0.5332 |
Reason for stopping exercise after 8 weeks (leg discomfort, breathing discomfort, both or none) (NCT00530842)
Timeframe: 8 weeks
| Intervention | Participants (Number) | |||
|---|---|---|---|---|
| Leg discomfort | Breathing discomfort | Both (leg and breathing discomfort) | None | |
| Fluticasone + Salmeterol | 72 | 131 | 78 | 28 |
| Tiotropium + Salmeterol | 88 | 112 | 82 | 27 |
Reason for stopping exercise after 4 weeks (leg discomfort, breathing discomfort, both or none) (NCT00530842)
Timeframe: 4 weeks
| Intervention | Participants (Number) | |||
|---|---|---|---|---|
| Leg discomfort | Breathing discomfort | Both (leg and breathing discomfort) | None | |
| Fluticasone + Salmeterol | 72 | 119 | 78 | 40 |
| Tiotropium + Salmeterol | 89 | 104 | 78 | 38 |
Isotime Borg leg discomfort scale after 8 weeks, Unit on a Scale (min. 0, max. 10), 0 = no leg dyscomfort, 10 = worst imaginable leg dyscomfort (NCT00530842)
Timeframe: 8 weeks
| Intervention | Unit on a Scale (Mean) |
|---|---|
| Tiotropium + Salmeterol | 4.64 |
| Fluticasone + Salmeterol | 4.53 |
Isotime Borg leg discomfort scale after 4 weeks, Unit on a Scale (min. 0, max. 10), 0 = no leg dyscomfort, 10 = worst imaginable leg dyscomfort (NCT00530842)
Timeframe: 4 weeks
| Intervention | Unit on a Scale (Mean) |
|---|---|
| Tiotropium + Salmeterol | 4.63 |
| Fluticasone + Salmeterol | 4.63 |
Isotime Borg dyspnea scale after 8 weeks, Unit on a Scale (min. 0, max 10), 0 = no dyspnea, 10 = worst imaginable dyspnea (NCT00530842)
Timeframe: 8 weeks
| Intervention | Unit on a Scale (Mean) |
|---|---|
| Tiotropium + Salmeterol | 4.77 |
| Fluticasone + Salmeterol | 4.98 |
Isotime Borg dyspnea scale after 4 weeks, Unit on a Scale (min. 0, max. 10), 0 = no dyspnea, 10 = worst imaginable dyspnea (NCT00530842)
Timeframe: 4 weeks
| Intervention | Unit on a Scale (Mean) |
|---|---|
| Tiotropium + Salmeterol | 4.80 |
| Fluticasone + Salmeterol | 5.02 |
Trough TGV/TLC (Thoracic Gas Volume over Total Lung Capacity) after 8 weeks (measured by bodyphlethysmography) (NCT00530842)
Timeframe: 8 weeks
| Intervention | Percent of TGV over TLC (Mean) |
|---|---|
| Tiotropium + Salmeterol | 69.87 |
| Fluticasone + Salmeterol | 70.94 |
Trough TGV/TLC (Thoracic Gas Volume over Total Lung Capacity) after 4 weeks (measured by bodyphlethysmography) (NCT00530842)
Timeframe: 4 weeks
| Intervention | Percent of TGV over TLC (Mean) |
|---|---|
| Tiotropium + Salmeterol | 70.59 |
| Fluticasone + Salmeterol | 70.99 |
Trough RV/TLC (Residual Volume over Total Lung Capacity) after 8 weeks (measured by bodyphlethysmography) (NCT00530842)
Timeframe: 8 weeks
| Intervention | Percent of RV over TLC (Mean) |
|---|---|
| Tiotropium + Salmeterol | 56.10 |
| Fluticasone + Salmeterol | 57.18 |
Trough RV/TLC (Residual Volume over Total Lung Capacity) after 4 weeks (measured by bodyphlethysmography) (NCT00530842)
Timeframe: 4 weeks
| Intervention | Percent of RV over TLC (Mean) |
|---|---|
| Tiotropium + Salmeterol | 56.57 |
| Fluticasone + Salmeterol | 57.47 |
Post-dose TGV/TLC (Thoracic Gas Volume over Total Lung Capacity) after 8 weeks (measured by bodyphlethysmography) (NCT00530842)
Timeframe: 8 weeks
| Intervention | Percent of TGV over TLC (Mean) |
|---|---|
| Tiotropium + Salmeterol | 67.65 |
| Fluticasone + Salmeterol | 68.85 |
Post-dose TGV/TLC (Thoracic Gas Volume over Total Lung Capacity) after 4 weeks (measured by bodyphlethysmography) (NCT00530842)
Timeframe: 4 weeks
| Intervention | Percent of TGV over TLC (Mean) |
|---|---|
| Tiotropium + Salmeterol | 68.43 |
| Fluticasone + Salmeterol | 69.22 |
Post-dose RV/TLC (Residual Volume over Total Lung Capacity) after 8 weeks (measured by bodyphlethysmography) (NCT00530842)
Timeframe: 8 weeks
| Intervention | Percent of RV over TLC (Mean) |
|---|---|
| Tiotropium + Salmeterol | 52.79 |
| Fluticasone + Salmeterol | 55.02 |
Post-dose RV/TLC (Residual Volume over Total Lung Capacity) after 4 weeks (measured by bodyphlethysmography) (NCT00530842)
Timeframe: 4 weeks
| Intervention | Percent of RV over TLC (Mean) |
|---|---|
| Tiotropium + Salmeterol | 53.09 |
| Fluticasone + Salmeterol | 55.07 |
Trough TLC (Total Lung Capacity) after 8 weeks (measured by bodyphlethysmography) (NCT00530842)
Timeframe: 8 weeks
| Intervention | Litres (Mean) |
|---|---|
| Tiotropium + Salmeterol | 7.47 |
| Fluticasone + Salmeterol | 7.39 |
Trough TLC (Total Lung Capacity) after 4 weeks (measured by bodyphlethysmography) (NCT00530842)
Timeframe: 4 weeks
| Intervention | Litres (Mean) |
|---|---|
| Tiotropium + Salmeterol | 7.52 |
| Fluticasone + Salmeterol | 7.51 |
Trough TGV(FRC) (Thoracic Gas Volume) after 8 weeks (measured by bodyphlethysmography) (NCT00530842)
Timeframe: 8 weeks
| Intervention | Litres (Mean) |
|---|---|
| Tiotropium + Salmeterol | 5.24 |
| Fluticasone + Salmeterol | 5.25 |
Trough TGV(FRC) (Thoracic Gas Volume) after 4 weeks (measured by bodyphlethysmography) (NCT00530842)
Timeframe: 4 weeks
| Intervention | Litres (Mean) |
|---|---|
| Tiotropium + Salmeterol | 5.32 |
| Fluticasone + Salmeterol | 5.34 |
Trough RV (Residual Volume) after 8 weeks (measured by bodyphlethysmography) (NCT00530842)
Timeframe: 8 weeks
| Intervention | Litres (Mean) |
|---|---|
| Tiotropium + Salmeterol | 4.23 |
| Fluticasone + Salmeterol | 4.25 |
Trough RV (Residual Volume) after 4 weeks (measured by bodyphlethysmography) (NCT00530842)
Timeframe: 4 weeks
| Intervention | Litres (Mean) |
|---|---|
| Tiotropium + Salmeterol | 4.28 |
| Fluticasone + Salmeterol | 4.35 |
Trough IRV (Inspiratory Reserve Volume) after 8 weeks (measured by bodyphlethysmography) (NCT00530842)
Timeframe: 8 weeks
| Intervention | Litres (Mean) |
|---|---|
| Tiotropium + Salmeterol | 1.48 |
| Fluticasone + Salmeterol | 1.41 |
Trough IRV (Inspiratory Reserve Volume) after 4 weeks (measured by bodyphlethysmography) (NCT00530842)
Timeframe: 4 weeks
| Intervention | Litres (Mean) |
|---|---|
| Tiotropium + Salmeterol | 1.47 |
| Fluticasone + Salmeterol | 1.42 |
Trough IC (Inspiratory Capacity) after 8 weeks (measured by bodyphlethysmography) (NCT00530842)
Timeframe: 8 weeks
| Intervention | Litres (Mean) |
|---|---|
| Tiotropium + Salmeterol | 2.33 |
| Fluticasone + Salmeterol | 2.23 |
Post-dose TLC (Total Lung Capacity) after 8 weeks (measured by bodyphlethysmography) (NCT00530842)
Timeframe: 8 weeks
| Intervention | Litres (Mean) |
|---|---|
| Tiotropium + Salmeterol | 7.36 |
| Fluticasone + Salmeterol | 7.36 |
Post-dose TLC (Total Lung Capacity) after 4 weeks (measured by bodyphlethysmography) (NCT00530842)
Timeframe: 4 weeks
| Intervention | Litres (Mean) |
|---|---|
| Tiotropium + Salmeterol | 7.33 |
| Fluticasone + Salmeterol | 7.47 |
Post-dose RV (Residual Volume) after 8 weeks (measured by bodyphlethysmography) (NCT00530842)
Timeframe: 8 weeks
| Intervention | Litres (Mean) |
|---|---|
| Tiotropium + Salmeterol | 3.92 |
| Fluticasone + Salmeterol | 4.07 |
Post-dose RV (Residual Volume) after 4 weeks (measured by bodyphlethysmography) (NCT00530842)
Timeframe: 4 weeks
| Intervention | Litres (Mean) |
|---|---|
| Tiotropium + Salmeterol | 3.91 |
| Fluticasone + Salmeterol | 4.14 |
Post-dose IRV (Inspiratory Reserve Volume) after 8 weeks (measured by bodyphlethysmography) (NCT00530842)
Timeframe: 8 weeks
| Intervention | Litres (Mean) |
|---|---|
| Tiotropium + Salmeterol | 1.62 |
| Fluticasone + Salmeterol | 1.55 |
Post-dose IRV (Inspiratory Reserve Volume) after 4 weeks (measured by bodyphlethysmography) (NCT00530842)
Timeframe: 4 weeks
| Intervention | Litres (Mean) |
|---|---|
| Tiotropium + Salmeterol | 1.62 |
| Fluticasone + Salmeterol | 1.55 |
Post-dose IC (Inspiratory Capacity) after 8 weeks (measured by bodyphlethysmography) (NCT00530842)
Timeframe: 8 weeks
| Intervention | Litres (Mean) |
|---|---|
| Tiotropium + Salmeterol | 2.47 |
| Fluticasone + Salmeterol | 2.35 |
Trough FVC (Forced Vital Capacity) after 8 weeks (measured by spirometry) (NCT00530842)
Timeframe: 8 weeks
| Intervention | Litres (Mean) |
|---|---|
| Tiotropium + Salmeterol | 3.06 |
| Fluticasone + Salmeterol | 2.94 |
Post-dose TGV(FRC) (Thoracic Gas Volume) after 4 weeks (NCT00530842)
Timeframe: 4 weeks
| Intervention | Litres (Mean) |
|---|---|
| Tiotropium + Salmeterol | 5.00 |
| Fluticasone + Salmeterol | 5.19 |
Post-dose TGV(FRC) (Thoracic Gas Volume; co-primary endpoint) after 8 weeks (NCT00530842)
Timeframe: 8 weeks
| Intervention | Litres (Mean) |
|---|---|
| Tiotropium + Salmeterol | 4.99 |
| Fluticasone + Salmeterol | 5.07 |
Post-dose SVC (Slow Vital Capacity) after 4 weeks (measured by spirometry) (NCT00530842)
Timeframe: 4 weeks
| Intervention | Litres (Mean) |
|---|---|
| Tiotropium + Salmeterol | 3.39 |
| Fluticasone + Salmeterol | 3.27 |
Post-dose SVC (Slow Vital Capacity) after 8 weeks (measured by spirometry) (NCT00530842)
Timeframe: 8 weeks
| Intervention | Litres (Mean) |
|---|---|
| Tiotropium + Salmeterol | 3.42 |
| Fluticasone + Salmeterol | 3.28 |
Trough SVC (Slow Vital Capacity) after 4 weeks (measured by spirometry) (NCT00530842)
Timeframe: 4 weeks
| Intervention | Litres (Mean) |
|---|---|
| Tiotropium + Salmeterol | 3.19 |
| Fluticasone + Salmeterol | 3.12 |
Trough SVC (Slow Vital Capacity) after 8 weeks (measured by spirometry) (NCT00530842)
Timeframe: 8 weeks
| Intervention | Litres (Mean) |
|---|---|
| Tiotropium + Salmeterol | 3.22 |
| Fluticasone + Salmeterol | 3.12 |
Post-dose IC (Inspiratory Capacity) after 4 weeks (measured by bodyphlethysmography) (NCT00530842)
Timeframe: 4 weeks
| Intervention | Litres (Mean) |
|---|---|
| Tiotropium + Salmeterol | 2.46 |
| Fluticasone + Salmeterol | 2.37 |
Post-dose FEV1 (Forced Expiratory Volume in 1 second) after 8 weeks (measured by spirometry) (NCT00530842)
Timeframe: 8 weeks
| Intervention | Litres (Mean) |
|---|---|
| Tiotropium + Salmeterol | 1.62 |
| Fluticasone + Salmeterol | 1.55 |
Post-dose percent predicted FEV1 (Forced Expiratory Volume in 1 second) according to ECCS after 4 weeks (measured by spirometry) (NCT00530842)
Timeframe: 4 weeks
| Intervention | Percent of predicted FEV1 (Mean) |
|---|---|
| Tiotropium + Salmeterol | 54.96 |
| Fluticasone + Salmeterol | 52.64 |
Post-dose percent predicted FEV1 (Forced Expiratory Volume in 1 second) according to ECCS after 8 weeks (measured by spirometry) (NCT00530842)
Timeframe: 8 weeks
| Intervention | Percent of predicted FEV1 (Mean) |
|---|---|
| Tiotropium + Salmeterol | 54.99 |
| Fluticasone + Salmeterol | 52.59 |
Trough FEV1 (Forced Expiratory Volume in 1 second) after 4 weeks (measured by spirometry) (NCT00530842)
Timeframe: 4 weeks
| Intervention | Litres (Mean) |
|---|---|
| Tiotropium + Salmeterol | 1.48 |
| Fluticasone + Salmeterol | 1.45 |
Trough FEV1 (Forced Expiratory Volume in 1 second) after 8 weeks (measured by spirometry) (NCT00530842)
Timeframe: 8 weeks
| Intervention | Litres (Mean) |
|---|---|
| Tiotropium + Salmeterol | 1.48 |
| Fluticasone + Salmeterol | 1.44 |
Trough percent predicted FEV1 (Forced Expiratory Volume in 1 second) according to ECCS after 4 weeks (measured by spirometry) (NCT00530842)
Timeframe: 4 weeks
| Intervention | Percent of predicted FEV1 (Mean) |
|---|---|
| Tiotropium + Salmeterol | 50.40 |
| Fluticasone + Salmeterol | 49.26 |
Trough percent predicted FEV1 (Forced Expiratory Volume in 1 second) according to ECCS after 8 weeks (measured by spirometry) (NCT00530842)
Timeframe: 8 weeks
| Intervention | Percent of predicted FEV1 (Mean) |
|---|---|
| Tiotropium + Salmeterol | 50.27 |
| Fluticasone + Salmeterol | 49.12 |
Reason for stopping exercise at baseline (leg discomfort, breathing discomfort, both or none) (NCT00530842)
Timeframe: baseline
| Intervention | Participants (Number) | |||
|---|---|---|---|---|
| Leg discomfort | Breathing discomfort | Both (leg and breathing discomfort) | None | |
| Fluticasone + Salmeterol | 53 | 132 | 92 | 32 |
| Tiotropium + Salmeterol | 53 | 132 | 92 | 32 |
Post-dose FVC (Forced Vital Capacity) after 8 weeks (measured by spirometry) (NCT00530842)
Timeframe: 8 weeks
| Intervention | Litres (Mean) |
|---|---|
| Tiotropium + Salmeterol | 3.26 |
| Fluticasone + Salmeterol | 3.11 |
Trough FVC (Forced Vital Capacity) after 4 weeks (measured by spirometry) (NCT00530842)
Timeframe: 4 weeks
| Intervention | Litres (Mean) |
|---|---|
| Tiotropium + Salmeterol | 3.04 |
| Fluticasone + Salmeterol | 2.93 |
Post-dose FVC (Forced Vital Capacity) after 4 weeks (measured by spirometry) (NCT00530842)
Timeframe: 4 weeks
| Intervention | Litres (Mean) |
|---|---|
| Tiotropium + Salmeterol | 3.25 |
| Fluticasone + Salmeterol | 3.11 |
Trough IC (Inspiratory Capacity) after 4 weeks (measured by bodyphlethysmography) (NCT00530842)
Timeframe: 4 weeks
| Intervention | Litres (Mean) |
|---|---|
| Tiotropium + Salmeterol | 2.28 |
| Fluticasone + Salmeterol | 2.23 |
Peak Borg dyspnea scale after 8 weeks, Unit on a Scale (min. 0, max 10) (NCT00530842)
Timeframe: 8 weeks
| Intervention | Unit on a Scale (Mean) |
|---|---|
| Tiotropium + Salmeterol | 6.52 |
| Fluticasone + Salmeterol | 6.61 |
Peak Borg leg discomfort scale after 8 weeks, Unit on a Scale (min. 0, max 10) (NCT00530842)
Timeframe: 8 weeks
| Intervention | Unit on a Scale (Mean) |
|---|---|
| Tiotropium + Salmeterol | 6.10 |
| Fluticasone + Salmeterol | 5.86 |
Endurance time to the point of symptom limitation after 4 weeks during a constant work rate exercise test at 75% Wcap (co-primary endpoint) (NCT00530842)
Timeframe: 4 weeks
| Intervention | Seconds (Median) |
|---|---|
| Tiotropium + Salmeterol | 458 |
| Fluticasone + Salmeterol | 450 |
Endurance time to the point of symptom limitation after 8 weeks during a constant work rate exercise test at 75% Wcap (co-primary endpoint) (NCT00530842)
Timeframe: 8 weeks
| Intervention | Seconds (Median) |
|---|---|
| Tiotropium + Salmeterol | 463 |
| Fluticasone + Salmeterol | 453 |
Post-dose FEV1 (Forced Expiratory Volume in 1 second) over FVC (Forced Vital Capacity) after 4 weeks (measured by spirometry) (NCT00530842)
Timeframe: 4 weeks
| Intervention | Percent of FEV1 over FVC (Mean) |
|---|---|
| Tiotropium + Salmeterol | 50.90 |
| Fluticasone + Salmeterol | 50.91 |
Post-dose FEV1 (Forced Expiratory Volume in 1 second) over FVC (Forced Vital Capacity) after 8 weeks (measured by spirometry) (NCT00530842)
Timeframe: 8 weeks
| Intervention | Percent of FEV1 over FVC (Mean) |
|---|---|
| Tiotropium + Salmeterol | 50.77 |
| Fluticasone + Salmeterol | 50.66 |
Trough FEV1 (Forced Expiratory Volume in 1 second) over FVC (Forced Vital Capacity) after 4 weeks (measured by spirometry) (NCT00530842)
Timeframe: 4 weeks
| Intervention | Percent of FEV1 over FVC (Mean) |
|---|---|
| Tiotropium + Salmeterol | 49.74 |
| Fluticasone + Salmeterol | 50.62 |
Trough FEV1 (Forced Expiratory Volume in 1 second) over FVC (Forced Vital Capacity) after 8 weeks (measured by spirometry) (NCT00530842)
Timeframe: 8 weeks
| Intervention | Percent of FEV1 over FVC (Mean) |
|---|---|
| Tiotropium + Salmeterol | 49.16 |
| Fluticasone + Salmeterol | 49.67 |
Post-dose FEV1 (Forced Expiratory Volume in 1 second) after 4 weeks (measured by spirometry) (NCT00530842)
Timeframe: 4 weeks
| Intervention | Litres (Mean) |
|---|---|
| Tiotropium + Salmeterol | 1.62 |
| Fluticasone + Salmeterol | 1.55 |
An exacerbation was defined as an increase or new onset of more than 1 symptom (cough, sputum, wheezing, dyspnoea, chest tightness), with at least 1 symptom lasting at least 3 days and requiring treatment with systemic steroids and/or antibiotics (moderate exacerbation) or hospitalisation (severe exacerbation). (NCT00563381)
Timeframe: 52 weeks
| Intervention | exacerbations per patient-year (Mean) |
|---|---|
| Tiotropium | 0.33 |
| Salmeterol | 0.41 |
An exacerbation was defined as an increase or new onset of more than 1 symptom (cough, sputum, wheezing, dyspnoea, chest tightness), with at least 1 symptom lasting at least 3 days and requiring treatment with systemic steroids and/or antibiotics (moderate exacerbation) or hospitalisation (severe exacerbation). (NCT00563381)
Timeframe: 52 weeks
| Intervention | exacerbations per patient-year (Mean) |
|---|---|
| Tiotropium | 0.23 |
| Salmeterol | 0.28 |
An exacerbation was defined as an increase or new onset of more than 1 symptom (cough, sputum, wheezing, dyspnoea, chest tightness), with at least 1 symptom lasting at least 3 days and requiring treatment with systemic steroids and/or antibiotics (moderate exacerbation) or hospitalisation (severe exacerbation). (NCT00563381)
Timeframe: 52 weeks
| Intervention | exacerbations per patient-year (Mean) |
|---|---|
| Tiotropium | 0.53 |
| Salmeterol | 0.59 |
An exacerbation was defined as an increase or new onset of more than 1 symptom (cough, sputum, wheezing, dyspnoea, chest tightness), with at least 1 symptom lasting at least 3 days and requiring treatment with systemic steroids and/or antibiotics (moderate exacerbation) or hospitalisation (severe exacerbation). (NCT00563381)
Timeframe: 52 weeks
| Intervention | Hospitalizations per patient-year (Mean) |
|---|---|
| Tiotropium | 0.09 |
| Salmeterol | 0.13 |
(NCT00563381)
Timeframe: 52 weeks
| Intervention | exacerbations per patient-year (Mean) |
|---|---|
| Tiotropium | 0.64 |
| Salmeterol | 0.72 |
An exacerbation was defined as an increase or new onset of more than 1 symptom (cough, sputum, wheezing, dyspnoea, chest tightness), with at least 1 symptom lasting at least 3 days and requiring treatment with systemic steroids and/or antibiotics (moderate exacerbation) or hospitalisation (severe exacerbation). (NCT00563381)
Timeframe: 52 weeks
| Intervention | Participants (Number) | |
|---|---|---|
| Participants with (at least one) event | Participants with no event | |
| Salmeterol | 1414 | 2255 |
| Tiotropium | 1277 | 2430 |
PEFR means peak expiratory flow rate and is measured in liter per minute (NCT00563381)
Timeframe: 16 weeks
| Intervention | liter per minute (L/min) (Mean) |
|---|---|
| Tiotropium | 229.72 |
| Salmeterol | 230.57 |
PEFR means peak expiratory flow rate and is measured in liter per minute (NCT00563381)
Timeframe: 16 weeks
| Intervention | liter per minute (L/min) (Mean) |
|---|---|
| Tiotropium | 229.95 |
| Salmeterol | 230.43 |
PEFR means peak expiratory flow rate and is measured in liter per minute (NCT00563381)
Timeframe: 16 weeks
| Intervention | liter per minute (L/min) (Mean) |
|---|---|
| Tiotropium | 229.35 |
| Salmeterol | 230.13 |
PEFR means peak expiratory flow rate and is measured in liter per minute (NCT00563381)
Timeframe: 16 weeks
| Intervention | liter per minute (L/min) (Mean) |
|---|---|
| Tiotropium | 228.80 |
| Salmeterol | 229.81 |
An exacerbation was defined as an increase or new onset of more than 1 symptom (cough, sputum, wheezing, dyspnoea, chest tightness), with at least 1 symptom lasting at least 3 days and requiring treatment with systemic steroids and/or antibiotics (moderate exacerbation) or hospitalisation (severe exacerbation). (NCT00563381)
Timeframe: 52 weeks
| Intervention | Participants (Number) | |
|---|---|---|
| Participants with (at least one) event | Participants with no event | |
| Salmeterol | 336 | 3333 |
| Tiotropium | 262 | 3445 |
First occurrence analysed by Cox regression as time to first exacerbation or discontinuation of trial medication because of worsening of underlying disease, whichever comes first and reported as hazard ratio. An exacerbation was defined as an increase or new onset of more than 1 symptom (cough, sputum, wheezing, dyspnoea, chest tightness), with at least 1 symptom lasting at least 3 days and requiring treatment with systemic steroids and/or antibiotics (moderate exacerbation) or hospitalisation (severe exacerbation). (NCT00563381)
Timeframe: 52 weeks
| Intervention | number of first occurrences (Number) |
|---|---|
| Tiotropium | 1316 |
| Salmeterol | 1448 |
First occurrence analysed by Cox regression as time to first exacerbation leading to hospitalisation and reported as hazard ratio. An exacerbation was defined as an increase or new onset of more than 1 symptom (cough, sputum, wheezing, dyspnoea, chest tightness), with at least 1 symptom lasting at least 3 days and requiring treatment with systemic steroids and/or antibiotics (moderate exacerbation) or hospitalisation (severe exacerbation). (NCT00563381)
Timeframe: 52 weeks
| Intervention | number of first occurrences (Number) |
|---|---|
| Tiotropium | 262 |
| Salmeterol | 336 |
PEFR means peak expiratory flow rate and is measured in liter per minute (NCT00563381)
Timeframe: 16 weeks
| Intervention | liter per minute (L/min) (Mean) |
|---|---|
| Tiotropium | 227.37 |
| Salmeterol | 229.25 |
First occurrence analysed by Cox regression as time to first exacerbation and reported as hazard ratio. An exacerbation was defined as an increase or new onset of more than 1 symptom (cough, sputum, wheezing, dyspnoea, chest tightness), with at least 1 symptom lasting at least 3 days and requiring treatment with systemic steroids and/or antibiotics (moderate exacerbation) or hospitalisation (severe exacerbation). (NCT00563381)
Timeframe: 52 weeks
| Intervention | number of first occurrences (Number) |
|---|---|
| Tiotropium | 1277 |
| Salmeterol | 1414 |
(NCT00563381)
Timeframe: 52 weeks
| Intervention | Participants (Number) | |
|---|---|---|
| Participants with (at least one) event | Participants with no event | |
| Salmeterol | 648 | 3021 |
| Tiotropium | 585 | 3122 |
PEFR means peak expiratory flow rate and is measured in liter per minute (NCT00563381)
Timeframe: 16 weeks
| Intervention | liter per minute (L/min) (Mean) |
|---|---|
| Tiotropium | 228.27 |
| Salmeterol | 229.37 |
PEFR means peak expiratory flow rate and is measured in liter per minute (NCT00563381)
Timeframe: 16 weeks
| Intervention | liter per minute (L/min) (Mean) |
|---|---|
| Tiotropium | 226.31 |
| Salmeterol | 228.38 |
PEFR means peak expiratory flow rate and is measured in liter per minute (NCT00563381)
Timeframe: 16 weeks
| Intervention | liter per minute (L/min) (Mean) |
|---|---|
| Tiotropium | 225.15 |
| Salmeterol | 227.21 |
PEFR means peak expiratory flow rate and is measured in liter per minute (NCT00563381)
Timeframe: 16 weeks
| Intervention | liter per minute (L/min) (Mean) |
|---|---|
| Tiotropium | 232.06 |
| Salmeterol | 232.65 |
PEFR means peak expiratory flow rate and is measured in liter per minute (NCT00563381)
Timeframe: 16 weeks
| Intervention | liter per minute (L/min) (Mean) |
|---|---|
| Tiotropium | 231.64 |
| Salmeterol | 232.75 |
PEFR means peak expiratory flow rate and is measured in liter per minute (NCT00563381)
Timeframe: 16 weeks
| Intervention | liter per minute (L/min) (Mean) |
|---|---|
| Tiotropium | 231.19 |
| Salmeterol | 232.42 |
PEFR means peak expiratory flow rate and is measured in liter per minute (NCT00563381)
Timeframe: 16 weeks
| Intervention | liter per minute (L/min) (Mean) |
|---|---|
| Tiotropium | 231.23 |
| Salmeterol | 231.89 |
PEFR means peak expiratory flow rate and is measured in liter per minute (NCT00563381)
Timeframe: 16 weeks
| Intervention | liter per minute (L/min) (Mean) |
|---|---|
| Tiotropium | 231.04 |
| Salmeterol | 232.04 |
PEFR means peak expiratory flow rate and is measured in liter per minute (NCT00563381)
Timeframe: 16 weeks
| Intervention | liter per minute (L/min) (Mean) |
|---|---|
| Tiotropium | 230.61 |
| Salmeterol | 231.91 |
PEFR means peak expiratory flow rate and is measured in liter per minute (NCT00563381)
Timeframe: 16 weeks
| Intervention | liter per minute (L/min) (Mean) |
|---|---|
| Tiotropium | 230.30 |
| Salmeterol | 231.27 |
PEFR means peak expiratory flow rate and is measured in liter per minute (NCT00563381)
Timeframe: 16 weeks
| Intervention | liter per minute (L/min) (Mean) |
|---|---|
| Tiotropium | 222.85 |
| Salmeterol | 224.45 |
Occurrence analysed by Cox regression as time to premature discontinuation of trial medication and reported as hazard ratio (NCT00563381)
Timeframe: 52 weeks
| Intervention | number of first occurrences (Number) |
|---|---|
| Tiotropium | 585 |
| Salmeterol | 648 |
First occurrence analysed by Cox regression as time to first exacerbation treated with systemic steroids and antibiotics and reported as hazard ratio. An exacerbation was defined as an increase or new onset of more than 1 symptom (cough, sputum, wheezing, dyspnoea, chest tightness), with at least 1 symptom lasting at least 3 days and requiring treatment with systemic steroids and/or antibiotics (moderate exacerbation) or hospitalisation (severe exacerbation). (NCT00563381)
Timeframe: 52 weeks
| Intervention | number of first occurrences (Number) |
|---|---|
| Tiotropium | 562 |
| Salmeterol | 671 |
First occurrence analysed by Cox regression as time to first exacerbation treated with systemic steroids and reported as hazard ratio. An exacerbation was defined as an increase or new onset of more than 1 symptom (cough, sputum, wheezing, dyspnoea, chest tightness), with at least 1 symptom lasting at least 3 days and requiring treatment with systemic steroids and/or antibiotics (moderate exacerbation) or hospitalisation (severe exacerbation). (NCT00563381)
Timeframe: 52 weeks
| Intervention | number of first occurrences (Number) |
|---|---|
| Tiotropium | 715 |
| Salmeterol | 852 |
First occurrence analysed by Cox regression as time to first exacerbation treated with antibiotics and reported as hazard ratio. An exacerbation was defined as an increase or new onset of more than 1 symptom (cough, sputum, wheezing, dyspnoea, chest tightness), with at least 1 symptom lasting at least 3 days and requiring treatment with systemic steroids and/or antibiotics (moderate exacerbation) or hospitalisation (severe exacerbation). (NCT00563381)
Timeframe: 52 weeks
| Intervention | number of first occurrences (Number) |
|---|---|
| Tiotropium | 1154 |
| Salmeterol | 1259 |
Total number of puffs from the albuterol (rescue) inhaler during the previous 24 hours (excluding those puffs for preventive use). (NCT00565266)
Timeframe: Albuterol rescue puffs were measured daily during each of the three 14-week treatment periods. The primary analysis constructed the change between week 14 and week 0.
| Intervention | puffs per day (Least Squares Mean) |
|---|---|
| Tio + 1xICS | -0.11 |
| LABA + 1xICS | -0.16 |
| 2xICS | -0.07 |
Scores on the Asthma Control Questionnaire range from 0 to 6, with a higher score indicating worse asthma control. (NCT00565266)
Timeframe: The asthma control questionnaire score was measured on four occasions during each of the three 14-week treatment periods. The primary analysis constructed the change between week 14 and week 0.
| Intervention | units on a scale (Least Squares Mean) |
|---|---|
| Tio + 1xICS | -0.22 |
| LABA + 1xICS | -0.31 |
| 2xICS | -0.03 |
Scores on the Asthma Quality-of-Life Questionnaire range from 1 to 7, with a higher score indicating a better quality of life. (NCT00565266)
Timeframe: The asthma quality-of-life questionnaire score was measured on four occasions during each of the three 14-week treatment periods. The primary analysis constructed the change between week 14 and week 0.
| Intervention | units on a scale (Least Squares Mean) |
|---|---|
| Tio + 1xICS | 0.15 |
| LABA + 1xICS | 0.28 |
| 2xICS | 0.05 |
(NCT00565266)
Timeframe: FEV1 was measured on four occasions during each of the three 14-week treatment periods. The primary analysis constructed the change between week 14 and week 0.
| Intervention | liters (Least Squares Mean) |
|---|---|
| Tio + 1xICS | 0.12 |
| LABA + 1xICS | 0.01 |
| 2xICS | 0.02 |
(NCT00565266)
Timeframe: AM PEF was measured daily during each of the three 14-week treatment periods. The primary analysis constructed the change between week 14 and week 0.
| Intervention | Liters per minute (Least Squares Mean) |
|---|---|
| Tio + 1xICS | 24.4 |
| LABA + 1xICS | 18.0 |
| 2xICS | -1.4 |
An asthma control day was defined as a day in which there were no symptoms and no albuterol (rescue) puffs. (NCT00565266)
Timeframe: An asthma control day was determined daily during each of the three 14-week treatment periods. The primary analysis constructed the change between week 14 and week 0.
| Intervention | proportion of asthma control days (Least Squares Mean) |
|---|---|
| Tio + 1xICS | 0.13 |
| LABA + 1xICS | 0.14 |
| 2xICS | 0.05 |
"Asthma symptoms were recorded as 0 (absent = no symptom )~(mild = symptom was minimally troublesome, i.e. not sufficient to interfere with normal daily activity or sleep)~(moderate = symptom was sufficiently troublesome to interfere with normal daily activity or sleep)~(severe = symptom was so severe as to prevent normal activity and/or sleep )" (NCT00565266)
Timeframe: Asthma symptoms were measured daily during each of the three 14-week treatment periods. The primary analysis constructed the change between week 14 and week 0.
| Intervention | units on a scale (Least Squares Mean) |
|---|---|
| Tio + 1xICS | -0.09 |
| LABA + 1xICS | -0.04 |
| 2xICS | 0.03 |
VO_2 is the maximum capacity of an individual's body to transport and use oxygen during incremental exercise. Percentage change = final value - initial value/initial value x 100 (NCT00578968)
Timeframe: first visit of first study period, first visit of second study period (approximately 6 weeks later)
| Intervention | percentage of change in VO_2 (Mean) |
|---|---|
| Tiotropium | 2.06 |
| Placebo | -4.60 |
Cardiac index (CI): A cardiodynamic measure based on the cardiac output, which is the amount of blood the left ventricle ejects into the systemic circulation in one minute, measured in liters per minute (l/min). Cardiac output is indexed to a patient's body size by dividing by the body surface area (m^2) to yield the cardiac index. Percentage change = final value - initial value/initial value x 100 (NCT00578968)
Timeframe: first visit of first study period, first visit of second study period (approximately 6 weeks later)
| Intervention | percentage of change in CI (Mean) |
|---|---|
| Tiotropium | -4.91 |
| Placebo | -9.08 |
FEV_1 is the volume exhaled during the first second of a forced expiratory maneuver started from the level of total lung capacity. Percentage change = final value - initial value/initial value x 100 (NCT00578968)
Timeframe: first visit of first study period, first visit of second study period (approximately 6 weeks later)
| Intervention | Percentage of change in FEV_1 (Mean) |
|---|---|
| Tiotropium | 8.81 |
| Placebo | -6.30 |
Vital capacity is the maximum amount of air a person can expel from the lungs after a maximum inspiration. A person's vital capacity can be measured by a spirometer which can be a wet or regular spirometer. In combination with other physiological measurements, the vital capacity can help make a diagnosis of underlying lung disease. Percentage change = final value - initial value/initial value x 100 (NCT00578968)
Timeframe: first visit of first study period, first visit of second study period (approximately 6 weeks later)
| Intervention | percentage of change in FVC (Mean) |
|---|---|
| Tiotropium | 11.55 |
| Placebo | -6.20 |
Heart rate is the number of heartbeats per unit of time, typically expressed as beats per minute (bpm). Percentage change = final value - initial value/initial value x 100 (NCT00578968)
Timeframe: first visit of first study period, first visit of second study period (approximately 6 weeks later)
| Intervention | Percentage of change in HR (Mean) |
|---|---|
| Tiotropium | -7.05 |
| Placebo | -1.32 |
Stroke volume - the volume of blood ejected from a ventricle at each beat of the heart, equal to the difference between the end-diastolic volume and the end-systolic volume. The stroke volume index is a method of relating the stroke volume to the size of the person by dividing the stroke volume by the BSA (m^2). Percentage change = final value - initial value/initial value x 100 (NCT00578968)
Timeframe: first visit of first study period, first visit of second study period (approximately 6 weeks later)
| Intervention | Percentage of change in SVI (Mean) |
|---|---|
| Tiotropium | -3.80 |
| Placebo | -6.26 |
Cardiac index (CI): A cardiodynamic measure based on the cardiac output, which is the amount of blood the left ventricle ejects into the systemic circulation in one minute, measured in liters per minute (l/min). Cardiac output is indexed to a patient's body size by dividing by the body surface area (m^2) to yield the cardiac index. (NCT00578968)
Timeframe: first visit of first study period
| Intervention | L/min/m^2 (Mean) |
|---|---|
| Tiotropium | 5.34 |
| Placebo | 6.70 |
VO_2 is the maximum capacity of an individual's body to transport and use oxygen during incremental exercise. (NCT00578968)
Timeframe: first visit of first study period
| Intervention | L/min (Mean) |
|---|---|
| Tiotropium | 1.33 |
| Placebo | 1.65 |
Stroke volume - the volume of blood ejected from a ventricle at each beat of the heart, equal to the difference between the end-diastolic volume and the end-systolic volume. The stroke volume index is a method of relating the stroke volume to the size of the person by dividing the stroke volume by the BSA (m^2). (NCT00578968)
Timeframe: first visit of first study period
| Intervention | mL/m^2 (Mean) |
|---|---|
| Tiotropium | 44.62 |
| Placebo | 50.06 |
Cardiac index (CI): A cardiodynamic measure based on the cardiac output, which is the amount of blood the left ventricle ejects into the systemic circulation in one minute, measured in liters per minute (l/min). Cardiac output is indexed to a patient's body size by dividing by the body surface area (m^2) to yield the cardiac index. (NCT00578968)
Timeframe: first study visit of first study period
| Intervention | L/min/m^2 (Mean) |
|---|---|
| Tiotropium | 2.31 |
| Placebo | 2.49 |
FEV_1 is the volume exhaled during the first second of a forced expiratory maneuver started from the level of total lung capacity. (NCT00578968)
Timeframe: first study visit of first study period
| Intervention | L/sec (Mean) |
|---|---|
| Tiotropium | 1.48 |
| Placebo | 2.00 |
Vital capacity is the maximum amount of air a person can expel from the lungs after a maximum inspiration. A person's vital capacity can be measured by a spirometer which can be a wet or regular spirometer. In combination with other physiological measurements, the vital capacity can help make a diagnosis of underlying lung disease. (NCT00578968)
Timeframe: First study visit of first study period
| Intervention | Liters (Mean) |
|---|---|
| Tiotropium | 2.79 |
| Placebo | 3.80 |
Predicted normal values for vital capacity can be calculated online (based on previous research) and depends on age, sex, height, weight and ethnicity. Percentage was calculated by observed FVC/predicted FVC X 100. (NCT00578968)
Timeframe: First visit of first period
| Intervention | percentage of predicted FVC (Mean) |
|---|---|
| Tiotropium | 71.24 |
| Placebo | 85.27 |
Stroke volume - the volume of blood ejected from a ventricle at each beat of the heart, equal to the difference between the end-diastolic volume and the end-systolic volume. The stroke volume index is a method of relating the stroke volume to the size of the person by dividing the stroke volume by the BSA (m^2). (NCT00578968)
Timeframe: first study visit of first study period
| Intervention | mL/m^2 (Mean) |
|---|---|
| Tiotropium | 30.08 |
| Placebo | 32.55 |
Heart rate is the number of heartbeats per unit of time, typically expressed as beats per minute (bpm). Heart rate was measured in the first study period prior to the intervention at resting and at peak exercise states. (NCT00578968)
Timeframe: first visit of first study period, second visit of first study period
| Intervention | beats per minute (bpm) (Mean) | |
|---|---|---|
| Baseline Resting, V1-1st study period | Baseline Peak Exercise, V2-1st study period | |
| COPD Participants | 79.4 | 127.8 |
| Healthy Controls | 72.7 | 153.6 |
Heart rate is the number of heartbeats per unit of time, typically expressed as beats per minute (bpm). Heart rate was measured in the first study period prior to the intervention at resting and at peak exercise states. (NCT00578968)
Timeframe: first study visit of first study period
| Intervention | bpm (Mean) | |
|---|---|---|
| Pretreatment Resting HR, V1-1st study period | Pretreatment Peak Exercise HR, V1-1st study period | |
| Placebo | 78.33 | 135.33 |
| Tiotropium | 80.50 | 120.17 |
Cardiac index: A cardiodynamic measure based on the cardiac output, which is the amount of blood the left ventricle ejects into the systemic circulation in one minute, measured in liters per minute (l/min). Cardiac output is indexed to a patient's body size by dividing by the body surface area (m^2) to yield the cardiac index. (NCT00578968)
Timeframe: second visit of first study period
| Intervention | L/min/m^2 (Mean) |
|---|---|
| COPD Participants | 6.02 |
| Healthy Controls | 7.61 |
VO_2 is the maximum capacity of an individual's body to transport and use oxygen during incremental exercise. (NCT00578968)
Timeframe: second visit of first study period
| Intervention | L/min (Mean) |
|---|---|
| COPD Participants | 1.52 |
| Healthy Controls | 2.29 |
Stroke volume - the volume of blood ejected from a ventricle at each beat of the heart, equal to the difference between the end-diastolic volume and the end-systolic volume. The stroke volume index is a method of relating the stroke volume to the size of the person by dividing the stroke volume by the BSA (m^2). (NCT00578968)
Timeframe: second visit of first study period
| Intervention | mL/m^2 (Mean) |
|---|---|
| COPD Participants | 47.3 |
| Healthy Controls | 52.7 |
Cardiac index: A cardiodynamic measure based on the cardiac output, which is the amount of blood the left ventricle ejects into the systemic circulation in one minute, measured in liters per minute (l/min). Cardiac output is indexed to a patient's body size by dividing by the body surface area (m^2) to yield the cardiac index. (NCT00578968)
Timeframe: First visit of first study period
| Intervention | L/min/m^2 (Mean) |
|---|---|
| COPD Participants | 2.4 |
| Healthy Controls | 2.36 |
Predicted normal values for Forced Expiratory Volume in 1 second can be calculated online (based on previous research) and depends on age, sex, height, weight and ethnicity. Percentage was calculated by observed FEV_1/predicted FEV_1 X 100. (NCT00578968)
Timeframe: first visit of first study period
| Intervention | percentage of predicted FEV_1 (Mean) |
|---|---|
| COPD Participants | 51.6 |
| Healthy Controls | 97.5 |
FEV_1 is the volume exhaled during the first second of a forced expiratory maneuver started from the level of total lung capacity. (NCT00578968)
Timeframe: first visit of first study period
| Intervention | L/sec (Mean) |
|---|---|
| COPD Participants | 1.74 |
| Healthy Controls | 3.22 |
Vital capacity is the maximum amount of air a person can expel from the lungs after a maximum inspiration. A person's vital capacity can be measured by a spirometer which can be a wet or regular spirometer. In combination with other physiological measurements, the vital capacity can help make a diagnosis of underlying lung disease. (NCT00578968)
Timeframe: First visit of first study period
| Intervention | Liters (Mean) |
|---|---|
| COPD Participants | 3.29 |
| Healthy Controls | 4.20 |
Predicted normal values for vital capacity can be calculated online (based on previous research) and depends on age, sex, height, weight and ethnicity. Percentage was calculated by observed FVC/predicted FVC X 100. (NCT00578968)
Timeframe: First visit of first study period
| Intervention | percentage of predicted FVC (Mean) |
|---|---|
| COPD Participants | 78.3 |
| Healthy Controls | 99.4 |
Cardiac index (CI): A cardiodynamic measure based on the cardiac output, which is the amount of blood the left ventricle ejects into the systemic circulation in one minute, measured in liters per minute (l/min). Cardiac output is indexed to a patient's body size by dividing by the body surface area (m^2) to yield the cardiac index. Percentage change = final value - initial value/initial value x 100 (NCT00578968)
Timeframe: first visit of first study period, first visit of second study period (approximately 6 weeks later)
| Intervention | percentage of change in CI (Mean) |
|---|---|
| Tiotropium | 2.46 |
| Placebo | -11.80 |
Heart rate is the number of heartbeats per unit of time, typically expressed as beats per minute (bpm). Percentage change = final value - initial value/initial value x 100 (NCT00578968)
Timeframe: first visit of first study period, first visit of second study period (approximately 6 weeks later)
| Intervention | percentage of change in HR (Mean) |
|---|---|
| Tiotropium | 0.27 |
| Placebo | -7.05 |
Stroke volume - the volume of blood ejected from a ventricle at each beat of the heart, equal to the difference between the end-diastolic volume and the end-systolic volume. The stroke volume index is a method of relating the stroke volume to the size of the person by dividing the stroke volume by the BSA (m^2). Percentage change = final value - initial value/initial value x 100 (NCT00578968)
Timeframe: first visit of first study period, first visit of second study period (approximately 6 weeks later)
| Intervention | percentage of change in SVI (Mean) |
|---|---|
| Tiotropium | 3.11 |
| Placebo | -4.95 |
Stroke volume - the volume of blood ejected from a ventricle at each beat of the heart, equal to the difference between the end-diastolic volume and the end-systolic volume. The stroke volume index is a method of relating the stroke volume to the size of the person by dividing the stroke volume by the body surface area (BSA) (m^2). (NCT00578968)
Timeframe: first visit of first study period
| Intervention | mL/m^2 (Mean) |
|---|---|
| COPD Participants | 31.3 |
| Healthy Controls | 39.7 |
Forced vital capacity (FVC) post-dose response at end of the observation (Visit 3/week 8 ) vs. baseline (Visit 1/week 0) (NCT00613574)
Timeframe: baseline and final visit (8 weeks)
| Intervention | liters (Mean) |
|---|---|
| Spiriva® (Tiotropium Bromide) | 0.31 |
Inspiratory capacity (IC) post-dose response at end of the observation (Visit 3/week 8) vs. baseline (Visit 1/week 0) at selected sites (NCT00613574)
Timeframe: Visit 1 to Visit 3 (baseline and 8 weeks)
| Intervention | liters (Mean) |
|---|---|
| Spiriva® (Tiotropium Bromide) | 0.18 |
Forced expiratory volume in 1 second (FEV1) post-dose response at the end of the observation (Visit 3/week 8) versus (vs.) baseline (Visit 1/week 0) (NCT00613574)
Timeframe: baseline and final visit (8 weeks)
| Intervention | liters (Mean) |
|---|---|
| Spiriva® (Tiotropium Bromide) | 0.29 |
Patient Global Assessment of Spiriva® efficacy with a 4-point scale (1=excellent efficacy&tolerability, 4=poor) at end of the observation (Visit 3/week 8). (NCT00613574)
Timeframe: final visit (8 weeks)
| Intervention | participants (Number) | |||
|---|---|---|---|---|
| Excellent | Good | Satisfactory | Poor | |
| Spiriva® (Tiotropium Bromide) | 141 | 198 | 60 | 2 |
Patient Global Assessment of Spiriva® tolerability with a 4-point scale (1=excellent efficacy&tolerability, 4=poor) at end of the observation (Visit 3/week 8). (NCT00613574)
Timeframe: final visit (8 weeks)
| Intervention | participants (Number) | |||
|---|---|---|---|---|
| Excellent | Good | Satisfactory | Poor | |
| Spiriva® (Tiotropium Bromide) | 246 | 139 | 16 | 0 |
Physician Global Assessment of Spiriva® tolerability with a 4-point scale (1=excellent efficacy&tolerability, 4=poor) at end of the observation (Visit 3/week 8). (NCT00613574)
Timeframe: final visit (8 weeks)
| Intervention | participants (Number) | |||
|---|---|---|---|---|
| Excellent | Good | Satisfactory | Poor | |
| Spiriva® (Tiotropium Bromide) | 246 | 144 | 11 | 0 |
Physician Global Assessment of Spiriva® efficacy with a 4-point scale (1=excellent efficacy&tolerability, 4=poor) at end of the observation (Visit 3/week 8). (NCT00613574)
Timeframe: final visit (8 weeks)
| Intervention | participants (Number) | |||
|---|---|---|---|---|
| Excellent | Good | Satisfactory | Poor | |
| Spiriva® (Tiotropium Bromide) | 159 | 195 | 45 | 2 |
FEV1 was measured with spirometry conducted according to internationally accepted standards. Trough FEV1 was defined as the mean of FEV1 measurements at 23 h 10 min and 23 h 45 min post Day 14 dose measured on the morning of Day 15 in each treatment period. The model used for analysis contained the (period) baseline FEV1 as covariate. The (period) baseline FEV1 was defined as the value measured before the study drug administration in that treatment period. (NCT00615459)
Timeframe: 23 hours 10 minutes and 23 hours 45 minutes post-dose on Day 15 of each treatment period
| Intervention | Liters (Least Squares Mean) |
|---|---|
| Indacaterol 150 μg | 1.53 |
| Indacaterol 300 μg | 1.51 |
| Tiotropium 18 μg | 1.48 |
| Placebo | 1.36 |
FEV1 was measured with spirometry conducted according to internationally accepted standards. The peak effect on Day 1 was defined as the maximum FEV1 during the first 4 hour on that day. FEV1 measurements taken within 6 hour of rescue use were set to missing before the peak FEV1 (0-4 hour) was calculated. The model used for analysis contained the (period) baseline FEV1 as covariate. The (period) baseline FEV1 was defined as the value measured before the study drug administration in that treatment period. (NCT00615459)
Timeframe: Day 1 (from 0 to 4 hours post morning dose)
| Intervention | Liters (Least Squares Mean) |
|---|---|
| Indacaterol 150 μg | 1.65 |
| Indacaterol 300 μg | 1.67 |
| Tiotropium 18 μg | 1.62 |
| Placebo | 1.48 |
Rating scale ranging from very good (best value) to not satisfactory (worst value) (NCT00615992)
Timeframe: Protocol-defined treatment period between initiation of therapy with Spiriva and the final visit (21 to 28 days)
| Intervention | Participants (Number) | |||
|---|---|---|---|---|
| Very good | Good | Satisfactory | Not satisfactory | |
| Spiriva® (Tiotropium Bromide) | 540 | 102 | 5 | 0 |
Rating scale ranging from very good (best value) to not satisfactory (worst value) (NCT00615992)
Timeframe: Protocol-defined treatment period between initiation of therapy with Spiriva and the final visit (21 to 28 days)
| Intervention | Participants (Number) | |||
|---|---|---|---|---|
| Very good | Good | Satisfactory | Not satisfactory | |
| Spiriva® (Tiotropium Bromide) | 407 | 205 | 36 | 0 |
Rating scale ranging from very good (best value) to not satisfactory (worst value) (NCT00615992)
Timeframe: Protocol-defined treatment period between initiation of therapy with Spiriva and the final visit (21 to 28 days)
| Intervention | Participants (Number) | |||
|---|---|---|---|---|
| Very good | Good | Satisfactory | Not satisfactory | |
| Spiriva® (Tiotropium Bromide) | 493 | 142 | 11 | 1 |
The scores are final, not a difference in score. Rating scale scored from 0 (no restrictions in activities) to 4 (severe restrictions) (NCT00615992)
Timeframe: Protocol-defined treatment period between initiation of therapy with Spiriva and the final visit (21 to 28 days)
| Intervention | points on a scale (Mean) |
|---|---|
| Spiriva® (Tiotropium Bromide) | 1.1 |
The scores are final, not a difference in score. Rating scale scored from 0 (no restrictions in activities) to 4 (severe restrictions) (NCT00615992)
Timeframe: Protocol-defined treatment period between initiation of therapy with Spiriva and the final visit (21 to 28 days)
| Intervention | points on a scale (Mean) |
|---|---|
| Spiriva® (Tiotropium Bromide) | 1.1 |
Rating scale ranging from very good (best value) to not satisfactory (worst value) (NCT00615992)
Timeframe: Protocol-defined treatment period between initiation of therapy with Spiriva and the final visit (21 to 28 days)
| Intervention | Participants (Number) | |||
|---|---|---|---|---|
| Very good | Good | Satisfactory | Not satisfactory | |
| Spiriva® (Tiotropium Bromide) | 373 | 217 | 53 | 3 |
"The extent of satisfaction with tiotropium bromide treatment was evaluated based on the changes of the Global COPD Assessment performed by the physician. This evaluation was done with the help of an 8-point scale rated from 1 (Poor) to 8 (Excellent) following the question Overall, how is the COPD of your patient?" (NCT00624377)
Timeframe: Baseline and 8 weeks
| Intervention | Units on a Scale (Mean) |
|---|---|
| Spiriva 18µg With HandiHaler Device on COPD Patients | 2.84 |
"The extent of satisfaction with tiotropium bromide treatment was evaluated based on the changes of the Global COPD Assessment performed by the physician. This evaluation was done with the help of an 8-point scale rated from 1 (Poor) to 8 (Excellent) following the question Overall, how is the COPD of your patient?" (NCT00624377)
Timeframe: Baseline and 8 weeks
| Intervention | Units on a Scale (Mean) |
|---|---|
| Spiriva 18µg With HandiHaler Device on COPD Patients | 1.16 |
"The extent of satisfaction with tiotropium bromide treatment was evaluated based on the changes of the Global COPD Assessment performed by the physician. This evaluation was done with the help of an 8-point scale rated from 1 (Poor) to 8 (Excellent) following the question Overall, how is the COPD of your patient?" (NCT00624377)
Timeframe: Baseline and 8 weeks
| Intervention | Units on a Scale (Mean) |
|---|---|
| Spiriva 18µg With HandiHaler Device on COPD Patients | 1.54 |
FEV1: Average values for FEV1 in healthy people depend mainly on sex and age. Values of between 80% and 120% of the average value is considered normal. FEV1 < 80% of the predicted value in combination with an FEV1/FVC < 70% confirms the presence of airflow limitation that is not fully reversible (NCT00624377)
Timeframe: Baseline and 8 weeks
| Intervention | liter per second (Mean) |
|---|---|
| Spiriva 18µg With HandiHaler Device on COPD Patients | 6.27 |
"The extent of satisfaction with tiotropium bromide treatment was evaluated based on the changes of the Global COPD Assessment performed by the physician. This evaluation was done with the help of an 8-point scale rated from 1 (Poor) to 8 (Excellent) following the question Overall, how is the COPD of your patient?" (NCT00624377)
Timeframe: Baseline and 8 weeks
| Intervention | Units on a Scale (Mean) |
|---|---|
| Spiriva 18µg With HandiHaler Device on COPD Patients | 1.19 |
"The extent of satisfaction with tiotropium bromide treatment was evaluated based on the changes of the Global COPD Assessment performed by the physician. This evaluation was done with the help of an 8-point scale rated from 1 (Poor) to 8 (Excellent) following the question Overall, how is the COPD of your patient?" (NCT00624377)
Timeframe: Baseline and 8 weeks
| Intervention | Units on a Scale (Mean) |
|---|---|
| Spiriva 18µg With HandiHaler Device on COPD Patients | 1.72 |
FEV1/FVC (FEV1%) is the ratio of FEV1 to FVC. In healthy adults this should be approximately 75-80%. In obstructive diseases, the value often decreased (<80%, often ~45%). (NCT00624377)
Timeframe: Baseline and 8 weeks
| Intervention | Ratio (Mean) |
|---|---|
| Spiriva 18µg With HandiHaler Device on COPD Patients | 4.36 |
The Physician has been asked to record any prescribed and other medication used for COPD (at the physician discretion) at every visit. (NCT00624377)
Timeframe: 8 weeks
| Intervention | Percentage of Participants (Number) |
|---|---|
| Spiriva 18µg With HandiHaler Device on COPD Patients | 76 |
"Peak FEV1 was defined as the highest FEV1 reading observed within 3 hours after inhalation of the last morning dose of each randomized treatment.~Peak FEV1 response is defined as change from baseline:~Peak FEV1 response = Peak FEV1 - FEV1 (Baseline). The FEV1 baseline value is defined as the pre-dose FEV1 measurement in the morning at the randomization visit just prior to administration of the first dose of randomized treatment. Mean is adjusted mean." (NCT00662792)
Timeframe: At baseline and within 3 hours post-morning dose after 6 weeks of treatment.
| Intervention | Liter (Mean) |
|---|---|
| 7.5 µg /25 µg Tio /Salmeterol (T+S_PE) | 0.502 |
| 18µg Tiotropium (Tio18GEL) | 0.449 |
| 50 µg Salmeterol MDPI (Salm50DPI) | 0.359 |
| 18 µg Tiotropium Free Combination (T18GEL+S_DPI) | 0.556 |
"The FVC AUC was defined as the area under the FVC curve (AUC) normalised for time. It was calculated from time 12 to 24 h (FVC AUC12-24), using the trapezoidal rule divided by the corresponding duration (i.e. 12 h) to give the results in L.~AUC12-24h response is defined as the change from baseline:~FVC AUC12-24h response = FVC AUC12-24h - FVC (Baseline). The FVC baseline value is defined as the pre-dose FVC measurement in the morning at the randomization visit just prior to administration of the first dose of randomized treatment. Mean is adjusted mean." (NCT00662792)
Timeframe: At baseline and 10 minutes (min) prior to inhalation and 30 min, 60 min, 2, 10, 11 and 12 hours after inhalation of the evening dose after 6 weeks of treatment.
| Intervention | Liter (Mean) |
|---|---|
| 7.5 µg /25 µg Tio /Salmeterol (T+S_PE) | 0.163 |
| 18µg Tiotropium (Tio18GEL) | 0.076 |
| 50 µg Salmeterol MDPI (Salm50DPI) | 0.043 |
| 18 µg Tiotropium Free Combination (T18GEL+S_DPI) | 0.245 |
"Peak FEV1 was defined as the highest FEV1 reading observed within 3 hours after inhalation of the last morning dose of each randomized treatment. Peak FEV1 response is defined as change from baseline:~Peak FEV1 response = Peak FEV1 - FEV1 (Baseline). The FEV1 baseline value is defined as the pre-dose FEV1 measurement in the morning at the randomization visit just prior to administration of the first dose of randomized treatment. Mean is adjusted mean." (NCT00662792)
Timeframe: At baseline and within 3 hours post-morning dose after 6 weeks of treatment.
| Intervention | Liter (Mean) |
|---|---|
| 7.5 µg /25 µg Tio /Salmeterol (T+S_PE) | 0.296 |
| 18µg Tiotropium (Tio18GEL) | 0.229 |
| 50 µg Salmeterol MDPI (Salm50DPI) | 0.161 |
| 18 µg Tiotropium Free Combination (T18GEL+S_DPI) | 0.320 |
"Trough PEF is determined at the end of each treatment period and is defined as the pre-dose PEF measured just prior to the last administration of the morning dose of randomized treatment. Trough PEF response is defined as the change from baseline:~Trough PEF response = Trough PEF - PEF (Baseline) The PEF baseline value is defined as the pre-dose PEF measurement in the morning at the randomization visit just prior to administration of the first dose of randomized treatment. Mean is adjusted mean." (NCT00662792)
Timeframe: At baseline and 5 minutes prior to the last administration of the morning dose after 6 weeks of treatment.
| Intervention | Liter/minutes (L/min) (Mean) |
|---|---|
| 7.5 µg /25 µg Tio /Salmeterol (T+S_PE) | 14.4 |
| 18µg Tiotropium (Tio18GEL) | 11.3 |
| 50 µg Salmeterol MDPI (Salm50DPI) | 7.1 |
| 18 µg Tiotropium Free Combination (T18GEL+S_DPI) | 22.9 |
Response in mean number of days with night-time awakenings. Per treatment period, the mean number days with awakening during the night was calculated. Per 6-week treatment period the data obtained after the first 3 weeks was used for calculating this mean. Mean number of days with night-time awakenings response is defined as the change from baseline. The baseline value, mean number of days with night-time awakenings (Baseline), is defined as the mean of the number of days with night-time awakenings obtained from the last week preceding the randomization visit. (NCT00662792)
Timeframe: At baseline and last 3 weeks of 6-week treatment period.
| Intervention | Days (Mean) |
|---|---|
| 7.5 µg /25 µg Tio /Salmeterol (T+S_PE) | -0.06 |
| 18 µg Tiotropium (Tio18GEL) | -0.06 |
| 50 µg Salmeterol MDPI (Salm50DPI) | -0.05 |
| 18 µg Tiotropium Free Combination (T18GEL+S_DPI) | 0.07 |
"Per treatment period, the mean number days with awakening (only chronic obstructive pulmonary disease (COPD) related awakenings) during the night was calculated. Per 6-week treatment period the data obtained after the first 3 weeks was used for calculating the mean.~Mean number of days with COPD related awakenings response is defined as the change from baseline.~The baseline value, mean number of days with COPD related awakenings (Baseline), is defined as the mean of the number of days with COPD related awakenings obtained from the last week preceding the randomization visit." (NCT00662792)
Timeframe: At baseline and last 3 weeks of 6-week treatment period.
| Intervention | Days (Mean) |
|---|---|
| 7.5 µg /25 µg Tio /Salmeterol (T+S_PE) | -0.05 |
| 18 µg Tiotropium (Tio18GEL) | -0.04 |
| 50 µg Salmeterol MDPI (Salm50DPI) | -0.04 |
| 18 µg Tiotropium Free Combination (T18GEL+S_DPI) | -0.07 |
Per treatment period, the mean number of awakening (only chronic obstructive pulmonary disease (COPD) related awakenings) during the night was calculated. Per 6-week treatment period the data obtained after the first 3 weeks was used for calculating this mean. Mean number of COPD related awakenings response is defined as the change from baseline. The baseline value, mean number of COPD related awakenings (Baseline), is defined as the mean of the number of days with COPD related awakenings obtained from the last week preceding the randomization visit. (NCT00662792)
Timeframe: At baseline and last 3 weeks of 6-week treatment period.
| Intervention | Awakenings (Mean) |
|---|---|
| 7.5 µg /25 µg Tio /Salmeterol (T+S_PE) | -0.02 |
| 18 µg Tiotropium (Tio18GEL) | -0.02 |
| 50 µg Salmeterol MDPI (Salm50DPI) | -0.04 |
| 18 µg Tiotropium Free Combination (T18GEL+S_DPI) | -0.08 |
"PEF(L/min) AUC0-12(h) response is defined as the change from baseline. AUC0-12(h) was calculated as the area under the curve from 0 to 12 hours using the trapezoidal rule, divided by the full duration (12 hours) to report in liter/minutes.~PEF AUC0-12h response = PEF AUC0-12h - PEF (Baseline). The PEF baseline value is defined as the pre-dose PEF measurement in the morning at the randomization visit just prior to administration of the first dose of randomized treatment. Mean is adjusted mean." (NCT00662792)
Timeframe: At baseline and 10 minutes (min) prior and 30 min, 60 min, 2, 3, 4, 6, 8, 10 and 12 hours after inhalation of the morning dose after 6 weeks of treatment.
| Intervention | Liter/minutes (L/min) (Mean) |
|---|---|
| 7.5 µg /25 µg Tio /Salmeterol (T+S_PE) | 34.5 |
| 18µg Tiotropium (Tio18GEL) | 22.5 |
| 50 µg Salmeterol MDPI (Salm50DPI) | 10.2 |
| 18 µg Tiotropium Free Combination (T18GEL+S_DPI) | 37.8 |
"PEF(L/min) AUC0-24(h) response is defined as the change from baseline. AUC0-24(h) was calculated as the area under the curve from 0 to 24 hours using the trapezoidal rule, divided by the full duration (24 hours) to report in liter/minutes.~PEF AUC0-24h response = PEF AUC0-24h - PEF (Baseline). The PEF baseline value is defined as the pre-dose PEF measurement in the morning at the randomization visit just prior to administration of the first dose of randomized treatment. Mean is adjusted mean." (NCT00662792)
Timeframe: At baseline and 10 minutes (min) prior and 60 min, 2, 3, 4, 6, 8, 10 and 12 hours after inhalation of the morning dose and 30 min, 60 min, 2, 10, 11, and 12 hours after inhalation of the evening dose after 6 weeks of treatment.
| Intervention | Liter/minutes (L/min) (Mean) |
|---|---|
| 7.5 µg /25 µg Tio /Salmeterol (T+S_PE) | 20.8 |
| 18µg Tiotropium (Tio18GEL) | 10.6 |
| 50 µg Salmeterol MDPI (Salm50DPI) | 3.4 |
| 18 µg Tiotropium Free Combination (T18GEL+S_DPI) | 28.9 |
"PEF(L/min) AUC12-24(h) response is defined as the change from baseline. AUC12-24(h) was calculated as the area under the curve from 12 to 24 hours using the trapezoidal rule, divided by the full duration (12 hours) to report in liter/minutes.~PEF AUC12-24h response = PEF AUC12-24h - PEF (Baseline). The PEF baseline value is defined as the pre-dose PEF measurement in the morning at the randomization visit just prior to administration of the first dose of randomized treatment. Mean is adjusted mean." (NCT00662792)
Timeframe: At baseline and 10 minutes (min) prior and 30 min, 60 min, 2, 10, 11 and 12 hours after inhalation of the evening dose after 6 weeks of treatment.
| Intervention | Liter/minutes (L/min) (Mean) |
|---|---|
| 7.5 µg /25 µg Tio /Salmeterol (T+S_PE) | 7.3 |
| 18µg Tiotropium (Tio18GEL) | -1.3 |
| 50 µg Salmeterol MDPI (Salm50DPI) | -3.4 |
| 18 µg Tiotropium Free Combination (T18GEL+S_DPI) | 20.0 |
"Response in individual forced expiratory volume in 1 second (FEV1) over a 24 hour observation period. Response is defined as change from baseline.~Means are adjusted for treatment, centre, treatment period and patient within centre." (NCT00662792)
Timeframe: At baseline, pre-dose and 0.5, 1, 2, 3, 4, 6, 8, 10, 12, 12.5, 13, 14, 22, 23, and 24 hours post morning dose after 6 weeks of treatment.
| Intervention | Liter (L) (Mean) | |||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| 0 hour | 0.5 hour | 1 hour | 2 hour | 3 hour | 4 hour | 6 hour | 8 hour | 10 hour | 12 hour | 12.5 hour | 13 hour | 14 hour | 22 hour | 23 hour | 24 hour | |
| 18 µg Tiotropium Free Combination (T18GEL+S_DPI) | 0.097 | 0.204 | 0.236 | 0.277 | 0.277 | 0.262 | 0.218 | 0.185 | 0.166 | 0.137 | 0.147 | 0.153 | 0.172 | 0.068 | 0.116 | 0.147 |
| 18µg Tiotropium (Tio18GEL) | 0.032 | 0.129 | 0.139 | 0.163 | 0.167 | 0.162 | 0.121 | 0.098 | 0.080 | 0.060 | 0.048 | 0.043 | 0.040 | -0.057 | 0.018 | 0.058 |
| 50 µg Salmeterol MDPI (Salm50DPI) | 0.003 | 0.068 | 0.084 | 0.108 | 0.111 | 0.102 | 0.064 | 0.044 | 0.006 | -0.007 | 0.021 | 0.035 | 0.031 | -0.034 | 0.008 | 0.024 |
| 7.5 µg /25 µg Tio /Salmeterol (T+S_PE) | 0.062 | 0.180 | 0.211 | 0.242 | 0.257 | 0.231 | 0.209 | 0.167 | 0.138 | 0.117 | 0.101 | 0.105 | 0.115 | 0.005 | 0.071 | 0.112 |
Response in forced vital capacity (FVC) over a 24 hour observation period. Response is defined as change from baseline. (NCT00662792)
Timeframe: At baseline, pre-dose and 0.5, 1, 2, 3, 4, 6, 8, 10, 12, 12.5, 13, 14, 22, 23 and 24 hours post morning dose after 6 weeks of treatment.
| Intervention | Liter (Mean) | |||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| 0 hour | 0.5 hour | 1 hour | 2 hours | 3 hours | 4 hours | 6 hours | 8 hours | 10 hours | 12 hours | 12.5 hours | 13 hours | 14 hours | 22 hours | 23 hours | 24 hours | |
| 18 µg Tiotropium Free Combination (T18GEL+S_DPI) | 0.229 | 0.395 | 0.411 | 0.464 | 0.457 | 0.463 | 0.399 | 0.355 | 0.306 | 0.258 | 0.273 | 0.266 | 0.287 | 0.191 | 0.243 | 0.280 |
| 18µg Tiotropium (Tio18GEL) | 0.165 | 0.302 | 0.332 | 0.330 | 0.319 | 0.312 | 0.254 | 0.225 | 0.185 | 0.142 | 0.131 | 0.116 | 0.122 | 0.001 | 0.098 | 0.153 |
| 50 µg Salmeterol MDPI (Salm50DPI) | 0.095 | 0.200 | 0.220 | 0.243 | 0.252 | 0.223 | 0.179 | 0.141 | 0.051 | 0.051 | 0.066 | 0.106 | 0.082 | -0.014 | 0.043 | 0.089 |
| 7.5 µg /25 µg Tio /Salmeterol (T+S_PE) | 0.139 | 0.354 | 0.386 | 0.409 | 0.425 | 0.396 | 0.368 | 0.309 | 0.264 | 0.229 | 0.206 | 0.194 | 0.225 | 0.081 | 0.176 | 0.208 |
"Trough FVC1 is determined at the end of each 6-week treatment period and is defined as the pre-dose FVC1 measured just prior to the last administration of the morning dose of randomized treatment.~Trough FVC1 response is defined as the change from baseline:~Trough FVC1 response = Trough FVC1 - FVC1 (Baseline) The FVC1 baseline value is defined as the pre-dose FVC1 measurement in the morning at the randomization visit just prior to administration of the first dose of randomized treatment. Mean is adjusted mean." (NCT00662792)
Timeframe: At baseline and 5 minutes prior to the last administration of the morning dose after 6 weeks of treatment.
| Intervention | Liter (Mean) |
|---|---|
| 7.5 µg /25 µg Tio /Salmeterol (T+S_PE) | 0.139 |
| 18µg Tiotropium (Tio18GEL) | 0.165 |
| 50 µg Salmeterol MDPI (Salm50DPI) | 0.095 |
| 18 µg Tiotropium Free Combination (T18GEL+S_DPI) | 0.229 |
"Response in individual peak expiratory flow (PEF) over a 24 hour observation period. Response is defined as change from baseline.~Means are adjusted for treatment, centre, treatment period and patient within centre." (NCT00662792)
Timeframe: At baseline, pre-dose and 0.5, 1, 2, 3, 4, 6, 8, 10, 12, 12.5, 13, 14, 22, 23, and 24 hours post morning dose after 6 weeks of treatment.
| Intervention | Liter/minutes (L/min) (Mean) | |||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| 0 hour | 0.5 hour | 1 hour | 2 hours | 3 hours | 4 hours | 6 hours | 8 hours | 10 hours | 12 hours | 12.5 hours | 13 hours | 14 hours | 22 hours | 23 hours | 24 hours | |
| 18 µg Tiotropium Free Combination (T18GEL+S_DPI) | 22.9 | 34.3 | 41.0 | 47.0 | 49.9 | 46.5 | 38.9 | 35.5 | 28.8 | 26.8 | 26.6 | 25.3 | 27.9 | 10.1 | 18.1 | 24.0 |
| 18µg Tiotropium (Tio18GEL) | 11.3 | 20.1 | 22.2 | 27.6 | 27.9 | 26.4 | 25.0 | 23.3 | 19.0 | 11.8 | 5.5 | 5.8 | 4.5 | -11.7 | 2.3 | 9.6 |
| 50 µg Salmeterol MDPI (Salm50DPI) | 7.1 | 13.7 | 14.6 | 18.5 | 17.1 | 17.2 | 11.1 | 8.6 | 1.9 | -0.6 | -0.7 | 2.6 | 1.4 | -9.7 | -5.7 | 2.0 |
| 7.5 µg /25 µg Tio /Salmeterol (T+S_PE) | 14.4 | 30.8 | 35.5 | 42.2 | 45.0 | 41.9 | 37.8 | 33.9 | 26.9 | 23.4 | 13.6 | 12.0 | 15.6 | -4.2 | 9.1 | 14.0 |
"Response (change from baseline) in mean number of days with rescue medication use in day-time, night-time and 24-hours. Per treatment period, the response in mean number of days using rescue medication was calculated for day-time (from inhalation of morning dose until 12 hours thereafter), night-time (from inhalation of evening dose until 12 hours thereafter) and 24h-total (from inhalation of morning dose until 24 hours thereafter) separately.~Per 6-week treatment period the data obtained after the first 3 weeks was used for calculating means. Mean is adjusted mean." (NCT00662792)
Timeframe: At baseline and last 3 weeks of 6-week treatment period.
| Intervention | Days (Mean) | ||
|---|---|---|---|
| Daytime | Night-time | 24 hours | |
| 18 µg Tiotropium (Tio18GEL) | -0.01 | -0.06 | -0.04 |
| 18 µg Tiotropium Free Combination (T18GEL+S_DPI) | -0.11 | -0.14 | -0.14 |
| 50 µg Salmeterol MDPI (Salm50DPI) | -0.06 | -0.07 | -0.06 |
| 7.5 µg /25 µg Tio /Salmeterol (T+S_PE) | -0.08 | -0.15 | -0.13 |
"Response in mean number of puffs of rescue medication. Per treatment period, the response in mean number of puffs rescue medication used was calculated, for day-time (from inhalation of morning dose until 12 hours thereafter), night-time (from inhalation of evening dose until 12 hours thereafter) and 24h-total (from inhalation of morning dose until 24 hours thereafter) separately. Per 6-week treatment period the data obtained after the first 3 weeks was used for calculating means. Night-time, day-time and 24h-total mean number of puffs rescue medication used responses are defined as the change from night-time, day-time and 24h-total baseline, respectively.~The baseline values, night-time, day-time and 24h-total mean mean number of puffs rescue medication used (Baseline), are defined as the mean of the night-time, day-time and 24h-total values, respectively obtained from the last week preceding the randomisation visit." (NCT00662792)
Timeframe: At baseline and last 3 weeks of 6-week treatment period.
| Intervention | Puffs (Mean) | ||
|---|---|---|---|
| Daytime | Night-time | Over 24 hours | |
| 18 µg Tiotropium (Tio18GEL) | -0.27 | 0.01 | -0.23 |
| 18 µg Tiotropium Free Combination (T18GEL+S_DPI) | -0.65 | -0.28 | -0.92 |
| 50 µg Salmeterol MDPI (Salm50DPI) | -0.25 | -0.07 | -0.30 |
| 7.5 µg /25 µg Tio /Salmeterol (T+S_PE) | -0.61 | -0.16 | -0.76 |
"Per treatment period, the morning mean FEV1 (mean of the pre-dose morning FEV1 measurements) and evening mean FEV1 (mean of the pre-dose evening FEV1 measurement) were calculated. Per treatment period the data obtained after the first 3 weeks were used for calculating these means.~Morning and evening mean FEV1 responses are defined as the change from morning and evening baseline, respectively. The baseline values, morning and evening mean FEV1(Baseline), are defined as the mean of the morning and evening values, respectively obtained from the last week preceding the randomization visit .~Mean is adjusted for treatment, centre, treatment period and patient within centre." (NCT00662792)
Timeframe: At baseline and last 3 weeks of 6-week treatment period.
| Intervention | Liter (L) (Mean) | |
|---|---|---|
| FEV1, morning | FEV1, evening | |
| 18 µg Tiotropium Free Combination (T18GEL+S_DPI) | 0.075 | 0.075 |
| 18µg Tiotropium (Tio18GEL) | 0.013 | 0.038 |
| 50 µg Salmeterol MDPI (Salm50DPI) | 0.026 | -0.010 |
| 7.5 µg /25 µg Tio /Salmeterol (T+S_PE) | 0.052 | 0.094 |
"The mean PEF is defined as the mean of the values obtained during the weeks after the first three weeks of treatment. Morning and evening mean PEF were calculated and analyzed separately. PEF was measured twice daily (in the morning prior to inhalation of study medication and in the evening prior to inhalation of study medication).~Morning and evening mean PEF response are defined as the change from morning and evening baseline, respectively.~Morning and evening mean PEF baseline are defined as the mean of the morning and evening values, respectively obtained from the last week preceding the randomization visit.~Mean is adjusted for treatment, center, treatment period and patient within center." (NCT00662792)
Timeframe: At baseline and last 3 weeks of 6-week treatment period.
| Intervention | Liter / minute (L/min) (Mean) | |
|---|---|---|
| PEF, morning | PEF, evening | |
| 18 µg Tiotropium Free Combination (T18GEL+S_DPI) | 14.8 | 15.2 |
| 18µg Tiotropium (Tio18GEL) | 1.2 | 5.8 |
| 50 µg Salmeterol MDPI (Salm50DPI) | 0.6 | -6.4 |
| 7.5 µg /25 µg Tio /Salmeterol (T+S_PE) | 6.8 | 16.7 |
"Trough FEV1 is determined at the end of each treatment period and is defined as the pre-dose FEV1 measured just prior to the last administration of the morning dose of randomized treatment.~Trough FEV1 response is defined as the change from baseline:~Trough FEV1 response = Trough FEV1 - FEV1 (Baseline) The FEV1 baseline value is defined as the pre-dose FEV1 measurement in the morning at the randomization visit just prior to administration of the first dose of randomized treatment. Mean is adjusted mean." (NCT00662792)
Timeframe: At baseline and 5 minutes prior to the last administration of the morning dose after 6 weeks of treatment.
| Intervention | Liter (Mean) |
|---|---|
| 7.5 µg /25 µg Tio /Salmeterol (T+S_PE) | 0.062 |
| 18µg Tiotropium (Tio18GEL) | 0.032 |
| 50 µg Salmeterol MDPI (Salm50DPI) | 0.003 |
| 18 µg Tiotropium Free Combination (T18GEL+S_DPI) | 0.097 |
"Peak PEF was defined as the highest PEF reading observed within 3 hours after inhalation of the last morning dose of randomized treatment.~Peak PEF response is defined as change from baseline:~Peak PEF response = Peak PEF - PEF (Baseline). The PEF baseline value is defined as the pre-dose PEF measurement in the morning at the randomization visit just prior to administration of the first dose of randomized treatment. Mean is adjusted mean." (NCT00662792)
Timeframe: At baseline and within 3 hours post-morning dose after 6 weeks of treatment.
| Intervention | Liter/minutes (L/min) (Mean) |
|---|---|
| 7.5 µg /25 µg Tio /Salmeterol (T+S_PE) | 53.9 |
| 18µg Tiotropium (Tio18GEL) | 40.6 |
| 50 µg Salmeterol MDPI (Salm50DPI) | 30.8 |
| 18 µg Tiotropium Free Combination (T18GEL+S_DPI) | 59.0 |
"FVC AUC was defined as the area under the FVC curve normalized for time. It was calculated from time 0 to 12 h (FVC AUC0-12), using the trapezoidal rule divided by the corresponding duration (12 h) to give the results in liter (L). FVC AUC0-12h response is defined as the change from baseline:~FVC AUC0-12h response = FVC AUC0-12h - FVC (Baseline). The baseline value for FVC based parameters is defined as the pre-dose FVC measurement in the morning at the randomization visit just prior to administration of the first dose of randomized treatment. Mean is adjusted mean." (NCT00662792)
Timeframe: At baseline and 10 minutes (min) prior to inhalation and 30 min, 60 min, 2, 3, 4, 6, 8, 10 and 12 hours after inhalation of the morning dose after 6 weeks of treatment.
| Intervention | Liter (Mean) |
|---|---|
| 7.5 µg /25 µg Tio /Salmeterol (T+S_PE) | 0.337 |
| 18µg Tiotropium (Tio18GEL) | 0.253 |
| 50 µg Salmeterol MDPI (Salm50DPI) | 0.160 |
| 18 µg Tiotropium Free Combination (T18GEL+S_DPI) | 0.381 |
The FVC AUC was defined as the area under the FVC curve (AUC) normalised for time. It was calculated from time 0 to 24 h (FVC AUC0-24), using the trapezoidal rule divided by the corresponding duration (i.e. 24 h) to give the results in L. AUC response was defined as the change from the baseline FVC; baseline was defined as the FVC measured on randomisation visit. Mean is adjusted mean. (NCT00662792)
Timeframe: At baseline and 10 minutes (min) prior and 60 min, 2, 3, 4, 6, 8, 10 and 12 hour after inhalation the morning dose and 30 min, 60 min, 2, 10, 11, and 12 hours after inhalation of the evening dose after 6 weeks of treatment.
| Intervention | Liter (Mean) |
|---|---|
| 7.5 µg /25 µg Tio /Salmeterol (T+S_PE) | 0.250 |
| 18µg Tiotropium (Tio18GEL) | 0.165 |
| 50 µg Salmeterol MDPI (Salm50DPI) | 0.102 |
| 18 µg Tiotropium Free Combination (T18GEL+S_DPI) | 0.313 |
"The FEV1 AUC was defined as the area under the FEV1 curve (AUC) normalised for time. It was calculated from time 12 to 24 h (FEV1 AUC12-24), using the trapezoidal rule divided by the corresponding duration (i.e. 12 h) to give the results in L.~AUC12-24h response is defined as the change from baseline:~FEV1 AUC12-24h response = FEV1 AUC12-24h - FEV1 (Baseline). The FEV1 baseline value is defined as the pre-dose FEV1 measurement in the morning at the randomization visit (Visit 2) just prior to administration of the first dose of randomized treatment. Mean is adjusted mean." (NCT00662792)
Timeframe: At baseline and 10 minutes (min) prior to inhalation and 30 min, 60 min, 2, 10, 11, and 12 hours after inhalation of the evening dose after 6 weeks of treatment.
| Intervention | Liter (L) (Mean) |
|---|---|
| 7.5 µg /25 µg Tio /Salmeterol (T+S_PE) | 0.068 |
| 18 µg Tiotropium (Tio18GEL) | 0.003 |
| 50 µg Salmeterol MDPI (Salm50DPI) | 0.003 |
| 18 µg Tiotropium Free Combination (T18GEL+S_DPI) | 0.124 |
"FEV1 AUC was defined as the area under the FEV1 curve normalized for time. It was calculated from time 0 to 24 h (FEV1 AUC0-24), using the trapezoidal rule divided by the corresponding duration (24 h) to give the results in liter (L). FEV1 AUC0-24h response is defined as the change from baseline:~FEV1 AUC0-24h response = FEV1 AUC0-24h - FEV1 (Baseline). The FEV1 baseline value is defined as the pre-dose FEV1 measurement in the morning at the randomization visit just prior to administration of the first dose of randomized treatment. Mean is adjusted mean." (NCT00662792)
Timeframe: At baseline and 10 minutes (min) prior and 60 min, 2, 3, 4, 6, 8, 10 and 12 hours after inhalation of the morning dose and 30 min, 60 min, 2, 10, 11, and 12 hours after inhalation of the evening dose after 6 weeks of treatment.
| Intervention | Liter (Mean) |
|---|---|
| 7.5 µg /25 µg Tio /Salmeterol (T+S_PE) | 0.128 |
| 18µg Tiotropium (Tio18GEL) | 0.060 |
| 50 µg Salmeterol MDPI (Salm50DPI) | 0.030 |
| 18 µg Tiotropium Free Combination (T18GEL+S_DPI) | 0.167 |
"FEV1 AUC was defined as the area under the FEV1 curve normalized for time. It was calculated from time 0 to 12 h (FEV1 AUC0-12), using the trapezoidal rule divided by the corresponding duration (12 h) to give the results in liter (L). FEV1 AUC0-12h response is defined as the change from baseline:~FEV1 AUC0-12h response = FEV1 AUC0-12h - FEV1 (Baseline). The FEV1 baseline value is defined as the pre-dose FEV1 measurement in the morning at the randomization visit just prior to administration of the first dose of randomized treatment. Mean is adjusted mean." (NCT00662792)
Timeframe: At baseline and 10 minutes (min) prior to inhalation and 30 min, 60 min, 2, 3, 4, 6, 8, 10 and 12 hours after inhalation of the morning dose after 6 weeks of treatment.
| Intervention | Liter (L) (Mean) |
|---|---|
| 7.5 µg /25 µg Tio /Salmeterol (T+S_PE) | 0.187 |
| 18 µg Tiotropium (Tio18GEL) | 0.117 |
| 50 µg Salmeterol MDPI (Salm50DPI) | 0.057 |
| 18 µg Tiotropium Free Combination (T18GEL+S_DPI) | 0.211 |
"Response in average shortness of breath (SOB) score at night. The SOB measured the shortness of breath, ranging from 1 to 5, where 1 = not at all, 2 = a little bit, 3 = somewhat, 4 = quite a bit and 5 = very much. A higher score indicates a worse outcome.~Per 6-week treatment period the data obtained after the first 3 weeks was used for calculating the mean." (NCT00662792)
Timeframe: At baseline and last 3 weeks of 6-week treatment period.
| Intervention | Score on a scale (Mean) |
|---|---|
| 7.5 µg /25 µg Tio /Salmeterol (T+S_PE) | -0.06 |
| 18 µg Tiotropium (Tio18GEL) | -0.04 |
| 50 µg Salmeterol MDPI (Salm50DPI) | -0.06 |
| 18 µg Tiotropium Free Combination (T18GEL+S_DPI) | -0.11 |
Number of participants with drug related adverse events. (NCT00662792)
Timeframe: From first drug administration until last drug administration (average duration of 42 days) + 30 days, up to 91 days for T+S_PE, up to 98 days for Tio18GEL, up 89 days for Salm50DPI and up to 113 days for T18GEL+S_DPI.
| Intervention | Participants (Count of Participants) |
|---|---|
| 7.5 µg /25 µg Tio /Salmeterol (T+S_PE) | 0 |
| 18 µg Tiotropium (Tio18GEL) | 2 |
| 50 µg Salmeterol MDPI (Salm50DPI) | 2 |
| 18 µg Tiotropium Free Combination (T18GEL+S_DPI) | 2 |
"Marked changes from baseline in vital signs were defined as followed:~Systolic blood pressure~Increase of ≥25 millimetre of mercury (mmHg) above baseline~Decrease below 100 mmHg if not at that level at baseline and a decrease of >10 mmHg below baseline~Diastolic blood pressure~Increase above 90 mmHg and an increase of >10 mmHg above baseline~Decrease below 60 mmHg if not at that level at baseline and a decrease of >10 mmHg below baseline~Pulse~Increase above 100 bpm if not at that level at baseline and an increase of >10 bpm above baseline~Decrease below 60 bpm if not at that level at baseline and a decrease of >10 bpm below baseline~Baseline is defined as the pre-dose measurement at randomisation visit." (NCT00662792)
Timeframe: At baseline and 6 hours following the morning dose of study medication after 6 weeks of treatment.
| Intervention | Participants (Count of Participants) | |||||
|---|---|---|---|---|---|---|
| Increase in systolic blood pressure | Increase in diastolic blood pressure | Increase in pulse rate | Decrease in systolic blood pressure | Decrease in diastolic blood pressure | Decrease in pulse rate | |
| 18 µg Tiotropium (Tio18GEL) | 18 | 16 | 10 | 4 | 7 | 7 |
| 18 µg Tiotropium Free Combination (T18GEL+S_DPI) | 15 | 14 | 13 | 4 | 5 | 2 |
| 50 µg Salmeterol MDPI (Salm50DPI) | 16 | 11 | 9 | 3 | 3 | 7 |
| 7.5 µg /25 µg Tio /Salmeterol (T+S_PE) | 18 | 16 | 6 | 3 | 5 | 6 |
TDI is a multidimensional clinical instrument developed to provide a comprehensive assessment of change in dyspnea after an intervention, considering three components (functional impairment, magnitude of task, and magnitude of effort). It ranges from -9 (major deterioration) to +9 (major improvement). (NCT00680056)
Timeframe: After 2 week of each treatment
| Intervention | score on scale (Mean) |
|---|---|
| Formoterol Plus Placebo (Tiotropium) Treatment | 2.9 |
| Formoterol Plus Tiotropium Treatment | 3.8 |
Percentage change from baseline in time to the limit of tolerance on a high intensity constant-speed treadmill exercise test (with a speed corresponding to 80% of that obtained during incremental test) (NCT00680056)
Timeframe: Baseline and after 2 weeks with each treatment
| Intervention | Percentage change (Mean) |
|---|---|
| Formoterol Plus Placebo (Tiotropium) Treatment | 68 |
| Formoterol Plus Tiotropium Treatment | 124 |
"Measured a 8-point scale, from 1 (poor) to 8 (excellent), as judged by the physician, over 4 weeks of treatment.~The physician made a global evaluation at the end of the Baseline Period (Test Day 1) and at each visit thereafter. These assessments were made prior to pulmonary function testing and reflected the physician's opinion of the patient's overall clinical condition. This evaluation was based on the need for concomitant medication, number and severity of COPD exacerbations since the last visit, severity of cough, ability to exercise, amount of wheezing, and other relevant clinical observations.~The means are adjusted, based on an ANCOVA with terms for baseline, treatment, centre (centre random, all other effects fixed)." (NCT00696020)
Timeframe: 1 week, 2 weeks and 4 weeks
| Intervention | units on a scale (Least Squares Mean) | ||
|---|---|---|---|
| Day 8 | Day 15 | Day 29 | |
| 5 µg Tiotropium | 5.139 | 5.272 | 5.264 |
| Tiotropium+Olodaterol 5/10 μg | 5.149 | 5.104 | 5.252 |
| Tiotropium+Olodaterol 5/2 μg | 5.102 | 5.130 | 5.295 |
| Tiotropium+Olodaterol 5/5 μg | 5.185 | 5.382 | 5.447 |
"Trough FEV1 (forced expiratory volume in 1 second) was defined as the mean of the 2 FEV1 values (performed at 1 h and 10 min prior to study medication inhalation) at the end of the dosing interval, 24 hours post-drug administration. Trough FEV1 response was defined as the change from baseline in trough FEV1. Baseline FEV1 was defined as the mean of the 2 pre-treatment FEV1 values measured at Visit 2 (-1 h and -10 min) prior to administration of the first dose of study medication.~The means are adjusted, based on ANCOVA with terms for baseline, treatment, centre (centre random, all other effects fixed).~Comparisons between groups are presented for Day 15." (NCT00696020)
Timeframe: Baseline, 1 week and 2 weeks
| Intervention | L (Least Squares Mean) | |
|---|---|---|
| Day 8 | Day 15 | |
| 5 µg Tiotropium | 0.093 | 0.099 |
| Tiotropium+Olodaterol 5/10 μg | 0.166 | 0.154 |
| Tiotropium+Olodaterol 5/2 μg | 0.149 | 0.141 |
| Tiotropium+Olodaterol 5/5 μg | 0.154 | 0.159 |
"Trough FVC (forced vital capacity) was defined as the mean of the 2 FVC values (performed at 1 h and 10 min prior to study medication inhalation) at the end of the dosing interval, 24 hours post-drug administration. Trough FVC response was defined as the change from baseline in trough FVC. Baseline FVC was defined as the mean of the 2 pre-treatment FVC values measured at Visit 2 (-1 h and -10 min) prior to administration of the first dose of study medication.~The means are adjusted, based on an ANCOVA with terms for baseline, treatment, centre (centre random, all other effects fixed).~Comparisons between groups are presented for Day 29." (NCT00696020)
Timeframe: Baseline, 1 week, 2 weeks and 4 weeks
| Intervention | L (Least Squares Mean) | ||
|---|---|---|---|
| Day 8 | Day 15 | Day 29 | |
| 5 µg Tiotropium | 0.156 | 0.171 | 0.189 |
| Tiotropium+Olodaterol 5/10 μg | 0.275 | 0.285 | 0.306 |
| Tiotropium+Olodaterol 5/2 μg | 0.215 | 0.196 | 0.191 |
| Tiotropium+Olodaterol 5/5 μg | 0.265 | 0.280 | 0.288 |
"The patient will record twice daily peak flow measurements using an AM2+ device. The evening measurement will be performed at bedtime.~The means are adjusted, based on an ANCOVA with terms for baseline, treatment, centre (centre random, all other effects fixed)." (NCT00696020)
Timeframe: Throughout the 4 weeks treatment period
| Intervention | L/min (Mean) | |||
|---|---|---|---|---|
| Week 1 | Week 2 | Week 3 | Week 4 | |
| 5 µg Tiotropium | 249.10 | 247.10 | 249.78 | 246.77 |
| Tiotropium+Olodaterol 5/10 μg | 268.58 | 266.40 | 265.67 | 265.50 |
| Tiotropium+Olodaterol 5/2 μg | 260.86 | 260.73 | 258.20 | 253.12 |
| Tiotropium+Olodaterol 5/5 μg | 267.47 | 267.31 | 268.16 | 266.61 |
The means are adjusted, Based on an ANCOVA with terms for baseline, treatment, centre (centre random, all other effects fixed). (NCT00696020)
Timeframe: Throughout the 4 weeks treatment period
| Intervention | occasion(s) (Least Squares Mean) | |||
|---|---|---|---|---|
| Week 1 | Week 2 | Week 3 | Week 4 | |
| 5 µg Tiotropium | 1.905 | 1.784 | 1.947 | 2.017 |
| Tiotropium+Olodaterol 5/10 μg | 1.669 | 1.477 | 1.563 | 1.482 |
| Tiotropium+Olodaterol 5/2 μg | 1.512 | 1.610 | 1.650 | 1.615 |
| Tiotropium+Olodaterol 5/5 μg | 1.504 | 1.476 | 1.492 | 1.602 |
"The patient will record twice daily peak flow measurements using an Asthma Monitor®Am2+ (AM2+) device. Morning measurements will be performed immediately upon arising after the patient has cleared out mucus, prior to administration of trial and/or rescue medication.~The means are adjusted, based on an ANCOVA with terms for baseline, treatment, centre (centre random, all other effects fixed)." (NCT00696020)
Timeframe: Throughout the 4 week treatment period
| Intervention | L/min (Least Squares Mean) | |||
|---|---|---|---|---|
| Week 1 | Week 2 | Week 3 | Week 4 | |
| 5 µg Tiotropium | 227.81 | 228.57 | 228.82 | 226.49 |
| Tiotropium+Olodaterol 5/10 μg | 248.76 | 247.77 | 248.33 | 247.30 |
| Tiotropium+Olodaterol 5/2 μg | 244.43 | 240.87 | 239.61 | 234.14 |
| Tiotropium+Olodaterol 5/5 μg | 248.84 | 249.99 | 249.39 | 249.17 |
"Area under the concentration-time curve of Olodaterol in plasma at steady state (AUC(0-1h,ss)) from 0 to 1 hour post dosing after 4 weeks of treatment.~No results displayed for Tiotropium+Olodaterol 5/2 μg because there were zero total participants analyzed for this outcome measure." (NCT00696020)
Timeframe: Pre-dose, 5 min, 10 min, 20 min, 40 min, 1 h, 3 h, and 6 h after the last dose.
| Intervention | pg*h/mL (Geometric Mean) |
|---|---|
| Tiotropium+Olodaterol 5/5 μg | 3.97 |
| Tiotropium+Olodaterol 5/10 μg | 5.82 |
Area under the concentration-time curve of Tiotropium at steady state (AUC(0-3h,ss)) from 0 to 3 hours post dosing after 4 weeks of treatment. (NCT00696020)
Timeframe: Pre-dose, 5 min, 10 min, 20 min, 40 min, 1 h, 3 h, and 6 h after the last dose.
| Intervention | pg*h/mL (Geometric Mean) |
|---|---|
| 5 µg Tiotropium | 21.8 |
| Tiotropium+Olodaterol 5/2 μg | 21.9 |
| Tiotropium+Olodaterol 5/5 μg | 21.9 |
| Tiotropium+Olodaterol 5/10 μg | 21.0 |
"PEF (peak expiratory flow rate L/min) peak(0-3h) is the maximum post-dose value during the first 3 hours after first administration and after 1, 2 and 4 weeks of treatment. Response is defined as change from the baseline value. Baseline was defined as the mean of the 2 pre-treatment values measured at Visit 2 (-1 h and -10 min) prior to administration of the first dose of study medication.~The means are adjusted, based on an ANCOVA with terms for baseline, treatment, centre (centre random, all other effects fixed).~Comparisons between groups are presented for Day 29." (NCT00696020)
Timeframe: 5 min (only for week 1 and 2), 30 min, 1 h, 2 h and 3 h after inhalation at baseline and after 1 week, 2 weeks and 4 weeks
| Intervention | L (Least Squares Mean) | |||
|---|---|---|---|---|
| Day 1 | Day 8 | Day 15 | Day 29 | |
| 5 µg Tiotropium | 43.051 | 47.819 | 48.129 | 47.104 |
| Tiotropium+Olodaterol 5/10 μg | 62.360 | 73.828 | 73.886 | 76.461 |
| Tiotropium+Olodaterol 5/2 μg | 53.801 | 69.792 | 79.890 | 70.519 |
| Tiotropium+Olodaterol 5/5 μg | 53.853 | 69.254 | 71.916 | 65.800 |
"Maximum measured concentration of Olodaterol in plasma at steady state (Cmax,ss) after 4 weeks of treatment.~No results displayed for Tiotropium+Olodaterol 5/2 μg because there were zero total participants analyzed for this outcome measure." (NCT00696020)
Timeframe: Pre-dose, 5 min, 10 min, 20 min, 40 min, 1 h, 3 h, and 6 h after the last dose.
| Intervention | pg/mL (Geometric Mean) |
|---|---|
| Tiotropium+Olodaterol 5/5 μg | 4.39 |
| Tiotropium+Olodaterol 5/10 μg | 6.87 |
Maximum measured concentration of Tiotropium in plasma at steady state (Cmax,ss) after 4 weeks treatment. (NCT00696020)
Timeframe: Pre-dose, 5 min, 10 min, 20 min, 40 min, 1 h, 3 h, and 6 h after the last dose.
| Intervention | pg/mL (Geometric Mean) |
|---|---|
| 5 µg Tiotropium | 13.3 |
| Tiotropium+Olodaterol 5/2 μg | 13.9 |
| Tiotropium+Olodaterol 5/5 μg | 12.4 |
| Tiotropium+Olodaterol 5/10 μg | 14.4 |
"FEV1 (forced expiratory volume in 1 second) AUC(0-6h) response is defined as change from the baseline value. AUC(0-6h) will be calculated as the area under the curve from 0 to 6 hours on test day 29 using the trapezoidal rule, divided by the full duration (6 hours) to report in litres. Baseline was defined as the mean of the 2 pre-treatment values measured at Visit 2 (-1 h and -10 min) prior to administration of the first dose of study medication.~The means are adjusted, based on ANCOVA with terms for baseline, treatment, and centre (centre random, all other effects fixed)." (NCT00696020)
Timeframe: 1 h and 10 min prior to inhalation at baseline and after 4 weeks and 30 min, 1 h, 2 h, 3 h, 4 h, 5 h and 6h after inhalation at baseline and after 4 weeks (Day 29)
| Intervention | L (Least Squares Mean) |
|---|---|
| 5 µg Tiotropium | 0.194 |
| Tiotropium+Olodaterol 5/2 μg | 0.282 |
| Tiotropium+Olodaterol 5/5 μg | 0.280 |
| Tiotropium+Olodaterol 5/10 μg | 0.322 |
"FVC (forced vital capacity) AUC(0-6h) response is defined as change from the baseline value. AUC(0-6h) will be calculated as the area under the curve from 0 to 6 hours on test day 29 using the trapezoidal rule, divided by the full duration (6 hours) to report in litres. Baseline was defined as the mean of the 2 pre-treatment values measured at Visit 2 (-1 h and -10 min) prior to administration of the first dose of study medication.~The means are adjusted, based on an ANCOVA with terms for baseline, treatment, centre (centre random, all other effects fixed)." (NCT00696020)
Timeframe: 1 h and 10 min prior to inhalation at baseline and after 4 weeks and 30 min, 1 h, 2 h, 3 h, 4 h, 5 h and 6h after inhalation at baseline and after 4 weeks (Day 29)
| Intervention | L (Least Squares Mean) |
|---|---|
| 5 µg Tiotropium | 0.309 |
| Tiotropium+Olodaterol 5/2 μg | 0.429 |
| Tiotropium+Olodaterol 5/5 μg | 0.492 |
| Tiotropium+Olodaterol 5/10 μg | 0.547 |
"Patient's Global Rating at the end of the 4 week treatment period.~Patients rated their health (respiratory condition) at Day 29 (compared to the day before they commenced treatment with study medication) on a 7-point scale as very much better (1), much better (2), a little better (3), no change (4), a little worse (5), much worse (6), or very much worse (7). The assessment was made prior to pulmonary function testing and all other study procedures. The Patient's Global Rating was also completed before the Physician's Global Evaluation.~The means are adjusted, based on an ANCOVA with terms for treatment, centre (centre random, treatment effect fixed)." (NCT00696020)
Timeframe: 4 weeks
| Intervention | units on a patient's global rating score (Least Squares Mean) |
|---|---|
| 5 µg Tiotropium | 2.866 |
| Tiotropium+Olodaterol 5/2 μg | 2.598 |
| Tiotropium+Olodaterol 5/5 μg | 2.368 |
| Tiotropium+Olodaterol 5/10 μg | 2.377 |
"PEF (peak expiratory flow rate L/min) AUC(0-6h) response is defined as change from the baseline value. AUC(0-6h) will be calculated as the area under the curve from 0 to 6 hours on test day 29 using the trapezoidal rule, divided by the full duration (6 hours) to report in litres. Baseline was defined as the mean of the 2 pre-treatment values measured at Visit 2 (-1 h and -10 min) prior to administration of the first dose of study medication.~The means are adjusted, based on an ANCOVA with terms for baseline, treatment, centre (centre random, all other effects fixed)." (NCT00696020)
Timeframe: 1 h and 10 min prior to inhalation at baseline and after 4 weeks and 30 min, 1 h, 2 h, 3 h, 4 h, 5 h and 6h after inhalation at baseline and after 4 weeks (Day 29)
| Intervention | L (Least Squares Mean) |
|---|---|
| 5 µg Tiotropium | 30.576 |
| Tiotropium+Olodaterol 5/2 μg | 53.443 |
| Tiotropium+Olodaterol 5/5 μg | 50.319 |
| Tiotropium+Olodaterol 5/10 μg | 58.368 |
"Time from last dosing to maximum concentration of Olodaterol in plasma at steady state (tmax,ss) after 4 weeks treatment.~No results displayed for Tiotropium+Olodaterol 5/2 μg because there were zero total participants analyzed for this outcome measure." (NCT00696020)
Timeframe: Pre-dose, 5 min, 10 min, 20 min, 40 min, 1 h, 3 h, and 6 h after the last dose.
| Intervention | hours (Median) |
|---|---|
| Tiotropium+Olodaterol 5/5 μg | 0.167 |
| Tiotropium+Olodaterol 5/10 μg | 0.183 |
"Possible clinically significant anormalities (laboratory data); marked changes from baseline for vital signs, notable change in ECG and new onset of ECG abnormalities. New abnormal findings or worsening of baseline conditions were reported as Adverse Events (AEs).~All AEs with an onset after the first dose of study medication up to 21 days after the last dose of study medication were to have been assigned to the Treatment Period." (NCT00696020)
Timeframe: From first dose up to 21 days after last dose of study medication.
| Intervention | participants (Number) |
|---|---|
| 5 µg Tiotropium | 1 |
| Tiotropium+Olodaterol 5/2 μg | 0 |
| Tiotropium+Olodaterol 5/5 μg | 0 |
| Tiotropium+Olodaterol 5/10 μg | 0 |
Time from last dosing to maximum concentration of Tiotropium in plasma at steady state (tmax,ss) after 4 weeks of treatment. (NCT00696020)
Timeframe: Pre-dose, 5 min, 10 min, 20 min, 40 min, 1 h, 3 h, and 6 h after the last dose.
| Intervention | hours (Median) |
|---|---|
| 5 µg Tiotropium | 0.133 |
| Tiotropium+Olodaterol 5/2 μg | 0.100 |
| Tiotropium+Olodaterol 5/5 μg | 0.083 |
| Tiotropium+Olodaterol 5/10 μg | 0.133 |
"Trough FEV1 (Forced expiratory volume in 1 second) was defined as the mean of the two FEV1 values (performed at 1 h and 10 min prior to study medication inhalation) at the end of the dosing interval, 24 hours post-drug administration. Trough FEV1 response was defined as the change from baseline in trough FEV1. Baseline FEV1 was defined as the mean of the 2 pre-treatment FEV1 values measured at Visit 2 (-1 h and -10 min) prior to administration of the first dose of study medication.~The means are adjusted, based on ANCOVA with terms for baseline, treatment, and centre (centre random, all other effects fixed)." (NCT00696020)
Timeframe: Baseline and 4 weeks
| Intervention | L (Least Squares Mean) |
|---|---|
| 5 µg Tiotropium | 0.110 |
| Tiotropium+Olodaterol 5/2 μg | 0.134 |
| Tiotropium+Olodaterol 5/5 μg | 0.143 |
| Tiotropium+Olodaterol 5/10 μg | 0.168 |
"FEV1 (forced expiratory volume in 1 second) AUC(6-12h) response is defined as change from the baseline value. AUC(6-12h) will be calculated as the area under the curve from 6 to 12 hours on the various test days using the trapezoidal rule, divided by the full duration (6 hours) to report in litres. Baseline was defined as the mean of the 2 pre-treatment values measured at Visit 2 (-1 h and -10 min) prior to administration of the first dose of study medication.~The means are adjusted, based on ANCOVA with terms for baseline, treatment, and centre (centre random, all other effects fixed).~Comparisons between groups are presented for Day 29." (NCT00696020)
Timeframe: 6 h, 9 h and 12 h after inhalation at baseline and after 1 week, 2 weeks and 4 weeks
| Intervention | L (Least Squares Mean) | |||
|---|---|---|---|---|
| Day 1 | Day 8 | Day 15 | Day 29 | |
| 5 µg Tiotropium | 0.143 | 0.169 | 0.142 | 0.145 |
| Tiotropium+Olodaterol 5/10 μg | 0.175 | 0.172 | 0.169 | 0.180 |
| Tiotropium+Olodaterol 5/2 μg | 0.181 | 0.203 | 0.197 | 0.189 |
| Tiotropium+Olodaterol 5/5 μg | 0.209 | 0.219 | 0.205 | 0.193 |
"Response is defined as change from the baseline value. AUC(0-3h) (area under the curve) was calculated as the area under the curve from 0 to 3 hours on the various test days using the trapezoidal rule, divided by the full duration (3 hours) to report in litres. Baseline FEV1 was defined as the mean of the 2 pre-treatment FEV1 values measured at Visit 2 (-1 h and -10 min) prior to administration of the first dose of study medication~The means are adjusted, based on an ANCOVA with terms for baseline, treatment, centre (centre random, all other effects fixed).~Comparisons between groups are presented for Day 29." (NCT00696020)
Timeframe: 1 h and 10 min prior to inhalation and 5 min (only for week 1 and 2), 30 min, 1 h, 2 h and 3 h after inhalation at baseline and after 1, 2 and 4 weeks
| Intervention | L (Least Squares Mean) | |||
|---|---|---|---|---|
| Day 1 | Day 8 | Day 15 | Day 29 | |
| 5 µg Tiotropium | 0.161 | 0.204 | 0.201 | 0.191 |
| Tiotropium+Olodaterol 5/10 μg | 0.225 | 0.315 | 0.309 | 0.316 |
| Tiotropium+Olodaterol 5/2 μg | 0.201 | 0.289 | 0.288 | 0.276 |
| Tiotropium+Olodaterol 5/5 μg | 0.229 | 0.302 | 0.305 | 0.270 |
"FEV1 (forced expiratory volume in 1 second) peak(0-3h) is the maximum post-dose value during the first 3 hours after first administration and after 1, 2 and 4 weeks of treatment. Response is defined as change from the baseline value. Baseline was defined as the mean of the 2 pre-treatment values measured at Visit 2 (-1 h and -10 min) prior to administration of the first dose of study medication.~The means are adjusted, based on an ANCOVA with terms for baseline, treatment, centre (centre random, all other effects fixed).~Comparisons between groups are presented for Day 29." (NCT00696020)
Timeframe: 5 min (only for week 1 and 2), 30 min, 1 h, 2 h and 3 h after inhalation at baseline and after 1 week, 2 weeks and 4 weeks
| Intervention | L (Least Squares Mean) | |||
|---|---|---|---|---|
| Day 1 | Day 8 | Day 15 | Day 29 | |
| 5 µg Tiotropium | 0.249 | 0.276 | 0.276 | 0.266 |
| Tiotropium+Olodaterol 5/10 μg | 0.321 | 0.397 | 0.386 | 0.410 |
| Tiotropium+Olodaterol 5/2 μg | 0.284 | 0.359 | 0.361 | 0.353 |
| Tiotropium+Olodaterol 5/5 μg | 0.311 | 0.378 | 0.391 | 0.348 |
"FVC (forced vital capacity) AUC(0-3h) response is defined as change from the baseline value. AUC(0-3h) was calculated as the area under the curve from 0 to 3 hours on the various test days using the trapezoidal rule, divided by the full duration (3 hours) to report in litres. Baseline FVC was defined as the mean of the 2 pre-treatment FVC values measured at Visit 2 (-1 h and -10 min) prior to administration of the first dose of study medication.~The means are adjusted, based on an ANCOVA with terms for baseline, treatment, centre (centre random, all other effects fixed).~Comparisons between groups are presented for Day 29." (NCT00696020)
Timeframe: 1 h and 10 min prior to inhalation and 5 min (only for week 1 and 2), 30 min, 1 h, 2 h and 3 h after inhalation at baseline and after 1, 2 and 4 weeks
| Intervention | L (Least Squares Mean) | |||
|---|---|---|---|---|
| Day 1 | Day 8 | Day 15 | Day 29 | |
| 5 µg Tiotropium | 0.268 | 0.310 | 0.327 | 0.308 |
| Tiotropium+Olodaterol 5/10 μg | 0.410 | 0.537 | 0.554 | 0.547 |
| Tiotropium+Olodaterol 5/2 μg | 0.331 | 0.441 | 0.437 | 0.424 |
| Tiotropium+Olodaterol 5/5 μg | 0.413 | 0.493 | 0.513 | 0.492 |
"FVC (forced vital capacity) peak(0-3h) is the maximum post-dose value during the first 3 hours after first administration and after 1, 2 and 4 weeks of treatment. Response is defined as change from the baseline value. Baseline was defined as the mean of the 2 pre-treatment values measured at Visit 2 (-1 h and -10 min) prior to administration of the first dose of study medication.~The means are adjusted, based on an ANCOVA with terms for baseline, treatment, centre (centre random, all other effects fixed).~Comparisons between groups are presented for Day 29." (NCT00696020)
Timeframe: 5 min (only for week 1 and 2), 30 min, 1 h, 2 h and 3 h after inhalation at baseline and after 1 week, 2 weeks and 4 weeks
| Intervention | L (Least Squares Mean) | |||
|---|---|---|---|---|
| Day 1 | Day 8 | Day 15 | Day 29 | |
| 5 µg Tiotropium | 0.428 | 0.437 | 0.465 | 0.431 |
| Tiotropium+Olodaterol 5/10 μg | 0.583 | 0.690 | 0.697 | 0.696 |
| Tiotropium+Olodaterol 5/2 μg | 0.476 | 0.560 | 0.586 | 0.562 |
| Tiotropium+Olodaterol 5/5 μg | 0.576 | 0.615 | 0.648 | 0.634 |
"PEF (peak expiratory flow rate L/min) AUC(6-12h) response is defined as change from the baseline value. AUC(6-12h) will be calculated as the area under the curve from 6 to 12 hours on the various test days using the trapezoidal rule, divided by the full duration (6 hours) to report in litres/min. Baseline was defined as the mean of the 2 pre-treatment values measured at Visit 2 (-1 h and -10 min) prior to administration of the first dose of study medication.~The means are adjusted, based on ANCOVA with terms for baseline, treatment, and centre (centre random, all other effects fixed).~Comparisons between groups are presented for Day 29." (NCT00696020)
Timeframe: 6 h, 9 h and 12 h after inhalation at baseline and after 1 week, 2 weeks and 4 weeks
| Intervention | L/min (Least Squares Mean) | |||
|---|---|---|---|---|
| Day 1 | Day 8 | Day 15 | Day 29 | |
| 5 µg Tiotropium | 29.261 | 30.139 | 27.512 | 28.396 |
| Tiotropium+Olodaterol 5/10 μg | 41.852 | 47.924 | 45.798 | 47.289 |
| Tiotropium+Olodaterol 5/2 μg | 41.838 | 47.625 | 42.179 | 41.502 |
| Tiotropium+Olodaterol 5/5 μg | 45.179 | 48.503 | 52.249 | 48.212 |
"PEF (peak expiratory flow rate L/min) AUC(0-3h) response is defined as change from the baseline value. AUC(0-3h) will be calculated as the area under the curve from 0 to 3 hours on the various test days using the trapezoidal rule, divided by the full duration (3 hours) to report in litres/min. Baseline was defined as the mean of the 2 pre-treatment values measured at Visit 2 (-1 h and -10 min) prior to administration of the first dose of study medication.~The means are adjusted, based on an ANCOVA with terms for baseline, treatment, centre (centre random, all other effects fixed).~Comparisons between groups are presented for Day 29." (NCT00696020)
Timeframe: 1 h and 10 min prior to inhalation and 5 min (only for week 1 and 2), 30 min, 1 h, 2 h and 3 h after inhalation at baseline and after 1, 2 and 4 weeks
| Intervention | L/min (Least Squares Mean) | |||
|---|---|---|---|---|
| Day 1 | Day 8 | Day 15 | Day 29 | |
| 5 µg Tiotropium | 21.973 | 29.701 | 32.108 | 29.734 |
| Tiotropium+Olodaterol 5/10 μg | 40.027 | 53.448 | 54.289 | 56.688 |
| Tiotropium+Olodaterol 5/2 μg | 35.738 | 52.816 | 54.527 | 52.091 |
| Tiotropium+Olodaterol 5/5 μg | 35.350 | 49.722 | 53.829 | 48.503 |
(NCT00706446)
Timeframe: 1 year
| Intervention | Participants (Count of Participants) |
|---|---|
| 1 - Tiotropium Plus ICS in the Arg/Arg Genotype | 3 |
| 2 - Tiotropium Plus ICS in the Arg/Gly Genotype | 15 |
| 3 - Tiotropium Plus ICS in the Gly/Gly Genotype | 6 |
| 4 - Salmeterol or Formoterol Plus ICS in the Arg/Arg Genotype | 6 |
| 5 - Salmeterol or Formoterol Plus ICS in the Arg/Gly Genotype | 12 |
| 6 - Salmeterol or Formoterol Plus ICS in the Gly/Gly Genotype | 9 |
"12-lead ECG QT intervals baseline and change from baseline at other time points in milliseconds.~Statistics for each planned time from baseline to day 29." (NCT00720499)
Timeframe: Baseline, then 10min, 1h after drug administration on day 1, 30min before and 10min after drug administration on day 15, in addition 1h after drug administration on day 29
| Intervention | mS (Mean) | |||||||
|---|---|---|---|---|---|---|---|---|
| Baseline | Day1 0:10 | Day1 1:00 (N=138, 138) | Day15 -0:30 (N=137, 137) | Day15 0:10 (N=135, 136) | Day29 -0:30 (N=134, 136) | Day29 0:10 (N=132, 135) | Day29 1:00 (N=132, 135) | |
| Olo 2 µg + Tio 5 µg | 382.73 | 1.59 | 2.97 | -0.09 | 1.44 | -0.59 | 2.27 | 3.14 |
| Olo 5 µg + Tio 5 µg | 381.33 | 2.69 | 2.33 | -1.76 | 0.53 | -3.14 | -1.73 | 0.2 |
"12-lead ECG QRS intervals baseline and change from baseline at other time points in milliseconds~Statistics for each planned time from baseline to day 29." (NCT00720499)
Timeframe: Baseline, then 10min, 1h after drug administration on day 1, 30min before and 10min after drug administration on day 15, in addition 1h after drug administration on day 29
| Intervention | mS (Mean) | |||||||
|---|---|---|---|---|---|---|---|---|
| Baseline | Day1 0:10 | Day1 1:00 | Day15 -0:30 (N=137, 137) | Day15 0:10 (N=135, 136) | Day29 -0:30 (N=134, 136) | Day29 0:10 (N=132, 135) | Day29 1:00 (N=132, 135) | |
| Olo 2 µg + Tio 5 µg | 92.71 | -0.28 | -0.47 | -0.55 | -0.67 | -0.44 | -1.27 | -0.33 |
| Olo 5 µg + Tio 5 µg | 92.41 | -0.65 | 0.31 | -0.44 | -0.32 | -0.75 | -0.82 | -0.39 |
"12-lead ECG PR intervals baseline and change from baseline at other timepoints in milliseconds.~Statistics for each planned time from baseline to day 29." (NCT00720499)
Timeframe: Baseline, then 10min, 1h after drug administration on day 1, 30min before and 10min after drug administration on day 15, in addition 1h after drug administration on day 29
| Intervention | mS (Mean) | |||||||
|---|---|---|---|---|---|---|---|---|
| Baseline | Day1 0:10 | Day1 1:00 (N=139, 137) | Day15 -0:30 (N=136, 137) | Day15 0:10 (N=135, 136) | Day29 -0:30 (N=134, 135) | Day29 0:10 (N=132, 135) | Day29 1:00 (N=132, 135) | |
| Olo 2 µg + Tio 5 µg | 160.03 | -1.02 | 2.12 | 0.55 | 0.28 | -1.29 | -0.29 | 1.98 |
| Olo 5 µg + Tio 5 µg | 160.69 | -1.86 | 0.09 | -0.95 | -1.24 | -0.19 | -2.05 | 0.22 |
"12-lead Electrocardiogram (ECG) Heart rate baseline and change from baseline values at other time points in Beats Per Minute (BPM)~Statistics for each planned time from baseline to day 29." (NCT00720499)
Timeframe: Baseline, then 10min, 1h after drug administration on day 1, 30min before and 10min after drug administration on day 15, in addition 1h after drug administration on day 29
| Intervention | BPM (Mean) | |||||||
|---|---|---|---|---|---|---|---|---|
| Baseline | Day1 0:10 | Day1 1:00 | Day15 -0:30 (N=137, 137) | Day15 0:10 (N=135, 136) | Day29 -0:30 (N=134, 136) | Day29 0:10 (N=132, 135) | Day29 1:00 (N=132, 135) | |
| Olo 2 µg + Tio 5 µg | 72.96 | -1.44 | -2.09 | 0.42 | -1.61 | -0.69 | -2.14 | -2.34 |
| Olo 5 µg + Tio 5 µg | 72.38 | -1.01 | -1.6 | 1.1 | -0.79 | 1.68 | -0.24 | -0.73 |
"Individual FVC measurements [L] at each time point~The categories correspond to the planned times for FVC measurements on Day 29.~The presented means are adjusted." (NCT00720499)
Timeframe: 1h, 10min before drug administration and 5min, 30min, 1h, 2h, 3h, 4h, 5h, 6h after drug administration on day 29
| Intervention | Litres (Mean) | |||||||||
|---|---|---|---|---|---|---|---|---|---|---|
| -1:00 | -0:10 | 0:05 | 0:30 | 1:00 | 2:00 | 3:00 | 4:00 | 5:00 | 6:00 | |
| Olo 2 µg + Tio 5 µg | 2.894 | 2.892 | 3.009 | 3.067 | 3.093 | 3.154 | 3.147 | 3.143 | 3.109 | 3.061 |
| Olo 5 µg + Tio5 µg | 2.899 | 2.907 | 3.032 | 3.083 | 3.112 | 3.189 | 3.201 | 3.204 | 3.131 | 3.083 |
"Trough FEV1 was defined as the mean of the 2 FEV1 values at the end of the dosing interval, 24 hours post-drug administration.~Response is defined as the change from baseline, baseline is defined as the mean of the 2 pre-treatment timepoints (-1 hour and -10 minutes) before first drug administration in each treatment period.~The presented means are adjusted based on an ANCOVA with terms for baseline, treatment, centre, patient within centre and period (all effects fixed)." (NCT00720499)
Timeframe: 1 hour (h), 10 minutes (min) before drug administration and 5min, 30min, 1h, 2h, 3h, 4h, 5h, 6h after drug administration on day 29
| Intervention | Litres (Mean) |
|---|---|
| Olo 2 µg + Tio 5 µg | 0.057 |
| Olo 5 µg + Tio5 µg | 0.055 |
"Response is defined as the change from baseline, baseline is defined as the mean of the 2 pre-treatment timepoints (-1 hour and -10 minutes) before first drug administration in each treatment period.~The presented means are adjusted based on an ANCOVA with terms for baseline, treatment, centre, patient within centre and period (all effects fixed)." (NCT00720499)
Timeframe: 1h, 10min before drug administration and 5min, 30min, 1h, 2h, 3h after drug administration on day 15
| Intervention | Litres (Mean) |
|---|---|
| Olo 2 µg + Tio 5 µg | 0.037 |
| Olo 5 µg + Tio5 µg | 0.059 |
"PEFR AUC (6-12h) response [L] on day 29.~Response is defined as the change from baseline, baseline is defined as the mean of the 2 pre-treatment timepoints (-1 hour and -10 minutes) before first drug administration in each treatment period.~The presented means are adjusted based on an ANCOVA with terms for baseline, treatment, centre, patient within centre and period (all effects fixed)." (NCT00720499)
Timeframe: 1 hour (h) and 10 minutes before drug administration on day 1 and 6h, 9h and 12h after drug administration on day 29
| Intervention | Litres / minute (Mean) |
|---|---|
| Olo 2 µg + Tio 5 µg | 24.830 |
| Olo 5 µg + Tio 5 µg | 24.130 |
"FVC peak 0-3h response [L] on day 29.~Response is defined as the change from baseline, baseline is defined as the mean of the 2 pre-treatment timepoints (-1 hour and -10 minutes) before first drug administration in each treatment period.~The presented means are adjusted based on an ANCOVA with terms for baseline, treatment, centre, patient within centre and period (all effects fixed)." (NCT00720499)
Timeframe: 1h, 10min before drug administration and 5min, 30min, 1h, 2h, 3h after drug administration on day 29
| Intervention | Litres (Mean) |
|---|---|
| Olo 2 µg + Tio 5 µg | 0.444 |
| Olo 5 µg + Tio5 µg | 0.490 |
"FVC AUC (0-6h) response [L] on day 29.~Response is defined as the change from baseline, baseline is defined as the mean of the 2 pre-treatment timepoints (-1 hour and -10 minutes) before first drug administration in each treatment period.~The presented means are adjusted based on an ANCOVA with terms for baseline, treatment, centre, patient within centre and period (all effects fixed)." (NCT00720499)
Timeframe: 1h, 10min before drug administration and 5min, 30min, 1h, 2h, 3h, 4h, 5h, 6h after drug administration on day 29
| Intervention | Litres (Mean) |
|---|---|
| Olo 2 µg + Tio 5 µg | 0.283 |
| Olo 5 µg + Tio5 µg | 0.318 |
"FEV1, AUC (0-6h) response [L] on day 29.~Response is defined as the change from baseline, baseline is defined as the mean of the 2 pre-treatment timepoints (-1 hour and -10 minutes) before first drug administration in each treatment period.~The presented means are adjusted based on an ANCOVA with terms for baseline, treatment, centre, patient within centre and period (all effects fixed)." (NCT00720499)
Timeframe: 1h, 10min before drug administration and 5min, 30min, 1h, 2h, 3h, 4h, 5h, 6h after drug administration on day 29
| Intervention | Litres (Mean) |
|---|---|
| Olo 2 µg + Tio 5 µg | 0.202 |
| Olo 5 µg + Tio5 µg | 0.206 |
"FEV1 (unsupervised) AUC (6-12h) response [L] on day 29.~Response is defined as the change from baseline, baseline is defined as the mean of the 2 pre-treatment timepoints (-1 hour and -10 minutes) before first drug administration in each treatment period.~The presented means are adjusted based on an ANCOVA with terms for baseline, treatment, centre, patient within centre and period (all effects fixed)." (NCT00720499)
Timeframe: 6 hours (h), 9h and 12h after drug administration on day 29
| Intervention | Litres (Mean) |
|---|---|
| Olo 2 µg + Tio 5 µg | 0.106 |
| Olo 5 µg + Tio5 µg | 0.114 |
"Weekly mean number of occasions of rescue therapy used per day (as occasion require (PRN) salbutamol [albuterol]) on weeks 1,2,3 and 4.~The means presented are the adjusted mean of weekly mean." (NCT00720499)
Timeframe: Weeks 1,2,3 and 4
| Intervention | number of occasions / day (Mean) | |||
|---|---|---|---|---|
| Week 1 | Week 2 | Week 3 | Week 4 | |
| Olo 2 µg + Tio 5 µg | 1.294 | 1.472 | 1.369 | 1.403 |
| Olo 5 µg + Tio 5 µg | 1.305 | 1.352 | 1.367 | 1.363 |
"Weekly mean morning PEFR [L/min] on weeks 1,2,3 and 4.~The presented means are adjusted." (NCT00720499)
Timeframe: Weeks 1,2,3 and 4
| Intervention | Litres / minute (Mean) | |||
|---|---|---|---|---|
| Week 1 | Week 2 | Week 3 | Week 4 | |
| Olo 2 µg + Tio 5 µg | 244.16 | 242.38 | 242.31 | 242.90 |
| Olo 5 µg + Tio 5 µg | 245.28 | 243.72 | 242.97 | 244.56 |
"Weekly mean evening PEFR [L/min] on weeks 1,2,3 and 4.~The presented means are adjusted." (NCT00720499)
Timeframe: Weeks 1,2,3 and 4
| Intervention | Litres / minute (Mean) | |||
|---|---|---|---|---|
| Week 1 | Week 2 | Week 3 | Week 4 | |
| Olo 2 µg + Tio 5 µg | 262.21 | 261.08 | 258.62 | 261.38 |
| Olo 5 µg + Tio 5 µg | 265.51 | 262.47 | 260.32 | 260.34 |
"Trough Forced Vital Capacity (FVC) response [L] on days 15 and 29.~Response is defined as the change from baseline, baseline is defined as the mean of the 2 pre-treatment timepoints (-1 hour and -10 minutes) before first drug administration in each treatment period.~The presented means are adjusted based on an ANCOVA with terms for baseline, treatment, centre, patient within centre and period (all effects fixed)." (NCT00720499)
Timeframe: 1h, 10min before drug administration and 5min, 30min, 1h, 2h, 3h after drug administration on day 15, in addition 4h, 5h, 6h after drug administration on day 29
| Intervention | Litres (Mean) | |
|---|---|---|
| Day 15 | Day 29 | |
| Olo 2 µg + Tio 5 µg | 0.072 | 0.066 |
| Olo 5 µg + Tio5 µg | 0.104 | 0.076 |
"Physician's global evaluation score on days 15 and 29~The score was evaluated on a 8-points scale :~Poor : 1,2~Fair : 3,4~Good : 5,6~Excellent : 7,8~The presented means are adjusted" (NCT00720499)
Timeframe: Days 15 and 29
| Intervention | units on a scale (Mean) | |
|---|---|---|
| Day 15 | Day 29 | |
| Olo 2 µg + Tio 5 µg | 5.084 | 5.085 |
| Olo 5 µg + Tio 5 µg | 5.079 | 5.065 |
"PEFR peak 0-3h response [L/min] on days 1, 15 and 29.~Response is defined as the change from baseline, baseline is defined as the mean of the 2 pre-treatment timepoints (-1 hour and -10 minutes) before first drug administration in each treatment period.~The presented means are adjusted based on an ANCOVA with terms for baseline, treatment, centre, patient within centre and period (all effects fixed)." (NCT00720499)
Timeframe: 1h, 10min before drug administration and 5min, 30min, 1h, 2h, 3h after drug administration on days 1, 15 and 29
| Intervention | Litres / minute (Mean) | ||
|---|---|---|---|
| Day 1 | Day 15 | Day 29 | |
| Olo 2 µg + Tio 5 µg | 49.125 | 46.355 | 52.497 |
| Olo 5 µg + Tio 5 µg | 48.946 | 52.835 | 55.596 |
"Peak Expiratory Flow Rate (PEFR) AUC (0-3h) response [L/min] on days 1, 15 and 29.~Response is defined as the change from baseline, baseline is defined as the mean of the 2 pre-treatment timepoints (-1 hour and -10 minutes) before first drug administration in each treatment period.~The presented means are adjusted based on an ANCOVA with terms for baseline, treatment, centre, patient within centre and period (all effects fixed)." (NCT00720499)
Timeframe: 1h, 10min before drug administration and 5min, 30min, 1h, 2h, 3h after drug administration on days 1, 15 and 29
| Intervention | Litres / minute (Mean) | ||
|---|---|---|---|
| Day 1 | Day 15 | Day 29 | |
| Olo 2 µg + Tio 5 µg | 27.159 | 27.817 | 32.395 |
| Olo 5 µg + Tio 5 µg | 28.143 | 34.128 | 33.947 |
Overall marked changes from baseline in systolic blood pressure, diastolic blood pressure and pulse rate. (NCT00720499)
Timeframe: Baseline to week 14
| Intervention | participants (Number) | |||||
|---|---|---|---|---|---|---|
| Systolic blood pressure increased | Systolic blood pressure decreased | Diastolic blood pressure increased | Diastolic blood pressure decreased | Pulse rate increased | Pulse rate decreased | |
| Olo 2 µg + Tio 5 µg | 16 | 10 | 19 | 13 | 10 | 19 |
| Olo 5 µg + Tio 5 µg | 23 | 11 | 15 | 17 | 13 | 10 |
"Patient global rating scores treatment comparison after 4 weeks~The score was evaluated on a 7-point scale :~1 : very much better~2 : much better~3 : a little better~4 : no change~5 : a little worse~6 : much worse~7 : very much worse~The presented means are adjusted." (NCT00720499)
Timeframe: 4 weeks
| Intervention | units on a scale (Mean) |
|---|---|
| Olo 2 µg + Tio 5 µg | 3.207 |
| Olo 5 µg + Tio 5 µg | 3.093 |
"Individual FEV1 measurements [L] at each time point on Day 29.~The presented means are adjusted." (NCT00720499)
Timeframe: 1h, 10min before drug administration and 5min, 30min, 1h, 2h, 3h, 4h, 5h, 6h after drug administration on day 29
| Intervention | Litres (Mean) | |||||||||
|---|---|---|---|---|---|---|---|---|---|---|
| -1:00 | -0:10 | 0:05 | 0:30 | 1:00 | 2:00 | 3:00 | 4:00 | 5:00 | 6:00 | |
| Olo 2 µg + Tio 5 µg | 1.426 | 1.434 | 1.497 | 1.541 | 1.570 | 1.617 | 1.601 | 1.582 | 1.571 | 1.547 |
| Olo 5 µg + Tio5 µg | 1.417 | 1.438 | 1.498 | 1.534 | 1.570 | 1.614 | 1.606 | 1.606 | 1.570 | 1.551 |
"FVC AUC (0-3h) response [L] on days 1, 15 and 29.~Response is defined as the change from baseline, baseline is defined as the mean of the 2 pre-treatment timepoints (-1 hour and -10 minutes) before first drug administration in each treatment period.~The presented means are adjusted based on an ANCOVA with terms for baseline, treatment, centre, patient within centre and period (all effects fixed)." (NCT00720499)
Timeframe: 1h, 10min before drug administration and 5min, 30min, 1h, 2h, 3h after drug administration on days 1, 15 and 29
| Intervention | Litres (Mean) | ||
|---|---|---|---|
| Day 1 | Day 15 | Day 29 | |
| Olo 2 µg + Tio 5 µg | 0.273 | 0.271 | 0.275 |
| Olo 5 µg + Tio5 µg | 0.275 | 0.308 | 0.303 |
"FEV1 peak value over the time from 0 to 3 hours (peak 0-3h) response [L] on days 1, 15 and 29.~Response is defined as the change from baseline, baseline is defined as the mean of the 2 pre-treatment timepoints (-1 hour and -10 minutes) before first drug administration in each treatment period.~The presented means are adjusted based on an ANCOVA with terms for baseline, treatment, centre, patient within centre and period (all effects fixed)." (NCT00720499)
Timeframe: 1h, 10min before drug administration and 5min, 30min, 1h, 2h, 3h after drug administration on days 1, 15 and 29
| Intervention | Litres (Mean) | ||
|---|---|---|---|
| Day 1 | Day 15 | Day 29 | |
| Olo 2 µg + Tio 5 µg | 0.269 | 0.257 | 0.288 |
| Olo 5 µg + Tio5 µg | 0.262 | 0.279 | 0.294 |
"FEV1 Area Under the Curve (AUC) 0-3h, response [L] on days 1, 15 and 29.~Response is defined as the change from baseline, baseline is defined as the mean of the 2 pre-treatment timepoints (-1 hour and -10 minutes) before first drug administration in each treatment period.~The presented means are adjusted based on an ANCOVA with terms for baseline, treatment, centre, patient within centre and period (all effects fixed)." (NCT00720499)
Timeframe: 1h, 10min before drug administration and 5min, 30min, 1h, 2h, 3h after drug administration on days 1, 15 and 29
| Intervention | Litres (Mean) | ||
|---|---|---|---|
| Day 1 | Day 15 | Day 29 | |
| Olo 2 µg + Tio 5 µg | 0.168 | 0.174 | 0.201 |
| Olo 5 µg + Tio5 µg | 0.173 | 0.194 | 0.200 |
Clinically significant abnormalities for blood chemistry, haematology, urinalysis and physical examination (NCT00720499)
Timeframe: 14 weeks
| Intervention | participants (Number) | ||
|---|---|---|---|
| Creatinine phosphokinase increased | Eosinophils increased | Urinalysis | |
| Olo 2 µg + Tio 5 µg | 8 | 3 | 0 |
| Olo 5 µg + Tio 5 µg | 7 | 3 | 0 |
"12-lead ECG corrected heart rate (QT) interval, using Fridericia method (QTcF), baseline and change from baseline at other time points in milliseconds.~Statistics for each planned time from baseline to day 29." (NCT00720499)
Timeframe: Baseline, then 10min, 1h after drug administration on day 1, 30min before and 10min after drug administration on day 15, in addition 1h after drug administration on day 29
| Intervention | mS (Mean) | |||||||
|---|---|---|---|---|---|---|---|---|
| Baseline | Day1 0:10 | Day1 1:00 (N=138, 138) | Day15 -0:30 (N=137, 137) | Day15 0:10 (N=135, 136) | Day29 -0:30 (N=134, 136) | Day29 0:10 (N=132, 135) | Day29 1:00 (N=132, 135) | |
| Olo 2 µg + Tio 5 µg | 405.63 | -0.89 | -0.69 | 0.55 | -1.16 | -1.35 | -1.22 | -0.56 |
| Olo 5 µg + Tio 5 µg | 403.53 | 0.97 | -0.61 | -0.03 | -1.02 | -0.24 | -2.08 | -1.05 |
"12-lead ECG heart rate corrected QT interval, using Bazett method (QTcB), baseline and change from baseline at other time points in milliseconds.~Statistics for each planned time from baseline to day 29." (NCT00720499)
Timeframe: Baseline, then 10min, 1h after drug administration on day 1, 30min before and 10min after drug administration on day 15, in addition 1h after drug administration on day 29
| Intervention | mS (Mean) | |||||||
|---|---|---|---|---|---|---|---|---|
| Baseline | Day1 0:10 | Day1 1:00 (N=138, 138) | Day15 -0:30 (N=137, 137) | Day15 0:10 (N=135, 136) | Day29 -0:30 (N=134, 136) | Day29 0:10 (N=132, 135) | Day29 1:00 (N=132, 135) | |
| Olo 2 µg + Tio 5 µg | 418.12 | -2.18 | -2.57 | 0.93 | -2.51 | -1.87 | -3.13 | -2.55 |
| Olo 5 µg + Tio 5 µg | 415.56 | 0.05 | -2.2 | 0.91 | -1.76 | 1.43 | -2.33 | -1.69 |
Outcome measure description: Change from baseline in percent predicted Forced Expiratory Volume in one second (FEV1) Area Under the Curve from 0 to 4 hours (AUC0-4). Calculated as percent predicted at week 12 minus percent predicted at baseline. (NCT00737100)
Timeframe: Baseline, Week 12
| Intervention | Percentage change (Least Squares Mean) |
|---|---|
| Placebo | -1.74 |
| Tiotropium Respimat 2.5 Micrograms | 1.20 |
| Tiotropium Respimat 5 Micrograms | 1.65 |
Cmax,ss represents the maximum measured concentration of tiotropium in plasma at steady state. (NCT00737100)
Timeframe: pre-dose, and 5 minutes (min), 20 min, 1 hour (h), and 2 h post-dose
| Intervention | pg/mL (Geometric Mean) |
|---|---|
| Tiotropium Respimat 2.5 Micrograms | 6.49 |
| Tiotropium Respimat 5 Micrograms | 9.95 |
Change from baseline in static lung hyperinflation as measured by RV/TLC. Calculated as percent predicted at week 12 minus percent predicted at baseline. (NCT00737100)
Timeframe: Baseline, Week 12
| Intervention | Percentage change (Least Squares Mean) |
|---|---|
| Placebo | -0.01 |
| Tiotropium Respimat 2.5 Micrograms | 0.00 |
| Tiotropium Respimat 5 Micrograms | 0.04 |
Ae0-4,ss represents the amount of tiotropium that is eliminated in urine from time 0 to 4 hours at steady state (NCT00737100)
Timeframe: pre-dose, and 5 minutes (min), 20 min, 1 hour (h), and 2 h post-dose
| Intervention | ng (Geometric Mean) |
|---|---|
| Tiotropium Respimat 2.5 Micrograms | 114 |
| Tiotropium Respimat 5 Micrograms | 245 |
The Cystic Fibrosis questionnaire (CFQ) is a disease-specific instrument that measures health-related quality of life (HRQOL) for adolescents with CF - parent questionnaire. This validation questionnaire consists of 50 items on generic and disease-specific scales. The scores range from 0 to 100, with higher scores indicating better health. (NCT00737100)
Timeframe: 12 weeks
| Intervention | units on a scale (Mean) | ||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|
| Physical (N=46, 45, 53) | Emotion (N=46, 45, 52) | Vitality (N=46, 44, 53) | School (N=46, 45, 52) | Eat (N=46, 43, 49) | Body (N=46, 45, 52) | Treat (N=46, 45, 52) | Health (N=46, 45, 52) | Respirat (N=45, 43, 50) | Digest (N=46, 43, 50) | Weight (N=45, 45, 49) | |
| Placebo | -0.1 | -0.3 | -0.1 | -4.8 | -2.2 | -3.9 | -2.4 | -2.7 | -2.8 | -0.7 | -5.2 |
| Tiotropium Respimat 2.5 Micrograms | 4.9 | 0.0 | 3.3 | 2.2 | -0.8 | -1.7 | 2.5 | 3.5 | -2.2 | -1.8 | 1.5 |
| Tiotropium Respimat 5 Micrograms | 0.2 | -0.1 | -1.5 | 0.4 | 3.4 | -3.2 | -0.2 | -3.0 | -6.0 | 1.1 | 4.1 |
The Cystic Fibrosis questionnaire (CFQ) is a disease-specific instrument that measures health-related quality of life (HRQOL) for adults with CF. This validation questionnaire consists of 50 items on generic and disease-specific scales. The scores range from 0 to 100, with higher scores indicating better health. (NCT00737100)
Timeframe: 12 weeks
| Intervention | units on a scale (Mean) | |||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Physical (N=99, 102, 105) | Role (N=94, 100, 103) | Vitality (N=99, 101, 105) | Emotion (N=99, 101, 105) | Social (N=99, 101, 106) | Body (N=99,101, 106) | Eat (N=99,101,106) | Treat (N=99, 101, 106) | Health (N=99, 101, 106) | Weight (N=95, 101, 103) | Respirat (N=93, 101, 103) | Digest (N=93, 101, 103) | |
| Placebo | -2.5 | 0.7 | -2.3 | -1.1 | -1.1 | 0.4 | 1.5 | 0.9 | -1.9 | 1.4 | -1.3 | 0.8 |
| Tiotropium Respimat 2.5 Micrograms | -0.0 | -2.7 | -1.8 | -1.3 | -1.0 | -0.9 | 0.2 | -1.4 | -3.2 | -3.3 | -3.7 | -1.3 |
| Tiotropium Respimat 5 Micrograms | -2.9 | -2.1 | -3.3 | 0.1 | -0.8 | 1.7 | 0.0 | -1.7 | -0.6 | -0.0 | -1.8 | 0.3 |
The Cystic Fibrosis questionnaire (CFQ) is a disease-specific instrument that measures health-related quality of life (HRQOL) for adolescents (age 6-13) with CF. This validation questionnaire consists of 50 items on generic and disease-specific scales. The scores range from 0 to 100, with higher scores indicating better health. (NCT00737100)
Timeframe: 12 weeks
| Intervention | units on a scale (Mean) | |||||||
|---|---|---|---|---|---|---|---|---|
| Physical (N=46, 42, 54) | Body (N=46, 42, 55) | School (N=46, 42, 55) | Eat (N=46, 42, 55) | Treat (N=46, 42, 55) | Respirat (N=46, 42, 55) | Digest (N=46, 42, 55) | ||
| Placebo | 1.1 | 1.1 | 2.8 | 1.2 | -1.4 | 0.2 | -1.4 | -5.1 |
| Tiotropium Respimat 2.5 Micrograms | 3.2 | -1.6 | -0.3 | 4.2 | -2.4 | -1.9 | 1.2 | 2.4 |
| Tiotropium Respimat 5 Micrograms | -1.9 | -1.1 | -0.1 | 2.4 | 1.6 | 5.7 | -3.0 | -3.0 |
Forced Expiratory Flow at 25-75% of vital capacity (FEF25-75). Calculated as percent predicted at week 12 minus percent predicted at baseline. (NCT00737100)
Timeframe: Baseline, Week 12
| Intervention | Percentage change (Least Squares Mean) |
|---|---|
| Placebo | -1.40 |
| Tiotropium Respimat 2.5 Micrograms | 2.78 |
| Tiotropium Respimat 5 Micrograms | 3.94 |
Change from baseline in percent predicted trough Forced Vital Capacity (FVC). Calculated as percent predicted at week 12 minus percent predicted at baseline. (NCT00737100)
Timeframe: Baseline, Week 12
| Intervention | Percentage change (Least Squares Mean) |
|---|---|
| Placebo | -0.39 |
| Tiotropium Respimat 2.5 Micrograms | 0.47 |
| Tiotropium Respimat 5 Micrograms | 0.81 |
Outcome measure description: The RSSQ questionnaire is used to determine the presence or absence of an exacerbation during the recall period. (NCT00737100)
Timeframe: 12 weeks
| Intervention | Participants (Number) | |
|---|---|---|
| At least one pulmonary exacerbation | No pulmonary exacerbation | |
| Placebo | 16 | 151 |
| Tiotropium Respimat 2.5 Micrograms | 13 | 153 |
| Tiotropium Respimat 5 Micrograms | 12 | 163 |
Change from baseline in percent predicted Forced Vital Capacity (FVC) Area Under the Curve from 0 to 4 hours (AUC0-4). Calculated as percent predicted at week 12 minus percent predicted at baseline. (NCT00737100)
Timeframe: Baseline, Week 12
| Intervention | Percentage change (Least Squares Mean) |
|---|---|
| Placebo | -1.30 |
| Tiotropium Respimat 2.5 Micrograms | 0.53 |
| Tiotropium Respimat 5 Micrograms | 1.81 |
Outcome measure description: Change from baseline in percent predicted trough Forced Expiratory Volume in one second. Calculated as percent predicted at week 12 minus percent predicted at baseline. (NCT00737100)
Timeframe: Baseline, Week 12
| Intervention | Percentage change (Least Squares Mean) |
|---|---|
| Placebo | -1.44 |
| Tiotropium Respimat 2.5 Micrograms | 0.81 |
| Tiotropium Respimat 5 Micrograms | 0.78 |
Clinical Relevant Abnormalities for Vital Signs and Laboratory evaluation. Any new or clinically relevant worsening of baseline conditions was reported as Adverse Event. (NCT00737100)
Timeframe: From first drug administration until 30 days after last drug administration (up to 121 days)
| Intervention | participants (Number) | ||||||||
|---|---|---|---|---|---|---|---|---|---|
| Blood chloride decreased | Blood glucose increased | Blood pressure increased | Blood sodium decreased | Eosinophil count increased | Hepatic enzyme increased | Oxygen saturation decreased | Vitamin K decreased | White blood cell count increased | |
| Placebo | 0 | 1 | 2 | 0 | 0 | 2 | 0 | 1 | 0 |
| Tiotropium Respimat 2.5 Micrograms | 0 | 1 | 1 | 0 | 1 | 0 | 0 | 0 | 1 |
| Tiotropium Respimat 5 Micrograms | 1 | 0 | 0 | 1 | 0 | 0 | 1 | 0 | 0 |
Tmax,ss represents the time from dosing to the maximum concentration of tiotropium in plasma (NCT00737100)
Timeframe: pre-dose, and 5 minutes (min), 20 min, 1 hour (h), and 2 h post-dose
| Intervention | h (Median) |
|---|---|
| Tiotropium Respimat 2.5 Micrograms | 0.0830 |
| Tiotropium Respimat 5 Micrograms | 0.0830 |
The AQLQ(S) total score was calculated as the mean of the responses to 32 questions for the domains Symptoms, Activity Limitations, Emotional Function and Environmental Stimuli and was analysed as an absolute value. The AQLQ(S) total score ranges from 1 (worst controlled) to 7 (best). MMRM results. Means are adjusted for treatment, centre, visit, baseline, treatment*visit and baseline*visit. (NCT00772538)
Timeframe: 48 weeks
| Intervention | Scores on a scale (Mean) |
|---|---|
| Placebo | 5.109 |
| Tio R5 | 5.147 |
For the ACQ, the total score was calculated as the mean of the responses to 7 questions and was analysed as an absolute value. The score ranges from 0 (no impairment) to 6 (maximum impairment). MMRM results. Means are adjusted for treatment, centre, visit, baseline, treatment*visit and baseline*visit. (NCT00772538)
Timeframe: 24 weeks
| Intervention | Scores on a scale (Mean) |
|---|---|
| Placebo | 2.120 |
| Tio R5 | 1.995 |
Weekly means obtained during the last 7 days before week 24 visit were compared (measured by patients at home using the asthma monitor device). The response is defined as the change of the weekly mean from the baseline weekly mean. MMRM results. Means are adjusted for treatment, centre, visit, baseline, treatment*visit and baseline*visit. (NCT00772538)
Timeframe: Baseline and last 7 days before week 24 visit
| Intervention | Days (Mean) |
|---|---|
| Placebo | 0.105 |
| Tio R5 | 0.105 |
The AUC0-3h was calculated as area under the curve from zero to 3 hours using the trapezoidal rule divided by the observation time (3 hours) to report in litres. The trough value was assigned to zero time. Response was defined as change from baseline in FEV1 AUC0-3h after a treatment period of 24 weeks. MMRM results. Means are adjusted for treatment, centre, visit, baseline, treatment*visit baseline*visit. (NCT00772538)
Timeframe: Baseline and 24 weeks
| Intervention | Liter (Mean) |
|---|---|
| Placebo | 0.229 |
| Tio R5 | 0.315 |
The AUC0-3h was calculated as area under the curve from zero to 3 hours using the trapezoidal rule divided by the observation time (3 hours) to report in litres. The trough value was assigned to zero time. Response was defined as change from baseline in FVC AUC0-3h after a treatment period of 24 weeks. MMRM results. Means are adjusted for treatment, centre, visit, baseline, treatment*visit baseline*visit. (NCT00772538)
Timeframe: Baseline and 24 weeks
| Intervention | Liter (Mean) |
|---|---|
| Placebo | 0.230 |
| Tio R5 | 0.328 |
The AUC0-3h was calculated as area under the curve from zero to 3 hours using the trapezoidal rule divided by the observation time (3 hours) to report in litres. The trough value was assigned to zero time. Response was defined as change from baseline in FVC AUC0-3h after a treatment period of 48 weeks. MMRM results. Means are adjusted for treatment, centre, visit, baseline, treatment*visit baseline*visit. (NCT00772538)
Timeframe: Baseline and 48 weeks
| Intervention | Liter (Mean) |
|---|---|
| Placebo | 0.223 |
| Tio R5 | 0.344 |
Weekly means obtained during the last 7 days before week 24 visit were compared (measured by patients at home using the asthma monitor device). The PEF variability is the absolute difference between morning and evening PEF value divided by their mean, expressed as a percent. Response was defined as change from baseline. MMRM results. Means are adjusted for treatment, centre, visit, baseline, treatment*visit and baseline*visit. (NCT00772538)
Timeframe: Baseline and last 7 days before week 24 visit
| Intervention | Percent (Mean) |
|---|---|
| Placebo | -0.997 |
| Tio R5 | -0.714 |
Weekly means obtained during the last 7 days before week 24 visit were compared (measured by patients at home using the asthma monitor device). Response was defined as change from baseline. MMRM results. Means are adjusted for treatment, centre, visit, baseline, treatment*visit and baseline*visit. (NCT00772538)
Timeframe: Baseline and last 7 days before week 24 visit
| Intervention | L/min (Mean) |
|---|---|
| Placebo | -3.865 |
| Tio R5 | 19.402 |
Weekly means obtained during the last 7 days before week 24 visit were compared (measured by patients at home using the asthma monitor device). Response was defined as change from baseline. MMRM results. Means are adjusted for treatment, centre, visit, baseline, treatment*visit and baseline*visit. (NCT00772538)
Timeframe: Baseline and last 7 days before week 24 visit
| Intervention | Liter (Mean) |
|---|---|
| Placebo | -0.055 |
| Tio R5 | 0.062 |
Weekly means obtained during the last 7 days before week 24 visit were compared (measured by patients at home using the asthma monitor device). Response was defined as change from baseline. MMRM results. Means are adjusted for treatment, centre, visit, baseline, treatment*visit and baseline*visit. (NCT00772538)
Timeframe: Baseline and last 7 days before week 24 visit
| Intervention | Liter (Mean) |
|---|---|
| Placebo | -0.050 |
| Tio R5 | 0.075 |
Weekly means obtained during the last 7 days before week 24 visit were compared (measured by patients at home using the asthma monitor device). Response was defined as change from baseline. MMRM results. Means are adjusted for treatment, centre, visit, baseline, treatment*visit and baseline*visit. (NCT00772538)
Timeframe: Baseline and last 7 days before week 24 visit
| Intervention | L/min (Mean) |
|---|---|
| Placebo | -6.996 |
| Tio R5 | 15.297 |
Weekly means obtained during the last 7 days before week 24 visit were compared. The response is defined as the change of the weekly mean from the baseline weekly mean. The use of PRN salbutamol (albuterol rescue medication) is determined by the number of puffs of rescue therapy used per day. MMRM results. Means are adjusted for treatment, centre, visit, baseline, treatment*visit and baseline*visit. (NCT00772538)
Timeframe: Baseline and last 7 days before week 24 visit
| Intervention | Puffs (Mean) |
|---|---|
| Placebo | -0.714 |
| Tio R5 | -0.806 |
Asthma exacerbations (including severe, non-severe; symptomatic, asymptomatic) were pre-defined as an episode of progressive increase in 1 or more asthma symptoms (e.g. shortness of breath, cough, wheezing, chest tightness or some combination of these symptoms). Additionally, decrease of patients best PEF a.m. of 30 percent or more from the patients mean PEF a.m. for at least 2 consecutive days was considered to be an objective marker of asthma exacerbation. (NCT00772538)
Timeframe: 48 weeks
| Intervention | Participants (Number) |
|---|---|
| Placebo | 137 |
| Tio R5 | 116 |
(NCT00772538)
Timeframe: 48 weeks
| Intervention | Participants (Number) |
|---|---|
| Placebo | 10 |
| Tio R5 | 8 |
Severe asthma exacerbations were pre-defined as all asthma exacerbations that required treatment with systemic (including oral) corticosteroids for at least 3 days or (in case of ongoing and pre-existing systemic corticosteroid therapy) that required at least a doubling of the previous daily dose of systemic corticosteroids for at least 3 days. (NCT00772538)
Timeframe: 48 weeks
| Intervention | Participants (Number) |
|---|---|
| Placebo | 68 |
| Tio R5 | 53 |
Peak FVC 0-3h response was defined as the difference between the maximum FVC measured within the first 3 hours post dosing after a treatment period of 24 weeks and the FVC baseline measurement (10 minutes before the first dose of trial medication). Mixed Model Repeated Measure (MMRM) results. Means are adjusted for treatment, centre, visit, baseline, treatment*visit and baseline*visit. (NCT00772538)
Timeframe: Baseline and 24 weeks
| Intervention | Liter (Mean) |
|---|---|
| Placebo | 0.355 |
| Tio R5 | 0.445 |
Peak FEV1 0-3h response was defined as the difference between the maximum FEV1 measured within the first 3 hours post dosing after a treatment period of 48 weeks and the FEV1 baseline measurement (10 minutes before the first dose of trial medication). Mixed Model Repeated Measure (MMRM) results. Means are adjusted for treatment, centre, visit, baseline, treatment*visit and baseline*visit. (NCT00772538)
Timeframe: Baseline and 48 weeks
| Intervention | Liter (Mean) |
|---|---|
| Placebo | 0.295 |
| Tio R5 | 0.367 |
Peak FEV1 0-3h response was defined as the difference between the maximum FEV1 measured within the first 3 hours post dosing after a treatment period of 24 weeks and the FEV1 baseline measurement (10 minutes before the first dose of trial medication). Mixed Model Repeated Measure (MMRM) results. Means are adjusted for treatment, centre, visit, baseline, treatment*visit and baseline*visit. (NCT00772538)
Timeframe: Baseline and 24 weeks
| Intervention | Liter (Mean) |
|---|---|
| Placebo | 0.315 |
| Tio R5 | 0.401 |
Peak FVC 0-3h response was defined as the difference between the maximum FVC measured within the first 3 hours post dosing after a treatment period of 48 weeks and the FVC baseline measurement (10 minutes before the first dose of trial medication). MMRM results. Means are adjusted for treatment, centre, visit, baseline, treatment*visit and baseline*visit. (NCT00772538)
Timeframe: Baseline and 48 weeks
| Intervention | Liter (Mean) |
|---|---|
| Placebo | 0.337 |
| Tio R5 | 0.462 |
The AQLQ(S) total score was calculated as the mean of the responses to 32 questions for the domains Symptoms, Activity Limitations, Emotional Function and Environmental Stimuli and was analysed as an absolute value. The AQLQ(S) total score ranges from 1 (worst controlled) to 7 (best). MMRM results. Means are adjusted for treatment, centre, visit, baseline, treatment*visit and baseline*visit. (NCT00772538)
Timeframe: 24 weeks
| Intervention | Scores on a scale (Mean) |
|---|---|
| Placebo | 5.084 |
| Tio R5 | 5.125 |
Severe asthma exacerbations were pre-defined as all asthma exacerbations that required treatment with systemic (including oral) corticosteroids for at least 3 days or (in case of ongoing and pre-existing systemic corticosteroid therapy) that required at least a doubling of the previous daily dose of systemic corticosteroids for at least 3 days. (NCT00772538)
Timeframe: 48 weeks
| Intervention | Days (Median) |
|---|---|
| Placebo | NA |
| Tio R5 | NA |
The trough FEV1 is defined as the pre-dose FEV1 measured 10 minutes before the last administration of randomised treatment. Trough FEV1 response was defined as the difference between the trough FEV1 measured after a treatment period of 48 weeks and the FEV1 baseline measurement. MMRM results. Means are adjusted for treatment, centre, visit, baseline, treatment*visit and baseline*visit. (NCT00772538)
Timeframe: Baseline and 48 weeks
| Intervention | Liter (Mean) |
|---|---|
| Placebo | 0.087 |
| Tio R5 | 0.129 |
The trough FEV1 is defined as the pre-dose FEV1 measured 10 minutes before the last administration of randomised treatment. Trough FEV1 response was defined as the difference between the trough FEV1 measured after a treatment period of 24 weeks and the FEV1 baseline measurement. MMRM results. Means are adjusted for treatment, centre, visit, baseline, treatment*visit and baseline*visit. (NCT00772538)
Timeframe: Baseline and 24 weeks
| Intervention | Liter (Mean) |
|---|---|
| Placebo | 0.056 |
| Tio R5 | 0.144 |
The trough FVC is defined as the pre-dose FVC measured 10 minutes before the last administration of randomised treatment. Trough FVC response was defined as the difference between the trough FVC measured after a treatment period of 24 weeks and the FVC baseline measurement. MMRM results. Means are adjusted for treatment, centre, visit, baseline, treatment*visit and baseline*visit. (NCT00772538)
Timeframe: Baseline and 24 weeks
| Intervention | Liter (Mean) |
|---|---|
| Placebo | 0.022 |
| Tio R5 | 0.157 |
The trough FVC is defined as the pre-dose FVC measured 10 minutes before the last administration of randomised treatment. Trough FVC response was defined as the difference between the trough FVC measured after a treatment period of 48 weeks and the FVC baseline measurement. MMRM results. Means are adjusted for treatment, centre, visit, baseline, treatment*visit and baseline*visit. (NCT00772538)
Timeframe: Baseline and 48 weeks
| Intervention | Liter (Mean) |
|---|---|
| Placebo | 0.062 |
| Tio R5 | 0.173 |
Asthma exacerbations (including severe, non-severe; symptomatic, asymptomatic) were pre-defined as an episode of progressive increase in 1 or more asthma symptoms (e.g. shortness of breath, cough, wheezing, chest tightness or some combination of these symptoms). Additionally, decrease of patients best PEF a.m. of 30 percent or more from the patients mean PEF a.m. for at least 2 consecutive days was considered to be an objective marker of asthma exacerbation. (NCT00772538)
Timeframe: 48 weeks
| Intervention | Participants (Number) | |||||||||
|---|---|---|---|---|---|---|---|---|---|---|
| 0 exacerbations | 1 exacerbation | 2 exacerbations | 3 exacerbations | 4 exacerbations | 5 exacerbations | 6 exacerbations | 7-10 exacerbations | 11-20 exacerbations | 21+ exacerbations | |
| Placebo | 85 | 47 | 21 | 18 | 8 | 12 | 12 | 13 | 4 | 2 |
| Tio R5 | 121 | 49 | 23 | 13 | 6 | 4 | 2 | 14 | 5 | 0 |
(NCT00772538)
Timeframe: 48 weeks
| Intervention | Participants (Number) | ||
|---|---|---|---|
| 0 hospitalisations | 1 hospitalisations | 2+ hospitalisations | |
| Placebo | 212 | 9 | 1 |
| Tio R5 | 229 | 6 | 2 |
Severe asthma exacerbations were pre-defined as all asthma exacerbations that required treatment with systemic (including oral) corticosteroids for at least 3 days or (in case of ongoing and pre-existing systemic corticosteroid therapy) that required at least a doubling of the previous daily dose of systemic corticosteroids for at least 3 days. (NCT00772538)
Timeframe: 48 weeks
| Intervention | Participants (Number) | |||||||
|---|---|---|---|---|---|---|---|---|
| 0 exacerbations | 1 exacerbation | 2 exacerbations | 3 exacerbations | 4 exacerbations | 5 exacerbations | 6 exacerbations | 7-10 exacerbations | |
| Placebo | 154 | 39 | 15 | 5 | 6 | 2 | 1 | 0 |
| Tio R5 | 184 | 37 | 10 | 3 | 0 | 2 | 0 | 1 |
"The responder rate as assessed by the Asthma Control Questionnaire (ACQ) determined at 24-weeks and 48-weeks (on combined data from the two twin trials 205.416 (NCT00772538) and 205.417 (NCT00776984)). A patient was considered to be a responder if he or she was reported with an improvement (decrease) in the ACQ total score of at least 0.5 points.~The ACQ total score was calculated as the mean of the responses to 7 questions and was analysed as an absolute value. The score ranges from 0 (no impairment) to 6 (maximum impairment).~This outcome definition is taken from the primary outcome definition for the twin trials 205.418 (NCT01172808) and 205.419 (NCT01172821) of the same development program." (NCT00772538)
Timeframe: 24 weeks, 48 weeks
| Intervention | percentage of participants (Number) | |
|---|---|---|
| 24 weeks | 48 weeks | |
| Placebo | 46.9 | 45.2 |
| Tio R5 | 53.9 | 58.1 |
The AUC0-3h was calculated as area under the curve from zero to 3 hours using the trapezoidal rule divided by the observation time (3 hours) to report in litres. The trough value was assigned to zero time. Response was defined as change from baseline in FEV1 AUC0-3h after a treatment period of 48 weeks. MMRM results. Means are adjusted for treatment, centre, visit, baseline, treatment*visit baseline*visit. (NCT00772538)
Timeframe: Baseline and 48 weeks
| Intervention | Liter (Mean) |
|---|---|
| Placebo | 0.217 |
| Tio R5 | 0.289 |
For the ACQ, the total score was calculated as the mean of the responses to 7 questions and was analysed as an absolute value. The score ranges from 0 (no impairment) to 6 (maximum impairment). MMRM results. Means are adjusted for treatment, centre, visit, baseline, treatment*visit and baseline*visit. (NCT00772538)
Timeframe: 48 weeks
| Intervention | Scores on a scale (Mean) |
|---|---|
| Placebo | 2.107 |
| Tio R5 | 1.986 |
The trough FEV1 is defined as the pre-dose FEV1 measured 10 minutes before the last administration of randomised treatment. Trough FEV1 response was defined as the difference between the trough FEV1 measured after a treatment period of 24 weeks and the FEV1 baseline measurement. MMRM results. Means are adjusted for treatment, centre, visit, baseline, treatment*visit and baseline*visit. (NCT00776984)
Timeframe: Baseline and 24 weeks
| Intervention | Liter (Mean) |
|---|---|
| Placebo | 0.044 |
| Tio R5 | 0.155 |
For the ACQ, the total score was calculated as the mean of the responses to 7 questions and was analysed as an absolute value. The score ranges from 0 (no impairment) to 6 (maximum impairment). MMRM results. Means are adjusted for treatment, centre, visit, baseline, treatment*visit and baseline*visit. (NCT00776984)
Timeframe: 24 weeks
| Intervention | Score on a scale (Mean) |
|---|---|
| Placebo | 2.210 |
| Tio R5 | 2.011 |
Weekly means obtained during the last 7 days before week 24 visit were compared (measured by patients at home using the asthma monitor device). The response is defined as the change of the weekly mean from the baseline weekly mean. MMRM results. Means are adjusted for treatment, centre, visit, baseline, treatment*visit and baseline*visit. (NCT00776984)
Timeframe: Baseline and last 7 days before week 24 visit
| Intervention | Days (Mean) |
|---|---|
| Placebo | 0.065 |
| Tio R5 | 0.077 |
The AUC0-3h was calculated as area under the curve from zero to 3 hours using the trapezoidal rule divided by the observation time (3 hours) to report in litres. The trough value was assigned to zero time. Response was defined as change from baseline in FEV1 AUC0-3h after a treatment period of 48 weeks. MMRM results. Means are adjusted for treatment, centre, visit, baseline, treatment*visit baseline*visit. (NCT00776984)
Timeframe: Baseline and 48 weeks
| Intervention | Liter (Mean) |
|---|---|
| Placebo | 0.172 |
| Tio R5 | 0.310 |
Severe asthma exacerbations were pre-defined as all asthma exacerbations that required treatment with systemic (including oral) corticosteroids for at least 3 days or (in case of ongoing and pre-existing systemic corticosteroid therapy) that required at least a doubling of the previous daily dose of systemic corticosteroids for at least 3 days. (NCT00776984)
Timeframe: 48 weeks
| Intervention | Participants (Number) |
|---|---|
| Placebo | 81 |
| Tio R5 | 69 |
Peak FVC 0-3h response was defined as the difference between the maximum FVC measured within the first 3 hours post dosing after a treatment period of 24 weeks and the FVC baseline measurement (10 minutes before the first dose of trial medication). Mixed Model Repeated Measure (MMRM) results. Means are adjusted for treatment, centre, visit, baseline, treatment*visit and baseline*visit. (NCT00776984)
Timeframe: Baseline and 24 weeks
| Intervention | Liter (Mean) |
|---|---|
| Placebo | 0.323 |
| Tio R5 | 0.416 |
(NCT00776984)
Timeframe: 48 weeks
| Intervention | Participants (Number) |
|---|---|
| Placebo | 10 |
| Tio R5 | 8 |
Asthma exacerbations (including severe, non-severe; symptomatic, asymptomatic) were pre-defined as an episode of progressive increase in 1 or more asthma symptoms (e.g. shortness of breath, cough, wheezing, chest tightness or some combination of these symptoms). Additionally, decrease of patients best PEF a.m. of 30 percent or more from the patients mean PEF a.m. for at least 2 consecutive days was considered to be an objective marker of asthma exacerbation. (NCT00776984)
Timeframe: 48 weeks
| Intervention | Participants (Number) |
|---|---|
| Placebo | 150 |
| Tio R5 | 110 |
Weekly means obtained during the last 7 days before week 24 visit were compared (measured by patients at home using the asthma monitor device). Response was defined as change from baseline. MMRM results. Means are adjusted for treatment, centre, visit, baseline, treatment*visit and baseline*visit. (NCT00776984)
Timeframe: Baseline and last 7 days before week 24 visit
| Intervention | L/min (Mean) |
|---|---|
| Placebo | -3.258 |
| Tio R5 | 17.396 |
The AUC0-3h was calculated as area under the curve from zero to 3 hours using the trapezoidal rule divided by the observation time (3 hours) to report in litres. The trough value was assigned to zero time. Response was defined as change from baseline in FEV1 AUC0-3h after a treatment period of 24 weeks. MMRM results. Means are adjusted for treatment, centre, visit, baseline, treatment*visit baseline*visit. (NCT00776984)
Timeframe: Baseline and 24 weeks
| Intervention | Liter (Mean) |
|---|---|
| Placebo | 0.164 |
| Tio R5 | 0.307 |
Weekly means obtained during the last 7 days before week 24 visit were compared (measured by patients at home using the asthma monitor device). Response was defined as change from baseline. MMRM results. Means are adjusted for treatment, centre, visit, baseline, treatment*visit and baseline*visit. (NCT00776984)
Timeframe: Baseline and last 7 days before week 24 visit
| Intervention | Liter (Mean) |
|---|---|
| Placebo | -0.015 |
| Tio R5 | 0.122 |
Peak FEV1 0-3h response was defined as the difference between the maximum FEV1 measured within the first 3 hours post dosing after a treatment period of 48 weeks and the FEV1 baseline measurement (10 minutes before the first dose of trial medication). Mixed Model Repeated Measure (MMRM) results. Means are adjusted for treatment, centre, visit, baseline, treatment*visit and baseline*visit. (NCT00776984)
Timeframe: Baseline and 48 weeks
| Intervention | Liter (Mean) |
|---|---|
| Placebo | 0.245 |
| Tio R5 | 0.397 |
Peak FEV1 0-3h response was defined as the difference between the maximum FEV1 measured within the first 3 hours post dosing after a treatment period of 24 weeks and the FEV1 baseline measurement (10 minutes before the first dose of trial medication). Mixed Model Repeated Measure (MMRM) results. Means are adjusted for treatment, centre, visit, baseline, treatment*visit and baseline*visit. (NCT00776984)
Timeframe: Baseline and 24 weeks
| Intervention | Liter (Mean) |
|---|---|
| Placebo | 0.248 |
| Tio R5 | 0.401 |
Weekly means obtained during the last 7 days before week 24 visit were compared (measured by patients at home using the asthma monitor device). Response was defined as change from baseline. MMRM results. Means are adjusted for treatment, centre, visit, baseline, treatment*visit and baseline*visit. (NCT00776984)
Timeframe: Baseline and last 7 days before week 24 visit
| Intervention | L/min (Mean) |
|---|---|
| Placebo | -7.295 |
| Tio R5 | 25.158 |
Weekly means obtained during the last 7 days before week 24 visit were compared (measured by patients at home using the asthma monitor device). The PEF variability is the absolute difference between morning and evening PEF value divided by their mean, expressed as a percent. Response was defined as change from baseline. MMRM results. Means are adjusted for treatment, centre, visit, baseline, treatment*visit and baseline*visit. (NCT00776984)
Timeframe: Baseline and last 7 days before week 24 visit
| Intervention | Percent (Mean) |
|---|---|
| Placebo | -1.808 |
| Tio R5 | -0.611 |
The AUC0-3h was calculated as area under the curve from zero to 3 hours using the trapezoidal rule divided by the observation time (3 hours) to report in litres. The trough value was assigned to zero time. Response was defined as change from baseline in FVC AUC0-3h after a treatment period of 48 weeks. MMRM results. Means are adjusted for treatment, centre, visit, baseline, treatment*visit baseline*visit. (NCT00776984)
Timeframe: Baseline and 48 weeks
| Intervention | Liter (Mean) |
|---|---|
| Placebo | 0.190 |
| Tio R5 | 0.299 |
Peak FVC 0-3h response was defined as the difference between the maximum FVC measured within the first 3 hours post dosing after a treatment period of 48 weeks and the FVC baseline measurement (10 minutes before the first dose of trial medication). MMRM results. Means are adjusted for treatment, centre, visit, baseline, treatment*visit and baseline*visit. (NCT00776984)
Timeframe: Baseline and 48 weeks
| Intervention | Liter (Mean) |
|---|---|
| Placebo | 0.305 |
| Tio R5 | 0.420 |
Severe asthma exacerbations were pre-defined as all asthma exacerbations that required treatment with systemic (including oral) corticosteroids for at least 3 days or (in case of ongoing and pre-existing systemic corticosteroid therapy) that required at least a doubling of the previous daily dose of systemic corticosteroids for at least 3 days. (NCT00776984)
Timeframe: 48 weeks
| Intervention | Days (Median) |
|---|---|
| Placebo | NA |
| Tio R5 | NA |
The AQLQ(S) total score was calculated as the mean of the responses to 32 questions for the domains Symptoms, Activity Limitations, Emotional Function and Environmental Stimuli and was analysed as an absolute value. The AQLQ(S) total score ranges from 1 (worst controlled) to 7 (best). MMRM results. Means are adjusted for treatment, centre, visit, baseline, treatment*visit and baseline*visit. (NCT00776984)
Timeframe: 24 weeks
| Intervention | Scores on a scale (Mean) |
|---|---|
| Placebo | 4.869 |
| Tio R5 | 5.047 |
The trough FEV1 is defined as the pre-dose FEV1 measured 10 minutes before the last administration of randomised treatment. Trough FEV1 response was defined as the difference between the trough FEV1 measured after a treatment period of 48 weeks and the FEV1 baseline measurement. MMRM results. Means are adjusted for treatment, centre, visit, baseline, treatment*visit and baseline*visit. (NCT00776984)
Timeframe: Baseline and 48 weeks
| Intervention | Liter (Mean) |
|---|---|
| Placebo | 0.063 |
| Tio R5 | 0.155 |
Weekly means obtained during the last 7 days before week 24 visit were compared (measured by patients at home using the asthma monitor device). Response was defined as change from baseline. MMRM results. Means are adjusted for treatment, centre, visit, baseline, treatment*visit and baseline*visit. (NCT00776984)
Timeframe: Baseline and last 7 days before week 24 visit
| Intervention | Liter (Mean) |
|---|---|
| Placebo | 0.006 |
| Tio R5 | 0.096 |
The AUC0-3h was calculated as area under the curve from zero to 3 hours using the trapezoidal rule divided by the observation time (3 hours) to report in litres. The trough value was assigned to zero time. Response was defined as change from baseline in FVC AUC0-3h after a treatment period of 24 weeks. MMRM results. Means are adjusted for treatment, centre, visit, baseline, treatment*visit baseline*visit. (NCT00776984)
Timeframe: Baseline and 24 weeks
| Intervention | Liter (Mean) |
|---|---|
| Placebo | 0.187 |
| Tio R5 | 0.295 |
"The responder rate as assessed by the Asthma Control Questionnaire (ACQ) determined at 24-weeks and 48-weeks (on combined data from the two twin trials 205.416 (NCT00772538) and 205.417 (NCT00776984)). A patient was considered to be a responder if he or she was reported with an improvement (decrease) in the ACQ total score of at least 0.5 points.~The ACQ total score was calculated as the mean of the responses to 7 questions and was analysed as an absolute value. The score ranges from 0 (no impairment) to 6 (maximum impairment).~This outcome definition is taken from the primary outcome definition for the twin trials 205.418 (NCT01172808) and 205.419 (NCT01172821) of the same development program." (NCT00776984)
Timeframe: 24 weeks, 48 weeks
| Intervention | percentage of participants (Number) | |
|---|---|---|
| 24 weeks | 48 weeks | |
| Placebo | 46.9 | 45.2 |
| Tio R5 | 53.9 | 58.1 |
Severe asthma exacerbations were pre-defined as all asthma exacerbations that required treatment with systemic (including oral) corticosteroids for at least 3 days or (in case of ongoing and pre-existing systemic corticosteroid therapy) that required at least a doubling of the previous daily dose of systemic corticosteroids for at least 3 days. (NCT00776984)
Timeframe: 48 weeks
| Intervention | Participants (Number) | ||||||||
|---|---|---|---|---|---|---|---|---|---|
| 0 severe asthma exacerbations | 1 severe asthma exacerbation | 2 severe asthmaexacerbations | 3 severe asthma exacerbations | 4 severe asthma exacerbations | 5 severe asthma exacerbations | 6 severe asthma exacerbations | 7-10 severe asthma exacerbations | 11-20 severe asthma exacerbations | |
| Placebo | 151 | 51 | 19 | 5 | 3 | 2 | 0 | 0 | 1 |
| Tio R5 | 147 | 38 | 17 | 8 | 3 | 1 | 1 | 1 | 0 |
(NCT00776984)
Timeframe: 48 weeks
| Intervention | Participants (Number) | ||
|---|---|---|---|
| 0 hospitalisations | 1 hospitalisations | 2+ hospitalisations | |
| Placebo | 222 | 9 | 1 |
| Tio R5 | 208 | 6 | 2 |
Asthma exacerbations (including severe, non-severe; symptomatic, asymptomatic) were pre-defined as an episode of progressive increase in 1 or more asthma symptoms (e.g. shortness of breath, cough, wheezing, chest tightness or some combination of these symptoms). Additionally, decrease of patients best PEF a.m. of 30 percent or more from the patients mean PEF a.m. for at least 2 consecutive days was considered to be an objective marker of asthma exacerbation. (NCT00776984)
Timeframe: 48 weeks
| Intervention | Participants (Number) | |||||||||
|---|---|---|---|---|---|---|---|---|---|---|
| 0 asthma exacerbations | 1 asthma exacerbation | 2 asthma exacerbations | 3 asthma exacerbations | 4 asthma exacerbations | 5 asthma exacerbations | 6 asthma exacerbations | 7-10 asthma exacerbations | 11-20 asthma exacerbations | 21+ asthma exacerbations | |
| Placebo | 82 | 53 | 27 | 13 | 14 | 9 | 9 | 10 | 13 | 2 |
| Tio R5 | 106 | 44 | 22 | 8 | 10 | 3 | 2 | 8 | 11 | 2 |
The trough FVC is defined as the pre-dose FVC measured 10 minutes before the last administration of randomised treatment. Trough FVC response was defined as the difference between the trough FVC measured after a treatment period of 48 weeks and the FVC baseline measurement. MMRM results. Means are adjusted for treatment, centre, visit, baseline, treatment*visit and baseline*visit. (NCT00776984)
Timeframe: Baseline and 48 weeks
| Intervention | Liter (Mean) |
|---|---|
| Placebo | 0.072 |
| Tio R5 | 0.142 |
The trough FVC is defined as the pre-dose FVC measured 10 minutes before the last administration of randomised treatment. Trough FVC response was defined as the difference between the trough FVC measured after a treatment period of 24 weeks and the FVC baseline measurement. MMRM results. Means are adjusted for treatment, centre, visit, baseline, treatment*visit and baseline*visit. (NCT00776984)
Timeframe: Baseline and 24 weeks
| Intervention | Liter (Mean) |
|---|---|
| Placebo | 0.044 |
| Tio R5 | 0.150 |
Weekly means obtained during the last 7 days before week 24 visit were compared. The response is defined as the change of the weekly mean from the baseline weekly mean. The use of PRN salbutamol (albuterol rescue medication) is determined by the number of puffs of rescue therapy used per day. MMRM results. Means are adjusted for treatment, centre, visit, baseline, treatment*visit and baseline*visit. (NCT00776984)
Timeframe: Baseline and last 7 days before week 24 visit
| Intervention | Puffs (Mean) |
|---|---|
| Placebo | -0.881 |
| Tio R5 | -1.144 |
For the ACQ, the total score was calculated as the mean of the responses to 7 questions and was analysed as an absolute value. The score ranges from 0 (no impairment) to 6 (maximum impairment). MMRM results. Means are adjusted for treatment, centre, visit, baseline, treatment*visit and baseline*visit. (NCT00776984)
Timeframe: 48 weeks
| Intervention | Scores on a scale (Mean) |
|---|---|
| Placebo | 2.159 |
| Tio R5 | 2.027 |
The AQLQ(S) total score was calculated as the mean of the responses to 32 questions for the domains Symptoms, Activity Limitations, Emotional Function and Environmental Stimuli and was analysed as an absolute value. The AQLQ(S) total score ranges from 1 (worst controlled) to 7 (best). MMRM results. Means are adjusted for treatment, centre, visit, baseline, treatment*visit and baseline*visit. (NCT00776984)
Timeframe: 48 weeks
| Intervention | Scores on a scale (Mean) |
|---|---|
| Placebo | 4.945 |
| Tio R5 | 5.085 |
Change from baseline was calculated as the Endpoint (defined as the last recorded measure of AM pre-dose FVC fore each participant) value minus the baseline value. FVC is defined as the amount of air that can forcibly be blown out after a full inspiration. (NCT00784550)
Timeframe: Baseline and Endpoint (defined as the last recorded measure [up to Week 24] of AM pre-dose FVC for each participant)
| Intervention | ml (Mean) |
|---|---|
| FSC + Tio | 95 |
| Tiotropium | -28 |
Change from baseline was calculated as the Endpoint (defined as the last recorded measure of 2 hour post-dose FVC for each participant) value minus the baseline value. FVC is defined as the amount of air that can forcibly be blown out after a full inspiration (FVC). (NCT00784550)
Timeframe: Baseline and Endpoint (defined as the last recorded measure of 2 hour post-dose FVC [up to Week 24] for each participant)
| Intervention | ml (Mean) |
|---|---|
| FSC + Tio | 265 |
| Tiotropium | 87 |
Change from baseline was calculated as the Endpoint (defined as the last recorded measure of AM pre-dose IC for each participant) value minus the baseline value. IC is defined as the amount of air that can be inhaled after a normal expiration. IC is a measure of pulmonary function. (NCT00784550)
Timeframe: Baseline and Endpoint (defined as the last recorded measure of AM pre-dose IC [up to Week 24] for each participant)
| Intervention | ml (Mean) |
|---|---|
| FSC + Tio | 107 |
| Tiotropium | -8 |
Change from baseline was calculated as the Endpoint (defined as the last recorded measure of 2 hour post-dose FEV1 for each participant) value minus the baseline value. FEV1 is defined as the amount of air expelled from the lungs in one second after a full inspiration and is a measure of pulmonary function. (NCT00784550)
Timeframe: Baseline and Endpoint (defined as the last recorded measure [taken up to Week 24] of 2 hour post-dose FEV1 for each participant)
| Intervention | ml (Mean) |
|---|---|
| FSC + Tio | 233 |
| Tiotropium | 77 |
The CRQ-SAS measures 4 domains of functioning of participants with COPD: mastery (amount of control the participant feels he/she has over COPD symptoms); fatigue (how tired the participant feels); emotional function (how anxious/depressed the participant feels); and dyspnea (how short of breath the participant feels during physical activities). Each domain is measured on a scale of 1-7 (1=maximum impairment; 7=no impairment). Each domain score is calculated separately. (NCT00784550)
Timeframe: Baseline and Endpoint (defined as the last recorded score [up to Week 24 or the early withdrawal visit] on each of the questions on this questionnaire)
| Intervention | points on a scale (Mean) | |||
|---|---|---|---|---|
| Mastery | Fatigue | Emotional Function | Dyspnea | |
| FSC + Tio | 0.28 | 0.23 | 0.24 | 0.21 |
| Tiotropium | 0.04 | 0.17 | 0.16 | 0.19 |
Change from baseline was calculated as the Endpoint (defined as the last recorded measure of AM pre-dose FEV1 for each participant) value minus the baseline value. FEV1 is defined as the amount of air expelled from the lungs in one second after a full inspiration and is a measure of pulmonary function. (NCT00784550)
Timeframe: Baseline and Endpoint (defined as the last recorded measure [taken up to Week 24] of AM pre-dose FEV1 for each participant)
| Intervention | milliliters (ml) (Mean) |
|---|---|
| FSC + Tio | 101 |
| Tiotropium | -16 |
The primary objective of the study was to demonstrate the non-inferiority of indacaterol vs. tiotropium with respect to 24 hour post dose (trough) FEV1 after 12 weeks of treatment in patients with severe COPD. Trough FEV1 was defined as the average of the 23 hours 10 min and the 23 hours 45 min post dose values. Trough FEV1 was analyzed using a mixed model for the PPS-S. The model contained treatment as a fixed effect with the baseline FEV1, FEV1 prior to inhalation and FEV1 15 min post-inhalation of salbutamol/albuterol (components of SABA reversibility at Visit 2), FEV1 prior to inhalation and FEV1 60 min post-inhalation of ipratropium (components of anti-cholinergic reversibility at Visit 3) as covariates. Smoking history (current or ex-smoker) was included as a factor in the model. (NCT00845728)
Timeframe: 12 weeks
| Intervention | Liters (Least Squares Mean) |
|---|---|
| Indacaterol | 1.134 |
| Tiotropium | 1.145 |
COPD exacerbations were defined as :Worsening of 2 or more major symptoms for at least 2 consecutive days: dyspnea; sputum volume; suputum purulence AND requiring treatment with systemic corticosteroids and/or antibiotics OR Worsening of any 1 major symptom together with any 1 of the following minor symptoms for at least 2 consecutive days: Sore throat; colds; fever without other cause; increased cough; increase wheeze AND requiring treatment with systemic glucocorticosteroids and/or antibiotics. The rate was analyzed using a linear model assuming a negative binomial distribution for the PPS-E. The time at risk for a patient was defined as the length of time the patient was in the study and the log(length of time in the study) was used as the offset variable in the model. (NCT00845728)
Timeframe: 52 weeks
| Intervention | Exacerbations per patient per year (Number) |
|---|---|
| Indacaterol | 0.79 |
| Tiotropium | 0.61 |
FEV1 was measured with spirometry conducted according to internationally accepted standards. Measurements were made at 23 hours 10 minutes and 23 hours 45 minutes post-dose on Day 2. The analysis included baseline FEV1, FEV1 pre-dose and 10-15 minutes post-dose of salbutamol/albuterol during screening, and FEV1 pre-dose and 1 hour post-dose of ipratropium during screening as covariates. (NCT00846586)
Timeframe: 24 hours post-dose on Day 2
| Intervention | Liters (Least Squares Mean) |
|---|---|
| Indacaterol 150 μg and Tiotropium 18 μg | 1.36 |
| Tiotropium 18 μg | 1.27 |
FEV1 was measured with spirometry conducted according to internationally accepted standards. Measurements were made at 23 hours 10 minutes and 23 hours 45 minutes post-dose at the end of the study (Week 12 + 1 day, Day 85). The analysis included baseline FEV1, FEV1 pre-dose and 10-15 minutes post-dose of salbutamol/albuterol during screening, and FEV1 pre-dose and 1 hour post-dose of ipratropium during screening as covariates. (NCT00846586)
Timeframe: 24 hours post-dose at the end of treatment (Week 12 + 1 day, Day 85)
| Intervention | Liters (Least Squares Mean) |
|---|---|
| Indacaterol 150 μg and Tiotropium 18 μg | 1.38 |
| Tiotropium 18 μg | 1.30 |
FEV1 was measured with spirometry conducted according to internationally accepted standards. Measurements were made at 5 and 30 minutes; and 1, 2, 3, 4, 6, and 8 hours post-dose at the end of the study (Week 12, Day 84). Standardized FEV1 AUC was calculated by the trapezoidal rule. The analysis included baseline FEV1, FEV1 pre-dose and 10-15 minutes post-dose of salbutamol/albuterol during screening, and FEV1 pre-dose and 1 hour post-dose of ipratropium during screening as covariates. (NCT00846586)
Timeframe: From 5 minutes to 8 hours post-dose at the end of treatment (Week 12, Day 84)
| Intervention | Liters (Least Squares Mean) |
|---|---|
| Indacaterol 150 μg and Tiotropium 18 μg | 1.50 |
| Tiotropium 18 μg | 1.38 |
FEV1 was measured with spirometry conducted according to internationally accepted standards. Measurements were made at 5 and 30 minutes; and 1, 2, 3, 4, 6, and 8 hours post-dose on Day 1. Standardized FEV1 AUC was calculated by the trapezoidal rule. The analysis included baseline FEV1, FEV1 pre-dose and 10-15 minutes post-dose of salbutamol/albuterol during screening, and FEV1 pre-dose and 1 hour post-dose of ipratropium during screening as covariates. (NCT00846586)
Timeframe: From 5 minutes to 8 hours post-dose on Day 1
| Intervention | Liters (Least Squares Mean) |
|---|---|
| Indacaterol 150 μg and Tiotropium 18 μg | 1.40 |
| Tiotropium 18 μg | 1.32 |
FEV1 was measured with spirometry conducted according to internationally accepted standards. Measurements were made at 5 and 30 minutes; and 1, 2, 3, and 4 hours post-dose on Day 1. Standardized FEV1 AUC was calculated by the trapezoidal rule. The analysis included baseline FEV1, FEV1 pre-dose and 10-15 minutes post-dose of salbutamol/albuterol during screening, and FEV1 pre-dose and 1 hour post-dose of ipratropium during screening as covariates. (NCT00846586)
Timeframe: From 5 minutes to 4 hours post-dose on Day 1
| Intervention | Liters (Least Squares Mean) |
|---|---|
| Indacaterol 150 μg and Tiotropium 18 μg | 1.38 |
| Tiotropium 18 μg | 1.31 |
FEV1 was measured with spirometry conducted according to internationally accepted standards. Measurements were made at 5 and 30 minutes; and 1, 2, 3, and 4 hours post-dose at the end of treatment (Week 12). Standardized FEV1 AUC was calculated by the trapezoidal rule. The analysis included baseline FEV1, FEV1 pre-dose and 10-15 minutes post-dose of salbutamol/albuterol during screening, and FEV1 pre-dose and 1 hour post-dose of ipratropium during screening as covariates. (NCT00846586)
Timeframe: From 5 minutes to 4 hours post-dose at the end of treatment (Week 12)
| Intervention | Liters (Least Squares Mean) |
|---|---|
| Indacaterol 150 μg and Tiotropium 18 μg | 1.52 |
| Tiotropium 18 μg | 1.38 |
(NCT00868231)
Timeframe: Day 15
| Intervention | Liters (Least Squares Mean) |
|---|---|
| Aclidininum Bromide 400 μg Bid | 0.297 |
| Tiotropium 18 μg Once-daily | 0.345 |
| Placebo | 0.009 |
(NCT00868231)
Timeframe: Day 1
| Intervention | Liters (Least Squares Mean) |
|---|---|
| Aclidininum Bromide 400 μg Bid | 0.310 |
| Tiotropium 18 μg Once-daily | 0.215 |
| Placebo | -0.051 |
(NCT00868231)
Timeframe: Day 15
| Intervention | Liters (Least Squares Mean) |
|---|---|
| Aclidininum Bromide 400 μg Bid | 0.281 |
| Tiotropium 18 μg Once-daily | 0.219 |
| Placebo | -0.039 |
(NCT00868231)
Timeframe: Day 1
| Intervention | Liters (Least Squares Mean) |
|---|---|
| Aclidininum Bromide 400 μg Bid | 0.293 |
| Tiotropium 18 μg Once-daily | 0.150 |
| Placebo | -0.127 |
(NCT00868231)
Timeframe: Day 1
| Intervention | Liters (Least Squares Mean) |
|---|---|
| Aclidininum Bromide 400 μg Bid | 0.230 |
| Tiotropium 18 μg Once-daily | 0.178 |
| Placebo | 0.016 |
(NCT00868231)
Timeframe: Day 1
| Intervention | Liters (Least Squares Mean) |
|---|---|
| Aclidininum Bromide 400 μg Bid | 0.202 |
| Tiotropium 18 μg Once-daily | 0.101 |
| Placebo | -0.060 |
(NCT00868231)
Timeframe: Day 15
| Intervention | Liters (Least Squares Mean) |
|---|---|
| Aclidininum Bromide 400 μg Bid | 0.224 |
| Tiotropium 18 μg Once-daily | 0.087 |
| Placebo | -0.095 |
(NCT00868231)
Timeframe: Day 15
| Intervention | Liters (Least Squares Mean) |
|---|---|
| Aclidininum Bromide 400 μg Bid | 0.174 |
| Tiotropium 18 μg Once-daily | 0.096 |
| Placebo | -0.032 |
(NCT00868231)
Timeframe: Day 1
| Intervention | Liters (Least Squares Mean) |
|---|---|
| Aclidininum Bromide 400 μg Bid | 0.331 |
| Tiotropium 18 μg Once-daily | 0.289 |
| Placebo | 0.005 |
(NCT00868231)
Timeframe: Day 15
| Intervention | Liters (Least Squares Mean) |
|---|---|
| Aclidininum Bromide 400 μg Bid | 0.236 |
| Tiotropium 18 μg Once-daily | 0.260 |
| Placebo | 0.015 |
(NCT00868231)
Timeframe: Day 1
| Intervention | Liters (Least Squares Mean) |
|---|---|
| Aclidininum Bromide 400 μg Bid | 0.211 |
| Tiotropium 18 μg Once-daily | 0.138 |
| Placebo | -0.024 |
(NCT00868231)
Timeframe: Day 15
| Intervention | Liters (Least Squares Mean) |
|---|---|
| Aclidininum Bromide 400 μg Bid | 0.226 |
| Tiotropium 18 μg Once-daily | 0.178 |
| Placebo | -0.006 |
We measured the change in the number of coughs following capsaicin inhalation challenge from baseline followed by 30 days of treatment with spiriva (NCT00870896)
Timeframe: 30 days
| Intervention | coughs per dose of capsaicin (Mean) |
|---|---|
| Group 1 | 2.5 |
We measured the change in FEV1/FVC ratio at baseline and following 30 days of treatment with Spiriva.Change in ratio reflects the percentage value (ratio) at 30 days minus the percentage value (ratio) at baseline x 100 (NCT00870896)
Timeframe: 30 days
| Intervention | percentage change (Mean) |
|---|---|
| Change in FEV1/FVC | 3 |
Change in FEV1 ( in liters) at baseline and following 30 days of treatment with Spiriva (NCT00870896)
Timeframe: 30 days
| Intervention | liters (Mean) |
|---|---|
| Spirometry | .315 |
FEV1 was measured with spirometry conducted according to internationally accepted standards. Trough FEV1 was defined as the average of measurements made 23 hours 10 minutes and 23 hours 45 minutes post-dose at the end of the study. The analysis included baseline FEV1, FEV1 pre-dose and 10-15 minutes post-dose of salbutamol/albuterol during screening, and FEV1 pre-dose and 1 hour post-dose of ipratropium during screening as covariates. (NCT00877383)
Timeframe: End of the study (Week 12 + 1 day, Day 85)
| Intervention | Liters (Least Squares Mean) |
|---|---|
| Indacaterol 150 μg and Tiotropium 18 μg | 1.34 |
| Tiotropium 18 μg | 1.27 |
FEV1 was measured with spirometry conducted according to internationally accepted standards. Measurements were made at 5 and 30 minutes; and 1, 2, 3, 4, 6, and 8 hours post-dose on Day 1. The standardized AUC FEV1 was calculated as the sum of trapezoids divided by the length of time. The analysis included baseline FEV1, FEV1 pre-dose and 10-15 minutes post-dose of salbutamol/albuterol during screening, and FEV1 pre-dose and 1 hour post-dose of ipratropium during screening as covariates. (NCT00877383)
Timeframe: From 5 minutes to 8 hours post-dose on Day 1
| Intervention | Liters (Least Squares Mean) |
|---|---|
| Indacaterol 150 μg and Tiotropium 18 μg | 1.40 |
| Tiotropium 18 μg | 1.33 |
FEV1 was measured with spirometry conducted according to internationally accepted standards. Measurements were made at 5 and 30 minutes; and 1, 2, 3, and 4 hours post-dose at the end of the study (Week 12, Day 84). The standardized AUC FEV1 was calculated as the sum of trapezoids divided by the length of time. The analysis included baseline FEV1, FEV1 pre-dose and 10-15 minutes post-dose of salbutamol/albuterol during screening, and FEV1 pre-dose and 1 hour post-dose of ipratropium during screening as covariates. (NCT00877383)
Timeframe: From 5 minutes to 4 hours post-dose at the end of the study (Week 12, Day 84)
| Intervention | Liters (Least Squares Mean) |
|---|---|
| Indacaterol 150 μg and Tiotropium 18 μg | 1.48 |
| Tiotropium 18 μg | 1.34 |
FEV1 was measured with spirometry conducted according to internationally accepted standards. Measurements were made at 5 and 30 minutes; and 1, 2, 3, and 4 hours post-dose on Day 1. The standardized AUC FEV1 was calculated as the sum of trapezoids divided by the length of time. The analysis included baseline FEV1, FEV1 pre-dose and 10-15 minutes post-dose of salbutamol/albuterol during screening, and FEV1 pre-dose and 1 hour post-dose of ipratropium during screening as covariates. (NCT00877383)
Timeframe: From 5 minutes to 4 hours post-dose on Day 1
| Intervention | Liters (Least Squares Mean) |
|---|---|
| Indacaterol 150 μg and Tiotropium 18 μg | 1.38 |
| Tiotropium 18 μg | 1.32 |
FEV1 was measured with spirometry conducted according to internationally accepted standards. Measurements were made at 5 and 30 minutes; and 1, 2, 3, 4, 6, and 8 hours post-dose at the end of the study (Week 12, Day 84). The standardized AUC FEV1 was calculated as the sum of trapezoids divided by the length of time. The analysis included baseline FEV1, FEV1 pre-dose and 10-15 minutes post-dose of salbutamol/albuterol during screening, and FEV1 pre-dose and 1 hour post-dose of ipratropium during screening as covariates. (NCT00877383)
Timeframe: From 5 minutes to 8 hours post-dose at the end of the study (Week 12, Day 84)
| Intervention | Liters (Least Squares Mean) |
|---|---|
| Indacaterol 150 μg and Tiotropium 18 μg | 1.46 |
| Tiotropium 18 μg | 1.34 |
FEV1 was measured with spirometry conducted according to internationally accepted standards. Trough FEV1 was defined as the average of measurements made 23 hours 10 minutes and 23 hours 45 minutes post-dose on Day 2. The analysis included baseline FEV1, FEV1 pre-dose and 10-15 minutes post-dose of salbutamol/albuterol during screening, and FEV1 pre-dose and 1 hour post-dose of ipratropium during screening as covariates. (NCT00877383)
Timeframe: 24 hours post-dose on Day 2
| Intervention | Liters (Least Squares Mean) |
|---|---|
| Indacaterol 150 μg and Tiotropium 18 μg | 1.34 |
| Tiotropium 18 μg | 1.26 |
Spirometry was conducted according to internationally accepted standards. FEV1 was measured at 5 and 30 minutes; and 1, 2, and 4 hours post-dose on Week 12. Standardized FEV1 AUC (5 minutes-4 hour) post-dose at week 12 was calculated based on the trapezoidal rule, and was adjusted for the area per time unit by using the scheduled time of measurements for FEV1. Mixed model used baseline FEV1, FEV1 prior to and 10-15 minutes post inhalation of salbutamol/albuterol, FEV1 prior to and 1 hour post inhalation of ipratropium, and inhaled corticosteroid use at baseline as covariates. (NCT00900731)
Timeframe: 5 minutes to 4 hours post-dose at the end of treatment (week 12)
| Intervention | Liter (Least Squares Mean) |
|---|---|
| Indacaterol 150 µg | 1.51 |
| Tiotropium 18 µg | 1.52 |
Participants recorded the number of puffs of rescue medication taken in the previous 12 hours each evening in an electronic diary. The number of daytime puffs per day over the 12 weeks of treatment was divided by the number of days to derive the mean number per day of daytime puffs of rescue medication for each participant. Mixed model used baseline number of daytime puffs per day of rescue medication, FEV1 prior to and 10-15 minutes post inhalation of salbutamol/albuterol, FEV1 prior to and 1 hour post inhalation of ipratropium, and inhaled corticosteroid use at baseline as covariates. (NCT00900731)
Timeframe: Baseline, up to 12 weeks
| Intervention | Puffs (Least Squares Mean) |
|---|---|
| Indacaterol 150 µg | -0.90 |
| Tiotropium 18 µg | -0.59 |
Participants recorded the number of puffs of rescue medication taken in the previous 12 hours each morning in an electronic diary. The number of nighttime puffs per day over the 12 weeks of treatment was divided by the number of days to derive the mean number per day of nighttime puffs of rescue medication for each participant. Mixed model used baseline number of nighttime puffs per day of rescue medication, FEV1 prior to and 10-15 minutes post inhalation of salbutamol/albuterol, FEV1 prior to and 1 hour post inhalation of ipratropium, and inhaled corticosteroid use at baseline as covariates. (NCT00900731)
Timeframe: Baseline, up to 12 weeks
| Intervention | Puffs (Least Squares Mean) |
|---|---|
| Indacaterol 150 µg | -0.52 |
| Tiotropium 18 µg | -0.28 |
Participants recorded the number of puffs of rescue medication taken in the previous 12 hours each morning and evening in an electronic diary. The number of puffs per day over the 12 weeks of treatment was divided by the number of days to derive the mean number per day of puffs of rescue medication for each participant. Mixed model used baseline number of puffs per day of rescue medication, FEV1 prior to and 10-15 minutes post inhalation of salbutamol/albuterol, FEV1 prior to and 1 hour post inhalation of ipratropium, and inhaled corticosteroid use at baseline as covariates. (NCT00900731)
Timeframe: Baseline, up to 12 weeks
| Intervention | Puffs (Least Squares Mean) |
|---|---|
| Indacaterol 150 µg | -1.40 |
| Tiotropium 18 µg | -0.85 |
SGRQ is a health related quality of life questionnaire consisting of 50 items in three domains: symptoms (frequency and severity), activity (that cause or are limited by breathlessness) and impacts (social functioning & psychological disturbances resulting from airway disease). The total score is 0 to 100 with a higher score indicating greater impairment of health status. Mixed model used baseline SGRQ, FEV1 prior to and 10-15 minutes post inhalation of salbutamol/albuterol, FEV1 prior to and 1 hour post inhalation of ipratropium, and inhaled corticosteroid use at baseline as covariates. (NCT00900731)
Timeframe: 12 weeks
| Intervention | Score on a scale (Least Squares Mean) |
|---|---|
| Indacaterol 150 µg | 37.1 |
| Tiotropium 18 µg | 39.2 |
TDI focal score is based on three domains: functional impairment, magnitude of task and magnitude of effort. Each domain is scored from -3 (major deterioration) to 3 (major improvement) to give an overall TDI focal score of -9 to 9 with a negative score indicating a deterioration from baseline. A 1 unit difference in the TDI focal score is clinically significant. Mixed model used baseline dyspnea index, FEV1 prior to and 10-15 minutes post inhalation of salbutamol/albuterol, FEV1 prior to and 1 hour post inhalation of ipratropium, and inhaled corticosteroid use at baseline as covariates. (NCT00900731)
Timeframe: 12 weeks
| Intervention | Score on a scale (Least Squares Mean) |
|---|---|
| Indacaterol 150 µg | 2.01 |
| Tiotropium 18 µg | 1.43 |
Spirometry was conducted according to internationally accepted standards. Trough FEV1 was defined as the average of the 23 hour 10 minute and 23 hour 45 minute post-dose FEV1 readings. Mixed model used baseline FEV1, FEV1 prior to and 10-15 minutes post inhalation of salbutamol/albuterol, FEV1 prior to and 1 hour post inhalation of ipratropium, and inhaled corticosteroid use at baseline as covariates. (NCT00900731)
Timeframe: End of treatment (Week 12)
| Intervention | Liters (Least Squares Mean) |
|---|---|
| Indacaterol 150 µg | 1.44 |
| Tiotropium 18 µg | 1.43 |
A day with no rescue medication was defined as any day in the diary that the participant used no puffs of rescue medication. The percentage of days with no rescue medication was calculated by dividing the number of days with no rescue medication over the 12 week treatment period by the number of evaluable days and multiplying by 100. Mixed model used baseline percentage of days with no rescue medication, FEV1 prior to and 10-15 minutes post inhalation of salbutamol/albuterol, FEV1 prior to and 1 hour post inhalation of ipratropium, and inhaled corticosteroid use at baseline as covariates. (NCT00900731)
Timeframe: Up to 12 weeks
| Intervention | Percentage of days (Least Squares Mean) |
|---|---|
| Indacaterol 150 µg | 46.1 |
| Tiotropium 18 µg | 41.4 |
"A night with no nighttime awakenings was defined as any night where the patient did not wake up due to 1 or more of 6 symptoms (respiratory symptoms, cough, wheeze, amount of sputum, color of sputum, and breathlessness). Symptoms occurring during the previous 12 hours were recorded each morning and evening by the patient in an electronic diary. The percentage of nights with 'no nighttime awakenings' was calculated as the total number of nights with no nighttime awakenings over the 52 week treatment period divided by the total number of nights where diary recordings were made." (NCT00929110)
Timeframe: Baseline to Week 52
| Intervention | Percentage of nights (Least Squares Mean) |
|---|---|
| Glycopyrronium Bromide 50 μg | 57.36 |
| Placebo to Glycopyrronium Bromide | 52.15 |
| Tiotropium 18 μg | 55.47 |
"Trough FVC is defined as the average of the post-dose 23 h 15 min and the 23 h 45 min FVC values. Just prior to FVC measurement, patients performed normal tidal breathing. The patient was given a few breaths warning before being told At the end of the next normal breath out, take a deep breath all the way in; they were then verbally encouraged to make a maximal effort before relaxing. The analysis included the same covariates as the primary Outcome Measure." (NCT00929110)
Timeframe: Day 1, Week 12, Week 26, and Week 52
| Intervention | Liters (Least Squares Mean) | |||
|---|---|---|---|---|
| Day 1 | Week 12 (n=442, 204, 217) | Week 26 (n=418, 196, 208) | Week 52 (n=395, 186, 201) | |
| Glycopyrronium Bromide 50 μg | 2.936 | 2.985 | 2.962 | 2.866 |
| Placebo to Glycopyrronium Bromide | 2.757 | 2.802 | 2.758 | 2.687 |
| Tiotropium 18 μg | 2.930 | 2.970 | 2.892 | 2.866 |
FEV1 was measured with spirometry conducted according to internationally accepted standards. Trough FEV1 was defined as the average of measurements made 23 hours 15 minutes and 23 hours 45 minutes post-dose. The analysis included the same covariates as the primary Outcome Measure. (NCT00929110)
Timeframe: Day 1, Week 26, and Week 52
| Intervention | Liters (Least Squares Mean) | ||
|---|---|---|---|
| Day 1 | Week 26 (n=451, 219, 233) | Week 52 (n=416, 196, 210) | |
| Glycopyrronium Bromide 50 μg | 1.478 | 1.458 | 1.412 |
| Placebo to Glycopyrronium Bromide | 1.388 | 1.324 | 1.303 |
| Tiotropium 18 μg | 1.471 | 1.408 | 1.392 |
"Just prior to FVC measurement, patients performed normal tidal breathing. The patient was given a few breaths warning before being told At the end of the next normal breath out, take a deep breath all the way in; they were then verbally encouraged to make a maximal effort before relaxing. The analysis included the same covariates as the primary Outcome Measure. Data was not collected at all time points for all Days and Weeks." (NCT00929110)
Timeframe: 5, 15, and 30 minutes; and 1, 2, 3, 4 hours post-dose at Days 1 and 15; and Weeks 5, 9, 12, 16, 20, 26, 34, 42, 50, and 52
| Intervention | Liters (Least Squares Mean) | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Day 1, minute 5 (n=495, 255, 253) | Day 1, minute 15 (n=502, 255, 254) | Day 1, minute 30 (n=507, 252, 254) | Day 1, hour 1 (n=511, 256, 254) | Day 1, hour 2 (n=513, 253, 252) | Day 1, hour 3 (n=510, 248, 252) | Day 1, hour 4 (n=504, 239, 250) | Day 1, hour 23, minute 15 (n=481, 243, 239) | Day 1, hour 23, minute 45 (n=474, 239, 232) | Day 15, minute 5 (n=498, 223, 243) | Day 15, minute 15 (n=487, 229, 239) | Day 15, minute 30 (n=503, 233, 242) | Day 15, hour 1 (n=501, 229, 240) | Week 5, minute 5 (n=476, 221, 231) | Week 5, minute 15 (n=479, 222, 234) | Week 5, minute 30 (n=480, 223, 234) | Week 9, minute 5 (n=454, 217, 227) | Week 9, minute 15 (n=459, 220, 225) | Week 9, minute 30 (n=460, 220, 226) | Week 12, minute 5 (n=453, 212, 230) | Week 12, minute 15 (n=448, 205, 222) | Week 12, minute 30 (n=455, 212, 226) | Week 12, hour 1 (n=455, 210, 227) | Week 12, hour 2 (n=446, 207, 225) | Week 12, hour 3 (n=444, 204, 225) | Week 12, hour 4 (n=437, 202, 224) | Week 12, hour 23, minute 15 (n=430, 200, 214) | Week 12, hour 23, minute 45 (n=426, 195, 205) | Week 16, minute 5 (n=429, 207, 218) | Week 16, minute 15 (n=428, 209, 219) | Week 16, minute 30 (n=433, 209, 220) | Week 20, minute 5 (n=430, 206, 218) | Week 20, minute 15 (n=430, 207, 220) | Week 20, minute 30 (n=431, 207, 221) | Week 26, minute 5 (421, 202, 213) | Week 26, minute 15 (n=414, 200, 207) | Week 26, minute 30 (n=424, 206, 213) | Week 26, hour 1 (n=425, 206, 212) | Week 26, hour 2 (n=420, 203, 208) | Week 26, hour 3 (n=416, 204, 213) | Week 26, hour 4 (n=416, 203, 208) | Week 26, hour 23, minute 15 (n=405, 187, 202) | Week 26, hour 23, minute 45 (n=401, 185, 198) | Week 34, minute 5 (n=408, 194, 212) | Week 34, minute 15 (n=407, 191, 214) | Week 34, minute 30 (n=410, 196, 215) | Week 34, hour 1 (n=412, 195, 215) | Week 42, minute 5 (n=398, 189, 199) | Week 42, minute 15 (n=405, 188, 201) | Week 42, minute 30 (n=405, 189, 201) | Week 50, minute 5 (n=386, 185, 199) | Week 50, minute 15 (n=391, 187, 203) | Week 50, minute 30 (n=392, 186, 204) | Week 52, minute 5 (n=401, 188, 197) | Week 52, minute 15 (n=394, 183, 200) | Week 52, minute 30 (n=402, 189, 202) | Week 52, hour 1 (n=404, 190, 201) | Week 52, hour 2 (n=402, 186, 202) | Week 52, hour 3 (n=400, 186, 199) | Week 52, hour 4 (n=397, 184, 199) | Week 52, hour 23, minute 15 (n=388, 183, 198) | Week 52, hour 23, minute 45 (n=395, 185, 199) | |
| Glycopyrronium Bromide 50 μg | 2.915 | 2.982 | 3.004 | 3.074 | 3.119 | 3.129 | 3.076 | 2.926 | 2.930 | 2.984 | 3.016 | 3.028 | 3.068 | 3.004 | 3.024 | 3.085 | 3.047 | 3.050 | 3.079 | 2.991 | 3.003 | 2.985 | 3.062 | 3.093 | 3.129 | 3.050 | 2.991 | 2.977 | 3.016 | 3.029 | 3.063 | 2.985 | 3.020 | 3.058 | 2.956 | 2.980 | 2.983 | 3.034 | 3.049 | 3.097 | 3.022 | 2.971 | 2.952 | 2.967 | 2.983 | 3.002 | 3.014 | 2.982 | 3.001 | 3.016 | 2.925 | 2.971 | 2.999 | 2.899 | 2.942 | 2.923 | 2.992 | 2.997 | 3.029 | 2.984 | 2.866 | 2.869 |
| Placebo to Glycopyrronium Bromide | 2.731 | 2.719 | 2.692 | 2.732 | 2.762 | 2.811 | 2.767 | 2.745 | 2.749 | 2.760 | 2.748 | 2.756 | 2.757 | 2.768 | 2.771 | 2.804 | 2.767 | 2.764 | 2.768 | 2.726 | 2.735 | 2.707 | 2.741 | 2.801 | 2.839 | 2.793 | 2.799 | 2.799 | 2.753 | 2.737 | 2.747 | 2.744 | 2.749 | 2.774 | 2.733 | 2.713 | 2.715 | 2.721 | 2.777 | 2.831 | 2.776 | 2.758 | 2.759 | 2.713 | 2.718 | 2.690 | 2.711 | 2.727 | 2.713 | 2.734 | 2.729 | 2.729 | 2.731 | 2.673 | 2.701 | 2.666 | 2.696 | 2.727 | 2.742 | 2.725 | 2.675 | 2.694 |
| Tiotropium 18 μg | 2.856 | 2.903 | 2.937 | 2.975 | 3.033 | 3.073 | 3.031 | 2.923 | 2.923 | 2.980 | 3.030 | 3.018 | 3.023 | 3.011 | 3.024 | 3.063 | 3.029 | 3.046 | 3.079 | 2.978 | 3.004 | 2.987 | 3.048 | 3.065 | 3.096 | 3.054 | 2.985 | 2.946 | 3.009 | 3.002 | 3.036 | 2.966 | 2.994 | 3.028 | 2.945 | 2.959 | 2.949 | 2.997 | 3.036 | 3.065 | 3.021 | 2.901 | 2.883 | 2.919 | 2.948 | 2.947 | 2.959 | 2.983 | 3.001 | 3.021 | 2.942 | 2.962 | 2.998 | 2.916 | 2.969 | 2.962 | 3.011 | 3.005 | 3.020 | 2.991 | 2.865 | 2.868 |
"Just prior to FVC measurement, patients performed normal tidal breathing. The patient was given a few breaths warning before being told At the end of the next normal breath out, take a deep breath all the way in; they were then verbally encouraged to make a maximal effort before relaxing. The analysis included the same covariates as the primary Outcome Measure. Data was not collected at all time points for all Days and Weeks." (NCT00929110)
Timeframe: 5, 15, and 30 minutes; 1, 2, 3, 4, 6, 8, 10, and 12 hours; 23 hours 15 minutes; and 23 hours 45 minutes post-dose at Days 1 and 15; and Weeks 5, 9, 12, 16, 20, 26, 34, 42, 50, and 52
| Intervention | Liters (Least Squares Mean) | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Day 1, minute 5 (n=135, 74, 74) | Day 1, minute 15 (n=139, 75, 74) | Day 1, minute 30 (n=143, 77, 74) | Day 1, hour 1 (n=144, 76, 75) | Day 1, hour 2 (n=144, 75, 75) | Day 1, hour 3 (n=143, 74, 73) | Day 1, hour 4 (n=144, 70, 74) | Day 1, hour 6 (n=142, 71, 74) | Day 1, hour 8 (n=137, 70, 75) | Day1, hour 10 (n=134, 72, 75) | Day 1, hour 12 (n=130, 69, 70) | Day 1, hour 23, minute 15 (n=129, 71, 72) | Day 1, hour 23, minute 45 (n=128, 74, 75) | Day 15, minute 5 (n=135, 65, 73) | Day 15, minute 15 (n=133, 70, 72) | Day 15, minute 30 (n= 139, 70, 74) | Day 15, hour 1 (n=140, 68, 74) | Week 5, minute 5 (n=134, 66, 68) | Week 5, minute 15 (n=136, 67, 70) | Week 5, minute 30 (n=135, 67, 70) | Week 9, minute 5 (n=128, 66, 70) | Week 9, minute 15 (n=130, 66, 71) | Week 9, minute 30 (n=130, 67, 71) | Week 12, minute 5 (n=130, 69, 70) | Week 12, minute 15 (n=129, 67, 66) | Week 12, minute 30 (n=133, 69, 67) | Week 12, hour 1 (n=132, 67, 69) | Week 12, hour 2 (n=129, 65, 68) | Week 12, hour 3 (n=126, 64, 69) | Week 12, hour 4 (n=124, 64, 68) | Week 12, hour 6 (n=123, 63, 69) | Week 12, hour 8 (n=121, 64, 69) | Week 12, hour 10 (n=124, 61, 69) | Week 12, hour 12 (n=122, 58, 68) | Week 12, hour 16 (n=109, 56, 57) | Week 12, hour 22 (n=117, 60, 63) | Week 12, hour 23, minute 15 (n=126, 66, 67) | Week 12, hour 23, minute 45 (n=124, 65, 63) | Week 16, minute 5 (n=123, 65, 64) | Week 16, minute 15 (n=124, 65, 65) | Week 16, minute 30 (n=125, 65, 65) | Week 20, minute 5 (n=125, 66, 63) | Week 20, minute 15 (n=124, 65, 63) | Week 20, minute 30 (n=125, 65, 63) | Week 26, minute 5 (n=123, 62, 64) | Week 26, minute 15 (n=121, 61, 61) | Week 26, minute 30 (n=125, 64, 64) | Week 26, hour 1 (n=127, 64, 64) | Week 26, hour 2 (n=124, 64, 63) | Week 26, hour 3 (n=124, 64, 64) | Week 26, hour 4 (n=124, 64, 62) | Week 26, hour 23, minute 15 (n=120, 55, 61) | Week 26, hour 23, minute 45 (n=117, 56, 61) | Week 34, minute 5 (n=125, 62, 63) | Week 34, minute 15 (n=123, 62, 63) | Week 34, minute 30 (n=125, 62, 62) | Week 34, hour 1 (n=125, 62, 63) | Week 42, minute 5 (n=119, 61, 58) | Week 42, minute 15 (n=123, 61, 58) | Week 42, minute 30 (n=123, 61, 58) | Week 50, minute 5 (n=120, 60, 57) | Week 50, minute 15 (n=123, 60, 57) | Week 50, minute 30 (n=123, 60, 58) | Week 52, minute 5 (n=124, 60, 57) | Week 52, minute 15 (n=122, 59, 58) | Week 52, minute 30 (n=125, 62, 58) | Week 52, hour 1 (n=125, 62, 57) | Week 52, hour 2 (n=124, 61, 58) | Week 52, hour 3 (n=123, 62, 56) | Week 52, hour 4 (n=121, 60, 55) | Week 52, hour 6 (n=118, 59, 54) | Week 52, hour 8 (n=119, 59, 54) | Week 52, hour 10 (n=119, 59, 55) | Week 52, hour 12 (n=120, 58, 52) | Week 52, hour 16 (n=117, 53, 46) | Week 52, hour 22 (n=118, 60, 52) | Week 52, hour 23, 15 minutes (n=121, 62, 57) | Week 52, hour 23, 45 minutes (n=122, 61, 57) | |
| Glycopyrronium Bromide 50 μg | 3.027 | 3.050 | 3.055 | 3.148 | 3.179 | 3.190 | 3.138 | 3.173 | 3.071 | 3.134 | 3.030 | 2.991 | 3.014 | 3.051 | 3.103 | 3.134 | 3.152 | 3.139 | 3.165 | 3.248 | 3.195 | 3.167 | 3.231 | 3.060 | 3.081 | 3.058 | 3.164 | 3.190 | 3.240 | 3.119 | 3.158 | 3.083 | 3.130 | 3.072 | 2.933 | 2.924 | 3.091 | 3.055 | 3.156 | 3.156 | 3.198 | 3.093 | 3.112 | 3.157 | 2.994 | 3.041 | 3.054 | 3.077 | 3.110 | 3.210 | 3.111 | 3.056 | 2.998 | 3.023 | 3.016 | 3.081 | 3.072 | 3.033 | 3.022 | 3.057 | 3.022 | 3.042 | 3.094 | 2.940 | 2.960 | 2.939 | 3.031 | 3.062 | 3.108 | 3.021 | 2.986 | 2.961 | 3.000 | 2.881 | 2.857 | 2.812 | 2.888 | 2.855 |
| Placebo to Glycopyrronium Bromide | 2.826 | 2.802 | 2.752 | 2.791 | 2.802 | 2.826 | 2.783 | 2.846 | 2.804 | 2.865 | 2.709 | 2.800 | 2.817 | 2.793 | 2.790 | 2.825 | 2.770 | 2.866 | 2.850 | 2.884 | 2.826 | 2.823 | 2.821 | 2.728 | 2.740 | 2.696 | 2.737 | 2.784 | 2.864 | 2.745 | 2.852 | 2.760 | 2.860 | 2.771 | 2.701 | 2.673 | 2.862 | 2.826 | 2.864 | 2.801 | 2.815 | 2.781 | 2.770 | 2.778 | 2.700 | 2.692 | 2.700 | 2.678 | 2.771 | 2.871 | 2.791 | 2.803 | 2.752 | 2.731 | 2.731 | 2.687 | 2.703 | 2.716 | 2.695 | 2.723 | 2.731 | 2.702 | 2.731 | 2.645 | 2.640 | 2.625 | 2.617 | 2.714 | 2.716 | 2.694 | 2.690 | 2.637 | 2.687 | 2.636 | 2.542 | 2.604 | 2.678 | 2.607 |
| Tiotropium 18 μg | 2.956 | 2.991 | 2.979 | 3.041 | 3.049 | 3.119 | 3.102 | 3.148 | 3.074 | 3.119 | 3.012 | 2.988 | 2.994 | 3.014 | 3.103 | 3.078 | 3.060 | 3.071 | 3.092 | 3.180 | 3.097 | 3.101 | 3.149 | 3.023 | 3.018 | 3.027 | 3.098 | 3.155 | 3.146 | 3.084 | 3.120 | 3.011 | 3.117 | 3.020 | 2.880 | 2.870 | 3.110 | 3.004 | 3.104 | 3.082 | 3.112 | 2.993 | 3.029 | 3.050 | 2.954 | 2.976 | 2.994 | 3.016 | 3.080 | 3.176 | 3.086 | 2.932 | 2.895 | 2.881 | 2.898 | 2.971 | 2.963 | 3.069 | 3.065 | 3.098 | 2.963 | 2.937 | 2.985 | 2.860 | 2.935 | 2.929 | 2.980 | 3.021 | 3.053 | 2.978 | 2.982 | 2.942 | 3.012 | 2.849 | 2.772 | 2.716 | 2.852 | 2.797 |
FEV1 was measured with spirometry conducted according to internationally accepted standards. Measurements were made at 5, 15, and 30 minutes; and 1, 2, 3, and 4 hours post-dose. Standardized FEV1 AUC was calculated by the trapezoidal rule. The analysis included the same covariates as the primary Outcome Measure. (NCT00929110)
Timeframe: From 5 minutes to 4 hours post-dose at Day 1 and Weeks 12, 26, and 52
| Intervention | Liters (Least Squares Mean) | |||
|---|---|---|---|---|
| Day 1 | Week 12 (n=460, 214, 232) | Week 26 (n=430, 206, 216) | Week 52 (n=405, 192, 203) | |
| Glycopyrronium Bromide 50 μg | 1.570 | 1.560 | 1.546 | 1.502 |
| Placebo to Glycopyrronium Bromide | 1.373 | 1.384 | 1.369 | 1.336 |
| Tiotropium 18 μg | 1.514 | 1.531 | 1.495 | 1.487 |
FEV1 was measured with spirometry conducted according to internationally accepted standards. Measurements were made at 5, 15, and 30 minutes; 1, 2, 3, 4, 6, 8, 10, and 12 hours; 23 hours 15 minutes; and 23 hours 45 minutes post-dose. Standardized FEV1 AUC was calculated by the trapezoidal rule. The analysis included the same covariates as the primary Outcome Measure. (NCT00929110)
Timeframe: From 5 minutes to 23 hours 45 minutes post-dose at Weeks 12 and 52
| Intervention | Liters (Least Squares Mean) | |
|---|---|---|
| Week 12 | Week 52 (n=125, 62, 58) | |
| Glycopyrronium Bromide 50 μg | 1.486 | 1.445 |
| Placebo to Glycopyrronium Bromide | 1.380 | 1.339 |
| Tiotropium 18 μg | 1.459 | 1.379 |
FEV1 was measured with spirometry conducted according to internationally accepted standards. The analysis included the same covariates as the primary Outcome Measure. Data was not collected at all time points for all Days and Weeks. (NCT00929110)
Timeframe: 5, 15, and 30 minutes; and 1, 2, 3, 4 hours post-dose at Days 1 and 15; and Weeks 5, 9, 12, 16, 20, 26, 34, 42, 50, and 52
| Intervention | Liters (Least Squares Mean) | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Day 1, minute 5 (n=495, 255, 253) | Day 1, minute 15 (n=502, 255, 254) | Day 1, minute 30 (n=507, 252, 254) | Day 1, hour 1 (n=511, 256, 254) | Day 1, hour 2 (n=513, 253, 252) | Day 1, hour 3 (n=510, 248, 252) | Day 1, hour 4 (n=504, 239, 250) | Day 1, hour 23, minute 15 (n=481, 243, 239) | Day 1, hour 23, minute 45 (n=474, 239, 232) | Day 15, minute 5 (n=498, 223, 243) | Day 15, minute 15 (n=487, 229, 239) | Day 15, minute 30 (n=503, 233, 242) | Day 15, hour 1 (n=501, 229, 240) | Week 5, minute 5 (n=476, 221, 231) | Week 5, minute 15 (n=479, 222, 234) | Week 5, minute 30 (n=480, 223, 234) | Week 9, minute 5 (n=454, 217, 227) | Week 9, minute 15 (n=459, 220, 225) | Week 9, minute 30 (n=460, 220, 226) | Week 12, minute 5 (n=453, 212, 230) | Week 12, minute 15 (n=448, 205, 222) | Week 12, minute 30 (n=455, 212, 226) | Week 12, hour 1 (n=455, 210, 227) | Week 12, hour 2 (n=446, 207, 225) | Week 12, hour 3 (n=444, 204, 225) | Week 12, hour 4 (n=437, 202, 224) | Week 12, hour 23, minute 15 (n=430, 200, 214) | Week 12, hour 23, minute 45 (n=426, 195, 205) | Week 16, minute 5 (n=429, 207, 218) | Week 16, minute 15 (n=428, 209, 219) | Week 16, minute 30 (n=433, 209, 220) | Week 20, minute 5 (n=430, 206, 218) | Week 20, minute 15 (n=430, 207, 220) | Week 20, minute 30 (n=431, 207, 221) | Week 26, minute 5 (421, 202, 213) | Week 26, minute 15 (n=414, 200, 207) | Week 26, minute 30 (n=424, 206, 213) | Week 26, hour 1 (n=425, 206, 212) | Week 26, hour 2 (n=420, 203, 208) | Week 26, hour 3 (n=416, 204, 213) | Week 26, hour 4 (n=416, 203, 208) | Week 26, hour 23, minute 15 (n=405, 187, 202) | Week 26, hour 23, minute 45 (n=401, 185, 198) | Week 34, minute 5 (n=408, 194, 212) | Week 34, minute 15 (n=407, 191, 214) | Week 34, minute 30 (n=410, 196, 215) | Week 34, hour 1 (n=412, 195, 215) | Week 42, minute 5 (n=398, 189, 199) | Week 42, minute 15 (n=405, 188, 201) | Week 42, minute 30 (n=405, 189, 201) | Week 50, minute 5 (n=386, 185, 199) | Week 50, minute 15 (n=391, 187, 203) | Week 50, minute 30 (n=392, 186, 204) | Week 52, minute 5 (n=401, 188, 197) | Week 52, minute 15 (n=394, 183, 200) | Week 52, minute 30 (n=402, 189, 202) | Week 52, hour 1 (n=404, 190, 201) | Week 52, hour 2 (n=402, 186, 202) | Week 52, hour 3 (n=400, 186, 199) | Week 52, hour 4 (n=397, 184, 199) | Week 52, hour 23, minute 15 (n=388, 183, 198) | Week 52, hour 23, minute 45 (n=395, 185, 199) | |
| Glycopyrronium Bromide 50 μg | 1.443 | 1.501 | 1.524 | 1.552 | 1.612 | 1.590 | 1.590 | 1.459 | 1.482 | 1.491 | 1.527 | 1.538 | 1.561 | 1.509 | 1.538 | 1.564 | 1.529 | 1.550 | 1.569 | 1.502 | 1.527 | 1.522 | 1.556 | 1.595 | 1.592 | 1.558 | 1.481 | 1.493 | 1.514 | 1.530 | 1.546 | 1.495 | 1.525 | 1.544 | 1.479 | 1.504 | 1.513 | 1.541 | 1.570 | 1.570 | 1.547 | 1.464 | 1.474 | 1.481 | 1.508 | 1.518 | 1.534 | 1.489 | 1.511 | 1.518 | 1.454 | 1.496 | 1.504 | 1.436 | 1.471 | 1.471 | 1.499 | 1.526 | 1.525 | 1.504 | 1.419 | 1.424 |
| Placebo to Glycopyrronium Bromide | 1.357 | 1.359 | 1.357 | 1.353 | 1.397 | 1.389 | 1.396 | 1.364 | 1.390 | 1.368 | 1.371 | 1.368 | 1.379 | 1.371 | 1.389 | 1.396 | 1.366 | 1.376 | 1.378 | 1.349 | 1.352 | 1.352 | 1.364 | 1.423 | 1.414 | 1.416 | 1.381 | 1.413 | 1.373 | 1.372 | 1.372 | 1.351 | 1.362 | 1.362 | 1.339 | 1.340 | 1.341 | 1.345 | 1.388 | 1.398 | 1.384 | 1.326 | 1.354 | 1.338 | 1.333 | 1.331 | 1.331 | 1.342 | 1.344 | 1.350 | 1.336 | 1.341 | 1.341 | 1.305 | 1.323 | 1.319 | 1.325 | 1.363 | 1.344 | 1.346 | 1.303 | 1.320 |
| Tiotropium 18 μg | 1.402 | 1.437 | 1.468 | 1.484 | 1.549 | 1.560 | 1.549 | 1.457 | 1.473 | 1.472 | 1.514 | 1.504 | 1.525 | 1.488 | 1.508 | 1.525 | 1.499 | 1.515 | 1.531 | 1.477 | 1.501 | 1.491 | 1.528 | 1.558 | 1.561 | 1.534 | 1.457 | 1.472 | 1.487 | 1.491 | 1.505 | 1.464 | 1.495 | 1.498 | 1.429 | 1.458 | 1.451 | 1.487 | 1.524 | 1.526 | 1.504 | 1.415 | 1.426 | 1.422 | 1.443 | 1.444 | 1.464 | 1.459 | 1.477 | 1.496 | 1.429 | 1.462 | 1.475 | 1.419 | 1.451 | 1.451 | 1.482 | 1.511 | 1.509 | 1.501 | 1.397 | 1.411 |
FEV1 was measured with spirometry conducted according to internationally accepted standards. The analysis included the same covariates as the primary Outcome Measure. Data was not collected at all time points for all Days and Weeks. (NCT00929110)
Timeframe: 5, 15, and 30 minutes; 1, 2, 3, 4, 6, 8, 10, and 12 hours; 23 hours 15 minutes; and 23 hours 45 minutes post-dose at Days 1 and 15; and Weeks 5, 9, 12, 16, 20, 26, 34, 42, 50, and 52
| Intervention | Liters (Least Squares Mean) | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Day 1, minute 5 (n=135, 74, 74) | Day 1, minute 15 (n=139, 75, 74) | Day 1, minute 30 (n=143, 77, 74) | Day 1, hour 1 (n=144, 76, 75) | Day 1, hour 2 (n=144, 75, 75) | Day 1, hour 3 (n=143, 74, 73) | Day 1, hour 4 (n=144, 70, 74) | Day 1, hour 6 (n=142, 71, 74) | Day 1, hour 8 (n=137, 70, 75) | Day1, hour 10 (n=134, 72, 75) | Day 1, hour 12 (n=130, 69, 70) | Day 1, hour 23, minute 15 (n=129, 71, 72) | Day 1, hour 23, minute 45 (n=128, 74, 75) | Day 15, minute 5 (n=135, 65, 73) | Day 15, minute 15 (n=133, 70, 72) | Day 15, minute 30 (n= 139, 70, 74) | Day 15, hour 1 (n=140, 68, 74) | Week 5, minute 5 (n=134, 66, 68) | Week 5, minute 15 (n=136, 67, 70) | Week 5, minute 30 (n=135, 67, 70) | Week 9, minute 5 (n=128, 66, 70) | Week 9, minute 15 (n=130, 66, 71) | Week 9, minute 30 (n=130, 67, 71) | Week 12, minute 5 (n=130, 69, 70) | Week 12, minute 15 (n=129, 67, 66) | Week 12, minute 30 (n=133, 69, 67) | Week 12, hour 1 (n=132, 67, 69) | Week 12, hour 2 (n=129, 65, 68) | Week 12, hour 3 (n=126, 64, 69) | Week 12, hour 4 (n=124, 64, 68) | Week 12, hour 6 (n=123, 63, 69) | Week 12, hour 8 (n=121, 64, 69) | Week 12, hour 10 (n=124, 61, 69) | Week 12, hour 12 (n=122, 58, 68) | Week 12, hour 16 (n=109, 56, 57) | Week 12, hour 22 (n=117, 60, 63) | Week 12, hour 23, minute 15 (n=126, 66, 67) | Week 12, hour 23, minute 45 (n=124, 65, 63) | Week 16, minute 5 (n=123, 65, 64) | Week 16, minute 15 (n=124, 65, 65) | Week 16, minute 30 (n=125, 65, 65) | Week 20, minute 5 (n=125, 66, 63) | Week 20, minute 15 (n=124, 65, 63) | Week 20, minute 30 (n=125, 65, 63) | Week 26, minute 5 (n=123, 62, 64) | Week 26, minute 15 (n=121, 61, 61) | Week 26, minute 30 (n=125, 64, 64) | Week 26, hour 1 (n=127, 64, 64) | Week 26, hour 2 (n=124, 64, 63) | Week 26, hour 3 (n=124, 64, 64) | Week 26, hour 4 (n=124, 64, 62) | Week 26, hour 23, minute 15 (n=120, 55, 61) | Week 26, hour 23, minute 45 (n=117, 56, 61) | Week 34, minute 5 (n=125, 62, 63) | Week 34, minute 15 (n=123, 62, 63) | Week 34, minute 30 (n=125, 62, 62) | Week 34, hour 1 (n=125, 62, 63) | Week 42, minute 5 (n=119, 61, 58) | Week 42, minute 15 (n=123, 61, 58) | Week 42, minute 30 (n=123, 61, 58) | Week 50, minute 5 (n=120, 60, 57) | Week 50, minute 15 (n=123, 60, 57) | Week 50, minute 30 (n=123, 60, 58) | Week 52, minute 5 (n=124, 60, 57) | Week 52, minute 15 (n=122, 59, 58) | Week 52, minute 30 (n=125, 62, 58) | Week 52, hour 1 (n=125, 62, 57) | Week 52, hour 2 (n=124, 61, 58) | Week 52, hour 3 (n=123, 62, 56) | Week 52, hour 4 (n=121, 60, 55) | Week 52, hour 6 (n=118, 59, 54) | Week 52, hour 8 (n=119, 59, 54) | Week 52, hour 10 (n=119, 59, 55) | Week 52, hour 12 (n=120, 58, 52) | Week 52, hour 16 (n=117, 53, 46) | Week 52, hour 22 (n=118, 60, 52) | Week 52, hour 23, 15 minutes (n=121, 62, 57) | Week 52, hour 23, 45 minutes (n=122, 61, 57) | |
| Glycopyrronium Bromide 50 μg | 1.494 | 1.548 | 1.561 | 1.583 | 1.639 | 1.629 | 1.599 | 1.578 | 1.544 | 1.546 | 1.522 | 1.471 | 1.518 | 1.494 | 1.530 | 1.551 | 1.575 | 1.550 | 1.575 | 1.630 | 1.562 | 1.583 | 1.603 | 1.497 | 1.523 | 1.517 | 1.557 | 1.596 | 1.600 | 1.584 | 1.558 | 1.535 | 1.541 | 1.522 | 1.431 | 1.420 | 1.518 | 1.513 | 1.538 | 1.557 | 1.570 | 1.518 | 1.535 | 1.576 | 1.483 | 1.521 | 1.529 | 1.546 | 1.590 | 1.614 | 1.577 | 1.477 | 1.483 | 1.515 | 1.529 | 1.567 | 1.557 | 1.512 | 1.520 | 1.537 | 1.490 | 1.529 | 1.545 | 1.456 | 1.502 | 1.483 | 1.525 | 1.554 | 1.558 | 1.535 | 1.494 | 1.473 | 1.478 | 1.451 | 1.377 | 1.391 | 1.447 | 1.434 |
| Placebo to Glycopyrronium Bromide | 1.416 | 1.428 | 1.409 | 1.404 | 1.445 | 1.435 | 1.415 | 1.426 | 1.431 | 1.415 | 1.369 | 1.396 | 1.446 | 1.421 | 1.411 | 1.417 | 1.409 | 1.448 | 1.452 | 1.481 | 1.417 | 1.441 | 1.427 | 1.385 | 1.373 | 1.362 | 1.369 | 1.434 | 1.443 | 1.442 | 1.443 | 1.408 | 1.435 | 1.422 | 1.360 | 1.349 | 1.456 | 1.470 | 1.430 | 1.422 | 1.409 | 1.393 | 1.380 | 1.391 | 1.361 | 1.377 | 1.353 | 1.364 | 1.422 | 1.442 | 1.416 | 1.374 | 1.401 | 1.359 | 1.360 | 1.353 | 1.352 | 1.394 | 1.412 | 1.391 | 1.357 | 1.375 | 1.368 | 1.337 | 1.380 | 1.366 | 1.356 | 1.418 | 1.384 | 1.381 | 1.370 | 1.358 | 1.349 | 1.369 | 1.277 | 1.314 | 1.362 | 1.337 |
| Tiotropium 18 μg | 1.447 | 1.485 | 1.483 | 1.514 | 1.569 | 1.587 | 1.560 | 1.575 | 1.545 | 1.537 | 1.480 | 1.481 | 1.499 | 1.490 | 1.537 | 1.516 | 1.540 | 1.525 | 1.543 | 1.584 | 1.520 | 1.534 | 1.549 | 1.474 | 1.481 | 1.488 | 1.519 | 1.565 | 1.566 | 1.535 | 1.520 | 1.479 | 1.532 | 1.487 | 1.378 | 1.371 | 1.520 | 1.488 | 1.515 | 1.530 | 1.535 | 1.453 | 1.479 | 1.502 | 1.415 | 1.464 | 1.439 | 1.462 | 1.520 | 1.555 | 1.519 | 1.416 | 1.405 | 1.407 | 1.425 | 1.452 | 1.472 | 1.490 | 1.491 | 1.517 | 1.422 | 1.452 | 1.470 | 1.377 | 1.428 | 1.407 | 1.439 | 1.479 | 1.487 | 1.468 | 1.461 | 1.418 | 1.419 | 1.347 | 1.329 | 1.282 | 1.387 | 1.359 |
FEV1 was measured with spirometry conducted according to internationally accepted standards. Trough FEV1 was defined as the average of measurements made 23 hours 15 minutes and 23 hours 45 minutes post-dose. The analysis included baseline FEV1 measurement, baseline inhaled corticosteroid use (Yes/No), FEV1 prior to inhalation of short-acting β2 agonist (SABA), and FEV1 45 min post-inhalation of SABA as covariates. (NCT00929110)
Timeframe: Week 12
| Intervention | Liters (Least Squares Mean) |
|---|---|
| Glycopyrronium Bromide 50 μg | 1.469 |
| Placebo to Glycopyrronium Bromide | 1.372 |
| Tiotropium 18 μg | 1.455 |
The TDI measured changes in dyspnea from baseline during treatment and included 3 domains: Functional impairment (activities of daily living), magnitude of task (intensity of activity), and magnitude of effort (difficulty breathing). Each domain was rated from -3 to 3 (major deterioration-major improvement). The total score ranged from -9 to 9; minus scores indicate deterioration. The analysis included the same covariates as the primary Outcome Measure. (NCT00929110)
Timeframe: Week 26
| Intervention | Units on a scale (Least Squares Mean) |
|---|---|
| Glycopyrronium Bromide 50 μg | 2.13 |
| Placebo to Glycopyrronium Bromide | 1.32 |
| Tiotropium 18 μg | 2.26 |
Time to first moderate or severe COPD exacerbation was calculated as the number of days from baseline to the day on which the patient experienced the first moderate or severe COPD exacerbation. A COPD exacerbation was considered to be moderate if treatment with systemic corticosteroids and/or antibiotic was required. A COPD exacerbation was considered to be severe if treatment for moderate severity and hospitalization was required. (NCT00929110)
Timeframe: Baseline to Week 52 (patients with no moderate or severe exacerbations who completed the study were censored at the final visit date, which may have exceeded 52 weeks)
| Intervention | Days (Median) |
|---|---|
| Glycopyrronium Bromide 50 μg | 363.0 |
| Placebo to Glycopyrronium Bromide | 231.0 |
| Tiotropium 18 μg | 364.0 |
A COPD exacerbation was considered to be moderate if treatment with systemic corticosteroids and/or antibiotic was required. A COPD exacerbation was considered to be severe if treatment for moderate severity and hospitalization was required. (NCT00929110)
Timeframe: Baseline to Week 52
| Intervention | Percentage of participants (Number) |
|---|---|
| Glycopyrronium Bromide 50 μg | 32.8 |
| Placebo to Glycopyrronium Bromide | 40.2 |
| Tiotropium 18 μg | 30.1 |
The number of moderate or severe exacerbations of COPD per year during the study was calculated by dividing the total number of exacerbations during the study by the total number of years of treatment. A COPD exacerbation was considered to be moderate if treatment with systemic corticosteroids and/or antibiotic was required. A COPD exacerbation was considered to be severe if treatment for moderate severity and hospitalization was required. (NCT00929110)
Timeframe: Baseline to Week 52
| Intervention | Exacerbations per treatment year (Number) |
|---|---|
| Glycopyrronium Bromide 50 μg | 0.54 |
| Placebo to Glycopyrronium Bromide | 0.80 |
| Tiotropium 18 μg | 0.62 |
The SGRQ contained 51 patient-rated items divided into three components: Symptoms (respiratory symptoms, their frequency, and severity), Activity (activities that cause or are limited by breathlessness), and Impacts (social functioning and psychological disturbances resulting from airway disease). A total score for the 3 components was calculated and ranged from 0 to 100. Higher values indicate greater impairment of QoL. The analysis included the same covariates as the primary Outcome Measure. (NCT00929110)
Timeframe: Week 52
| Intervention | Units on a scale (Least Squares Mean) |
|---|---|
| Glycopyrronium Bromide 50 μg | 40.85 |
| Placebo to Glycopyrronium Bromide | 44.16 |
| Tiotropium 18 μg | 41.32 |
The daily total symptom score was defined as the sum of the morning and evening patient self-reported diary assessments of 6 symptoms (respiratory symptoms/impact on daily activities, cough, wheeze, amount of sputum, color of sputum, and breathlessness). Means for baseline (14 day maximum run-in period) and the 52 week treatment period were calculated. Mean scores ranged from 0-18, with a higher score indicating worse symptoms. A negative change score indicated improvement. (NCT00929110)
Timeframe: Baseline to Week 52
| Intervention | Units on a scale (Least Squares Mean) |
|---|---|
| Glycopyrronium Bromide 50 μg | -1.85 |
| Placebo to Glycopyrronium Bromide | -1.42 |
| Tiotropium 18 μg | -1.87 |
The number of puffs of rescue medication taken in the previous 12 hours was recorded in the Patient Diary in the morning and evening. The mean daily number of puffs of rescue medication taken was calculated by dividing the number of puffs of rescue medication per day over the 52 weeks of the study by the number of days with non-missing rescue medication data. Rescue medication data recorded during the 14 day run-in period was used to calculate the baseline. The analysis included the same covariates as the primary Outcome Measure. A positive change score indicates more puffs taken. (NCT00929110)
Timeframe: Baseline to Week 52
| Intervention | Puffs (Least Squares Mean) |
|---|---|
| Glycopyrronium Bromide 50 μg | -1.58 |
| Placebo to Glycopyrronium Bromide | -1.20 |
| Tiotropium 18 μg | -1.83 |
"A day with no daytime symptoms was defined as any day where the patient recorded no cough, no wheeze, no production of sputum, no feeling of breathlessness (other than when running), and no puffs of rescue medication during the previous 12 hours in evening entry in the electronic patient diary. The percentage of days with no daytime symptoms was calculated as the total number of days with no daytime symptoms over the 52 week treatment period divided by the total number of days where diary recordings were made." (NCT00929110)
Timeframe: Baseline to Week 52
| Intervention | Percentage of days (Least Squares Mean) |
|---|---|
| Glycopyrronium Bromide 50 μg | 6.54 |
| Placebo to Glycopyrronium Bromide | 3.81 |
| Tiotropium 18 μg | 7.14 |
"A day able to perform usual daily activities was defined as any day where the patient recorded in their electronic diary in the evening that they were not prevented from performing their usual daily activities due to respiratory symptoms during the previous 12 hours. The percentage of days able to perform usual daily activities was calculated as the total number of days able to perform usual daily activities over the 52 week treatment period divided by the total number of days where diary recordings were made." (NCT00929110)
Timeframe: Baseline to Week 52
| Intervention | Percentage of days (Least Squares Mean) |
|---|---|
| Glycopyrronium Bromide 50 μg | 38.02 |
| Placebo to Glycopyrronium Bromide | 36.18 |
| Tiotropium 18 μg | 38.09 |
FEV1 was measured with spirometry conducted according to internationally accepted standards. Measurements were made at 5, 15, and 30 minutes; and 1, 2, 3, 4, 6, 8 10, and 12 hours post-dose. Standardized FEV1 AUC was calculated by the trapezoidal rule. The analysis included the same covariates as the primary Outcome Measure. (NCT00929110)
Timeframe: From 5 minutes to 12 hours post-dose at Day 1 and Weeks 12 and 52
| Intervention | Liters (Least Squares Mean) | ||
|---|---|---|---|
| Day 1 | Week 12 (n=133, 69, 70) | Week 52 (n=125, 62, 58) | |
| Glycopyrronium Bromide 50 μg | 1.566 | 1.539 | 1.492 |
| Placebo to Glycopyrronium Bromide | 1.407 | 1.398 | 1.364 |
| Tiotropium 18 μg | 1.534 | 1.505 | 1.424 |
Average systolic blood pressure value (NCT00939211)
Timeframe: 0, 30 min, 2 h, 4 h
| Intervention | mmHg (Mean) |
|---|---|
| AZD9164 100 Mcg First, Then Placebo for Spiriva | 125.5 |
| AZD9164 400 Mcg First, Then Placebo for Spiriva | 127.9 |
| AZD9164 1200 Mcg First, Then Placebo for Spiriva | 127.3 |
| Spiriva 18 Mcg First, Then Placebo for AZD9164 | 128.0 |
| Placebo for Spiriva First, Then Placebo for AZD9164 | 126.5 |
15 min FEV1 value (NCT00939211)
Timeframe: 15 min
| Intervention | L (Mean) |
|---|---|
| AZD9164 100 Mcg First, Then Placebo for Spiriva | 1.42 |
| AZD9164 400 Mcg First, Then Placebo for Spiriva | 1.30 |
| AZD9164 1200 Mcg First, Then Placebo for Spiriva | 1.25 |
| Spiriva 18 Mcg First, Then Placebo for AZD9164 | 1.55 |
| Placebo for Spiriva First, Then Placebo for AZD9164 | 1.49 |
Maximum plasma concentration of AZD9164 (NCT00939211)
Timeframe: 0, 5 min, 15 min, 30 min, 60 min, 90 min, 2 h, 4 h, 6 h, 8 h, 12 h, 24 h
| Intervention | nmol/L (Geometric Mean) |
|---|---|
| AZD9164 100 Mcg First, Then Placebo for Spiriva | 0.529 |
| AZD9164 400 Mcg First, Then Placebo for Spiriva | 3.629 |
| AZD9164 1200 Mcg First, Then Placebo for Spiriva | 20.02 |
Average pulse value (NCT00939211)
Timeframe: 0, 30 min, 2 h, 4 h
| Intervention | bpm (Mean) |
|---|---|
| AZD9164 100 Mcg First, Then Placebo for Spiriva | 61.1 |
| AZD9164 400 Mcg First, Then Placebo for Spiriva | 62.9 |
| AZD9164 1200 Mcg First, Then Placebo for Spiriva | 64.8 |
| Spiriva 18 Mcg First, Then Placebo for AZD9164 | 60.2 |
| Placebo for Spiriva First, Then Placebo for AZD9164 | 61.3 |
Average QTcF value (NCT00939211)
Timeframe: 0, 30 min, 2 h, 4 h
| Intervention | ms (Mean) |
|---|---|
| AZD9164 100 Mcg First, Then Placebo for Spiriva | 400 |
| AZD9164 400 Mcg First, Then Placebo for Spiriva | 399 |
| AZD9164 1200 Mcg First, Then Placebo for Spiriva | 396 |
| Spiriva 18 Mcg First, Then Placebo for AZD9164 | 401 |
| Placebo for Spiriva First, Then Placebo for AZD9164 | 398 |
Maximum FEV1 value (NCT00939211)
Timeframe: 0, 15 min, 30 min, 60 min, 2 h, 4 h, 6 h, 8 h, 10 h, 12 h, 14 h, 18 h, 22 h, 24 h
| Intervention | L (Mean) |
|---|---|
| AZD9164 100 Mcg First, Then Placebo for Spiriva | 1.71 |
| AZD9164 400 Mcg First, Then Placebo for Spiriva | 1.79 |
| AZD9164 1200 Mcg First, Then Placebo for Spiriva | 1.72 |
| Spiriva 18 Mcg First, Then Placebo for AZD9164 | 1.71 |
| Placebo for Spiriva First, Then Placebo for AZD9164 | 1.63 |
Average heart rate value (NCT00939211)
Timeframe: 0, 30 min, 2 h, 4 h
| Intervention | bpm (Mean) |
|---|---|
| AZD9164 100 Mcg First, Then Placebo for Spiriva | 61.0 |
| AZD9164 400 Mcg First, Then Placebo for Spiriva | 62.8 |
| AZD9164 1200 Mcg First, Then Placebo for Spiriva | 65.2 |
| Spiriva 18 Mcg First, Then Placebo for AZD9164 | 61.1 |
| Placebo for Spiriva First, Then Placebo for AZD9164 | 61.3 |
Area under the AZD9164 plasma concentration curve (NCT00939211)
Timeframe: 0, 5 min, 15 min, 30 min, 60 min, 90 min, 2 h, 4 h, 6 h, 8 h, 12 h, 24 h
| Intervention | nmol*h/L (Geometric Mean) |
|---|---|
| AZD9164 100 Mcg First, Then Placebo for Spiriva | 2.90 |
| AZD9164 400 Mcg First, Then Placebo for Spiriva | 15.2 |
| AZD9164 1200 Mcg First, Then Placebo for Spiriva | 58.1 |
Average FEV1 value (NCT00939211)
Timeframe: 0, 15 min, 30 min, 60 min, 2 h, 4 h, 6 h, 8 h, 10 h, 12 h, 14 h, 18 h, 22 h, 24 h
| Intervention | L (Mean) |
|---|---|
| AZD9164 100 Mcg First, Then Placebo for Spiriva | 1.57 |
| AZD9164 400 Mcg First, Then Placebo for Spiriva | 1.63 |
| AZD9164 1200 Mcg First, Then Placebo for Spiriva | 1.56 |
| Spiriva 18 Mcg First, Then Placebo for AZD9164 | 1.58 |
| Placebo for Spiriva First, Then Placebo for AZD9164 | 1.50 |
Trough FEV1 value (NCT00939211)
Timeframe: 22 h, 24 h, 26 h
| Intervention | L (Mean) |
|---|---|
| AZD9164 100 Mcg First, Then Placebo for Spiriva | 1.58 |
| AZD9164 400 Mcg First, Then Placebo for Spiriva | 1.63 |
| AZD9164 1200 Mcg First, Then Placebo for Spiriva | 1.62 |
| Spiriva 18 Mcg First, Then Placebo for AZD9164 | 1.57 |
| Placebo for Spiriva First, Then Placebo for AZD9164 | 1.52 |
Average diastolic blood pressure value (NCT00939211)
Timeframe: 0, 30 min, 2 h, 4 h
| Intervention | mmHg (Mean) |
|---|---|
| AZD9164 100 Mcg First, Then Placebo for Spiriva | 73.1 |
| AZD9164 400 Mcg First, Then Placebo for Spiriva | 75.6 |
| AZD9164 1200 Mcg First, Then Placebo for Spiriva | 74.2 |
| Spiriva 18 Mcg First, Then Placebo for AZD9164 | 74.8 |
| Placebo for Spiriva First, Then Placebo for AZD9164 | 73.5 |
Serial FEV1 for OQ dosing is recorded at the pre-AM dose (time 0 h) and at 1, 3, 6, 9, 12,13, 15, 18, 21, 24 and 28 hs after the AM dose on D 14. For BID dosing, the 12 h AM dose corresponds to the pre-PM dose, 13 h AM dose corresponds to the 1 h PM dose, 15 h AM dose corresponds to the 3 h PM dose, 18 h AM corresponds to the 6 h PM dose, 21 h AM dose corresponds to 9 h PM dose, 24 h AM dose corresponds to the 12 h PM dose and 28 h AM dose corresponds to the 16 h PM dose in the table. Analysis performed using a mixed model with covariates of mean BL, period BL, trt, period, time, time by period BL interaction, time by mean BL interaction and time by trt interaction as fixed effects and par. as a random effect. BL is the FEV1 value recorded pre-dose on D 1 of each TP; mean BL is the mean of the BLs for each par. and period BL is the difference between the BL and the mean BL in each TP for each par. Change from BL for each TP is the trough FEV1 at Day 15 minus the BL value for that TP. (NCT00950807)
Timeframe: Baseline and Day (D) 14 of each treatment period (TP; up to Study Day 70)
| Intervention | Liters (Mean) | |||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Pre-AM dose, n=152,34,33,35,37,30,32,33,32,34 | 1 hour AM, n=151,34,31,35,37,29,32,33,32,34 | 3 hour AM, n=150,34,32,35,37,29,31,33,32,34 | 6 hour AM, n=151,34,33,35,37,30,32,33,31,34 | 9 hour AM, n=149,33,33,34,37,30,31,32,32,33 | 12 hour AM, n=150,34,33,34,37,30,31,32,32,33 | 13 hour AM, n=147,33,33,35,37,29,31,33,32,33 | 15 hour AM, n=151,34,33,35,37,29,30,33,32,34 | 18 hour AM, n=148,33,33,35,36,29,31,33,32,34 | 21 hour AM, n=150,34,33,35,37,29,29,33,32,34 | 24 hour AM, n=150,34,33,35,37,29,31,33,32,34 | 28 hour AM, n=145,34,33,35,37,29,31,33,32,34 | |
| Placebo | -0.002 | 0.022 | -0.003 | -0.019 | -0.033 | -0.068 | -0.082 | -0.085 | -0.145 | -0.147 | -0.051 | 0.065 |
| Tio 18 µg QD | 0.129 | 0.229 | 0.191 | 0.152 | 0.105 | 0.153 | 0.065 | 0.036 | -0.097 | -0.060 | 0.047 | 0.108 |
| UMEC 1000 µg QD | 0.120 | 0.072 | 0.148 | 0.105 | 0.076 | 0.074 | 0.096 | 0.050 | 0.001 | 0.006 | 0.142 | 0.191 |
| UMEC 125 µg BID | 0.139 | 0.132 | 0.112 | 0.100 | 0.104 | 0.099 | 0.018 | 0.054 | 0.016 | 0.029 | 0.091 | 0.219 |
| UMEC 125 µg QD | 0.101 | 0.164 | 0.158 | 0.114 | 0.077 | 0.083 | 0.077 | 0.051 | 0.002 | 0.035 | 0.093 | 0.177 |
| UMEC 250 µg BID | 0.152 | 0.142 | 0.153 | 0.141 | 0.099 | 0.074 | 0.048 | 0.096 | -0.048 | -0.005 | 0.139 | 0.185 |
| UMEC 250 µg QD | 0.167 | 0.140 | 0.222 | 0.149 | 0.123 | 0.084 | 0.071 | 0.069 | -0.018 | -0.036 | 0.045 | 0.212 |
| UMEC 500 µg QD | 0.095 | 0.056 | 0.142 | 0.120 | 0.118 | 0.096 | 0.103 | 0.038 | -0.007 | 0.004 | 0.088 | 0.143 |
| UMEC 62.5 µg BID | 0.096 | 0.159 | 0.153 | 0.090 | 0.105 | 0.058 | 0.066 | 0.085 | -0.020 | -0.059 | 0.021 | 0.164 |
| UMEC 62.5 µg QD | 0.140 | 0.246 | 0.157 | 0.137 | 0.121 | 0.087 | 0.071 | 0.074 | -0.053 | 0.009 | 0.067 | 0.179 |
FEV1 is a measure of lung function and is defined as the maximal amount of air that can be forcefully exhaled in one second. Trough FEV1 on Treatment Day 15 is defined as the value obtained 24 hours after the morning dose administered on Day 14. Analysis were performed using a mixed model with covariates of mean Baseline, period Baseline, treatment and period as fixed effects and participant as a random effect. Baseline is the FEV1 value recorded pre-dose on Day 1 of each treatment period; mean Baseline is the mean of the Baselines for each participant and period Baseline is the difference between the Baseline and the mean Baseline in each treatment period for each participant. Change from Baseline for each treatment period is the trough FEV1 at Day 15 minus the Baseline value for that treatment period. (NCT00950807)
Timeframe: Baseline and Day 15 of each treatment period (up to Study Day 71)
| Intervention | Liters (Least Squares Mean) |
|---|---|
| Placebo | -0.047 |
| UMEC 62.5 µg QD | 0.081 |
| UMEC 125 µg QD | 0.099 |
| UMEC 250 µg QD | 0.048 |
| UMEC 500 µg QD | 0.092 |
| UMEC 1000 µg QD | 0.138 |
| UMEC 62.5 µg BID | 0.032 |
| UMEC 125 µg BID | 0.087 |
| UMEC 250 µg BID | 0.124 |
| Tio 18 µg QD | 0.058 |
FEV1 is a measure of lung function and is defined as the maximal amount of air that can be forcefully exhaled in one second. The weighted mean FEV1 was derived by calculating the area under the FEV1/time curve (AUC) using the trapezoidal rule, and then dividing the value by the time interval over which the AUC was calculated. The weighted mean FEV1 was calculated using 0-24 hour (h) post-dose measurements at Day 14 of each treatment period, which included pre-dose and post-dose 1, 3, 6, 9, 12, 13, 15, 18, 21 and 24 hours. Analysis performed using a mixed model with covariates mean BL, period BL, treatment and period as fixed effects and participant as a random effect. BL is the FEV1 value recorded pre-dose on Day 1 of each TP; mean BL is the mean of the BLs for each participant and period BL is the difference between the BL and the mean BL in each TP for each participant. Change from BL for each TP is the trough FEV1 at Day 15 minus the BL value for that TP. (NCT00950807)
Timeframe: Baseline and Day 14 of each treatment period (TP; up to Study Day 70)
| Intervention | Liters (Least Squares Mean) |
|---|---|
| Placebo | -0.059 |
| UMEC 62.5 µg QD | 0.085 |
| UMEC 125 µg QD | 0.077 |
| UMEC 250 µg QD | 0.077 |
| UMEC 500 µg QD | 0.072 |
| UMEC 1000 µg QD | 0.080 |
| UMEC 62.5 µg BID | 0.062 |
| UMEC 125 µg BID | 0.083 |
| UMEC 250 µg BID | 0.075 |
| Tio 18 µg QD | 0.069 |
Change from baseline in on-treatment exercise capacity measured by six-minute walk test (6-MWT); change was calculated as week score minus baseline score. Statistical analysis results are presented only for the week 52 visit as this is the primary timepoint of interest. (NCT00975195)
Timeframe: Baseline and week 18 and 52 visits
| Intervention | meters (Least Squares Mean) | |
|---|---|---|
| Week 18 visit (N=1111, 1110) | Week 52 visit (N=1013, 987) | |
| Fluticasone Maintenance | 3.89 | 3.94 |
| Fluticasone Withdrawal | 1.94 | 0.42 |
Change from baseline in on-treatment Forced Expiratory Volume in One Second (FEV1) as measured by home based spirometry. Change was calculated as week score minus baseline score. The weekly mean was defined as the mean of the measurements taken during the last 7 days prior to the visit date, and was calculated if ≥4 of the 7 days had non-missing measurements. Statistical analysis results are presented only for the week 52 visit as this is the primary timepoint of interest. (NCT00975195)
Timeframe: Baseline and week 6, 12, 18, 27, 36, 45 and 52 visits
| Intervention | Litres (Least Squares Mean) | ||||||
|---|---|---|---|---|---|---|---|
| Week 6 visit (N=893, 939) | Week 12 visit (N=910, 930) | Week 18 visit (N=913, 901) | Week 27 visit (N=863, 843) | Week 36 visit (N=854, 845) | Week 45 visit (N=830, 815) | Week 52 visit (N=785, 788) | |
| Fluticasone Maintenance | -0.049 | -0.050 | -0.051 | -0.056 | -0.059 | -0.061 | -0.067 |
| Fluticasone Withdrawal | -0.053 | -0.056 | -0.093 | -0.092 | -0.099 | -0.103 | -0.115 |
Change from baseline in on-treatment forced vital capacity (FVC) as measured by home based spirometry. Change was calculated as week score minus baseline score. The weekly mean was defined as the mean of the measurements taken during the last 7 days prior to the visit date, and was calculated if ≥4 of the 7 days had non-missing measurements. Statistical analysis results are presented only for the week 52 visit as this is the primary timepoint of interest. (NCT00975195)
Timeframe: Baseline and week 6, 12, 18, 27, 36, 45 and 52 visits
| Intervention | Litres (Least Squares Mean) | ||||||
|---|---|---|---|---|---|---|---|
| Week 6 visit (N=893, 939) | Week 12 visit (N=910, 930) | Week 18 visit (N=913, 901) | Week 27 visit (N=863, 843) | Week 36 visit (N=854, 845) | Week 45 visit (N=830, 815) | Week 52 visit (N=785, 788) | |
| Fluticasone Maintenance | -0.116 | -0.113 | -0.122 | -0.123 | -0.135 | -0.141 | -0.157 |
| Fluticasone Withdrawal | -0.089 | -0.105 | -0.124 | -0.147 | -0.158 | -0.168 | -0.201 |
Change from baseline in on-treatment lung function as measured by trough forced expiratory volume in one second (FEV1); change was calculated as week score minus baseline score. Statistical analysis results are presented only for the week 52 visit as this is the primary timepoint of interest. (NCT00975195)
Timeframe: Baseline and week 6, 12, 18 and 52 visits
| Intervention | Litres (Least Squares Mean) | |||
|---|---|---|---|---|
| Week 6 visit (N=1135, 1135) | Week 12 visit (N=1114, 1092) | Week 18 visit (N=1077, 1058) | Week 52 visit (N=970, 935) | |
| Fluticasone Maintenance | -0.009 | -0.011 | -0.011 | -0.016 |
| Fluticasone Withdrawal | -0.011 | -0.018 | -0.050 | -0.059 |
Change from baseline in on-treatment peak expiratory flow rate (PEFR) as measured by home based spirometry; change was calculated as week score minus baseline score. Statistical analysis results are presented only for the week 52 visit as this is the primary timepoint of interest. (NCT00975195)
Timeframe: Baseline and week 6, 12, 18, 27, 36, 45 and 52 visits
| Intervention | Litres/sec (Least Squares Mean) | ||||||
|---|---|---|---|---|---|---|---|
| Week 6 visit (N=893, 939) | Week 12 visit (N=910, 930) | Week 18 visit (N=913, 901) | Week 27 visit (N=863, 843) | Week 36 visit (N=854, 845) | Week 45 visit (N=830, 815) | Week 52 visit (N=785, 788) | |
| Fluticasone Maintenance | -0.228 | -0.266 | -0.295 | -0.319 | -0.352 | -0.368 | -0.377 |
| Fluticasone Withdrawal | -0.230 | -0.290 | -0.435 | -0.430 | -0.473 | -0.490 | -0.538 |
Change from baseline in on-treatment physical health status as determined by body mass index (BMI); change was calculated as week score minus baseline score. Statistical analysis results are presented only for the week 52 visit as this is the primary timepoint of interest. (NCT00975195)
Timeframe: Baseline and week 18 and 52 visits
| Intervention | kg/m2 (Least Squares Mean) | |
|---|---|---|
| Week 18 visit (N=1143, 1146) | Week 52 visit (N=1047, 1021) | |
| Fluticasone Maintenance | 0.030 | 0.004 |
| Fluticasone Withdrawal | 0.040 | -0.009 |
"Change from baseline in on-treatment physician global evaluation. The evaluation reflected the physician's opinion of the patient's overall condition and was based on the need for concomitant medication, the number and severity of exacerbations, the severity of cough, the ability to exercise, the amount of wheezing and any other relevant clinical observations. Patients were graded on a scale of 1 (poor) to 8 (excellent). Change was calculated as week score minus baseline score.~Statistical analysis results are presented only for the week 52 visit as this is the primary timepoint of interest." (NCT00975195)
Timeframe: Baseline and week 27 and 52 visits
| Intervention | units on a scale (Least Squares Mean) | |
|---|---|---|
| Week 27 visit (N=1113, 1093) | Week 52 visit (N=1041, 1014) | |
| Fluticasone Maintenance | 0.10 | 0.19 |
| Fluticasone Withdrawal | 0.04 | 0.08 |
"Change from baseline in on-treatment St Georges Respiratory Questionnaire (SGRQ) scores: Activity domain. Scores range from 0 to 100, with higher scores indicating more limitations. Change was calculated as week score minus baseline score.~Statistical analysis results are presented only for the week 52 visit as this is the primary timepoint of interest." (NCT00975195)
Timeframe: Baseline and week 27 and 52 visits
| Intervention | units on a scale (Least Squares Mean) | |
|---|---|---|
| Week 27 visit (N=1002, 988) | Week 52 visit (N=942, 916) | |
| Fluticasone Maintenance | 0.09 | -0.19 |
| Fluticasone Withdrawal | 0.85 | 0.78 |
"Change from baseline in on-treatment St Georges Respiratory Questionnaire (SGRQ) scores: Impact Domain. Scores range from 0 to 100, with higher scores indicating more limitations. Change was calculated as week score minus baseline score.~Statistical analysis results are presented only for the week 52 visit as this is the primary timepoint of interest." (NCT00975195)
Timeframe: Baseline and week 27 and 52 visits
| Intervention | units on a scale (Least Squares Mean) | |
|---|---|---|
| Week 27 visit (N=1004, 998) | Week 52 visit (N=946, 921) | |
| Fluticasone Maintenance | -0.78 | -0.08 |
| Fluticasone Withdrawal | 0.35 | 1.27 |
"Change from baseline in on-treatment St Georges Respiratory Questionnaire (SGRQ) scores: Total score. Scores range from 0 to 100, with higher scores indicating more limitations. Change was calculated as week score minus baseline score.~Statistical analysis results are presented only for the week 52 visit as this is the primary timepoint of interest." (NCT00975195)
Timeframe: Baseline and week 27 and 52 visits
| Intervention | units on a scale (Least Squares Mean) | |
|---|---|---|
| Week 27 visit (N=996, 986) | Week 52 visit (N=939, 913) | |
| Fluticasone Maintenance | -0.42 | -0.07 |
| Fluticasone Withdrawal | 0.55 | 1.15 |
"Change from baseline in on-treatment dyspnoea as measured by the Modified Medical Research Council (MMRC) dyspnoea scale; change was calculated as week score minus baseline score. Negative changes from baseline indicate an improvement in health.~Scale from 0 to 4:~0 = not troubled by breathlessness, except during strenuous exercise~1 = short of breath when hurrying or walking up a slight hill~2 = walks slower than contemporaries on the same level because of breathlessness, or has to stop for breath when walking at own pace~3 = stops for breath after approximately 100 yards, or after a few minutes on the level~4 = too breathless to leave the house, or breathless when dressing or undressing~No breathlessness was given a score of -1~Statistical analysis results are presented only for the week 52 visit as this is the primary timepoint of interest." (NCT00975195)
Timeframe: Baseline and week 18 and 52 visits
| Intervention | units on a scale (Least Squares Mean) | |
|---|---|---|
| Week 18 visit (N=1140, 1143) | Week 52 visit (N=1043, 1019) | |
| Fluticasone Maintenance | -0.030 | -0.028 |
| Fluticasone Withdrawal | -0.001 | 0.035 |
Severity of on-treatment COPD exacerbations: for each patient, the worst applicable category was taken (i.e. none, mild, moderate or severe) (NCT00975195)
Timeframe: During randomised treatment, up to 488 days
| Intervention | percentage of participants (Number) | ||||
|---|---|---|---|---|---|
| None and patient completed randomised treatment | None and patient discontinued randomised treatment | Mild | Moderate | Severe | |
| Fluticasone Maintenance | 42.9 | 10.2 | 2.7 | 30.8 | 13.4 |
| Fluticasone Withdrawal | 41.2 | 9.8 | 2.3 | 31.5 | 15.2 |
"Time to first severe on-treatment COPD exacerbation. Exacerbations were considered severe if the patient was held and treated for an acute respiratory condition in an urgent care department or an observation unit for >6 hours, the patient was treated at home by a mobile urgent care team or the patient was admitted to hospital.~The measure type displays the 25th percentile and its 95% confidence interval." (NCT00975195)
Timeframe: During randomised treatment, up to 488 days
| Intervention | days (Number) |
|---|---|
| Fluticasone Maintenance | NA |
| Fluticasone Withdrawal | 419.0 |
"Number of moderate or severe on-treatment COPD exacerbations, based on a 7-day gap rule: exacerbations where the onset date of the second exacerbation event was ≤7 days after the end date of the first exacerbation event were combined and counted as moderate or severe if ≥1 of the contributing exacerbation events was moderate or severe. Exacerbations were considered severe if the patient was held and treated for an acute respiratory condition in an urgent care department or an observation unit for >6 hours, the patient was treated at home by a mobile urgent care team or the patient was admitted to hospital. Exacerbations were considered moderate if they required prescription of antibiotics and/or systemic steroids.~Measured values show adjusted mean event rate." (NCT00975195)
Timeframe: During randomised treatment, up to 488 days
| Intervention | exacerbations per patient-year (Mean) |
|---|---|
| Fluticasone Maintenance | 0.91 |
| Fluticasone Withdrawal | 0.95 |
"Number of on-treatment COPD exacerbations of any severity, based on a 7-day gap rule: exacerbations where the onset date of the second exacerbation event was ≤7 days after the end date of the first exacerbation event were combined.~Measured values show adjusted event rate." (NCT00975195)
Timeframe: During randomised treatment, up to 488 days
| Intervention | exacerbations per patient-year (Mean) |
|---|---|
| Fluticasone Maintenance | 1.03 |
| Fluticasone Withdrawal | 1.08 |
"Number of severe on-treatment COPD exacerbations based on a 7-day gap rule: exacerbations where the onset date of the second exacerbation event was ≤7 days after the end date of the first exacerbation event were combined and counted as severe if ≥1 of the contributing exacerbation events was severe. Exacerbations were considered severe if the patient was held and treated for an acute respiratory condition in an urgent care department or an observation unit for >6 hours, the patient was treated at home by a mobile urgent care team or the patient was admitted to hospital.~Measured values show adjusted event rate." (NCT00975195)
Timeframe: During randomised treatment, up to 488 days
| Intervention | exacerbations per patient-year (Mean) |
|---|---|
| Fluticasone Maintenance | 0.20 |
| Fluticasone Withdrawal | 0.23 |
"Change from baseline in on-treatment St Georges Respiratory Questionnaire (SGRQ) scores: Symptoms domain. Scores range from 0 to 100, with higher scores indicating more limitations. Change was calculated as week score minus baseline score.~Statistical analysis results are presented only for the week 52 visit as this is the primary timepoint of interest." (NCT00975195)
Timeframe: Baseline and week 27 and 52 visits
| Intervention | units on a scale (Least Squares Mean) | |
|---|---|---|
| Week 27 visit (N=1010, 998) | Week 52 visit (N=955, 921) | |
| Fluticasone Maintenance | 0.12 | 0.51 |
| Fluticasone Withdrawal | 0.62 | 1.11 |
Presence (yes vs no) of at least one moderate or severe on-treatment COPD exacerbation, displayed as a percentage. Exacerbations were considered severe if the patient was held and treated for an acute respiratory condition in an urgent care department or an observation unit for >6 hours, the patient was treated at home by a mobile urgent care team or the patient was admitted to hospital. Exacerbations were considered moderate if they required prescription of antibiotics and/or systemic steroids. (NCT00975195)
Timeframe: During randomised treatment, up to 488 days
| Intervention | percentage of participants (Number) |
|---|---|
| Fluticasone Maintenance | 44.2 |
| Fluticasone Withdrawal | 46.7 |
Presence (yes vs no) of at least one on-treatment COPD exacerbation of any severity, displayed as a percentage. (NCT00975195)
Timeframe: During randomised treatment, up to 488 days
| Intervention | percentage of participants (Number) |
|---|---|
| Fluticasone Maintenance | 46.9 |
| Fluticasone Withdrawal | 49.0 |
Presence (yes vs no) of at least one severe on-treatment COPD exacerbation, displayed as a percentage. Exacerbations were considered severe if the patient was held and treated for an acute respiratory condition in an urgent care department or an observation unit for >6 hours, the patient was treated at home by a mobile urgent care team or the patient was admitted to hospital. (NCT00975195)
Timeframe: During randomised treatment, up to 488 days
| Intervention | percentage of participants (Number) |
|---|---|
| Fluticasone Maintenance | 13.4 |
| Fluticasone Withdrawal | 15.2 |
"A Chronic Obstructive Pulmonary Disease (COPD) exacerbation was defined as an increase or new onset of ≥2 lower respiratory symptoms related to COPD, with ≥1 symptom lasting ≥3 days, requiring a change in treatment. Lower respiratory symptoms included shortness of breath, sputum production (volume), sputum purulence, cough, wheezing and chest tightness. A change in treatment included: hospitalisation/treatment in an urgent care unit, prescription of antibiotics and/or systemic steroids or a significant change of prescribed respiratory medication such as theophyllines, long-acting beta-agonists or inhaled corticosteroids. Exacerbations were considered severe if the patient was held and treated for an acute respiratory condition in an urgent care department or an observation unit for >6 hours, the patient was treated at home by a mobile urgent care team or the patient was admitted to hospital.The measure type displays the 25th percentile and its 95% confidence interval." (NCT00975195)
Timeframe: During randomised treatment, up to 488 days
| Intervention | days (Number) |
|---|---|
| Fluticasone Maintenance | 107.0 |
| Fluticasone Withdrawal | 110.0 |
"Change from baseline in on-treatment cough and expectoration as measured by the cough and sputum assessment questionnaire (CASA-Q) (selected sites only): Cough symptoms domain. Change was calculated as week score minus baseline score. Response options for the items in this domain range from not at all/never to a lot/always on a five-point scale. Domain items were reverse scored, summed and transformed to a domain score ranging from 0 to 100 where a higher score is associated with less symptoms due to cough.~Statistical analysis results are presented only for the week 52 visit as this is the primary timepoint of interest." (NCT00975195)
Timeframe: Baseline and week 12, 18 and 52 visits
| Intervention | units on a scale (Least Squares Mean) | ||
|---|---|---|---|
| Week 12 visit (N=309, 318) | Week 18 visit (N=305, 312) | Week 52 visit (N=270, 268) | |
| Fluticasone Maintenance | -0.32 | -1.47 | -1.69 |
| Fluticasone Withdrawal | -0.85 | -3.34 | -3.26 |
"Change from baseline in on-treatment cough and expectoration as measured by the cough and sputum assessment questionnaire (CASA-Q) (selected sites only): Sputum impact domain. Change was calculated as week score minus baseline score. Response options for the items in this domain range from not at all/never to a lot/always on a five-point scale. Domain items were reverse scored, summed and transformed to a domain score ranging from 0 to 100 where a higher score is associated with less impact due to sputum.~Statistical analysis results are presented only for the week 52 visit as this is the primary timepoint of interest." (NCT00975195)
Timeframe: Baseline and week 12, 18 and 52 visits
| Intervention | units on a scale (Least Squares Mean) | ||
|---|---|---|---|
| Week 12 visit (N=308, 317) | Week 18 visit (N=303, 310) | Week 52 visit (N=267, 267) | |
| Fluticasone Maintenance | -2.26 | -2.38 | -4.29 |
| Fluticasone Withdrawal | -1.63 | -3.31 | -4.15 |
"Change from baseline in on-treatment cough and expectoration as measured by the cough and sputum assessment questionnaire (CASA-Q) (selected sites only): Cough impact domain. Change was calculated as week score minus baseline score. Response options for the items in this domain range from not at all/never to extremely/always on a five-point scale. Domain items were reverse scored, summed and transformed to a domain score ranging from 0 to 100 where a higher score is associated with less impact due to cough.~Statistical analysis results are presented only for the week 52 visit as this is the primary timepoint of interest." (NCT00975195)
Timeframe: Baseline and week 12, 18 and 52 visits
| Intervention | units on a scale (Least Squares Mean) | ||
|---|---|---|---|
| Week 12 visit (N=307, 319) | Week 18 visit (N=302, 312) | Week 52 visit (N=268, 269) | |
| Fluticasone Maintenance | -1.65 | -2.87 | -4.51 |
| Fluticasone Withdrawal | -1.24 | -3.71 | -5.54 |
"Change from baseline in on-treatment cough and expectoration as measured by the cough and sputum assessment questionnaire (CASA-Q) (selected sites only): Sputum symptoms domain. Change was calculated as week score minus baseline score. Response options for the items in this domain range from not at all/never to extremely/always on a five-point scale. Domain items were reverse scored, summed and transformed to a domain score ranging from 0 to 100 where a higher score is associated with less symptoms due to sputum.~Statistical analysis results are presented only for the week 52 visit as this is the primary timepoint of interest." (NCT00975195)
Timeframe: Baseline and week 12, 18 and 52 visits
| Intervention | units on a scale (Least Squares Mean) | ||
|---|---|---|---|
| Week 12 visit (N=308, 317) | Week 18 visit (N=302, 311) | Week 52 visit (N=269, 268) | |
| Fluticasone Maintenance | -1.36 | -2.71 | -5.10 |
| Fluticasone Withdrawal | -1.24 | -1.93 | -2.45 |
"Time to first on-treatment COPD exacerbation of any severity. The measure type displays the 25th percentile and its 95% confidence interval." (NCT00975195)
Timeframe: During randomised treatment, up to 488 days
| Intervention | days (Number) |
|---|---|
| Fluticasone Maintenance | 365.0 |
| Fluticasone Withdrawal | 346.0 |
Change from baseline in on-treatment BODE index (Body mass index, airflow Obstruction, Dyspnea and Exercise capacity index), a composite score ranging from 0 (best) to 10 (worst); change was calculated as week score minus baseline score. Statistical analysis results are presented only for the week 52 visit as this is the primary timepoint of interest. (NCT00975195)
Timeframe: Baseline and week 18 and 52 visits
| Intervention | units on a scale (Least Squares Mean) | |
|---|---|---|
| Week 18 visit (N=1038, 1024) | Week 52 visit (N=931, 907) | |
| Fluticasone Maintenance | -0.06 | -0.03 |
| Fluticasone Withdrawal | 0.06 | 0.14 |
FVC was measured with spirometry conducted according to internationally accepted standards. Measurements were made 30, 60, 120, 180, and 240 minutes post-dose. The standardized AUC FEV1 was calculated as the sum of trapezoids divided by the length of time. (NCT00999908)
Timeframe: 4 hour period following inhalation of study treatment
| Intervention | Liters (Mean) |
|---|---|
| Indacaterol 150 μg | 3.140 |
| Tiotropium 18 μg | 3.176 |
| Placebo | 3.048 |
During the 4 hours following inhalation of the study treatment, inspiratory capacity (IC) was measured with spirometry conducted according to internationally accepted standards. IC was measured 3 times each at 30, 60, 120, 180, and 240 minutes post-dose and the highest value was reported in liters. (NCT00999908)
Timeframe: 4 hour period following inhalation of study treatment
| Intervention | Liters (Mean) |
|---|---|
| Indacaterol 150 μg | 2.705 |
| Tiotropium 18 μg | 2.630 |
| Placebo | 2.557 |
FEV1 was measured with spirometry conducted according to internationally accepted standards. Measurements were made 30, 60, 120, 180, and 240 minutes post-dose. The standardized AUC FEV1 was calculated as the sum of trapezoids divided by the length of time. (NCT00999908)
Timeframe: 4 hour period following inhalation of study treatment
| Intervention | Liters (Mean) |
|---|---|
| Indacaterol 150 μg | 1.744 |
| Tiotropium 18 μg | 1.767 |
| Placebo | 1.642 |
FEV1 was measured with spirometry conducted according to internationally accepted standards. FEV1 was measured 30 minutes post-dose. Analysis of variance model was used with the factors: center, period, treatment, and patients within center. (NCT01012765)
Timeframe: 21 days
| Intervention | Liters (Least Squares Mean) |
|---|---|
| Indacaterol | 1.92 |
| Placebo | 1.68 |
| Tiotropium | 1.91 |
IC was measured with spirometry conducted according to internationally accepted standards. Peak IC was defined as the maximum IC of the mean over the 3 values which were measured each at 30min, 2 hour, 3 hour and 4 hour post dose by body plethysmography. Analysis of variance model was used with the factors: center, period, treatment, and patients within center. (NCT01012765)
Timeframe: 21 days
| Intervention | Liters (Least Squares Mean) |
|---|---|
| Indacaterol | 2.69 |
| Placebo | 2.48 |
| Tiotropium | 2.63 |
Peak RV was measured with spirometry conducted according to internationally accepted standards. Peak RV was calculated as the Total Lung Capacity minus the maximum of the three Inspiratory Vital Capacity measurements which were measured each at 30 min, 2 hours, 3 hours and 4 hours post dose (at days 21, 55 and 89). Analysis of variance model was used with the factors: center, period, treatment, and patients within center. (NCT01012765)
Timeframe: 21 days
| Intervention | Liters (Least Squares Mean) |
|---|---|
| Indacaterol | 3.77 |
| Placebo | 4.17 |
| Tiotropium | 3.79 |
Peak RV/TLC ratio was measured with spirometry conducted according to internationally accepted standards. Peak RV/TLC was defined as the peak RV/peak TLC. Analysis of variance model was used with the factors: center, period, treatment, and patients within center. (NCT01012765)
Timeframe: 21 days
| Intervention | Ratio (Least Squares Mean) |
|---|---|
| Indacaterol | 0.52 |
| Placebo | 0.57 |
| Tiotropium | 0.53 |
Peak sRaw was measured with spirometry conducted according to internationally accepted standards. Peak sRaw was the mean of the three measurements which were measured each at 30 min, 2 hours, 3 hours and 4 hours post dose (at days 21, 55 and 89). Analysis of variance model was used with the factors: center, period, treatment, and patients within center. (NCT01012765)
Timeframe: 21 days
| Intervention | kPa*sec (Least Squares Mean) |
|---|---|
| Indacaterol | 2.05 |
| Placebo | 3.08 |
| Tiotropium | 2.00 |
TLC was measured with spirometry conducted according to internationally accepted standards. Peak TLC was calculated as the mean of the three Functional Residual Capacity peak measurements plus the mean of the three Inspiratory Capacity measurements which were measured each at 30 min, 2 hours, 3 hours and 4 hours post dose (at days 21, 55 and 89). Analysis of variance model was used with the factors: center, period, treatment, and patients within center. (NCT01012765)
Timeframe: 21 days
| Intervention | Liters (Least Squares Mean) |
|---|---|
| Indacaterol | 7.25 |
| Placebo | 7.38 |
| Tiotropium | 7.25 |
FEV1 was measured with spirometry conducted according to internationally accepted standards. FEV1 was measured pre-dose after 20 days of treatment. Analysis of variance model was used with the factors: center, period, treatment, and patients within center. (NCT01012765)
Timeframe: 20 days
| Intervention | Liters (Least Squares Mean) |
|---|---|
| Indacaterol | 1.80 |
| Placebo | 1.61 |
| Tiotropium | 1.78 |
Trough IC was measured with spirometry conducted according to internationally accepted standards. Trough IC was calculated as the mean of the three measurements of pre-dose body plethysmography (days 21, 55 and 89). Analysis of variance model was used with the factors: center, period, treatment, and patients within center. (NCT01012765)
Timeframe: 20 days
| Intervention | Liters (Least Squares Mean) |
|---|---|
| Indacaterol | 2.43 |
| Placebo | 2.28 |
| Tiotropium | 2.39 |
Adjusted means of the FVC peak 0-3h response [L] after 4 weeks of treatment. Baseline was defined as the mean of the 2 pre-treatment FEV1 values measured on day 1 (-1 hour and -10 minutes) prior to administration of the first dose of study drug. (NCT01040403)
Timeframe: Baseline and 1 h, 10 min pre-dose and 5 min, 30 min, 1 h, 2 h, 3 h post-dose on day 29
| Intervention | Litres (Mean) |
|---|---|
| Olo 5 | 0.415 |
| T+O 1.25/5 | 0.570 |
| T+O 2.5/5 | 0.563 |
| T+O 5/5 | 0.542 |
| Olo 10 | 0.411 |
| T+O 1.25/10 | 0.585 |
| T+O 2.5/10 | 0.593 |
| T+O 5/10 | 0.615 |
Adjusted means of the weekly mean number of puffs of rescue medication during the whole day : the rescue medication was a salbutamol [albuterol] dose (100 mcg per puff). (NCT01040403)
Timeframe: Weeks 1 and 4
| Intervention | number of puffs per day (Mean) | |
|---|---|---|
| Week 1 | Week 4 | |
| Olo 10 | 1.423 | 1.561 |
| Olo 5 | 1.511 | 1.391 |
| T+O 1.25/10 | 1.465 | 1.344 |
| T+O 1.25/5 | 1.298 | 1.502 |
| T+O 2.5/10 | 1.172 | 1.198 |
| T+O 2.5/5 | 1.191 | 1.299 |
| T+O 5/10 | 1.244 | 1.315 |
| T+O 5/5 | 1.446 | 1.444 |
Systolic and diastolic blood pressure recorded in conjunction with spirometry change from baseline on day 29 in millimetres of mercury (mmHg). (NCT01040403)
Timeframe: Baseline and 30 min post-dose on day 29
| Intervention | mmHg (Mean) | |
|---|---|---|
| Systolic blood pressure | Diastolic blood pressure | |
| Olo 10 | -3.4 | -3.0 |
| Olo 5 | -7.2 | -3.8 |
| T+O 1.25/10 | -5.5 | -3.0 |
| T+O 1.25/5 | -6.0 | -2.8 |
| T+O 2.5/10 | -3.8 | -2.5 |
| T+O 2.5/5 | -5.6 | -2.5 |
| T+O 5/10 | -2.2 | -0.4 |
| T+O 5/5 | -4.8 | -3.0 |
"Adjusted means of the Physicians Global Evaluation of the patient's respiratory condition on days 1 and 29.~The score was evaluated on a 8-points scale :~Poor : 1,2~Fair : 3,4~Good : 5,6~Excellent : 7,8" (NCT01040403)
Timeframe: Days 1 and 29
| Intervention | units on a scale (Mean) | |
|---|---|---|
| Day 1 | Day 29 | |
| Olo 10 | 4.747 | 5.109 |
| Olo 5 | 4.618 | 4.985 |
| T+O 1.25/10 | 4.464 | 5.280 |
| T+O 1.25/5 | 4.631 | 5.146 |
| T+O 2.5/10 | 4.634 | 5.165 |
| T+O 2.5/5 | 4.484 | 5.248 |
| T+O 5/10 | 4.690 | 5.227 |
| T+O 5/5 | 4.579 | 5.070 |
Adjusted means of the Peak Expiratory Flow (PEF) AUC 0-3h and AUC 0-6h responses in Litres / minute (L/min) after 4 weeks of treatment, calculated using the trapezoidal rule, divided by the duration (3 h, 6 h) to report in litres. Baseline was defined as the mean of the 2 pre-treatment FEV1 values measured on day 1 (-1 hour and -10 minutes) prior to administration of the first dose of study drug. (NCT01040403)
Timeframe: Baseline and 1 h, 10 min pre-dose and 5 min, 30 min, 1 h, 2 h, 3 h post dose for AUC0-3h and 1 h, 10 min pre-dose and 5 min, 30 min, 1 h, 2 h, 3 h 4 h, 5 h, 6 h postdose for AUC0-6h on day 29
| Intervention | L/min (Mean) | |
|---|---|---|
| AUC 0-3h | AUC 0-6h | |
| Olo 10 | 29.713 | 31.831 |
| Olo 5 | 25.542 | 28.071 |
| T+O 1.25/10 | 48.032 | 51.485 |
| T+O 1.25/5 | 44.301 | 46.822 |
| T+O 2.5/10 | 53.224 | 54.593 |
| T+O 2.5/5 | 50.698 | 54.081 |
| T+O 5/10 | 52.531 | 57.367 |
| T+O 5/5 | 55.346 | 57.418 |
Adjusted means of the PEF measurements [L/min] at each time point on day 29. Baseline was defined as the mean of the 2 pre-treatment FEV1 values measured on day 1 (-1 hour and -10 minutes) prior to administration of the first dose of study drug. (NCT01040403)
Timeframe: Baseline and 1 h, 10 min pre-dose and 0 min, 5 min, 30 min, 1 h, 2 h, 3 h, 4 h, 5 h, 6 h post-dose on day 29
| Intervention | L/min (Mean) | ||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|
| Timepoint -1:00 hr response | Timepoint -0:10 hr response | Timepoint 0:00 hr response | Timepoint 0:05 hr response | Timepoint 0:30 hr response | Timepoint 1:00 hr response | Timepoint 2:00 hr response | Timepoint 3:00 hr response | Timepoint 4:00 hr response | Timepoint 5:00 hr response | Timepoint 6:00 hr response | |
| Olo 10 | 249.356 | 253.921 | 251.517 | 259.301 | 264.909 | 263.293 | 272.318 | 274.334 | 274.466 | 269.220 | 270.707 |
| Olo 5 | 246.557 | 245.661 | 245.758 | 254.967 | 257.326 | 261.890 | 269.187 | 269.067 | 266.451 | 272.141 | 268.680 |
| T+O 1.25/10 | 263.134 | 264.808 | 263.757 | 271.071 | 280.836 | 283.326 | 291.503 | 295.008 | 293.986 | 293.039 | 290.283 |
| T+O 1.25/5 | 260.901 | 264.412 | 262.239 | 267.969 | 275.045 | 279.892 | 287.181 | 292.962 | 286.382 | 287.917 | 284.028 |
| T+O 2.5/10 | 267.013 | 268.772 | 267.623 | 276.004 | 287.502 | 288.427 | 298.394 | 296.641 | 293.617 | 294.713 | 293.466 |
| T+O 2.5/5 | 263.662 | 265.177 | 264.202 | 273.340 | 279.309 | 287.635 | 295.820 | 296.736 | 297.483 | 293.878 | 295.843 |
| T+O 5/10 | 266.913 | 266.506 | 266.187 | 275.727 | 288.289 | 288.585 | 294.627 | 300.582 | 302.539 | 300.335 | 299.234 |
| T+O 5/5 | 269.754 | 271.793 | 270.565 | 275.329 | 286.288 | 289.866 | 300.076 | 303.099 | 297.415 | 295.911 | 295.703 |
Adjusted means of the FVC measurements [L] at each time point on day 29. Baseline was defined as the mean of the 2 pre-treatment FEV1 values measured on day 1 (-1 hour and -10 minutes) prior to administration of the first dose of study drug. (NCT01040403)
Timeframe: Baseline and 1 h, 10 min pre-dose and 0 min, 5 min, 30 min, 1 h, 2 h, 3 h, 4 h, 5 h, 6 h post-dose on day 29
| Intervention | Litres (Mean) | ||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|
| Timepoint -1:00 hr response | Timepoint -0:10 hr response | Timepoint 0:00 hr response | Timepoint 0:05 hr response | Timepoint 0:30 hr response | Timepoint 1:00 hr response | Timepoint 2:00 hr response | Timepoint 3:00 hr response | Timepoint 4:00 hr response | Timepoint 5:00 hr response | Timepoint 6:00 hr response | |
| Olo 10 | 2.877 | 2.904 | 2.889 | 3.009 | 3.019 | 3.032 | 3.071 | 3.081 | 3.054 | 3.019 | 3.028 |
| Olo 5 | 2.877 | 2.891 | 2.882 | 2.999 | 3.018 | 3.036 | 3.077 | 3.067 | 3.054 | 3.061 | 3.035 |
| T+O 1.25/10 | 3.006 | 3.036 | 3.020 | 3.141 | 3.190 | 3.204 | 3.258 | 3.264 | 3.266 | 3.222 | 3.228 |
| T+O 1.25/5 | 2.961 | 3.007 | 2.981 | 3.130 | 3.171 | 3.174 | 3.216 | 3.222 | 3.181 | 3.193 | 3.163 |
| T+O 2.5/10 | 3.012 | 3.032 | 3.020 | 3.147 | 3.192 | 3.215 | 3.249 | 3.267 | 3.227 | 3.214 | 3.208 |
| T+O 2.5/5 | 2.996 | 3.009 | 3.002 | 3.120 | 3.145 | 3.190 | 3.234 | 3.233 | 3.204 | 3.188 | 3.197 |
| T+O 5/10 | 3.007 | 3.032 | 3.016 | 3.148 | 3.219 | 3.239 | 3.275 | 3.303 | 3.281 | 3.252 | 3.261 |
| T+O 5/5 | 2.954 | 3.012 | 2.982 | 3.087 | 3.172 | 3.162 | 3.208 | 3.200 | 3.183 | 3.178 | 3.179 |
Adjusted means of the FEV1 measurements [L] at each time point on day 29. Baseline was defined as the mean of the 2 pre-treatment FEV1 values measured on day 1 (-1 hour and -10 minutes) prior to administration of the first dose of study drug. (NCT01040403)
Timeframe: Baseline and 1 h, 10 min pre-dose and 0 min, 5 min, 30 min, 1 h, 2 h, 3 h, 4 h, 5 h, 6 h post-dose on day 29
| Intervention | Litres (Mean) | ||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|
| Timepoint -1:00 hr response | Timepoint -0:10 hr response | Timepoint 0:00 hr response | Timepoint 0:05 hr response | Timepoint 0:30 hr response | Timepoint 1:00 hr response | Timepoint 2:00 hr response | Timepoint 3:00 hr response | Timepoint 4:00 hr response | Timepoint 5:00 hr response | Timepoint 6:00 hr response | |
| Olo 10 | 1.414 | 1.447 | 1.431 | 1.491 | 1.524 | 1.527 | 1.556 | 1.567 | 1.563 | 1.540 | 1.547 |
| Olo 5 | 1.410 | 1.431 | 1.419 | 1.483 | 1.516 | 1.521 | 1.552 | 1.553 | 1.543 | 1.549 | 1.517 |
| T+O 1.25/10 | 1.467 | 1.498 | 1.482 | 1.576 | 1.605 | 1.627 | 1.661 | 1.671 | 1.663 | 1.640 | 1.636 |
| T+O 1.25/5 | 1.464 | 1.487 | 1.473 | 1.555 | 1.570 | 1.595 | 1.625 | 1.648 | 1.621 | 1.622 | 1.605 |
| T+O 2.5/10 | 1.504 | 1.526 | 1.514 | 1.593 | 1.643 | 1.658 | 1.699 | 1.690 | 1.676 | 1.655 | 1.656 |
| T+O 2.5/5 | 1.481 | 1.488 | 1.484 | 1.553 | 1.597 | 1.622 | 1.656 | 1.659 | 1.654 | 1.626 | 1.631 |
| T+O 5/10 | 1.500 | 1.527 | 1.511 | 1.601 | 1.660 | 1.675 | 1.711 | 1.716 | 1.708 | 1.688 | 1.687 |
| T+O 5/5 | 1.491 | 1.516 | 1.503 | 1.563 | 1.630 | 1.633 | 1.687 | 1.671 | 1.659 | 1.654 | 1.647 |
Adjusted means of the FVC AUC 0-3h and AUC 0-6h responses [L] after 4 weeks of treatment, calculated using the trapezoidal rule, divided by the duration (3 h, 6 h) to report in litres. Baseline was defined as the mean of the 2 pre-treatment FEV1 values measured on day 1 (-1 hour and -10 minutes) prior to administration of the first dose of study drug. (NCT01040403)
Timeframe: Baseline and 1 h, 10 min pre-dose and 5 min, 30 min, 1 h, 2 h, 3 h post dose for AUC0-3h and 1 h, 10 min pre-dose and 5 min, 30 min, 1 h, 2 h, 3 h 4 h, 5 h, 6 h postdose for AUC0-6h on day 29
| Intervention | Litres (Mean) | |
|---|---|---|
| AUC 0-3h | AUC 0-6h | |
| Olo 10 | 0.279 | 0.277 |
| Olo 5 | 0.278 | 0.282 |
| T+O 1.25/10 | 0.455 | 0.466 |
| T+O 1.25/5 | 0.422 | 0.421 |
| T+O 2.5/10 | 0.454 | 0.456 |
| T+O 2.5/5 | 0.429 | 0.432 |
| T+O 5/10 | 0.479 | 0.490 |
| T+O 5/5 | 0.410 | 0.414 |
Adjusted means of forced expiratory volume in one second (FEV1) area under the curve (AUC) 0-3 hour and AUC 0-6 hour responses [L] after 4 weeks treatment calculated using the trapezoidal rule, divided by the duration (3 h, 6 h) to report in litres. Baseline was defined as the mean of the 2 pre-treatment FEV1 values measured on day 1 (-1 hour and -10 minutes) prior to administration of the first dose of study drug. (NCT01040403)
Timeframe: Baseline and 1 h, 10 min pre-dose and 5 min, 30 min, 1 h, 2 h, 3 h post dose for AUC0-3h and 1 h, 10 min pre-dose and 5 min, 30 min, 1 h, 2 h, 3 h 4 h, 5 h, 6 h postdose for AUC0-6h on day 29
| Intervention | Litres (Mean) | |
|---|---|---|
| AUC 0-3h | AUC 0-6h | |
| Olo 10 | 0.191 | 0.198 |
| Olo 5 | 0.183 | 0.188 |
| T+O 1.25/10 | 0.288 | 0.296 |
| T+O 1.25/5 | 0.258 | 0.267 |
| T+O 2.5/10 | 0.319 | 0.320 |
| T+O 2.5/5 | 0.280 | 0.287 |
| T+O 5/10 | 0.334 | 0.342 |
| T+O 5/5 | 0.302 | 0.307 |
Adjusted means of trough FVC (forced vital capacity) response [L] after 4 weeks treatment. The trough was defined as the mean of the 1 h pre-dose and 10 min pre-dose measurements on day 29. Baseline was defined as the mean of the 2 pre-treatment FEV1 values measured on day 1 (-1 hour and -10 minutes) prior to administration of the first dose of study drug. (NCT01040403)
Timeframe: Baseline and 1 hour pre-dose and 10 minutes pre-dose on day 29
| Intervention | Litres (Mean) |
|---|---|
| Olo 5 | 0.114 |
| T+O 1.25/5 | 0.214 |
| T+O 2.5/5 | 0.234 |
| T+O 5/5 | 0.215 |
| Olo 10 | 0.122 |
| T+O 1.25/10 | 0.253 |
| T+O 2.5/10 | 0.253 |
| T+O 5/10 | 0.249 |
Adjusted means of the trough forced expiratory volume in one second (FEV1) response (L) after four weeks treatment. The trough was defined as the mean of the 1 h pre-dose and 10 min pre-dose measurements on day 29. Baseline was defined as the mean of the 2 pre-treatment FEV1 values measured on day 1 (-1 hour and -10 minutes) prior to administration of the first dose of study drug. (NCT01040403)
Timeframe: Baseline and 1 hour pre-dose and 10 minutes pre-dose on day 29
| Intervention | Litres (Mean) |
|---|---|
| Olo 5 | 0.071 |
| T+O 1.25/5 | 0.125 |
| T+O 2.5/5 | 0.136 |
| T+O 5/5 | 0.155 |
| Olo 10 | 0.083 |
| T+O 1.25/10 | 0.134 |
| T+O 2.5/10 | 0.166 |
| T+O 5/10 | 0.163 |
Pulse rate recorded in conjunction with spirometry change from baseline at 30 minutes post-dose on day 29 in beats per minute (bpm). (NCT01040403)
Timeframe: Baseline and 30 min post-dose on day 29
| Intervention | bpm (Mean) |
|---|---|
| Olo 5 | -2.4 |
| T+O 1.25/5 | -2.8 |
| T+O 2.5/5 | -3.1 |
| T+O 5/5 | -1.8 |
| Olo 10 | -2.1 |
| T+O 1.25/10 | -3.6 |
| T+O 2.5/10 | -2.4 |
| T+O 5/10 | -1.0 |
Adjusted means of the Peak Expiratory flow from 0 to 3 hours response in L/min after the first dose of treatment. Baseline was defined as the mean of the 2 pre-treatment FEV1 values measured on day 1 (-1 hour and -10 minutes) prior to administration of the first dose of study drug. (NCT01040403)
Timeframe: Baseline and 1 h, 10 min pre-dose and 5 min, 30 min, 1 h, 2 h, 3 h post-dose on day 1
| Intervention | L/min (Mean) |
|---|---|
| Olo 5 | 52.129 |
| T+O 1.25/5 | 53.298 |
| T+O 2.5/5 | 56.565 |
| T+O 5/5 | 57.318 |
| Olo 10 | 51.980 |
| T+O 1.25/10 | 54.966 |
| T+O 2.5/10 | 56.896 |
| T+O 5/10 | 59.412 |
Adjusted means of the peak expiratory flow from 0 to 3 hours (PEF peak 0-3h) response in L/min after 4 weeks of treatment. Baseline was defined as the mean of the 2 pre-treatment FEV1 values measured on day 1 (-1 hour and -10 minutes) prior to administration of the first dose of study drug. (NCT01040403)
Timeframe: Baseline 1 h, 10 min pre-dose and 5 min, 30 min, 1 h, 2 h, 3 h post-dose on day 29
| Intervention | L/min (Mean) |
|---|---|
| Olo 5 | 46.010 |
| T+O 1.25/5 | 64.693 |
| T+O 2.5/5 | 69.610 |
| T+O 5/5 | 76.108 |
| Olo 10 | 49.025 |
| T+O 1.25/10 | 66.767 |
| T+O 2.5/10 | 73.140 |
| T+O 5/10 | 74.120 |
Adjusted means of the Area under the curve from 0 to 3 h response in Litres / minutes of the peak expiratory flow after the first dose, calculated using the trapezoidal rule, divided by the duration (3 hours) to report in litres. Baseline was defined as the mean of the 2 pre-treatment FEV1 values measured on day 1 (-1 hour and -10 minutes) prior to administration of the first dose of study drug. (NCT01040403)
Timeframe: Baseline and 1 h, 10 min pre-dose and 5 min, 30 min, 1 h, 2 h, 3 h post-dose on day 1
| Intervention | L/min (Mean) |
|---|---|
| Olo 5 | 30.575 |
| T+O 1.25/5 | 32.891 |
| T+O 2.5/5 | 35.053 |
| T+O 5/5 | 35.243 |
| Olo 10 | 31.724 |
| T+O 1.25/10 | 33.213 |
| T+O 2.5/10 | 34.987 |
| T+O 5/10 | 38.846 |
"Adjusted means of the Global Rating of the patients' health (respiratory condition) on day 29.~The score was evaluated on a 7-point scale :~1 : very much better~2 : much better~3 : a little better~4 : no change~5 : a little worse~6 : much worse~7 : very much worse" (NCT01040403)
Timeframe: Day 29
| Intervention | units on a scale (Mean) |
|---|---|
| Olo 5 | 3.357 |
| T+O 1.25/5 | 3.135 |
| T+O 2.5/5 | 2.916 |
| T+O 5/5 | 3.208 |
| Olo 10 | 3.262 |
| T+O 1.25/10 | 2.880 |
| T+O 2.5/10 | 3.130 |
| T+O 5/10 | 2.936 |
Adjusted mean of the FVC peak 0-3h response [L] after the first dose. Baseline was defined as the mean of the 2 pre-treatment FEV1 values measured on day 1 (-1 hour and -10 minutes) prior to administration of the first dose of study drug. (NCT01040403)
Timeframe: Baseline and 1 h, 10 min pre-dose and 5 min, 30 min, 1 h, 2 h, 3 h post-dose on day 1
| Intervention | Litres (Mean) |
|---|---|
| Olo 5 | 0.473 |
| T+O 1.25/5 | 0.423 |
| T+O 2.5/5 | 0.481 |
| T+O 5/5 | 0.462 |
| Olo 10 | 0.436 |
| T+O 1.25/10 | 0.547 |
| T+O 2.5/10 | 0.517 |
| T+O 5/10 | 0.505 |
Adjusted means of the FVC AUC 0-3h response [L] after first dose, calculated using the trapezoidal rule, divided by the duration (3 hours) to report in litres. Baseline was defined as the mean of the 2 pre-treatment FEV1 values measured on day 1 (-1 hour and -10 minutes) prior to administration of the first dose of study drug. (NCT01040403)
Timeframe: Baseline and 1 h, 10 min pre-dose and 5 min, 30 min, 1 h, 2 h, 3 h post-dose on days 1
| Intervention | Litres (Mean) |
|---|---|
| Olo 5 | 0.333 |
| T+O 1.25/5 | 0.285 |
| T+O 2.5/5 | 0.326 |
| T+O 5/5 | 0.319 |
| Olo 10 | 0.303 |
| T+O 1.25/10 | 0.393 |
| T+O 2.5/10 | 0.363 |
| T+O 5/10 | 0.359 |
Adjusted means of the FEV1 peak 0-3h response [L] after the first dose of treatment. Baseline was defined as the mean of the 2 pre-treatment FEV1 values measured on day 1 (-1 hour and -10 minutes) prior to administration of the first dose of study drug. (NCT01040403)
Timeframe: Baseline and 1 h, 10 min pre-dose and 5 min, 30 min, 1 h, 2 h, 3 h post-dose on day 1
| Intervention | Litres (Mean) |
|---|---|
| Olo 5 | 0.287 |
| T+O 1.25/5 | 0.267 |
| T+O 2.5/5 | 0.300 |
| T+O 5/5 | 0.298 |
| Olo 10 | 0.270 |
| T+O 1.25/10 | 0.324 |
| T+O 2.5/10 | 0.315 |
| T+O 5/10 | 0.317 |
Adjusted means of the FEV1 peak value over the time from 0 to 3 hours (peak 0-3h) response [L] after 4 weeks of treatment. Baseline was defined as the mean of the 2 pre-treatment FEV1 values measured on day 1 (-1 hour and -10 minutes) prior to administration of the first dose of study drug. (NCT01040403)
Timeframe: Baseline and 1 h, 10 min pre-dose and 5 min, 30 min, 1 h, 2 h, 3 h post-dose on day 29
| Intervention | Litres (Mean) |
|---|---|
| Olo 5 | 0.264 |
| T+O 1.25/5 | 0.353 |
| T+O 2.5/5 | 0.355 |
| T+O 5/5 | 0.379 |
| Olo 10 | 0.267 |
| T+O 1.25/10 | 0.374 |
| T+O 2.5/10 | 0.399 |
| T+O 5/10 | 0.412 |
Adjusted means of Forced Expiratory Volume in One Second (FEV1) Area Under Curve (AUC) 0-3h response [L] after the first dose, calculated using the trapezoidal rule, divided by the duration (3 hours) to report in litres. Baseline was defined as the mean of the 2 pre-treatment FEV1 values measured on day 1 (-1 hour and -10 minutes) prior to administration of the first dose of study drug. (NCT01040403)
Timeframe: Baseline and 1 h, 10 min pre-dose and 5 min, 30 min, 1 h, 2 h, 3 h post-dose on day 1
| Intervention | Litres (Mean) |
|---|---|
| Olo 5 | 0.204 |
| T+O 1.25/5 | 0.181 |
| T+O 2.5/5 | 0.209 |
| T+O 5/5 | 0.205 |
| Olo 10 | 0.188 |
| T+O 1.25/10 | 0.227 |
| T+O 2.5/10 | 0.219 |
| T+O 5/10 | 0.230 |
Response was defined as change from baseline. Study baseline FVC was defined as the mean of the available pre-dose FVC values prior to first dose of first treatment period. Means are adjusted using a mixed effects model with treatment and period as fixed effects and patient as a random effect and study baseline as a continuous covariate. FVC AUC 12-24h was calculated using the trapezoidal rule, divided by the observation time to report in litres. (NCT01040689)
Timeframe: 1 h and 10 min prior to dose on the first day of the first treatment period (study baseline) and 12 h, 22 h, 23 h, and 23 h 50 min relative to last dose after six weeks of treatment
| Intervention | Liter (Mean) |
|---|---|
| Placebo | -0.166 |
| Olo 5 mcg qd | 0.030 |
| Olo 10 mcg qd | 0.086 |
| Tio 18 mcg qd | 0.018 |
Response was defined as change from baseline. Study baseline FVC was defined as the mean of the available pre-dose FVC values prior to the first dose in the first treatment period. Means are adjusted using a mixed effects model with treatment and period as fixed effects and patient as a random effect and study baseline as a continuous covariate. FVC AUC 0-3h was calculated using the trapezoidal rule, divided by the observation time to report in litres. (NCT01040689)
Timeframe: 1 hour (h) and 10 minutes (min) prior to dose on the first day of the treatment period (study baseline) and -30 min, 30 min, 60 min, 2 h, 3 h relative to first dose of treatment
| Intervention | Liter (Mean) |
|---|---|
| Placebo | -0.024 |
| Olo 5 mcg qd | 0.244 |
| Olo 10 mcg qd | 0.288 |
| Tio 18 mcg qd | 0.191 |
Response was defined as change from baseline. Study baseline FVC was defined as the mean of the available pre-dose FVC values prior to the first dose in the first treatment period. Means are adjusted using a mixed effects model with treatment and period as fixed effects and patient as a random effect and study baseline as a continuous covariate. FVC AUC 0-3h was calculated using the trapezoidal rule, divided by the observation time to report in litres. (NCT01040689)
Timeframe: 1 hour (h) and 10 minutes (min) prior to dose on the first day of the first treatment period (study baseline) and -30 min, 30 min, 60 min, 2 h, 3 h relative to last dose after six weeks of treatment.
| Intervention | Liter (Mean) |
|---|---|
| Placebo | -0.083 |
| Olo 5 mcg qd | 0.234 |
| Olo 10 mcg qd | 0.235 |
| Tio 18 mcg qd | 0.219 |
Response was defined as change from baseline. Study baseline FVC was defined as the mean of the available pre-dose FVC values prior to first dose in first treatment period. Means are adjusted using a mixed effects model with treatment and period as fixed effects and patient as a random effect and study baseline as a continuous covariate. FVC AUC 0-24h was calculated using the trapezoidal rule, divided by the observation time to report in litres. (NCT01040689)
Timeframe: 1 hour (h) and 10 minutes (min) prior to dose on the first day of the first treatment period (study baseline) and -30 min, 30 min, 60 min, 2 h, 3 h, 4 h, 6h, 8h, 10h, 12 h, 22 h, 23 h, and 23 h 50 min relative to last dose after six weeks of treatment.
| Intervention | Liter (Mean) |
|---|---|
| Placebo | -0.138 |
| Olo 5 mcg qd | 0.101 |
| Olo 10 mcg qd | 0.139 |
| Tio 18 mcg qd | 0.091 |
Response was defined as change from baseline. Study baseline FVC was defined as the mean of the available pre-dose FVC values prior to first dose in first treatment period. Means are adjusted using a mixed effects model with treatment and period as fixed effects and patient as a random effect and study baseline as a continuous covariate. FVC AUC 0-12h was calculated using the trapezoidal rule, divided by the observation time to report in litres. (NCT01040689)
Timeframe: 1 hour (h) and 10 minutes (min) prior to dose on the first day of the first treatment period (study baseline) and -30 min (zero time), 30 min, 60 min, 2 h, 3 h, 4 h, 6 h, 8 h, 10 h, 12h relative to last dose after six weeks of treatment.
| Intervention | Liter (Mean) |
|---|---|
| Placebo | -0.110 |
| Olo 5 mcg qd | 0.172 |
| Olo 10 mcg qd | 0.192 |
| Tio 18 mcg qd | 0.166 |
Response was defined as change from baseline. Study baseline FEV1 was defined as the mean of the available pre-dose FEV1 values prior to the first dose of the first treatment period. Means are adjusted using a mixed effects model with treatment and period as fixed effects and patient as a random effect and study baseline as a continuous covariate. FEV1 AUC 0-3h was calculated from 0-3hours post-dose using the trapezoidal rule, divided by the observation time (3 h) to report in litres. (NCT01040689)
Timeframe: 1 hour (h) prior and 10 minutes (min) prior to first dose of the first treatment period (study baseline) and -30 min, 30 min, 60 min, 2 h , 3 h, relative to the last dose of treatment after six weeks of treatment.
| Intervention | Liter (Mean) |
|---|---|
| Placebo | -0.045 |
| Olo 5 mcg qd | 0.161 |
| Olo 10 mcg qd | 0.170 |
| Tio 18 mcg qd | 0.137 |
Response was defined as change from baseline. Study baseline FEV1 was defined as the mean of the available pre-dose FEV1 values prior to the first dose of the first treatment period. Means are adjusted using a mixed effects model with treatment and period as fixed effects and patient as a random effect and study baseline as a continuous covariate. FEV1 AUC 0-3h was calculated from 0-3hours post-dose using the trapezoidal rule, divided by the observation time (3 h) to report in litres. (NCT01040689)
Timeframe: 1 hour (h) prior and 10 minutes (min) prior to first dose of the first period (study baseline) and -30 min, 30 min, 60 min, 2 h , 3 h, relative to the first dose of treatment period
| Intervention | Liter (Mean) |
|---|---|
| Placebo | -0.021 |
| Olo 5 mcg qd | 0.161 |
| Olo 10 mcg qd | 0.191 |
| Tio 18 mcg qd | 0.111 |
Response was defined as change from baseline. Study baseline FEV1 was defined as the mean of the available pre-dose FEV1 values at the first visit of the first treatment period. Means are adjusted using a mixed effects model with treatment and period as fixed effects and patient as a random effect and study baseline as a continuous covariate. FEV1 AUC 0-24h was calculated from 0-24 hours post-dose using the trapezoidal rule, divided by the observation time (24h) to report in litres. (NCT01040689)
Timeframe: 1 hour (h) and 10 minutes (min) prior to am dose on the first day of the first treatment period (study baseline) and -30 min, 30 min, 60 min, 2 h, 3 h, 4 h, 6h, 8h, 10h, 12 h, 22 h, 23 h, and 23 h 50 min relative to am dose after six weeks of treatment
| Intervention | Liter (Mean) |
|---|---|
| Placebo | -0.075 |
| Olo 5 mcg qd | 0.083 |
| Olo 10 mcg qd | 0.117 |
| Tio 18 mcg qd | 0.073 |
Response was defined as change from baseline. Study baseline FEV1 was defined as the mean of the -1 hour and -10 minute measurements performed in the morning of the first treatment visit for the first period, just prior to administration of the morning dose of randomized treatment. Means are adjusted using a mixed effects model with treatment and period as fixed effects and patient as a random effect and study baseline as a continuous covariate. FEV1 AUC 12-24h was calculated from 12-24 hours post-dose using the trapezoidal rule, divided by the observation time (12h) to report in litres. (NCT01040689)
Timeframe: 1 h and 10 min prior to am dose on the first day of the first treatment period (study baseline) and 12 h, 22 h, 23 h, and 23 h 50 min relative to am dose after six weeks of treatment
| Intervention | Liter (Mean) |
|---|---|
| Placebo | -0.095 |
| Olo 5 mcg qd | 0.036 |
| Olo 10 mcg qd | 0.082 |
| Tio 18 mcg qd | 0.027 |
Response was defined as change from baseline. Study baseline FEV1 was defined as the mean of the -1 hour and -10 minute measurements performed in the morning of the first treatment visit for the first period, just prior to administration of the morning dose of randomized treatment. Means are adjusted using a mixed effects model with treatment and period as fixed effects and patient as a random effect and study baseline as a continuous covariate. FEV1 AUC 0-12h was calculated from 0-12 hours post-dose using the trapezoidal rule, divided by the observation time (12h) to report in litres. (NCT01040689)
Timeframe: 1 hour (h) and 10 minutes (min) prior to am dose on the first day of the first treatment period (study baseline) and -30 min (zero time), 30 min, 60 min, 2 hour (h) , 3 h, 4 h, 6 h, 8 h, 10 h, 12 h relative to am dose after six weeks of treatment
| Intervention | Liter (Mean) |
|---|---|
| Placebo | -0.054 |
| Olo 5 mcg qd | 0.131 |
| Olo 10 mcg qd | 0.152 |
| Tio 18 mcg qd | 0.119 |
Response was defined as change from baseline. Study baseline peak FEV1 was defined as the mean of the available pre-dose peak FEV1 values prior to first dose of first treatment period. Peak FEV1 (0-3h) values were obtained within 0 - 3 hours after the last dose after six weeks of treatment. Means are adjusted using a mixed effects model with treatment and period as fixed effects and patient as a random effect and study baseline as a continuous covariate. (NCT01040689)
Timeframe: Study baseline and 6 weeks
| Intervention | Liter (Mean) |
|---|---|
| Placebo | 0.019 |
| Olo 5 mcg qd | 0.232 |
| Olo 10 mcg qd | 0.253 |
| Tio 18 mcg qd | 0.220 |
Response was defined as change from baseline. Study baseline trough FVC was defined as the mean of the available pre-dose trough FVC values prior to first dose in first treatment period. Trough values were mean of the values obtained 23 h and 23 h 50 min after the last dose of study drug after six weeks of treatment. Means are adjusted using a mixed effects model with treatment and period as fixed effects and patient as a random effect and study baseline as a continuous covariate. (NCT01040689)
Timeframe: Study baseline and 6 weeks
| Intervention | Liter (Mean) |
|---|---|
| Placebo | -0.082 |
| Olo 5 mcg qd | 0.103 |
| Olo 10 mcg qd | 0.130 |
| Tio 18 mcg qd | 0.046 |
Clinical relevant Abnormalities for Vital Signs, Blood Chemistry, Haematology, Urinalysis and ECG. New abnormal findings or worsenings of baseline conditions were reported as Adverse Events related to treatment (cardiac disorders and investigations). (NCT01040689)
Timeframe: 6 weeks
| Intervention | percentage of participants (Number) | |
|---|---|---|
| Palpitations | Investigations | |
| Olo 10 mcg | 1.0 | 0.0 |
| Olo 5 mcg | 0.0 | 0.0 |
| Placebo | 0.0 | 0.0 |
| Tiotropium (Tio) 18 mcg qd | 0.0 | 0.0 |
Response was defined as change from baseline. Study baseline trough FEV1 was defined as the mean of the available pre-dose trough FEV1 values prior to first dose of first treatment period. Trough values were the mean of values obtained 23 hours and 23h 50min post the last dose of study drug after six weeks of treatment . Means are adjusted using a mixed effects model with treatment and period as fixed effects and patient as a random effect and study baseline as a continuous covariate. (NCT01040689)
Timeframe: Study baseline and 6 weeks
| Intervention | Liter (Mean) |
|---|---|
| Placebo | -0.043 |
| Olo 5 mcg qd | 0.090 |
| Olo 10 mcg qd | 0.104 |
| Tio 18 mcg qd | 0.054 |
Response was defined as change from baseline. Study baseline peak FVC was defined as the mean of the available pre-dose peak FVC values prior to first dose in first treatment period. Peak FVC (0-3h) was obtained within 0 - 3 hours after the last dose of study drug after 6 weeks of treatment. Means are adjusted using a mixed effects model with treatment and period as fixed effects and patient as a random effect and study baseline as a continuous covariate. (NCT01040689)
Timeframe: Study baseline and 6 weeks
| Intervention | Liter (Mean) |
|---|---|
| Placebo | 0.086 |
| Olo 5 mcg qd | 0.386 |
| Olo 10 mcg qd | 0.383 |
| Tio 18 mcg qd | 0.381 |
Response was defined as change from baseline. Study baseline peak FEV1 was defined as the mean of the available pre-dose peak FEV1 values prior to first dose of first treatment period. Peak FEV1 (0-3h) values were obtained within 0 - 3 hours after the first dose of treatment. Means are adjusted using a mixed effects model with treatment and period as fixed effects and patient as a random effect and study baseline as a continuous covariate. (NCT01040689)
Timeframe: Study baseline and first day of dosing
| Intervention | Liter (Mean) |
|---|---|
| Placebo | 0.040 |
| Olo 5 mcg qd | 0.253 |
| Olo 10 mcg qd | 0.279 |
| Tio 18 mcg qd | 0.201 |
Clinical relevant Abnormalities for Vital Signs, Blood Chemistry, Haematology, Urinalysis and ECG. New abnormal findings or worsenings of baseline conditions were reported as Adverse Events related to treatment (cardiac disorders and investigations). (NCT01040728)
Timeframe: 6 weeks
| Intervention | participants (Number) | ||
|---|---|---|---|
| Potassium increased | Atrial fibrillation | Palpitations | |
| Olo 10 mcg | 0 | 1 | 1 |
| Olo 5 mcg | 0 | 0 | 0 |
| Placebo | 1 | 0 | 0 |
| Tiotropium (Tio) 18 mcg qd | 0 | 0 | 0 |
Response was defined as change from baseline. Study baseline FEV1 was defined as the mean of the available pre-dose FEV1 values prior to the first dose of the treatment at the first treatment visit for the first period. Means are adjusted using a mixed effects model with treatment and period as fixed effects and patient as a random effect and study baseline as a continuous covariate. FEV1 AUC 0-3h was calculated from 0-3hours post-dose using the trapezoidal rule, divided by the observation time (3 h) to report in litres. (NCT01040728)
Timeframe: 1 hour (h) prior and 10 minutes (min) prior to the am dose on the first day of the first treatment period (study baseline) and -30 min, 30 min, 60 min, 2 h , 3 h, relative to the first dose of treatment period
| Intervention | Liter (Mean) |
|---|---|
| Placebo | 0.018 |
| Olo 5 mcg qd | 0.232 |
| Olo 10 mcg qd | 0.256 |
| Tio 18 mcg qd | 0.169 |
Response was defined as change from baseline. Study baseline trough FEV1 was defined as the mean of the available pre-dose trough FEV1 values prior to first dose of treatment for the first period. Trough values were the mean of values obtained 23h and 23 h 50 min after the last dose of study drug after six weeks of treatment . Means are adjusted using a mixed effects model with treatment and period as fixed effects and patient as a random effect and study baseline as a continuous covariate. (NCT01040728)
Timeframe: Study baseline and 6 weeks
| Intervention | Liter (Mean) |
|---|---|
| Placebo | 0.003 |
| Olo 5 mcg qd | 0.137 |
| Olo 10 mcg qd | 0.146 |
| Tio 18 mcg qd | 0.161 |
Response was defined as change from baseline. Study baseline FVC was defined as the mean of the available pre-dose FVC values prior to the first dose of treatment for the first period. Means are adjusted using a mixed effects model with treatment and period as fixed effects and patient as a random effect and study baseline as a continuous covariate. FVC AUC 0-3h was calculated using the trapezoidal rule, divided by the observation time to report in litres. (NCT01040728)
Timeframe: 1 hour (h) and 10 minutes (min) prior to the am dose on the first day of the first treatment period (study baseline) and -30 min, 30 min, 60 min, 2 h, 3 h relative to last dose of treatment after six weeks of treatment
| Intervention | Liter (Mean) |
|---|---|
| Placebo | 0.044 |
| Olo 5 mcg qd | 0.388 |
| Olo 10 mcg qd | 0.397 |
| Tio 18 mcg qd | 0.414 |
Response was defined as change from baseline. Study baseline FEV1 was defined as the mean of the -1 hour and -10 minute measurements performed in the morning of the first treatment visit for the first period, just prior to administration of the first morning dose of randomized treatment. Means are adjusted using a mixed effects model with treatment and period as fixed effects and patient as a random effect and study baseline as a continuous covariate. FEV1 AUC 0-12h was calculated from 0-12 hours post-dose using the trapezoidal rule, divided by the observation time (12h) to report in litres. (NCT01040728)
Timeframe: 1 hour (h) and 10 minutes (min) prior to the am dose on the first day of the first treatment period (study baseline) and -30 min (zero time), 30 min, 60 min, 2 hour (h) , 3 h, 4 h, 6 h, 8 h, 10 h, 12 h relative to am dose after six weeks of treatment
| Intervention | Liter (Mean) |
|---|---|
| Placebo | -0.008 |
| Olo 5 mcg qd | 0.189 |
| Olo 10 mcg qd | 0.213 |
| Tio 18 mcg qd | 0.213 |
Response was defined as change from baseline. Study baseline FVC was defined as the mean of the available pre-dose FVC values prior to first dose of treatment for the first period. Means are adjusted using a mixed effects model with treatment and period as fixed effects and patient as a random effect and study baseline as a continuous covariate. FVC AUC 12-24h was calculated using the trapezoidal rule, divided by the observation time to report in litres. (NCT01040728)
Timeframe: 1 h and 10 min prior to the am dose on the first day of the first treatment period (study baseline) and 12 h, 22 h, 23 h, and 23 h 50 min relative to last dose after six weeks of treatment
| Intervention | Liter (Mean) |
|---|---|
| Placebo | -0.109 |
| Olo 5 mcg qd | 0.169 |
| Olo 10 mcg qd | 0.155 |
| Tio 18 mcg qd | 0.192 |
Response was defined as change from baseline. Study baseline FEV1 was defined as the mean of the -1 hour and -10 minute measurements performed in the morning of the first treatment visit for the first period, just prior to administration of the first morning dose of randomized treatment. Means are adjusted using a mixed effects model with treatment and period as fixed effects and patient as a random effect and study baseline as a continuous covariate. FEV1 AUC 12-24h was calculated from 12-24 hours post-dose using the trapezoidal rule, divided by the observation time (12h) to report in litres. (NCT01040728)
Timeframe: 1 h and 10 min prior to the am dose on the first day of the first treatment period (study baseline) and 12 h, 22 h, 23 h, and 23 h 50 min relative to am dose after six weeks of treatment
| Intervention | Liter (Mean) |
|---|---|
| Placebo | -0.059 |
| Olo 5 mcg qd | 0.094 |
| Olo 10 mcg qd | 0.111 |
| Tio 18 mcg qd | 0.105 |
Response was defined as change from baseline. Study baseline FEV1 was defined as the mean of the available pre-dose FEV1 values prior to the first dose at the first randomized treatment visit for the first period. Means are adjusted using a mixed effects model with treatment and period as fixed effects and patient as a random effect and study baseline as a continuous covariate. FEV1 AUC 0-24h was calculated from 0-24 hours post-dose using the trapezoidal rule, divided by the observation time (24h) to report in litres. (NCT01040728)
Timeframe: 1 hour (h) and 10 minutes (min) prior to am dose on the first day of the first treatment period (study baseline) and -30 min, 30 min, 60 min, 2 h, 3 h, 4 h, 6h, 8h, 10h, 12 h, 22 h, 23 h, and 23 h 50 min relative to am dose after six weeks of treatment
| Intervention | Liter (Mean) |
|---|---|
| Placebo | -0.033 |
| Olo 5 mcg qd | 0.142 |
| Olo 10 mcg qd | 0.158 |
| Tio 18 mcg qd | 0.159 |
Response was defined as change from baseline. Study baseline FEV1 was defined as the mean of the available pre-dose FEV1 values prior to the first dose of treatment for the first period. Means are adjusted using a mixed effects model with treatment and period as fixed effects and patient as a random effect and study baseline as a continuous covariate. FEV1 AUC 0-3h was calculated from 0-3hours post-dose using the trapezoidal rule, divided by the observation time (3 h) to report in litres. (NCT01040728)
Timeframe: 1 hour (h) prior and 10 minutes (min) prior to the am dose on the first day of the first treatment period (study baseline) and -30 min, 30 min, 60 min, 2 h , 3 h, relative to the first dose of treatment after six weeks of treatment
| Intervention | Liter (Mean) |
|---|---|
| Placebo | 0.011 |
| Olo 5 mcg qd | 0.225 |
| Olo 10 mcg qd | 0.255 |
| Tio 18 mcg qd | 0.246 |
Response was defined as change from baseline. Study baseline FVC was defined as the mean of the available pre-dose FVC values prior to first dose of treatment for the first period. Means are adjusted using a mixed effects model with treatment and period as fixed effects and patient as a random effect and study baseline as a continuous covariate. FVC AUC 0-12h was calculated using the trapezoidal rule, divided by the observation time to report in litres. (NCT01040728)
Timeframe: 1 hour (h) and 10 minutes (min) prior to the am dose on the first day of the first treatment period (study baseline) and -30 min (zero time), 30 min, 60 min, 2 h, 3 h, 4 h, 6 h, 8 h, 10 h, 12h relative to last dose after six weeks of treatment.
| Intervention | Liter (Mean) |
|---|---|
| Placebo | -0.006 |
| Olo 5 mcg qd | 0.324 |
| Olo 10 mcg qd | 0.321 |
| Tio 18 mcg qd | 0.364 |
Response was defined as change from baseline. Study baseline FVC was defined as the mean of the available pre-dose FVC values prior to first dose of treatment for the first period. Means are adjusted using a mixed effects model with treatment and period as fixed effects and patient as a random effect and study baseline as a continuous covariate. FVC AUC 0-24h was calculated using the trapezoidal rule, divided by the observation time to report in litres. (NCT01040728)
Timeframe: 1 hour (h) and 10 minutes (min) prior to am dose on the first day of the first treatment period (study baseline) and -30 min, 30 min, 60 min, 2 h, 3 h, 4 h, 6h, 8h, 10h, 12 h, 22 h, 23 h, and 23 h 50 min relative to last dose after six weeks of treatment
| Intervention | Liter (Mean) |
|---|---|
| Placebo | -0.057 |
| Olo 5 mcg qd | 0.247 |
| Olo 10 mcg qd | 0.226 |
| Tio 18 mcg qd | 0.278 |
Response was defined as change from baseline. Study baseline peak FEV1 was defined as the mean of the available pre-dose peak FEV1 values prior to first dose of treatment for the first period. Peak FEV1 (0-3h) values were obtained within 0 - 3 hours after the first dose of treatment. Means are adjusted using a mixed effects model with treatment and period as fixed effects and patient as a random effect and study baseline as a continuous covariate. (NCT01040728)
Timeframe: Study baseline and first day of dosing
| Intervention | Liter (Mean) |
|---|---|
| Placebo | 0.076 |
| Olo 5 mcg qd | 0.313 |
| Olo 10 mcg qd | 0.342 |
| Tio 18 mcg qd | 0.251 |
Response was defined as change from baseline. Study baseline peak FEV1 was defined as the mean of the available pre-dose peak FEV1 values prior to first dose of treatment for the first period. Peak FEV1 (0-3h) values were obtained within 0 - 3 hours after the last dose after six weeks of treatment. Means are adjusted using a mixed effects model with treatment and period as fixed effects and patient as a random effect and study baseline as a continuous covariate. (NCT01040728)
Timeframe: Study baseline and 6 weeks
| Intervention | Liter (Mean) |
|---|---|
| Placebo | 0.082 |
| Olo 5 mcg qd | 0.290 |
| Olo 10 mcg qd | 0.325 |
| Tio 18 mcg qd | 0.325 |
Response was defined as change from baseline. Study baseline peak FVC was defined as the mean of the available pre-dose peak FVC values prior to first dose of treatment for the first period. Peak FVC (0-3h) was obtained within 0 - 3 hours after the last am dose of study drug after 6 weeks of treatment. Means are adjusted using a mixed effects model with treatment and period as fixed effects and patient as a random effect and study baseline as a continuous covariate. (NCT01040728)
Timeframe: Study baseline and 6 weeks
| Intervention | Liter (Mean) |
|---|---|
| Placebo | 0.191 |
| Olo 5 mcg qd | 0.526 |
| Olo 10 mcg qd | 0.537 |
| Tio 18 mcg qd | 0.569 |
Response was defined as change from baseline. Study baseline FVC was defined as the mean of the available pre-dose FVC values prior to the first dose of treatment for the first period. Means are adjusted using a mixed effects model with treatment and period as fixed effects and patient as a random effect and study baseline as a continuous covariate. FVC AUC 0-3h was calculated using the trapezoidal rule, divided by the observation time to report in litres. (NCT01040728)
Timeframe: 1 hour (h) and 10 minutes (min) prior to the am dose on the first day of the first treatment period (study baseline) and -30 min, 30 min, 60 min, 2 h, 3 h relative to first dose of treatment
| Intervention | Liter (Mean) |
|---|---|
| Placebo | 0.053 |
| Olo 5 mcg qd | 0.423 |
| Olo 10 mcg qd | 0.419 |
| Tio 18 mcg qd | 0.316 |
Response was defined as change from baseline. Study baseline trough FVC was defined as the mean of the available pre-dose trough FVC values prior to first dose of treatment for the first period. Trough values were the mean of obtained 23 h and 23 h 50 min after the last dose of study drug after six weeks of treatment . Means are adjusted using a mixed effects model with treatment and period as fixed effects and patient as a random effect and study baseline as a continuous covariate. (NCT01040728)
Timeframe: Study baseline and 6 weeks
| Intervention | Liter (Mean) |
|---|---|
| Placebo | -0.001 |
| Olo 5 mcg qd | 0.243 |
| Olo 10 mcg qd | 0.215 |
| Tio 18 mcg qd | 0.255 |
Inspiratory capacity (IC) during CWR exercise testing measured at isotime (isotime was established during CWR exercise testing at baseline). Isotime is the minimum exercise time among all tests. Constant work rate exercise means the exercise is done under constant work rate. (NCT01072396)
Timeframe: baseline, six weeks of treatment
| Intervention | liter (Least Squares Mean) |
|---|---|
| Placebo | 0.0035 |
| Tiotropium | 0.07 |
CWR exercise duration calculated as the length of time of the exercise period (NCT01072396)
Timeframe: six weeks of treatment
| Intervention | seconds (Least Squares Mean) |
|---|---|
| Placebo | 6.0796 |
| Tiotropium | 6.1458 |
Modified Borg Scale is a participant rating of the intensity of dyspnea measured on a scale ranging from 0 (Nothing at all) to 10 (Maximal, most severe ever experienced). (NCT01072396)
Timeframe: baseline, six weeks of treatment
| Intervention | Scores on a scale (Least Squares Mean) |
|---|---|
| Placebo | -0.0485 |
| Tiotropium | -0.2544 |
Change from BaseLine in mean evening pre-dose daily peak flow rate on Day 7 (NCT01085045)
Timeframe: Day 7
| Intervention | Liters / Minute (Least Squares Mean) |
|---|---|
| GFF MDI 72/9.6 μg | 35.0945 |
| GFF MDI 36/9.6 μg | 30.817 |
| GP MDI 36 μg | 18.487 |
| FF MDI 9.6 μg | 17.190 |
| FF MDI 7.2 μg | 14.805 |
| Foradil 12 μg | 17.789 |
Change from BaseLine in mean morning post-dose daily peak flow rate on Day 7 (NCT01085045)
Timeframe: Day 7
| Intervention | Liters / Minute (Least Squares Mean) |
|---|---|
| GFF MDI 72/9.6 μg | 56.666 |
| GFF MDI 36/9.6 μg | 53.411 |
| GP MDI 36 μg | 33.652 |
| Spiriva 18 μg | 27.668 |
| FF MDI 9.6 μg | 41.287 |
| FF MDI 7.2 μg | 38.712 |
| Foradil 12 μg | 39.132 |
Change from BaseLine in mean morning pre-dose daily peak flow rate on Day 7 (NCT01085045)
Timeframe: Day 7
| Intervention | Liters / Minute (Least Squares Mean) |
|---|---|
| GFF MDI 72/9.6 μg | 30.263 |
| GFF MDI 36/9.6 μg | 28.152 |
| GP MDI 36 μg | 16.439 |
| Spiriva 18 μg | 11.817 |
| FF MDI 9.6 μg | 12.424 |
| FF MDI 7.2 μg | 10.211 |
| Foradil 12 μg | 13.426 |
Change from Baseline in morning pre-dose FEV1 on Day 7 (NCT01085045)
Timeframe: Day 7
| Intervention | Liters (Least Squares Mean) |
|---|---|
| GFF MDI 72/9.6 μg | 0.193 |
| GFF MDI 36/9.6 μg | 0.170 |
| GP MDI 36 μg | 0.097 |
| Spiriva 18 μg | 0.097 |
| FF MDI 9.6 μg | 0.064 |
| FF MDI 7.2 μg | 0.073 |
| Foradil 12 μg | 0.101 |
Forced Expiratory Volume in One Second (FEV1) Area Under the Curve (AUC) 0-12 (normalized) relative to baseline FEV1 following 7-day dose administration (NCT01085045)
Timeframe: "Pre-dose, 15 minutes, 30 minutes, 1, 2, 4, 6, 8, 10, 11.5, and 12 hours post-dose on Day 7"
| Intervention | Liters (Least Squares Mean) |
|---|---|
| GFF MDI 72/9.6 μg | 1.537 |
| GFF MDI 36/9.6 μg | 1.529 |
| GP MDI 36 μg | 1.429 |
| Spiriva 18 μg | 1.434 |
| FF MDI 9.6 μg | 1.421 |
| FF MDI 7.2 μg | 1.413 |
| Foradil 12 μg | 1.437 |
Peak Change from Baseline Inspiratory Capacity on following 7-day dose administration (NCT01085045)
Timeframe: Day 7
| Intervention | Liters (Least Squares Mean) |
|---|---|
| GFF MDI 72/9.6 μg | 0.409 |
| GFF MDI 36/9.6 μg | 0.438 |
| GP MDI 36 μg | 0.331 |
| Spiriva 18 μg | 0.314 |
| FF MDI 9.6 μg | 0.359 |
| FF MDI 7.2 μg | 0.376 |
| Foradil 12 μg | 0.393 |
12 hour post-dose trough Forced Expiratory Volume in 1 second on Day 7 (NCT01085045)
Timeframe: Day 7
| Intervention | Liters (Least Squares Mean) |
|---|---|
| GFF MDI 72/9.6 μg | 1.405 |
| GFF MDI 36/9.6 μg | 1.441 |
| GP MDI 36 μg | 1.383 |
| Spiriva 18 μg | 1.398 |
| FF MDI 9.6 μg | 1.349 |
| FF MDI 7.2 μg | 1.378 |
| Foradil 12 μg | 1.358 |
Peak change from Baseline in FEV1 on Day 1 (NCT01085045)
Timeframe: Day 1
| Intervention | Liters (Least Squares Mean) |
|---|---|
| GFF MDI 72/9.6 μg | 0.370 |
| GFF MDI 36/9.6 μg | 0.357 |
| GP MDI 36 μg | 0.289 |
| Spiriva 18 μg | 0.266 |
| FF MDI 9.6 μg | 0.308 |
| FF MDI 7.2 μg | 0.310 |
| Foradil 12 μg | 0.299 |
Change from BaseLine in mean evening post-dose daily peak flow rate on Day 7 (NCT01085045)
Timeframe: Day 7
| Intervention | Liters / Minute (Least Squares Mean) |
|---|---|
| GFF MDI 72/9.6 μg | 53.863 |
| GFF MDI 36/9.6 μg | 58.326 |
| GP MDI 36 μg | 36.637 |
| Spiriva 18 μg | 24.253 |
| FF MDI 9.6 μg | 41.395 |
| FF MDI 7.2 μg | 37.192 |
| Foradil 12 μg | 39.323 |
Peak change from Baseline in Inspiratory Capacity (IC) on Day 1 (NCT01085045)
Timeframe: Day 1
| Intervention | Liters (Least Squares Mean) |
|---|---|
| GFF MDI 72/9.6 μg | 0.495 |
| GFF MDI 36/9.6 μg | 0.411 |
| GP MDI 36 μg | 0.430 |
| Spiriva 18 μg | 0.347 |
| FF MDI 9.6 μg | 0.362 |
| FF MDI 7.2 μg | 0.352 |
| Foradil 12 μg | 0.374 |
Time to Onset of Action where the improvement in FEV1 on Day 1 was >= 12% (NCT01085045)
Timeframe: Day 1
| Intervention | Percentage of Participants (Number) |
|---|---|
| GFF MDI 72/9.6 μg | 86.84 |
| GFF MDI 36/9.6 μg | 87.18 |
| GP MDI 36 μg | 73.68 |
| Spiriva 18 μg | 66.07 |
| FF MDI 9.6 μg | 84.48 |
| FF MDI 7.2 μg | 82.54 |
| Foradil 12 μg | 85.19 |
Time to Onset of Action where the improvement in FEV1 on Day 1 was >=10% (NCT01085045)
Timeframe: Day 1
| Intervention | Participants (Number) | ||||
|---|---|---|---|---|---|
| 15 Minutes | 30 Minutes | 60 Minutes | 120 Minutes | No onset | |
| FF MDI 7.2 μg | 34 | 12 | 4 | 2 | 9 |
| FF MDI 9.6 μg | 37 | 10 | 4 | 0 | 6 |
| Foradil 12 μg | 30 | 6 | 6 | 3 | 5 |
| GFF MDI 36/9.6 μg | 20 | 7 | 6 | 1 | 5 |
| GFF MDI 72/9.6 μg | 22 | 5 | 4 | 2 | 3 |
| GP MDI 36 μg | 14 | 10 | 3 | 4 | 6 |
| Spiriva 18 μg | 22 | 4 | 7 | 5 | 16 |
Peak change from Baseline (BL) in FEV1 on Day 7 (NCT01085045)
Timeframe: Day 7
| Intervention | Liters (Least Squares Mean) |
|---|---|
| GFF MDI 72/9.6 μg | 0.438 |
| GFF MDI 36/9.6 μg | 0.440 |
| GP MDI 36 μg | 0.313 |
| Spiriva 18 μg | 0.298 |
| FF MDI 9.6 μg | 0.337 |
| FF MDI 7.2 μg | 0.330 |
| Foradil 12 μg | 0.356 |
Following albuterol plus tiotropium inhalation, FVC increments ≥12 per cent as compared to baseline, in an individual subject, were considered as evidence of response to bronchodilators, according to the American Thoracic Society-European Respiratory Society standard criteria [Pellegrino et al. Eur Respir J 2005; 26: 948-968]. They were calculated as follows: [FVC, expressed in liters (L), after bronchodilators - FVC (L) before bronchodilators/FVC (L) before bronchodilators x 100]. (NCT01112241)
Timeframe: Baseline and 90 min after bronchodilators
| Intervention | per cent positive change (Mean) | |
|---|---|---|
| Responsives to bronchodilators (n=5) | Unresponsives to bronchodilators (n=12) | |
| Albuterol Plus Tiotropium | 24 | 2 |
Following albuterol plus tiotropium inhalation, FEV1 increments ≥12 per cent as compared to baseline, in an individual subject, were considered as evidence of response to bronchodilators, according to the American Thoracic Society-European Respiratory Society standard criteria [Pellegrino et al. Eur Respir J 2005; 26: 948-968]. They were calculated as follows: [FEV1, expressed in liters (L), after bronchodilators - FEV1 (L) before bronchodilators/FEV1 (L) before bronchodilators x 100]. (NCT01112241)
Timeframe: Baseline and 90 min after bronchodilators
| Intervention | per cent positive change (Mean) | |
|---|---|---|
| Responsives to bronchodilators (n=4) | Unresponsives to bronchodilators (n=13) | |
| Albuterol Plus Tiotropium | 14 | 7 |
Following albuterol plus tiotropium inhalation, RV decrements ≥0.30 liters (L) as compared to baseline, in an individual subject, were considered as evidence of response to bronchodilators, according to O'Donnell et al. [Eur Respir J 2001; 18: 914-920]. They were calculated as follows: [RV (L), before bronchodilators - RV (L) after bronchodilators]. (NCT01112241)
Timeframe: Baseline and 90 min after bronchodilators
| Intervention | absolute negative change (liters) (Mean) | |
|---|---|---|
| Responsives to bronchodilators (n=8) | Unresponsives to bronchodilators (n=9) | |
| Albuterol Plus Tiotropium | 0.65 | 0.00 |
Following albuterol plus tiotropium inhalation, FEV1 increments ≥0.20 liters (L) as compared to baseline, in an individual subject, were considered as evidence of response to bronchodilators, according to the American Thoracic Society-European Respiratory Society standard criteria [Pellegrino et al. Eur Respir J 2005; 26: 948-968]. They were calculated as follows: [FEV1 (L) after bronchodilators - FEV1 (L) before bronchodilators]. (NCT01112241)
Timeframe: Baseline and 90 min after bronchodilators
| Intervention | absolute positive change (liters) (Mean) | |
|---|---|---|
| Responsives to bronchodilators (n=4) | Unresponsives to bronchodilators (n=13) | |
| Albuterol Plus Tiotropium | 0.26 | 0.12 |
Following albuterol plus tiotropium inhalation, FRC decrements ≥0.30 liters (L) as compared to baseline, in an individual subject, were considered as evidence of response to bronchodilators, according to O'Donnell et al. [Eur Respir J 2001; 18: 914-920]. They were calculated as follows: [FRC (L), before bronchodilators - FRC (L) after bronchodilators]. (NCT01112241)
Timeframe: Baseline and 90 min after bronchodilators
| Intervention | absolute negative change (liters) (Mean) | |
|---|---|---|
| Responsives to bronchodilators (n=4) | Unresponsives to bronchodilators (n=13) | |
| Albuterol Plus Tiotropium | 0.78 | 0.07 |
Following albuterol plus tiotropium inhalation, RV decrements ≥10 per cent as compared to baseline, in an individual subject, were considered as evidence of response to bronchodilators, according to O'Donnell et al. [Eur Respir J 2001; 18: 914-920]. They were calculated as follows: [RV, expressed in liters (L), before bronchodilators - RV (L) after bronchodilators/RV (L) after bronchodilators x 100]. (NCT01112241)
Timeframe: Baseline and 90 min after bronchodilators
| Intervention | per cent negative change (Mean) | |
|---|---|---|
| Responsives to bronchodilators (n=8) | Unresponsives to bronchodilators (n=9) | |
| Albuterol Plus Tiotropium | 19 | 0 |
Following albuterol plus tiotropium inhalation, FVC increments ≥0.20 liters (L) compared with baseline, in an individual subject, were considered as evidence of response to bronchodilators, according to the American Thoracic Society-European Respiratory Society standard criteria [Pellegrino et al. Eur Respir J 2005; 26: 948-968]. They were calculated as follows: [FVC (L) after bronchodilators - FVC (L) before bronchodilators]. (NCT01112241)
Timeframe: Baseline and 90 min after bronchodilators
| Intervention | absolute positive change (liters) (Mean) | |
|---|---|---|
| Responsives to bronchodilators (n=5) | Unresponsives to bronchodilators (n=12) | |
| Albuterol Plus Tiotropium | 0.65 | 0.07 |
Following albuterol plus tiotropium inhalation, V'part increments ≥40 per cent as compared to baseline, in an individual subject, were considered as evidence of response to bronchodilators, according to Pellegrino et al. [Chest 1998; 114:1607-1612]. They were calculated as follows: [V'part, expressed in liters.second-1 (L.s-1), after bronchodilators - V'part (L.s-1) before bronchodilators/V'part (L.s-1) before bronchodilators x 100]. (NCT01112241)
Timeframe: Baseline and 90 min after bronchodilators
| Intervention | per cent positive change (Mean) | |
|---|---|---|
| Responsives to bronchodilators (n=9) | Unresponsives to bronchodilators (n=8) | |
| Albuterol Plus Tiotropium | 59 | 17 |
Following albuterol plus tiotropium inhalation, V'max increments ≥40 per cent as compared to baseline, in an individual subject, were considered as evidence of response to bronchodilators, according to Pellegrino et al. [Chest 1998; 114:1607-1612]. They were calculated as follows: [V'max, expressed in liters.second-1 (L.s-1), after bronchodilators - V'max (L.s-1) before bronchodilators/V'max (L.s-1) before bronchodilators x 100]. (NCT01112241)
Timeframe: Baseline and 90 min after bronchodilators
| Intervention | per cent positive change (Mean) | |
|---|---|---|
| Responsives to bronchodilators (n=4) | Unresponsives to bronchodilators (n=13) | |
| Albuterol Plus Tiotropium | 66 | 14 |
Following albuterol plus tiotropium inhalation, FRC decrements ≥10 per cent as compared to baseline, in an individual subject, were considered as evidence of response to bronchodilators, according to O'Donnell et al. [Eur Respir J 2001; 18: 914-920]. They were calculated as follows: [FRC, expressed in liters (L), before bronchodilators - FRC (L) after bronchodilators/FRC (L) after bronchodilators x 100]. (NCT01112241)
Timeframe: Baseline and 90 min after bronchodilators
| Intervention | per cent negative change (Mean) | |
|---|---|---|
| Responsives to bronchodilators (n=4) | Unresponsives to bronchodilators (n=13) | |
| Albuterol Plus Tiotropium | 16 | 2 |
Patients recorded rescue medication use in a paper patient diary. If a patient required the use of salbutamol as rescue medication due to an increase in COPD symptoms, the number of inhalations (puffs) taken was recorded in the patient diary. (NCT01119937)
Timeframe: 52 weeks
| Intervention | change in puffs (Mean) |
|---|---|
| NVA237 | -0.16 |
| Tiotropium | -0.27 |
Clinically notable hematology values were: hemoglobin - male <11.5g/dL, female <9.5 g/dL; hematocrit - male <37%, female <32%; white cell count - <2800µL or >16000µL; platelets - <7.5 10*4/µL or >70.0 10*4/µL (NCT01119937)
Timeframe: 52 weeks
| Intervention | participants (Number) | |||||||
|---|---|---|---|---|---|---|---|---|
| Hemoglobin - male (n = 121, 38) | Hemoglobin - female (n = 121, 38) | Hematocrit - male (n = 121, 38) | Hematocrit - female (n = 121, 38) | White cell count - <2800/µL | White cell count - >16000/µL | Platelets - <7.5 10*4/µL | Platelets - >70.0 10*4/µL | |
| NVA237 | 3 | 0 | 3 | 0 | 0 | 0 | 1 | 0 |
| Tiotropium | 2 | 0 | 4 | 0 | 1 | 0 | 0 | 0 |
Clinically notable change from baseline was and increase from baseline of 30 or greater milliseconds (ms). (NCT01119937)
Timeframe: 52 weeks
| Intervention | participants (Number) | |
|---|---|---|
| Increase from baseline 30 to 60 ms | Increase from baseline >60 ms | |
| NVA237 | 6 | 2 |
| Tiotropium | 1 | 0 |
Clinically notable vital sign values were: pulse rate - low, <40 bpm or <=50 bpm and decrease from baseline >=15bpm; pulse rate high, >130 bpm or >=120bpm and increase from baseline >=15 bpm. Systolic blood pressure - low, <75 mmHg or <=90 mmHg and decrease from baseline >=20 mmHg; high, >200 mmHg or >=180 mmHg and increase from baseline >=20 mmHg. Diastolic blood pressure - low, <40 mmHg or <=50 mmHg and decrease from baseline >=15 mmHg; high, >115 mmHg or >=105 mmHg and increase from baseline >=15 mmHg. (NCT01119937)
Timeframe: 52 weeks
| Intervention | participants (Number) | ||||||||
|---|---|---|---|---|---|---|---|---|---|
| Pulse rate - low | Pulse rate - high | Pulse rate - low or high | Systolic blood pressure - low | Systolic blood pressure - high | Systolic blood pressure - low or high | Diastolic blood pressure - low | Diastolic blood pressure - high | Diastolic blood pressure - low or high | |
| NVA237 | 0 | 0 | 0 | 0 | 1 | 1 | 1 | 2 | 3 |
| Tiotropium | 1 | 0 | 1 | 0 | 0 | 0 | 0 | 0 | 0 |
Clinically notable biochemistry values were: total protein - <4.0 g/dL or >9.5 g/dL; albumin <2.5 g/dL; bilirubin (total) >1.9 mg/dL; BUN >27 mg/dL; creatinine >1.99 mg/dL; AST >3 x ULN U/L; ALT >3 x ULN U/L; ALP >3 x ULN U/L; y-GTP >3 x ULN U/L; sodium <125 mEq/L or >160 mEq/L; potassium <3.0 mEq/L or >6.0 mEq/L; glucose <51.0 mg/dL or >180.0 mg/dL (NCT01119937)
Timeframe: 52 weeks
| Intervention | participants (Number) | |||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Total protein - <4.0 g/dL | Total protein - >9.5 g/dL | Albumin - <2.5 g/dL | Bilirubin (total) - >1.9 mg/dL | BUN - >27 mg/dL | Creatinine - >1.99 mg/dL | AST - >3 x ULN U/L | ALT - >3 x ULN U/L | ALP - >3 x ULN U/L | Y-GTP - >3 x ULN U/L | Sodium - <125 mEq/L | Sodium - >160 mEq/L | Potassium - <3.0 mEq/L | Potassium - >6.0 mEq/L | Glucose - <51.0 mg/dL | Glucose - >180.0 mg/dL | |
| NVA237 | 0 | 0 | 0 | 2 | 3 | 0 | 1 | 0 | 0 | 5 | 0 | 0 | 1 | 0 | 0 | 11 |
| Tiotropium | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 1 | 4 | 0 | 0 | 0 | 0 | 0 | 3 |
Moderate COPD exacerbations were defined as: worsening of 2 or more of the following major symptoms for at least 2 consecutive days - dyspnea, sputum volume and sputum purulence; OR a worsening of any 1 major symptom with any 1 of the following minor symptoms for at least 2 consecutive days - sore throat, colds, fever without other cause, increased cough or increased wheeze, requiring treatment with systemic glucocorticosteroids or antibiotics or both. Severe COPD exacerbations were defined as: conditions for Moderate COPD exacerbation and hospitalization was required. (NCT01119937)
Timeframe: 52 weeks
| Intervention | participants (Number) | ||||
|---|---|---|---|---|---|
| 0 exacerbations | 1 exacerbation | 2 exacerbations | 3 exacerbations | > = 4 exacerbations | |
| NVA237 | 99 | 17 | 5 | 1 | 1 |
| Tiotropium | 31 | 5 | 3 | 0 | 1 |
Adverse events are defined as any unfavorable and unintended diagnosis, symptom, sign (including an abnormal lab finding), syndrome or disease which either occurs during study, having been absent at baseline, or, if present at baseline, appears to worsen. Serious adverse events are any untoward medical occurrences that result in death, are life threatening, require (or prolong) hospitalization, cause persistent or significant disability/incapacity, result in congenital anomalies or birth defects, or are other conditions which in judgments of the investigators represent significant hazards. (NCT01119937)
Timeframe: 52 weeks
| Intervention | participants (Number) | ||
|---|---|---|---|
| Adverse events | Serious adverse events | Death | |
| NVA237 | 102 | 16 | 0 |
| Tiotropium | 33 | 6 | 0 |
Pre-dose FVC is defined as the average of the measurements at 45 and 15 minutes pre-dose. (NCT01119937)
Timeframe: Weeks 12, 24, 36 and 52
| Intervention | liters (Mean) | |||
|---|---|---|---|---|
| Week 12 | Week 24 | Week 36 (n = 106, 36) | Week 52 (n = 103, 33) | |
| NVA237 | 0.221 | 0.218 | 0.208 | 0.195 |
| Tiotropium | 0.220 | 0.179 | 0.146 | 0.126 |
Pre-dose FEV1 is defined as the average of the measurements at 45 and 15 minutes pre-dose. (NCT01119937)
Timeframe: Weeks 12, 24, 36 and 52
| Intervention | liters (Mean) | |||
|---|---|---|---|---|
| Week 12 | Week 24 | Week 36 (n = 106, 36) | Week 52 (n = 103, 33) | |
| NVA237 | 0.101 | 0.094 | 0.084 | 0.068 |
| Tiotropium | 0.173 | 0.144 | 0.112 | 0.127 |
Moderate COPD exacerbations were defined as: worsening of 2 or more of the following major symptoms for at least 2 consecutive days - dyspnea, sputum volume and sputum purulence; OR a worsening of any 1 major symptom with any 1 of the following minor symptoms for at least 2 consecutive days - sore throat, colds, fever without other cause, increased cough or increased wheeze, requiring treatment with systemic glucocorticosteroids or antibiotics or both. Severe COPD exacerbations were defined as: conditions for Moderate COPD exacerbation and hospitalization was required. Participants who withdraw from the study and do not experience a moderate or severe exacerbation are censored at the date of withdrawal. Participants who complete the study and do not experience a moderate or severe exacerbation are censored at the completion visit date. (NCT01119937)
Timeframe: 52 weeks
| Intervention | days (Number) |
|---|---|
| NVA237 | 362 |
| Tiotropium | 359 |
SGRQ is a health related quality of life questionnaire consisting of 51 items in three components: symptoms, activity, and impacts. The lowest possible value is zero and the highest 100. Higher values correspond to greater impairment in quality of life. (NCT01119937)
Timeframe: Weeks 12, 24, 36, 52
| Intervention | score on a scale (Mean) | |||
|---|---|---|---|---|
| Week 12 | Week 24 | Week 36 | Week 52 | |
| NVA237 | -2.57 | -1.77 | -2.54 | -2.68 |
| Tiotropium | -2.31 | -3.24 | -0.93 | 0.36 |
"A Chronic Obstructive Pulmonary Disease (COPD) exacerbation was defined as a worsening of two or more of the following major symptoms for at least 2 consecutive days: dyspnea, sputum volume or sputum purulence OR a worsening of any 1 major symptom together with an increase in any 1 of the following minor symptoms for at least 2 consecutive days: sore throat, colds (nasal discharge and/or nasal congestion), fever without other cause, cough or wheezing. A COPD exacerbation was considered of moderate severity if treatment with systemic glucocorticosteroids or antibiotics or both was required and severe if hospitalization was required. An emergency room (ER) visit of longer than 24 hours was considered a hospitalization.~Rate of moderate or severe exacerbations per year = total number of moderate or severe exacerbations / total number of treatment years" (NCT01120691)
Timeframe: 76 weeks
| Intervention | Exacerbations per year (Number) |
|---|---|
| QVA149 | 0.94 |
| Open-label Tiotropium | 1.06 |
The number of exacerbation days is defined as the sum of the duration of days recorded as an exacerbation for all exacerbations recorded per patient. (NCT01120691)
Timeframe: 64 weeks
| Intervention | Days (Mean) | ||
|---|---|---|---|
| systemic corticosteroids [n= 97, 108, 109] | antibiotics [n= 195, 177, 177] | corticosteroids and antibiotic [n= 266, 290, 270] | |
| NVA237 | 25.22 | 18.10 | 26.18 |
| Open-label Tiotropium | 17.57 | 25.94 | 22.03 |
| QVA149 | 20.49 | 25.08 | 22.10 |
"A Chronic Obstructive Pulmonary Disease (COPD) exacerbation was defined as a worsening of two or more of the following major symptoms for at least 2 consecutive days: dyspnea, sputum volume or sputum purulence OR a worsening of any 1 major symptom together with an increase in any 1 of the following minor symptoms for at least 2 consecutive days: sore throat, colds (nasal discharge and/or nasal congestion), fever without other cause, cough or wheezing. A COPD exacerbation was considered of moderate severity if treatment with systemic glucocorticosteroids or antibiotics or both was required and severe if hospitalization was required. An emergency room (ER) visit of longer than 24 hours was considered a hospitalization.~Rate of moderate or severe exacerbations per year = total number of moderate or severe exacerbations / total number of treatment years" (NCT01120691)
Timeframe: 64 weeks
| Intervention | days (Median) |
|---|---|
| QVA149 | 296 |
| NVA237 | 287 |
| Open-label Tiotropium | 331 |
Time to Study Withdrawal or Premature Discontinuation for Any Reason was analyzed for each treatment group using a Kaplan-Meier estimation for the modified safety set. Patients who did not discontinue early were censored at the final visit of the treatment phase. (NCT01120691)
Timeframe: 64 weeks
| Intervention | days (Median) |
|---|---|
| QVA149 | NA |
| NVA237 | NA |
| Open-label Tiotropium | NA |
A day with no rescue medication use is defined from the diary data as any day where the patient recorded no rescue medicine use during the previous 12 hours. The percentage of days is calculated by the number of days with no rescue medicine use/total number of days with evaluable data X 100. A mixed model was used with treatment as a fixed effect with baseline number of puffs and FEV1 prior to inhalation and FEV1 60 minutes post inhalation of two short acting bronchodilators (components of reversibility at Day -14) as covariates. The model also included baseline smoking status (current/ex-smoker), baseline ICS use (Yes/No) and region as fixed effects with center nested within region as a random effect. (NCT01120691)
Timeframe: Baseline (14 day run-in), 64 weeks
| Intervention | percentage of days (Least Squares Mean) |
|---|---|
| QVA149 | 29.36 |
| NVA237 | 21.65 |
| Open-label Tiotropium | 23.86 |
Percentage of Patients With Study Withdrawal or Premature Discontinuation for Any Reason was analyzed for each treatment group using a Kaplan-Meier estimation for the modified safety set. Patients who did not discontinue early were censored at the final visit of the treatment phase. (NCT01120691)
Timeframe: 64 weeks
| Intervention | percentage of participants (Number) |
|---|---|
| QVA149 | 21.8 |
| NVA237 | 27.3 |
| Open-label Tiotropium | 24.2 |
Rate of moderate or severe exacerbations per year = total number of moderate or severe exacerbations / total number of treatment years (NCT01120691)
Timeframe: 64 weeks
| Intervention | exacerbations per year (Number) |
|---|---|
| QVA149 | 0.46 |
| NVA237 | 0.58 |
| Open-label Tiotropium | 0.54 |
"A Chronic Obstructive Pulmonary Disease (COPD) exacerbation was defined as a worsening of two or more of the following major symptoms for at least 2 consecutive days: dyspnea, sputum volume or sputum purulence OR a worsening of any 1 major symptom together with an increase in any 1 of the following minor symptoms for at least 2 consecutive days: sore throat, colds (nasal discharge and/or nasal congestion), fever without other cause, cough or wheezing. A COPD exacerbation was considered of moderate severity if treatment with systemic glucocorticosteroids or antibiotics or both was required and severe if hospitalization was required. An emergency room (ER) visit of longer than 24 hours was considered a hospitalization.~Rate of moderate or severe exacerbations per year = total number of moderate or severe exacerbations / total number of treatment years" (NCT01120691)
Timeframe: 64 weeks
| Intervention | Exacerbations per year (Number) |
|---|---|
| QVA149 | 0.94 |
| NVA237 | 1.07 |
The severe or less FEV1 % predicted (post bronchodilator)>=30%; very severe=> FEV1 % predicted(the post bronchodilator)<30%.Number of puffs of rescue medication taken in the previous 12 hours was recorded in patient diary in the morning and in the evening for 26 weeks.The total number of puffs per day was calculated and divided by the number of days with data to determine the mean daily number of puffs of rescue medication for each patient.Rescue medication data recorded during the 14 day run-in was used to calculate the baseline.A negative change from baseline indicates improvement. A mixed model was used with treatment as a fixed effect with baseline number of puffs and FEV1 prior to inhalation and FEV1 60 minutes post inhalation of two short acting bronchodilators (components of reversibility at Day -14) as covariates. (NCT01120691)
Timeframe: Baseline (14 day run-in), 64 weeks
| Intervention | # puffs (Least Squares Mean) | |
|---|---|---|
| Mean Daily # puffs Severe or Less(n=565,575,561) | Mean Daily # puffs Very Severe (n=143,149,148) | |
| NVA237 | -1.5 | -1.1 |
| Open-label Tiotropium | -1.6 | -1.0 |
| QVA149 | -2.3 | -2.1 |
St. George's Respiratory Questionnaire (SGRQ) is a health related quality of life questionnaire consisting of 51 items in three components: symptoms, activity, and impacts. The lowest possible value is zero and the highest 100. Higher values correspond to greater impairment in quality of life. Mixed model used baseline SGRQ, baseline inhaled corticosteroid (ICS) use, Forced Expiratory Volume in 1 Second (FEV1) prior to inhalation of short acting beta-agonist (SABA), and FEV1 45 minutes post-inhalation of SABA as covariates. SGRQ total score is the sum of the scores from the three components; symptoms, activity and impacts. (NCT01120691)
Timeframe: 12, 26, 38, 52 and 64 weeks
| Intervention | units on a scale (Least Squares Mean) | ||||
|---|---|---|---|---|---|
| Week 12 (n= 694,694,676) | Week 26 (n= 684,677,658) | Week 38 (n= 648,626,635) | Week 52 (n= 625,593,613) | Week 64 (n= 600,564,579) | |
| NVA237 | 47.13 | 45.93 | 45.53 | 45.96 | 45.46 |
| Open-label Tiotropium | 47.62 | 45.77 | 45.86 | 46.21 | 46.08 |
| QVA149 | 44.69 | 44.06 | 42.72 | 43.38 | 43.39 |
"Pulmonary function assessments were performed using centralized spirometry. The spirometer was customized and programmed according to the requirements of the study protocol in accordance with American Thoracic Society (ATS) standards.~Pre-dose Forced Vital Capacity (FVC) is defined as the average of the -15 minutes and the -45 minutes FVC values. Baseline is defined as the average of the -45 minutes and -15 minutes FVC values taken on day 1 prior to first dose. FVC data taken within 6h of rescue medication or within 7 days of systemic corticosteroid is excluded from this analysis" (NCT01120691)
Timeframe: 4, 12, 26, 38, 52 and 64 weeks
| Intervention | L (liters) (Least Squares Mean) | |||||
|---|---|---|---|---|---|---|
| predose FVC Week 4 (n= 656,654,630) | predose FVC Week 12 (n= 623,621,619) | predose FVC Week 26 (n= 604,577,599) | predose FVC Week 38 (n= 592,548,580) | predose FVC Week 52 (n= 557,538,547) | predose FVC Week 64 (n= 549,502,526) | |
| NVA237 | 2.59 | 2.63 | 2.60 | 2.65 | 2.58 | 2.57 |
| Open-label Tiotropium | 2.60 | 2.65 | 2.61 | 2.63 | 2.58 | 2.59 |
| QVA149 | 2.74 | 2.77 | 2.73 | 2.76 | 2.68 | 2.67 |
"Pulmonary function assessments were performed using centralized spirometry. The spirometer was customized and programmed according to the requirements of the study protocol in accordance with American Thoracic Society (ATS) standards.~Spirometry measurements taken were FEV1 at -45 minutes and -15 minutes pre-dose. Three acceptable maneuvers had to be performed for each time point. The FEV1 values recorded had to be the highest values measured irrespective of whether or not they occurred on the same curve.~The mixed model for analysis contained treatment as a fixed effect with average of the 45 minutes and 15 minutes pre dose FEV1 measurements at day 1 as the baseline measurement, FEV1 prior to inhalation and FEV1 60 minutes post inhalation of two short acting bronchodilators (components of reversibility at -14 Day) as covariates." (NCT01120691)
Timeframe: 4, 12, 26, 38, 52 and 64 weeks
| Intervention | L (liters) (Least Squares Mean) | |||||
|---|---|---|---|---|---|---|
| predose FEV1 Week 4 (n= 656,654,630) | predose FEV1 Week 12 (n= 666,663,653) | predose FEV1 Week 26 (n= 604,577,599) | predose FEV1 Week 38 (n= 593,549,583) | predose FEV1 Week 52 (n= 557,538,548) | predose FEV1 Week 64 (n= 549,504,530) | |
| NVA237 | 0.99 | 1.01 | 0.99 | 1.00 | 0.98 | 0.98 |
| Open-label Tiotropium | 1.00 | 1.01 | 1.00 | 1.00 | 0.99 | 0.99 |
| QVA149 | 1.08 | 1.08 | 1.07 | 1.08 | 1.05 | 1.05 |
Cumulative rates were estimated using Anderson and Gill method. Chronic Obstructive Pulmonary Disease (COPD) exacerbations are considered to be moderate if treatment with systemic corticosteroids and/or antibiotics was required. COPD exacerbations are considered to be severe if treatment for moderate severity and hospitalization were required. Rate of moderate or severe exacerbations per year = total number of moderate or severe exacerbations / total number of treatment years (NCT01120691)
Timeframe: 26, 52, 64, 76 weeks
| Intervention | exacerbations per year (Number) | |||
|---|---|---|---|---|
| 26 weeks | 52 weeks | 64 weeks | 76 weeks | |
| NVA237 | 0.65 | 1.13 | 1.36 | 1.59 |
| Open-label Tiotropium | 0.63 | 1.11 | 1.31 | 1.55 |
| QVA149 | 0.57 | 0.99 | 1.19 | 1.39 |
Mean evening PEF assessed by patients at home. Response was defined as the change from baseline. Analysis adjusted for treatment, period, patient and baseline using a mixed model. (NCT01122680)
Timeframe: Baseline and 4 weeks
| Intervention | Litre/min (Least Squares Mean) |
|---|---|
| Placebo | -0.552 |
| Tio R1.25 | 5.985 |
| Tio R2.5 | 18.971 |
| Tio R5 | 16.565 |
FEV1 (AUC0-3h) will be calculated as the area under the curve from 0 to 3hours using the trapezoidal rule divided by the observation time (3 hours) to report in litres. Response was defined as the change from baseline. Analysis adjusted for treatment, period, patient and baseline using a mixed model. (NCT01122680)
Timeframe: Baseline and 4 weeks
| Intervention | Litre (Least Squares Mean) |
|---|---|
| Placebo | 0.363 |
| Tio R1.25 | 0.455 |
| Tio R2.5 | 0.434 |
| Tio R5 | 0.497 |
FVC (AUC0-3h) will be calculated as the area under the curve from 0 to 3hours using the trapezoidal rule divided by the observation time (3 hours) to report in litres. Response was defined as the change from baseline. Analysis adjusted for treatment, period, patient and baseline using a mixed model. (NCT01122680)
Timeframe: Baseline and 4 weeks
| Intervention | Litre (Least Squares Mean) |
|---|---|
| Placebo | 0.413 |
| Tio R1.25 | 0.441 |
| Tio R2.5 | 0.417 |
| Tio R5 | 0.429 |
The FVC peak (0-3h) response is determined at the end of the 4 week treatment period. This is the difference between the maximum FVC measured within the first 3 hours post dosing and the FVC baseline measurement. Analysis adjusted for treatment, period, patient and baseline using a mixed model. (NCT01122680)
Timeframe: Baseline and 4 weeks
| Intervention | Litre (Least Squares Mean) |
|---|---|
| Placebo | 0.546 |
| Tio R1.25 | 0.554 |
| Tio R2.5 | 0.554 |
| Tio R5 | 0.548 |
The FEV1 peak (0-3h) response is determined at the end of the 4 week treatment period. This is the difference between the maximum FEV1 measured within the first 3 hours post dosing and the FEV1 baseline measurement. Analysis adjusted for treatment, period, patient and baseline using a mixed model. (NCT01122680)
Timeframe: Baseline and 4 weeks
| Intervention | Litre (Least Squares Mean) |
|---|---|
| Placebo | 0.489 |
| Tio R1.25 | 0.556 |
| Tio R2.5 | 0.546 |
| Tio R5 | 0.602 |
The trough FVC response is defined as the pre-dose FVC measured just prior to the last administration of randomised treatment. Response was defined as the change from baseline. Analysis adjusted for treatment, period, patient and baseline using a mixed model. (NCT01122680)
Timeframe: Baseline and 4 weeks
| Intervention | Litre (Least Squares Mean) |
|---|---|
| Placebo | 0.357 |
| Tio R1.25 | 0.375 |
| Tio R2.5 | 0.381 |
| Tio R5 | 0.400 |
ACQ is a questionnaire consisting of a seven point Likert scale ranging from 0 to 6, whereby 0 represents good control and 6 represents poor control of asthma. The scale describes the frequency and severity of asthma symptoms. Analysis adjusted for treatment, period, patient and baseline using a mixed model. (NCT01122680)
Timeframe: 4 weeks
| Intervention | Units on a scale (Least Squares Mean) |
|---|---|
| Placebo | 1.371 |
| Tio R1.25 | 1.189 |
| Tio R2.5 | 1.366 |
| Tio R5 | 1.287 |
Mean number of inhalations (puffs) of unscheduled rescue salbutamol therapy during whole day. Analysis adjusted for treatment, period, patient and baseline using a mixed model. (NCT01122680)
Timeframe: Baseline and 4 weeks
| Intervention | Puffs/day (Least Squares Mean) |
|---|---|
| Placebo | -0.412 |
| Tio R1.25 | -0.635 |
| Tio R2.5 | -0.521 |
| Tio R5 | -0.528 |
Mean number of nighttime awakenings due to asthma symptoms as assessed by patients eDiary incorporated in the AM3® device. Analysis adjusted for treatment, period, patient and baseline using a mixed model. (NCT01122680)
Timeframe: Baseline and last week of treatment (week 4)
| Intervention | Night awakenings per week (Least Squares Mean) |
|---|---|
| Placebo | -0.086 |
| Tio R1.25 | -0.027 |
| Tio R2.5 | -0.074 |
| Tio R5 | -0.066 |
Mean morning PEF assessed by patients at home. Response was defined as the change from baseline. Analysis adjusted for treatment, period, patient and baseline using a mixed model. (NCT01122680)
Timeframe: Baseline and 4 weeks
| Intervention | Litre/min (Least Squares Mean) |
|---|---|
| Placebo | 7.267 |
| Tio R1.25 | 18.613 |
| Tio R2.5 | 23.185 |
| Tio R5 | 20.491 |
The trough FEV1 is defined as the pre-dose FEV1 measured just prior to the last administration of randomised treatment. Response was defined as the change from baseline. Analysis adjusted for treatment, period, patient and baseline using a mixed model. (NCT01122680)
Timeframe: Baseline and 4 weeks
| Intervention | Litre (Least Squares Mean) |
|---|---|
| Placebo | 0.292 |
| Tio R1.25 | 0.384 |
| Tio R2.5 | 0.353 |
| Tio R5 | 0.442 |
"Individual FEV1 measurements at each time-point (personal best). Response was defined as the change from baseline. Analysis adjusted for treatment, period, patient and baseline using a mixed model." (NCT01122680)
Timeframe: Baseline and 4 weeks (10 min pre-dose, 30 min, 1,2,3 hours post-dose)
| Intervention | Litre (Least Squares Mean) | ||||
|---|---|---|---|---|---|
| Timepoint -0:10 hr response | Timepoint 0:30 hr response | Timepoint 1:00 hr response | Timepoint 2:00 hr response | Timepoint 3:00 hr response | |
| Placebo | 0.292 | 0.337 | 0.353 | 0.394 | 0.396 |
| Tio R1.25 | 0.384 | 0.456 | 0.456 | 0.467 | 0.467 |
| Tio R2.5 | 0.353 | 0.407 | 0.416 | 0.453 | 0.489 |
| Tio R5 | 0.442 | 0.486 | 0.505 | 0.501 | 0.497 |
FEF 25-75% is the mean forced expiratory flow between 25% and 75% of the FVC determined at the end of the 4-week treatment period. This is often referred to as the maximum midexpiratory flow. Analysis adjusted for treatment, period, patient and baseline using a mixed model. (NCT01122680)
Timeframe: Baseline and 4 weeks (10 min pre-dose, 30 min, 1,2,3 hours post-dose)
| Intervention | Litre (Least Squares Mean) | ||||
|---|---|---|---|---|---|
| Timepoint -0:10 hr response | Timepoint 0:30 hr response | Timepoint 1:00 hr response | Timepoint 2:00 hr response | Timepoint 3:00 hr response | |
| Placebo | 0.242 | 0.268 | 0.321 | 0.357 | 0.329 |
| Tio R1.25 | 0.533 | 0.643 | 0.655 | 0.678 | 0.662 |
| Tio R2.5 | 0.380 | 0.513 | 0.569 | 0.607 | 0.616 |
| Tio R5 | 0.566 | 0.647 | 0.641 | 0.622 | 0.620 |
"Individual FVC measurements at each time-point (personal best). Response was defined as the change from baseline. Analysis adjusted for treatment, period, patient and baseline using a mixed model." (NCT01122680)
Timeframe: Baseline and 4 weeks (10 min pre-dose, 30 min, 1,2,3 hours post-dose)
| Intervention | Litre (Least Squares Mean) | ||||
|---|---|---|---|---|---|
| Timepoint -0:10 hr response | Timepoint 0:30 hr response | Timepoint 1:00 hr response | Timepoint 2:00 hr response | Timepoint 3:00 hr response | |
| Placebo | 0.357 | 0.397 | 0.417 | 0.429 | 0.430 |
| Tio R1.25 | 0.375 | 0.434 | 0.443 | 0.438 | 0.461 |
| Tio R2.5 | 0.381 | 0.394 | 0.387 | 0.444 | 0.454 |
| Tio R5 | 0.400 | 0.409 | 0.448 | 0.423 | 0.456 |
The V'E was measured in the participants during the ESWT using the OMS. The system consisted of a volume transducer, oxygen sensor, and carbon dioxide sensor and allowed breath-by-breath measurement of pulmonary gas exchange parameters. The V'E was collected in liters and then regressed over the conduct of the exercise test measured in minutes. The V'E per time slope was calculated for each participant by fitting a linear regression line to the V'E recorded for each participant during the ESWT. V'E per time slope results were compared between treatment groups as means of the regression lines. (NCT01124422)
Timeframe: Baseline (Week 3) and Week 8
| Intervention | Liter (L)/min (Mean) |
|---|---|
| TIO+Placebo | -0.7 |
| TIO+FSC | -0.2 |
The RR and VT of the participants at isotime were measured during the ESWT using the OMS. The ratio of RR per VT (value of RR divided by value of VT) at isotime was calculated. Change from Baseline in RR/VT at isotime was calculated as the value at Week 8 minus the value at Baseline. (NCT01124422)
Timeframe: Baseline (Week 3) and Week 8
| Intervention | breaths/min/L (Mean) |
|---|---|
| TIO+Placebo | 2.7 |
| TIO+FSC | -2.5 |
The respiratory exchange ratio was calculated as the ratio of VCO2 and VO2. The ratio of the amount of carbon dioxide and oxygen in the hemoglobin of the participants was measured during the ESWT using the OMS. The system consisted of oxygen and carbon dioxide sensors and allowed breath-by-breath measurement of pulmonary gas exchange parameters. Change from Baseline in RER was calculated as the value at Week 8 minus the value at Baseline. (NCT01124422)
Timeframe: Baseline (Week 3) and Week 8
| Intervention | Ratio of VCO2 and VO2 (Mean) |
|---|---|
| TIO+Placebo | -0.01 |
| TIO+FSC | 0.01 |
RR is defined as the number of breaths taken within a set amount of time (typically within 60 secs). The RR of the participants at isotime was measured during the ESWT using the OMS. Change from Baseline in RR at isotime was calculated as the value at Week 8 minus the value at Baseline. (NCT01124422)
Timeframe: Baseline (Week 3) and Week 8
| Intervention | breaths/min (Mean) |
|---|---|
| TIO+Placebo | 0.8 |
| TIO+FSC | -0.5 |
RR is defined as the number of breaths taken within a set amount of time (typically within 60 secs). The RR of the participants was measured during the ESWT using the OMS. The system consisted of volume transducer oxygen and carbon dioxide sensors and allowed breath-by-breath measurement of pulmonary gas exchange parameters. The RR per time slope was calculated for each participant by fitting a linear regression line to the RR recorded for each participant during the ESWT. RR per time slope results were compared between treatment groups as means of these regression lines. (NCT01124422)
Timeframe: Baseline (Week 3) and Week 8
| Intervention | breaths/min/min (Mean) |
|---|---|
| TIO+Placebo | -0.1 |
| TIO+FSC | -0.5 |
VT is defined as the lung volume representing the normal volume of air displaced between normal inspiration and expiration when extra effort is not applied. The normal value is approximately 500 mL or 7 mL/kg body weight. The VT of the participants at isotime was measured during the ESWT using the OMS. Change from Baseline in VT at isotime was calculated as the value at Week 8 minus the value at Baseline. (NCT01124422)
Timeframe: Baseline (Week 3) and Week 8
| Intervention | L (Mean) |
|---|---|
| TIO+Placebo | -0.10 |
| TIO+FSC | 0.08 |
VT is the lung volume representing the normal volume of air displaced between normal inspiration and expiration when extra effort is not applied (normal value is approximately 500 mL or 7 mL/kg body weight). VT was measured during the ESWT using the OMS, consisting of volume transducer O2 and CO2 sensors and allowing breath-by-breath measurement of pulmonary gas exchange parameters. The participant's VT per time slope was calculated by fitting a linear regression line (RL) to their VT during the ESWT. VT per time slope results were compared between treatment groups as means of these RLs. (NCT01124422)
Timeframe: Baseline (Week 3) and Week 8
| Intervention | L/min (Mean) |
|---|---|
| TIO+Placebo | -0.02 |
| TIO+FSC | 0 |
The BDI-TDI is a multidimensional dyspnea measurement. The BDI, administered at Week 4, consisted of 3 items (functional impairment, magnitude of task in exertional capacity, and magnitude of effort) requiring recall over the previous 4 weeks. BDI scores ranged from 0 (very severe impairment) to 4 (no impairment); the summed total score = 0 to 12. The TDI, administered at Week 8 as a follow-up of the BDI, consisted of the same 3 items requiring recall over the previous 4 weeks. TDI scores ranged from -3 (major deterioration) to +3 (major improvement); the summed total score = -9 to 9. (NCT01124422)
Timeframe: BDI: Week 4; TDI: Week 8
| Intervention | Scores on a scale (Mean) | |
|---|---|---|
| BDI; n=130; 122 | TDI; n=121, 115 | |
| TIO+FSC | 6.9 | 1.4 |
| TIO+Placebo | 6.7 | 1.1 |
Resting IC is the volume of gas that can be taken into the lungs in a full inhalation at the resting position. The resting IC was measured before and after dosing. Change from Baseline in pre-dose resting IC was calculated as the pre-dose value at Week 8 minus the pre-dose value at Week 4. Change from Baseline in post-dose resting IC was calculated as the post-dose value at Week 8 minus the pre-dose value at Week 4. (NCT01124422)
Timeframe: Baseline (Week 4) and Week 8
| Intervention | Milliliters (mL) (Mean) | |
|---|---|---|
| Pre-dose | Post-dose | |
| TIO+FSC | 60 | 167 |
| TIO+Placebo | -29 | 73 |
The CRQ-SAS, a self-administered tool used to assess health-related quality-of-life (HRQOL), consists of 20 questions (q.) in 4 domains: Dyspnea (5 q.), Fatigue (4 q.), Emotional Function (7 q.), and Mastery (4 q.). Participants rated their experience on a 7-point scale in response to each q.: 1 (maximum impairment) to 7 (no impairment); higher scores indicate better HRQOL. Individual q. were equally weighted, and domain scores (range=1-7) were calculated as the mean across the non-missing items within each domain (domain scores were calculated although an individual item score was missing). (NCT01124422)
Timeframe: Week 4 and Week 8
| Intervention | Scores on a scale (Mean) | |||
|---|---|---|---|---|
| Mastery Score | Fatigue Score | Emotional Function Score | Dyspnea Score | |
| TIO+FSC | 0.09 | 0.26 | 0.13 | 0.32 |
| TIO+Placebo | 0.07 | 0.11 | 0.10 | 0.21 |
EDS is used to measure the level of breathlessness due to exercise, assessed using a 10-point modified Borg scale at 2-minute intervals during the ESWT: 0=no difficulty in breathing at all, 10=maximal breathing difficulty (BD). The participant pointed to the level on the scale correlating with his BD, and the local study coordinator confirmed that level verbally to him. Change from Baseline was calculated as the value at Week 8 minus the value at Baseline. A dyspnea score/time slope was calculated by fitting a linear regression line to the dyspnea scores reported during the exercise tests. (NCT01124422)
Timeframe: Baseline (Week 3) and Week 8
| Intervention | Scores on a scale/minute (Mean) |
|---|---|
| TIO+Placebo | -0.1 |
| TIO+FSC | -0.06 |
EDS at isotime (last common time point for an exercise assessment [i.e., last Borg score time point of the shortest exercise test for each participant]) was assessed using a 10-point modified Borg scale. Change from Baseline in EDS at isotime was calculated as the value at Week 8 minus the value at Baseline. (NCT01124422)
Timeframe: Baseline (Week 3) and Week 8
| Intervention | Scores on a scale (Mean) |
|---|---|
| TIO+Placebo | -0.3 |
| TIO+FSC | -0.5 |
The EIC was measured at 2 to 3.5 minutes during the exercise period. Change from Baseline in EIC was calculated as the value at Week 8 minus the value at Baseline. (NCT01124422)
Timeframe: Baseline (Week 3) and Week 8
| Intervention | mL (Mean) |
|---|---|
| TIO+Placebo | -148.3 |
| TIO+FSC | 200 |
EET is defined as the time taken by a participant to exert himself during an exercise. EET was calculated based on the Endurance Shuttle Walk test (ESWT). The ESWT is a standardized, externally controlled, constant-paced field test for the assessment of endurance capacity in participants with chronic lung disease. Change from Baseline in EET was calculated as the value at Week 8 minus the value at Baseline. (NCT01124422)
Timeframe: Baseline (Week 3) and Week 8
| Intervention | Seconds (sec) (Mean) |
|---|---|
| TIO+Placebo | 23.3 |
| TIO+FSC | 6.0 |
EIC is the volume of gas that can be taken into the lungs in a full inhalation during exercise. Participants were asked to undergo the IC test every 2 minutes during exercise and at the end of the exercise, to follow changes in operational lung volumes that occured in association with exercise. Change from Baseline in EIC was calculated as the value at the end of exercise at Week 8 minus the value at the end of exercise at Baseline. (NCT01124422)
Timeframe: Baseline (Week 3) and Week 8
| Intervention | mL (Mean) |
|---|---|
| TIO+Placebo | -7.4 |
| TIO+FSC | 46.6 |
The amount of CO2 in the hemoglobin of the participants was measured during the ESWT using the OMS. The system consisted of a carbon dioxide sensor and allowed breath-by-breath measurement of pulmonary gas exchange parameters. The V'CO2 per time slope was calculated for each participant by fitting a linear regression line to the V'CO2 recorded for each participant during the ESWT. V'CO2 per time slope results were compared between treatment groups as means of these regression lines. Change from Baseline in V'CO2 per time slope was calculated as the value at Week 8 minus the value at Baseline. (NCT01124422)
Timeframe: Baseline (Week 3) and Week 8
| Intervention | mL/min (Mean) |
|---|---|
| TIO+Placebo | -17.4 |
| TIO+FSC | -0.7 |
The V'O2 was measured during the ESWT using the Oxycon Mobile System (OMS), a portable telemetric monitoring system consisting of an oxygen sensor allowing for breath-by-breath measurement of gas exchange parameters in the lungs. The V'O2 was collected in units of mL and then regressed over the conduct of the exercise test measured in minutes. The V'O2 per time slope was calculated for each participant (par.) by fitting a linear regression line to the V'O2 recorded for each par. during the ESWT. V'O2 per time slope results were compared between treatment groups as means of these regression lin (NCT01124422)
Timeframe: Baseline (Week 3) and Week 8
| Intervention | mL/minute (min) (Mean) |
|---|---|
| TIO+Placebo | -13.3 |
| TIO+FSC | -6.1 |
HR is defined as the number of heartbeats per unit of time, typically expressed as beats per minute (bpm). It was measured during the ESWT using the OMS. The HR was collected in units of bpm and then regressed over the conduct of the exercise test measured in minutes. The HR per time slope was calculated for each participant by fitting a linear regression line to the HR recorded for each participant during the exercise test. HR per time slope results were compared between treatment groups as means of these regression lines. (NCT01124422)
Timeframe: Baseline (Week 3) and Week 8
| Intervention | bpm/min (Mean) |
|---|---|
| TIO+Placebo | -1.1 |
| TIO+FSC | 0.7 |
HR was measured during the course of the ESWT in the non-OMS subgroup using pulse oximetry. The HR per time slope was calculated for each participant by fitting a linear regression line to the HR recorded for each participant during the ESWT. HR per time slope results were compared between treatment groups as means of these regression lines. Change from Baseline in HR was calculated as the value at Week 8 minus the value at Baseline. (NCT01124422)
Timeframe: Baseline (Week 3) and Week 8
| Intervention | bpm/min (Mean) |
|---|---|
| TIO+Placebo | -0.8 |
| TIO+FSC | -0.6 |
Time to onset of first major adverse cardiovascular event (MACE). MACE was defined as: Fatal event in the system organ classes of cardiac and vascular disorders, Preferred terms: sudden death, cardiac death, sudden cardiac death, Outcome events of myocardial infarction (serious and non-serious), Outcome events of stroke (serious and non-serious) and Outcome events of TIA (serious and non-serious). The results presented below are for the number of patients with MACE. (NCT01126437)
Timeframe: Up to 3 years
| Intervention | number of patients with MACE (Number) |
|---|---|
| Tiotropium 2.5 mcg and Placebo | 224 |
| Tiotropium 5 mcg and Placebo | 222 |
| Tiotropium 18 mcg and Placebo | 202 |
"COPD exacerbation defined as a complex of lower respiratory events/symptoms (increase of new onset) related to the underlying COPD, with duration of three days or more, requiring a change in treatment where a complex of lower respiratory event/symptoms was defined as having at least two of the following: shortness of breath, sputum production (volume), occurrence of purulent sputum, cough, wheezing, chest tightness and where a required change in treatment includes the following:Prescription of antibiotics and/or systemic steroids, and/or a newly prescribed maintenance respiratory medication (i.e., bronchodilators including theophyllines).~Exacerbations classified as follows:~Mild:a new prescription of maintenance bronchodilator only Moderate:antibiotics or systemic steroids without hospitalization Severe:hospitalization.~Results presented below are number of patients with moderate to severe exacerbations." (NCT01126437)
Timeframe: Up to 3 years
| Intervention | number of patients with event (Number) |
|---|---|
| Tiotropium 2.5 mcg and Placebo | 2769 |
| Tiotropium 5 mcg and Placebo | 2694 |
| Tiotropium 18 mcg and Placebo | 2732 |
"Defined as a complex of lower respiratory events/symptoms (increase of new onset) related to the underlying COPD, with duration of three days or more, requiring a change in treatment where a complex of lower respiratory event/symptoms was defined as having at least two of the following: shortness of breath, sputum production (volume), occurrence of purulent sputum, cough, wheezing, chest tightness and where a required change in treatment includes the following:Prescription of antibiotics and/or systemic steroids, and/or a newly prescribed maintenance respiratory medication (i.e., bronchodilators including theophyllines).~Onset of exacerbation was defined by the onset of first recorded symptom. The end of exacerbation was decided by the investigator based on clinical judgement.~Exacerbations were classified as follows:~Mild:a new prescription of maintenance bronchodilator only Moderate:antibiotics or systemic steroids without hospitalization Severe:hospitalization." (NCT01126437)
Timeframe: Up to 3 years
| Intervention | days to event (Median) |
|---|---|
| Tiotropium 2.5 mcg and Placebo | 707 |
| Tiotropium 5 mcg and Placebo | 756 |
| Tiotropium 18 mcg and Placebo | 719 |
The results presented below are number of patients with death from MACE. (NCT01126437)
Timeframe: Up to 3 years
| Intervention | Number of deaths from MACE (Number) |
|---|---|
| Tiotropium 2.5 mcg and Placebo | 119 |
| Tiotropium 5 mcg and Placebo | 113 |
| Tiotropium 18 mcg and Placebo | 101 |
Number of patients with all-cause mortality (NCT01126437)
Timeframe: Up to 3 years
| Intervention | Number of deaths (Number) |
|---|---|
| Tiotropium 2.5 mcg and Placebo | 440 |
| Tiotropium 5 mcg and Placebo | 423 |
| Tiotropium 18 mcg and Placebo | 439 |
Total number of hospitalizations associated with COPD exacerbation. (NCT01126437)
Timeframe: Up to 3 years
| Intervention | number of hospitalizations (Number) |
|---|---|
| Tiotropium 2.5 mcg and Placebo | 1316 |
| Tiotropium 5 mcg and Placebo | 1284 |
| Tiotropium 18 mcg and Placebo | 1216 |
"The number of COPD exacerbations. COPD exacerbation defined as a complex of lower respiratory events/symptoms (increase of new onset) related to the underlying COPD, with duration of three days or more, requiring a change in treatment where a complex of lower respiratory event/symptoms was defined as having at least two of the following: shortness of breath, sputum production (volume), occurrence of purulent sputum, cough, wheezing, chest tightness and where a required change in treatment includes the following:Prescription of antibiotics and/or systemic steroids, and/or a newly prescribed maintenance respiratory medication (i.e., bronchodilators including theophyllines)." (NCT01126437)
Timeframe: Up to 3 years
| Intervention | number of COPD exacerbations (Number) |
|---|---|
| Tiotropium 2.5 mcg and Placebo | 6565 |
| Tiotropium 5 mcg and Placebo | 6425 |
| Tiotropium 18 mcg and Placebo | 6504 |
Trough forced expiratory volume in one second (FEV1) over 120 weeks (in a substudy of 1370 patients) (NCT01126437)
Timeframe: Up to 3 years
| Intervention | Liter (Least Squares Mean) |
|---|---|
| Tiotropium 2.5 mcg and Placebo | 1.258 |
| Tiotropium 5 mcg and Placebo | 1.285 |
| Tiotropium 18 mcg and Placebo | 1.295 |
The results presented below are for the patients with hospitalizations due to COPD exacerbations. (NCT01126437)
Timeframe: Up to 3 years
| Intervention | Number of patients with event (Number) |
|---|---|
| Tiotropium 2.5 mcg and Placebo | 869 |
| Tiotropium 5 mcg and Placebo | 826 |
| Tiotropium 18 mcg and Placebo | 811 |
Mixed Model Repeated Measure (MMRM) results. Response was defined as change from baseline. Means are adjusted for treatment, period, patient and study baseline. Measurements performed in relation to evening dosing. AUC0-24h calculated using the trapezoidal rule divided by the observation time (24 hours) to report in litres. (NCT01152450)
Timeframe: 10 minutes (min) prior to first dose (baseline) and -10 min, 30 min, 60 min, 2 hours (h) , 3 h, 4 h , 11 h 50 min, 12 h 30 min, 13 h, 14 h, 15 h, 16 h, 18 h, 20 h, 22 h, 23 h, and 23 h 50 min related to evening dose at week 4
| Intervention | L (Mean) |
|---|---|
| Placebo | 0.091 |
| Tio R2.5 Bid | 0.241 |
| Tio R5 qd | 0.250 |
MMRM results. Response was defined as change from baseline. Means are adjusted for treatment, period, patient and study baseline. PEF variability is the absolute difference between morning and evening PEF value divided by the mean of these two values, expressed as a percent (weekly means obtained during the last week of each period of randomised treatment will be compared). (NCT01152450)
Timeframe: Baseline and during week 4
| Intervention | Percent (Mean) |
|---|---|
| Placebo | 0.296 |
| Tio R2.5 Bid | 0.619 |
| Tio R5 qd | 0.685 |
MMRM results. Response was defined as change from baseline. Means are adjusted for treatment, period, patient and study baseline. AUC0-24h calculated using the trapezoidal rule divided by the observation time (24 hours) to report in litres/min. (NCT01152450)
Timeframe: 10 min prior to first dose (baseline) and -10 min, 30 min, 60 min, 2 h, 3 h, 4 h , 11 h 50 min, 12 h 30 min, 13 h, 14 h, 15 h, 16 h, 18 h, 20 h, 22 h, 23 h, and 23 h 50 min related to evening dose at week 4
| Intervention | L/min (Mean) |
|---|---|
| Placebo | 8.589 |
| Tio R2.5 Bid | 38.831 |
| Tio R5 qd | 42.899 |
MMRM results. Response was defined as change from baseline. Means are adjusted for treatment, period, patient and study baseline. Measured following each dosing determined at the end of each 4 week treatment period. (NCT01152450)
Timeframe: Baseline and 4 weeks
| Intervention | L (Mean) |
|---|---|
| Placebo | 0.302 |
| Tio R2.5 Bid | 0.380 |
| Tio R5 qd | 0.350 |
MMRM results. Response was defined as change from baseline. Means are adjusted for treatment, period, patient and study baseline. Weekly means obtained during the last week of each period of randomised treatment will be compared. (NCT01152450)
Timeframe: Baseline and during week 4
| Intervention | Puffs (Mean) |
|---|---|
| Placebo | -0.841 |
| Tio R2.5 Bid | -0.917 |
| Tio R5 qd | -1.016 |
MMRM results. Response was defined as change from baseline. Means are adjusted for treatment, period, patient and study baseline. Measured following each dosing determined at the end of each 4 week treatment period. AUC0-12h calculated using the trapezoidal rule divided by the observation time (12 hours) to report in litres. (NCT01152450)
Timeframe: 10 min prior to first dose (baseline) and -10 min, 30 min, 60 min, 2 h, 3 h, 4 h and 11 h 50 min related to evening dose at week 4
| Intervention | L (Mean) |
|---|---|
| Placebo | -0.026 |
| Tio R2.5 Bid | 0.099 |
| Tio R5 qd | 0.074 |
MMRM results. Response was defined as change from baseline. Means are adjusted for treatment, period, patient and study baseline. Measured by patients at home using the AM2+ device. (NCT01152450)
Timeframe: Baseline and during week 4 of each treatment period
| Intervention | L/min (Mean) |
|---|---|
| Placebo | -1.560 |
| Tio R2.5 Bid | 28.360 |
| Tio R5 qd | 27.096 |
MMRM results. Response was defined as change from baseline. Means are adjusted for treatment, period, patient and study baseline. Measured by patients at home using the AM2+ device. (NCT01152450)
Timeframe: Baseline and during week 4 of each treatment period
| Intervention | L/min (Mean) |
|---|---|
| Placebo | 1.953 |
| Tio R2.5 Bid | 23.281 |
| Tio R5 qd | 24.310 |
MMRM results. Response was defined as change from baseline. Means are adjusted for treatment, period, patient and study baseline. Measured following the evening trial-drug inhalation at the end of each 4 week period of randomised treatment. (NCT01152450)
Timeframe: Baseline and 4 weeks
| Intervention | L (Mean) |
|---|---|
| Placebo | 0.337 |
| Tio R2.5 Bid | 0.469 |
| Tio R5 qd | 0.468 |
MMRM results. Response was defined as change from baseline. Means are adjusted for treatment, period, patient and study baseline. Measured following the respective dosing determined at the end of each 4 week period of randomised treatment. AUC0-12h calculated using the trapezoidal rule divided by the observation time (12 hours) to report in litres. (NCT01152450)
Timeframe: 10 min prior to first dose (baseline) and -10 min, 30 min, 60 min, 2 h, 3 h, 4 h and 11 h 50 min related to evening dose at week 4
| Intervention | L (Mean) |
|---|---|
| Placebo | 0.048 |
| Tio R2.5 Bid | 0.217 |
| Tio R5 qd | 0.233 |
MMRM results. Response was defined as change from baseline. Means are adjusted for treatment, period, patient and study baseline. AUC0-24h calculated using the trapezoidal rule divided by the observation time (24 hours) to report in litres. (NCT01152450)
Timeframe: 10 min prior to first dose (baseline) and -10 min, 30 min, 60 min, 2 h, 3 h, 4 h , 11 h 50 min, 12 h 30 min, 13 h, 14 h, 15 h, 16 h, 18 h, 20 h, 22 h, 23 h, and 23 h 50 min related to evening dose at week 4
| Intervention | L (Mean) |
|---|---|
| Placebo | 0.003 |
| Tio R2.5 Bid | 0.104 |
| Tio R5 qd | 0.087 |
MMRM results. Response was defined as change from baseline. Means are adjusted for treatment, period, patient and study baseline. Measured following the respective dosing determined at the end of each 4 week period of randomised treatment. AUC12-24h calculated using the trapezoidal rule divided by the observation time (12 hours) to report in litres. (NCT01152450)
Timeframe: 10 min prior to first dose (baseline) and 11 h 50 min, 12 h 30 min, 13 h, 14 h, 15 h, 16 h, 18 h, 20 h, 22 h, 23 h, and 23 h 50 min related to evening dose at week 4
| Intervention | L (Mean) |
|---|---|
| Placebo | 0.135 |
| Tio R2.5 Bid | 0.264 |
| Tio R5 qd | 0.266 |
MMRM results. Response was defined as change from baseline. Means are adjusted for treatment, period, patient and study baseline. Measured following each dosing determined at the end of each 4 week treatment period. AUC12-24h calculated using the trapezoidal rule divided by the observation time (12 hours) to report in litres. (NCT01152450)
Timeframe: 10 min prior to first dose (baseline) and 11 h 50 min, 12 h 30 min, 13 h, 14 h, 15 h, 16 h, 18 h, 20 h, 22 h, 23 h, and 23 h 50 min related to evening dose at week 4
| Intervention | L (Mean) |
|---|---|
| Placebo | 0.032 |
| Tio R2.5 Bid | 0.108 |
| Tio R5 qd | 0.100 |
MMRM results. Response was defined as change from baseline. Means are adjusted for treatment, period, patient and study baseline. Assessed by the patient's electronic diary (eDiary incorporated in the AM2+ device), obtained during the last week of each period of randomised treatment. (NCT01152450)
Timeframe: Baseline and during week 4
| Intervention | Night awakenings (Mean) |
|---|---|
| Placebo | -0.106 |
| Tio R2.5 Bid | -0.104 |
| Tio R5 qd | -0.102 |
MMRM results. Response was defined as change from baseline. Means are adjusted for treatment, period, patient and study baseline. Weekly means obtained during the last week of each period of randomised treatment will be compared. (NCT01152450)
Timeframe: Baseline and during week 4
| Intervention | Puffs (Mean) |
|---|---|
| Placebo | -0.562 |
| Tio R2.5 Bid | -0.564 |
| Tio R5 qd | -0.624 |
MMRM results. Response was defined as change from baseline. Means are adjusted for treatment, period, patient and study baseline. Weekly means obtained during the last week of each period of randomised treatment will be compared. (NCT01152450)
Timeframe: Baseline and during week 4
| Intervention | Puffs (Mean) |
|---|---|
| Placebo | -0.358 |
| Tio R2.5 Bid | -0.419 |
| Tio R5 qd | -0.432 |
MMRM results. Response was defined as change from baseline. Means are adjusted for treatment, period, patient and study baseline. (NCT01152450)
Timeframe: Baseline and 4 weeks
| Intervention | L/min (Mean) | ||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Timepoint -0:10 (hours:minutes) | Timepoint 0:30 (hours:minutes) | Timepoint 1:00 (hours:minutes) | Timepoint 2:00 (hours:minutes) | Timepoint 3:00 (hours:minutes) | Timepoint 4:00 (hours:minutes) | Timepoint 11:50 (hours:minutes) | Timepoint 12:30 (hours:minutes) | Timepoint 13:00 (hours:minutes) | Timepoint 14:00 (hours:minutes) | Timepoint 15:00 (hours:minutes) | Timepoint 16:00 (hours:minutes) | Timepoint 18:00 (hours:minutes) | Timepoint 20:00 (hours:minutes) | Timepoint 22:00 (hours:minutes) | Timepoint 23:00 (hours:minutes) | Timepoint 23:50 (hours:minutes) | |
| Placebo | 19.770 | 12.994 | 13.783 | 11.366 | 9.769 | 7.499 | -11.219 | 4.345 | 6.820 | 13.879 | 16.125 | 19.616 | 20.084 | 13.348 | 14.275 | 13.590 | 15.169 |
| Tio R2.5 Bid | 42.428 | 46.272 | 43.049 | 48.328 | 48.723 | 42.599 | 20.011 | 27.436 | 33.810 | 44.786 | 47.991 | 47.697 | 47.795 | 42.240 | 33.567 | 36.712 | 36.837 |
| Tio R5 qd | 57.897 | 58.436 | 53.138 | 55.826 | 50.747 | 50.077 | 26.201 | 33.887 | 34.582 | 43.371 | 45.699 | 46.441 | 48.790 | 40.888 | 41.635 | 38.384 | 37.595 |
MMRM results. Response was defined as change from baseline. Means are adjusted for treatment, period, patient and study baseline. (NCT01152450)
Timeframe: Baseline and 4 weeks
| Intervention | L (Mean) | ||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Timepoint -0:10 (hours:minutes) | Timepoint 0:30 (hours:minutes) | Timepoint 1:00 (hours:minutes) | Timepoint 2:00 (hours:minutes) | Timepoint 3:00 (hours:minutes) | Timepoint 4:00 (hours:minutes) | Timepoint 11:50 (hours:minutes) | Timepoint 12:30 (hours:minutes) | Timepoint 13:00 (hours:minutes) | Timepoint 14:00 (hours:minutes) | Timepoint 15:00 (hours:minutes) | Timepoint 16:00 (hours:minutes) | Timepoint 18:00 (hours:minutes) | Timepoint 20:00 (hours:minutes) | Timepoint 22:00 (hours:minutes) | Timepoint 23:00 (hours:minutes) | Timepoint 23:50 (hours:minutes) | |
| Placebo | 0.112 | 0.053 | 0.055 | 0.033 | -0.003 | -0.040 | -0.064 | 0.004 | 0.010 | 0.038 | 0.034 | 0.050 | 0.062 | 0.036 | 0.028 | 0.018 | -0.015 |
| Tio R2.5 Bid | 0.179 | 0.158 | 0.152 | 0.131 | 0.100 | 0.096 | 0.070 | 0.133 | 0.114 | 0.106 | 0.109 | 0.111 | 0.123 | 0.125 | 0.077 | 0.094 | 0.078 |
| Tio R5 qd | 0.168 | 0.130 | 0.124 | 0.093 | 0.057 | 0.065 | 0.060 | 0.103 | 0.102 | 0.120 | 0.124 | 0.116 | 0.113 | 0.088 | 0.096 | 0.062 | 0.052 |
MMRM results. Response was defined as change from baseline. Means are adjusted for treatment, period, patient and study baseline. (NCT01152450)
Timeframe: Baseline and 4 weeks
| Intervention | L (Mean) | ||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Timepoint -0:10 (hours:minutes) | Timepoint 0:30 (hours:minutes) | Timepoint 1:00 (hours:minutes) | Timepoint 2:00 (hours:minutes) | Timepoint 3:00 (hours:minutes) | Timepoint 4:00 (hours:minutes) | Timepoint 11:50 (hours:minutes) | Timepoint 12:30 (hours:minutes) | Timepoint 13:00 (hours:minutes) | Timepoint 14:00 (hours:minutes) | Timepoint 15:00 (hours:minutes) | Timepoint 16:00 (hours:minutes) | Timepoint 18:00 (hours:minutes) | Timepoint 20:00 (hours:minutes) | Timepoint 22:00 (hours:minutes) | Timepoint 23:00 (hours:minutes) | Timepoint 23:50 (hours:minutes) | |
| Placebo | 0.143 | 0.132 | 0.123 | 0.103 | 0.082 | 0.062 | -0.021 | 0.075 | 0.101 | 0.138 | 0.163 | 0.161 | 0.177 | 0.127 | 0.117 | 0.124 | 0.125 |
| Tio R2.5 Bid | 0.254 | 0.281 | 0.274 | 0.270 | 0.264 | 0.248 | 0.134 | 0.198 | 0.250 | 0.288 | 0.299 | 0.306 | 0.300 | 0.256 | 0.221 | 0.243 | 0.232 |
| Tio R5 qd | 0.275 | 0.304 | 0.289 | 0.297 | 0.268 | 0.263 | 0.150 | 0.217 | 0.237 | 0.282 | 0.308 | 0.313 | 0.308 | 0.245 | 0.244 | 0.223 | 0.224 |
MMRM results. Response was defined as change from baseline. Means are adjusted for treatment, period, patient and study baseline. Trough FVC is defined as FVC value (performed at 10 minutes prior to the evening trial-drug inhalation) at the end of each 4 week period of randomised treatment. (NCT01152450)
Timeframe: Baseline and 4 weeks
| Intervention | L (Mean) |
|---|---|
| Placebo | 0.112 |
| Tio R2.5 Bid | 0.179 |
| Tio R5 qd | 0.168 |
MMRM results. Response was defined as change from baseline. Means are adjusted for treatment, period, patient and study baseline. Trough FEV1 is defined as FEV1 value (performed at 10 minutes prior to the evening trial-drug inhalation) at the end of each 4 week period of randomised treatment. (NCT01152450)
Timeframe: Baseline and 4 weeks
| Intervention | L (Mean) |
|---|---|
| Placebo | 0.143 |
| Tio R2.5 Bid | 0.254 |
| Tio R5 qd | 0.275 |
Weekly means obtained during the last 7 days before week 24 measured by patients at home using the AM3 device. Response was defined as change from baseline. Means are adjusted for treatment, country, week, baseline, treatment by week, and baseline by week. (NCT01172808)
Timeframe: Baseline and last 7 days before week 24 visit
| Intervention | Litre (Mean) |
|---|---|
| Placebo | 0.021 |
| Tio R2.5 | 0.101 |
| Tio R5 | 0.073 |
| Salmeterol | 0.117 |
Response was defined as change from baseline (10 minutes before the first dose of trial medication at visit 2) determined at the end of the 24-week treatment. Means are adjusted for treatment, centre, week, baseline, treatment by week, and baseline by week. FEV1 AUC 0-3h was calculated from 0-3 hours post-dose using the trapezoidal rule, divided by the observation time (3h) to report in litres. (NCT01172808)
Timeframe: 24 weeks
| Intervention | Litre (Mean) |
|---|---|
| Placebo | -0.033 |
| Tio R2.5 | 0.192 |
| Tio R5 | 0.163 |
| Salmeterol | 0.182 |
Trough peak expiratory flow (PEF) response determined at the end of the 24-week treatment. Response was defined as change from baseline (10 minutes before the first dose of trial medication at visit 2). Means are adjusted for treatment, centre, week, baseline, treatment by week, and baseline by week. (NCT01172808)
Timeframe: 24 weeks
| Intervention | Litre/min (Mean) |
|---|---|
| Placebo | 2.913 |
| Tio R2.5 | 40.819 |
| Tio R5 | 36.590 |
| Salmeterol | 31.317 |
Weekly means obtained during the last 7 days before week 24 measured by patients at home using the AM3 device. Response was defined as change from baseline. Means are adjusted for treatment, country, week, baseline, treatment by week, and baseline by week. (NCT01172808)
Timeframe: Baseline and last 7 days before week 24 visit
| Intervention | Litre/min (Mean) |
|---|---|
| Placebo | -9.181 |
| Tio R2.5 | 18.978 |
| Tio R5 | 15.188 |
| Salmeterol | 19.727 |
Weekly means obtained during the last 7 days before week 24 measured by patients at home using the AM3 device. Response was defined as change from baseline. Means are adjusted for treatment, country, week, baseline, treatment by week, and baseline by week. (NCT01172808)
Timeframe: Baseline and last 7 days before week 24 visit
| Intervention | Litre (Mean) |
|---|---|
| Placebo | -0.000 |
| Tio R2.5 | 0.065 |
| Tio R5 | 0.039 |
| Salmeterol | 0.072 |
Daily use of salbutamol (albuterol) rescue medication as needed during the entire study period. Weekly means obtained during the last 7 days before week 24 measured by patients at home using the AM3 device. Response was defined as change from baseline. Means are adjusted for treatment, country, week, baseline, treatment by week, and baseline by week. (NCT01172808)
Timeframe: Baseline and last 7 days before week 24 visit
| Intervention | Number of Puffs (Mean) |
|---|---|
| Placebo | -0.962 |
| Tio R2.5 | -1.124 |
| Tio R5 | -0.818 |
| Salmeterol | -1.416 |
Response was defined as change from baseline (10 minutes before the first dose of trial medication at visit 2) determined at the end of the 24-week treatment. Means are adjusted for treatment, country, week, baseline, treatment by week, and baseline by week. FVC AUC 0-3h was calculated from 0-3 hours post-dose using the trapezoidal rule, divided by the observation time (3h) to report in litres. (NCT01172808)
Timeframe: 24 weeks
| Intervention | Litre (Mean) |
|---|---|
| Placebo | -0.066 |
| Tio R2.5 | 0.092 |
| Tio R5 | 0.041 |
| Salmeterol | 0.062 |
Weekly means obtained during the last 7 days before week 24 measured by patients at home using the AM3 device. Response was defined as change from baseline. Means are adjusted for treatment, country, week, baseline, treatment by week, and baseline by week. An asthma symptom-free day was defined as a day with no reported symptoms and no use of rescue medication. (NCT01172808)
Timeframe: Baseline and last 7 days before week 24 visit
| Intervention | Days (Mean) |
|---|---|
| Placebo | 0.162 |
| Tio R2.5 | 0.207 |
| Tio R5 | 0.157 |
| Salmeterol | 0.266 |
Peak forced vital capacity (FVC) response within 3 hours post-dose determined at the end of the 24-week treatment. Response was defined as change from baseline (10 minutes before the first dose of trial medication at visit 2). Means are adjusted for treatment, centre, week, baseline, treatment by week, and baseline by week. (NCT01172808)
Timeframe: 24 weeks
| Intervention | Litre (Mean) |
|---|---|
| Placebo | 0.045 |
| Tio R2.5 | 0.219 |
| Tio R5 | 0.148 |
| Salmeterol | 0.168 |
The responder rate as assessed by the Asthma Control Questionnaire (ACQ) determined at the end of the 24-week treatment period. A patient was considered to be a responder if he or she was reported with an improvement (decrease) in ACQ total score of at least 0.5 points. The ACQ total score was calculated as the mean of the responses to 7 questions and was analysed as an absolute value. The score ranges from 0 (no impairment) to 6 (maximum impairment). (NCT01172808)
Timeframe: 24 weeks
| Intervention | Percentage of Participants (Number) |
|---|---|
| Placebo | 53.2 |
| Tio R2.5 | 62.5 |
| Tio R5 | 66.7 |
| Salmeterol | 68.6 |
Weekly means obtained during the last 7 days before week 24 measured by patients at home using the AM3 device. Response was defined as change from baseline. Means are adjusted for treatment, country, week, baseline, treatment by week, and baseline by week. (NCT01172808)
Timeframe: Baseline and last 7 days before week 24 visit
| Intervention | Litre/min (Mean) |
|---|---|
| Placebo | -10.159 |
| Tio R2.5 | 20.432 |
| Tio R5 | 13.501 |
| Salmeterol | 22.467 |
Peak forced expiratory volume in one second (FEV1) response within 3 hours post-dose determined at the end of the 24-week treatment. Response was defined as change from baseline (10 minutes before the first dose of trial medication at visit 2). Means are adjusted for treatment, centre, week, baseline, treatment by week, and baseline by week. (NCT01172808)
Timeframe: 24 weeks
| Intervention | Litre (Mean) |
|---|---|
| Placebo | 0.053 |
| Tio R2.5 | 0.289 |
| Tio R5 | 0.250 |
| Salmeterol | 0.266 |
PEF daily variability was assesed by patients at home using the AM3 device. PEF variability is the absolute difference between morning and evening PEF value divided by their mean, based on the weekly mean response at week 24. Means are adjusted for treatment, centre, week, baseline, treatment by week, and baseline by week. (NCT01172808)
Timeframe: Last 7 days before week 24 visit
| Intervention | Percentage of mean PEF (Mean) |
|---|---|
| Placebo | -1.400 |
| Tio R2.5 | -1.958 |
| Tio R5 | 0.180 |
| Salmeterol | -2.300 |
Trough FEV1 response determined at the end of the 24-week treatment. Response was defined as change from baseline (10 minutes before the first dose of trial medication at visit 2). Means are adjusted for treatment, centre, week, baseline, treatment by week, and baseline by week. (NCT01172808)
Timeframe: 24 weeks
| Intervention | Litre (Mean) |
|---|---|
| Placebo | -0.036 |
| Tio R2.5 | 0.148 |
| Tio R5 | 0.115 |
| Salmeterol | 0.086 |
"The responder rate as assessed by the Asthma Control Questionnaire (ACQ) determined at the end of the 24-week treatment period (on combined data from the two twin trials 205.418 (NCT01172808) and 205.419 (NCT01172821)). A patient was considered to be a responder if he or she was reported with an improvement (decrease) in the ACQ total score of at least 0.5 points.~The ACQ total score was calculated as the mean of the responses to 7 questions and was analysed as an absolute value. The score ranges from 0 (no impairment) to 6 (maximum impairment)." (NCT01172808)
Timeframe: 24 weeks
| Intervention | Percentage of participants (Number) |
|---|---|
| Placebo | 57.7 |
| Tio R2.5 | 64.5 |
| Tio R5 | 64.3 |
| Salmeterol | 66.5 |
Time to first asthma exacerbation (including severe, non-severe; symptomatic, asymptomatic; i.e. any exacerbation) during the 24-week treatment period on combined data from the two twin trials 205.418 (NCT01172808) and 205.419 (NCT01172821) (NCT01172808)
Timeframe: 24 weeks
| Intervention | weeks (Median) |
|---|---|
| Placebo | NA |
| Tio R2.5 | NA |
| Tio R5 | NA |
| Salmeterol | NA |
Time to first severe asthma exacerbation during the 24-week treatment period on combined data from the two twin trials 205.418 (NCT01172808) and 205.419 (NCT01172821). (NCT01172808)
Timeframe: 24 weeks
| Intervention | weeks (Median) |
|---|---|
| Placebo | NA |
| Tio R2.5 | NA |
| Tio R5 | NA |
| Salmeterol | NA |
Control of asthma as assessed by the ACQ determined at the end of 24-week treatment. The ACQ contains 7 questions, each question has a 7 point scale from 0 (no symptoms) till 6 (highest intensity). Total score was defined as the sum of all items divided by the number of items. Means are adjusted for treatment, centre, week, baseline, treatment by week, and baseline by week. (NCT01172808)
Timeframe: 24 weeks
| Intervention | units on a scale (Mean) |
|---|---|
| Placebo | 1.563 |
| Tio R2.5 | 1.362 |
| Tio R5 | 1.431 |
| Salmeterol | 1.302 |
Total score from the Standardised Asthma Quality of Life Questionnaire (AQLQ(s)) determined at the end of 24-week treatment. The AQLQ(s) contains 32 questions, each question has a 7 point scale from 1 (highest intensity) till 7 (no symptoms). Total score was defined as the sum of all items divided by the number of items. Means are adjusted for treatment, centre, week, baseline, treatment by week, and baseline by week. (NCT01172808)
Timeframe: 24 weeks
| Intervention | units on a scale (Mean) |
|---|---|
| Placebo | 5.449 |
| Tio R2.5 | 5.522 |
| Tio R5 | 5.519 |
| Salmeterol | 5.654 |
Trough FVC response determined at the end of the 24-week treatment. Response was defined as change from baseline (10 minutes before the first dose of trial medication at visit 2). Means are adjusted for treatment, country, week, baseline, treatment by week, and baseline by week. (NCT01172808)
Timeframe: 24 weeks
| Intervention | Litre (Mean) |
|---|---|
| Placebo | -0.039 |
| Tio R2.5 | 0.086 |
| Tio R5 | 0.036 |
| Salmeterol | 0.028 |
Weekly means obtained during the last 7 days before week 24 measured by patients at home using the AM3 device. Response was defined as change from baseline. Means are adjusted for treatment, country, week, baseline, treatment by week, and baseline by week. An asthma symptom-free day was defined as a day with no reported symptoms and no use of rescue medication. (NCT01172821)
Timeframe: Baseline and last 7 days before week 24 visit
| Intervention | Days (Mean) |
|---|---|
| Placebo | 0.189 |
| Tio R2.5 | 0.164 |
| Tio R5 | 0.196 |
| Salmeterol | 0.195 |
The responder rate as assessed by the Asthma Control Questionnaire (ACQ) determined at the end of the 24-week treatment period. A patient was considered to be a responder if he or she was reported with an improvement (decrease) in ACQ total score of at least 0.5 points.The score ranges from 0 (no impairment) to 6 (maximum impairment). (NCT01172821)
Timeframe: 24 weeks
| Intervention | Percentage of participants (Number) |
|---|---|
| Placebo | 62.5 |
| Tio R2.5 | 66.4 |
| Tio R5 | 61.9 |
| Salmeterol | 64.4 |
Response was defined as change from baseline (10 minutes before the first dose of trial medication at visit 2) determined at the end of the 24- week treatment. Means are adjusted for treatment, centre, week, baseline, treatment by week, and baseline by week. FEV1 AUC 0-3h was calculated from 0-3 hours post-dose using the trapezoidal rule, divided by the observation time (3h) to report in litres. (NCT01172821)
Timeframe: 24 weeks
| Intervention | Litre (Mean) |
|---|---|
| Placebo | -0.005 |
| Tio R2.5 | 0.196 |
| Tio R5 | 0.158 |
| Salmeterol | 0.173 |
Response was defined as change from baseline (10 minutes before the first dose of trial medication at visit 2) determined at the end of the 24- week treatment. Means are adjusted for treatment, country, week, baseline, treatment by week, and baseline by week. FVC AUC 0-3h was calculated from 0-3 hours post-dose using the trapezoidal rule, divided by the observation time (3h) to report in litres. (NCT01172821)
Timeframe: 24 weeks
| Intervention | Litre (Mean) |
|---|---|
| Placebo | -0.065 |
| Tio R2.5 | 0.043 |
| Tio R5 | 0.024 |
| Salmeterol | 0.066 |
Weekly means obtained during the last 7 days before week 24 measured by patients at home using the AM3 device. Response was defined as change from baseline. Means are adjusted for treatment, country, week, baseline, treatment by week, and baseline by week (NCT01172821)
Timeframe: Baseline and last 7 days before week 24 visit
| Intervention | Litre/min (Mean) |
|---|---|
| Placebo | 2.764 |
| Tio R2.5 | 23.377 |
| Tio R5 | 27.521 |
| Salmeterol | 19.779 |
Peak forced expiratory volume in one second (FEV1) response within 3 hours post-dose determined at the end of the 24-week treatment. Response was defined as change from baseline (10 minutes before the first dose of trial medication at visit 2). Means are adjusted for treatment, centre, week, baseline, treatment by week, and baseline by week. (NCT01172821)
Timeframe: 24 weeks
| Intervention | Litre (Mean) |
|---|---|
| Placebo | 0.075 |
| Tio R2.5 | 0.287 |
| Tio R5 | 0.244 |
| Salmeterol | 0.252 |
Peak forced vital capacity (FVC) response within 3 hours post-dose determined at the end of the 24-week treatment. Response was defined as change from baseline (10 minutes before the first dose of trial medication at visit 2). Means are adjusted for treatment, centre, week, baseline, treatment by week, and baseline by week. (NCT01172821)
Timeframe: 24 weeks
| Intervention | Litre (Mean) |
|---|---|
| Placebo | 0.071 |
| Tio R2.5 | 0.181 |
| Tio R5 | 0.160 |
| Salmeterol | 0.188 |
PEF daily variability was assesed by patients at home using the AM3 device. PEF variability is the absolute difference between morning and evening PEF value divided by their mean, based on the weekly mean response at week 24. Means are adjusted for treatment, country, week, baseline, treatment by week, and baseline by week. (NCT01172821)
Timeframe: Last 7 days before week 24 visit
| Intervention | Percentage of Mean PEF (Mean) |
|---|---|
| Placebo | -0.448 |
| Tio R2.5 | -1.401 |
| Tio R5 | -0.627 |
| Salmeterol | -1.518 |
Control of asthma as assessed by the ACQ determined at the end of 24-week treatment. The ACQ contains 7 questions, each question has a 7 point scale from 0 (no symptoms) till 6 (highest intensity). Total score was defined as the sum of all items divided by the number of items and ranges from from 0 (no symptoms) till 6 (highest intensity). Means are adjusted for treatment, centre, week, baseline, treatment by week, and baseline by week. (NCT01172821)
Timeframe: 24 weeks
| Intervention | units on a scale (Mean) |
|---|---|
| Placebo | 1.442 |
| Tio R2.5 | 1.315 |
| Tio R5 | 1.359 |
| Salmeterol | 1.318 |
Time to first severe asthma exacerbation during the 24-week treatment period on combined data from the two twin trials 205.418 (NCT01172808) and 205.419 (NCT01172821) (NCT01172821)
Timeframe: 24 weeks
| Intervention | weeks (Median) |
|---|---|
| Placebo | NA |
| Tio R2.5 | NA |
| Tio R5 | NA |
| Salmeterol | NA |
"Total score from the Standardised Asthma Quality of Life Questionnaire (AQLQ(s)) determined at the end of 24-week treatment.~The AQLQ(s) contains 32 questions, each question has a 7 point scale from 1 (highest intensity) till 7 (no symptoms). Total score was defined as the sum of all items divided by the number of items and ranges from from 1 (highest intensity) till 7 (no symptoms). Means are adjusted for treatment, centre, week, baseline, treatment by week, and baseline by week." (NCT01172821)
Timeframe: 24 weeks
| Intervention | units on a scale (Mean) |
|---|---|
| Placebo | 5.551 |
| Tio R2.5 | 5.562 |
| Tio R5 | 5.548 |
| Salmeterol | 5.634 |
Trough peak expiratory flow (PEF) response determined at the end of the 24-week treatment. Response was defined as change from baseline (10 minutes before the first dose of trial medication at visit 2). Means are adjusted for treatment, centre, week, baseline, treatment by week, and baseline by week. (NCT01172821)
Timeframe: 24 weeks
| Intervention | Litre/min (Mean) |
|---|---|
| Placebo | 7.938 |
| Tio R2.5 | 36.698 |
| Tio R5 | 36.117 |
| Salmeterol | 29.352 |
Daily use of salbutamol (albuterol) rescue medication as needed during the entire study period. Weekly means obtained during the last 7 days before week 24 measured by patients at home using the AM3 device. Response was defined as change from baseline. Means are adjusted for treatment, country, week, baseline, treatment by week, and baseline by week. (NCT01172821)
Timeframe: Baseline and last 7 days before week 24 visit
| Intervention | Number of Puffs (Mean) |
|---|---|
| Placebo | -0.952 |
| Tio R2.5 | -1.123 |
| Tio R5 | -0.843 |
| Salmeterol | -1.078 |
Weekly means obtained during the last 7 days before week 24 measured by patients at home using the AM3 device. Response was defined as change from baseline. Means are adjusted for treatment, country, week, baseline, treatment by week, and baseline by week. (NCT01172821)
Timeframe: Baseline and last 7 days before week 24 visit
| Intervention | Litre (Mean) |
|---|---|
| Placebo | -0.002 |
| Tio R2.5 | 0.066 |
| Tio R5 | 0.064 |
| Salmeterol | 0.048 |
Weekly means obtained during the last 7 days before week 24 measured by patients at home using the AM3 device. Response was defined as change from baseline. Means are adjusted for treatment, country, week, baseline, treatment by week, and baseline by week. (NCT01172821)
Timeframe: Baseline and last 7 days before week 24 visit
| Intervention | Litre/min (Mean) |
|---|---|
| Placebo | -0.072 |
| Tio R2.5 | 15.919 |
| Tio R5 | 21.175 |
| Salmeterol | 11.617 |
Weekly means obtained during the last 7 days before week 24 measured by patients at home using the AM3 device. Response was defined as change from baseline. Means are adjusted for treatment, country, week, baseline, treatment by week, and baseline by week. (NCT01172821)
Timeframe: Baseline and last 7 days before week 24 visit
| Intervention | Litre (Mean) |
|---|---|
| Placebo | 0.020 |
| Tio R2.5 | 0.099 |
| Tio R5 | 0.084 |
| Salmeterol | 0.103 |
Trough FVC response determined at the end of the 24-week treatment. Response was defined as change from baseline (10 minutes before the first dose of trial medication at visit 2). Means are adjusted for treatment, country, week, baseline, treatment by week, and baseline by week. (NCT01172821)
Timeframe: 24 weeks
| Intervention | Litre (Mean) |
|---|---|
| Placebo | -0.048 |
| Tio R2.5 | 0.039 |
| Tio R5 | 0.035 |
| Salmeterol | 0.020 |
Trough FEV1 response determined at the end of the 24-week treatment. Response was defined as change from baseline (10 minutes before the first dose of trial medication at visit 2). Means are adjusted for treatment, centre, week, baseline, treatment by week, and baseline by week. (NCT01172821)
Timeframe: 24 weeks
| Intervention | Litre (Mean) |
|---|---|
| Placebo | -0.012 |
| Tio R2.5 | 0.164 |
| Tio R5 | 0.121 |
| Salmeterol | 0.094 |
Time to first asthma exacerbation (including severe, non-severe; symptomatic, asymptomatic; i.e. any exacerbation) during the 24-week treatment period on combined data from the two twin trials 205.418 (NCT01172808) and 205.419 (NCT01172821) (NCT01172821)
Timeframe: 24 weeks
| Intervention | weeks (Median) |
|---|---|
| Placebo | NA |
| Tio R2.5 | NA |
| Tio R5 | NA |
| Salmeterol | NA |
The responder rate as assessed by the Asthma Control Questionnaire (ACQ) determined at the end of the 24-week treatment period (on combined data from the two twin trials 205.418 (NCT01172808) and 205.419 (NCT01172821)). A patient was considered to be a responder if he or she was reported with an improvement (decrease) in the ACQ total score of at least 0.5 points. (NCT01172821)
Timeframe: 24 weeks
| Intervention | Percentage of participants (Number) |
|---|---|
| Placebo | 57.7 |
| Tio R2.5 | 64.5 |
| Tio R5 | 64.3 |
| Salmeterol | 66.5 |
MMRM results. Response was defined as change from baseline in percent of predicted at the end of 12-week double-blind treatment period and is therefore expressed in percent of predicted. Means are adjusted for treatment, visit, treatment-by-visit interaction, age group (<= 11, >=12), baseline and baseline-by-visit interaction. FVC AUC0-4h was normalised for time and was calculated using the trapezoidal rule divided by the observation time (4 h). (NCT01179347)
Timeframe: 30 minutes (min) before first dosing of study drug (defined as baseline), at 1 hour (h), 2 h , 3 h, and 4 h post dosing at day 1 and at 30 min before dosing, at 1 hour, 2 h , 3 h, and 4 h post dosing after 12 weeks.
| Intervention | Percent of predicted (Mean) |
|---|---|
| Placebo | 0.17 |
| Tio R5 qd | 1.27 |
MMRM results. Response was defined as change from baseline in percent of predicted at the end of 12-week double-blind treatment period and is therefore expressed in percent of predicted. FEF25-75 is also known as maximum mid-expiratory flow and was measured before bronchodilator (salbutamol) use. Means are adjusted for treatment, visit, treatment-by-visit interaction, age group (<= 11, >=12), baseline and baseline-by-visit interaction. (NCT01179347)
Timeframe: Baseline and 12 weeks
| Intervention | Percent of predicted (Mean) |
|---|---|
| Placebo | 2.15 |
| Tio R5 qd | 3.02 |
Selected questions from the Respiratory and Systemic Symptoms Questionnaire (RSSQ), the investigator assessment of physical findings and pulmonary function, and the use of intravenous antibiotics as a concomitant therapy were used to determine if a cystic fibrosis-related pulmonary exacerbation had occurred. (NCT01179347)
Timeframe: 12 weeks
| Intervention | Percentage of Participants (Number) |
|---|---|
| Placebo | 7.8 |
| Tio R5 qd | 8.9 |
MMRM results. Response was defined as change from baseline in percent of predicted at the end of 12-week double-blind treatment period and is therefore expressed in percent of predicted. Trough FEV1 was defined as the pre-dose FEV1 measured just prior to the administration of randomised treatment. Means are adjusted for treatment, visit, treatment-by-visit interaction, age group (<= 11, >=12), baseline and baseline-by-visit interaction. (NCT01179347)
Timeframe: Baseline and 12 weeks
| Intervention | Percent of predicted (Mean) |
|---|---|
| Placebo | 0.72 |
| Tio R5 qd | 2.12 |
MMRM results. Response was defined as change from baseline in percent of predicted at the end of 12-week double-blind treatment period and is therefore expressed in percent of predicted. Trough FCV was defined as the pre-dose FVC measured just prior to the administration of randomised treatment. Means are adjusted for treatment, visit, treatment-by-visit interaction, age group (<= 11, >=12), baseline and baseline-by-visit interaction. (NCT01179347)
Timeframe: Baseline and 12 weeks
| Intervention | Percent of predicted (Mean) |
|---|---|
| Placebo | 0.30 |
| Tio R5 qd | 1.51 |
Mixed Model Repeated Measurement (MMRM) results. Response was defined as change from baseline in percent of predicted at the end of 12-week double-blind treatment period and is therefore expressed in percent of predicted. Means are adjusted for treatment, visit, treatment-by-visit interaction, age group (<= 11, >=12), baseline and baseline-by-visit interaction. FEV1 AUC0-4h was normalised for time and was calculated using the trapezoidal rule divided by the observation time (4 h). (NCT01179347)
Timeframe: 30 minutes (min) before first dosing of study drug (defined as baseline), at 1 hour (h), 2 h , 3 h, and 4 h post dosing at day 1 and at 30 min before dosing, at 1 hour, 2 h , 3 h, and 4 h post dosing after 12 weeks.
| Intervention | Percent of predicted (Mean) |
|---|---|
| Placebo | 0.87 |
| Tio R5 qd | 2.51 |
Different format of CFQ-R are used depending of the patients' age. Adolescent and adult format of CFQ-R is used for patients of 14 years and older, for younger children a parent version and a children format is used. In case parent and children questionnaires were filled out, the children questionnaire is taken into account. Scores were calculated for each domain of the CFQ-R which are presented separately. A score of 100 corresponds to the highest quality of life possible, whereas a score of 0 corresponds to the lowest quality of life possible. Increasing score indicates better health. (NCT01179347)
Timeframe: Baseline and 12 weeks
| Intervention | Units on a scale (Mean) | |||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Adolescents: Physical (N=83, N=162) | Adolescents: Role (N=78, N=157) | Adolescents: Vitality (N=82, N=161) | Adolescents: Emotion (N=82, N=161) | Adolescents: Social (N=82, N=159) | Adolescents: Body Image (N=82, N=159) | Adolescents: Eating (N=82, N=161) | Adolescents: Treatment burden (N=82, N=160) | Adolescents: Health perseptions (N=82, N=159) | Adolescents: Weight (N=80, N=160) | Adolescents: Respiratory (N=80, N=159) | Adolescents: Digestion (N=80, N=159) | Children: Physical (N=47, N=93) | Children: Social (N=46, N=93) | Children: Body Image (N=46, N=93) | Children: Emotion (N=47, N=93) | Children: Eating (N=47, N=93) | Children: Treatment burden (N=46, N=93) | Children: Respiratory (N=46, N=93) | Children: Digestion (N=46, N=92) | |
| Placebo | -0.85 | 0.85 | -1.22 | -1.54 | -1.69 | 0.14 | -1.49 | 0.95 | -0.81 | -2.08 | 0.97 | -0.83 | -2.84 | 2.80 | -1.21 | -1.24 | 2.84 | 0.72 | -0.91 | 2.17 |
| Tio R5 qd | -0.15 | -0.42 | 0.05 | -0.99 | 0.70 | 3.14 | 1.38 | 0.56 | 0.77 | 3.75 | -0.77 | 0.49 | 1.43 | 1.59 | 4.66 | 1.12 | 0.72 | -0.48 | -1.61 | -1.09 |
The number of puffs of rescue medication taken in the previous 12 hours was record in patient diary in the morning and in the evening for 26 weeks. The total number of puffs per day was calculated and divided by the number of days with data to determine the mean daily number of puffs of rescue medication for each patient. Rescue medication data recorded during the 14 day run-in was used to calculate the baseline. A negative change from baseline indicates improvement. A mixed model was used with treatment as a fixed effect with baseline number of puffs and FEV1 prior to inhalation and FEV1 60 minutes post inhalation of two short acting bronchodilators (components of reversibility at Day -14) as covariates. The model also included baseline smoking status (current/ex-smoker), baseline ICS use (Yes/No) and region as fixed effects with center nested within region as a random effect. (NCT01202188)
Timeframe: Baseline, Week 12, Week 26
| Intervention | Puffs per day (Least Squares Mean) | |
|---|---|---|
| Change from Baseline (BL) at Week 12 | Change from BL at Week 26 (n=419,416,403,424,199) | |
| Glycopyrronium (NVA237) | -1.22 | -1.22 |
| Indacaterol (QAB149) | -1.46 | -1.57 |
| Indacaterol and Glycopyrronium (QVA149) | -1.82 | -1.88 |
| Placebo | -0.83 | -0.92 |
| Tiotropium | -1.28 | -1.34 |
(NCT01202188)
Timeframe: 26 Weeks
| Intervention | Percentage of participants (Number) | |
|---|---|---|
| Requiring hospitalization | Corticosteroids_Antibiotics-No hospitalization | |
| Glycopyrronium (NVA237) | 1.9 | 17.8 |
| Indacaterol (QAB149) | 2.5 | 19.7 |
| Indacaterol and Glycopyrronium (QVA149) | 2.1 | 16.7 |
| Placebo | 3.0 | 23.3 |
| Tiotropium | 1.0 | 16.9 |
SGRQ is a health related quality of life questionnaire consisting of 51 items in three areas: symptoms (respiratory symptoms and severity), activity (activities that cause or are limited by breathlessness) and impacts (social functioning and psychological disturbances due to airway disease). The total score is 0 to 100 with a higher score indicating poorer health status. A mixed model was used with treatment as a fixed effect with Baseline SGRQ and FEV1 prior to inhalation and FEV1 60 minutes post inhalation of two short acting bronchodilators (components of reversibility at Day -14) as covariates. The model also included baseline smoking status (current/ex-smoker), baseline ICS use (Yes/No) and region as fixed effects with center nested within region as a random effect. (NCT01202188)
Timeframe: Week 12, Week 26
| Intervention | Score on a scale (Least Squares Mean) | |
|---|---|---|
| 12 Weeks | 26 Weeks (n=441,443,430,450,196) | |
| Glycopyrronium (NVA237) | 39.40 | 38.19 |
| Indacaterol (QAB149) | 38.55 | 38.10 |
| Indacaterol and Glycopyrronium (QVA149) | 37.56 | 37.01 |
| Placebo | 41.55 | 40.02 |
| Tiotropium | 39.94 | 39.14 |
FEV1 was measured with spirometry conducted according to internationally accepted standards. Measurements were made at 5, 15, and 30 minutes; and 1, 2, 4, 8, 12 hours post-dose. The standardized AUC FEV1 was calculated as the sum of trapezoids divided by the length of time. A mixed model was used with treatment as a fixed effect with baseline FEV1 and FEV1 prior to inhalation and FEV1 60 minutes post inhalation of two short acting bronchodilators (components of reversibility at Day -14) as covariates. The model also included baseline smoking status (current/ex-smoker), baseline ICS use (Yes/No) and region as fixed effects with center nested within region as a random effect. (NCT01202188)
Timeframe: From 5 minutes to 12 hours post-dose Day 1 and Week 26
| Intervention | Liters (Least Squares Mean) | |
|---|---|---|
| Day1 | Week 26 (n=60,55,58,67,27) | |
| Glycopyrronium (NVA237) | 1.42 | 1.39 |
| Indacaterol (QAB149) | 1.40 | 1.39 |
| Indacaterol and Glycopyrronium (QVA149) | 1.50 | 1.52 |
| Placebo | 1.24 | 1.18 |
| Tiotropium | 1.38 | 1.39 |
FEV1 was measured with spirometry conducted according to internationally accepted standards. Measurements were made at 5, 15, and 30 minutes; and 1, 2, and 4 hours post-dose. The standardized AUC FEV1 was calculated as the sum of trapezoids divided by the length of time. A mixed model was used with treatment as a fixed effect with baseline FEV1 and FEV1 prior to inhalation and FEV1 60 minutes post inhalation of two short acting bronchodilators (components of reversibility at Day -14) as covariates. The model also included baseline smoking status (current/ex-smoker), baseline ICS use (Yes/No) and region as fixed effects with center nested within region as a random effect. (NCT01202188)
Timeframe: From 5 minutes to 4 hours post-dose Day 1 and Week 26
| Intervention | Liters (Least Squares Mean) | |
|---|---|---|
| Day 1 | Week 26 (n=433,418,412,435,186) | |
| Glycopyrronium (NVA237) | 1.49 | 1.43 |
| Indacaterol (QAB149) | 1.46 | 1.46 |
| Indacaterol and Glycopyrronium (QVA149) | 1.52 | 1.57 |
| Placebo | 1.30 | 1.23 |
| Tiotropium | 1.44 | 1.44 |
"Patients answered the question Did your respiratory symptoms stop you performing your usual activities today?-Not at all in their daily diary. The percentage of days is calculated by the number of days patient is able to perform daily activities/total number of days with evaluable data X 100. A mixed model was used with treatment as a fixed effect with baseline Percent of Days and FEV1 prior to inhalation and FEV1 60 minutes post inhalation of two short acting bronchodilators (components of reversibility at Day -14) as covariates. The model also included baseline smoking status (current/ex-smoker), baseline ICS use (Yes/No) and region as fixed effects with center nested within region as a random effect." (NCT01202188)
Timeframe: 26 Weeks
| Intervention | Percentage of days (Least Squares Mean) |
|---|---|
| Indacaterol and Glycopyrronium (QVA149) | 45.97 |
| Indacaterol (QAB149) | 40.94 |
| Glycopyrronium (NVA237) | 40.10 |
| Tiotropium | 37.52 |
| Placebo | 34.49 |
A day with no day time symptoms is defined from the diary data as any day where the patient recorded no coughing, no wheezing, no sputum production and no breathlessness during the previous 12 hours (approximately 8AM to 8PM). The percentage of days is calculated by the number of days with no daytime symptoms/total number of days with evaluable data X 100. A mixed model was used with treatment as a fixed effect with baseline Percent of days and FEV1 prior to inhalation and FEV1 60 minutes post inhalation of two short acting bronchodilators (components of reversibility at Day -14) as covariates. The model also included baseline smoking status (current/ex-smoker), baseline ICS use (Yes/No) and region as fixed effects with center nested within region as a random effect. (NCT01202188)
Timeframe: 26 Weeks
| Intervention | Percentage of days (Least Squares Mean) |
|---|---|
| Indacaterol and Glycopyrronium (QVA149) | 7.49 |
| Indacaterol (QAB149) | 9.17 |
| Glycopyrronium (NVA237) | 6.40 |
| Tiotropium | 5.54 |
| Placebo | 4.44 |
A day with no rescue medication use is defined from the diary data as any day where the patient recorded no rescue medicine use during the previous 12 hours. The percentage of days is calculated by the number of days with no rescue medicine use/total number of days with evaluable data X 100. A mixed model was used with treatment as a fixed effect with baseline number of puffs and FEV1 prior to inhalation and FEV1 60 minutes post inhalation of two short acting bronchodilators (components of reversibility at Day -14) as covariates. The model also included baseline smoking status (current/ex-smoker), baseline ICS use (Yes/No) and region as fixed effects with center nested within region as a random effect. (NCT01202188)
Timeframe: 26 Weeks
| Intervention | Percentage of days (Least Squares Mean) |
|---|---|
| Indacaterol and Glycopyrronium (QVA149) | 47.09 |
| Indacaterol (QAB149) | 44.81 |
| Glycopyrronium (NVA237) | 37.74 |
| Tiotropium | 36.51 |
| Placebo | 34.76 |
A day with no night time awakenings is defined from the diary data as any day where the patient did not wake up due to COPD symptoms. The percentage of nights is calculated by the number of days with no nighttime awakenings/total number of days with evaluable data X 100. A mixed model was used with treatment as a fixed effect with baseline Percent days and FEV1 prior to inhalation and FEV1 60 minutes post inhalation of two short acting bronchodilators (components of reversibility at Day -14) as covariates. The model also included baseline smoking status (current/ex-smoker), baseline ICS use (Yes/No) and region as fixed effects with center nested within region as a random effect. (NCT01202188)
Timeframe: 26 Weeks
| Intervention | Percentage of nights (Least Squares Mean) |
|---|---|
| Indacaterol and Glycopyrronium (QVA149) | 63.68 |
| Indacaterol (QAB149) | 62.48 |
| Glycopyrronium (NVA237) | 58.64 |
| Tiotropium | 60.00 |
| Placebo | 53.67 |
The number of puffs of rescue medication taken in the previous 12 hours was record in patient diary in the morning and in the evening for 26 weeks. The total number of puffs per day was calculated and divided by the number of days with data to determine the mean daily number of puffs of rescue medication for each patient. Rescue medication data recorded during the 14 day run-in was used to calculate the baseline. A negative change from baseline indicates improvement. A mixed model was used with treatment as a fixed effect with baseline number of puffs and FEV1 prior to inhalation and FEV1 60 minutes post inhalation of two short acting bronchodilators (components of reversibility at Day -14) as covariates. The model also included baseline smoking status (current/ex-smoker), baseline ICS use (Yes/No) and region as fixed effects with center nested within region as a random effect. (NCT01202188)
Timeframe: Baseline, Week 26
| Intervention | Puffs per day (Least Squares Mean) |
|---|---|
| Indacaterol and Glycopyrronium (QVA149) | -1.88 |
| Placebo | -0.92 |
SGRQ is a health related quality of life questionnaire consisting of 51 items in three areas: symptoms (respiratory symptoms and severity), activity (activities that cause or are limited by breathlessness) and impacts (social functioning and psychological disturbances due to airway disease). The total score is 0 to 100 with a higher score indicating poorer health status. (NCT01202188)
Timeframe: Baseline, Week 26
| Intervention | Percentage of participants (Number) |
|---|---|
| Indacaterol and Glycopyrronium (QVA149) | 63.7 |
| Indacaterol (QAB149) | 63.0 |
| Glycopyrronium (NVA237) | 60.5 |
| Tiotropium | 56.4 |
| Placebo | 56.6 |
A trained assessor interviewed the patient and graded the degree of impairment due to dyspnea (difficulty breathing) at Week 12 and Week 26. TDI focal score is based on three domains: functional impairment, magnitude of task and magnitude of effort. The BDI (baseline) was measured at Day 1. The TDI captures changes from baseline. Each domain is scored from -3 (major deterioration) to 3 (major improvement) to give an overall TDI focal score of -9 to 9. (NCT01202188)
Timeframe: Baseline, Week 26
| Intervention | Percentage of participants (Number) |
|---|---|
| Indacaterol and Glycopyrronium (QVA149) | 68.1 |
| Indacaterol (QAB149) | 64.6 |
| Glycopyrronium (NVA237) | 63.7 |
| Tiotropium | 59.2 |
| Placebo | 57.5 |
(NCT01202188)
Timeframe: 26 Weeks
| Intervention | Percentage of participants (Number) |
|---|---|
| Indacaterol and Glycopyrronium (QVA149) | 17.9 |
| Indacaterol (QAB149) | 21.6 |
| Glycopyrronium (NVA237) | 18.8 |
| Tiotropium | 17.7 |
| Placebo | 25.8 |
Rate of moderate or severe exacerbations per year = total number of moderate or severe exacerbations / total number of treatment years (NCT01202188)
Timeframe: 26 Weeks
| Intervention | Exacerbations per year (Number) |
|---|---|
| Indacaterol and Glycopyrronium (QVA149) | 0.46 |
| Indacaterol (QAB149) | 0.59 |
| Glycopyrronium (NVA237) | 0.52 |
| Tiotropium | 0.45 |
| Placebo | 0.75 |
SGRQ is a health related quality of life questionnaire consisting of 51 items in three areas: symptoms (respiratory symptoms and severity), activity (activities that cause or are limited by breathlessness) and impacts (social functioning and psychological disturbances due to airway disease). The total score is 0 to 100 with a higher score indicating poorer health status. A mixed model was used with treatment as a fixed effect with Baseline SGRQ and FEV1 prior to inhalation and FEV1 60 minutes post inhalation of two short acting bronchodilators (components of reversibility at Day -14) as covariates. The model also included baseline smoking status (current/ex-smoker), baseline ICS use (Yes/No) and region as fixed effects with center nested within region as a random effect. (NCT01202188)
Timeframe: 26 weeks
| Intervention | Score on a scale (Least Squares Mean) |
|---|---|
| Indacaterol and Glycopyrronium (QVA149) | 37.01 |
| Placebo | 40.02 |
FEV1 was measured with spirometry conducted according to internationally accepted standards. Measurements were made at 5, 15, and 30 minutes; and 1, 2, 4, 8, 12, 23 hours 15 minutes and 23 hours 45 minutes post-dose. The standardized AUC FEV1 was calculated as the sum of trapezoids divided by the length of time. A mixed model was used with treatment as a fixed effect with baseline FEV1 and FEV1 prior to inhalation and FEV1 60 minutes post inhalation of two short acting bronchodilators (components of reversibility at Day -14) as covariates. The model also included baseline smoking status (current/ex-smoker), baseline ICS use (Yes/No) and region as fixed effects with center nested within region as a random effect. (NCT01202188)
Timeframe: From 5 minutes to 23 hours 45 minutes post-dose Week 26
| Intervention | Liters (Least Squares Mean) |
|---|---|
| Indacaterol and Glycopyrronium (QVA149) | 1.46 |
| Indacaterol (QAB149) | 1.35 |
| Glycopyrronium (NVA237) | 1.35 |
| Tiotropium | 1.36 |
| Placebo | 1.15 |
A trained assessor interviewed the patient and graded the degree of impairment due to dyspnea (difficulty breathing). TDI focal score is based on three domains: functional impairment, magnitude of task and magnitude of effort. Each domain is scored from -3 (major deterioration) to 3 (major improvement) to give an overall TDI focal score of -9 to 9. Higher numbers indicate a better score. A mixed model was used with treatment as a fixed effect with Baseline Dyspnea Index Score and FEV1 prior to inhalation and FEV1 60 minutes post inhalation of two short acting bronchodilators (components of reversibility at Day -14) as covariates. The model also included baseline smoking status (current/ex-smoker), baseline ICS use (Yes/No) and region as fixed effects with center nested within region as a random effect. (NCT01202188)
Timeframe: Week 26
| Intervention | Score on a scale (Least Squares Mean) |
|---|---|
| Indacaterol and Glycopyrronium (QVA149) | 2.72 |
| Placebo | 1.63 |
Spirometry was performed according to internationally accepted standards. Trough FEV1 was defined as the mean of the 23 hour 15 minute and 23 hour 45 minute post-dose values. A mixed model was used with treatment as a fixed effect with baseline FEV1 and FEV1 prior to inhalation and FEV1 60 minutes post inhalation of two short acting bronchodilators (components of reversibility at Day -14) as covariates. The model also included baseline smoking status (current/ex-smoker), baseline ICS use (Yes/No) and region as fixed effects with center nested within region as a random effect. (NCT01202188)
Timeframe: 23 hours 15 minutes and 23 hour 45 minute post-dose Week 26
| Intervention | Liters (Least Squares Mean) |
|---|---|
| Indacaterol and Glycopyrronium (QVA149) | 1.45 |
| Indacaterol (QAB149) | 1.38 |
| Glycopyrronium (NVA237) | 1.36 |
Spirometry was performed according to internationally accepted standards. Trough FEV1 was defined as the mean of the 23 hour 15 minute and 23 hour 45 minute post-dose values. A mixed model was used with treatment as a fixed effect with baseline FEV1 and FEV1 prior to inhalation and FEV1 60 minutes post inhalation of two short acting bronchodilators (components of reversibility at Day -14) as covariates. The model also included baseline smoking status (current/ex-smoker), baseline ICS use (Yes/No) and region as fixed effects with center nested within region as a random effect. (NCT01202188)
Timeframe: 23 hours 15 minutes and 23 hour 45 minute post-dose Week 26
| Intervention | Liters (Least Squares Mean) |
|---|---|
| Indacaterol and Glycopyrronium (QVA149) | 1.46 |
| Tiotropium | 1.39 |
Spirometry was performed according to internationally accepted standards. Trough FEV1 was defined as the mean of the 23 hour 15 minute and 23 hour 45 minute post-dose values. A mixed model was used with treatment as a fixed effect with baseline FEV1 and FEV1 prior to inhalation and FEV1 60 minutes post inhalation of two short acting bronchodilators (components of reversibility at Day -14) as covariates. The model also included baseline smoking status (current/ex-smoker), baseline ICS use (Yes/No) and region as fixed effects with center nested within region as a random effect. (NCT01202188)
Timeframe: 23 hours 15 minutes and 23 hour 45 minute post-dose Week 26
| Intervention | Liters (Least Squares Mean) |
|---|---|
| Indacaterol and Glycopyrronium (QVA149) | 1.45 |
| Indacaterol (QAB149) | 1.38 |
| Glycopyrronium (NVA237) | 1.36 |
| Placebo | 1.25 |
"24-hourly mean heart rate was performed using a Holter Monitor at Weeks 12 and 26 in a subgroup of patients. Mixed model: heart rate = treatment + baseline heart rate + baseline smoking status + baseline ICS use + region + center (region) + error. Center was included as a random effect nested within region.~The 24-hourly mean heart rate is the mean heart rate over the 24 hour period, derived using hourly mean heart rate beats per minute." (NCT01202188)
Timeframe: Week 12, Week 26
| Intervention | beats per minute (Least Squares Mean) | |
|---|---|---|
| Week 12 (n=35,38,27,15) | Week 26 (n=36,36,26,16) | |
| Glycopyrronium (NVA237) | 79.4 | 80.5 |
| Indacaterol (QAB149) | 79.9 | 78.6 |
| Indacaterol and Glycopyrronium (QVA149) | 80.8 | 79.8 |
| Placebo | 78.9 | 77.0 |
"A trained assessor interviewed the patient and graded the degree of impairment due to dyspnea (difficulty breathing). BDI/TDI focal score is based on three domains: functional impairment, magnitude of task and magnitude of effort and captures changes from baseline. BDI was measured at day 1 prior to the first dose with domain scores ranging from 0=very severe to 4=no impairment and a total score ranging from 0 to 12(best). TDI captures changes from baseline. Each domain is scored from -3=major deterioration to 3=major improvement to give an overall TDI focal score of -9 to 9. Higher numbers indicate a better score.~A mixed model was used with treatment as a fixed effect with Baseline Dyspnea Index Score and FEV1 prior to inhalation and FEV1 60 minutes post inhalation of two short acting bronchodilators as covariates and included baseline smoking status, baseline inhaled corticosteroids and region as fixed effects with center nested within region as a random effect." (NCT01202188)
Timeframe: Baseline, Week 12, Week 26
| Intervention | Score on a scale (Least Squares Mean) | |||
|---|---|---|---|---|
| BDI_ baseline for Week 12 | TDI Week 12 | BDI_baseline for Week 26 (n=439,440,424,441,193) | TDI Week 26 (n=439,440,424,441,193) | |
| Glycopyrronium (NVA237) | 6.21 | 2.04 | 6.22 | 2.52 |
| Indacaterol (QAB149) | 6.28 | 2.18 | 6.28 | 2.47 |
| Indacaterol and Glycopyrronium (QVA149) | 6.45 | 2.44 | 6.45 | 2.72 |
| Placebo | 6.53 | 1.22 | 6.56 | 1.63 |
| Tiotropium | 6.43 | 1.81 | 6.46 | 2.21 |
The number of puffs of rescue medication taken in the previous 12 hours was record in patient diary in the morning and in the evening for 26 weeks. The total number of puffs in the morning and evening were calculated and divided by the number of days with data to determine the mean daily number of daytime and nighttime puffs. A mixed model was used with treatment as a fixed effect with baseline number of puffs and FEV1 prior to inhalation and FEV1 60 minutes post inhalation of two short acting bronchodilators (components of reversibility at Day -14) as covariates. The model also included baseline smoking status (current/ex-smoker), baseline (BL) ICS use (Yes/No) and region as fixed effects with center nested within region as a random effect. (NCT01202188)
Timeframe: Baseline, Week 26
| Intervention | Puffs (Least Squares Mean) | |
|---|---|---|
| Daytime Change from BL (n=415,410,395,418,195) | Nighttime Change from BL (n=418,413,399,422,198) | |
| Glycopyrronium (NVA237) | -0.75 | -0.48 |
| Indacaterol (QAB149) | -0.96 | -0.63 |
| Indacaterol and Glycopyrronium (QVA149) | -1.11 | -0.78 |
| Placebo | -0.58 | -0.34 |
| Tiotropium | -0.83 | -0.52 |
Defined as FEV1 measured just prior to the last administration of the morning dose of the randomised treatment. Means are adjusted for sequence, patients within sequences, period and treatment. (NCT01222533)
Timeframe: 4 weeks
| Intervention | Liter (Mean) |
|---|---|
| Placebo | 1.345 |
| Tio R1.25 | 1.432 |
| Tio R2.5 | 1.446 |
| Tio R5 | 1.466 |
| Tio HH18 | 1.473 |
Tmax,ss is the time from dosing to the maximum concentration of tiotropium in plasma-venous blood at steady-state. (NCT01222533)
Timeframe: Based on blood sampling for PK assessments done at 4 weeks at the following time points: 5 min before first dosing of study drug (baseline) and at 2 min , 5 min, 7 min, 9 min, 12 min, 15 min, 20 min, 30 min, 40 min, 1 h, 2 h, 4 h and 6 h post dosing.
| Intervention | hours (Median) |
|---|---|
| Tio R1.25 | 0.100 |
| Tio R2.5 | 0.0830 |
| Tio R5 | 0.117 |
| Tio HH18 | 0.117 |
"Mean HR evaluated over the entire 6.5 h Holter monitoring period. The arrhythmia variables were pre-specified for day 29 and analysed post-hoc for day 26. The lines Day 29 1st h and Day 26 1st h are related to the interval 0 h to 1 h, i.e. the first hour after dosing." (NCT01222533)
Timeframe: 6.5 hours (including pre dose)
| Intervention | bpm (Mean) | |||
|---|---|---|---|---|
| Day 29 6.5 h(N=115,115,115,116,113) | Day 29 1st h(N=114,113,115,115,111) | Day 26 6.5 h(N=115,110,113,110,112) | Day 26 1st h(N=115,109,113,107,109) | |
| Placebo | 76.97 | 73.87 | 75.76 | 70.75 |
| Tio HH18 | 77.31 | 73.71 | 75.81 | 70.21 |
| Tio R1.25 | 76.37 | 73.76 | 75.00 | 70.33 |
| Tio R2.5 | 77.75 | 74.39 | 76.25 | 71.11 |
| Tio R5 | 76.87 | 73.82 | 75.35 | 70.67 |
Total quantity of the analyte that is excreted in urine over the time interval 0 to 6 hours at steady state. (NCT01222533)
Timeframe: Based on urine sampling for PK assessments done at 4 weeks in the following intervals: -1 to 0 hour (h), 0 to 2 h and 2 to 6 h post-dosing.
| Intervention | ng (Geometric Mean) |
|---|---|
| Tio R1.25 | 88.7 |
| Tio R2.5 | 177 |
| Tio R5 | 387 |
| Tio HH18 | 522 |
AUC0-1h,ss is the area under the concentration time curve of tiotropium in plasma over the time interval 0 to 1 hour post-dose at steady-state. AUC0-1h,ss was calculated using the linear up/log down algorithm. (NCT01222533)
Timeframe: Based on blood sampling for PK assessments done at 4 weeks at the following time points: 5 minutes (min) before study drug (baseline) and at 2 min , 5 min, 7 min, 9 min, 12 min, 15 min, 20 min, 30 min, 40 min, 1 hour (h), 2 h, 4 h and 6 h post dosing.
| Intervention | pg*h/mL (Geometric Mean) |
|---|---|
| Tio R1.25 | 2.08 |
| Tio R2.5 | 3.16 |
| Tio R5 | 6.13 |
| Tio HH18 | 7.79 |
Means are adjusted for period, planned time, period*planned time, patient*planned time and patient*treatment*planned time. (NCT01222533)
Timeframe: 4 weeks
| Intervention | Liter (Mean) | |||||||
|---|---|---|---|---|---|---|---|---|
| Timepoint 0:00 (trough) | Timepoint 0:30 | Timepoint 1:00 | Timepoint 2:00 | Timepoint 3:00 | Timepoint 4:00 | Timepoint 5:00 | Timepoint 6:00 | |
| Placebo | 3.118 | 3.131 | 3.152 | 3.146 | 3.156 | 3.161 | 3.191 | 3.168 |
| Tio HH18 | 3.351 | 3.496 | 3.499 | 3.487 | 3.497 | 3.501 | 3.488 | 3.469 |
| Tio R1.25 | 3.255 | 3.390 | 3.449 | 3.443 | 3.466 | 3.468 | 3.459 | 3.417 |
| Tio R2.5 | 3.307 | 3.435 | 3.484 | 3.489 | 3.513 | 3.495 | 3.467 | 3.470 |
| Tio R5 | 3.356 | 3.473 | 3.488 | 3.499 | 3.516 | 3.505 | 3.501 | 3.473 |
"The outcome measure describes the number of patients with a Supraventricular Premature Beat (SVPB) run evaluated over the entire 6.5 h Holter monitoring period. Runs were defined as at least 3 premature beats in a row. The arrhythmia variables were pre-specified for day 29 and analysed post-hoc for day 26. The lines Day 29 1st h and Day 26 1st h are related to the interval 0 h to 1 h, i.e. the first hour after dosing." (NCT01222533)
Timeframe: 6.5 hours (including pre dose)
| Intervention | participants (Number) | |||
|---|---|---|---|---|
| Day 29 6.5 h | Day 29 1st h | Day 26 6.5 h | Day 26 1st h | |
| Placebo | 47 | 9 | 35 | 12 |
| Tio HH18 | 39 | 6 | 34 | 10 |
| Tio R1.25 | 36 | 16 | 34 | 6 |
| Tio R2.5 | 44 | 8 | 29 | 9 |
| Tio R5 | 34 | 5 | 36 | 11 |
FEV1 AUC0-6h calculated from zero time to 6 hours using the trapezoidal rule divided by 6 hours. Trough FEV1 will be assigned to zero time. Means are adjusted for sequence, patients within sequences, period and treatment. (NCT01222533)
Timeframe: 4 weeks
| Intervention | Liter (Mean) |
|---|---|
| Placebo | 1.371 |
| Tio R1.25 | 1.535 |
| Tio R2.5 | 1.556 |
| Tio R5 | 1.562 |
| Tio HH18 | 1.567 |
FVC AUC0-3h calculated from zero time to 3 hours using the trapezoidal rule divided by 3 hours. Trough FVC will be assigned to zero time. Means are adjusted for sequence, patients within sequences, period and treatment. (NCT01222533)
Timeframe: 4 weeks
| Intervention | Liter (Mean) |
|---|---|
| Placebo | 3.140 |
| Tio R1.25 | 3.421 |
| Tio R2.5 | 3.465 |
| Tio R5 | 3.479 |
| Tio HH18 | 3.480 |
"The outcome measure describes the number of patients with a Supraventricular Premature Beat (SVPB) single evaluated over the entire 6.5 h Holter monitoring period. The arrhythmia variables were pre-specified for day 29 and analysed post-hoc for day 26. The lines Day 29 1st h and Day 26 1st h are related to the interval 0 h to 1 h, i.e. the first hour after dosing." (NCT01222533)
Timeframe: 6.5 hours (including pre dose)
| Intervention | participants (Number) | |||
|---|---|---|---|---|
| Day 29 6.5 h | Day 29 1st h | Day 26 6.5 h | Day 26 1st h | |
| Placebo | 109 | 82 | 111 | 78 |
| Tio HH18 | 107 | 73 | 105 | 64 |
| Tio R1.25 | 112 | 77 | 102 | 74 |
| Tio R2.5 | 109 | 72 | 106 | 74 |
| Tio R5 | 108 | 82 | 98 | 61 |
"Maximum HR evaluated over the entire 6.5 h Holter monitoring period. The arrhythmia variables were pre-specified for day 29 and analysed post-hoc for day 26. The lines Day 29 1st h and Day 26 1st h are related to the interval 0 h to 1 h, i.e. the first hour after dosing." (NCT01222533)
Timeframe: 6.5 hours (including pre dose)
| Intervention | bpm (Mean) | |||
|---|---|---|---|---|
| Day 29 6.5 h(N=115,115,115,116,113) | Day 29 1st h(N=114,113,115,115,111) | Day 26 6.5 h(N=115,110,113,110,112) | Day 26 1st h(N=115,109,113,107,109) | |
| Placebo | 109.29 | 97.83 | 108.35 | 91.73 |
| Tio HH18 | 108.68 | 97.33 | 109.57 | 92.74 |
| Tio R1.25 | 109.57 | 99.20 | 107.37 | 91.51 |
| Tio R2.5 | 109.93 | 98.43 | 108.90 | 92.59 |
| Tio R5 | 109.34 | 97.16 | 107.65 | 91.60 |
"The outcome measure describes the number of patients with a Supraventricular Premature Beat (SVPB) event evaluated over the entire 6.5 h Holter monitoring period. The arrhythmia variables were pre-specified for day 29 and analysed post-hoc for day 26. The lines Day 29 1st h and Day 26 1st h are related to the interval 0 h to 1 h, i.e. the first hour after dosing." (NCT01222533)
Timeframe: 6.5 hours (including pre dose)
| Intervention | participants (Number) | |||
|---|---|---|---|---|
| Day 29 6.5 h | Day 29 1st h | Day 26 6.5 h | Day 26 1st h | |
| Placebo | 109 | 83 | 111 | 82 |
| Tio HH18 | 107 | 75 | 105 | 66 |
| Tio R1.25 | 112 | 79 | 103 | 74 |
| Tio R2.5 | 109 | 75 | 106 | 75 |
| Tio R5 | 108 | 84 | 98 | 62 |
"The outcome measure describes the number of patients with a Ventricular Premature Beat (VPB) event evaluated over the entire 6.5 h Holter monitoring period. The arrhythmia variables were pre-specified for day 29 and analysed post-hoc for day 26. The lines Day 29 1st h and Day 26 1st h are related to the interval 0 h to 1 h, i.e. the first hour after dosing." (NCT01222533)
Timeframe: 6.5 hours (including pre dose)
| Intervention | participants (Number) | |||
|---|---|---|---|---|
| Day 29 6.5 h | Day 29 1st h | Day 26 6.5 h | Day 26 1st h | |
| Placebo | 91 | 59 | 92 | 59 |
| Tio HH18 | 96 | 59 | 88 | 56 |
| Tio R1.25 | 99 | 63 | 82 | 49 |
| Tio R2.5 | 90 | 58 | 83 | 49 |
| Tio R5 | 96 | 50 | 89 | 49 |
"The outcome measure describes the number of patients with a Ventricular Premature Beat (VPB) pair evaluated over the entire 6.5 h Holter monitoring period. Pairs were defined as 2 consecutive premature beats in a row. The arrhythmia variables were pre-specified for day 29 and analysed post-hoc for day 26. The lines Day 29 1st h and Day 26 1st h are related to the interval 0 h to 1 h, i.e. the first hour after dosing." (NCT01222533)
Timeframe: 6.5 hours (including pre dose)
| Intervention | participants (Number) | |||
|---|---|---|---|---|
| Day 29 6.5 h | Day 29 1st h | Day 26 6.5 h | Day 26 1st h | |
| Placebo | 24 | 8 | 24 | 7 |
| Tio HH18 | 22 | 7 | 22 | 10 |
| Tio R1.25 | 19 | 6 | 20 | 10 |
| Tio R2.5 | 21 | 6 | 19 | 7 |
| Tio R5 | 16 | 6 | 21 | 6 |
"The outcome measure describes the number of patients with a Ventricular Premature Beat (VPB) run evaluated over the entire 6.5 h Holter monitoring period. Runs were defined as at least 3 premature beats in a row. The arrhythmia variables were pre-specified for day 29 and analysed post-hoc for day 26. The lines Day 29 1st h and Day 26 1st h are related to the interval 0 h to 1 h, i.e. the first hour after dosing." (NCT01222533)
Timeframe: 6.5 hours (including pre dose)
| Intervention | participants (Number) | |||
|---|---|---|---|---|
| Day 29 6.5 h | Day 29 1st h | Day 26 6.5 h | Day 26 1st h | |
| Placebo | 3 | 0 | 8 | 0 |
| Tio HH18 | 9 | 1 | 9 | 3 |
| Tio R1.25 | 5 | 3 | 7 | 2 |
| Tio R2.5 | 4 | 2 | 8 | 1 |
| Tio R5 | 10 | 2 | 9 | 4 |
"The outcome measure describes the number of patients with a Ventricular Premature Beat (VPB) single evaluated over the entire 6.5 h Holter monitoring period. The arrhythmia variables were pre-specified for day 29 and analysed post-hoc for day 26. The lines Day 29 1st h and Day 26 1st h are related to the interval 0 h to 1 h, i.e. the first hour after dosing." (NCT01222533)
Timeframe: 6.5 hours (including pre dose)
| Intervention | participants (Number) | |||
|---|---|---|---|---|
| Day 29 6.5 h | Day 29 1st h | Day 26 6.5 h | Day 26 1st h | |
| Placebo | 91 | 59 | 92 | 59 |
| Tio HH18 | 96 | 58 | 88 | 55 |
| Tio R1.25 | 99 | 63 | 82 | 49 |
| Tio R2.5 | 89 | 58 | 81 | 48 |
| Tio R5 | 94 | 50 | 88 | 49 |
Cmax,ss is the maximum measured concentration of tiotropium in plasma at steady-state. (NCT01222533)
Timeframe: Based on blood sampling for PK assessments done at 4 weeks at the following time points: 5 minutes (min) before study drug (baseline) and at 2 min , 5 min, 7 min, 9 min, 12 min, 15 min, 20 min, 30 min, 40 min, 1 hour (h), 2 h, 4 h and 6 h post dosing.
| Intervention | pg/ml (Geometric Mean) |
|---|---|
| Tio R1.25 | 2.81 |
| Tio R2.5 | 5.07 |
| Tio R5 | 10.5 |
| Tio HH18 | 12.9 |
FVC AUC0-6h calculated from zero time to 6 hours using the trapezoidal rule divided by 6 hours. Trough FVC will be assigned to zero time. Means are adjusted for sequence, patients within sequences, period and treatment. (NCT01222533)
Timeframe: 4 weeks
| Intervention | Liter (Mean) |
|---|---|
| Placebo | 3.153 |
| Tio R1.25 | 3.436 |
| Tio R2.5 | 3.472 |
| Tio R5 | 3.488 |
| Tio HH18 | 3.483 |
Means are adjusted for period, planned time, period*planned time, patient*planned time and patient*treatment*planned time. (NCT01222533)
Timeframe: 4 weeks
| Intervention | Liter (Mean) | |||||||
|---|---|---|---|---|---|---|---|---|
| Timepoint 0:00 (trough) | Timepoint 0:30 | Timepoint 1:00 | Timepoint 2:00 | Timepoint 3:00 | Timepoint 4:00 | Timepoint 5:00 | Timepoint 6:00 | |
| Placebo | 1.349 | 1.366 | 1.371 | 1.375 | 1.375 | 1.374 | 1.394 | 1.375 |
| Tio HH18 | 1.477 | 1.554 | 1.571 | 1.571 | 1.580 | 1.582 | 1.588 | 1.570 |
| Tio R1.25 | 1.436 | 1.501 | 1.529 | 1.543 | 1.556 | 1.557 | 1.562 | 1.536 |
| Tio R2.5 | 1.450 | 1.522 | 1.552 | 1.573 | 1.582 | 1.575 | 1.571 | 1.551 |
| Tio R5 | 1.470 | 1.541 | 1.560 | 1.572 | 1.584 | 1.578 | 1.579 | 1.558 |
Defined as the pre-dose FVC measured just prior to the last administration of the morning dose of the randomised treatment. Means are adjusted for sequence, patients within sequences, period and treatment. (NCT01222533)
Timeframe: 4 weeks
| Intervention | Liter (Mean) |
|---|---|
| Placebo | 3.116 |
| Tio R1.25 | 3.254 |
| Tio R2.5 | 3.304 |
| Tio R5 | 3.352 |
| Tio HH18 | 3.351 |
AUC0-6h,ss is the area under the concentration time curve of tiotropium in plasma over the time interval 0 to 6 hours post-dose at steady-state. AUC0-6h,ss was calculated using the linear up/log down algorithm. (NCT01222533)
Timeframe: Based on blood sampling for PK assessments done at 4 weeks at the following time points: 5 minutes (min) before study drug (baseline) and at 2 min , 5 min, 7 min, 9 min, 12 min, 15 min, 20 min, 30 min, 40 min, 1 hour (h), 2 h, 4 h and 6 h post dosing.
| Intervention | pg*h/ml (Geometric Mean) |
|---|---|
| Tio R1.25 | 10.0 |
| Tio R2.5 | 12.8 |
| Tio R5 | 22.1 |
| Tio HH18 | 28.4 |
FEV1 AUC0-3h calculated from zero time to 3 hours using the trapezoidal rule divided by 3 hours. Trough FEV1 will be assigned to zero time. Means are adjusted for sequence, patients within sequences, period and treatment. (NCT01222533)
Timeframe: 4 weeks
| Intervention | Liter (Mean) |
|---|---|
| Placebo | 1.366 |
| Tio R1.25 | 1.521 |
| Tio R2.5 | 1.546 |
| Tio R5 | 1.553 |
| Tio HH18 | 1.558 |
"The outcome measure describes the number of patients with a Supraventricular Premature Beat (SVPB) pair evaluated over the entire 6.5 h Holter monitoring period. Pairs were defined as 2 consecutive premature beats in a row. The arrhythmia variables were pre-specified for day 29 and analysed post-hoc for day 26. The lines Day 29 1st h and Day 26 1st h are related to the interval 0 h to 1 h, i.e. the first hour after dosing." (NCT01222533)
Timeframe: 6.5 hours (including pre dose)
| Intervention | participants (Number) | |||
|---|---|---|---|---|
| Day 29 6.5 h | Day 29 1st h | Day 26 6.5 h | Day 26 1st h | |
| Placebo | 48 | 17 | 41 | 18 |
| Tio HH18 | 53 | 16 | 45 | 13 |
| Tio R1.25 | 52 | 20 | 46 | 13 |
| Tio R2.5 | 55 | 19 | 29 | 10 |
| Tio R5 | 49 | 20 | 42 | 14 |
Cmin,ss is the minimum measured concentration of tiotropium in plasma at steady-state. (NCT01222533)
Timeframe: Based on blood sampling for PK assessments done at 4 weeks at the following time points: 5 min before first dosing of study drug (baseline) and at 2 min , 5 min, 7 min, 9 min, 12 min, 15 min, 20 min, 30 min, 40 min, 1 h, 2 h, 4 h and 6 h post dosing.
| Intervention | pg/mL (Geometric Mean) |
|---|---|
| Tio R1.25 | 1.16 |
| Tio R2.5 | 1.25 |
| Tio R5 | 1.57 |
| Tio HH18 | 1.76 |
Cpre,ss is the measured concentration of tiotropium in plasma before dosing at steady-state. (NCT01222533)
Timeframe: Based on blood sampling for PK assessments done at 4 weeks at the following time point: 5 minutes (min) before first dosing of study drug (baseline)
| Intervention | pg/mL (Geometric Mean) |
|---|---|
| Tio R1.25 | 1.57 |
| Tio R2.5 | 1.39 |
| Tio R5 | 1.60 |
| Tio HH18 | 1.71 |
Renal clearance of the drug over the time interval 0 to 6 hours at steady-state. CL R,0-6h,ss was calculated as the quotient of Ae0-6h,ss and AUC0-6h,ss. (NCT01222533)
Timeframe: Based on blood and urine sampling for PK assessments done at 4 weeks over 6 h post dosing.
| Intervention | mL/min (Geometric Mean) |
|---|---|
| Tio R1.25 | 256 |
| Tio R2.5 | 277 |
| Tio R5 | 307 |
| Tio HH18 | 310 |
MMRM results. Response was defined as change from baseline at the end of each 4-week treatment period. Means are adjusted for treatment, period, patient and study baseline. Trough FVC was measured just prior to the last administration of randomised treatment. (NCT01233284)
Timeframe: Baseline and 4 weeks
| Intervention | Litre (Mean) |
|---|---|
| Placebo | 0.004 |
| Tio R1.25 qd | 0.058 |
| Tio R2.5 qd | 0.076 |
| Tio R5 qd | 0.102 |
MMRM results. Response was defined as change from baseline at the end of of each 4-week treatment period. Means are adjusted for treatment, period, patient and study baseline. Trough FEV1 was measured just prior to the last administration of randomised treatment. (NCT01233284)
Timeframe: Baseline and 4 weeks
| Intervention | Litre (Mean) |
|---|---|
| Placebo | 0.006 |
| Tio R1.25 qd | 0.131 |
| Tio R2.5 qd | 0.138 |
| Tio R5 qd | 0.149 |
MMRM results. Response was defined as change from baseline at the end of each 4-week treatment period. Means are adjusted for treatment, period, patient and study baseline. FVC AUC0-3h was calculated using the trapezoidal rule divided by the observation time (3 hours) to report in litres. (NCT01233284)
Timeframe: 10 minutes (min) before drug administration and 30 min, 1h, 2h, 3h after drug administration
| Intervention | Litre (Mean) |
|---|---|
| Placebo | -0.028 |
| Tio R1.25 qd | 0.036 |
| Tio R2.5 qd | 0.047 |
| Tio R5 qd | 0.110 |
MMRM results. Response was defined as change from baseline at the end of of each 4-week treatment period. Means are adjusted for treatment, period, patient and study baseline. FEV1 AUC0-3h was calculated using the trapezoidal rule divided by the observation time (3 hours) to report in litres. (NCT01233284)
Timeframe: 10 minutes (min) before drug administration and 30 min, 1h, 2h, 3h after drug administration
| Intervention | Litre (Mean) |
|---|---|
| Placebo | 0.025 |
| Tio R1.25 qd | 0.154 |
| Tio R2.5 qd | 0.152 |
| Tio R5 qd | 0.203 |
Mixed model repeated measurement (MMRM) results. Response was defined as change from baseline at the end of of each 4-week treatment period. Means are adjusted for treatment, period, patient and study baseline. (NCT01233284)
Timeframe: 10 minutes (min) before drug administration and 30 min, 1h, 2h, 3h after drug administration
| Intervention | Litre (Mean) |
|---|---|
| Placebo | 0.116 |
| Tio R1.25 qd | 0.255 |
| Tio R2.5 qd | 0.244 |
| Tio R5 qd | 0.304 |
MMRM results. Response was defined as change from baseline at the end of of each 4-week treatment period. Means are adjusted for treatment, period, patient and study baseline. (NCT01233284)
Timeframe: 10 minutes (min) before drug administration and 30 min, 1h, 2h, 3h after drug administration
| Intervention | Litre (Mean) |
|---|---|
| Placebo | 0.092 |
| Tio R1.25 qd | 0.171 |
| Tio R2.5 qd | 0.163 |
| Tio R5 qd | 0.229 |
MMRM results. Response was defined as change from baseline at the end of each 4-week treatment period. Means are adjusted for treatment, period, patient and study baseline. Weekly means obtained during the last week of each period of randomised treatment will be compared (measured by patients at home using the AM2+ device). (NCT01233284)
Timeframe: Baseline and 4 weeks
| Intervention | Night awakenings (Mean) |
|---|---|
| Placebo | -0.156 |
| Tio R1.25 qd | -0.166 |
| Tio R2.5 qd | -0.162 |
| Tio R5 qd | -0.187 |
MMRM results. Response was defined as change from baseline at the end of each 4-week treatment period. Means are adjusted for treatment, period, patient and study baseline. Weekly means obtained during the last week of each period of randomised treatment will be compared (measured by patients at home using the AM2+ device). (NCT01233284)
Timeframe: Baseline and 4 weeks
| Intervention | Puffs (Mean) |
|---|---|
| Placebo | -0.314 |
| Tio R1.25 qd | -0.463 |
| Tio R2.5 qd | -0.452 |
| Tio R5 qd | -0.425 |
MMRM results. Response was defined as change from baseline at the end of each 4-week treatment period. Means are adjusted for treatment, period, patient and study baseline. (NCT01233284)
Timeframe: Baseline and 4 weeks
| Intervention | Litre (Mean) | ||||
|---|---|---|---|---|---|
| Timepoint -0:10 | Timepoint 0:30 | Timepoint 1:00 | Timepoint 2:00 | Timepoint 3:00 | |
| Placebo | 0.006 | 0.029 | 0.026 | 0.033 | 0.013 |
| Tio R1.25 qd | 0.131 | 0.160 | 0.148 | 0.158 | 0.160 |
| Tio R2.5 qd | 0.138 | 0.163 | 0.156 | 0.149 | 0.148 |
| Tio R5 qd | 0.149 | 0.209 | 0.205 | 0.218 | 0.191 |
MMRM results. Response was defined as change from baseline at the end of each 4-week treatment period. Means are adjusted for treatment, period, patient and study baseline. (NCT01233284)
Timeframe: Baseline and 4 weeks
| Intervention | Litre (Mean) | ||||
|---|---|---|---|---|---|
| Timepoint -0:10 | Timepoint 0:30 | Timepoint 1:00 | Timepoint 2:00 | Timepoint 3:00 | |
| Placebo | 0.004 | -0.028 | -0.031 | -0.022 | -0.050 |
| Tio R1.25 qd | 0.058 | 0.042 | 0.024 | 0.037 | 0.036 |
| Tio R2.5 qd | 0.076 | 0.060 | 0.041 | 0.045 | 0.033 |
| Tio R5 qd | 0.102 | 0.124 | 0.112 | 0.119 | 0.078 |
MMRM results. Response was defined as change from baseline at the end of each 4-week treatment period. Means are adjusted for treatment, period, patient and study baseline. (NCT01233284)
Timeframe: Baseline and 4 weeks
| Intervention | Litre/min (Mean) | ||||
|---|---|---|---|---|---|
| Timepoint -0:10 | Timepoint 0:30 | Timepoint 1:00 | Timepoint 2:00 | Timepoint 3:00 | |
| Placebo | 11.038 | 8.235 | 6.095 | 7.237 | 5.046 |
| Tio R1.25 qd | 30.567 | 32.163 | 34.070 | 34.544 | 34.620 |
| Tio R2.5 qd | 33.903 | 37.149 | 36.851 | 36.972 | 37.283 |
| Tio R5 qd | 34.787 | 39.325 | 41.260 | 42.694 | 40.624 |
MMRM results. Response was defined as change from baseline at the end of each 4-week treatment period. Means are adjusted for treatment, period, patient and study baseline. Weekly means obtained during the last week of each period of randomised treatment will be compared (measured by patients at home using the AM2+ device). (NCT01233284)
Timeframe: Baseline and 4 weeks
| Intervention | Puffs (Mean) |
|---|---|
| Placebo | -0.273 |
| Tio R1.25 qd | -0.357 |
| Tio R2.5 qd | -0.341 |
| Tio R5 qd | -0.360 |
MMRM results. Response was defined as change from baseline at the end of of each 4-week treatment period. Means are adjusted for treatment, period, patient and study baseline. FVC AUC0-12, FVC AUC12-24 and FVC AUC0-24 were calculated using the trapezoidal rule divided by the observation time (12h resp. 24h) to report in litres. (NCT01233284)
Timeframe: 10 minutes (min) before drug administration and 30 min, 1h, 2h, 3h, 4h, 11h 50min, 12h 30min, 13h, 14h, 15h, 16h, 18h, 20h, 22h, 23h, 23h 50min after drug administration
| Intervention | Litres (Mean) | ||
|---|---|---|---|
| FVC AUC0-12h | FVC AUC12-24h | FVC AUC0-24h | |
| Placebo | -0.052 | -0.021 | -0.036 |
| Tio R1.25 qd | 0.064 | 0.046 | 0.055 |
| Tio R2.5 qd | 0.157 | 0.177 | 0.167 |
| Tio R5 qd | 0.115 | 0.160 | 0.137 |
MMRM results. Response was defined as change from baseline at the end of each 4-week treatment period. Means are adjusted for treatment, period, patient and study baseline. Weekly means obtained during the last week of each period of randomised treatment will be compared (measured by patients at home using the AM2+ device). (NCT01233284)
Timeframe: Baseline and 4 weeks
| Intervention | Litre/min (Mean) |
|---|---|
| Placebo | 3.833 |
| Tio R1.25 qd | 25.084 |
| Tio R2.5 qd | 18.410 |
| Tio R5 qd | 25.414 |
MMRM results. Response was defined as change from baseline at the end of each 4-week treatment period. Means are adjusted for treatment, period, patient and study baseline. Weekly means obtained during the last week of each period of randomised treatment will be compared (measured by patients at home using the AM2+ device). (NCT01233284)
Timeframe: Baseline and 4 weeks
| Intervention | Litre/min (Mean) |
|---|---|
| Placebo | 4.395 |
| Tio R1.25 qd | 22.944 |
| Tio R2.5 qd | 22.290 |
| Tio R5 qd | 25.241 |
MMRM results. Response was defined as change from baseline at the end of each 4-week treatment period. Means are adjusted for treatment, period, patient and study baseline. PEF variability is the absolute difference between morning and evening PEF value divided by the mean of these two values, expressed as a percent . Weekly means obtained during the last week of each period of randomised treatment will be compared. (NCT01233284)
Timeframe: Baseline and 4 weeks
| Intervention | Percentage of the mean daily PEF (Mean) |
|---|---|
| Placebo | -0.171 |
| Tio R1.25 qd | -0.285 |
| Tio R2.5 qd | -0.711 |
| Tio R5 qd | -0.248 |
MMRM results. Response was defined as change from baseline at the end of of each 4-week treatment period. Means are adjusted for treatment, period, patient and study baseline. FEV1 AUC0-12, FEV1 AUC12-24 and FEV1 AUC0-24 were calculated using the trapezoidal rule divided by the observation time (12h resp. 24h) to report in litres. (NCT01233284)
Timeframe: 10 minutes (min) before drug administration and 30 min, 1h, 2h, 3h, 4h, 11h 50min, 12h 30min, 13h, 14h, 15h, 16h, 18h, 20h, 22h, 23h, 23h 50min after drug administration
| Intervention | Litres (Mean) | ||
|---|---|---|---|
| FEV1 AUC0-12h | FEV1 AUC12-24h | FEV1 AUC0-24h | |
| Placebo | -0.013 | 0.012 | -0.001 |
| Tio R1.25 qd | 0.105 | 0.093 | 0.099 |
| Tio R2.5 qd | 0.134 | 0.148 | 0.141 |
| Tio R5 qd | 0.128 | 0.208 | 0.168 |
MMRM results. Response was defined as change from baseline at the end of each 4-week treatment period. Means are adjusted for treatment, period, patient and study baseline. Weekly means obtained during the last week of each period of randomised treatment will be compared (measured by patients at home using the AM2+ device). (NCT01233284)
Timeframe: Baseline and 4 weeks
| Intervention | Puffs (Mean) |
|---|---|
| Placebo | -0.569 |
| Tio R1.25 qd | -0.802 |
| Tio R2.5 qd | -0.783 |
| Tio R5 qd | -0.769 |
"Change from baseline of area under the curve (AUC) from 0 to 3 h for FEV1 (FEV1 AUC 0-3h) after 24 weeks of treatment. The AUC was calculated by using the trapezoidal rule divided by the observation time (3h).~The measured values presented are actually adjusted means." (NCT01257230)
Timeframe: Baseline and 10 mins before drug administration and 30 mins, 1 hour (h), 2h, 3h after drug administration at 24 weeks
| Intervention | Litres (Mean) |
|---|---|
| Placebo Respimat | 0.281 |
| Tio R2.5 | 0.411 |
| Tio R5 | 0.463 |
"Change from baseline in Maximum forced vital capacity (FVC) measured within the first 3 h after administration of trial medication (FVC peak0-3h) after 24 weeks of treatment.~The measured values presented are actually adjusted means." (NCT01257230)
Timeframe: Baseline and 24 weeks
| Intervention | Litres (Mean) |
|---|---|
| Placebo Respimat | 0.331 |
| Tio R2.5 | 0.419 |
| Tio R5 | 0.403 |
The median time to first asthma exacerbation was not calculable, so the number of patients who experienced an asthma exacerbation are presented for the measured values. (NCT01257230)
Timeframe: Week 48
| Intervention | Participants (Number) |
|---|---|
| Placebo Respimat | 37 |
| Tio R2.5 | 34 |
| Tio R5 | 30 |
"Change from baseline in the number of puffs of rescue medication (salbutamol/albuterol) used during the night-time based on the weekly mean at week 24.~The measured values presented are actually adjusted means." (NCT01257230)
Timeframe: Baseline and week 24
| Intervention | Number of puffs of rescue medication (Mean) |
|---|---|
| Placebo Respimat | -0.144 |
| Tio R2.5 | -0.122 |
| Tio R5 | -0.032 |
The median time to first severe asthma exacerbation was not calculable, so the number of patients who experienced a severe asthma exacerbation are presented for the measured values. A severe asthma exacerbation was defined as a subgroup of all asthma exacerbations that required treatment with systemic corticosteroid for at least 3 days. (NCT01257230)
Timeframe: 48 weeks
| Intervention | Participants (Number) |
|---|---|
| Placebo Respimat | 9 |
| Tio R2.5 | 5 |
| Tio R5 | 2 |
"Change from baseline in Trough (pre-dose) Forced expiratory volume in 1 second (FEV1) measured at week 24.~The measured values presented are actually adjusted means." (NCT01257230)
Timeframe: Baseline and 24 weeks
| Intervention | Litres (Mean) |
|---|---|
| Placebo Respimat | 0.283 |
| Tio R2.5 | 0.367 |
| Tio R5 | 0.400 |
"Change from baseline of Trough (pre-dose) forced vital capacity (FVC) measured 10 min before the administration of trial medication after 24 weeks of treatment.~The measured values presented are actually adjusted means.." (NCT01257230)
Timeframe: Baseline and 24 weeks
| Intervention | Litres (Mean) |
|---|---|
| Placebo Respimat | 0.281 |
| Tio R2.5 | 0.345 |
| Tio R5 | 0.316 |
"Change from baseline in the number of puffs of rescue medication (salbutamol/albuterol) used during the day (24 hour period) based on the weekly mean at week 24.~The measured values presented are actually adjusted means." (NCT01257230)
Timeframe: Baseline and week 24
| Intervention | Number of puffs of rescue medication (Mean) |
|---|---|
| Placebo Respimat | -0.524 |
| Tio R2.5 | -0.556 |
| Tio R5 | -0.480 |
"Change from baseline in peak Forced expiratory volume in 1 second within the first 3 hours post dosing (FEV1 peak0-3) measured at week 24.~Note, the measured values presented are actually adjusted means." (NCT01257230)
Timeframe: Baseline and 24 weeks
| Intervention | Litres (Mean) |
|---|---|
| Placebo Respimat | 0.373 |
| Tio R2.5 | 0.507 |
| Tio R5 | 0.547 |
"Change from baseline in the number of puffs of rescue medication (salbutamol/albuterol) used during the daytime based on the weekly mean at week 24.~The measured values presented are actually adjusted means." (NCT01257230)
Timeframe: Baseline and Week 24
| Intervention | Number of puffs of rescue medication (Mean) |
|---|---|
| Placebo Respimat | -0.206 |
| Tio R2.5 | -0.209 |
| Tio R5 | -0.215 |
"Responder rates based on the ACQ total score after 24 weeks of treatment. Analysis was performed using the following categories and definitions: responder (change from trial baseline ≤-0.5), no change (-0.5
Timeframe: Week 24
| Intervention | percentage of participants (Number) | ||
|---|---|---|---|
| Responder | No change | Worsening | |
| Placebo Respimat | 66.7 | 27.5 | 5.8 |
| Tio R2.5 | 76.0 | 21.6 | 2.4 |
| Tio R5 | 74.6 | 23.1 | 2.2 |
"Responder rates based on the ACQ6 after 24 weeks of treatment. Analysis was performed using the following categories and definitions: responder (change from trial baseline ≤-0.5), no change (-0.5
Timeframe: Week 24
| Intervention | percentage of participants (Number) | ||
|---|---|---|---|
| Responder | No change | Worsening | |
| Placebo Respimat | 69.6 | 22.5 | 8.0 |
| Tio R2.5 | 76.8 | 20.0 | 3.2 |
| Tio R5 | 72.4 | 23.1 | 4.5 |
"Change from baseline in mean forced expiratory flow between 25% and 75% of the FVC (FEF25-75%), also known as maximum mid-expiratory flow, at individual time points after 24 weeks of treatment.~The measured values presented are actually adjusted means." (NCT01257230)
Timeframe: Baseline and 10 mins before drug administration and 30 mins, 1 hour (h), 2h, 3h after drug administration at 24 weeks
| Intervention | Litres per second (Mean) | ||||
|---|---|---|---|---|---|
| 10 minutes pre-dose (n=137, 119, 131) | 30 minutes post-dose | 1 hour post-dose | 2 hours post-dose | 3 hours post-dose | |
| Placebo Respimat | 0.332 | 0.372 | 0.359 | 0.403 | 0.347 |
| Tio R2.5 | 0.461 | 0.536 | 0.596 | 0.615 | 0.653 |
| Tio R5 | 0.609 | 0.763 | 0.835 | 0.857 | 0.850 |
"Change from baseline of area under the curve (AUC) from 0 to 3 h for FVC (FVC AUC0-3h) after 24 weeks of treatment. The AUC was calculated by using the trapezoidal rule divided by the observation time (3h).~The measured values presented are actually adjusted means." (NCT01257230)
Timeframe: Baseline and 10 mins before drug administration and 30 mins, 1 hour (h), 2h, 3h after drug administration at 24 weeks
| Intervention | Litres (Mean) |
|---|---|
| Placebo Respimat | 0.240 |
| Tio R2.5 | 0.330 |
| Tio R5 | 0.311 |
"Change from baseline in Asthma Control Questionnaire (ACQ) total score measured at week 24.~The ACQ is a scale containing 7 questions, each question has a 7-point scale which ranges from 0 to 6; a score of 0 corresponds to no impairment and a score of 6 corresponds to maximum impairment. ACQ total score was calculated as the mean of the responses to all 7 questions.~The measured values presented are actually adjusted means." (NCT01257230)
Timeframe: Baseline and week 24
| Intervention | Units on a scale (Mean) |
|---|---|
| Placebo Respimat | 1.213 |
| Tio R2.5 | 1.053 |
| Tio R5 | 1.116 |
"Change from baseline in AQC6 score at week 24.~The ACQ6 score is calculated as the mean of the responses to the first 6 questions of the ACQ. The ACQ is a scale containing 7 questions, each question has a 7-point scale which ranges from 0 to 6; a score of 0 corresponds to no impairment and a score of 6 corresponds to maximum impairment.~The measured values presented are actually adjusted means." (NCT01257230)
Timeframe: Baseline and week 24
| Intervention | units on a scale (Mean) |
|---|---|
| Placebo Respimat | 1.173 |
| Tio R2.5 | 1.026 |
| Tio R5 | 1.119 |
"Responder rates based on the ACQ6 score after 12 weeks of treatment. Analysis was performed using the following categories and definitions: responder (change from trial baseline <= -0.5), no change (-0.5 < change from trial baseline <0.5) and worsening (change from trial baseline >= 0.5).~The ACQ is a scale containing 7 questions, each question has a 7- point scale which ranges from 0 to 6; a score of 0 corresponds to no impairment and a score of 6 corresponds to maximum impairment. ACQ6 is calculated as the mean of the responses to the first 6 questions of the ACQ6.~No statistical testing was performed on ACQ6 responders." (NCT01277523)
Timeframe: 12 weeks
| Intervention | percentage of participants (Number) | ||
|---|---|---|---|
| Responder | No Change | Worsening | |
| Placebo Respimat | 74.1 | 23.7 | 2.2 |
| Tio R2.5 | 74.0 | 19.7 | 6.3 |
| Tio R5 | 74.6 | 23.1 | 2.3 |
Clinically relevant abnormalities for physical examination, ECG, vital signs and laboratory tests. New abnormal findings or worsening of baseline conditions were reported as adverse events. (NCT01277523)
Timeframe: From first drug administration until 30 days after last drug intake, up to 142 days
| Intervention | percentage of participants (Number) | |
|---|---|---|
| Peak expiratory flow rate decreased | Blood glucose decreased | |
| Placebo Respimat | 9.6 | 0.0 |
| Tio R2.5 | 7.1 | 0.8 |
| Tio R5 | 3.8 | 0.0 |
"Responder rates based on the ACQ total score after 12 weeks of treatment. Analysis was performed using the following categories and definitions: responder (change from trial baseline ≤-0.5), no change (-0.5
Timeframe: 12 weeks
| Intervention | percentage of participants (Number) | ||
|---|---|---|---|
| Responder | No Change | Worsening | |
| Placebo Respimat | 73.3 | 23.7 | 3.0 |
| Tio R2.5 | 74.8 | 22.0 | 3.1 |
| Tio R5 | 73.1 | 26.2 | 0.8 |
"Change from baseline in the number of puffs of rescue medication (salbutamol/albuterol) used during the night-time based on the weekly mean at week 12.~Measured values presented are actually adjusted means" (NCT01277523)
Timeframe: Baseline and 12 weeks
| Intervention | Number of puffs of rescue medication (Mean) |
|---|---|
| Placebo Respimat | -0.180 |
| Tio R2.5 | -0.092 |
| Tio R5 | -0.159 |
"Change from baseline in the number of puffs of rescue medication (salbutamol/albuterol) used during the daytime based on the weekly mean at week 12.~Measured values presented are actually adjusted means." (NCT01277523)
Timeframe: Baseline and 12 weeks
| Intervention | Number of puffs of rescue medication (Mean) |
|---|---|
| Placebo Respimat | -0.262 |
| Tio R2.5 | -0.295 |
| Tio R5 | -0.312 |
"Change from baseline in the number of puffs of rescue medication (salbutamol/albuterol) used during the day (24 hour period) based on the weekly mean at week 12.~The measured values presented are actually adjusted means." (NCT01277523)
Timeframe: Baseline and 12 weeks
| Intervention | Number of puffs of rescue medication (Mean) |
|---|---|
| Placebo Respimat | -0.482 |
| Tio R2.5 | -0.483 |
| Tio R5 | -0.540 |
"Change from baseline in Trough (pre-dose) Forced expiratory volume in 1 second (FEV1) measured at week 12.~Measured values presented are actually adjusted means." (NCT01277523)
Timeframe: Baseline and 12 weeks
| Intervention | litres (Mean) |
|---|---|
| Placebo Respimat | 0.230 |
| Tio R2.5 | 0.345 |
| Tio R5 | 0.284 |
"Time in days to first severe asthma exacerbation during the 12 week treatment period. The median time to first severe asthma exacerbation was not calculable, so the number of patients who experienced a severe asthma exacerbation are presented for the measured values.~A severe asthma exacerbation was defined as a subgroup of all asthma exacerbations that required an initiation of treatment with systemic corticosteroids for at least 3 days or, in case of ongoing and pre-existing systemic corticosteroid therapy, requiring at least doubling of previous daily doses of systemic corticosteroids for at least 3 days." (NCT01277523)
Timeframe: 12 weeks
| Intervention | participants (Number) |
|---|---|
| Placebo Respimat | 1 |
| Tio R2.5 | 1 |
| Tio R5 | 2 |
"Change from baseline in Maximum forced vital capacity (FVC) measured within the first 3 hours after administration of trial medication (FVC peak0-3h) after 12 weeks of treatment.~The measured values presented are actually adjusted means." (NCT01277523)
Timeframe: Baseline and 12 weeks
| Intervention | Litres (Mean) |
|---|---|
| Placebo Respimat | 0.279 |
| Tio R2.5 | 0.370 |
| Tio R5 | 0.342 |
"Change from baseline of area under the curve (AUC) from 0 to 3 hours for FVC (Forced vital capacity) (FVC AUC0-3h) after 12 weeks of treatment. The AUC was calculated by using the trapezoidal rule divided by the observation time (3h).~Measured values presented are actually adjusted means." (NCT01277523)
Timeframe: Baseline and 10 mins before drug administration and 30 mins, 1 hour (h), 2h, 3h after drug administration at 12 weeks
| Intervention | litres (Mean) |
|---|---|
| Placebo Respimat | 0.175 |
| Tio R2.5 | 0.262 |
| Tio R5 | 0.227 |
"Change from baseline in peak forced expiratory volume in 1 second within the first 3 hours post dosing (FEV1 peak0-3) measured at week 12.~Measured values presented are actually adjusted means." (NCT01277523)
Timeframe: Baseline and 12 weeks
| Intervention | litres (Mean) |
|---|---|
| Placebo Respimat | 0.438 |
| Tio R2.5 | 0.550 |
| Tio R5 | 0.528 |
"Change from baseline of area under the curve (AUC) from 0 to 3 hours for FEV1 (FEV1 AUC 0-3h) after 12 weeks of treatment. The AUC was calculated by using the trapezoidal rule divided by the observation time (3h).~Measured values presented are actually adjusted means." (NCT01277523)
Timeframe: Baseline and 10 mins before drug administration and 30 mins, 1 hour (h), 2h, 3h after drug administration at 12 weeks
| Intervention | Litres (Mean) |
|---|---|
| Placebo Respimat | 0.336 |
| Tio R2.5 | 0.449 |
| Tio R5 | 0.423 |
"Change from baseline in Asthma Control Questionnaire (ACQ) 6 score measured at week 12~The ACQ is a scale containing 7 questions, each question has a 7 point scale which ranges from 0 to 6. A score of 0 corresponds to no impairment and a score of 6 corresponds to maximum impairment. ACQ6 score is calculated as the mean of the responses to the first 6 questions of the ACQ6.~The measured values presented are actually adjusted means." (NCT01277523)
Timeframe: Baseline and 12 weeks
| Intervention | units on a scale (Mean) |
|---|---|
| Placebo Respimat | 1.144 |
| Tio R2.5 | 1.262 |
| Tio R5 | 1.197 |
"Change from baseline in Asthma Control Questionnaire (ACQ) total score measured at week 12.~The ACQ is a scale containing 7 questions. Each question has a 7 point scale which ranges from 0 to 6. A score of 0 corresponds to no impairment and a score of 6 corresponds to maximum impairment. ACQ total score is calculated as the mean of the responses to all 7 questions.~The measured values presented are actually adjusted means." (NCT01277523)
Timeframe: Baseline and 12 weeks
| Intervention | units on a scale (Mean) |
|---|---|
| Placebo Respimat | 1.234 |
| Tio R2.5 | 1.292 |
| Tio R5 | 1.270 |
Time in days to first asthma exacerbation during the 12 week treatment period. The median time to first asthma exacerbation was not calculable, so the number of patients who experienced an asthma exacerbation are presented for the measured values. (NCT01277523)
Timeframe: 12 weeks
| Intervention | participants (Number) |
|---|---|
| Placebo Respimat | 25 |
| Tio R2.5 | 18 |
| Tio R5 | 15 |
Pre-dose FVC is defined as the average of the measurements at 45 and 15 min pre-dose. Baseline is defined as the pre-dose FVC value on Day 1 (Week 1). (NCT01285492)
Timeframe: Weeks 3, 6, 12, 24, 36, 52
| Intervention | Litres (Mean) | |||||
|---|---|---|---|---|---|---|
| Week 3 (117, 38) | Week 6 (115, 38) | Week 12 (113, 38) | Week 24 (113, 37) | Week 36 (105, 37) | Week 52 (104, 37) | |
| QVA149 | 0.314 | 0.310 | 0.335 | 0.330 | 0.264 | 0.261 |
| Tiotropium | 0.213 | 0.173 | 0.279 | 0.206 | 0.167 | 0.112 |
Pre-dose FEV1 is defined as the average of the measurements at 45 and 15 min pre-dose. Baseline is defined as the pre-dose FEV1 value on Day 1 (Week 1). (NCT01285492)
Timeframe: Weeks 3, 6, 12, 24, 36, 52
| Intervention | Litres (Mean) | |||||
|---|---|---|---|---|---|---|
| Week 3 (117, 38) | Week 6 (115, 38) | Week 12 (113, 38) | Week 24 (113, 37) | Week 36 (105, 37) | Week 52 (104, 37) | |
| QVA149 | 0.206 | 0.202 | 0.209 | 0.198 | 0.182 | 0.189 |
| Tiotropium | 0.093 | 0.083 | 0.139 | 0.115 | 0.082 | 0.052 |
Clinically notable vital sign values were: pulse rate - low, <40 bpm or <=50 bpm and decrease from baseline >=15bpm; pulse rate high, >130 bpm or >=120bpm and increase from baseline >=15 bpm. Systolic blood pressure - low, <75 mmHg or <=90 mmHg and decrease from baseline >=20 mmHg; high, >200 mmHg or >=180 mmHg and increase from baseline >=20 mmHg. Diastolic blood pressure - low, <40 mmHg or <=50 mmHg and decrease from baseline >=15 mmHg; high, >115 mmHg or >=105 mmHg and increase from baseline >=15 mmHg. (NCT01285492)
Timeframe: 52 weeks
| Intervention | Participants (Number) | ||||||||
|---|---|---|---|---|---|---|---|---|---|
| Pulse rate: low | Pulse rate: high | Pulse rate: low or high | Systolic blood pressure - low | Systolic blood pressure - high | Systolic blood pressure - low or high | Diastolic blood pressure - low | Diastolic blood pressure - high | Diastolic blood pressure - low or high | |
| QVA149 | 0 | 0 | 0 | 4 | 0 | 4 | 3 | 2 | 5 |
| Tiotropium | 0 | 0 | 0 | 0 | 1 | 1 | 0 | 1 | 1 |
Clinically notable hematology values were: hemoglobin - male <11.5g/dL, female <9.5 g/dL; hematocrit - male <37%, female <32%; white cell count - <2800µL or >16000µL; platelets - <7.5 10*4/µL or >70.0 10*4/µL (NCT01285492)
Timeframe: 52 weeks
| Intervention | Participants (Number) | |||||||
|---|---|---|---|---|---|---|---|---|
| Hemoglobin: male (n = 113, 36) | Hemoglobin: female (n = 5, 2) | Hematocrit: male (n = 113, 36) | Hematocrit: female (n = 5, 2) | White Cell Count < 2800 (n = 118, 38) | White Cell Count > 2800 (n = 118, 38) | Platelets < 7.5 (n = 118, 38) | Platelets > 70.0 (n = 118, 38) | |
| QVA149 | 3 | 0 | 6 | 0 | 0 | 0 | 0 | 0 |
| Tiotropium | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 |
Clinically notable change from baseline was an increase from baseline of 30 or greater milliseconds (ms). (NCT01285492)
Timeframe: 52 weeks
| Intervention | Participants (Number) | |||
|---|---|---|---|---|
| Males: QTc > 450 ms (n = 111, 36) | Females: QTc > 470 ms (n = 5, 2) | Increase from baseline 30 to 60 ms (n = 116, 38) | Increase from baseline > 60 ms (n = 116, 38) | |
| QVA149 | 6 | 0 | 12 | 1 |
| Tiotropium | 0 | 0 | 3 | 0 |
Clinically notable biochemistry values were: total protein - <4.0 g/dL or >9.5 g/dL; albumin <2.5 g/dL; bilirubin (total) >1.9 mg/dL; BUN >27 mg/dL; creatinine >1.99 mg/dL; AST >3 x ULN U/L; ALT >3 x ULN U/L; ALP >3 x ULN U/L; y-GTP >3 x ULN U/L; sodium <125 mEq/L or >160 mEq/L; potassium <3.0 mEq/L or >6.0 mEq/L; glucose <51.0 mg/dL or >180.0 mg/dL (NCT01285492)
Timeframe: 52 weeks
| Intervention | Participants (Number) | |||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Total protein - <4.0 g/dL (n = 118, 38) | Total protein - > 9.5 g/dL (n = 118, 38) | albumin <2.5 g/dL (n = 118, 38) | bilirubin (total) >1.9 mg/dL (n = 118, 38) | BUN >27 mg/dL (n = 118, 38) | creatinine >1.99 mg/dL (n = 118, 38) | AST >3 x ULN U/L (n = 118, 38) | ALT >3 x ULN U/L (n = 118, 38) | ALP >3 x ULN U/L (n = 118, 38) | y-GTP >3 x ULN (n = 118, 38) | sodium <125 mEq/L (n = 118, 38) | sodium >160 mEq/L (n = 118, 38) | potassium <3.0 mEq/ (n = 118, 38) | potassium >6.0 mEq/ (n = 118, 38) | glucose <51.0 mg/dL (n = 118, 38) | glucose >180.0 mg/dL (n = 118, 38) | |
| QVA149 | 0 | 0 | 0 | 0 | 1 | 0 | 0 | 0 | 0 | 2 | 0 | 0 | 0 | 0 | 0 | 7 |
| Tiotropium | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 2 | 0 | 0 | 0 | 0 | 0 | 3 |
An AE was the appearance or worsening of any undesirable sign, symptom, or medical condition occurring after starting the study drug even if the event was not considered to be related to study drug. Study drug includes the investigational drug under evaluation and the comparator drug or placebo that was given during any phase of the study. Adverse events starting on or after the time of the first inhalation of study drug were classified as a treatment emergent adverse event. (NCT01285492)
Timeframe: 52 weeks
| Intervention | Participants (Number) | ||
|---|---|---|---|
| Adverse Events (AEs) | Serious Advers Events (SAEs) | Death | |
| QVA149 | 101 | 19 | 1 |
| Tiotropium | 28 | 2 | 0 |
"Average Change in Asthma Control Score Per Participant Over 12 Months Using the Asthma Control Questionnaire (ACQ).~The ACQ has six questions regarding symptoms, rescue short-acting β-agonist use and one about FEV1 % predicted. A 7-point scale (0 = no impairment, 6 = maximum impairment) is used for each question and the ACQ score is the mean value of these questions - hence between 0 (totally controlled) and 6 (severely uncontrolled)." (NCT01290874)
Timeframe: from baseline to 12 months
| Intervention | units on a scale (Mean) |
|---|---|
| Tiotropium | -0.70 |
| Salmeterol or Formoterol | -0.66 |
Average Change in Rescue Medication Use Per Participant Over 12 Months. Monthly questionnaires will evaluate the amount of rescue medication subjects have used on average, measured in puffs per day. (NCT01290874)
Timeframe: from baseline to 12 months
| Intervention | units on a scale (Mean) |
|---|---|
| Tiotropium | -0.92 |
| Salmeterol or Formoterol | -0.97 |
We summarize the survival experience using mean number of exacerbations/person-year and compare it using the log-rank test comparing kaplan-meier survival curve. (NCT01290874)
Timeframe: evaluated monthly (on average) via questionnaire for 12 months
| Intervention | event per person-year (Mean) |
|---|---|
| Tiotropium | 0.37 |
| Salmeterol or Formoterol | 0.42 |
Average change in lung function (FEV1) evaluated by spirometry per participant over 12 months (NCT01290874)
Timeframe: from baseline to 12 months
| Intervention | liters (Mean) |
|---|---|
| Tiotropium | -0.018 |
| Salmeterol or Formoterol | 0.003 |
"Average Change in Asthma Symptom Utility Score Per Participant Over 12 Months Using the Asthma Symptom Utility Index (ASUI).~The ASUI is an 11-item preference-based outcome measure used in clinical trials and cost-effectiveness studies for asthma and is designed to assess the frequency and severity of cough, wheeze, dyspnea, nighttime awakenings, and side effects, weighted according to patient preferences.~4-point Likert scale to assess frequency (not at all, 1 to 3 days, 4 to 7 days, and 8 to 14 days) and severity (not applicable, mild, moderate and severe); scores range from 0 (worst possible symptoms) to 1 (no symptoms)." (NCT01290874)
Timeframe: from baseline to 12 months
| Intervention | units on a scale (Mean) |
|---|---|
| Tiotropium | 0.11 |
| Salmeterol or Formoterol | 0.10 |
"Average Change in Asthma Quality of Life Score Per Participant Over 12 Months Using the Asthma Quality of Life Questionnaire (AQLQ).~The AQLQ has 32 questions in four domains (symptoms, activity limitation, emotional function, and environmental stimuli) and measures the functional problems that are troublesome to individuals with asthma. Symptoms (11 items), Activity Limitation (12 items, 5 of which are individualized), Emotional Function (5 items), and Environmental Exposure (4 items); 7-point Likert scale (7 = not impaired at all - 1 = severely impaired); scores range 1-7, with higher scores indicating better quality of life." (NCT01290874)
Timeframe: from baseline to 12 months
| Intervention | units on a scale (Mean) |
|---|---|
| Tiotropium | 1.00 |
| Salmeterol or Formoterol | 1.02 |
"The effect of indacaterol and glycopyrronium bromide (QVA149) compared to placebo was measured using exertional dyspnea Borg CR10 Scale® (After 3 weeks of treatment, before, during and after exercise, patients were asked to rate the intensity of their breathing and leg discomfort using the Borg CR10 Scale®). This scale consists of 12-point score that the participants pointed to so as to indicate their level of dyspnea before and during exercise testing (where 0 indicates no breathlessness at all and 12 indicates maximum breathlessness).~A reduction in this score indicates an improvement." (NCT01294787)
Timeframe: 3 weeks
| Intervention | units on a scale (Least Squares Mean) |
|---|---|
| QVA149 | 3.77 |
| Tiotropium | 3.59 |
| Placebo | 3.87 |
The effect of indacaterol and glycopyrronium bromide (QVA149) compared to placebo was measured by exercise endurance time (in seconds) during a sub-maximal constant load cycle ergometry test ((SMETT)which is a cycle exercise test) after three weeks of treatment. (NCT01294787)
Timeframe: 3 weeks
| Intervention | Seconds (Least Squares Mean) |
|---|---|
| QVA149 | 507.8 |
| Placebo | 448.3 |
The effect of a single dose of indacaterol and glycopyrronium bromide (QVA149) compared to placebo was measured with respect to exercise endurance time during sub-maximal constant load cycle ergometry test ((SMETT)cycle exercise test). (NCT01294787)
Timeframe: Day 1
| Intervention | Seconds (Least Squares Mean) |
|---|---|
| QVA149 | 492.8 |
| Tiotropium | 481.0 |
| Placebo | 468.8 |
Effect of QVA149 110/50 µg o.d. compared with tiotropium 18 µg o.d. in patients with moderate to severe COPD with respect to exercise endurance was measured by a sub-maximal constant load cycle ergometry test ((SMETT)cycle exercise test) after three weeks of treatment. (NCT01294787)
Timeframe: 3 weeks
| Intervention | Seconds (Least Squares Mean) |
|---|---|
| Indacaterol and Glycopyrronium Bromide (QVA149) | 507.8 |
| Tiotropium | 514 |
The effect of indacaterol and glycopyrronium bromide (QVA149) compared to placebo was measured using dynamic inspiratory capacity at isotime during sub-maximal constant load cycle ergometry test ((SMETT)a cycle exercise test), after three weeks of treatment. (NCT01294787)
Timeframe: 3 weeks
| Intervention | Liters (Least Squares Mean) |
|---|---|
| QVA149 | 2.42 |
| Tiotropium | 2.29 |
| Placebo | 2.11 |
The effect of indacaterol and glycopyrronium bromide (QVA149) compared to placebo was measured using trough 24 hour post dose Forced Expiratory Volume in one second (FEV1) after three weeks of treatment. (NCT01294787)
Timeframe: 3 weeks
| Intervention | Liters (Least Squares Mean) |
|---|---|
| QVA149 | 1.53 |
| Tiotropium | 1.43 |
| Placebo | 1.33 |
The effect of indacaterol and glycopyrronium bromide (QVA149) compared to placebo was measured using trough 24 hour post dose inspiratory capacity after three weeks of treatment. (NCT01294787)
Timeframe: 3 weeks
| Intervention | Liters (Least Squares Mean) |
|---|---|
| QVA149 | 2.25 |
| Tiotropium | 2.10 |
| Placebo | 2.06 |
The effect of indacaterol and glycopyrronium bromide (QVA149) compared to placebo was measured using the pulmonary function test for Functional Residual Capacity (FRC) on day 1 and day 21, at 5 min and 15 min post dose as determined by body plethysmography. (NCT01294787)
Timeframe: day 1 and day 21
| Intervention | Liters (Least Squares Mean) | |||
|---|---|---|---|---|
| Day 1- 5 min post-dose | Day 1- 15 min post-dose | Day 21- 5 min post-dose | Day 21- 15 min post-dose | |
| Placebo | 4.98 | 4.92 | 5.00 | 4.91 |
| QVA149 | 4.68 | 4.62 | 4.58 | 4.53 |
| Tiotropium | 4.78 | 4.63 | 4.66 | 4.55 |
The effect of indacaterol and glycopyrronium bromide (QVA149) compared to placebo was measured using dynamic inspiratory capacity post-dose pre-exercise after three weeks of treatment. (NCT01294787)
Timeframe: 3 weeks
| Intervention | Liters (Least Squares Mean) |
|---|---|
| Indacaterol and Glycopyrronium Bromide (QVA149) | 2.34 |
| Tiotropium | 2.19 |
| Placebo | 2.01 |
The effect of indacaterol and glycopyrronium bromide (QVA149) compared to placebo was measured using the pulmonary function test for Residual Volume (RV) on day 1 and day 21, at 5 min and 15 min post dose as determined by body plethysmography. (NCT01294787)
Timeframe: day 1 and day 21
| Intervention | Liters (Least Squares Mean) | |||
|---|---|---|---|---|
| Day 1 - 5 min post-dose | Day 1 - 15 min post-dose | Day 21- 5 min post-dose | Day 21- 15 min post-dose | |
| Placebo | 3.94 | 3.89 | 4.03 | 3.96 |
| QVA149 | 3.66 | 3.63 | 3.58 | 3.54 |
| Tiotropium | 3.89 | 3.66 | 3.69 | 3.59 |
The effect of indacaterol and glycopyrronium bromide (QVA149) compared to placebo was measured using the pulmonary function test for Slow Vital Capacity (SVC) on day 1 and day 21, at 5 min and 15 min post dose as determined by body plethysmography. (NCT01294787)
Timeframe: day 1 and day 21
| Intervention | Liters (Least Squares Mean) | |||
|---|---|---|---|---|
| Day 1- 5 min post-dose | Day 1- 15 min post-dose | Day 21- 5 min post-dose | Day 21- 15 min post-dose | |
| Placebo | 3.14 | 3.16 | 3.08 | 3.09 |
| QVA149 | 3.37 | 3.43 | 3.37 | 3.38 |
| Tiotropium | 3.22 | 3.32 | 3.26 | 3.29 |
The effect of indacaterol and glycopyrronium bromide (QVA149) compared to placebo was measured using the pulmonary function test for Specific Airway Conductance (SGaw) on day 1 and day 21, at 5 min and 15 min post dose as determined by body plethysmography. (NCT01294787)
Timeframe: day 1 and day 21
| Intervention | Kilo Pascal per second (Least Squares Mean) | |||
|---|---|---|---|---|
| Day 1- 5 min post-dose | Day 1- 15 min post-dose | Day 21- 5 min post-dose | Day 21- 15 min post-dose | |
| Placebo | 0.50 | 0.50 | 0.50 | 0.47 |
| QVA149 | 0.71 | 0.71 | 0.76 | 0.79 |
| Tiotropium | 0.58 | 0.79 | 0.64 | 0.67 |
The effect of indacaterol and glycopyrronium bromide (QVA149) compared to placebo on leg discomfort was measured using Borg CR10 Scale® during sub-maximal constant load cycle ergometry test after three weeks treatment. (NCT01294787)
Timeframe: 3 weeks
| Intervention | units on a scale (Least Squares Mean) |
|---|---|
| QVA149 | 4.53 |
| Tiotropium | 4.57 |
| Placebo | 4.43 |
The AUC0-3h was calculated as area under the curve from zero to 3 hours using the trapezoidal rule divided by the observation time (3 hours) to report in litres. The trough value was assigned to zero time. Response was defined as change from baseline in FVC AUC0-3h after a treatment period of 12 weeks. MMRM results. Means are adjusted for treatment, pooled centre, visit, baseline, treatment*visit baseline*visit. (NCT01316380)
Timeframe: Baseline and 12 weeks
| Intervention | Liter (Least Squares Mean) |
|---|---|
| Placebo | -0.000 |
| Tio R2.5 | 0.101 |
| Tio R5 | 0.061 |
The trough FEV1 is defined as the pre-dose FEV1 measured 10 minutes before the last administration of randomised treatment. Trough FEV1 response was defined as the difference between the trough FEV1 measured after a treatment period of 12 weeks and the trough FEV1 baseline measurement. MMRM results. Means are adjusted for treatment, pooled centre, visit, baseline, treatment*visit and baseline*visit. (NCT01316380)
Timeframe: Baseline and 12 weeks
| Intervention | Liter (Least Squares Mean) |
|---|---|
| Placebo | 0.015 |
| Tio R2.5 | 0.125 |
| Tio R5 | 0.137 |
The AUC0-3h was calculated as area under the curve from zero to 3 hours using the trapezoidal rule divided by the observation time (3 hours) to report in litres. The trough value was assigned to zero time. Response was defined as change from baseline in FEV1 AUC0-3h after a treatment period of 12 weeks. MMRM results. Means are adjusted for treatment, pooled centre, visit, baseline, treatment*visit baseline*visit. (NCT01316380)
Timeframe: Baseline and 12 weeks
| Intervention | Liter (Least Squares Mean) |
|---|---|
| Placebo | 0.048 |
| Tio R2.5 | 0.198 |
| Tio R5 | 0.174 |
Peak FVC 0-3h response was defined as the difference between the maximum FVC measured within the first 3 hours post dosing after a treatment period of 12 weeks and the FVC baseline measurement (10 minutes before the first dose of trial medication). Mixed Model Repeated Measure (MMRM) results. Means are adjusted for treatment, pooled centre, visit, baseline, treatment*visit and baseline*visit. (NCT01316380)
Timeframe: Baseline and 12 weeks
| Intervention | Liter (Least Squares Mean) |
|---|---|
| Placebo | 0.126 |
| Tio R2.5 | 0.231 |
| Tio R5 | 0.183 |
Peak FEV1 0-3h response was defined as the difference between the maximum FEV1 measured within the first 3 hours post dosing after a treatment period of 12 weeks and the FEV1 baseline measurement (10 minutes before the first dose of trial medication). Mixed Model Repeated Measure (MMRM) results. Means are adjusted for treatment, pooled centre, visit, baseline, treatment*visit and baseline*visit. (NCT01316380)
Timeframe: Baseline and 12 weeks
| Intervention | Liter (Least Squares Mean) |
|---|---|
| Placebo | 0.134 |
| Tio R2.5 | 0.293 |
| Tio R5 | 0.262 |
An asthma exacerbation was defined as an episode of progressive increase in 1 or more asthma symptom that were outside the patient's usual range of day-to-day asthma symptoms and lasted for at least 2 consecutive days or as a decrease in a patient's best morning PEF of 30% or more from a patient's mean morning PEF for at least 2 consecutive days that may or may not have been accompanied by symptoms. (NCT01316380)
Timeframe: 12 weeks
| Intervention | Days (Median) |
|---|---|
| Placebo | NA |
| Tio R2.5 | NA |
| Tio R5 | NA |
"Use of PRN (pro re nata, or as necessary) salbutamol/albuterol rescue medication (puffs during 24 h period), determined as a weekly mean response from baseline for each week during the treatment period as well as for the last 7 days before treatment stop/Visit 5.~The mean was adjusted for treatment, centre, week, baseline, treatment*week and baseline*week." (NCT01316380)
Timeframe: Baseline and 12 weeks
| Intervention | puffs of rescue medication (Mean) |
|---|---|
| Placebo | -0.815 |
| Tio R2.5 | -0.594 |
| Tio R5 | -0.848 |
Severe asthma exacerbations are defined as all asthma exacerbations that required treatment with systemic (including oral) corticosteroids for at least 3 days. (NCT01316380)
Timeframe: 12 weeks
| Intervention | Days (Median) |
|---|---|
| Placebo | NA |
| Tio R2.5 | NA |
| Tio R5 | NA |
For the ACQ, the total score was calculated as the mean of the responses to 6 self administered questions and one question which was completed by clinical staff based upon pre-bronchodilator FEV1. The score ranges from 0 (no impairment) to 6 (maximum impairment). Response was categorised as: responder (change from baseline <= -0.5), no change (-0.5
Timeframe: 12 weeks
| Intervention | Number of patients (Number) | ||
|---|---|---|---|
| Responder | No change | Worsening | |
| Placebo | 91 | 61 | 2 |
| Tio R2.5 | 91 | 48 | 10 |
| Tio R5 | 90 | 57 | 5 |
"Use of PRN (pro re nata, or as necessary) salbutamol/albuterol rescue medication (puffs during nighttime), determined as a weekly mean response from baseline for each week during the treatment period as well as for the last 7 days before treatment stop/Visit 5.~The mean was adjusted for treatment, centre, week, baseline, treatment*week and baseline*week." (NCT01316380)
Timeframe: Baseline and 12 weeks
| Intervention | puffs of rescue medication (Mean) |
|---|---|
| Placebo | -0.376 |
| Tio R2.5 | -0.245 |
| Tio R5 | -0.386 |
"Use of PRN (pro re nata, or as necessary) salbutamol/albuterol rescue medication (puffs during daytime), determined as a weekly mean response from baseline for each week during the treatment period as well as for the last 7 days before treatment stop/Visit 5.~The mean was adjusted for treatment, centre, week, baseline, treatment*week and baseline*week." (NCT01316380)
Timeframe: Baseline and 12 weeks
| Intervention | puffs of rescue medication (Mean) |
|---|---|
| Placebo | -0.428 |
| Tio R2.5 | -0.331 |
| Tio R5 | -0.436 |
FEV1 is a measure of lung function and is defined as the maximal amount of air that can be forcefully exhaled in one second. Trough FEV1 measurements were taken electronically by spirometry on Days 2, 28, 56, 84, 112, 168, and 169. Baseline is defined as the mean of the assessments made 30 minutes pre-dose and 5 minutes pre-dose on Treatment Day 1. Trough FEV1 is defined as the mean of the FEV1 values obtained at 23 and 24 hours after the previous morning's dosing (ie., trough FEV1 on Day 169 is the mean of the FEV1 values obtained 23 and 24 hours after the morning dosing on Day 168). Change from Baseline at a particular visit was calculated as the trough FEV1 at that visit minus Baseline. Analysis was performed using a repeated measures model with covariates of treatment, Baseline , smoking status, center group, day, and day by Baseline and day by treatment interactions. ITT=Intent-to-Treat; par.=participants. . (NCT01316900)
Timeframe: Baseline and Day 169
| Intervention | Liters (Least Squares Mean) |
|---|---|
| VI 25 µg | 0.121 |
| UMEC/VI 62.5/25 µg | 0.211 |
| UMEC/VI 125/25 µg | 0.209 |
| TIO 18 µg | 0.121 |
FEV1 is a measure of lung function and is defined as the maximal amount of air that can be forcefully exhaled in one second. The WM FEV1 was derived by calculating the area under the FEV1/time curve (AUC) using the trapezoidal rule, and then dividing the value by the time interval over which the AUC was calculated. The WM was calculated at Days 1, 84, and Day 168 using the 0-6-hour post-dose FEV1 measurements collected on that day, which included pre-dose (Day 1: 30 minutes [min] and 5 min prior to dosing; other serial visits: 23 and 24 hours after the previous morning dose) and post-dose at 15 minutes, 30 minutes, 1 hour, 3 hours, and 6 hours. Change from BL at a particular visit was calculated as WM at that visit minus BL. Analysis was performed using a repeated measures model with covariates of treatment, BL (mean of the two assessments made 30 minutes and 5 minutes pre-dose on Day 1), smoking status, center group, day, and day by BL and day by treatment interactions. (NCT01316900)
Timeframe: Baseline and Day 168
| Intervention | Liters (Least Squares Mean) |
|---|---|
| VI 25 µg | 0.178 |
| UMEC/VI 62.5/25 µg | 0.254 |
| UMEC/VI 125/25 µg | 0.263 |
| TIO 18 µg | 0.181 |
The newly developed SOBDA questionnaire assesses dyspnea or shortness of breath (SOB) with daily activities. The SOBDA questionnaire is made up of 13 items completed by the participant (par.) each evening prior to bedtime, when the par. is instructed to reflect on the current day's activities. The daily score is computed as the mean of the scores on the 13 items (>=7 items must have non-missing responses for this to be calculated). The par. is assigned a weekly mean SOBDA score ranging from 1 to 4 (greater scores indicate more severe breathlessness with daily activities) based on the mean of 7 days of data (>=4 of 7 days must be completed for a weekly mean to be calculated). Change from BL is the mean weekly SOBDA score minus BL. Analysis was performed using MMRM with covariates of treatment, BL (mean score in the week prior to treatment), smoking status, center group, week, week by BL and week by treatment interactions. This MMRM analysis only included Weeks 4, 8, 12, and 24. (NCT01316900)
Timeframe: Baseline and Week 24
| Intervention | Scores on a scale (Least Squares Mean) |
|---|---|
| VI 25 µg | -0.16 |
| UMEC/VI 62.5/25 µg | -0.18 |
| UMEC/VI 125/25 µg | -0.18 |
| TIO 18 µg | -0.18 |
FEV1 is a measure of lung function and is defined as the maximal amount of air that can be forcefully exhaled in one second. The WM FEV1 was derived by calculating the area under the FEV1/time curve (AUC) using the trapezoidal rule, and then dividing the value by the time interval over which the AUC was calculated. The WM was calculated at Days 1, 84, and Day 168 using the 0-6-hour post-dose FEV1 measurements collected on that day, which included pre-dose (Day 1: 30 minutes [min] and 5 min prior to dosing; other serial visits: 23 and 24 hours after the previous morning dose) and post-dose at 15 minutes, 30 minutes, 1 hour, 3 hours, and 6 hours. Change from BL at a particular visit was calculated as WM at that visit minus BL. Analysis was performed using a repeated measures model with covariates of treatment, BL (mean of the two assessments made 30 minutes and 5 minutes pre-dose on Day 1), smoking status, center group, day, and day by BL and day by treatment interactions. (NCT01316913)
Timeframe: Baseline and Day 168
| Intervention | Liters (Least Squares Mean) |
|---|---|
| UMEC 125 µg QD | 0.206 |
| UMEC/VI 62.5/25 µg QD | 0.276 |
| UMEC/VI 125/25 µg QD | 0.282 |
| TIO18 µg QD | 0.180 |
FEV1 is a measure of lung function and is defined as the maximal amount of air that can be forcefully exhaled in one second. Trough FEV1 measurements were taken electronically by spirometry on Days 2, 28, 56, 84, 112, 168, and 169. Baseline is defined as the mean of the assessments made 30 minutes pre-dose and 5 minutes pre-dose on Treatment Day 1. Trough FEV1 is defined as the mean of the FEV1 values obtained at 23 and 24 hours after the previous morning's dosing (i.e., trough FEV1 on Day 169 is the mean of the FEV1 values obtained 23 and 24 hours after the morning dosing on Day 168). Change from Baseline at a particular visit was calculated as the trough FEV1 at that visit minus Baseline. Analysis was performed using a repeated measures model with covariates of treatment, Baseline, smoking status, center group, day, and day by Baseline and day by treatment interactions. ITT=Intent-to-Treat. (NCT01316913)
Timeframe: Baseline and Day 169
| Intervention | Liters (Least Squares Mean) |
|---|---|
| UMEC 125 µg QD | 0.186 |
| UMEC/VI 62.5/25 µg QD | 0.208 |
| UMEC/VI 125/25 QD | 0.223 |
| TIO18 µg QD | 0.149 |
The newly developed SOBDA questionnaire assesses dyspnea or shortness of breath (SOB) with daily activities. The SOBDA questionnaire is made up of 13 items completed by the participant (par.) each evening prior to bedtime, when the par. is instructed to reflect on the current day's activities. The daily score is computed as the mean of the scores on the 13 items (>=7 items must have non-missing responses for this to be calculated). The par. is assigned a weekly mean SOBDA score ranging from 1 to 4 (greater scores indicate more severe breathlessness with daily activities) based on the mean of 7 days of data (>=4 of 7 days must be completed for a weekly mean to be calculated). Change from BL is the mean weekly SOBDA score minus BL. Analysis was performed using MMRM with covariates of treatment, BL (mean score in the week prior to treatment), smoking status, center group, week, week by BL and week by treatment interactions. This MMRM analysis only included Weeks 4, 8, 12, and 24. (NCT01316913)
Timeframe: Baseline and Week 24
| Intervention | scores on a scale (Least Squares Mean) |
|---|---|
| UMEC 125 µg QD | -0.19 |
| UMEC/VI 62.5/25 µg QD | -0.29 |
| UMEC/VI 125/25 µg QD | -0.33 |
| TIO18 µg QD | -0.21 |
Medical costs are associated with COPD-related medical care (claims submitted with a primary International Classification of Diseases, 9th Revision, Clinical Modification diagnosis of COPD) and pharmaceutical care (treatment arm medications, oral corticosteroids, oral antibiotics, short-acting beta-agonists, long-acting beta-agonists [LABA], inhaled corticosteroids [ICS], ICS/LABA combinations, etc.. Means are adjusted for age, sex, geographic region, pre-initial treatment comorbidities, and COPD-related utilization. Total costs are the sum of medical care and pharmacy costs. (NCT01331694)
Timeframe: Incurred over the 12 month period after initial treatment arm prescription
| Intervention | United States dollars (Mean) | ||
|---|---|---|---|
| Medical | Pharmacy | Total | |
| Cost Population: FSC | 1076 | 972 | 2068 |
| Cost Population: IP | 2481 | 614 | 2841 |
| Cost Population: TIO | 1419 | 985 | 2408 |
The first COPD event occurring after 30 days from initial treatment arm prescription was measured. Four categories of COPD events were analyzed; either a hospitalization or emergency department visit; an emergency department visit; an outpatient visit followed by an oral corticosteroid prescription claim within 10 days; an outpatient visit followed by an oral antibiotic prescription claim within 10 days. (NCT01331694)
Timeframe: Anytime from 30 days to 12 months after initial treatment arm prescription
| Intervention | days (Mean) | |||
|---|---|---|---|---|
| Hospitalization or emergency department visit | Emergency department visit | Outpatient visit with oral steroid fill | Outpatient visit with antibiotic fill | |
| Risk Population TIO | 321.59 | 328.48 | 331.23 | 326.70 |
| Risk Population: FSC | 325.17 | 330.24 | 332.74 | 329.96 |
| Risk Population: IP | 315.89 | 324.47 | 328.23 | 326.73 |
The number of participants with any of the following COPD-related exacerbations during the follow-up period was computed: COPD-related hospitalization, emergency room (ER) visit, or physician visit with a prescription (Rx) for oral corticosteroid (OCS) or antibiotic within 5 days of the visit. The index date is defined as the date of first chronologically occurring COPD maintenance medication of interest during an identification period spanning January 1, 2004 to June 30, 2008. (NCT01337336)
Timeframe: Maximum of 1 year after index date (January 1, 2004 to June 30, 2009)
| Intervention | participants (Number) |
|---|---|
| FSC Cohort | 200 |
| AC Cohort | 674 |
The number of COPD-related exacerbations was identified during the follow-up period. Five types of COPD-related exacerbations were defined: -COPD-related hospitalization, ER visit, physician visit with a prescription (Rx) for oral corticosteroid or antibiotic within 5 days of the visit, combined occurrence of COPD-related hospitalization/ER visit, or combined occurrence of any COPD-related exacerbation. The index date is defined as the date of first chronologically occurring COPD maintenance medication of interest during an identification period spanning January 1, 2004 to June 30, 2008. (NCT01337336)
Timeframe: Maximum of 1 year after index date (January 1, 2004 through June 30, 2009)
| Intervention | number of exacerbations (Mean) | ||||
|---|---|---|---|---|---|
| COPD-related hospitalization | COPD-related ER visit | COPD-related physician (phy)+Rx visit | COPD-related hospitalization/ER visit | COPD-related hospitalization/ER visit/phy+Rx visit | |
| AC Cohort | 0.07 | 0.07 | 0.20 | 0.14 | 0.34 |
| FSC Cohort | 0.04 | 0.06 | 0.19 | 0.09 | 0.29 |
The number of participants with a COPD-related exacerbation was identified during the follow-up period. Four types of COPD-related exacerbations were defined: COPD-related hospitalization, ER visit, physician visit with a prescription (Rx) for oral corticosteroid or antibiotic within 5 days of the visit, or combined occurrence of COPD-related hospitalization/ER visit. The index date is defined as the date of first chronologically occurring COPD maintenance medication of interest during an identification period spanning January 1, 2004 to June 30, 2008. (NCT01337336)
Timeframe: Maximum of 1 year after index date (January 1, 2004 through June 30, 2009)
| Intervention | participants (Number) | |||
|---|---|---|---|---|
| COPD-related hospitalization | COPD-related ER visit | COPD-related physician + Rx visit | COPD-related hospitalization/ER visit | |
| AC Cohort | 168 | 171 | 448 | 307 |
| FSC Cohort | 35 | 37 | 156 | 63 |
Cost categories included medical, pharmacy, and total (calculated as the sum of medical and pharmacy). COPD-related medical costs were computed using claims with a primary diagnosis of COPD, and COPD-related pharmacy costs were computed using the paid amounts of pharmacy claims for prescription medication used for COPD.The index date is defined as the date of first chronologically occurring COPD maintenance medication of interest during an identification period spanning January 1, 2004 to June 30, 2008. (NCT01337336)
Timeframe: Maximum of 1 year after index date (January 1, 2004 through June 30, 2009)
| Intervention | United States (US) dollars (Mean) | ||
|---|---|---|---|
| COPD-related total costs | COPD-related pharmacy costs | COPD-related medical costs | |
| AC Cohort | 1687 | 684 | 1003 |
| FSC Cohort | 1604 | 934 | 670 |
Weekly mean PEFpm response was defined as change from baseline at week 52 (NCT01340209)
Timeframe: baseline and week 52
| Intervention | L/min (Least Squares Mean) |
|---|---|
| Placebo Respimat | -10.357 |
| Tiotropium Respimat (2.5 µg) | 1.101 |
| Tiotropium Respimat (5 μg) | 6.041 |
Trough FEV1 response was defined as change from baseline at week 52 (NCT01340209)
Timeframe: baseline and week 52
| Intervention | Liter (Least Squares Mean) |
|---|---|
| Placebo Respimat | 0.075 |
| Tiotropium Respimat (2.5 µg) | 0.087 |
| Tiotropium Respimat (5 μg) | 0.187 |
Weekly mean PEFam response was defined as change from baseline at week 52 (NCT01340209)
Timeframe: baseline and week 52
| Intervention | L/min (Least Squares Mean) |
|---|---|
| Placebo Respimat | 2.288 |
| Tiotropium Respimat (2.5 µg) | 10.934 |
| Tiotropium Respimat (5 μg) | 8.504 |
"Weekly mean PEF variability response was defined as change from baseline at week 52.~The PEF variability is the absolute difference between morning and evening PEF value, divided by their mean, expressed as a percent. Response was defined as change from baseline." (NCT01340209)
Timeframe: baseline and week 52
| Intervention | percentage (Least Squares Mean) |
|---|---|
| Placebo Respimat | -0.367 |
| Tiotropium Respimat (2.5 µg) | -0.968 |
| Tiotropium Respimat (5 μg) | 0.197 |
Response of weekly mean number of puffs of rescue medication during the whole day at week 52. Response was defined as change from baseline. (NCT01340209)
Timeframe: baseline and week 52
| Intervention | Puffs (Mean) |
|---|---|
| Placebo Respimat | -0.25 |
| Tiotropium Respimat (2.5 µg) | -0.29 |
| Tiotropium Respimat (5 μg) | -0.22 |
Trough PEF response was defined as change from baseline at week 52 (NCT01340209)
Timeframe: baseline and week 52
| Intervention | L/min (Least Squares Mean) |
|---|---|
| Placebo Respimat | 35.078 |
| Tiotropium Respimat (2.5 µg) | 35.576 |
| Tiotropium Respimat (5 μg) | 69.254 |
Trough FVC response was defined as change from baseline at week 52 (NCT01340209)
Timeframe: baseline and week 52
| Intervention | Liter (Least Squares Mean) |
|---|---|
| Placebo Respimat | 0.122 |
| Tiotropium Respimat (2.5 µg) | 0.085 |
| Tiotropium Respimat (5 μg) | 0.204 |
"Response of weekly mean score of asthma symptoms during the day at week 52. Response was defined as change from baseline.~5-point verbal rating scale, with answer 1 representing no impairment at all and answer 5 representing the greatest impairment." (NCT01340209)
Timeframe: baseline and week 52
| Intervention | Scores on a scale (Mean) |
|---|---|
| Placebo Respimat | -0.24 |
| Tiotropium Respimat (2.5 µg) | -0.15 |
| Tiotropium Respimat (5 μg) | -0.17 |
"Response of weekly mean score of asthma symptoms in the morning at week 52. Response was defined as change from baseline.~5-point verbal rating scale, with answer 1 representing no impairment at all and answer 5 representing the greatest impairment." (NCT01340209)
Timeframe: baseline and week 52
| Intervention | Scores on a scale (Mean) |
|---|---|
| Placebo Respimat | -0.22 |
| Tiotropium Respimat (2.5 µg) | -0.14 |
| Tiotropium Respimat (5 μg) | -0.21 |
The primary endpoint is the number of patients with drug-related adverse events (NCT01340209)
Timeframe: after the first dose of trial medication and within 30 days after the last dose of trial medication, up to 409
| Intervention | participants (Number) |
|---|---|
| Placebo Respimat | 3 |
| Tiotropium Respimat (2.5 µg) | 6 |
| Tiotropium Respimat (5 μg) | 10 |
The trough FEV1 data for both the once-daily (QD) and twice-daily (BID) UMEC doses were included in a parametric analysis in order to evaluate trough FEV1dose response. The Day 8 dataset and a pooled dataset for Day 7 and Day 8 were analyzed separately and reported. The rationale for pooling Day 7 and Day 8 (post-hoc analysis) was to ensure informative interpretation of FEV1 response as a function of dose given the repeated measures for trough FEV1 response within each participant on different days. The fixed-effects parameters of the dose response model include Emax (the maximum predicted FEV1 response), ED50 (potency), and S0 (estimated Baseline FEV1). FEV1 is a measure of lung function and is defined as the maximal amount of air that can be forcefully exhaled in one second. Data for Emax and S0 are reported in this table. mITT=Modified Intent-to-Treat; par.=participants; BL=Baseline. (NCT01372410)
Timeframe: Day 7 and Day 8 of each treatment period (up to Study Day 50)
| Intervention | Liters (Geometric Mean) | |||
|---|---|---|---|---|
| Day 8, Emax, n=157 | Pooled Day 7 and Day 8, Emax, n=160 | Day 8, S0, n=157 | Pooled Day 7 and 8, S0, n=160 | |
| All Study Treatments | 0.185 | 0.156 | 1.24 | 1.24 |
FEV1 is a measure of lung function and is defined as the maximal amount of air that can be forcefully exhaled in one second. Trough FEV1 on Treatment Day 8 is defined as the value obtained 24 hours after the morning dose administered on Day 7. Analysis was performed using a mixed model with covariates of mean Baseline, period Baseline, treatment, and period as fixed effects and participant as a random effect. Baseline is the FEV1 value recorded pre-dose on Day 1 of each treatment period, mean Baseline is the mean of the Baselines for each participant, and period Baseline is the difference between the Baseline and the mean Baseline in each treatment period for each particiapant. Change from Baseline for each treatment period is the trough FEV1 at Day 8 minus the Baseline value for that treatment period. (NCT01372410)
Timeframe: Baseline and Day 8 of each treatment period (up to Study Day 50)
| Intervention | Liters (Least Squares Mean) |
|---|---|
| Placebo | -0.074 |
| UMEC 15.6 µg QD | 0.038 |
| UMEC 31.25 µg QD | 0.027 |
| UMEC 62.5 µg QD | 0.049 |
| UMEC 125 µg QD | 0.109 |
| UMEC 15.6 µg BID | 0.051 |
| UMEC 31.25 µg BID | 0.065 |
| TIO 18 µg QD | 0.027 |
Serial FEV1 for once daily dosing is recorded at the pre-AM dose (AMD; time 0 hour [h]) and at 1, 3, 6, 9, 12,13, 15, 23, and 24 hours after the AMD on Day 7. For twice daily dosing, the 12 h AMD corresponds to the pre-PM dose (PMD), the 13 h AMD corresponds to the 1 h PMD, the 15 h AMD corresponds to the 3 h PMD, the 23 h AMD corresponds to the 11 h PMD, and the 24 h AMD corresponds to the 12 h PMD in this table. Analysis was performed using a mixed model with covariates of mean BL, period BL, treatment, period, time, time by period BL interaction, time by mean BL interaction, and time by treatment interaction as fixed effects and participant as a random effect. BL is the value recorded pre-dose on Day 1 of each TP, mean BLis the mean of the BLs for each participant, and period BL is the difference between the BL and the mean BL in each TP for each participant. Change from BL for each timepoint within a TP is the serial FEV1 measure at that timepoint minus the BL value for that TP. (NCT01372410)
Timeframe: Baseline and Day 7 of each treatment period (TP; up to Study Day 49)
| Intervention | Liters (Least Squares Mean) | |||||||||
|---|---|---|---|---|---|---|---|---|---|---|
| Pre-AMD, n=59, 58, 55, 59, 60, 54, 57, 54 | 1 h AMD, n=59, 59, 56, 59, 60, 55, 57, 56 | 3 h AMD, n=59, 59, 56, 59, 59, 55, 57, 56 | 6 h AMD, n=59, 59, 55, 59, 59, 55, 57, 56 | 9 h AMD, n=59, 59, 56, 59, 58, 55, 56, 56 | 12 h AMD/Pre-PMD, n=59, 59, 56, 59, 59, 55, 57, 56 | 13 h AMD/1 h PMD, n=59, 59, 56, 59, 58, 55, 57, 56 | 15 h AMD/3 h PMD, n=59, 58, 56, 58, 59, 55, 57, 56 | 23 h AMD/11 h PMD, n=59, 57, 56, 59, 59, 55, 57,56 | 24 h AMD/12 h PMD, n=59, 58, 56, 59, 59, 55, 57,56 | |
| Placebo | -0.007 | -0.006 | -0.013 | -0.054 | -0.072 | -0.086 | -0.085 | -0.112 | -0.101 | -0.065 |
| TIO 18 µg QD | 0.084 | 0.176 | 0.180 | 0.128 | 0.094 | 0.081 | 0.061 | 0.037 | 0.002 | 0.049 |
| UMEC 125 µg QD | 0.122 | 0.167 | 0.176 | 0.088 | 0.132 | 0.103 | 0.103 | 0.073 | 0.073 | 0.146 |
| UMEC 15.6 µg BID | 0.069 | 0.128 | 0.126 | 0.045 | 0.070 | 0.048 | 0.063 | 0.041 | 0.001 | 0.083 |
| UMEC 15.6 µg QD | 0.068 | 0.086 | 0.082 | 0.056 | 0.040 | 0.022 | -0.001 | -0.008 | 0.006 | 0.070 |
| UMEC 31.25 µg BID | 0.097 | 0.135 | 0.120 | 0.081 | 0.038 | 0.048 | 0.041 | 0.047 | 0.33 | 0.084 |
| UMEC 31.25 µg QD | 0.067 | 0.112 | 0.132 | 0.067 | 0.050 | 0.028 | -0.003 | 0.004 | -0.006 | 0.065 |
| UMEC 62.5 µg QD | 0.065 | 0.107 | 0.082 | 0.056 | 0.084 | 0.043 | 0.026 | 0.022 | 0.012 | 0.067 |
The trough FEV1 data for both the once-daily (QD) and twice-daily (BID) UMEC doses were included in a parametric analysis in order to evaluate dose response. Both a Day 8 dataset and a pooled dataset for Day 7 and Day 8 were analyzed and reported. The rationale for pooling Day 7 and Day 8 (post-hoc analysis) was to ensure informative interpretation of FEV1 response as a function of dose given the repeated measures for trough FEV1 response within each participant on different days. ED50 is defined as the potency and is the dose that yields 50% of Emax (maximum predicted FEV1 response). FEV1 is a measure of lung function and is defined as the maximal amount of air that can be forcefully exhaled in one second. (NCT01372410)
Timeframe: Day 7 and Day 8 of each treatment period (up to Study Day 50)
| Intervention | micrograms (Geometric Mean) | |
|---|---|---|
| Day 8, ED50, n=157 | Pooled Day 7 and Day 8, ED50, n=160 | |
| All Study Treatments | 37.4 | 38.2 |
The trough FEV1 data for both the once-daily (QD) and twice-daily (BID) UMEC doses were included in a parametric analysis in order to evaluate dose response. Both a Day 8 dataset and a pooled dataset for Day 7 and Day 8 were analyzed and reported. The rationale for pooling Day 7 and Day 8 (post-hoc analysis) was to ensure informative interpretation of FEV1 response as a function of dose given the repeated measures for trough FEV1 response within each participant on different days. β-FEV1MB-S0 is defined as the covariate (Baseline trough FEV1) effect on the mean Baseline trough FEV1 estimate (S0). FEV1 is a measure of lung function and is defined as the maximal amount of air that can be forcefully exhaled in one second. (NCT01372410)
Timeframe: Day 7 and Day 8 of each treatment period (up to Study Day 50)
| Intervention | fraction of mean estimated Baseline FEV1 (Number) | |
|---|---|---|
| Day 8, βFEV1MB-S0, n=157 | Pooled Day 7 and 8, βFEV1MB-S0, n=160 | |
| All Study Treatments | 0.691 | 0.686 |
FEV1 is a measure of lung function and is defined as the maximal amount of air that can be forcefully exhaled in one second. The weighted mean FEV1 was derived by calculating the area under the FEV1/time curve (AUC) using the trapezoidal rule, and then dividing the value by the time interval over which the AUC was calculated. The weighted mean FEV1 was calculated using 0-24 hour post-dose measurements at Day 7 of each treatment period, which included pre-dose and post-dose 1, 3, 6, 9, 12, 13, 15, 23, and 24 hours. Analysis was performed using a mixed model with covariates of mean BL, period BL, treatment, and period as fixed effects and participant as a random effect. BL is the FEV1 value recorded pre-dose on Day 1 of each TP, mean BL is the mean of the BLs for each participant, and period BL is the difference between the BL and the mean BL in each TP for each participant. Change from BL for each TP is the weighted mean FEV1 at Day 7 minus the BL value for that TP. (NCT01372410)
Timeframe: Baseline and Day 7 of each treatment period (TP; up to Study Day 49)
| Intervention | Liters (Least Squares Mean) |
|---|---|
| Placebo | -0.074 |
| UMEC 15.6 µg QD | 0.043 |
| UMEC 31.25 µg QD | 0.045 |
| UMEC 62.5 µg QD | 0.059 |
| UMEC 125 µg QD | 0.100 |
| UMEC 15.6 µg BID | 0.062 |
| UMEC 31.25 µg BID | 0.068 |
| TIO 18 µg QD | 0.084 |
A severe exacerbation is defined as one with a primary diagnosis of COPD. A moderate exacerbation is an ED visit with a primary diagnosis of COPD, a physician visit with a diagnosis of COPD and a prescription for an oral corticosteroid, a physician visit with a diagnosis code for COPD and an antibiotic for respiratory infection, or physician administration of nebulized albuterol within 3 days of an office visit. Incidence rate is calculated by dividing the number of exacerbations by the number of person years. Person years adjust for different lengths of follow up for participants. (NCT01381406)
Timeframe: Data were collected over a maximum period of 4 years
| Intervention | exacerbations per 100 person years (Number) | ||
|---|---|---|---|
| Any exacerbation | Severe exacerbation | Moderate exacerbation | |
| TIO Plus FSC/Salmeterol Xinafoate in Combination (TIO + FSC) | 75.38 | 5.06 | 69.74 |
| Tiotropium Bromide (TIO) | 95.58 | 7.86 | 88.65 |
Unadjusted incidence rates per 100 person years of chronic obstructive pulmonary disease (COPD)-related hospitalizations and emergency department visits by treatment group are presented. Incidence rate is calculated by dividing the number of healthcare service encounters by the number of person years of follow up. Person years adjust for different lengths of follow up for individual participants (NCT01381406)
Timeframe: Data were collected over a maximum period of 4 years
| Intervention | visits per 100 person years (Number) | ||
|---|---|---|---|
| COPD-related hospital and emergency room visits | Hospitalizations | Emergency department visits | |
| TIO Plus FSC/Salmeterol Xinafoate in Combination (TIO + FSC) | 75.38 | 7.43 | 9.90 |
| Tiotropium Bromide (TIO) | 95.58 | 11.14 | 12.63 |
The mean costs of health care encounters adjusted to control for baseline differences between treatment groups and reported in 2008 United States dollars as calculated with the consumer price index (CPI) are presented. CPI is standard multiplier for adjusting the cost of goods and services to a single year. Total costs include pharmacy and medical costs. Medical costs were computed from the paid amounts of medical claims with a primary diagnosis code for COPD. COPD-related pharmacy costs were computed from paid amounts of COPD-related prescription medications. (NCT01381406)
Timeframe: Data were collected over a maximum period of 4 years
| Intervention | United States dollars (Mean) | ||
|---|---|---|---|
| Total costs | Pharmacy Costs | Medical costs | |
| TIO Plus FSC/Salmeterol Xinafoate in Combination (TIO + FSC) | 721 | 223 | 490 |
| Tiotropium Bromide (TIO) | 721 | 190 | 543 |
Mean number of nighttime awakenings due to asthma symptoms as assessed by patients eDiary incorporated in the AM3® device. Analysis adjusted for treatment, period, patient and baseline using a mixed model. The scores for this question used the following scale where: 1='Did not wake up', 2='Woke up once', 3='Woke up 2-5 times', 4='Woke up more than 5 times' and 5='Was awake all night'. (NCT01383499)
Timeframe: Baseline and last week of treatment (week 4)
| Intervention | scores on a scale (Least Squares Mean) |
|---|---|
| Placebo | -0.135 |
| Tio R1.25 | -0.104 |
| Tio R2.5 | -0.080 |
| Tio R5 | -0.099 |
ACQ is a questionnaire consisting of seven point Likert scale ranging from 0 to 6, whereby 0 represents good control and 6 represents poor control of asthma. The scale describes the frequency and severity of asthma symptoms. Analysis adjusted for treatment, period, patient and baseline using a mixed model. (NCT01383499)
Timeframe: 4 weeks
| Intervention | Score (Least Squares Mean) |
|---|---|
| Placebo | 0.966 |
| Tio R1.25 | 0.909 |
| Tio R2.5 | 0.846 |
| Tio R5 | 0.879 |
The FEV1 peak (0-3h) response is determined at the end of the 4 week treatment period. This is the difference between the maximum FEV1 measured within the first 3 hours post dosing and the FEV1 baseline measurement. Analysis adjusted for treatment, period, patient and baseline using a mixed model. (NCT01383499)
Timeframe: Baseline and 4 weeks
| Intervention | Litre (Least Squares Mean) |
|---|---|
| Placebo | 0.185 |
| Tio R1.25 | 0.261 |
| Tio R2.5 | 0.290 |
| Tio R5 | 0.272 |
The FVC peak (0-3h) response is determined at the end of the 4 week treatment period. This is the difference between the maximum FVC measured within the first 3 hours post dosing and the FVC baseline measurement. Analysis adjusted for treatment, period, patient and baseline using a mixed model. (NCT01383499)
Timeframe: Baseline and 4 weeks
| Intervention | Litre (Least Squares Mean) |
|---|---|
| Placebo | 0.202 |
| Tio R1.25 | 0.208 |
| Tio R2.5 | 0.253 |
| Tio R5 | 0.239 |
FVC (AUC0-3h) will be calculated as the area under the curve from 0 to 3 hours using the trapezoidal rule divided by the observation time (3 hours) to report in litres. Response was defined as the change from baseline. Analysis adjusted for treatment, period, patient and baseline using a mixed model. (NCT01383499)
Timeframe: Baseline and 4 weeks
| Intervention | Litre (Least Squares Mean) |
|---|---|
| Placebo | 0.087 |
| Tio R1.25 | 0.097 |
| Tio R2.5 | 0.134 |
| Tio R5 | 0.110 |
The trough FVC response is defined as the pre-dose FVC measured just prior to the last administration of randomised treatment. Response was defined as the change from baseline. Analysis adjusted for treatment, period, patient and baseline using a mixed model. (NCT01383499)
Timeframe: Baseline and 4 weeks
| Intervention | Litre (Least Squares Mean) |
|---|---|
| Placebo | 0.060 |
| Tio R1.25 | 0.109 |
| Tio R2.5 | 0.107 |
| Tio R5 | 0.113 |
Mean Evening PEF assessed by patients at home. Response was defined as the change from baseline. Analysis adjusted for treatment, period, patient and baseline using a mixed model. (NCT01383499)
Timeframe: Baseline and 4 weeks
| Intervention | Litre/min (Least Squares Mean) |
|---|---|
| Placebo | -0.568 |
| Tio R1.25 | 9.910 |
| Tio R2.5 | 6.991 |
| Tio R5 | 15.910 |
Mean morning PEF assessed by patients at home. Response was defined as the change from baseline. Analysis adjusted for treatment, period, patient and baseline using a mixed model. (NCT01383499)
Timeframe: Baseline and 4 weeks
| Intervention | Litre/min (Least Squares Mean) |
|---|---|
| Placebo | -0.928 |
| Tio R1.25 | 14.474 |
| Tio R2.5 | 12.045 |
| Tio R5 | 15.439 |
The trough FEV1 is defined as the pre-dose FEV1 measured just prior to the last administration of randomised treatment. Response was defined as the change from baseline. Analysis adjusted for treatment, period, patient and baseline using a mixed model. (NCT01383499)
Timeframe: Baseline and 4 weeks
| Intervention | Litre (Least Squares Mean) |
|---|---|
| Placebo | 0.085 |
| Tio R1.25 | 0.160 |
| Tio R2.5 | 0.190 |
| Tio R5 | 0.183 |
Mean number of inhalations (puffs) of unscheduled rescue salbutamol therapy during whole day (24 h, daytime and night-time use). Analysis adjusted for treatment, period, patient and baseline using a mixed model. (NCT01383499)
Timeframe: Baseline and 4 weeks
| Intervention | Puffs (Least Squares Mean) | ||
|---|---|---|---|
| 24 h | Daytime | Night-time | |
| Placebo | -0.664 | -0.338 | -0.354 |
| Tio R1.25 | -0.691 | -0.348 | -0.355 |
| Tio R2.5 | -0.314 | -0.130 | -0.180 |
| Tio R5 | -0.550 | -0.258 | -0.272 |
FEV1 (AUC0-3h) will be calculated as the area under the curve from 0 to 3 hours using the trapezoidal rule divided by the observation time (3 hours) to report in litres. Response was defined as the change from baseline. Analysis adjusted for treatment, period, patient and baseline using a mixed model. (NCT01383499)
Timeframe: Baseline and 4 weeks
| Intervention | Litre (Least Squares Mean) |
|---|---|
| Placebo | 0.110 |
| Tio R1.25 | 0.178 |
| Tio R2.5 | 0.208 |
| Tio R5 | 0.201 |
Moderate COPD exacerbations were defined as the occurrence of a COPD-related emergency department (ED) visit or a COPD-related office visit that is closely followed by a prescription claim for oral steroids or antibiotics. Severe exacerbations were defined as the occurrence of a COPD-related hospital admission. (NCT01387178)
Timeframe: 1 year
| Intervention | number of exacerbations (Mean) | ||
|---|---|---|---|
| Moderate Exacerbation | Severe Exacerbation | Any Exacerbation | |
| Fluticasone Propionate/Salmeterol 250 Micrograms (µg)/50 µg | 0.35 | 0.05 | 0.4 |
| Tiotropium Bromide 18 µg | 0.29 | 0.05 | 0.34 |
(NCT01387178)
Timeframe: 1 year
| Intervention | number of encounters (Number) | ||||
|---|---|---|---|---|---|
| Inpatient services | Emergency department visits | Inpatient and emergency department visits | Office visits | Other outpatient/ancillary services | |
| Fluticasone Propionate/Salmeterol 250 Micrograms (µg)/50 µg | 2155 | 3085 | 3673 | 7833 | 7243 |
| Tiotropium Bromide 18 µg | 1792 | 2312 | 2817 | 6295 | 5859 |
The mean cost per participant for COPD-related healthcare interventions for one year following the index date (first pharmacy claim for fluticasone propionate/salmeterol 250 µg/50 µg [FSC] or tiotropium bromide [TIO]) was calculated. Total medical costs included inpatient, emergency department, and outpatient costs associated with the treatment of COPD. Total pharmacy costs included costs of all COPD-related medications, and total healthcare costs included all medical and pharmacy costs that were related to COPD treatment. These costs were unadjusted and reflect the actual costs. (NCT01387178)
Timeframe: 1 year
| Intervention | United States (US) dollars (Mean) | |||||||
|---|---|---|---|---|---|---|---|---|
| Inpatient services | Emergency department visits | Inpatient and emergency department visits | Office visits | Other outpatient/ancillary services | Total medical costs | Total pharmacy costs | Total healthcare utilization | |
| Fluticasone Propionate/Salmeterol 250 Micrograms (µg)/50 µg | 688 | 55 | 743 | 231 | 734 | 1709 | 1291 | 3000 |
| Tiotropium Bromide 18 µg | 867 | 52 | 919 | 293 | 879 | 2091 | 1209 | 3299 |
PWV is defined as the speed of travel of the pressure pulse along an arterial segment and can be obtained for any arterial segment accessible to palpation. aPWV is measured with tonometers positioned transcutaneously at the base of the common carotid artery and over the femoral artery. PWV increases with arterial stiffness and is defined by the Moens-Korteweg equation: PWV=square root of Eh/2pR, where E is Young's modulus of the arterial wall, h is the wall thickness, R is the arterial radius at the end of diastole, and p is the blood density. Change from Baseline was calculated as the Day 84 value minus the Baseline value. The analysis was performed using a repeated measures model with covariates of treatment, visit, age, gender, smoking status at screening, geographical region, Baseline aPWV, and interaction terms of Baseline by visit and treatment by visit. (NCT01395888)
Timeframe: Baseline to Day 84 (Early Withdrawal)
| Intervention | meters per second (m/sec) (Least Squares Mean) |
|---|---|
| FF/VI 100/25 µg | -0.859 |
| Tiotropium Bromide 18 µg | -1.118 |
Change in pre-dose morning PEF from run-in period to whole treatment period (NCT01397890)
Timeframe: Mean of daily measurements in run-in period (the last 10 days before randomization) and mean of daily measurements measured before inhalation of study drug in whole treatment period of 12 weeks
| Intervention | L/min (Least Squares Mean) |
|---|---|
| Symbicort+Spiriva | 12.271 |
| Spiriva | -5.198 |
Change in the number of inhalations of reliever medication during day from run-in period to the first week on treatment (NCT01397890)
Timeframe: Mean of daily measurements in run-in period (the last 10 days before randomization) and mean of daily measurements measured during day in the first week on treatment
| Intervention | times/day (Least Squares Mean) |
|---|---|
| Symbicort+Spiriva | -0.457 |
| Spiriva | -0.082 |
Change in the number of inhalations of reliever medication during day from run-in period to the last week on treatment (NCT01397890)
Timeframe: Mean of daily measurements in run-in period (the last 10 days before randomization) and mean of daily measurements measured during day in the last week on treatment, up to 12 weeks
| Intervention | times/day (Least Squares Mean) |
|---|---|
| Symbicort+Spiriva | -0.750 |
| Spiriva | -0.082 |
Change in the number of inhalations of reliever medication during day from run-in period to the whole treatment period (NCT01397890)
Timeframe: Mean of daily measurements in run-in period (the last 10 days before randomization) and mean of daily measurements measured during day in the whole treatment period of 12 weeks
| Intervention | times/day (Least Squares Mean) |
|---|---|
| Symbicort+Spiriva | -0.685 |
| Spiriva | -0.134 |
Change in the number of inhalations of reliever medication during day from run-in period to the first week on treatment (NCT01397890)
Timeframe: Mean of daily measurements in run-in period (the last 10 days before randomization) and mean of daily measurements measured during night in the first week on treatment
| Intervention | times/day (Least Squares Mean) |
|---|---|
| Symbicort+Spiriva | -0.113 |
| Spiriva | 0.011 |
Change in pre-dose morning PEF (Peak Expiratory Flow) from run-in period to first week of treatment (NCT01397890)
Timeframe: Mean of daily measurements in run-in period (the last 10 days before randomization) and mean of daily measurements measured before inhalation of study drug in the first week of treatment
| Intervention | L/min (Least Squares Mean) |
|---|---|
| Symbicort+Spiriva | 13.405 |
| Spiriva | -0.182 |
Change in the number of inhalations of reliever medication during night from run-in period to the last week on treatment (NCT01397890)
Timeframe: Mean of daily measurements in run-in period (the last 10 days before randomization) and mean of daily measurements measured during day in the last week on treatment, up to 12 weeks
| Intervention | times/day (Least Squares Mean) |
|---|---|
| Symbicort+Spiriva | -0.174 |
| Spiriva | 0.062 |
Change in the number of inhalations of reliever medication during night from run-in period to the whole treatment period (NCT01397890)
Timeframe: Mean of daily measurements in run-in period (the last 10 days before randomization) and mean of daily measurements measured during day in the whole treatment period of 12 weeks
| Intervention | times/day (Least Squares Mean) |
|---|---|
| Symbicort+Spiriva | -0.241 |
| Spiriva | -0.010 |
Change in breathing symptom score (from 0:none to 4:severe) from run-in period (NCT01397890)
Timeframe: Mean of daily measurements in run-in period (the last 10 days before randomization) and mean of daily measurements in the whole treatment period of 12 weeks
| Intervention | score on a scale (Least Squares Mean) |
|---|---|
| Symbicort+Spiriva | -0.372 |
| Spiriva | -0.110 |
Change in Cough symptom score (from 0:none to 4:severe) from run-in period (NCT01397890)
Timeframe: Mean of daily measurements in run-in period (the last 10 days before randomization) and mean of daily measurements in the whole treatment period of 12 weeks
| Intervention | score on a scale (Least Squares Mean) |
|---|---|
| Symbicort+Spiriva | -0.311 |
| Spiriva | -0.169 |
Change in Sputum symptom score (from 0:none to 4:severe) from run-in period (NCT01397890)
Timeframe: Mean of daily measurements in run-in period (the last 10 days before randomization) and mean of daily measurements in the whole treatment period of 12 weeks
| Intervention | score on a scale (Least Squares Mean) |
|---|---|
| Symbicort+Spiriva | -0.216 |
| Spiriva | -0.094 |
Severe exacerbations requiring systemic steroids (oral ≥3 days or parenteral) or hospitalisation or emergency room treatment due to worsening of COPD symptoms (NCT01397890)
Timeframe: Whole treatment period of 12 weeks
| Intervention | exacerbations/participant/12 weeks (Least Squares Mean) |
|---|---|
| Symbicort+Spiriva | 0.182 |
| Spiriva | 0.307 |
Ratio of post-dose FEV1 at 5 minutes to baseline value (NCT01397890)
Timeframe: Baseline (-2 weeks) and mean in treatment period (1, 6, 12 weeks) measured at 5 minutes after inhalation of study drug
| Intervention | Ratio (Geometric Mean) |
|---|---|
| Symbicort+Spiriva | 1.128 |
| Spiriva | 1.045 |
Ratio of post-dose FEV1 at 60 minutes to baseline value (NCT01397890)
Timeframe: Baseline (measured before inhalation of study drug at week 0) and mean in treatment period (measured at 1 hour after inhalation of study drug at weeks 0, 1, 6, 12)
| Intervention | Ratio (Geometric Mean) |
|---|---|
| Symbicort+Spiriva | 1.164 |
| Spiriva | 1.072 |
Ratio of post-dose FVC at 5 minutes to baseline value (NCT01397890)
Timeframe: Baseline (measured before inhalation of study drug at week 0) and mean in treatment period (measured at 5 minutes after inhalation of study drug at weeks 0, 1, 6, 12)
| Intervention | Ratio (Geometric Mean) |
|---|---|
| Symbicort+Spiriva | 1.096 |
| Spiriva | 1.044 |
Ratio of post-dose FVC at 60 minutes to baseline value (NCT01397890)
Timeframe: Baseline (measured before inhalation of study drug at week 0) and mean in treatment period (measured at 1 hour after inhalation of study drug at weeks 0, 1, 6, 12)
| Intervention | Ratio (Geometric Mean) |
|---|---|
| Symbicort+Spiriva | 1.116 |
| Spiriva | 1.059 |
Ratio of post-dose IC at 60 minutes to baseline value (NCT01397890)
Timeframe: Baseline (measured before inhalation of study drug at week 0) and mean in treatment period (measured at 1 hour after inhalation of study drug at weeks 0, 1, 6, 12)
| Intervention | Ratio (Geometric Mean) |
|---|---|
| Symbicort+Spiriva | 1.154 |
| Spiriva | 1.087 |
Change in post-dose morning PEF at 5 minutes from run-in period to first week of treatment (NCT01397890)
Timeframe: Mean of daily measurements in run-in period (the last 10 days before randomization) and mean of daily measurements measured at 5 minutes after inhalation of study drug in the first week of treatment
| Intervention | L/min (Least Squares Mean) |
|---|---|
| Symbicort+Spiriva | 17.412 |
| Spiriva | 0.220 |
Change in post-dose morning PEF at 5 minutes from run-period to last week of treatment (NCT01397890)
Timeframe: Mean of daily measurements in run-in period (the last 10 days before randomization) and mean of daily measurements measured at 5 minutes after inhalation of study drug in the last week of treatment, up to 12 weeks
| Intervention | L/min (Least Squares Mean) |
|---|---|
| Symbicort+Spiriva | 23.379 |
| Spiriva | -3.049 |
Change in post-dose morning PEF at 5 minutes from run-period to whole treatment period (NCT01397890)
Timeframe: Mean of daily measurements in run-in period (the last 10 days before randomization) and mean of daily measurements measured at 5 minutes after inhalation of study drug in whole treatment period of 12 weeks
| Intervention | L/min (Least Squares Mean) |
|---|---|
| Symbicort+Spiriva | 15.880 |
| Spiriva | -2.591 |
Ratio of pre-dose FEV1 (Forced Expiratory Volume in 1 second) in treatment period to baseline value (NCT01397890)
Timeframe: Baseline (week 0) and mean in treatment period (weeks 1, 6, 12) measured before inhalation of study drug
| Intervention | Ratio (Geometric Mean) |
|---|---|
| Symbicort+Spiriva | 1.050 |
| Spiriva | 1.006 |
Ratio of pre-dose FVC (Forced Vital Capacity) in treatment period to baseline value (NCT01397890)
Timeframe: Baseline (measured before inhalation of study drug at week 0) and mean in treatment period (measured at 1 hour after inhalation of study drug at weeks 0, 1, 6, 12)
| Intervention | Ratio (Geometric Mean) |
|---|---|
| Symbicort+Spiriva | 1.032 |
| Spiriva | 1.013 |
Ratio of pre-dose IC (Inspiratory Capacity) in treatment period to baseline value (NCT01397890)
Timeframe: Baseline (week 0) and mean in treatment period (weeks 1, 6, 12) measured before inhalation of study drug
| Intervention | Ratio (Geometric Mean) |
|---|---|
| Symbicort+Spiriva | 1.042 |
| Spiriva | 1.022 |
Change in pre-dose morning PEF (Peak Expiratory Flow) from run-in period to last week of treatment (NCT01397890)
Timeframe: Mean of daily measurements in run-in period (the last 10 days before randomization) and mean of daily measurements measured before inhalation of study drug in the last week of treatment, up to 12 weeks
| Intervention | L/min (Least Squares Mean) |
|---|---|
| Symbicort+Spiriva | 15.753 |
| Spiriva | -4.550 |
Spirometry measurements were conducted in accordance with the current ATS/ERS 2005 guidelines. Clinically meaningful is defined as when the change from baseline (mean of the two pre-dose values at Day 1) in 24 hour trough FEV1 on a SUN-101 treatment is more than 100 mL compared to the mean change in trough FEV1 from all subjects on the placebo treatment. (NCT01426009)
Timeframe: Day 1 and Day 7
| Intervention | number of participants (Number) | |
|---|---|---|
| Day 1 | Day 7 | |
| EP-101 Via Nebulizer (eFlow®) 200 mcg | 24 | 37 |
| EP-101 Via Nebulizer (eFlow®) 25 mcg | 18 | 29 |
| EP-101 Via Nebulizer (eFlow®) 50 mcg | 29 | 30 |
| EP-101 Via Nebulizer (eFlow®)100 mcg | 24 | 34 |
| Ipratropium Bromide Inhalation Solution | 24 | 27 |
| Tiotropium Bromide Via (Spiriva® Handihaler®) | 26 | 37 |
percentage of subjects with clinically meaningful change from pre-dose in trough FEV1 on Day 1 and Day 7 Spirometry measurements were conducted in accordance with the current ATS/ERS 2005 guidelines. (NCT01426009)
Timeframe: Day 1 and Day 7
| Intervention | percentage of participants (Number) | |
|---|---|---|
| Day 1 | Day 7 | |
| EP-101 Via Nebulizer (eFlow®) 200 mcg | 35.3 | 51.4 |
| EP-101 Via Nebulizer (eFlow®) 25 mcg | 25.0 | 40.3 |
| EP-101 Via Nebulizer (eFlow®) 50 mcg | 38.7 | 40.0 |
| EP-101 Via Nebulizer (eFlow®)100 mcg | 32.0 | 46.6 |
| Ipratropium Bromide Inhalation Solution | 33.8 | 37.5 |
| Tiotropium Bromide Via (Spiriva® Handihaler®) | 34.7 | 48.7 |
Spirometry measurements were conducted in accordance with the current ATS/ERS 2005 guidelines. Trough FEV1 was defined as the mean of the spirometry values collected at 23 hours 30 minutes and 24 hours post dose for Day 1 and Day 7 within each Treatment Period. Baseline was calculated as the mean of the FEV1 values at 45 minutes and 15 minutes prior to the morning dose at Day 1 of each Treatment Period. Change from baseline was calculated as the trough FEV1 value minus the baseline for Day 1 and Day 7. (NCT01426009)
Timeframe: Day 1 and Day 7
| Intervention | liters (Mean) | |
|---|---|---|
| Trough FEV1 - day 1 | Trough FEV1 - day 7 | |
| EP-101 Via Nebulizer (eFlow®) 200 mcg | 0.0632 | 0.0840 |
| EP-101 Via Nebulizer (eFlow®) 25 mcg | 0.0477 | 0.0478 |
| EP-101 Via Nebulizer (eFlow®) 50 mcg | 0.1009 | 0.0699 |
| EP-101 Via Nebulizer (eFlow®)100 mcg | 0.0648 | 0.0666 |
| Ipratropium Bromide Inhalation Solution | 0.0933 | 0.0292 |
| Placebo | 0.0301 | -0.155 |
| Tiotropium Bromide Via (Spiriva® Handihaler®) | 0.0740 | 0.0564 |
AEs are defined as existing conditions which worsen or events which occur during the course of the clinical trial after treatment. Vital signs were performed during the screening period to confirm study eligibility and at the final study visit. ECGs were performed during the screening period to confirm study eligibility. Vital signs and ECG were additionally collected within 30 minutes pre-dose; and 30 minutes, and 1, 2, 4, 6, 12 hours, and 23 hours 45 minutes post-dose within each treatment period. Clinical laboratory assessments were conducted during the screening period, at each study visit during each treatment period, and at the final study visit. (NCT01426009)
Timeframe: Day 1 through Day 7
| Intervention | Participants (Count of Participants) | ||||
|---|---|---|---|---|---|
| Treatment emergent AEs | Clinical signicant abnormal vital signs | Clinically significant abnormal ECG values Day 1 | Clinically significant abnormal ECG values Day 7 | Clinicall significant abnormal lab valuesday1-day7 | |
| EP-101 Via Nebulizer (eFlow®) 200 mcg | 26 | 0 | 11 | 11 | 2 |
| EP-101 Via Nebulizer (eFlow®) 25 mcg | 23 | 0 | 10 | 7 | 1 |
| EP-101 Via Nebulizer (eFlow®) 50 mcg | 23 | 0 | 7 | 5 | 0 |
| EP-101 Via Nebulizer (eFlow®)100 mcg | 28 | 2 | 13 | 8 | 2 |
| Ipratropium Bromide Inhalation Solution | 19 | 1 | 5 | 3 | 1 |
| Placebo | 25 | 1 | 6 | 7 | 3 |
| Tiotropium Bromide Via (Spiriva® Handihaler®) | 12 | 0 | 8 | 8 | 0 |
Spirometry measurements were conducted in accordance with the current ATS/ERS 2005 guidelines (NCT01426009)
Timeframe: Day 1 and Day 7
| Intervention | liters (Mean) | |
|---|---|---|
| Day 1 | Day 7 | |
| EP-101 Via Nebulizer (eFlow®) 200 mcg | 1.455 | 1.453 |
| EP-101 Via Nebulizer (eFlow®) 25 mcg | 1.469 | 1.482 |
| EP-101 Via Nebulizer (eFlow®) 50 mcg | 1.498 | 1.496 |
| EP-101 Via Nebulizer (eFlow®)100 mcg | 1.443 | 1.462 |
| Ipratropium Bromide Inhalation Solution | 1.601 | 1.594 |
| Placebo | 1.356 | 1.348 |
| Tiotropium Bromide Via (Spiriva® Handihaler®) | 1.434 | 1.475 |
Mean number of puffs of daily rescue medication (NCT01426009)
Timeframe: Day 1 through Day 7
| Intervention | average daily number of puffs (Mean) |
|---|---|
| EP-101 Via Nebulizer (eFlow®) 25 mcg | 1.34 |
| EP-101 Via Nebulizer (eFlow®) 50 mcg | 1.11 |
| EP-101 Via Nebulizer (eFlow®)100 mcg | 1.48 |
| EP-101 Via Nebulizer (eFlow®) 200 mcg | 1.29 |
| Ipratropium Bromide Inhalation Solution | 1.42 |
| Tiotropium Bromide Via (Spiriva® Handihaler®) | 1.33 |
| Placebo | 1.59 |
Spirometry measurements were conducted in accordance with the current ATS/ERS 2005 guidelines. The standardized FEV1 AUC(0-12hr and 12-24hr) on Day 1 and Day 7 was calculated using the trapezoidal rule from the changes in FEV1 at Day 1 and Day 7, respectively, from the baseline value (the mean of the two FEV1 values at 45 minutes and 15 minutes prior to morning dose at Day 1 of the respective Treatment Periods) and dividing by the actual length of the time interval. (NCT01426009)
Timeframe: Day 1 and Day 7
| Intervention | liters (Mean) | |||||
|---|---|---|---|---|---|---|
| AUC 0-12 on Day 1 | AUC 12-24 on Day 1 | AUC 0-24 on Day 1 | AUC 0-12 on Day 7 | AUC 12-24 on Day 7 | AUC 0-24 on Day 7 | |
| EP-101 Via Nebulizer (eFlow®) 200 mcg | 0.1720 | 0.0645 | 0.1194 | 0.1438 | 0.0614 | 0.1030 |
| EP-101 Via Nebulizer (eFlow®) 25 mcg | 0.1001 | 0.0039 | 0.0525 | 0.1034 | 0.0112 | 0.0579 |
| EP-101 Via Nebulizer (eFlow®) 50 mcg | 0.1520 | 0.0681 | 0.1107 | 0.1411 | 0.0540 | 0.0980 |
| EP-101 Via Nebulizer (eFlow®)100 mcg | 0.1414 | 0.0413 | 0.0919 | 0.1329 | 0.0278 | 0.0812 |
| Ipratropium Bromide Inhalation Solution | 0.1990 | 0.0987 | 0.1496 | 0.1603 | 0.0357 | 0.1009 |
| Placebo | 0.0130 | -0.0245 | -0.0073 | -0.0098 | 0.0698 | -0.0395 |
| Tiotropium Bromide Via (Spiriva® Handihaler®) | 0.1213 | 0.0499 | 0.0872 | 0.1256 | 0.0283 | 0.0776 |
"Mahler Transitional Dyspnoea Index (TDI) focal score on Day 43 From the Two Twin Trials, present 1237.5 (NCT01431274) and 1237.6 (NCT01431287).~The Mahler Dyspnoea questionnaire is an instrument which measures change from the baseline state The TDI focal score was used to measure the effect of Tio+Olo FDC on patients' dyspnoea after 24 weeks of treatment (Day 169). The focal score is the sum of the subscale scores for Functional Impairment, Magnitude of Effort and Magnitude of Task. Scores for each subscale range from -3 to 3 so that the Focal score ranges from -9 to 9. For all subscale scores and the Focal score a higher value indicates a better outcome. Number of participants analyzed are the number of patients contributing to the mixed effect repeated measures model (MMRM) in each treatment group." (NCT01431274)
Timeframe: Day 43
| Intervention | points on a scale (Least Squares Mean) |
|---|---|
| Olodaterol (5 μg) | 1.453 |
| Tiotropium (2.5 μg) | 1.430 |
| Tiotropium (5 μg) | 1.408 |
| Tio+Olo FDC (2.5/5 μg) | 1.876 |
| Tio+Olo FDC (5/5 μg) | 2.048 |
"Mahler Transitional Dyspnoea Index (TDI) focal score on Day 85 From the Two Twin Trials, present 1237.5 (NCT01431274) and 1237.6 (NCT01431287).~The Mahler Dyspnoea questionnaire is an instrument which measures change from the baseline state The TDI focal score was used to measure the effect of Tio+Olo FDC on patients' dyspnoea after 24 weeks of treatment (Day 169). The focal score is the sum of the subscale scores for Functional Impairment, Magnitude of Effort and Magnitude of Task. Scores for each subscale range from -3 to 3 so that the Focal score ranges from -9 to 9. For all subscale scores and the Focal score a higher value indicates a better outcome.~Number of participants analyzed are the number of patients contributing to the mixed effect repeated measures model (MMRM) in each treatment group." (NCT01431274)
Timeframe: Day 85
| Intervention | points on a scale (Least Squares Mean) |
|---|---|
| Olodaterol (5 μg) | 1.506 |
| Tiotropium (2.5 μg) | 1.698 |
| Tiotropium (5 μg) | 1.702 |
| Tio+Olo FDC (2.5/5 μg) | 1.925 |
| Tio+Olo FDC (5/5 μg) | 2.136 |
The SGRQ is designed to measure health impairment in patients with COPD. It is divided into 2 parts: part 1 produces the symptoms score, and part 2 the activity and impacts scores. A total score is also produced. Each subscale score is the sum of the weights for the items in the subscale as a percent of the sum of the weights for a patient in the worst possible condition. The total score uses the same calculation except that the weights are summed over the entire questionnaire. The individual subscales as well as the total score can range from 0 to 100 with a lower score denoting a better health status. Number of participants analyzed are the number of patients contributing to the mixed effect repeated measures model (MMRM) in each treatment group. (NCT01431274)
Timeframe: Day 169
| Intervention | points on a scale (Least Squares Mean) |
|---|---|
| Olodaterol (5 μg) | 38.366 |
| Tiotropium (2.5 μg) | 37.792 |
| Tiotropium (5 μg) | 37.907 |
| Tio+Olo FDC (2.5/5 μg) | 37.335 |
| Tio+Olo FDC (5/5 μg) | 36.674 |
The SGRQ is designed to measure health impairment in patients with COPD. It is divided into 2 parts: part 1 produces the symptoms score, and part 2 the activity and impacts scores. A total score is also produced. Each subscale score is the sum of the weights for the items in the subscale as a percent of the sum of the weights for a patient in the worst possible condition. The total score uses the same calculation except that the weights are summed over the entire questionnaire. The individual subscales as well as the total score can range from 0 to 100 with a lower score denoting a better health status. Number of participants analyzed are the number of patients contributing to the mixed effect repeated measures model (MMRM) in each treatment group. (NCT01431274)
Timeframe: Day 365
| Intervention | points on a scale (Least Squares Mean) |
|---|---|
| Olodaterol (5 μg) | 38.989 |
| Tiotropium (2.5 μg) | 37.609 |
| Tiotropium (5 μg) | 37.581 |
| Tio+Olo FDC (2.5/5 μg) | 37.553 |
| Tio+Olo FDC (5/5 μg) | 37.138 |
"Trough FEV1 was defined as the FEV1 value at the end of the dosing interval (24 hours), calculated as the mean of the pre-dose measurements.~Trough FEV1 response was defined as trough FEV1 minus baseline FEV1. Baseline was defined as the mean of the 2 pre-dose measurements performed~1 h and 10 min prior to administration of the first dose of randomised treatment at Day1.~Number of participants analyzed are the number of patients contributing to the mixed effect repeated measures (MMRM) model in each treatment group." (NCT01431274)
Timeframe: 1 h and 10 min prior to dose on the first day of randomized treatment (baseline) and at 1 hr and 10 min pre-dose on day 85.
| Intervention | Litres (Least Squares Mean) |
|---|---|
| Olodaterol (5 μg) | 0.057 |
| Tiotropium (2.5 μg) | 0.077 |
| Tiotropium (5 μg) | 0.070 |
| Tio+Olo FDC (2.5/5 μg) | 0.128 |
| Tio+Olo FDC (5/5 μg) | 0.146 |
The SGRQ is designed to measure health impairment in patients with COPD. It is divided into 2 parts: part 1 produces the symptoms score, and part 2 the activity and impacts scores. A total score is also produced. Each subscale score is the sum of the weights for the items in the subscale as a percent of the sum of the weights for a patient in the worst possible condition. The total score uses the same calculation except that the weights are summed over the entire questionnaire. The individual subscales as well as the total score can range from 0 to 100 with a lower score denoting a better health status. Number of participants analyzed are the number of patients contributing to the mixed effect repeated measures model (MMRM) in each treatment group. (NCT01431274)
Timeframe: Day 85
| Intervention | points on a scale (Least Squares Mean) |
|---|---|
| Olodaterol (5 μg) | 38.832 |
| Tiotropium (2.5 μg) | 37.821 |
| Tiotropium (5 μg) | 37.822 |
| Tio+Olo FDC (2.5/5 μg) | 37.304 |
| Tio+Olo FDC (5/5 μg) | 36.691 |
"Trough FVC was defined as the FVC value at the end of the dosing interval (24 hours), calculated as the mean of the pre-dose measurements.~Trough FVC response was defined as trough FVC minus baseline FVC. Baseline was defined as the mean of the 2 pre-dose measurements performed 1 h and 10 min prior to administration of the first dose at visit 2 (day 1).~Number of participants analyzed are the number of patients contributing to the mixed effect repeated measures (MMRM) model in each treatment group.~The adjusted means (SE) were obtained from fitting an Mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment-by-test day interaction, baseline and baseline-by-test day interaction, patient as random effect, and spatial power covariance structure for within-patient errors and Kenward-Roger approximation for denominator degrees of freedom." (NCT01431274)
Timeframe: 1 h and 10 min prior to dose on the first day of randomized treatment (baseline) and at 10 min pre-dose on day 15
| Intervention | Litres (Least Squares Mean) |
|---|---|
| Olodaterol (5 μg) | 0.149 |
| Tiotropium (2.5 μg) | 0.222 |
| Tiotropium (5 μg) | 0.220 |
| Tio+Olo FDC (2.5/5 μg) | 0.270 |
| Tio+Olo FDC (5/5 μg) | 0.296 |
"Trough FEV1 was defined as the FEV1 value at the end of the dosing interval (24 hours), calculated as the mean of the pre-dose measurements.~Trough FEV1 response was defined as trough FEV1 minus baseline FEV1. Baseline was defined as the mean of the 2 pre-dose measurements performed~1 h and 10 min prior to administration of the first dose of randomised treatment at Day1.~Number of participants analyzed are the number of patients contributing to the mixed effect repeated measures (MMRM) model in each treatment group." (NCT01431274)
Timeframe: 1 h and 10 min prior to dose on the first day of randomized treatment (baseline) and at 10 min pre-dose on day 43.
| Intervention | Litres (Least Squares Mean) |
|---|---|
| Olodaterol (5 μg) | 0.083 |
| Tiotropium (2.5 μg) | 0.097 |
| Tiotropium (5 μg) | 0.088 |
| Tio+Olo FDC (2.5/5 μg) | 0.120 |
| Tio+Olo FDC (5/5 μg) | 0.163 |
"Trough FEV1 was defined as the FEV1 value at the end of the dosing interval (24 hours), calculated as the mean of the pre-dose measurements.~Trough FEV1 response was defined as trough FEV1 minus baseline FEV1. Baseline was defined as the mean of the 2 pre-dose measurements performed~1 h and 10 min prior to administration of the first dose of randomised treatment at Day1.~Number of participants analyzed are the number of patients contributing to the mixed effect repeated measures (MMRM) model in each treatment group." (NCT01431274)
Timeframe: 1 h and 10 min prior to dose on the first day of randomized treatment (baseline) and at 1 hr and 10 min pre-dose on day 365
| Intervention | Litres (Least Squares Mean) |
|---|---|
| Olodaterol (5 μg) | -0.000 |
| Tiotropium (2.5 μg) | 0.028 |
| Tiotropium (5 μg) | 0.036 |
| Tio+Olo FDC (2.5/5 μg) | 0.075 |
| Tio+Olo FDC (5/5 μg) | 0.099 |
"Trough FEV1 was defined as the FEV1 value at the end of the dosing interval (24 hours) and was calculated as the mean of the 2 FEV1 measurements performed at 23 h and at 23 h 50 min after inhalation of study medication at the clinic visit on the previous day.~Trough FEV1 response was defined as trough FEV1 minus baseline FEV1. Baseline was defined as the mean of the 2 pre-dose measurements performed 1 h and 10 min prior to administration of the first dose at visit 2 (day 1).~The adjusted means (SE) were obtained from fitting an MMRM including fixed effects of treatment, planned test day, treatment-by-test day interaction, baseline and baseline-by-test day interaction, patient as random effect, and spatial power covariance structure for within-patient errors and Kenward-Roger approximation for denominator degrees of freedom.~Number of participants analyzed are the number of patients contributing to the mixed effect repeated measures (MMRM) model in each treatment group." (NCT01431274)
Timeframe: 1 h and 10 min prior to dose on the first day of randomized treatment (baseline) and at 23 h and at 23 h 50 min after inhalation of study medication on Day 170
| Intervention | Litres (Least Squares Mean) |
|---|---|
| Olodaterol (5 μg) | 0.054 |
| Tiotropium (2.5 μg) | 0.083 |
| Tiotropium (5 μg) | 0.065 |
| Tio+Olo FDC (2.5/5 μg) | 0.111 |
| Tio+Olo FDC (5/5 μg) | 0.136 |
"Trough FEV1 was defined as the FEV1 value at the end of the dosing interval (24 hours), calculated as the mean of the pre-dose measurements.~Trough FEV1 response was defined as trough FEV1 minus baseline FEV1. Baseline was defined as the mean of the 2 pre-dose measurements performed~1 h and 10 min prior to administration of the first dose of randomised treatment at Day1.~Number of participants analyzed are the number of patients contributing to the mixed effect repeated measures (MMRM) model in each treatment group." (NCT01431274)
Timeframe: 1 h and 10 min prior to dose on the first day of randomized treatment (baseline) and at 10 min pre-dose on day 15
| Intervention | Litres (Least Squares Mean) |
|---|---|
| Olodaterol (5 μg) | 0.085 |
| Tiotropium (2.5 μg) | 0.101 |
| Tiotropium (5 μg) | 0.094 |
| Tio+Olo FDC (2.5/5 μg) | 0.132 |
| Tio+Olo FDC (5/5 μg) | 0.157 |
"FEV1 AUC(0-3h) was calculated as the area under the FEV1- time curve from 0 to 3 h post-dose using the trapezoidal rule, divided by the duration (3 h) to report in litres. FEV1 AUC(0-3h) response was defined as FEV1 AUC(0-3h) minus baseline FEV1. Baseline was defined as the mean of the 2 pre-dose measurements performed 1 h and 10 min prior to administration of the first dose of randomised treatment at Day1.~The adjusted means (SE) were obtained from fitting an Mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment-by-test day interaction, baseline and baseline-by-test day interaction, patient as random effect, and spatial power covariance structure for within-patient errors and Kenward-Roger approximation for denominator degrees of freedom.~Number of participants analyzed are the number of patients contributing to the mixed effect repeated measures (MMRM) model in each treatment group." (NCT01431274)
Timeframe: 1 hour (h) and 10 minutes (min) prior to dose to on the first day of randomized treatment and on Day 85 and 5 min, 15 min, 30 min, 1 h, 2 h, 3 h post-dose on Day 85.
| Intervention | Litres (Least Squares Mean) |
|---|---|
| Olodaterol (5 μg) | 0.161 |
| Tiotropium (2.5 μg) | 0.176 |
| Tiotropium (5 μg) | 0.162 |
| Tio+Olo FDC (2.5/5 μg) | 0.271 |
| Tio+Olo FDC (5/5 μg) | 0.289 |
"FEV1 AUC(0-3h) was calculated as the area under the FEV1- time curve from 0 to 3 h post-dose using the trapezoidal rule, divided by the duration (3 h) to report in litres. FEV1 AUC(0-3h) response was defined as FEV1 AUC(0-3h) minus baseline FEV1. Baseline was defined as the mean of the 2 pre-dose measurements performed 1 h and 10 min prior to administration of the first dose at visit 2 (day 1).~The adjusted means (SE) were obtained from fitting an Mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment-by-test day interaction, baseline and baseline-by-test day interaction, patient as random effect, and spatial power covariance structure for within-patient errors and Kenward-Roger approximation for denominator degrees of freedom. Number of participants analyzed are the number of patients contributing to the MMRM model in each treatment group." (NCT01431274)
Timeframe: 1 hour (h) and 10 minutes (min) prior to dose to on the first day of randomized treatment and on Day 169 and 5 min, 15 min, 30 min, 1 h, 2 h, 3 h post-dose on Day 169.
| Intervention | Litres (Least Squares Mean) |
|---|---|
| Olodaterol (5 μg) | 0.133 |
| Tiotropium (2.5 μg) | 0.148 |
| Tiotropium (5 μg) | 0.139 |
| Tio+Olo FDC (2.5/5 μg) | 0.241 |
| Tio+Olo FDC (5/5 μg) | 0.256 |
"FEV1 AUC(0-3h) was calculated as the area under the FEV1- time curve from 0 to 3 h post-dose using the trapezoidal rule, divided by the duration (3 h) to report in litres. FEV1 AUC(0-3h) response was defined as FEV1 AUC(0-3h) minus baseline FEV1. Baseline was defined as the mean of the 2 pre-dose measurements performed 1 h and 10 min prior to administration of the first dose of randomised treatment at Day1.~The adjusted means (SE) were obtained from fitting an Mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment-by-test day interaction, baseline and baseline-by-test day interaction, patient as random effect, and spatial power covariance structure for within-patient errors and Kenward-Roger approximation for denominator degrees of freedom.~Number of participants analyzed are the number of patients contributing to the mixed effect repeated measures (MMRM) model in each treatment group." (NCT01431274)
Timeframe: 1 hour (h) and 10 minutes (min) prior to dose to on the first day of randomized treatment and on Day 365 and 5 min, 15 min, 30 min, 1 h, 2 h, 3 h post-dose on Day 365.
| Intervention | Litres (Least Squares Mean) |
|---|---|
| Olodaterol (5 μg) | 0.096 |
| Tiotropium (2.5 μg) | 0.116 |
| Tiotropium (5 μg) | 0.122 |
| Tio+Olo FDC (2.5/5 μg) | 0.214 |
| Tio+Olo FDC (5/5 μg) | 0.237 |
"FVC AUC(0-3h) was calculated as the area under the FVC- time curve from 0 to 3 h post-dose using the trapezoidal rule, divided by the duration (3 h) to report in litres.~FVC AUC(0-3h) response was defined as FVC AUC(0-3h) minus baseline FVC. Baseline was defined as the mean of the 2 pre-dose measurements performed 1 h and 10 min prior to administration of the first dose at visit 2 (day 1).~The adjusted means (SE) were obtained from fitting an Mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment-by-test day interaction, baseline and baseline-by-test day interaction, patient as random effect, and spatial power covariance structure for within-patient errors and Kenward-Roger approximation for denominator degrees of freedom.~Number of participants analyzed are the number of patients contributing to the mixed effect repeated measures (MMRM) model in each treatment group." (NCT01431274)
Timeframe: 1 hour (h) and 10 minutes (min) prior to dose to 5 min, 15 min, 30 min, 1 h, 2 h, 3 h post-dose on the first day of randomized treatment.
| Intervention | Litres (Least Squares Mean) |
|---|---|
| Olodaterol (5 μg) | 0.350 |
| Tiotropium (2.5 μg) | 0.277 |
| Tiotropium (5 μg) | 0.289 |
| Tio+Olo FDC (2.5/5 μg) | 0.400 |
| Tio+Olo FDC (5/5 μg) | 0.427 |
"FVC AUC(0-3h) was calculated as the area under the FVC- time curve from 0 to 3 h post-dose using the trapezoidal rule, divided by the duration (3 h) to report in litres.~FVC AUC(0-3h) response was defined as FVC AUC(0-3h) minus baseline FVC. Baseline was defined as the mean of the 2 pre-dose measurements performed 1 h and 10 min prior to administration of the first dose at visit 2 (day 1).~The adjusted means (SE) were obtained from fitting an Mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment-by-test day interaction, baseline and baseline-by-test day interaction, patient as random effect, and spatial power covariance structure for within-patient errors and Kenward-Roger approximation for denominator degrees of freedom.~Number of participants analyzed are the number of patients contributing to the mixed effect repeated measures (MMRM) model in each treatment group." (NCT01431274)
Timeframe: 1 hour (h) and 10 minutes (min) prior to dose to on the first day of randomized treatment and on Day 169 and 5 min, 15 min, 30 min, 1 h, 2 h, 3 h post-dose on Day 169.
| Intervention | Litres (Least Squares Mean) |
|---|---|
| Olodaterol (5 μg) | 0.212 |
| Tiotropium (2.5 μg) | 0.279 |
| Tiotropium (5 μg) | 0.254 |
| Tio+Olo FDC (2.5/5 μg) | 0.386 |
| Tio+Olo FDC (5/5 μg) | 0.407 |
"FVC AUC(0-3h) was calculated as the area under the FVC- time curve from 0 to 3 h post-dose using the trapezoidal rule, divided by the duration (3 h) to report in litres.~FVC AUC(0-3h) response was defined as FVC AUC(0-3h) minus baseline FVC. Baseline was defined as the mean of the 2 pre-dose measurements performed 1 h and 10 min prior to administration of the first dose at visit 2 (day 1).~The adjusted means (SE) were obtained from fitting an Mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment-by-test day interaction, baseline and baseline-by-test day interaction, patient as random effect, and spatial power covariance structure for within-patient errors and Kenward-Roger approximation for denominator degrees of freedom.~Number of participants analyzed are the number of patients contributing to the mixed effect repeated measures (MMRM) model in each treatment group." (NCT01431274)
Timeframe: 1 hour (h) and 10 minutes (min) prior to dose to on the first day of randomized treatment and on Day 365 and 5 min, 15 min, 30 min, 1 h, 2 h, 3 h post-dose on Day 365.
| Intervention | Litres (Least Squares Mean) |
|---|---|
| Olodaterol (5 μg) | 0.172 |
| Tiotropium (2.5 μg) | 0.241 |
| Tiotropium (5 μg) | 0.221 |
| Tio+Olo FDC (2.5/5 μg) | 0.364 |
| Tio+Olo FDC (5/5 μg) | 0.377 |
"FVC AUC(0-3h) was calculated as the area under the FVC- time curve from 0 to 3 h post-dose using the trapezoidal rule, divided by the duration (3 h) to report in litres.~FVC AUC(0-3h) response was defined as FVC AUC(0-3h) minus baseline FVC.Baseline was defined as the mean of the 2 pre-dose measurements performed 1 h and 10 min prior to administration of the first dose at visit 2 (day 1).~The adjusted means (SE) were obtained from fitting an Mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment-by-test day interaction, baseline and baseline-by-test day interaction, patient as random effect, and spatial power covariance structure for within-patient errors and Kenward-Roger approximation for denominator degrees of freedom.~Number of participants analyzed are the number of patients contributing to the mixed effect repeated measures (MMRM) model in each treatment group." (NCT01431274)
Timeframe: 1 hour (h) and 10 minutes (min) prior to dose to on the first day of randomized treatment and on Day 85 and 5 min, 15 min, 30 min, 1 h, 2 h, 3 h post-dose on Day 85.
| Intervention | Litres (Least Squares Mean) |
|---|---|
| Olodaterol (5 μg) | 0.247 |
| Tiotropium (2.5 μg) | 0.318 |
| Tiotropium (5 μg) | 0.275 |
| Tio+Olo FDC (2.5/5 μg) | 0.432 |
| Tio+Olo FDC (5/5 μg) | 0.469 |
"FEV1 AUC(0-3h) was calculated as the area under the FEV1- time curve from 0 to 3 h post-dose using the trapezoidal rule, divided by the duration (3 h) to report in litres.~FEV1 AUC(0-3h) response was defined as FEV1 AUC(0-3h) minus baseline FEV1. Baseline was defined as the mean of the 2 pre-dose measurements performed 1 h and 10 min prior to administration of the first dose of randomised treatment at Day1.~The adjusted means (SE) were obtained from fitting an Mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment-by-test day interaction, baseline and baseline-by-test day interaction, patient as random effect, and spatial power covariance structure for within-patient errors and Kenward-Roger approximation for denominator degrees of freedom.~Number of participants analyzed are the number of patients contributing to the mixed effect repeated measures (MMRM) model in each treatment group." (NCT01431274)
Timeframe: 1 hour (h) and 10 minutes (min) prior to dose to 5 min, 15 min, 30 min, 1 h, 2 h, 3 h post-dose on the first day of randomized treatment.
| Intervention | Litres (Least Squares Mean) |
|---|---|
| Olodaterol (5 μg) | 0.205 |
| Tiotropium (2.5 μg) | 0.148 |
| Tiotropium (5 μg) | 0.157 |
| Tio+Olo FDC (2.5/5 μg) | 0.226 |
| Tio+Olo FDC (5/5 μg) | 0.237 |
"FEV1 AUC(0-24h) was calculated as the area under the FEV1- time curve from 0 to 24 h post-dose using the trapezoidal rule, divided by the duration (24 h) to report in litres. FEV1 AUC(0-24h) response was defined as FEV1 AUC(0-24h) minus baseline FEV1. Baseline was defined as the mean of the 2 pre-dose measurements performed 1 h and 10 min prior to administration of the first dose at visit 2 (day 1).~The adjusted mean (SE) were obtained from fitting an ANCOVA model with categorical effect of treatment and baseline as covariate.~Number of participants analyzed are the number of patients contributing to the ANCOVA model in each treatment group." (NCT01431274)
Timeframe: 1 hour (h) and 10 minutes (min) prior to dose to on the first day of randomized treatment and on Day 169 and 5 min, 15 min, 30 min, 1 h, 2 h, 3 h, 4 h, 5 h, 6 h, 8 h, 10 h, 12 h, 23 h, 23 h and 50 min post-dose on Day 169.
| Intervention | Litres (Least Squares Mean) |
|---|---|
| Olodaterol (5 μg) | 0.108 |
| Tiotropium (2.5 μg) | 0.083 |
| Tiotropium (5 μg) | 0.100 |
| Tio+Olo FDC (2.5/5 μg) | 0.159 |
| Tio+Olo FDC (5/5 μg) | 0.206 |
"FEV1 AUC(0-12h) was calculated as the area under the FEV1- time curve from 0 to 12 h post-dose using the trapezoidal rule, divided by the duration (12 h) to report in litres.~FEV1 AUC(0-12h) response was defined as FEV1 AUC(0-12h) minus baseline FEV1. Baseline was defined as the mean of the 2 pre-dose measurements performed 1 h and 10 min prior to administration of the first dose at visit 2 (day 1).~The adjusted mean (SE) were obtained from fitting an ANCOVA model with categorical effect of treatment and baseline as covariate.~Number of participants analyzed are the number of patients contributing to the ANCOVA model in each treatment group." (NCT01431274)
Timeframe: 1 hour (h) and 10 minutes (min) prior to dose to on the first day of randomized treatment and on Day 169 and 5 min, 15 min, 30 min, 1 h, 2 h, 3 h, 4 h, 5 h, 6 h, 8 h, 10 h, 12 h post-dose on Day 169.
| Intervention | Litres (Least Squares Mean) |
|---|---|
| Olodaterol (5 μg) | 0.131 |
| Tiotropium (2.5 μg) | 0.109 |
| Tiotropium (5 μg) | 0.127 |
| Tio+Olo FDC (2.5/5 μg) | 0.202 |
| Tio+Olo FDC (5/5 μg) | 0.250 |
"Mahler Transitional Dyspnoea Index (TDI) focal score on Day 365 From the Two Twin Trials, present 1237.5 (NCT01431274) and 1237.6 (NCT01431287).~The Mahler Dyspnoea questionnaire is an instrument which measures change from the baseline state The TDI focal score was used to measure the effect of Tio+Olo FDC on patients' dyspnoea after 24 weeks of treatment (Day 169). The focal score is the sum of the subscale scores for Functional Impairment, Magnitude of Effort and Magnitude of Task. Scores for each subscale range from -3 to 3 so that the Focal score ranges from -9 to 9. For all subscale scores and the Focal score a higher value indicates a better outcome. Number of participants analyzed are the number of patients contributing to the mixed effect repeated measures model (MMRM) in each treatment group." (NCT01431274)
Timeframe: Day 365
| Intervention | points on a scale (Least Squares Mean) |
|---|---|
| Olodaterol (5 μg) | 1.411 |
| Tiotropium (2.5 μg) | 1.450 |
| Tiotropium (5 μg) | 1.736 |
| Tio+Olo FDC (2.5/5 μg) | 1.782 |
| Tio+Olo FDC (5/5 μg) | 2.058 |
"FVC AUC(0-24h) was calculated as the area under the FVC- time curve from 0 to 24 h post-dose using the trapezoidal rule, divided by the duration (24 h) to report in litres.~FVC AUC(0-24h) response was defined as FVC AUC(0-24h) minus baseline FVC. Baseline was defined as the mean of the 2 pre-dose measurements performed 1 h and 10 min prior to administration of the first dose at visit 2 (day 1).~The adjusted mean (SE) were obtained from fitting an ANCOVA model with categorical effect of treatment and baseline as covariate.~Number of participants analyzed are the number of patients contributing to the ANCOVA model in each treatment group." (NCT01431274)
Timeframe: 1 hour (h) and 10 minutes (min) prior to dose to on the first day of randomized treatment and on Day 169 and 5 min, 15 min, 30 min, 1 h, 2 h, 3 h, 4 h, 5 h, 6 h, 8 h, 10 h, 12 h, 23 h, 23 h and 50 min post-dose on Day 169.
| Intervention | Litres (Least Squares Mean) |
|---|---|
| Olodaterol (5 μg) | 0.192 |
| Tiotropium (2.5 μg) | 0.141 |
| Tiotropium (5 μg) | 0.203 |
| Tio+Olo FDC (2.5/5 μg) | 0.297 |
| Tio+Olo FDC (5/5 μg) | 0.329 |
"Trough FVC was defined as the FVC value at the end of the dosing interval (24 hours), calculated as the mean of the pre-dose measurements.~Trough FVC response was defined as trough FVC minus baseline FVC. Baseline was defined as the mean of the 2 pre-dose measurements performed 1 h and 10 min prior to administration of the first dose at visit 2 (day 1).~Number of participants analyzed are the number of patients contributing to the mixed effect repeated measures (MMRM) model in each treatment group.~The adjusted means (SE) were obtained from fitting an Mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment-by-test day interaction, baseline and baseline-by-test day interaction, patient as random effect, and spatial power covariance structure for within-patient errors and Kenward-Roger approximation for denominator degrees of freedom." (NCT01431274)
Timeframe: 1 h and 10 min prior to dose on the first day of randomized treatment (baseline) and on Day 365.
| Intervention | Litres (Least Squares Mean) |
|---|---|
| Olodaterol (5 μg) | 0.014 |
| Tiotropium (2.5 μg) | 0.114 |
| Tiotropium (5 μg) | 0.108 |
| Tio+Olo FDC (2.5/5 μg) | 0.155 |
| Tio+Olo FDC (5/5 μg) | 0.191 |
"Trough FVC was defined as the FVC value at the end of the dosing interval (24 hours), calculated as the mean of the pre-dose measurements.~Trough FVC response was defined as trough FVC minus baseline FVC. Baseline was defined as the mean of the 2 pre-dose measurements performed 1 h and 10 min prior to administration of the first dose at visit 2 (day 1).~Number of participants analyzed are the number of patients contributing to the mixed effect repeated measures (MMRM) model in each treatment group.~The adjusted means (SE) were obtained from fitting an Mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment-by-test day interaction, baseline and baseline-by-test day interaction, patient as random effect, and spatial power covariance structure for within-patient errors and Kenward-Roger approximation for denominator degrees of freedom." (NCT01431274)
Timeframe: 1 h and 10 min prior to dose on the first day of randomized treatment (baseline) and on day 85
| Intervention | Litres (Least Squares Mean) |
|---|---|
| Olodaterol (5 μg) | 0.077 |
| Tiotropium (2.5 μg) | 0.168 |
| Tiotropium (5 μg) | 0.144 |
| Tio+Olo FDC (2.5/5 μg) | 0.230 |
| Tio+Olo FDC (5/5 μg) | 0.265 |
"Trough FVC was defined as the FVC value at the end of the dosing interval (24 hours), calculated as the mean of the pre-dose measurements.~Trough FVC response was defined as trough FVC minus baseline FVC. Baseline was defined as the mean of the 2 pre-dose measurements performed 1 h and 10 min prior to administration of the first dose at visit 2 (day 1).~Number of participants analyzed are the number of patients contributing to the mixed effect repeated measures (MMRM) model in each treatment group.~The adjusted means (SE) were obtained from fitting an Mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment-by-test day interaction, baseline and baseline-by-test day interaction, patient as random effect, and spatial power covariance structure for within-patient errors and Kenward-Roger approximation for denominator degrees of freedom." (NCT01431274)
Timeframe: 1 h and 10 min prior to dose on the first day of randomized treatment (baseline) and at 10 min pre-dose on day 43
| Intervention | Litres (Least Squares Mean) |
|---|---|
| Olodaterol (5 μg) | 0.150 |
| Tiotropium (2.5 μg) | 0.206 |
| Tiotropium (5 μg) | 0.213 |
| Tio+Olo FDC (2.5/5 μg) | 0.254 |
| Tio+Olo FDC (5/5 μg) | 0.318 |
"Mahler Transitional Dyspnoea Index (TDI) focal score on Day 169 From the Two Twin Trials, present 1237.5 (NCT01431274) and 1237.6 (NCT01431287) is the key secondary endpoint.~The Mahler Dyspnoea questionnaire is an instrument which measures change from the baseline state The TDI focal score was used to measure the effect of Tio+Olo FDC on patients' dyspnoea after 24 weeks of treatment (Day 169). The focal score is the sum of the subscale scores for Functional Impairment, Magnitude of Effort and Magnitude of Task. Scores for each subscale range from -3 to 3 so that the Focal score ranges from -9 to 9. For all subscale scores and the Focal score a higher value indicates a better outcome. Number of participants analyzed are the number of patients contributing to the mixed effect repeated measures model (MMRM) in each treatment group." (NCT01431274)
Timeframe: Day 169
| Intervention | points on a scale (Least Squares Mean) |
|---|---|
| Olodaterol (5 μg) | 1.564 |
| Tiotropium (2.5 μg) | 1.690 |
| Tiotropium (5 μg) | 1.627 |
| Tio+Olo FDC (2.5/5 μg) | 1.980 |
| Tio+Olo FDC (5/5 μg) | 1.983 |
"Trough FEV1 was defined as the FEV1 value at the end of the dosing interval (24 hours), calculated as the mean of the pre-dose measurements.~Trough FEV1 response was defined as trough FEV1 minus baseline FEV1. Baseline was defined as the mean of the 2 pre-dose measurements performed~1 h and 10 min prior to administration of the first dose of randomised treatment at Day1.~Number of participants analyzed are the number of patients contributing to the mixed effect repeated measures (MMRM) model in each treatment group." (NCT01431274)
Timeframe: 1 h and 10 min prior to dose on the first day of randomized treatment (baseline) and at 1 hr and 10 min pre-dose on Day 169
| Intervention | Litres (Least Squares Mean) |
|---|---|
| Olodaterol (5 μg) | 0.033 |
| Tiotropium (2.5 μg) | 0.047 |
| Tiotropium (5 μg) | 0.050 |
| Tio+Olo FDC (2.5/5 μg) | 0.094 |
| Tio+Olo FDC (5/5 μg) | 0.112 |
"FVC AUC(0-12h) was calculated as the area under the FVC- time curve from 0 to 12 h post-dose using the trapezoidal rule, divided by the duration (12 h) to report in litres.~FVC AUC(0-12h) response was defined as FVC AUC(0-12h) minus baseline FVC. Baseline was defined as the mean of the 2 pre-dose measurements performed 1 h and 10 min prior to administration of the first dose at visit 2 (day 1).~The adjusted mean (SE) were obtained from fitting an ANCOVA model with categorical effect of treatment and baseline as covariate. Number of participants analyzed are the number of patients contributing to the ANCOVA model in each treatment group." (NCT01431274)
Timeframe: 1 hour (h) and 10 minutes (min) prior to dose to on the first day of randomized treatment and on Day 169 and 5 min, 15 min, 30 min, 1 h, 2 h, 3 h, 4 h, 5 h, 6 h, 8 h, 10 h, 12 h post-dose on Day 169.
| Intervention | Litres (Least Squares Mean) |
|---|---|
| Olodaterol (5 μg) | 0.227 |
| Tiotropium (2.5 μg) | 0.180 |
| Tiotropium (5 μg) | 0.248 |
| Tio+Olo FDC (2.5/5 μg) | 0.356 |
| Tio+Olo FDC (5/5 μg) | 0.388 |
"Trough FVC was defined as the FVC value at the end of the dosing interval (24 hours) and was calculated as the mean of the 2 FVC measurements performed at 23h and at 23h 50 min after inhalation of study medication at the clinic visit on the previous day.~Trough FVC response was defined as trough FVC minus baseline FVC. Baseline was defined as the mean of the 2 pre-dose measurements performed 1 h and 10 min prior to administration of the first dose at visit 2 (day 1).~The adjusted means (SE) were obtained from fitting an MMRM including fixed effects of treatment, planned test day, treatment-by-test day interaction, baseline and baseline-by-test day interaction, patient as random effect, and spatial power covariance structure for within-patient errors and Kenward-Roger approximation for denominator degrees of freedom.~Number of participants analyzed are the number of patients contributing to the mixed effect repeated measures (MMRM) model in each treatment group." (NCT01431274)
Timeframe: 1 h and 10 min prior to dose on the first day of randomized treatment (baseline) and at 23 h and at 23 h 50 min after inhalation of study medication on Day 170
| Intervention | Litres (Least Squares Mean) |
|---|---|
| Olodaterol (5 μg) | 0.093 |
| Tiotropium (2.5 μg) | 0.184 |
| Tiotropium (5 μg) | 0.169 |
| Tio+Olo FDC (2.5/5 μg) | 0.225 |
| Tio+Olo FDC (5/5 μg) | 0.246 |
"The SGRQ is designed to measure health impairment in patients with COPD. It is divided into 2 parts: part 1 produces the symptoms score, and part 2 the activity and impacts scores. A total score is also produced. Each subscale score is the sum of the weights for the items in the subscale as a percent of the sum of the weights for a patient in the worst possible condition. The total score uses the same calculation except that the weights are summed over the entire questionnaire. The individual subscales as well as the total score can range from 0 to 100 with a lower score denoting a better health status.~Number of participants analyzed are the number of patients contributing to the mixed effect repeated measures model (MMRM) in each treatment group." (NCT01431287)
Timeframe: Day 85
| Intervention | points on a scale (Least Squares Mean) |
|---|---|
| Olodaterol (5 μg) | 38.832 |
| Tiotropium (2.5 μg) | 37.821 |
| Tiotropium (5 μg) | 37.822 |
| Tio+Olo FDC (2.5/5 μg) | 37.304 |
| Tio+Olo FDC (5/5 μg) | 36.691 |
"FEV1 AUC(0-12h) was calculated as the area under the FEV1- time curve from 0 to 12 h post-dose using the trapezoidal rule, divided by the duration (12 h) to report in litres.~FEV1 AUC(0-12h) response was defined as FEV1 AUC(0-12h) minus baseline FEV1. Baseline was defined as the mean of the 2 pre-dose measurements performed 1 h and 10 min prior to administration of the first dose at visit 2 (day 1).~The adjusted mean (SE) were obtained from fitting an ANCOVA model with categorical effect of treatment and baseline as covariate.~Number of participants analyzed are the number of patients contributing to the ANCOVA model in each treatment group." (NCT01431287)
Timeframe: 1 hour (h) and 10 minutes (min) prior to dose to on the first day of randomized treatment and on Day 169 and 5 min, 15 min, 30 min, 1 h, 2 h, 3 h, 4 h, 5 h, 6 h, 8 h, 10 h, 12 h post-dose on Day 169
| Intervention | Litres (Least Squares Mean) |
|---|---|
| Olodaterol (5 μg) | 0.131 |
| Tiotropium (2.5 μg) | 0.109 |
| Tiotropium (5 μg) | 0.127 |
| Tio+Olo FDC (2.5/5 μg) | 0.202 |
| Tio+Olo FDC (5/5 μg) | 0.250 |
"FEV1 AUC(0-24h) was calculated as the area under the FEV1- time curve from 0 to 24 h post-dose using the trapezoidal rule, divided by the duration (24 h) to report in litres. FEV1 AUC(0-24h) response was defined as FEV1 AUC(0-24h) minus baseline FEV1. Baseline was defined as the mean of the 2 pre-dose measurements performed 1 h and 10 min prior to administration of the first dose at visit 2 (day 1).~The adjusted mean (SE) were obtained from fitting an ANCOVA model with categorical effect of treatment and baseline as covariate.~Number of participants analyzed are the number of patients contributing to the ANCOVA model in each treatment group." (NCT01431287)
Timeframe: 1 hour (h) and 10 minutes (min) prior to dose to on the first day of randomized treatment and on Day 169 and 5 min, 15 min, 30 min, 1 h, 2 h, 3 h, 4 h, 5 h, 6 h, 8 h, 10 h, 12 h, 23 h, 23 h and 50 min post-dose on Day 169
| Intervention | Litres (Least Squares Mean) |
|---|---|
| Olodaterol (5 μg) | 0.108 |
| Tiotropium (2.5 μg) | 0.083 |
| Tiotropium (5 μg) | 0.100 |
| Tio+Olo FDC (2.5/5 μg) | 0.159 |
| Tio+Olo FDC (5/5 μg) | 0.206 |
"FEV1 AUC(0-3h) was calculated as the area under the FEV1- time curve from 0 to 3 h post-dose using the trapezoidal rule, divided by the duration (3 h) to report in litres.~FEV1 AUC(0-3h) response was defined as FEV1 AUC(0-3h) minus baseline FEV1. Baseline was defined as the mean of the 2 pre-dose measurements performed 1 h and 10 min prior to administration of the first dose of randomised treatment at Day1.~The adjusted means (SE) were obtained from fitting an Mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment-by-test day interaction, baseline and baseline-by-test day interaction, patient as random effect, and spatial power covariance structure for within-patient errors and Kenward-Roger approximation for denominator degrees of freedom.~Number of participants analyzed are the number of patients contributing to the mixed effect repeated measures (MMRM) model in each treatment group." (NCT01431287)
Timeframe: 1 hour (h) and 10 minutes (min) prior to dose to 5 min, 15 min, 30 min, 1 h, 2 h, 3 h post-dose on the first day of randomized treatment
| Intervention | Litres (Least Squares Mean) |
|---|---|
| Olodaterol (5 μg) | 0.196 |
| Tiotropium (2.5 μg) | 0.135 |
| Tiotropium (5 μg) | 0.164 |
| Tio+Olo FDC (2.5/5 μg) | 0.228 |
| Tio+Olo FDC (5/5 μg) | 0.229 |
"FEV1 AUC(0-3h) was calculated as the area under the FEV1- time curve from 0 to 3 h post-dose using the trapezoidal rule, divided by the duration (3 h) to report in litres.~FEV1 AUC(0-3h) response was defined as FEV1 AUC(0-3h) minus baseline FEV1. Baseline was defined as the mean of the 2 pre-dose measurements performed 1 h and 10 min prior to administration of the first dose of randomised treatment at Day1.~The adjusted means (SE) were obtained from fitting an Mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment-by-test day interaction, baseline and baseline-by-test day interaction, patient as random effect, and spatial power covariance structure for within-patient errors and Kenward-Roger approximation for denominator degrees of freedom.~Number of participants analyzed are the number of patients contributing to the mixed effect repeated measures (MMRM) model in each treatment group." (NCT01431287)
Timeframe: 1 hour (h) and 10 minutes (min) prior to dose to on the first day of randomized treatment and on Day 365 and 5 min, 15 min, 30 min, 1 h, 2 h, 3 h post-dose on Day 365
| Intervention | Litres (Least Squares Mean) |
|---|---|
| Olodaterol (5 μg) | 0.105 |
| Tiotropium (2.5 μg) | 0.105 |
| Tiotropium (5 μg) | 0.124 |
| Tio+Olo FDC (2.5/5 μg) | 0.223 |
| Tio+Olo FDC (5/5 μg) | 0.237 |
"FEV1 AUC(0-3h) was calculated as the area under the FEV1- time curve from 0 to 3 h post-dose using the trapezoidal rule, divided by the duration (3 h) to report in litres.~FEV1 AUC(0-3h) response was defined as FEV1 AUC(0-3h) minus baseline FEV1. Baseline was defined as the mean of the 2 pre-dose measurements performed 1 h and 10 min prior to administration of the first dose of randomised treatment at Day1.~The adjusted means (SE) were obtained from fitting an Mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment-by-test day interaction, baseline and baseline-by-test day interaction, patient as random effect, and spatial power covariance structure for within-patient errors and Kenward-Roger approximation for denominator degrees of freedom.~Number of participants analyzed are the number of patients contributing to the mixed effect repeated measures (MMRM) model in each treatment group." (NCT01431287)
Timeframe: 1 hour (h) and 10 minutes (min) prior to dose to on the first day of randomized treatment and on Day 85 and 5 min, 15 min, 30 min, 1 h, 2 h, 3 h post-dose on Day 85
| Intervention | Litres (Least Squares Mean) |
|---|---|
| Olodaterol (5 μg) | 0.153 |
| Tiotropium (2.5 μg) | 0.165 |
| Tiotropium (5 μg) | 0.187 |
| Tio+Olo FDC (2.5/5 μg) | 0.272 |
| Tio+Olo FDC (5/5 μg) | 0.297 |
"FEV1 AUC(0-3h) was calculated as the area under the FEV1- time curve from 0 to 3 h post-dose using the trapezoidal rule, divided by the duration (3 h) to report in litres. FEV1 AUC(0-3h) response was defined as FEV1 AUC(0-3h) minus baseline FEV1. Baseline was defined as the mean of the 2 pre-dose measurements performed 1 h and 10 min prior to administration of the first dose at visit 2 (day 1).~The adjusted means (SE) were obtained from fitting an Mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment-by-test day interaction, baseline and baseline-by-test day interaction, patient as random effect, and spatial power covariance structure for within-patient errors and Kenward-Roger approximation for denominator degrees of freedom. Number of participants analyzed are the number of patients contributing to the MMRM model in each treatment group." (NCT01431287)
Timeframe: 1 hour (h) and 10 minutes (min) prior to dose to on the first day of randomized treatment and on Day 169 and 5 min, 15 min, 30 min, 1 h, 2 h, 3 h post-dose on Day 169
| Intervention | Litres (Least Squares Mean) |
|---|---|
| Olodaterol (5 μg) | 0.136 |
| Tiotropium (2.5 μg) | 0.125 |
| Tiotropium (5 μg) | 0.165 |
| Tio+Olo FDC (2.5/5 μg) | 0.256 |
| Tio+Olo FDC (5/5 μg) | 0.268 |
"FVC AUC(0-3h) was calculated as the area under the FVC- time curve from 0 to 3 h post-dose using the trapezoidal rule, divided by the duration (3 h) to report in litres.~FVC AUC(0-3h) response was defined as FVC AUC(0-3h) minus baseline FVC.Baseline was defined as the mean of the 2 pre-dose measurements performed 1 h and 10 min prior to administration of the first dose at visit 2 (day 1).~The adjusted means (SE) were obtained from fitting an Mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment-by-test day interaction, baseline and baseline-by-test day interaction, patient as random effect, and spatial power covariance structure for within-patient errors and Kenward-Roger approximation for denominator degrees of freedom.~Number of participants analyzed are the number of patients contributing to the mixed effect repeated measures (MMRM) model in each treatment group." (NCT01431287)
Timeframe: 1 hour (h) and 10 minutes (min) prior to dose to 5 min, 15 min, 30 min, 1 h, 2 h, 3 h post-dose on the first day of randomized treatment
| Intervention | Litres (Median) |
|---|---|
| Olodaterol (5 μg) | 0.341 |
| Tiotropium (2.5 μg) | 0.264 |
| Tiotropium (5 μg) | 0.298 |
| Tio+Olo FDC (2.5/5 μg) | 0.411 |
| Tio+Olo FDC (5/5 μg) | 0.397 |
"FVC AUC(0-3h) was calculated as the area under the FVC- time curve from 0 to 3 h post-dose using the trapezoidal rule, divided by the duration (3 h) to report in litres.~FVC AUC(0-3h) response was defined as FVC AUC(0-3h) minus baseline FVC. Baseline was defined as the mean of the 2 pre-dose measurements performed 1 h and 10 min prior to administration of the first dose at visit 2 (day 1).~The adjusted means (SE) were obtained from fitting an Mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment-by-test day interaction, baseline and baseline-by-test day interaction, patient as random effect, and spatial power covariance structure for within-patient errors and Kenward-Roger approximation for denominator degrees of freedom.~Number of participants analyzed are the number of patients contributing to the mixed effect repeated measures (MMRM) model in each treatment group." (NCT01431287)
Timeframe: 1 hour (h) and 10 minutes (min) prior to dose to on the first day of randomized treatment and on Day 169 and 5 min, 15 min, 30 min, 1 h, 2 h, 3 h post-dose on Day 169
| Intervention | Litres (Median) |
|---|---|
| Olodaterol (5 μg) | 0.231 |
| Tiotropium (2.5 μg) | 0.247 |
| Tiotropium (5 μg) | 0.283 |
| Tio+Olo FDC (2.5/5 μg) | 0.439 |
| Tio+Olo FDC (5/5 μg) | 0.429 |
"FVC AUC(0-3h) was calculated as the area under the FVC- time curve from 0 to 3 h post-dose using the trapezoidal rule, divided by the duration (3 h) to report in litres.~FVC AUC(0-3h) response was defined as FVC AUC(0-3h) minus baseline FVC. Baseline was defined as the mean of the 2 pre-dose measurements performed 1 h and 10 min prior to administration of the first dose at visit 2 (day 1).~The adjusted means (SE) were obtained from fitting an Mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment-by-test day interaction, baseline and baseline-by-test day interaction, patient as random effect, and spatial power covariance structure for within-patient errors and Kenward-Roger approximation for denominator degrees of freedom.~Number of participants analyzed are the number of patients contributing to the mixed effect repeated measures (MMRM) model in each treatment group." (NCT01431287)
Timeframe: 1 hour (h) and 10 minutes (min) prior to dose to on the first day of randomized treatment and on Day 365 and 5 min, 15 min, 30 min, 1 h, 2 h, 3 h post-dose on Day 365
| Intervention | Litres (Median) |
|---|---|
| Olodaterol (5 μg) | 0.180 |
| Tiotropium (2.5 μg) | 0.216 |
| Tiotropium (5 μg) | 0.198 |
| Tio+Olo FDC (2.5/5 μg) | 0.397 |
| Tio+Olo FDC (5/5 μg) | 0.381 |
"FVC AUC(0-3h) was calculated as the area under the FVC- time curve from 0 to 3 h post-dose using the trapezoidal rule, divided by the duration (3 h) to report in litres.~FVC AUC(0-3h) response was defined as FVC AUC(0-3h) minus baseline FVC.Baseline was defined as the mean of the 2 pre-dose measurements performed 1 h and 10 min prior to administration of the first dose at visit 2 (day 1).~The adjusted means (SE) were obtained from fitting an Mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment-by-test day interaction, baseline and baseline-by-test day interaction, patient as random effect, and spatial power covariance structure for within-patient errors and Kenward-Roger approximation for denominator degrees of freedom.~Number of participants analyzed are the number of patients contributing to the mixed effect repeated measures (MMRM) model in each treatment group." (NCT01431287)
Timeframe: 1 hour (h) and 10 minutes (min) prior to dose to on the first day of randomized treatment and on Day 85 and 5 min, 15 min, 30 min, 1 h, 2 h, 3 h post-dose on Day 85
| Intervention | Litres (Median) |
|---|---|
| Olodaterol (5 μg) | 0.250 |
| Tiotropium (2.5 μg) | 0.306 |
| Tiotropium (5 μg) | 0.326 |
| Tio+Olo FDC (2.5/5 μg) | 0.460 |
| Tio+Olo FDC (5/5 μg) | 0.469 |
"FVC AUC(0-12h) was calculated as the area under the FVC- time curve from 0 to 12 h post-dose using the trapezoidal rule, divided by the duration (12 h) to report in litres.~FVC AUC(0-12h) response was defined as FVC AUC(0-12h) minus baseline FVC. Baseline was defined as the mean of the 2 pre-dose measurements performed 1 h and 10 min prior to administration of the first dose at visit 2 (day 1).~The adjusted mean (SE) were obtained from fitting an ANCOVA model with categorical effect of treatment and baseline as covariate. Number of participants analyzed are the number of patients contributing to the ANCOVA model in each treatment group." (NCT01431287)
Timeframe: 1 hour (h) and 10 minutes (min) prior to dose to on the first day of randomized treatment and on Day 169 and 5 min, 15 min, 30 min, 1 h, 2 h, 3 h, 4 h, 5 h, 6 h, 8 h, 10 h, 12 h post-dose on Day 169
| Intervention | Litres (Least Squares Mean) |
|---|---|
| Olodaterol (5 μg) | 0.227 |
| Tiotropium (2.5 μg) | 0.180 |
| Tiotropium (5 μg) | 0.248 |
| Tio+Olo FDC (2.5/5 μg) | 0.356 |
| Tio+Olo FDC (5/5 μg) | 0.388 |
"FVC AUC(0-24h) was calculated as the area under the FVC- time curve from 0 to 24 h post-dose using the trapezoidal rule, divided by the duration (24 h) to report in litres.~FVC AUC(0-24h) response was defined as FVC AUC(0-24h) minus baseline FVC. Baseline was defined as the mean of the 2 pre-dose measurements performed 1 h and 10 min prior to administration of the first dose at visit 2 (day 1).~The adjusted mean (SE) were obtained from fitting an ANCOVA model with categorical effect of treatment and baseline as covariate.~Number of participants analyzed are the number of patients contributing to the ANCOVA model in each treatment group." (NCT01431287)
Timeframe: 1 hour (h) and 10 minutes (min) prior to dose to on the first day of randomized treatment and on Day 169 and 5 min, 15 min, 30 min, 1 h, 2 h, 3 h, 4 h, 5 h, 6 h, 8 h, 10 h, 12 h, 23 h, 23 h and 50 min post-dose on Day 169
| Intervention | Litres (Least Squares Mean) |
|---|---|
| Olodaterol (5 μg) | 0.192 |
| Tiotropium (2.5 μg) | 0.141 |
| Tiotropium (5 μg) | 0.203 |
| Tio+Olo FDC (2.5/5 μg) | 0.297 |
| Tio+Olo FDC (5/5 μg) | 0.329 |
"Mahler Transitional Dyspnoea Index (TDI) focal score on Day 169 From the Two Twin Trials, Present 1237.6 (NCT01431287) and 1237.5 (NCT01431274) is the key secondary endpoint.~The Mahler Dyspnoea questionnaire is an instrument which measures change from the baseline state The TDI focal score was used to measure the effect of Tio+Olo FDC on patients' dyspnoea after 24 weeks of treatment (Day 169). The focal score is the sum of the subscale scores for Functional Impairment, Magnitude of Effort and Magnitude of Task. Scores for each subscale range from -3 to 3 so that the Focal score ranges from -9 to 9. For all subscale scores and the Focal score a higher value indicates a better outcome.~Number of participants analyzed are the number of patients contributing to the mixed effect repeated measures model (MMRM) in each treatment group." (NCT01431287)
Timeframe: Day 169
| Intervention | points on a scale (Least Squares Mean) |
|---|---|
| Olodaterol (5 μg) | 1.564 |
| Tiotropium (2.5 μg) | 1.690 |
| Tiotropium (5 μg) | 1.627 |
| Tio+Olo FDC (2.5/5 μg) | 1.980 |
| Tio+Olo FDC (5/5 μg) | 1.983 |
"Mahler TDI focal score on Day 365 From the two twin trials, present 1237.6 (NCT01431287) and 1237.5 (NCT01431274).~The Mahler Dyspnoea questionnaire is an instrument which measures change from the baseline state The TDI focal score was used to measure the effect of Tio+Olo FDC on patients' dyspnoea after 24 weeks of treatment (Day 169). The focal score is the sum of the subscale scores for Functional Impairment, Magnitude of Effort and Magnitude of Task. Scores for each subscale range from -3 to 3 so that the Focal score ranges from -9 to 9. For all subscale scores and the Focal score a higher value indicates a better outcome.~Number of participants analyzed are the number of patients contributing to the mixed effect repeated measures model (MMRM) in each treatment group." (NCT01431287)
Timeframe: Day 365
| Intervention | points on a scale (Least Squares Mean) |
|---|---|
| Olodaterol (5 μg) | 1.411 |
| Tiotropium (2.5 μg) | 1.450 |
| Tiotropium (5 μg) | 1.736 |
| Tio+Olo FDC (2.5/5 μg) | 1.782 |
| Tio+Olo FDC (5/5 μg) | 2.058 |
"Mahler TDI focal score on Day 43 From the two twin trials, present 1237.6 (NCT01431287) and 1237.5 (NCT01431274).~The Mahler Dyspnoea questionnaire is an instrument which measures change from the baseline state The TDI focal score was used to measure the effect of Tio+Olo FDC on patients' dyspnoea after 24 weeks of treatment (Day 169). The focal score is the sum of the subscale scores for Functional Impairment, Magnitude of Effort and Magnitude of Task. Scores for each subscale range from -3 to 3 so that the Focal score ranges from -9 to 9. For all subscale scores and the Focal score a higher value indicates a better outcome.~Number of participants analyzed are the number of patients contributing to the mixed effect repeated measures model (MMRM) in each treatment group." (NCT01431287)
Timeframe: Day 43
| Intervention | points on a scale (Least Squares Mean) |
|---|---|
| Olodaterol (5 μg) | 1.453 |
| Tiotropium (2.5 μg) | 1.430 |
| Tiotropium (5 μg) | 1.408 |
| Tio+Olo FDC (2.5/5 μg) | 1.876 |
| Tio+Olo FDC (5/5 μg) | 2.048 |
"Mahler TDI focal score on Day 85 From the two twin trials, present 1237.6 (NCT01431287) and 1237.5 (NCT01431274).~The Mahler Dyspnoea questionnaire is an instrument which measures change from the baseline state The TDI focal score was used to measure the effect of Tio+Olo FDC on patients' dyspnoea after 24 weeks of treatment (Day 169). The focal score is the sum of the subscale scores for Functional Impairment, Magnitude of Effort and Magnitude of Task. Scores for each subscale range from -3 to 3 so that the Focal score ranges from -9 to 9. For all subscale scores and the Focal score a higher value indicates a better outcome.~Number of participants analyzed are the number of patients contributing to the mixed effect repeated measures model (MMRM) in each treatment group." (NCT01431287)
Timeframe: Day 85
| Intervention | points on a scale (Least Squares Mean) |
|---|---|
| Olodaterol (5 μg) | 1.506 |
| Tiotropium (2.5 μg) | 1.698 |
| Tiotropium (5 μg) | 1.702 |
| Tio+Olo FDC (2.5/5 μg) | 1.925 |
| Tio+Olo FDC (5/5 μg) | 2.136 |
"The SGRQ is designed to measure health impairment in patients with COPD. It is divided into 2 parts: part 1 produces the symptoms score, and part 2 the activity and impacts scores. A total score is also produced. Each subscale score is the sum of the weights for the items in the subscale as a percent of the sum of the weights for a patient in the worst possible condition. The total score uses the same calculation except that the weights are summed over the entire questionnaire. The individual subscales as well as the total score can range from 0 to 100 with a lower score denoting a better health status.~Number of participants analyzed are the number of patients contributing to the mixed effect repeated measures model (MMRM) in each treatment group." (NCT01431287)
Timeframe: Day 169
| Intervention | points on a scale (Least Squares Mean) |
|---|---|
| Olodaterol (5 μg) | 38.366 |
| Tiotropium (2.5 μg) | 37.792 |
| Tiotropium (5 μg) | 37.907 |
| Tio+Olo FDC (2.5/5 μg) | 37.335 |
| Tio+Olo FDC (5/5 μg) | 36.674 |
"The SGRQ is designed to measure health impairment in patients with COPD. It is divided into 2 parts: part 1 produces the symptoms score, and part 2 the activity and impacts scores. A total score is also produced. Each subscale score is the sum of the weights for the items in the subscale as a percent of the sum of the weights for a patient in the worst possible condition. The total score uses the same calculation except that the weights are summed over the entire questionnaire. The individual subscales as well as the total score can range from 0 to 100 with a lower score denoting a better health status.~Number of participants analyzed are the number of patients contributing to the mixed effect repeated measures model (MMRM) in each treatment group." (NCT01431287)
Timeframe: Day 365
| Intervention | points on a scale (Least Squares Mean) |
|---|---|
| Olodaterol (5 μg) | 38.989 |
| Tiotropium (2.5 μg) | 37.609 |
| Tiotropium (5 μg) | 37.581 |
| Tio+Olo FDC (2.5/5 μg) | 37.553 |
| Tio+Olo FDC (5/5 μg) | 37.138 |
"Trough FEV1 was defined as the FEV1 value at the end of the dosing interval (24 hours), calculated as the mean of the pre-dose measurements.~Trough FEV1 response was defined as trough FEV1 minus baseline FEV1. Baseline was defined as the mean of the 2 pre-dose measurements performed 1 h and 10 min prior to administration of the first dose of randomised treatment at Day1.~Number of participants analyzed are the number of patients contributing to the mixed effect repeated measures (MMRM) model in each treatment group." (NCT01431287)
Timeframe: 1 h and 10 min prior to dose on the first day of randomized treatment (baseline) and at 10 min pre-dose on day 15
| Intervention | Litres (Least Squares Mean) |
|---|---|
| Olodaterol (5 μg) | 0.083 |
| Tiotropium (2.5 μg) | 0.085 |
| Tiotropium (5 μg) | 0.112 |
| Tio+Olo FDC (2.5/5 μg) | 0.147 |
| Tio+Olo FDC (5/5 μg) | 0.148 |
"Trough FEV1 was defined as the FEV1 value at the end of the dosing interval (24 hours), calculated as the mean of the pre-dose measurements.~Trough FEV1 response was defined as trough FEV1 minus baseline FEV1. Baseline was defined as the mean of the 2 pre-dose measurements performed 1 h and 10 min prior to administration of the first dose of randomised treatment at Day1.~Number of participants analyzed are the number of patients contributing to the mixed effect repeated measures (MMRM) model in each treatment group." (NCT01431287)
Timeframe: 1 h and 10 min prior to dose on the first day of randomized treatment (baseline) and at 1hr and 10 min pre-dose on day 169
| Intervention | Litres (Least Squares Mean) |
|---|---|
| Olodaterol (5 μg) | 0.034 |
| Tiotropium (2.5 μg) | 0.041 |
| Tiotropium (5 μg) | 0.068 |
| Tio+Olo FDC (2.5/5 μg) | 0.111 |
| Tio+Olo FDC (5/5 μg) | 0.119 |
"Trough FEV1 was defined as the FEV1 value at the end of the dosing interval (24 hours) and was calculated as the mean of the 2 FEV1 measurements performed at 23 h and at 23 h 50 min after inhalation of study medication at the clinic visit on the previous day.~Trough FEV1 response was defined as trough FEV1 minus baseline FEV1. Baseline was defined as the mean of the 2 pre-dose measurements performed 1 h and 10 min prior to administration of the first dose at visit 2 (day 1).~The adjusted means (SE) were obtained from fitting an MMRM including fixed effects of treatment, planned test day, treatment-by-test day interaction, baseline and baseline-by-test day interaction, patient as random effect, and spatial power covariance structure for within-patient errors and Kenward-Roger approximation for denominator degrees of freedom.~Number of participants analyzed are the number of patients contributing to the mixed effect repeated measures (MMRM) model in each treatment group." (NCT01431287)
Timeframe: 1 h and 10 min prior to dose on the first day of randomized treatment (baseline) and at 23 h and at 23 h 50 min after inhalation of study medication on Day 170
| Intervention | Litres (Least Squares Mean) |
|---|---|
| Olodaterol (5 μg) | 0.057 |
| Tiotropium (2.5 μg) | 0.062 |
| Tiotropium (5 μg) | 0.096 |
| Tio+Olo FDC (2.5/5 μg) | 0.125 |
| Tio+Olo FDC (5/5 μg) | 0.145 |
"Trough FEV1 was defined as the FEV1 value at the end of the dosing interval (24 hours), calculated as the mean of the pre-dose measurements.~Trough FEV1 response was defined as trough FEV1 minus baseline FEV1. Baseline was defined as the mean of the 2 pre-dose measurements performed 1 h and 10 min prior to administration of the first dose of randomised treatment at Day1.~Number of participants analyzed are the number of patients contributing to the mixed effect repeated measures (MMRM) model in each treatment group." (NCT01431287)
Timeframe: 1 h and 10 min prior to dose on the first day of randomized treatment (baseline) and at 1 hr and 10 min pre-dose on day 365
| Intervention | Litres (Least Squares Mean) |
|---|---|
| Olodaterol (5 μg) | 0.011 |
| Tiotropium (2.5 μg) | 0.022 |
| Tiotropium (5 μg) | 0.040 |
| Tio+Olo FDC (2.5/5 μg) | 0.077 |
| Tio+Olo FDC (5/5 μg) | 0.093 |
"Trough FEV1 was defined as the FEV1 value at the end of the dosing interval (24 hours), calculated as the mean of the pre-dose measurements.~Trough FEV1 response was defined as trough FEV1 minus baseline FEV1. Baseline was defined as the mean of the 2 pre-dose measurements performed 1 h and 10 min prior to administration of the first dose of randomised treatment at Day1.~Number of participants analyzed are the number of patients contributing to the mixed effect repeated measures (MMRM) model in each treatment group." (NCT01431287)
Timeframe: 1 h and 10 min prior to dose on the first day of randomized treatment (baseline) and at 10 min pre-dose on day 43
| Intervention | Litres (Least Squares Mean) |
|---|---|
| Olodaterol (5 μg) | 0.070 |
| Tiotropium (2.5 μg) | 0.085 |
| Tiotropium (5 μg) | 0.103 |
| Tio+Olo FDC (2.5/5 μg) | 0.146 |
| Tio+Olo FDC (5/5 μg) | 0.150 |
"Trough FEV1 was defined as the FEV1 value at the end of the dosing interval (24 hours), calculated as the mean of the pre-dose measurements.~Trough FEV1 response was defined as trough FEV1 minus baseline FEV1. Baseline was defined as the mean of the 2 pre-dose measurements performed 1 h and 10 min prior to administration of the first dose of randomised treatment at Day1.~Number of participants analyzed are the number of patients contributing to the mixed effect repeated measures (MMRM) model in each treatment group." (NCT01431287)
Timeframe: 1 h and 10 min prior to dose on the first day of randomized treatment (baseline) and at 1hr and 10 min pre-dose on day 85
| Intervention | Litres (Least Squares Mean) |
|---|---|
| Olodaterol (5 μg) | 0.047 |
| Tiotropium (2.5 μg) | 0.081 |
| Tiotropium (5 μg) | 0.088 |
| Tio+Olo FDC (2.5/5 μg) | 0.129 |
| Tio+Olo FDC (5/5 μg) | 0.147 |
"Trough FVC was defined as the FVC value at the end of the dosing interval (24 hours), calculated as the mean of the pre-dose measurements.~Trough FVC response was defined as trough FVC minus baseline FVC. Baseline was defined as the mean of the 2 pre-dose measurements performed 1 h and 10 min prior to administration of the first dose at visit 2 (day 1).~Number of participants analyzed are the number of patients contributing to the mixed effect repeated measures (MMRM) model in each treatment group.~The adjusted means (SE) were obtained from fitting an Mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment-by-test day interaction, baseline and baseline-by-test day interaction, patient as random effect, and spatial power covariance structure for within-patient errors and Kenward-Roger approximation for denominator degrees of freedom." (NCT01431287)
Timeframe: 1 h and 10 min prior to dose on the first day of randomized treatment (baseline) and at 10 min pre-dose on day 15
| Intervention | Litres (Least Squares Mean) |
|---|---|
| Olodaterol (5 μg) | 0.163 |
| Tiotropium (2.5 μg) | 0.209 |
| Tiotropium (5 μg) | 0.222 |
| Tio+Olo FDC (2.5/5 μg) | 0.293 |
| Tio+Olo FDC (5/5 μg) | 0.285 |
"Trough FVC was defined as the FVC value at the end of the dosing interval (24 hours) and was calculated as the mean of the 2 FVC measurements performed at 23h and at 23h 50 min after inhalation of study medication at the clinic visit on the previous day.~Trough FVC response was defined as trough FVC minus baseline FVC. Baseline was defined as the mean of the 2 pre-dose measurements performed 1 h and 10 min prior to administration of the first dose at visit 2 (day 1).~The adjusted means (SE) were obtained from fitting an MMRM including fixed effects of treatment, planned test day, treatment-by-test day interaction, baseline and baseline-by-test day interaction, patient as random effect, and spatial power covariance structure for within-patient errors and Kenward-Roger approximation for denominator degrees of freedom.~Number of participants analyzed are the number of patients contributing to the mixed effect repeated measures (MMRM) model in each treatment group." (NCT01431287)
Timeframe: 1 h and 10 min prior to dose on the first day of randomized treatment (baseline) and at 23h and at 23h 50 min after inhalation of study medication on day 170
| Intervention | Litres (Least Squares Mean) |
|---|---|
| Olodaterol (5 μg) | 0.116 |
| Tiotropium (2.5 μg) | 0.163 |
| Tiotropium (5 μg) | 0.202 |
| Tio+Olo FDC (2.5/5 μg) | 0.266 |
| Tio+Olo FDC (5/5 μg) | 0.274 |
"Trough FVC was defined as the FVC value at the end of the dosing interval (24 hours), calculated as the mean of the pre-dose measurements.~Trough FVC response was defined as trough FVC minus baseline FVC. Baseline was defined as the mean of the 2 pre-dose measurements performed 1 h and 10 min prior to administration of the first dose at visit 2 (day 1).~Number of participants analyzed are the number of patients contributing to the mixed effect repeated measures (MMRM) model in each treatment group.~The adjusted means (SE) were obtained from fitting an Mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment-by-test day interaction, baseline and baseline-by-test day interaction, patient as random effect, and spatial power covariance structure for within-patient errors and Kenward-Roger approximation for denominator degrees of freedom." (NCT01431287)
Timeframe: 1 h and 10 min prior to dose on the first day of randomized treatment (baseline) and on day 365
| Intervention | Litres (Least Squares Mean) |
|---|---|
| Olodaterol (5 μg) | 0.028 |
| Tiotropium (2.5 μg) | 0.096 |
| Tiotropium (5 μg) | 0.097 |
| Tio+Olo FDC (2.5/5 μg) | 0.198 |
| Tio+Olo FDC (5/5 μg) | 0.184 |
"Trough FVC was defined as the FVC value at the end of the dosing interval (24 hours), calculated as the mean of the pre-dose measurements.~Trough FVC response was defined as trough FVC minus baseline FVC. Baseline was defined as the mean of the 2 pre-dose measurements performed 1 h and 10 min prior to administration of the first dose at visit 2 (day 1).~Number of participants analyzed are the number of patients contributing to the mixed effect repeated measures (MMRM) model in each treatment group.~The adjusted means (SE) were obtained from fitting an Mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment-by-test day interaction, baseline and baseline-by-test day interaction, patient as random effect, and spatial power covariance structure for within-patient errors and Kenward-Roger approximation for denominator degrees of freedom." (NCT01431287)
Timeframe: 1 h and 10 min prior to dose on the first day of randomized treatment (baseline) and at 10 min pre-dose on day 43
| Intervention | Litres (Least Squares Mean) |
|---|---|
| Olodaterol (5 μg) | 0.129 |
| Tiotropium (2.5 μg) | 0.206 |
| Tiotropium (5 μg) | 0.222 |
| Tio+Olo FDC (2.5/5 μg) | 0.281 |
| Tio+Olo FDC (5/5 μg) | 0.293 |
"Trough FVC was defined as the FVC value at the end of the dosing interval (24 hours), calculated as the mean of the pre-dose measurements.~Trough FVC response was defined as trough FVC minus baseline FVC. Baseline was defined as the mean of the 2 pre-dose measurements performed 1 h and 10 min prior to administration of the first dose at visit 2 (day 1).~Number of participants analyzed are the number of patients contributing to the mixed effect repeated measures (MMRM) model in each treatment group.~The adjusted means (SE) were obtained from fitting an Mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment-by-test day interaction, baseline and baseline-by-test day interaction, patient as random effect, and spatial power covariance structure for within-patient errors and Kenward-Roger approximation for denominator degrees of freedom." (NCT01431287)
Timeframe: 1 h and 10 min prior to dose on the first day of randomized treatment (baseline) and on day 85
| Intervention | Litres (Least Squares Mean) |
|---|---|
| Olodaterol (5 μg) | 0.063 |
| Tiotropium (2.5 μg) | 0.178 |
| Tiotropium (5 μg) | 0.184 |
| Tio+Olo FDC (2.5/5 μg) | 0.246 |
| Tio+Olo FDC (5/5 μg) | 0.274 |
Change from baseline in normalised FEV1 area under the curve over the 24-h period immediately after morning Investigational Medicinal Product administration (AUC0-24h ) after 6 weeks on treatment. The normalised AUC were calculated by means of a trapezoidal method, dividing by the corresponding time interval. (NCT01462929)
Timeframe: Week 6
| Intervention | Liters (Least Squares Mean) |
|---|---|
| Aclidinium Bromide 400 µg BID | 0.065 |
| Tiotropium 18 μg Once-daily | 0.055 |
| Placebo | -0.085 |
Change from baseline in normalised FEV1 area under the curve over the 12-h night-time period (AUC12-24) after 6 weeks of treatment. The normalised AUC were calculated by means of a trapezoidal method, dividing by the corresponding time interval. (NCT01462929)
Timeframe: Week 6
| Intervention | Liters (Least Squares Mean) |
|---|---|
| Aclidinium Bromide 400 µg BID | 0.032 |
| Tiotropium 18 μg Once-daily | -0.006 |
| Placebo | -0.128 |
"Time to recovery was assessed with the EXACT-PRO questionnaire tool. The EXACT-PRO was designed to collect data to quantify frequency, severity, and duration of exacerbations in patients with COPD including the onset of and the recovery from COPD exacerbations.~The EXACT-PRO is a 14-item questionnaire. Each attribute or item was assessed on a five- or six-point ordinal scale and summed to yield a total score that was converted to a 0-100 scale, with higher scores indicating a more severe health state or exacerbation.~The EXACT-PRO was answered by the patients on a daily basis in the evening." (NCT01483625)
Timeframe: 12 weeks
| Intervention | units on a scale (Geometric Mean) |
|---|---|
| Placebo | 48.44 |
| Tiotropium 18 mcg | 47.86 |
The trough Forced Vital Capacity (FVC) was defined as the FVC measurement prior to the next dosing of study drug and approximately 24 hours after the last inhalation of study drug. (NCT01483625)
Timeframe: 12 weeks
| Intervention | Litres (Least Squares Mean) |
|---|---|
| Placebo | 3.1537 |
| Tiotropium 18 mcg | 2.9097 |
The primary endpoint was trough forced expiratory volume in 1 second (FEV1) after 12 weeks on study drug. Trough forced expiratory volume in 1 second (FEV1)was defined as the FEV1 measurement prior to the next dosing of study drug and approximately 24 hours after the last inhalation of study drug. (NCT01483625)
Timeframe: 12 weeks
| Intervention | Litre (Least Squares Mean) |
|---|---|
| Placebo | 0.0378 |
| Tiotropium 18 mcg | 0.0947 |
Daily rescue albuterol use was recorded in the diary in response to the following question: How many puffs of rescue medication did you use during the last 24 hours? The weekly rescue medication use was derived by summing the daily uses over the 12 weeks and dividing this total by 12 weeks. (NCT01483625)
Timeframe: 12 weeks
| Intervention | puffs (Mean) |
|---|---|
| Placebo | 17.0 |
| Tiotropium 18 mcg | 12.9 |
"Responder status was determined at each clinic visit. The number and percentage of subjects in each of the following 3 classes were presented:~Subject recovered without change of therapy (subjects who received an additional course of antibiotics and/or systemic corticosteroids starting after Visit 1 were not included).~Subject recovered but had a change in therapy (subject received an additional course of antibiotics and/or systemic corticosteroids starting after Visit 1).~Subject did not recover." (NCT01483625)
Timeframe: 4 weeks
| Intervention | participants (Number) | ||
|---|---|---|---|
| Week 4: Responder without therapy change | Week 4: Responder with changed therapy | Week 4: Non-responder | |
| Placebo | 38 | 1 | 31 |
| Tiotropium 18 mcg | 39 | 2 | 26 |
"Responder status was determined at each clinic visit. The number and percentage of subjects in each of the following 3 classes were presented:~Subject recovered without change of therapy (subjects who received an additional course of antibiotics and/or systemic corticosteroids starting after Visit 1 were not included).~Subject recovered but had a change in therapy (subject received an additional course of antibiotics and/or systemic corticosteroids starting after Visit 1).~Subject did not recover." (NCT01483625)
Timeframe: 12 weeks
| Intervention | participants (Number) | ||
|---|---|---|---|
| Week 12: Responder without therapy change | Week 12: Responder with changed therapy | Week 12: Non-responder | |
| Placebo | 34 | 0 | 32 |
| Tiotropium 18 mcg | 34 | 0 | 24 |
Total Transient Dyspnea Index (TDI) is part of the BDI/TDI questionnaire where participants indicated whether they improved or deteriorated since their Baseline Dyspnea Index (BDI). The BDI and TDI each had 3 domains: activities, tasks, and effort. BDI domains were rated from 0 (very severe) to 4 (none) and the rates summed for the total BDI score ranging from 0 to 12; the lower the score the worse the severity of dyspnea. TDI domains were rated from -6 (major deterioration) to 6 (major improvement) and the rates summed for the total TDI score ranging from -18 to 18. However, to ensure comparability with the TDI paper version, all TDI values were divided by 2 before the analysis. If data was missing or insufficient for any one of the domains a BDI/TDI was calculated. BDI = Baseline Dyspnea Index taken 75 min prior to the first dose in each treatment period. TDI = Transition Dyspnea Index taken after 6 weeks of treatment 75 min prior to the last dose in each treatment period. (NCT01490125)
Timeframe: Baseline and 6 weeks
| Intervention | Units on a scale (Mean) | |
|---|---|---|
| BDI | TDI | |
| QVA149 + Placebo to Tiotropium | 7.34 | 0.98 |
| Tiotropium + Placebo to QVA149 | 7.31 | 0.47 |
Total Transient Dyspnea Index (TDI) is part of the BDI/TDI questionnaire where participants indicated whether they improved or deteriorated since their Baseline Dyspnea Index (BDI). The BDI and TDI each had 3 domains: activities, tasks, and effort. BDI domains were rated from 0 (very severe) to 4 (none) and the rates summed for the total BDI score ranging from 0 to 12; the lower the score the worse the severity of dyspnea. TDI domains were rated from -6 (major deterioration) to 6 (major improvement) and the rates summed for the total TDI score ranging from -18 to 18. However, to ensure comparability with the TDI paper version, all TDI values were divided by 2 before the analysis. If data was missing or insufficient for any one of the domains a BDI/TDI was calculated. BDI = Baseline Dyspnea Index taken 75 min prior to the first dose in each treatment period. TDI = Transition Dyspnea Index taken after 6 weeks of treatment 75 min prior to the last dose in each treatment period. (NCT01490125)
Timeframe: Baseline and 6 weeks
| Intervention | Units on a scale (Mean) | |
|---|---|---|
| BDI | TDI | |
| Placebo | 7.33 | -0.38 |
| QVA149 + Placebo to Tiotropium | 7.34 | 0.98 |
Forced Vital Capacity (FVC) is the total amount of air that can be exhaled by the patient after a full inhalation. The FVC was measured via spirometry conducted according to internationally accepted standards at 5 min-4 hr post dose of day 1 and week 6. (NCT01490125)
Timeframe: 5min-4hr at day 1 and week 6 post-dose
| Intervention | Liters (Least Squares Mean) | |
|---|---|---|
| Day 1 (n=210,219,217) | Week 6 (n= 205,209,206) | |
| Placebo | 3.020 | 2.957 |
| QVA149 + Placebo to Tiotropium | 3.340 | 3.393 |
| Tiotropium + Placebo to QVA149 | 3.249 | 3.269 |
Forced Expiratory Volume in 1 second (FEV1) was measured with spirometry conducted according to internationally accepted standards. Measurements were taken at 5 min- 4hr post-dose of day 1 and week 6. The standardized FEV1 Area under the curve (AUC) was calculated as the sum of trapezoids divided by the length of time. (NCT01490125)
Timeframe: 5min-4hr at day 1 and week 6 post-dose
| Intervention | Liters (Least Squares Mean) | |
|---|---|---|
| Day 1 (n=220,219,2117) | Week 6 (n=205,209,206) | |
| Placebo | 1.352 | 1.302 |
| QVA149 + Placebo to Tiotropium | 1.564 | 1.636 |
| Tiotropium + Placebo to QVA149 | 1.496 | 1.529 |
"The Capacity of Daily Living during the Morning (CDLM) is a self-administered daily assessment. The CDLM asks COPD patients to (i) report their ability to carry out 6 morning activities and (ii) rate the difficulty in performing those activities on a five point Likert-type scale ranging from not at all difficult to extremely difficult. For each of the six morning activities a score ranging from 0 (=so difficult that they could not carry out the activity by themselves) to 5 (not at all difficult to carry out the activity by themselves) is calculated by using the responses from the two questions for each activity. Daily CDLM is calculated using the scores average from the 6 morning activities. CDLM is calculated as the average daily CDLM score over 6 weeks of treatment. The change from baseline in CDLM score over 6 weeks is analyzed using a MIXED model with baseline CDLM score as a covariate. A CDLM score of 0.20 is considered to be a minimal clinically important difference." (NCT01490125)
Timeframe: Baseline and 6 weeks
| Intervention | Units on a scale (Least Squares Mean) |
|---|---|
| QVA149 + Placebo to Tiotropium | 0.09 |
| Tiotropium + Placebo to QVA149 | 0.08 |
| Placebo | -0.01 |
The number of puffs of rescue medication taken by participants, were collected each day during the study via entries in e-diaries (NCT01490125)
Timeframe: Baseline and 6 weeks
| Intervention | puffs (Least Squares Mean) |
|---|---|
| QVA149 + Placebo to Tiotropium | -1.02 |
| Tiotropium + Placebo to QVA149 | -0.57 |
| Placebo | 0.41 |
Spirometry was conducted according to internationally accepted standards. Trough FEV1 referred to the mean of FEV1 at 23:15h and 23:45h after the morning dose of study drug. The baseline was defined as the average of FEV1 values taken in the clinic 45min and 15min prior to the first dose of randomized treatment at Visit 3. A mixed model was used and contained treatment as a fixed effect with the baseline measurement of trough FEV1, FEV1 prior to inhalation of short acting bronchodilators, and FEV1 post-inhalation of bronchodilators and stratification factors as covariates. A positive change from baseline indicates improvement. (NCT01513460)
Timeframe: baseline, 4 weeks, 8 weeks, 12 weeks
| Intervention | Liters (Mean) | ||
|---|---|---|---|
| Week 4 | Week 8 | Week 12 | |
| Flu/Sal | -0.010 | -0.002 | -0.012 |
| NVA237 + Fluticasone/Salmeterol (Flu/Sal) | 0.077 | 0.084 | 0.089 |
| Tiotropium + Flu/Sal | 0.077 | 0.092 | 0.087 |
A night with 'no nighttime awakenings' is defined from diary data as any night where patient did not wake up due to symptoms. Total number of nights with 'no nighttime awakenings' over treatment period was divided by total number of nights where diary recordings have been made in order to derive percentage of 'no nighttime awakenings' which will be summarized by treatment and analyzed using a similar mixed model as specified for primary analysis. Diary data recorded during the 7 day run-in period was used to calculate baseline percentage of nights 'no nighttime awakenings'. (NCT01513460)
Timeframe: 12 weeks
| Intervention | Percentage of nights (Mean) |
|---|---|
| NVA237 + Fluticasone/Salmeterol (Flu/Sal) | 0.834 |
| Tiotropium + Flu/Sal | 0.816 |
| Flu/Sal | 0.823 |
Spirometry was conducted according to internationally accepted standards. Trough FEV1 referred to the mean of FEV1 at 23:15 hours and 23:45 hours after the morning dose of study drug. The baseline was defined as the average of FEV1 values taken in the clinic 45 min and 15 min prior to the first dose of randomized treatment at Visit 3. A mixed model was used and contained treatment as a fixed effect with the baseline measurement of trough FEV1, FEV1 prior to inhalation of short acting bronchodilators, and FEV1 post-inhalation of bronchodilators and stratification factors as covariates. A positive change from baseline indicates improvement. (NCT01513460)
Timeframe: baseline, 12 weeks
| Intervention | liters (Mean) |
|---|---|
| NVA237 + Fluticasone/Salmeterol (Flu/Sal) | 0.095 |
| Tiotropium + Flu/Sal | 0.102 |
The total number of puffs of rescue medication used over the last 12 h recorded in the morning (nighttime use) and in the evening (daytime use) over the full 12 weeks was divided by the total number of days with non-missing rescue data to derive the mean daytime and nighttime number of puffs of rescue medication. Change from baseline in the mean daytime and nighttime number of puffs of rescue medication was analyzed as for the change from baseline in the mean daily number of puffs of rescue medication. (NCT01513460)
Timeframe: baseline, 12 weeks
| Intervention | puffs of rescue medication (Mean) |
|---|---|
| NVA237 + Fluticasone/Salmeterol (Flu/Sal) | 2.191 |
| Tiotropium + Flu/Sal | 2.093 |
| Flu/Sal | 2.908 |
SGRQ-C is a health related quality of life questionnaire consisting of 40 items divided into two components: 1) symptoms, 2) activity& impacts. The lowest possible value is zero and the highest is 100. Higher values corresponded to greater impairment in quality of life. An analysis model included terms for treatment, baseline total SGRQ score, FEV1 and baseline smoking status. The model also contained as fixed effects the baseline total SGRQ score, FEV1 prior to inhalation of short acting bronchodilator, FEV1 post inhalation of short acting bronchodilator and stratification factors as covariates. A negative change from baseline indicates improvement. (NCT01513460)
Timeframe: 12 weeks
| Intervention | units on a scale (Mean) |
|---|---|
| NVA237 + Fluticasone/Salmeterol (Flu/Sal) | -2.806 |
| Tiotropium + Flu/Sal | -3.902 |
| Flu/Sal | -0.652 |
A 'day able to perform usual daily activities' was defined from diary data as any day where the patient was not prevented from performing their usual daily activities due to respiratory symptoms. The percentage of 'days able to perform usual daily activities' was derived and analyzed using a similar mixed model as specified for primary analysis as for the percentage of nights with 'no nighttime awakenings'. (NCT01513460)
Timeframe: 12 weeks
| Intervention | Percentage of days (Mean) |
|---|---|
| NVA237 + Fluticasone/Salmeterol (Flu/Sal) | 0.934 |
| Tiotropium + Flu/Sal | 0.946 |
| Flu/Sal | 0.903 |
Spirometry was conducted according to internationally accepted standards. Trough FEV1 referred to the mean of FEV1 at 23:15h and 23:45h after the morning dose of study drug. The baseline was defined as the average of FEV1 values taken in the clinic 45min and 15min prior to the first dose of randomized treatment at Visit 3. A mixed model was used and contained treatment as a fixed effect with the baseline measurement of trough FEV1, FEV1 prior to inhalation of short acting bronchodilators, and FEV1 post-inhalation of bronchodilators and stratification factors as covariates. A positive change from baseline indicates improvement. (NCT01513460)
Timeframe: baseline, 4 weeks, 8 weeks, 12 weeks
| Intervention | Liters (Mean) | ||
|---|---|---|---|
| Week 4 | Week 8 | Week 12 | |
| Flu/Sal | -0.010 | -0.002 | -0.012 |
| NVA237/Tiotropium+Flu/Sal | 0.077 | 0.088 | 0.088 |
Secondary endpoint was pre-exercise inspiratory capacity (IC) during constant work rate cycle ergometry to symptom limitation at 75% maximal work capacity (Wcap) on Day 1. (NCT01525615)
Timeframe: 1 day
| Intervention | liters (Least Squares Mean) |
|---|---|
| Placebo | 2.440 |
| Tio+Olo 2.5 / 5.0 µg | 2.642 |
| Tio+Olo 5.0 / 5.0 µg | 2.605 |
Secondary endpoint was adjusted mean 1-hour, post-dose Forced Expiratory Volume in one second (FEV1) observed after 12 weeks of treatment (NCT01525615)
Timeframe: 12 weeks
| Intervention | liters (Least Squares Mean) |
|---|---|
| Placebo | 1.527 |
| Tio+Olo 2.5 / 5.0 µg | 1.784 |
| Tio+Olo 5.0 / 5.0 µg | 1.778 |
Secondary endpoint was adjusted mean 1-hour, post-dose Forced Expiratory Volume in one second (FEV1) observed after 6 weeks of treatment (NCT01525615)
Timeframe: 6 weeks
| Intervention | liters (Least Squares Mean) |
|---|---|
| Placebo | 1.517 |
| Tio+Olo 2.5 / 5.0 µg | 1.790 |
| Tio+Olo 5.0 / 5.0 µg | 1.763 |
Secondary endpoint was adjusted mean 1-hour, post-dose Forced Expiratory Volume in one second (FEV1) observed on day 1 (NCT01525615)
Timeframe: 1 day
| Intervention | liters (Least Squares Mean) |
|---|---|
| Placebo | 1.509 |
| Tio+Olo 2.5 / 5.0 µg | 1.693 |
| Tio+Olo 5.0 / 5.0 µg | 1.679 |
Primary endpoint was endurance time during constant work rate cycle ergometry to symptom limitation at 75% of maximal work capacity after 12 weeks of treatment. The endurance time in seconds was transformed using log10 scale to correct skewness in endurance time on original scale and then the MMRM model was fitted to the log10-transformed data and the least square means and SEs were obtained. To present the results in a way easier for interpretation, the least square mean from the MMRM fitted to the log10-transformed data were transformed back taking 10 to the power of the least square estimate for the log10 of geometric mean and the corresponding SE was transformed using delta method to get the corresponding SEs of the geometric mean. (NCT01525615)
Timeframe: 12 weeks
| Intervention | seconds (Least Squares Mean) |
|---|---|
| Placebo | 463.63 |
| Tio+Olo 2.5 / 5.0 µg | 503.64 |
| Tio+Olo 5.0 / 5.0 µg | 527.51 |
Secondary endpoint was endurance time during constant work rate cycle ergometry to symptom limitation at 75% of maximal work capacity after 6 weeks of treatment.The endurance time in seconds was transformed using log10 scale to correct skewness in endurance time on original scale and then the MMRM model was fitted to the log10-transformed data and the least square means and SEs were obtained. To present the results in a way easier for interpretation, the least square mean from the MMRM fitted to the log10-transformed data were transformed back taking 10 to the power of the least square estimate for the log10 of geometric mean and the corresponding SE was transformed using delta method to get the corresponding SEs of the geometric mean. (NCT01525615)
Timeframe: 6 weeks
| Intervention | seconds (Least Squares Mean) |
|---|---|
| Placebo | 427.74 |
| Tio+Olo 2.5 / 5.0 µg | 522.26 |
| Tio+Olo 5.0 / 5.0 µg | 525.62 |
Secondary endpoint was endurance time during constant work rate cycle ergometry to symptom limitation at 75% of maximal work capacity on Day 1. Analysis of covariance model on log10 transformation data. Adjusted means are back transformed to report in original units. Standard errors (SEs) are calculated using the delta method. (NCT01525615)
Timeframe: 1 day
| Intervention | seconds (Least Squares Mean) |
|---|---|
| Placebo | 478.59 |
| Tio+Olo 2.5 / 5.0 µg | 527.69 |
| Tio+Olo 5.0 / 5.0 µg | 538.76 |
Key secondary endpoint was endurance time during endurance shuttle walk test to symptom limitation at 85% of predicted maximum oxygen consumption (VO2) peak after 12 weeks of treatment. The endurance time in seconds was transformed using log10 scale to correct skewness in endurance time on original scale and then the MMRM model was fitted to the log10-transformed data and the least square means and SEs were obtained. To present the results in a way easier for interpretation, the least square mean from the MMRM fitted to the log10-transformed data were transformed back taking 10 to the power of the least square estimate for the log10 of geometric mean and the corresponding SE was transformed using delta method to get the corresponding SEs of the geometric mean. (NCT01525615)
Timeframe: 12 weeks
| Intervention | seconds (Least Squares Mean) |
|---|---|
| Placebo | 311.41 |
| Tio+Olo 2.5 / 5.0 µg | 377.20 |
| Tio+Olo 5.0 / 5.0 µg | 376.39 |
Secondary endpoint was pre-exercise inspiratory capacity (IC) before constant work rate cycle ergometry to symptom limitation at 75% maximal work capacity (Wcap) after 12 weeks of treatment. (NCT01525615)
Timeframe: 12 weeks
| Intervention | liters (Least Squares Mean) |
|---|---|
| Placebo | 2.390 |
| Tio+Olo 2.5 / 5.0 µg | 2.597 |
| Tio+Olo 5.0 / 5.0 µg | 2.624 |
Secondary endpoint was pre-exercise inspiratory capacity (IC) during constant work rate cycle ergometry to symptom limitation at 75% maximal work capacity (Wcap) after 6 weeks of treatment. (NCT01525615)
Timeframe: 6 weeks
| Intervention | liters (Least Squares Mean) |
|---|---|
| Placebo | 2.402 |
| Tio+Olo 2.5 / 5.0 µg | 2.589 |
| Tio+Olo 5.0 / 5.0 µg | 2.627 |
"Secondary endpoint was the slope of the intensity of breathing discomfort during constant work rate cycle ergometry to symptom limitation at 75% of maximal work capacity after 12 weeks of treatment.~The intensity of breathing discomfort was rated on the Borg Scale with categories from 0 (nothing at all) to 10 (maximal). The slope of the intensity of breathing discomfort was defined as the Borg scale value of breathing discomfort at the end of exercise minus the Borg scale value of breathing discomfort at pre-exercise divided by the endurance time. A decrease in slope indicates favorable results." (NCT01525615)
Timeframe: 12 weeks
| Intervention | units / seconds (Least Squares Mean) |
|---|---|
| Placebo | 0.015 |
| Tio+Olo 2.5 / 5.0 µg | 0.013 |
| Tio+Olo 5.0 / 5.0 µg | 0.013 |
"Secondary endpoint was the slope of the intensity of breathing discomfort during constant work rate cycle ergometry to symptom limitation at 75% of maximal work capacity after 6 weeks of treatment.~The intensity of breathing discomfort was rated on the Borg Scale with categories from 0 (nothing at all) to 10 (maximal). The slope of the intensity of breathing discomfort was defined as the Borg scale value of breathing discomfort at the end of exercise minus the Borg scale value of breathing discomfort at pre-exercise divided by the endurance time. A decrease in slope indicates favorable results." (NCT01525615)
Timeframe: 6 weeks
| Intervention | units / seconds (Least Squares Mean) |
|---|---|
| Placebo | 0.016 |
| Tio+Olo 2.5 / 5.0 µg | 0.013 |
| Tio+Olo 5.0 / 5.0 µg | 0.013 |
"Secondary endpoint was the slope of the intensity of breathing discomfort during constant work rate cycle ergometry to symptom limitation at 75% of maximal work capacity after 1 day of treatment.~The intensity of breathing discomfort was rated on the Borg Scale with categories from 0 (nothing at all) to 10 (maximal). The slope of the intensity of breathing discomfort was defined as the Borg scale value of breathing discomfort at the end of exercise minus the Borg scale value of breathing discomfort at pre-exercise divided by the endurance time. A decrease in slope indicates slowing down in decline in breathing, i.e., favorable results." (NCT01525615)
Timeframe: 1 day
| Intervention | units / seconds (Least Squares Mean) |
|---|---|
| Placebo | 0.014 |
| Tio+Olo 2.5 / 5.0 µg | 0.012 |
| Tio+Olo 5.0 / 5.0 µg | 0.012 |
"Endurance time during constant work rate cycle ergometry (CWRCE) to symptom limitation at 75% work capacity (Wcap).~Wcap was defined as the maximum work rate achieved for at least 30 seconds during the incremental cycle ergometry performed at Visit 1.~The presented means are adjusted mean from the MMRM model." (NCT01533922)
Timeframe: 6 weeks
| Intervention | seconds (Geometric Mean) |
|---|---|
| Placebo | 375.45 |
| Olodaterol 5 µg | 453.38 |
| Tiotropium 5 µg | 457.16 |
| Tiotropium + Olodaterol 2.5/5 | 474.80 |
| Tiotropium + Olodaterol 5/5 | 454.08 |
"Forced Expiratory Volume in 1 Second (FEV1) (one hour post-dose)~The presented means are adjusted means from MMRM model." (NCT01533922)
Timeframe: 6 weeks
| Intervention | Litres (Mean) |
|---|---|
| Placebo | 1.497 |
| Olodaterol 5 µg | 1.689 |
| Tiotropium 5 µg | 1.706 |
| Tiotropium + Olodaterol 2.5/5 | 1.783 |
| Tiotropium + Olodaterol 5/5 | 1.820 |
"Inspiratory capacity (IC) at rest before constant work rate cycle ergometry to symptom limitation at 75% maximal work capacity (Wcap).~Wcap was defined as the maximum work rate achieved for at least 30 seconds during the incremental cycle ergometry performed at Visit 1.~The presented means are adjusted means from the MMRM (Mixed Effects Model Repeated Measures) model." (NCT01533922)
Timeframe: 6 weeks
| Intervention | Litres (Mean) |
|---|---|
| Placebo | 2.440 |
| Olodaterol 5 µg | 2.566 |
| Tiotropium 5 µg | 2.571 |
| Tiotropium + Olodaterol 2.5/5 | 2.658 |
| Tiotropium + Olodaterol 5/5 | 2.685 |
"Slope of the intensity of breathing discomfort during Constant Work Rate Cycle Ergometry (CWRCE) to symptom limitation at 75% Work capacity (Wcap). The intensity of breathing discomfort was rated using the modified Borg scale with ratings from 0 (nothing at all) to 10 (maximal).~Slope of breathing discomfort is defined as: (intensity of breathing discomfort at the end of exercise minus intensity of breathing discomfort at rest) / endurance time.~A decrease in slope indicates improvement.~The presented means are adjusted means from MMRM model." (NCT01533922)
Timeframe: 6 weeks
| Intervention | units on a scale / second (Mean) |
|---|---|
| Placebo | 0.018 |
| Olodaterol 5 µg | 0.016 |
| Tiotropium 5 µg | 0.016 |
| Tiotropium + Olodaterol 2.5/5 | 0.015 |
| Tiotropium + Olodaterol 5/5 | 0.016 |
"Inspiratory capacity (IC) at rest before constant work rate cycle ergometry to symptom limitation at 75% maximal work capacity (Wcap).~Wcap was defined as the maximum work rate achieved for at least 30 seconds during the incremental cycle ergometry performed at Visit 1.~The presented means are adjusted means from the MMRM (Mixed Effects Model Repeated Measures) model." (NCT01533935)
Timeframe: 6 weeks
| Intervention | Litres (Mean) |
|---|---|
| Placebo | 2.502 |
| Olodaterol 5 µg | 2.687 |
| Tiotropium 5 µg | 2.679 |
| Tiotropium + Olodaterol 2.5/5 | 2.776 |
| Tiotropium + Olodaterol 5/5 | 2.767 |
"Slope of the intensity of breathing discomfort (Borg Scale) during CWRCE to symptom limitation at 75% Wcap. The intensity of breathing discomfort was rated using the modified Borg scale with ratings from 0 (nothing at all) to 10 (maximal).~Slope is defined as : (intensity of breathing discomfort at the end of exercise minus intensity of breathing discomfort at rest) / endurance time.~A decrease in slope indicates improvement.~The presented means are adjusted means from MMRM model." (NCT01533935)
Timeframe: 6 weeks
| Intervention | units on a scale / s (Mean) |
|---|---|
| Placebo | 0.018 |
| Olodaterol 5 µg | 0.017 |
| Tiotropium 5 µg | 0.015 |
| Tiotropium + Olodaterol 2.5/5 | 0.014 |
| Tiotropium + Olodaterol 5/5 | 0.015 |
"Forced Expiratory Volume in 1 Second (FEV1) (one hour post-dose).~The presented means are adjusted means from MMRM model." (NCT01533935)
Timeframe: 6 weeks
| Intervention | Litres (Mean) |
|---|---|
| Placebo | 1.548 |
| Olodaterol 5 µg | 1.742 |
| Tiotropium 5 µg | 1.741 |
| Tiotropium + Olodaterol 2.5/5 | 1.852 |
| Tiotropium + Olodaterol 5/5 | 1.876 |
"Endurance time during constant work rate cycle ergometry (CWRCE) to symptom limitation at 75% Wcap~Wcap was defined as the maximum work rate achieved for at least 30 seconds during the incremental cycle ergometry performed at Visit 1.~The presented means are adjusted mean from the MMRM model." (NCT01533935)
Timeframe: 6 weeks
| Intervention | seconds (Geometric Mean) |
|---|---|
| Placebo | 410.77 |
| Olodaterol 5 µg | 419.06 |
| Tiotropium 5 µg | 446.50 |
| Tiotropium + Olodaterol 2.5/5 | 460.66 |
| Tiotropium + Olodaterol 5/5 | 465.68 |
"Trough Forced Expiratory Volume in 1 second Response. The trough was defined as the mean of the 1 h pre-dose and 10 min pre-dose measurements after 52 weeks. Baseline was defined as the mean of the 2 pre-treatment FEV1 values measured on day 1 (-1 hour and -10 minutes) prior to administration of the first dose of study drug.~Note: The Mean presented is the unadjusted mean." (NCT01536262)
Timeframe: Baseline and 1 h, 10 min pre-dose after 52 weeks
| Intervention | L (Mean) |
|---|---|
| Olodaterol (5 μg) | 0.075 |
| Tiotropium + Olodaterol (2.5 / 5 μg) | 0.168 |
| Tiotropium + Olodaterol (5 / 5 μg) | 0.143 |
Number (%) of patients with drug-related Adverse Events (AEs). (NCT01536262)
Timeframe: From first drug administration until 21 days after the last administration, upto 392 days
| Intervention | percentage of participants (Number) |
|---|---|
| Olodaterol (5 μg) | 4.9 |
| Tiotropium + Olodaterol (2.5 / 5 μg) | 5.0 |
| Tiotropium + Olodaterol (5 / 5 μg) | 7.3 |
"Forced Expiratory Volume in 1 second Area Under Curve (AUC0-3h) response. FEV1 AUC0-3h was calculated using the trapezoidal rule, divided by the duration (3 h) to report in litres. Baseline was defined as the mean of the 2 pre-treatment FEV1 values measured on day 1 (-1 hour and -10 minutes) prior to administration of the first dose of study drug.~Note: The Mean presented is the unadjusted mean." (NCT01536262)
Timeframe: Baseline and 1 h, 10 min pre-dose and 30 min, 1 h, 2 h, 3 h post-dose after 52 weeks
| Intervention | L (Mean) |
|---|---|
| Olodaterol (5 μg) | 0.132 |
| Tiotropium + Olodaterol (2.5 / 5 μg) | 0.260 |
| Tiotropium + Olodaterol (5 / 5 μg) | 0.237 |
"Trough Forced Vital Capacity (FVC) response after 6 weeks treatment period.~The trough was defined as the mean of the 23 h and 23 h50 min measurements and response was defined as the change from patient baseline.~Mean is actually the Adjusted mean.~The adjusted mean (SE) are obtained from fitting a mixed effect model repeated measures (MMRM) including fixed effects of treatment and period; period baseline and patient baseline as covariates; patient as a random effect; compound symmetry covariance structure for within-patient variation and Kenward-Roger approximation of denominator degrees of freedom." (NCT01559116)
Timeframe: day1 and week 6
| Intervention | Litres (L) (Mean) |
|---|---|
| Placebo | -0.025 |
| Olodaterol (5 µg) | 0.134 |
| Tiotropium (2.5 µg) | 0.115 |
| Tiotropium (5 µg) | 0.183 |
| Tiotropium+Olodaterol FDC (2.5/5 µg) | 0.282 |
| Tiotropium+Olodaterol FDC (5/5 µg) | 0.304 |
"Trough Forced Expiratory Volume in 1 second (FEV1) response after 6 weeks treatment period.~The trough was defined as the mean of the 23 h and 23 h50 min measurements and Response was defined as the change from patient baseline.~Mean is actually the Adjusted mean.~The adjusted mean (SE) are obtained from fitting a mixed effect model repeated measures (MMRM) including fixed effects of treatment and period; period baseline and patient baseline as covariates; patient as a random effect; compound symmetry covariance structure for within-patient variation and Kenward-Roger approximation of denominator degrees of freedom." (NCT01559116)
Timeframe: day 1 and week 6
| Intervention | Litres (Mean) |
|---|---|
| Placebo | -0.006 |
| Olodaterol (5 µg) | 0.109 |
| Tiotropium (2.5 µg) | 0.095 |
| Tiotropium (5 µg) | 0.122 |
| Tiotropium+Olodaterol FDC (2.5/5 µg) | 0.196 |
| Tiotropium+Olodaterol FDC (5/5 µg) | 0.201 |
"Peak (0-3h) Forced Vital Capacity (FVC) responses after 6 weeks treatment.~Peak was defined as the maximum value measured within the first 3 h post dosing and response was defined as the change from patient baseline.~Mean is actually the Adjusted mean.~The adjusted mean (SE) are obtained from fitting a mixed effect model repeated measures (MMRM) including fixed effects of treatment and period; period baseline and patient baseline as covariates; patient as a random effect; compound symmetry covariance structure for within-patient variation and Kenward-Roger approximation of denominator degrees of freedom." (NCT01559116)
Timeframe: day 1 and week 6
| Intervention | Litres (L) (Mean) |
|---|---|
| Placebo | 0.159 |
| Olodaterol (5 µg) | 0.463 |
| Tiotropium (2.5 µg) | 0.450 |
| Tiotropium (5 µg) | 0.470 |
| Tiotropium+Olodaterol FDC (2.5/5 µg) | 0.612 |
| Tiotropium+Olodaterol FDC (5/5 µg) | 0.621 |
"Peak (0-3h) Forced Expiratory Volume in 1 second (FEV1) response.~The peak was defined as the maximum value measured within the first 3 h post dosing and response was defined as the change from patient baseline.~Mean is actually the Adjusted mean.~The adjusted mean (SE) are obtained from fitting a mixed effect model repeated measures (MMRM) including fixed effects of treatment and period; period baseline and patient baseline as covariates; patient as a random effect; compound symmetry covariance structure for within-patient variation and Kenward-Roger approximation of denominator degrees of freedom." (NCT01559116)
Timeframe: day 1 and week 6
| Intervention | Litres (L) (Mean) |
|---|---|
| Placebo | 0.072 |
| Olodaterol (5 µg) | 0.291 |
| Tiotropium (2.5 µg) | 0.290 |
| Tiotropium (5 µg) | 0.300 |
| Tiotropium+Olodaterol FDC (2.5/5 µg) | 0.422 |
| Tiotropium+Olodaterol FDC (5/5 µg) | 0.411 |
"Area under the Forced Expiratory Volume in 1 second (FEV1) after 6 weeks treatement-time curve from 0 to 12 h post-dose, using the trapezoidal rule, divided by the duration (12h) to report in litres.~Mean is actually the Adjusted mean.~The adjusted mean (SE) are obtained from fitting a mixed effect model repeated measures (MMRM) including fixed effects of treatment and period; period baseline and patient baseline as covariates; patient as a random effect; compound symmetry covariance structure for within-patient variation and Kenward-Roger approximation of denominator degrees of freedom." (NCT01559116)
Timeframe: day 1 and week 6
| Intervention | Litres (L) (Mean) |
|---|---|
| Placebo | -0.013 |
| Olodaterol (5 µg) | 0.179 |
| Tiotropium (2.5 µg) | 0.171 |
| Tiotropium (5 µg) | 0.186 |
| Tiotropium+Olodaterol FDC (2.5/5 µg) | 0.310 |
| Tiotropium+Olodaterol FDC (5/5 µg) | 0.305 |
"Area under the Forced Expiratory Volume in 1 second (FEV1) after 6 weeks treatement-time curve from 12 to 24 h post-dose using the trapezoidal rule, divided by the duration (12 h) to report in litres.~Mean is actually the Adjusted mean.~The adjusted mean (SE) are obtained from fitting a mixed effect model repeated measures (MMRM) including fixed effects of treatment and period; period baseline and patient baseline as covariates; patient as a random effect; compound symmetry covariance structure for within-patient variation and Kenward-Roger approximation of denominator degrees of freedom." (NCT01559116)
Timeframe: day 1 and week 6
| Intervention | Litres (L) (Mean) |
|---|---|
| Placebo | -0.060 |
| Olodaterol (5 µg) | 0.079 |
| Tiotropium (2.5 µg) | 0.062 |
| Tiotropium (5 µg) | 0.081 |
| Tiotropium+Olodaterol FDC (2.5/5 µg) | 0.172 |
| Tiotropium+Olodaterol FDC (5/5 µg) | 0.182 |
"Area under the Forced Expiratory Volume in 1 second (FEV1) after 6 weeks treatement-time curve from 0 to 24 h post-dose, using the trapezoidal rule, divided by the duration (24 h) to report in litres.~Mean is actually the Adjusted mean.~The adjusted mean and standard error (SE) are obtained from fitting a mixed effect model repeated measures (MMRM) including fixed effects of treatment and period; period baseline and patient baseline as covariates; patient as a random effect; compound symmetry covariance structure for within-patient variation and Kenward-Roger approximation of denominator degrees of freedom." (NCT01559116)
Timeframe: day 1 and week 6
| Intervention | Litres (L) (Mean) |
|---|---|
| Placebo | -0.037 |
| Olodaterol (5 µg) | 0.129 |
| Tiotropium (2.5 µg) | 0.117 |
| Tiotropium (5 µg) | 0.133 |
| Tiotropium+Olodaterol FDC (2.5/5 µg) | 0.241 |
| Tiotropium+Olodaterol FDC (5/5 µg) | 0.244 |
"Area under the Forced Vital Capacity (FVC) after 6 weeks treatment period-time curve from 0 to 12 h post-dose using the trapezoidal rule, divided by the duration (12 h) to report in litres.~Mean is actually the Adjusted mean.~The adjusted mean (SE) are obtained from fitting a mixed effect model repeated measures (MMRM) including fixed effects of treatment and period; period baseline and patient baseline as covariates; patient as a random effect; compound symmetry covariance structure for within-patient variation and Kenward-Roger approximation of denominator degrees of freedom." (NCT01559116)
Timeframe: day 1 and week 6
| Intervention | Litres (L) (Mean) |
|---|---|
| Placebo | -0.023 |
| Olodaterol (5 µg) | 0.240 |
| Tiotropium (2.5 µg) | 0.249 |
| Tiotropium (5 µg) | 0.261 |
| Tiotropium+Olodaterol FDC (2.5/5 µg) | 0.420 |
| Tiotropium+Olodaterol FDC (5/5 µg) | 0.440 |
"Area under the Forced Vital Capacity (FVC) after 6 weeks treatment period-time curve from 0 to 24 h post-dose using the trapezoidal rule, divided by the duration (24 h) to report in litres.~Mean is actually the Adjusted mean.~The adjusted mean (SE) are obtained from fitting a mixed effect model repeated measures (MMRM) including fixed effects of treatment and period; period baseline and patient baseline as covariates; patient as a random effect; compound symmetry covariance structure for within-patient variation and Kenward-Roger approximation of denominator degrees of freedom." (NCT01559116)
Timeframe: day 1 and week 6
| Intervention | Litres(L) (Mean) |
|---|---|
| Placebo | -0.065 |
| Olodaterol (5 µg) | 0.158 |
| Tiotropium (2.5 µg) | 0.172 |
| Tiotropium (5 µg) | 0.191 |
| Tiotropium+Olodaterol FDC (2.5/5 µg) | 0.331 |
| Tiotropium+Olodaterol FDC (5/5 µg) | 0.368 |
"Area under the Forced Vital Capacity (FVC) after 6 weeks treatment period-time curve from 12 to 24 h post-dose using the trapezoidal rule, divided by the duration (12 h) to report in litres.~Mean is actually the Adjusted mean.~The adjusted mean (SE) are obtained from fitting a mixed effect model repeated measures (MMRM) including fixed effects of treatment and period; period baseline and patient baseline as covariates; patient as a random effect; compound symmetry covariance structure for within-patient variation and Kenward-Roger approximation of denominator degrees of freedom." (NCT01559116)
Timeframe: day 1 and week 6
| Intervention | Litres (L) (Mean) |
|---|---|
| Placebo | -0.108 |
| Olodaterol (5 µg) | 0.077 |
| Tiotropium (2.5 µg) | 0.095 |
| Tiotropium (5 µg) | 0.122 |
| Tiotropium+Olodaterol FDC (2.5/5 µg) | 0.243 |
| Tiotropium+Olodaterol FDC (5/5 µg) | 0.296 |
Peak change from baseline in IC (mean of 1 hr and 2 hr post-dose assessments) (NCT01566773)
Timeframe: Day 7 (mean of 1 hr and 2 hr post-dose assessments)
| Intervention | mL (Least Squares Mean) |
|---|---|
| GP MDI 18 µg BID | 302 |
| GP MDI 9 µg BID | 234 |
| GP MDI 4.6 µg BID | 254 |
| GP MDI 2.4 µg BID | 312 |
| GP MDI 1.2 µg BID | 195 |
| GP MDI 0.6 µg BID | 159 |
| Placebo MDI | 99 |
| Spiriva® Handihaler® | 390 |
Percentage of subjects achieving at least 12% improvement in FEV1. (NCT01566773)
Timeframe: Day 1
| Intervention | Percentage of participants (Number) |
|---|---|
| GP MDI 18 µg BID | 70 |
| GP MDI 9 µg BID | 59 |
| GP MDI 4.6 µg BID | 40 |
| GP MDI 2.4 µg BID | 47 |
| GP MDI 1.2 µg BID | 40 |
| GP MDI 0.6 µg BID | 31 |
| Spiriva® Handihaler® | 71 |
Time to Onset of Action (>10% Improvement in FEV1) on Day 1. (NCT01566773)
Timeframe: Day 1 (15 min, 30 min, 1 hr, 2 hrs, no onset within 2 hrs)
| Intervention | % of participants (Number) | ||||
|---|---|---|---|---|---|
| 15 minutes | 30 minutes | 1 hour | 2 hours | No onset within 2 hours | |
| GP MDI 0.6 µg BID | 7 | 9 | 17 | 7 | 59 |
| GP MDI 1.2 µg BID | 18 | 12 | 10 | 10 | 50 |
| GP MDI 18 µg BID | 29 | 22 | 26 | 0 | 24 |
| GP MDI 2.4 µg BID | 21 | 16 | 10 | 7 | 47 |
| GP MDI 4.6 µg BID | 14 | 9 | 11 | 11 | 56 |
| GP MDI 9 µg BID | 30 | 11 | 11 | 16 | 32 |
| Placebo MDI | 4 | 7 | 9 | 2 | 78 |
| Spiriva® Handihaler® | 39 | 15 | 15 | 11 | 20 |
Change from Baseline in Morning Pre-dose Trough FEV1 (mL) Averaging Treatment Day 7 and Day 14 (NCT01566773)
Timeframe: Day 1 through Day 14
| Intervention | Liter (Least Squares Mean) |
|---|---|
| GP MDI 18 µg BID | 0.088 |
| GP MDI 9 µg BID | 0.087 |
| GP MDI 4.6 µg BID | 0.090 |
| GP MDI 2.4 µg BID | 0.086 |
| GP MDI 1.2 µg BID | 0.056 |
| GP MDI 0.6 µg BID | 0.023 |
| Placebo MDI | 0.001 |
| Spiriva® Handihaler® | 0.141 |
Change from baseline in morning pre-dose trough FEV1 (average of the 60 and 30-minute pre-dose values on Treatment Day 7 minus the baseline) (NCT01566773)
Timeframe: Day 7 (average of the 60 and 30-minute pre-dose values on Treatment Day 7 minus the baseline)
| Intervention | mL (Least Squares Mean) |
|---|---|
| GP MDI 18 µg BID | 88 |
| GP MDI 9 µg BID | 90 |
| GP MDI 4.6 µg BID | 109 |
| GP MDI 2.4 µg BID | 96 |
| GP MDI 1.2 µg BID | 43 |
| GP MDI 0.6 µg BID | 23 |
| Placebo MDI | 10 |
| Spiriva® Handihaler® | 156 |
12-hour post-dose trough FEV1 was defined as the mean of the FEV1 assessments taken at 11.5 and 12 hours post-dose minus the baseline (NCT01566773)
Timeframe: Day 14 (Baseline, 11.5 and 12 hours post dose)
| Intervention | mL (Least Squares Mean) |
|---|---|
| GP MDI 18 µg BID | 116 |
| GP MDI 9 µg BID | 69 |
| GP MDI 4.6 µg BID | 99 |
| GP MDI 2.4 µg BID | 112 |
| GP MDI 1.2 µg BID | 66 |
| GP MDI 0.6 µg BID | 55 |
| Placebo MDI | 1 |
| Spiriva® Handihaler® | 164 |
Change from baseline in mean evening post-dose daily peak flow readings taken by subjects and recorded in subject diaries during each treatment period for subjects with more than 7 days of diary data (subjects taking Spiriva performed a single evening assessment) (NCT01566773)
Timeframe: Through the end of the 14-Day Treatment
| Intervention | L/min (Least Squares Mean) |
|---|---|
| GP MDI 18 µg BID | 41.4 |
| GP MDI 9 µg BID | 32.7 |
| GP MDI 4.6 µg BID | 24.7 |
| GP MDI 2.4 µg BID | 27.0 |
| GP MDI 1.2 µg BID | 19.4 |
| GP MDI 0.6 µg BID | 22.7 |
| Placebo MDI | 13.5 |
| Spiriva® Handihaler® | 35.9 |
Change from baseline in mean evening post-dose daily peak flow readings taken by subjects and recorded in subject diaries, up through Diary Day 7 of each treatment period (subjects taking Spiriva performed a single evening assessment) (NCT01566773)
Timeframe: Day 7
| Intervention | L/min (Least Squares Mean) |
|---|---|
| GP MDI 18 µg BID | 42.2 |
| GP MDI 9 µg BID | 30.3 |
| GP MDI 4.6 µg BID | 21.6 |
| GP MDI 2.4 µg BID | 24.3 |
| GP MDI 1.2 µg BID | 20.2 |
| GP MDI 0.6 µg BID | 22.1 |
| Placebo MDI | 11.0 |
| Spiriva Respimat | 35.6 |
Change from baseline in mean evening pre-dose daily peak flow readings taken by subjects and recorded in subject diaries during each treatment period for subjects with more than 7 days of diary data (subjects taking Spiriva performed a single evening assessment) (NCT01566773)
Timeframe: Treatment Day 1 to the end of the 14-Day Treatment, values were averaged for the end of treatment value (all subjects with diary data after Diary day 7)
| Intervention | L/min (Least Squares Mean) |
|---|---|
| GP MDI 18 µg BID | 15.7 |
| GP MDI 9 µg BID | 14.9 |
| GP MDI 4.6 µg BID | 7.2 |
| GP MDI 2.4 µg BID | 11.7 |
| GP MDI 1.2 µg BID | 5.0 |
| GP MDI 0.6 µg BID | 6.9 |
| Placebo MDI | 5.7 |
Change from baseline in mean evening pre-dose daily peak flow readings taken by subjects and recorded in subject diaries, up through Diary Day 7 of each treatment period (subjects taking Spiriva performed a single evening assessment) (NCT01566773)
Timeframe: Day 7
| Intervention | L/min (Least Squares Mean) |
|---|---|
| GP MDI 18 µg BID | 15.8 |
| GP MDI 9 µg BID | 12.6 |
| GP MDI 4.6 µg BID | 4.7 |
| GP MDI 2.4 µg BID | 11.2 |
| GP MDI 1.2 µg BID | 7.5 |
| GP MDI 0.6 µg BID | 5.9 |
| Placebo MDI | 3.3 |
Change from baseline in mean morning post-dose daily peak flow readings taken by subjects and recorded in subject diaries during each treatment period for subjects with more than 7 days of diary data (mean reading excluded reading taken pre-dose on Visit 2 [Treatment 1 Day 1] (NCT01566773)
Timeframe: Baseline, Treatment Day 1 and every day, to the end of the 14-Day Treatment period 30 minutes post dosing, values were averaged for the end of treatment value (all subjects with diary data after Diary day 7)
| Intervention | L/min (Least Squares Mean) |
|---|---|
| GP MDI 18 µg BID | 33.5 |
| GP MDI 9 µg BID | 26.7 |
| GP MDI 4.6 µg BID | 20.2 |
| GP MDI 2.4 µg BID | 20.3 |
| GP MDI 1.2 µg BID | 14.8 |
| GP MDI 0.6 µg BID | 14.3 |
| Placebo MDI | 5.3 |
| Spiriva® Handihaler® | 39.8 |
Peak change in Inspiratory Capacity (IC) mean of 1 and 2 hour post-dose assessments minus the baseline (NCT01566773)
Timeframe: Day 1 (1 hr and 2 hr post-dose )
| Intervention | mL (Least Squares Mean) |
|---|---|
| GP MDI 18 µg BID | 234 |
| GP MDI 9 µg BID | 263 |
| GP MDI 4.6 µg BID | 151 |
| GP MDI 2.4 µg BID | 183 |
| GP MDI 1.2 µg BID | 126 |
| GP MDI 0.6 µg BID | 82 |
| Placebo MDI | 80 |
| Spiriva® Handihaler® | 343 |
Change from baseline in morning post-dose daily PEFR (peak expiratory flow rate) taken by subjects and recorded in subject diaries, up through Diary Day 7 of each treatment period (excluding reading taken pre-dose on Visit 2 [Treatment Day 1]) (NCT01566773)
Timeframe: Day 7 (30 minutes post-dose)
| Intervention | L/min (Least Squares Mean) |
|---|---|
| GP MDI 18 µg BID | 32.3 |
| GP MDI 9 µg BID | 23.9 |
| GP MDI 4.6 µg BID | 17.2 |
| GP MDI 2.4 µg BID | 18.3 |
| GP MDI 1.2 µg BID | 14.3 |
| GP MDI 0.6 µg BID | 13.7 |
| Placebo MDI | 4.5 |
| Spiriva® Handihaler® | 38.0 |
Change from baseline in morning pre-dose trough FEV1 (average of the 60 and 30-minute pre-dose values on Treatment Day 14 minus the baseline) (NCT01566773)
Timeframe: Day 14 (average of the 60 and 30-minute pre-dose values on Treatment Day 14 minus the baseline)
| Intervention | mL (Least Squares Mean) |
|---|---|
| GP MDI 18 µg BID | 89 |
| GP MDI 9 µg BID | 80 |
| GP MDI 4.6 µg BID | 67 |
| GP MDI 2.4 µg BID | 77 |
| GP MDI 1.2 µg BID | 68 |
| GP MDI 0.6 µg BID | 29 |
| Placebo MDI | -8 |
| Spiriva® Handihaler® | 126 |
Peak change from baseline in IC (mean of 1 and 2 hour post-dose assessments minus the baseline) (NCT01566773)
Timeframe: Day 14 (mean of 1 and 2 hour post-dose assessments minus the baseline)
| Intervention | mL (Least Squares Mean) |
|---|---|
| GP MDI 18 µg BID | 280 |
| GP MDI 9 µg BID | 259 |
| GP MDI 4.6 µg BID | 288 |
| GP MDI 2.4 µg BID | 226 |
| GP MDI 1.2 µg BID | 261 |
| GP MDI 0.6 µg BID | 172 |
| Placebo MDI | 77 |
| Spiriva® Handihaler® | 284 |
Peak change from baseline in FEV1 (defined as the change at the highest value of FEV1 post-dose minus the baseline) (NCT01566773)
Timeframe: Day 7
| Intervention | mL (Least Squares Mean) |
|---|---|
| GP MDI 18 µg BID | 286 |
| GP MDI 9 µg BID | 269 |
| GP MDI 4.6 µg BID | 266 |
| GP MDI 2.4 µg BID | 235 |
| GP MDI 1.2 µg BID | 225 |
| GP MDI 0.6 µg BID | 166 |
| Placebo MDI | 114 |
| Spiriva® Handihaler® | 366 |
Change from baseline in mean morning pre-dose daily PEFR (peak expiratory flow rate) taken by subjects and recorded in subject diaries, up through Diary Day 7 of each treatment period (excluding reading taken pre-dose on Visit 2 [Treatment Day 1]) (NCT01566773)
Timeframe: Day 7 (60 minutes pre-dose, 30 minutes pre-dose)
| Intervention | L/min (Least Squares Mean) |
|---|---|
| GP MDI 18 µg BID | 8.0 |
| GP MDI 9 µg BID | 3.2 |
| GP MDI 4.6 µg BID | 0.2 |
| GP MDI 2.4 µg BID | 2.4 |
| GP MDI 1.2 µg BID | -2.4 |
| GP MDI 0.6 µg BID | -2.5 |
| Placebo MDI | -7.2 |
| Spiriva® Handihaler® | 12.7 |
Peak change from baseline in FEV1 (defined as the change at the highest value of FEV1 post-dose minus the baseline) (NCT01566773)
Timeframe: Day 14
| Intervention | mL (Least Squares Mean) |
|---|---|
| GP MDI 18 µg BID | 288 |
| GP MDI 9 µg BID | 288 |
| GP MDI 4.6 µg BID | 287 |
| GP MDI 2.4 µg BID | 261 |
| GP MDI 1.2 µg BID | 246 |
| GP MDI 0.6 µg BID | 188 |
| Placebo MDI | 130 |
| Spiriva® Handihaler® | 361 |
Highest value of FEV1 post dose on day 1 (NCT01566773)
Timeframe: Day 1
| Intervention | mL (Least Squares Mean) |
|---|---|
| GP MDI 18 µg BID | 231 |
| GP MDI 9 µg BID | 226 |
| GP MDI 4.6 µg BID | 165 |
| GP MDI 2.4 µg BID | 170 |
| GP MDI 1.2 µg BID | 136 |
| GP MDI 0.6 µg BID | 107 |
| Placebo MDI | 57 |
| Spiriva® Handihaler® | 270 |
Mean number of puffs of rescue medication recorded in subject diaries during each treatment period and by treatment and numbers of days treated (NCT01566773)
Timeframe: Day 14 (End of treatment)
| Intervention | Puffs (Mean) |
|---|---|
| GP MDI 18 µg BID | 0.85 |
| GP MDI 9 µg BID | 1.25 |
| GP MDI 4.6 µg BID | 1.19 |
| GP MDI 2.4 µg BID | 1.11 |
| GP MDI 1.2 µg BID | 1.43 |
| GP MDI 0.6 µg BID | 1.57 |
| Placebo MDI | 1.92 |
| Spiriva® Handihaler® | 0.87 |
Change from baseline in mean morning pre-dose daily peak flow readings taken by subjects and recorded in subject diaries during each treatment period for subjects with more than 7 days of diary data (mean reading excluded reading taken pre-dose on Visit 2 [Treatment 1 Day 1] (NCT01566773)
Timeframe: Baseline, Treatment Day 1 and every day, to the end of the 14-Day Treatment period before dosing, values were averaged for the end of treatment value (all subjects with diary data after Diary day 7)
| Intervention | L/min (Least Squares Mean) |
|---|---|
| GP MDI 18 µg BID | 8.6 |
| GP MDI 9 µg BID | 6.2 |
| GP MDI 4.6 µg BID | 2.0 |
| GP MDI 2.4 µg BID | 4.4 |
| GP MDI 1.2 µg BID | 0.3 |
| GP MDI 0.6 µg BID | -0.5 |
| Placebo MDI | -6.3 |
| Spiriva® Handihaler® | 14.8 |
Mean number of puffs of rescue medication recorded in subject diaries during each treatment period and by treatment and numbers of days treated (NCT01566773)
Timeframe: Day 7
| Intervention | Puffs (Mean) |
|---|---|
| GP MDI 18 µg BID | 0.9 |
| GP MDI 9 µg BID | 1.3 |
| GP MDI 4.6 µg BID | 1.2 |
| GP MDI 2.4 µg BID | 1.2 |
| GP MDI 1.2 µg BID | 1.5 |
| GP MDI 0.6 µg BID | 1.6 |
| Placebo MDI | 2.0 |
| Spiriva® Handihaler® | 0.9 |
Forced expiratory volume in 1 second (FEV1) normalized area under the curve 0-12 hours (AUC0-12) following chronic dosing for 14 days. (NCT01566773)
Timeframe: Day 14 (-1 hr, -30 min, 15 min, 30 min, 1 hr, 2 hr, 4 hr, 6 hr, 8 hr, 10 hr, 11.5 hr, 12 hr)
| Intervention | Liter (Least Squares Mean) |
|---|---|
| GP MDI 18 µg BID | 1.448 |
| GP MDI 9 µg BID | 1.416 |
| GP MDI 4.6 µg BID | 1.432 |
| GP MDI 2.4 µg BID | 1.416 |
| GP MDI 1.2 µg BID | 1.386 |
| GP MDI 0.6 µg BID | 1.353 |
| Placebo MDI | 1.290 |
| Spiriva® Handihaler® | 1.514 |
Change from baseline in morning pre-dose trough IC (average of the 60 and 30-minute pre-dose assessments minus the baseline) (NCT01566773)
Timeframe: Day 7
| Intervention | mL (Least Squares Mean) |
|---|---|
| GP MDI 18 µg BID | 137 |
| GP MDI 9 µg BID | 57 |
| GP MDI 4.6 µg BID | 101 |
| GP MDI 2.4 µg BID | 142 |
| GP MDI 1.2 µg BID | 73 |
| GP MDI 0.6 µg BID | 54 |
| Placebo MDI | 62 |
| Spiriva® Handihaler® | 184 |
Change from baseline for mean morning pre-dose trough IC (average of the 60 and 30-minute pre-dose assessments minus the baseline) (NCT01566773)
Timeframe: Day 14 (average of the 60 and 30-minute pre-dose assessments minus the baseline)
| Intervention | mL (Least Squares Mean) |
|---|---|
| GP MDI 18 µg BID | 94 |
| GP MDI 9 µg BID | 45 |
| GP MDI 4.6 µg BID | 64 |
| GP MDI 2.4 µg BID | 104 |
| GP MDI 1.2 µg BID | 69 |
| GP MDI 0.6 µg BID | 34 |
| Placebo MDI | 9 |
| Spiriva® Handihaler® | 138 |
Baseline Dyspnea Index (BDI)/Transition Dyspnea Index (TDI) focal score is based on three domains: functional impairment, magnitude of task and magnitude of effort and captures changes from baseline. BDI was measured at day 1 prior to the first dose with domain scores ranging from 0=very severe to 4=no impairment and a total score ranging from 0 to 12(best). TDI captures changes from baseline. Each domain is scored from -3=major deterioration to 3=major improvement to give an overall TDI focal score of -9 to 9. Higher numbers indicate a better score. missing values were replaced by the latest observed value (LOCF) (NCT01574651)
Timeframe: Week 26
| Intervention | Units on a scale (Mean) |
|---|---|
| QVA149 Plus Placebo to Tiotropium and Placebo to Formoterol | 1.34 |
| Tiotropium Plus Formoterol and Placebo to QVA149 | 0.87 |
"Part I of the SGRQ-C covers symptoms and is concerned with respiratory symptoms, their frequency and severity. Each questionnaire response has a unique empirically derived weight. A score was calculated from these weights. The lowest possible value is zero and the highest 100. A higher value corresponds to greater impairment of health status." (NCT01574651)
Timeframe: Baseline, Week 26
| Intervention | Score on a scale (Mean) | |
|---|---|---|
| Baseline (n=473,457) | Week 26 (n=476,458) | |
| QVA149 Plus Placebo to Tiotropium and Placebo to Formoterol | 64.10 | 58.31 |
| Tiotropium Plus Formoterol and Placebo to QVA149 | 64.29 | 60.16 |
FEV1 30min is the forced expiratory volume in one second measured 30 min after the morning dose. (NCT01574651)
Timeframe: Baseline, Week 26
| Intervention | Liters (Mean) | |
|---|---|---|
| Baseline (n=475,458) | Week 26 (n=476,458) | |
| QVA149 Plus Placebo to Tiotropium and Placebo to Formoterol | 1.517 | 1.605 |
| Tiotropium Plus Formoterol and Placebo to QVA149 | 1.495 | 1.565 |
SGRQ is a health related quality of life questionnaire consisting of 40 items in three areas: symptoms (respiratory symptoms and severity), activity (activities that cause or are limited by breathlessness) and impacts (social functioning and psychological disturbances due to airway disease). The total score is 0 to 100 with a higher score indicating poorer health status. For patients who completed the study but with missing SGRQ-C during treatment, the missing SGRQ-C were replaced by the last observation carried forward (LOCF). Symptom scores were expected to improve over treatment, therefore the replacement of missing values with earlier measurements did not result in overoptimistic imputation and this procedure could be regarded as conservative. (NCT01574651)
Timeframe: Baseline, week 26
| Intervention | Score on a scale (Mean) | |
|---|---|---|
| Baseline (n=452,441) | Week 26 (n=475,456) | |
| QVA149 Plus Placebo to Tiotropium and Placebo to Formoterol | 44.70 | 41.30 |
| Tiotropium Plus Formoterol and Placebo to QVA149 | 45.68 | 43.19 |
SGRQ is a health related quality of life questionnaire consisting of 40 items in three areas: symptoms (respiratory symptoms and severity), activity (activities that cause or are limited by breathlessness) and impacts (social functioning and psychological disturbances due to airway disease). The total score is 0 to 100 with a higher score indicating poorer health status. For patients who completed the study but with missing SGRQ-C during treatment, the missing SGRQ-C were replaced by the last observation carried forward (LOCF). Symptom scores were expected to improve over treatment, therefore the replacement of missing values with earlier measurements did not result in overoptimistic imputation and this procedure could be regarded as conservative. Superiority of QVA 110/50 μg to tiotropium 18 μg q.d. plus formoterol 12 μg b.i.d. in terms of health related quality of life as assessed by St George's Respiratory Questionnaire (SGRQ-C) after 26 weeks of treatment (NCT01574651)
Timeframe: Baseline, week 26
| Intervention | Score on a scale (Mean) | |
|---|---|---|
| Baseline (n=452,441) | Week 26 (n=475,456) | |
| QVA149 Plus Placebo to Tiotropium and Placebo to Formoterol | 44.70 | 41.30 |
| Tiotropium Plus Formoterol and Placebo to QVA149 | 45.68 | 43.19 |
Trough FEV1 is the mean value of FEV1 (forced expiratory volume in one second) measured at 23:15h and 23:45h after the morning doses. The baseline value was measured at day 1 prior to the first dose. (NCT01574651)
Timeframe: Baseline, Week 26
| Intervention | Liters (Mean) | |
|---|---|---|
| Baseline | Week 26 | |
| QVA149 Plus Placebo to Tiotropium and Placebo to Formoterol | 1.329 | 1.495 |
| Tiotropium Plus Formoterol and Placebo to QVA149 | 1.313 | 1.409 |
The percent of patients with at least one severe exacerbation within the 26 weeks that required hospitalization. COPD exacerbations were considered to be severe if hospitalization were required. (NCT01574651)
Timeframe: Week 26
| Intervention | Percent of participants (Number) |
|---|---|
| QVA149 Plus Placebo to Tiotropium and Placebo to Formoterol | 2.1 |
| Tiotropium Plus Formoterol and Placebo to QVA149 | 2.4 |
The percent of participants with at least one moderate exacerbation within the 26 weeks that required systemic corticosteroids and/or antibiotics during the treatment (NCT01574651)
Timeframe: Week 26
| Intervention | Percent of participants (Number) |
|---|---|
| QVA149 Plus Placebo to Tiotropium and Placebo to Formoterol | 10.9 |
| Tiotropium Plus Formoterol and Placebo to QVA149 | 13.3 |
The number of participants with at least one moderate or severe COPD exacerbation. COPD exacerbations are considered to be moderate if treatment with systemic corticosteroids and/or antibiotics was required. COPD exacerbations are considered to be severe if hospitalizations were required. (NCT01574651)
Timeframe: Week 26
| Intervention | Participants (Number) |
|---|---|
| QVA149 Plus Placebo to Tiotropium and Placebo to Formoterol | 62 |
| Tiotropium Plus Formoterol and Placebo to QVA149 | 70 |
FEV1 AUC 0-12 (NCT01587079)
Timeframe: Day 7
| Intervention | Liters (Least Squares Mean) |
|---|---|
| GP MDI 18 μg (PT001) | 1.452 |
| GFF MDI 18/9.6 μg (PT003) | 1.591 |
| GFF/MDI 9/9.6 μg | 1.547 |
| GFF MDI BID 4.6/9.6 μg | 1.539 |
| GFF MDI 2.4/9.6 μg (PT003) | 1.538 |
| GFF MDI 1.2/9.6 μg (PT003) | 1.508 |
| FF MDI 9.6 μg | 1.467 |
| Spiriva 18 μg QD | 1.489 |
Peak change from baseline IC (NCT01587079)
Timeframe: Day 7
| Intervention | Millliters (Least Squares Mean) |
|---|---|
| GP MDI BID 18 μg | 223 |
| GFF MDI BID 18/9.6 μg | 430 |
| GFF/MDI BID 9/9.6 μg | 441 |
| GFF MDI BID 4.6/9.6 μg | 409 |
| GFF MDI BID 2.4/9.6 μg | 368 |
| GFF MDI BID 1.2/9.6 μg | 371 |
| FF MDI BID 9.6 μg | 377 |
| Spiriva 18 μg QD | 241 |
Peak change from baseline in FEV1 Day 7 (NCT01587079)
Timeframe: Day 7
| Intervention | Millliters (Least Squares Mean) |
|---|---|
| GP MDI BID 18 μg | 300 |
| GFF MDI BID 18/9.6 μg | 444 |
| GFF/MDI BID 9/9.6 μg | 414 |
| GFF MDI BID 4.6/9.6 μg | 403 |
| GFF MDI BID 2.4/9.6 μg | 388 |
| GFF MDI BID 1.2/9.6 μg | 363 |
| FF MDI BID 9.6 μg | 332 |
| Spiriva 18 μg QD | 309 |
Change from baseline in mean evening post-dose daily peak flow readings (12 Hours post-dose for Spiriva) (NCT01587079)
Timeframe: Day 7
| Intervention | L/min (Least Squares Mean) |
|---|---|
| GP MDI 18 μg BID | 35.0 |
| GFF MDI 18/9.6 μg BID | 61.5 |
| GFF/MDI 9/9.6 μg BID | 56.1 |
| GFF MDI BID 4.6/9.6 μg BID | 51.5 |
| GFF MDI 2.4/9.6 μg BID | 53.7 |
| GFF MDI 1.2/9.6 μg BID | 53.8 |
| FF MDI 9.6 μg BID | 48.3 |
| Spiriva 18 μg QD | 30.3 |
Time to onset of action (>10% improvement in FEV1) (NCT01587079)
Timeframe: Day 1
| Intervention | Percentage (Number) | ||||
|---|---|---|---|---|---|
| 15 minutes | 30 minutes | 1 hour | 2 hours | No onset within 2 hours | |
| FF MDI BID 9.6 μg | 60 | 3 | 12 | 3 | 22 |
| GFF MDI BID 1.2/9.6 μg | 66 | 9 | 5 | 9 | 11 |
| GFF MDI BID 18/9.6 μg | 65 | 18 | 6 | 5 | 6 |
| GFF MDI BID 2.4/9.6 μg | 65 | 10 | 12 | 2 | 12 |
| GFF MDI BID 4.6/9.6 μg | 62 | 10 | 12 | 5 | 10 |
| GFF/MDI BID 9/9.6 μg | 51 | 13 | 11 | 7 | 18 |
| GP MDI BID 18 μg | 27 | 8 | 15 | 10 | 40 |
| Spiriva 18 μg QD | 37 | 21 | 11 | 5 | 26 |
Change from baseline at evening 12-hour post-dose trough FEV1 (NCT01587079)
Timeframe: Day 7
| Intervention | Millliters (Least Squares Mean) |
|---|---|
| GP MDI BID 18 μg | 99 |
| GFF MDI BID 18/9.6 μg | 196 |
| GFF/MDI BID 9/9.6 μg | 162 |
| GFF MDI BID 4.6/9.6 μg | 118 |
| GFF MDI BID 2.4/9.6 μg | 133 |
| GFF MDI BID 1.2/9.6 μg | 110 |
| FF MDI BID 9.6 μg | 73 |
| Spiriva 18 μg QD | 130 |
Peak change from Baseline in FEV1 on Treatment (NCT01587079)
Timeframe: Day 1
| Intervention | Milliliters (Least Squares Mean) |
|---|---|
| GP MDI BID 18 μg | 209 |
| GFF MDI BID 18/9.6 μg | 339 |
| GFF/MDI BID 9/9.6 μg | 329 |
| GFF MDI BID 4.6/9.6 μg | 348 |
| GFF MDI BID 2.4/9.6 μg | 333 |
| GFF MDI BID 1.2/9.6 μg | 312 |
| FF MDI BID 9.6 μg | 317 |
| Spiriva 18 μg QD | 238 |
Peak change from baseline in Inspiratory Capacity (NCT01587079)
Timeframe: Day 1
| Intervention | Milliliters (Least Squares Mean) |
|---|---|
| GP MDI BID 18 μg | 204 |
| GFF MDI BID 18/9.6 μg | 393 |
| GFF/MDI BID 9/9.6 μg | 320 |
| GFF MDI BID 4.6/9.6 μg | 387 |
| GFF MDI BID 2.4/9.6 μg | 347 |
| GFF MDI BID 1.2/9.6 μg | 348 |
| FF MDI BID 9.6 μg | 335 |
| Spiriva 18 μg QD | 233 |
Change from baseline in mean evening pre-dose daily peak flow readings (BID treatments only) (NCT01587079)
Timeframe: Day 7
| Intervention | L/min (Least Squares Mean) |
|---|---|
| GP MDI 18 μg BID | 11.7 |
| GFF MDI 18/9.6 μg BID | 32.5 |
| GFF/MDI 9/9.6 μg BID | 25.0 |
| GFF MDI 4.6/9.6 μg BID | 19.0 |
| GFF MDI 2.4/9.6 μg BID | 25.6 |
| GFF MDI 1.2/9.6 μg BID | 19.9 |
| FF MDI 9.6 μg BID | 16.5 |
Change from baseline in mean morning post-dose daily peak flow readings on (NCT01587079)
Timeframe: Day 7
| Intervention | L/min (Least Squares Mean) |
|---|---|
| GP MDI 18 μg BID | 31.0 |
| GFF MDI BID 18/9.6 μg | 58.8 |
| GFF/MDI BID 9/9.6 μg | 55.0 |
| GFF MDI BID 4.6/9.6 μg | 46.7 |
| GFF MDI BID 2.4/9.6 μg | 52.1 |
| GFF MDI 1.2/9.6 μg BID | 49.6 |
| FF MDI 9.6 μg BID | 43.2 |
| Spiriva 18 μg QD | 37.9 |
Change from baseline in mean morning pre-dose daily peak flow readings (NCT01587079)
Timeframe: Day 7
| Intervention | L/min (Least Squares Mean) |
|---|---|
| GP MDI 18 μg BID | 7.6 |
| GFF MDI 18/9.6 μg BID | 25.2 |
| GFF/MDI 9/9.6 μg BID | 16.6 |
| GFF MDI BID 4.6/9.6 μg | 12.4 |
| GFF MDI 2.4/9.6 μg BID | 18.0 |
| GFF MDI 1.2/9.6 μg BID | 13.8 |
| FF MDI 9.6 μg BID | 8.6 |
| Spiriva 18 μg QD | 11.6 |
Change from baseline in morning pre-dose trough FEV1 (NCT01587079)
Timeframe: Day 7
| Intervention | Milliliters (Least Squares Mean) |
|---|---|
| GP MDI BID 18 μg | 120 |
| GFF MDI BID 18/9.6 μg | 183 |
| GFF/MDI BID 9/9.6 μg | 150 |
| GFF MDI BID 4.6/9.6 μg | 154 |
| GFF MDI BID 2.4/9.6 μg | 163 |
| GFF MDI BID 1.2/9.6 μg | 130 |
| FF MDI BID 9.6 μg | 104 |
| Spiriva 18 μg QD | 122 |
Proportion of subjects achieving >=12% improvement in FEV1 (NCT01587079)
Timeframe: Day 1
| Intervention | Percentage (Number) |
|---|---|
| GP MDI BID 18 μg | 56 |
| GFF MDI BID 18/9.6 μg | 93 |
| GFF/MDI BID 9/9.6 μg | 85 |
| GFF MDI BID 4.6/9.6 μg | 84 |
| GFF MDI BID 2.4/9.6 μg | 86 |
| GFF MDI BID 1.2/9.6 μg | 83 |
| FF MDI BID 9.6 μg | 80 |
| GP MDI 18 μg (PT001) | 72 |
Change from baseline in morning pre-dose trough IC (NCT01587079)
Timeframe: Day 7
| Intervention | Millliters (Least Squares Mean) |
|---|---|
| GP MDI BID 18 μg | 109 |
| GFF MDI BID 18/9.6 μg | 185 |
| GFF/MDI BID 9/9.6 μg | 183 |
| GFF MDI BID 4.6/9.6 μg | 215 |
| GFF MDI BID 2.4/9.6 μg | 203 |
| GFF MDI BID 1.2/9.6 μg | 151 |
| FF MDI BID 9.6 μg | 129 |
| Spiriva 18 μg QD | 106 |
A day able to perform usual daily activities' is defined from diary data as any day where the patient was not prevented from performing their usual daily activities due to respiratory symptoms. (NCT01610037)
Timeframe: 52 weeks
| Intervention | Percentage of days (Mean) |
|---|---|
| QVA149 | 10.79 |
| Tiotropium 18 µg o.d | 6.54 |
| Placebo | 1.13 |
Pulmonary function assessments were performed using centralized spirometry according to international standards. Baseline FEV1 was defined as the average of the pre-dose FEV1 measured at -45 minutes (min) and -15 min at day 1. (NCT01610037)
Timeframe: Day 22, 43, 85, 183, 274 and 364
| Intervention | Liters (Least Squares Mean) | |||||
|---|---|---|---|---|---|---|
| Day 22 (n=378, 383, 361) | Day 43 (n=380, 375, 345) | Day 85 (n=373, 373, 340) | Day 183 (n=356, 358, 314) | Day 274 (n=343, 351, 303) | Day 364 (n=333, 346, 297) | |
| Placebo | -0.0148 | -0.0196 | -0.0506 | -0.0583 | -0.0601 | -0.0826 |
| QVA149 | 0.1733 | 0.1751 | 0.1752 | 0.1557 | 0.1463 | 0.1468 |
| Tiotropium 18 µg o.d | 0.1018 | 0.0961 | 0.0785 | 0.0714 | 0.0750 | 0.0559 |
Time to premature treatment discontinuation for each treatment group was displayed using a Kaplan-Meier curve. The date of last dose of study medication was considered as the event date and also as the censoring date for those patients who did not discontinue treatment early. The range of the 'time to treatment discontinuation' varied from 5-407 days in the Tiotropium group. Hence the model estimated lower limit of the median time to treatment discontinuation is greater than the scheduled treatment period of 52 weeks. (NCT01610037)
Timeframe: Time varied from 5 - 407 days
| Intervention | Days (Median) |
|---|---|
| QVA149 | NA |
| Tiotropium 18 µg o.d | NA |
| Placebo | NA |
"The SGRQ-C contains 40 items divided into two parts covering three aspects of health related to COPD: Part I covers Symptoms and is concerned with respiratory symptoms, their frequency and severity; Part II covers Activity and is concerned with activities that cause or are limited by breathlessness; Part II is also concerned with Impacts which covers a range of aspects concerned with social functioning and psychological disturbances resulting from airways disease. A score will be calculated for each of these three subscales and a Total score will also be calculated. In each case the lowest possible value is zero and the highest 100. Higher values correspond to greater impairment of health status." (NCT01610037)
Timeframe: Measurment at day 364
| Intervention | Score (Mean) |
|---|---|
| QVA149 | -6.79 |
| Tiotropium 18 µg o.d | -6.12 |
| Placebo | -2.18 |
A night with 'no nighttime awakenings' is defined from diary data as any night where the patient did not wake up due to symptoms. (NCT01610037)
Timeframe: 52 weeks
| Intervention | Percentage of nights (Mean) |
|---|---|
| QVA149 | 11.34 |
| Tiotropium 18 µg o.d | 10.66 |
| Placebo | 8.21 |
A day with 'no daytime symptoms' is defined from the diary data as any day where the patient has recorded in the evening no cough, no wheeze, no production of sputum and no feeling of breathlessness (other than when running) during the past 12 hours (approx. 8 am to 8 pm). (NCT01610037)
Timeframe: 52 weeks
| Intervention | Percentage of days (Mean) |
|---|---|
| QVA149 | 5.56 |
| Tiotropium 18 µg o.d | 4.72 |
| Placebo | 1.78 |
The overall rate of serious adverse events reported from initiation through 30 days post last dose. (NCT01610037)
Timeframe: Week 52
| Intervention | Participants (Number) |
|---|---|
| QVA149 | 55 |
| Tiotropium 18 µg o.d | 55 |
| Placebo | 50 |
The endpoint of all-cause mortality and serious CCV events (composite) was chosen to further characterize any discernible risks. The patients with an event in the analysis were those who had at least one of the 2 events namely, all-cause mortality and serious CCV, during treatment or within 30 days after the date of last dose of study drug. (NCT01610037)
Timeframe: 52 weeks
| Intervention | Percentage of participants (Number) |
|---|---|
| QVA149 | 3.9 |
| Tiotropium 18 µg o.d | 2 |
| Placebo | 1 |
The composite endpoint included all deaths and all serious CCV events, including MACE and events which were not considered MACE. A rigorous post hoc analysis was done on composite endpoint of CV deaths and major adverse cardiovascular events (MACE). The patients with an event in the analysis were those who had at least one of the 2 events namely, CV deaths and MACE, during treatment or within 30 days after the date of last dose of study drug. (NCT01610037)
Timeframe: 52 weeks
| Intervention | Percentage of participants (Number) |
|---|---|
| QVA149 | 1 |
| Tiotropium 18 µg o.d | 0.7 |
| Placebo | 0.7 |
The avg 60 min post dose forced expiratory volume in 1 second (FEV1) at visit 4, 5, 6, 7, 8 and 9 will be analyzed. (NCT01610037)
Timeframe: Day 1, 22, 43, 85, 183, 274 and 364
| Intervention | Liters (Mean) | ||||||
|---|---|---|---|---|---|---|---|
| Day 1 (n=403, 402, 399) | Day 22 (n=384, 381, 362) | Day 43 (n=380, 373, 351) | Day 85 (n=376, 371, 345) | Day 183 (n=364, 359, 317) | Day 274 (n=349, 352, 306) | Day 364 (n= 336, 347, 302) | |
| Placebo | 0.0281 | 1.5827 | 1.6209 | -0.0217 | -0.0253 | -0.0360 | -0.0533 |
| QVA149 | 0.2064 | 0.2883 | 0.2904 | 0.3026 | 0.2860 | 0.2749 | 0.2619 |
| Tiotropium 18 µg o.d | 0.1567 | 0.2077 | 0.2008 | 0.1913 | 0.1842 | 0.1681 | 0.1621 |
Pulmonary function assessments were performed using centralized spirometry according to international standards (NCT01610037)
Timeframe: Day 1, 22, 43, 85, 183, 274 and 364
| Intervention | Liters (Mean) | ||||||
|---|---|---|---|---|---|---|---|
| Day 1(n=403, 402, 399) | Day 22 (n=384, 381, 362) | Day 43 (n=380, 373, 351) | Day 85 (376, 371, 345) | Day 183 (n=364, 359, 317) | Day 274 (n=349, 352, 306) | Day 364 (n= 336, 347, 302) | |
| Placebo | 0.0630 | 0.0178 | 0.0274 | 0.0035 | -0.0283 | -0.0404 | -0.0498 |
| QVA149 | 0.3331 | 0.3971 | 0.4021 | 0.4169 | 0.3880 | 0.3582 | 0.3153 |
| Tiotropium 18 µg o.d | 0.2806 | 0.3123 | 0.2966 | 0.2867 | 0.2822 | 0.2821 | 0.2224 |
Patients will be provided with an electronic diary (eDiary) to record daily clinical symptoms, or rescue medication. The patients will be instructed to routinely complete the patient diary twice daily. There are 9 total symptom questions for a total possible score of 27 at each timepoint. A higher score means the patient is reporting more symptoms related to Chronic Obstructive Pulmonary Disease. The mean daily total symptom score, the mean daytime total symptom score and the mean nighttime total symptom score were calculated for each patient over 52 weeks. Diary data recorded during the 14 day run-in period were used to calculate the baseline. (NCT01610037)
Timeframe: 52 weeks
| Intervention | Score (Mean) | ||
|---|---|---|---|
| Daily total symptom score (n=395, 395, 385) | Daytime total symptom score (n= 380, 385, 374) | Nighttime total symptom score (n= 387, 388, 375) | |
| Placebo | -0.7683 | -0.5641 | -0.5984 |
| QVA149 | -1.3478 | -1.1688 | -0.9731 |
| Tiotropium 18 µg o.d | -1.2283 | -1.0669 | -0.9532 |
St. George's Respiratory Questionnaire (SGRQ) is a health related quality of life questionnaire consisting of 51 items in three areas: symptoms (respiratory symptoms and severity), activity (activities that cause or are limited by breathlessness) and impacts (social functioning and psychological disturbances due to airway disease). The total score is 0 to 100 with a higher score indicating poorer health status. ANCOVA model: SGRQ total score = treatment + baseline SGRQ score + baseline ICS use (Yes/No) + FEV1 reversibility components + baseline smoking status + region + center (region). (NCT01613326)
Timeframe: Week 12
| Intervention | Units on a scale (Least Squares Mean) |
|---|---|
| NVA237 | 39.42 |
| Tiotropium | 38.77 |
FEV1 is the amount of air which can be forcibly exhaled from the lungs in the first second of a forced exhalation, measured through spirometry testing. The trough in FEV1 was defined as the mean of two measurements at 23h 15min and 23h 45min post dosing. ANCOVA model: Trough FEV1 = treatment + baseline FEV1 + baseline Inhaled corticosteroid (ICS) use (Yes/No) + FEV1 reversibility components + baseline smoking status + region + center(region). This analysis excluded values within 6 hours of rescue medication use or 7 days of systemic corticosteroid. (NCT01613326)
Timeframe: Week 12
| Intervention | Liters (Least Squares Mean) |
|---|---|
| NVA237 | 1.398 |
| Tiotropium | 1.393 |
Forced Expiratory Volume in 1 second (FEV1) is the amount of air which can be forcibly exhaled from the lungs in the first second of a forced exhalation, measured through spirometry testing. The trough in FEV1 was defined as the mean of two measurements at 23hours 15min and 23 hours 45min post dosing. ANCOVA model: Trough FEV1 = treatment + baseline FEV1 + baseline Inhaled corticosteroid (ICS) use (Yes/No) + FEV1 reversibility components + baseline smoking status + region + center (region). This analysis excluded values within 6 hours of rescue medication use or 7 days of systemic corticosteroid use. (NCT01613326)
Timeframe: Week 12
| Intervention | Liters (Least Squares Mean) |
|---|---|
| NVA237 | 1.405 |
| Tiotropium | 1.405 |
"A day with no rescue medication use is defined from the diary data as any day where the patient recorded no rescue medicine use during the previous 12 hours.~Baseline mean daily, daytime and nighttime (combined) number of puffs is defined as the average of the respective number of puffs. Only patients with a value at both baseline and post-baseline visits were included." (NCT01613326)
Timeframe: Baseline and Day 1 to Week 12
| Intervention | puffs (Mean) | |
|---|---|---|
| Baseline | Day 1 to week 12 | |
| NVA237 | 4.09 | 2.76 |
| Tiotropium | 4.10 | 2.84 |
Event free rate was calculated as a percentage of participants who did not experience any moderate or severe COPD exacerbation leading to hospitalization/treatment with systemic corticosteroids/treatment with antibiotics. The event free rate reflects the percent of patients who did NOT have an exacerbation by 4, 8 and 12 weeks. Event-free rates are calculated at the end of the specified weeks (i.e. Day 29, Day 57 and Day 85) by the Kaplan Meier method. (NCT01613326)
Timeframe: Weeks 4, 8 and 12
| Intervention | percentage of participants (Number) | ||
|---|---|---|---|
| Week 4 | Week 8 | Week 12 | |
| NVA237 | 95.6 | 92.9 | 90.2 |
| Tiotropium | 96.6 | 93.8 | 92.4 |
Forced Vital Capacity (FVC) is the amount of air which can be forcibly exhaled from the lungs after taking the deepest breath possible. FVC was assessed via spirometry. ANCOVA model: FVC = treatment + baseline FVC + baseline Inhaled corticosteroid (ICS) use (Yes/No) + FEV1 reversibility components + baseline smoking status + region + center(region). Center is included as a random effect nested within region. (NCT01613326)
Timeframe: (5,15,30 min, 1, 2,3,4 h, 23h 15 min and 23h 45 min postdose of Day 1), (-45, -15 min predose, 5,15,30 min, 1h, 23h 15 min and 23h 45 min postdose of Week 4), (-45, -15 min predose, 5,15,30 min, 1, 2, 3,4 h, 23h 15 min and 23h 45 min postdose of Week 12)
| Intervention | Liters (Least Squares Mean) | |||||||||||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Day 1, 5 min (n= 283, 278) | Day 1, 15 min (n= 282, 276) | Day 1, 30 min (n= 285, 281) | Day 1, 1 hour (n= 291, 286) | Day 1, 2 hours (n= 290, 286) | Day 1, 3 hours (n= 291, 285) | Day 1, 4 hours (n= 285, 281) | Day 1, 23 h 15 min (n= 289, 279) | Day 1, 23 h 45 min (n= 285, 278) | Week 4, -45 min (n= 280, 280) | Week 4, -15 min (n= 278, 279) | Week 4, 5 min (n= 277, 274) | Week 4, 15 min (n= 271, 270) | Week 4, 30 min (n= 272, 276) | Week 4, 1 hr (n= 280, 282) | Week 4, 23 h 15 min (n= 278, 276) | Week 4, 23 h 45 min (n= 274, 276) | Week 12, -45 min (n= 286, 279) | Week 12, -15 min (n= 283, 279) | Week 12, 5 min (n= 283, 271) | Week 12, 15 min (n= 275, 271) | Week 12, 30 min (n= 282, 278) | Week 12, 1 hr (n= 286, 279) | Week 12, 2 hours (n= 278, 277) | Week 12, 3 hours (n= 281, 279) | Week 12, 4 hours (n= 282, 280) | Week 12, 23 h 15 min (n= 276, 266) | Week 12, 23 h 45 min (n= 278, 276) | |
| NVA237 | 2.925 | 3.004 | 3.036 | 3.036 | 3.061 | 3.135 | 3.073 | 2.911 | 2.942 | 2.933 | 2.879 | 2.954 | 3.021 | 3.005 | 3.068 | 2.982 | 2.953 | 2.889 | 2.827 | 2.929 | 2.945 | 2.963 | 3.011 | 3.008 | 3.014 | 2.964 | 2.923 | 2.929 |
| Tiotropium | 2.874 | 2.954 | 2.991 | 3.006 | 3.029 | 3.111 | 3.046 | 2.951 | 2.951 | 2.943 | 2.898 | 2.997 | 3.058 | 3.011 | 3.093 | 3.013 | 2.978 | 2.905 | 2.837 | 2.953 | 2.963 | 2.982 | 3.009 | 3.012 | 3.018 | 2.977 | 2.953 | 2.955 |
IC was measured with spirometry conducted according to internationally accepted standards. ANCOVA model: IC = treatment + baseline IC + baseline Inhaled corticosteroid (ICS) use (Yes/No) + FEV1 reversibility components + baseline smoking status + region + center(region). Center is included as a random effect nested within region. (NCT01613326)
Timeframe: (25 min, 1 h 55 min, 3 h 55 min, 23 h 40 min Day 1), (-20 min, 25 min, 23 h 40 min Week 4),(-20 min, 25 min, 1 h 55 min, 3 h 55 min, 23 h 40 min Week 12)
| Intervention | Liters (Least Squares Mean) | |||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Day 1, 25 min (n= 216, 214) | Day 1, 1 h 55 min (n= 212, 208) | Day 1, 3 h 55 min (n= 211, 207) | Day 1, 23 h 40 min (n= 213, 212) | Week 4, -20 min (n= 204, 204) | Week 4, 25 min (n= 201, 200) | Week 4, 23 h 40 min (n=199,205) | Week 12, -20 min (n= 205, 204) | Week 12, 25 min (n= 215, 205) | Week 12, 1 h 55 min (n= 213, 203) | Week 12, 3 h 55 min (n= 203, 207) | Week 12, 23 h 40 min (n= 208, 206) | |
| NVA237 | 2.378 | 2.433 | 2.343 | 2.247 | 2.231 | 2.335 | 2.284 | 2.198 | 2.292 | 2.344 | 2.313 | 2.228 |
| Tiotropium | 2.300 | 2.335 | 2.309 | 2.244 | 2.240 | 2.334 | 2.289 | 2.227 | 2.280 | 2.289 | 2.275 | 2.262 |
Participants completed eDiaries providing scores 0 to 3 for symptoms: Cough and wheeze (none, mild, moderate, severe); sputum volume (none, less than 5 mL, 5-25 mL, >25 mL); sputum color (none, white-grey, yellow, green); lowest level of activity causing breathlessness (never or only when running, when walking uphill or upstairs, when walking on flat ground, at rest). Symptoms in the morning, for the previous night (no waking due to symptoms, woke up once due to symptoms, woke up more than once due to symptoms, woke up frequently or could not sleep due to symptoms). Symptoms experienced during the day that had prevented them for performing normal activities (not at all, a little, quite a lot, completely). The mean change from baseline in the total scores and in the individual scores was summarized by treatment. Only participants with a value at both baseline and post-baseline were included. Possible total scores 0-18 (night); 0-36 (day). A higher score means worsening of symptoms. (NCT01613326)
Timeframe: 12 weeks
| Intervention | units on a scale (Mean) | |
|---|---|---|
| Baseline | Day 1 to Week 12 | |
| NVA237 | 7.21 | 5.96 |
| Tiotropium | 6.90 | 5.96 |
Spirometry was conducted according to internationally accepted standards. Peak FEV1 is the maximum FEV1 recorded during first 4 hours post dose. ANCOVA model: Peak FEV1 = treatment + baseline FEV1 + baseline Inhaled corticosteroid (ICS) use (Yes/No) + FEV1 reversibility components + baseline smoking status + region + center (region). Center is included as a random effect nested within region. This analysis excludes values within 6 hours of rescue medication use or 7 days of systemic corticosteroid use. (NCT01613326)
Timeframe: 5 min to 4 hours post-dose at Day 1 and Week 12
| Intervention | Liters (Least Squares Mean) | |
|---|---|---|
| Day 1 (n= 298, 292) | Week 12 (n= 290, 282) | |
| NVA237 | 1.575 | 1.577 |
| Tiotropium | 1.520 | 1.553 |
"Forced Expiratory Volume in one second (FEV1) was measured with spirometry conducted according to internationally accepted standards.~Area Under the Curve (AUC) is calculated using the trapezoidal rule using the existing FEV1 measurements (i.e., the missing FEV1 measurements are not interpolated).~ANCOVA model: FEV1 AUC = treatment + baseline FEV1 + baseline Inhaled corticosteroid (ICS) use (Yes/No) + FEV1 reversibility components + baseline smoking status + region + center(region). Center is included as a random effect nested within region." (NCT01613326)
Timeframe: Day 1 and week 12
| Intervention | Liters (Least Squares Mean) | |
|---|---|---|
| Day 1 (n=298, 292) | Week 12 (290, 282) | |
| NVA237 | 1.496 | 1.493 |
| Tiotropium | 1.438 | 1.470 |
"Transition Dyspnea Index (TDI) captures changes from baseline. The TDI score is based on three domains with each domain scored from -3 (major deterioration) to +3 (major improvement), to give an overall score of -9 to +9, a negative score indicating a deterioration from baseline. A TDI focal score of 1 is considered to be a clinically significant improvement from baseline.~ANCOVA model: TDI focal score = treatment + Baseline dyspnea index (BDI) + baseline Inhaled corticosteroid (ICS) use (Yes/No) + FEV1 reversibility components + baseline smoking status + region + center(region). Center is included as a random effect nested within region." (NCT01613326)
Timeframe: Weeks 4 and 12
| Intervention | Units on a scale (Least Squares Mean) | |
|---|---|---|
| Week 4 (n= 289, 287) | Week 12 (n= 290, 285) | |
| NVA237 | 2.209 | 1.990 |
| Tiotropium | 2.086 | 2.178 |
"FEV1 is the amount of air which can be forcibly exhaled from the lungs in the first second of a forced exhalation, measured through spirometry testing.~Trough FEV1 is defined as the average of the post-dose 23 h 15 min and the 23 h 45 min FEV1 values. Trough assessments taken outside 22 h 45 min - 24 h 15 min are excluded from this analysis.~ANCOVA model: Trough FEV1 = treatment + baseline FEV1 + baseline Inhaled corticosteroid (ICS) use (Yes/No) + FEV1 reversibility components + baseline smoking status + region + center(region). Center is included as a random effect nested within region." (NCT01613326)
Timeframe: Day 1 and Week 4
| Intervention | Liters (Least Squares Mean) | |
|---|---|---|
| Day 1 (n=296, 288) | Week 4 (n=284, 280) | |
| NVA237 | 1.385 | 1.416 |
| Tiotropium | 1.386 | 1.416 |
Forced Expiratory Volume in 1 second (FEV1) is the amount of air which can be forcibly exhaled from the lungs in the first second of a forced exhalation. FEV1 was analyzed using Analysis of Covariance (ANCOVA) model: FEV1 = treatment + baseline FEV1 + baseline Inhaled corticosteroid (ICS) use (Yes/No) + FEV1 reversibility components + baseline smoking status + region + center(region). Center is included as a random effect nested within region. (NCT01613326)
Timeframe: (5,15,30 min, 1, 2,3,4 h, 23h 15 min and 23h 45 min postdose of Day 1), (-45, -15 min predose, 5,15,30 min, 1h, 23h 15 min and 23h 45 min postdose of Week 4), (-45, -15 min predose, 5,15,30 min, 1, 2, 3,4 h, 23h 15 min and 23h 45 min postdose of Week 12)
| Intervention | Liters (Least Squares Mean) | |||||||||||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Day 1, 5 min (n= 283, 278) | Day 1, 15 min (n= 282, 276) | Day 1, 30 min (n= 285, 281) | Day 1, 1 hour (n= 291, 286) | Day 1, 2 hours (n= 290, 286) | Day 1, 3 hours (n= 291, 285) | Day 1, 4 hours (n= 285, 281) | Day 1, 23 h 15 min (n= 289, 279) | Day 1, 23 h 45 min (n= 285, 278) | Week 4, -45 min (n= 280, 280) | Week 4, -15 min (n= 278, 279) | Week 4, 5 min (n= 277, 274) | Week 4, 15 min (n= 271, 270) | Week 4, 30 min (n= 272, 276) | Week 4, 1 hr (n= 280, 282) | Week 4, 23 h 15 min (n= 278, 276) | Week 4, 23 h 45 min (n= 274, 276) | Week 12, -45 min (n= 286, 279) | Week 12, -15 min (n= 283, 279) | Week 12, 5 min (n= 283, 271) | Week 12, 15 min (n= 275, 271) | Week 12, 30 min (n= 282, 278) | Week 12, 1 hr (n= 286, 279) | Week 12, 2 hours (n= 278, 277) | Week 12, 3 hours (n= 281, 279) | Week 12, 4 hours (n= 282, 280) | Week 12, 23 h 15 min (n= 276, 266) | Week 12, 23 h 45 min (n= 278, 276) | |
| NVA237 | 1.382 | 1.428 | 1.442 | 1.482 | 1.517 | 1.527 | 1.490 | 1.384 | 1.381 | 1.403 | 1.388 | 1.422 | 1.459 | 1.454 | 1.513 | 1.422 | 1.418 | 1.394 | 1.377 | 1.430 | 1.440 | 1.461 | 1.500 | 1.507 | 1.506 | 1.473 | 1.414 | 1.415 |
| Tiotropium | 1.331 | 1.365 | 1.379 | 1.419 | 1.454 | 1.471 | 1.448 | 1.384 | 1.379 | 1.391 | 1.393 | 1.423 | 1.466 | 1.442 | 1.494 | 1.417 | 1.416 | 1.380 | 1.370 | 1.411 | 1.423 | 1.432 | 1.475 | 1.484 | 1.484 | 1.462 | 1.422 | 1.420 |
Pulmonary function was measured by FEV1. Trough FEV1 was defined as the 24-hour FEV1 assessment, which was obtained on Day 84. Baseline is defined as the mean of the two assessments made 30 minutes pre-dose and 5 minutes pre-dose on Treatment Day 1.Change from Baseline was calculated as the average of the Day 84 values minus the Baseline value. Analysis was performed using an ANCOVA model with covariates of BL FEV1, exacerbation history and reversibility stratum, smoking status at screening, country, and treatment group. (NCT01627327)
Timeframe: Baseline and Day 84
| Intervention | Liters (Least Squares Mean) |
|---|---|
| FF/VI 100/25 µg OD | 0.098 |
| TIO 18 µg OD | 0.093 |
Pulmonary function was measured by forced expiratory volume in one second (FEV1), defined as the maximal amount of air that can be forcefully exhaled from the lungs in one second. The weighted mean was calculated from the pre-dose FEV1 and post-dose FEV1 measurements at 5, 15, 30 minutes and 1, 2, 4, 6, 8, 12, 13, 14, 16, 20, and 24 hours on Treatment Day 84. Baseline trough FEV1 was the mean of the two assessments made 30 and 5 minutes pre-dose on Treatment Day 1. Change from Baseline (BL) was calculated as the average of the Day 84 values minus the Baseline value. Analysis was performed using an analysis of covariance (ANCOVA) model with covariates of BL FEV1, exacerbation history and reversibility stratum, smoking status at screening, country, and treatment group. (NCT01627327)
Timeframe: Baseline and Day 84
| Intervention | Liters (Least Squares Mean) |
|---|---|
| FF/VI 100/25 µg OD | 0.117 |
| TIO 18 µg OD | 0.095 |
Time to onset on Treatment Day 1 is defined as the time to an increase of 100 milliliters (mL) from Baseline in FEV1. Time of onset was calculated over 0 to 4 hours (5 minutes (min), 15 min, 30 min, 60 min, 120 min, and 240 min) post-dose. Time to onset was analyzed using a log-rank test, stratified by exacerbation history and reversibility stratum. (NCT01627327)
Timeframe: Baseline and Day 1
| Intervention | Minutes (Median) |
|---|---|
| FF/VI 100/25 µg OD | 17.0 |
| TIO 18 µg OD | 20.5 |
"Change from baseline in the weekly mean overnight asthma symptom score response as assessed by the PACD in the last week of the 12 week treatment period.~The overnight score is the score from the following question in the PACD, How much did your child cough last night after your child was put to bed for the night until he/she awoke this morning?. This endpoint was determined only for patients with 2 or more nights with symptoms per week during the baseline period. In this case, the baseline period is the 7 days used to derive the baseline value. A patient has a night with symptoms if the question was answered with scores 1, 2, 3, 4 or 5 or the patient received β-Agonist at least one time since he/she went to bed. A week was defined as 7 days.~Scores range from 0 (best) to 4 (worst), a value of 5 indicates severity of symptoms is unknown.~The measured values presented are adjusted means" (NCT01634113)
Timeframe: Baseline and 12 weeks
| Intervention | units on a scale (Mean) |
|---|---|
| Placebo Respimat | -0.671 |
| Tio R2.5 | -0.588 |
| Tio R5 | -0.655 |
Weekly percentage of days with use of salbutamol (albuterol) rescue medication at week 12. A week was defined as 7 days. (NCT01634113)
Timeframe: 12 weeks
| Intervention | percentage of days (Mean) |
|---|---|
| Placebo Respimat | 24.94 |
| Tio R2.5 | 24.23 |
| Tio R5 | 24.88 |
Change from baseline of area under the curve (AUC) from 0 to 3 h for FVC (FVC AUC0-3h) after 12 weeks of treatment. The AUC was calculated by using the trapezoidal rule divided by the observation time (3h). (NCT01634113)
Timeframe: 10 minutes before drug administration and 30 minutes, 1 hour (h), 2h and 3h after drug administration at baseline and week 12
| Intervention | Litres (Mean) |
|---|---|
| Placebo Respimat | 0.164 |
| Tio R2.5 | 0.035 |
| Tio R5 | 0.003 |
"Change from baseline in the weekly mean nighttime awakenings due to asthma symptoms as assessed by the PACD, in the last week of the 12 week treatment period.~The weekly mean was calculated as the average of the weekly scores for the question Did your child wake up during the night due to his/her asthma? The question was answered on a 5-point verbal rating scale, with scores ranging from 1 (did not wake up) to 5 (was awake all night). A week was defined as 7 days.~The measured values presented are adjusted means" (NCT01634113)
Timeframe: Baseline and 12 weeks
| Intervention | units on a scale (Mean) |
|---|---|
| Placebo Respimat | -0.318 |
| Tio R2.5 | -0.257 |
| Tio R5 | -0.392 |
Change from baseline in individual FEV1 measurements at each timepoint after 12 weeks (NCT01634113)
Timeframe: Baseline and 12 weeks
| Intervention | Litres (Mean) | ||||
|---|---|---|---|---|---|
| Time: 0 hours | Time: 30 minutes | Time: 1 hour | Time: 2 hours | Time: 3 hours | |
| Placebo Respimat | 0.06 | 0.11 | 0.11 | 0.12 | 0.10 |
| Tio R2.5 | 0.02 | 0.03 | 0.10 | 0.09 | 0.06 |
| Tio R5 | 0.09 | 0.12 | 0.12 | 0.04 | 0.05 |
"Weekly Percentage of days without asthma symptoms at week 12.~A day without asthma symptoms was defined as a day during which the patient experienced no asthma symptoms, did not use rescue medication (salbutamol/albuterol) and had no asthma exacerbation/worsening requiring systemic corticosteroids, or unscheduled visits to a doctor's office, emergency department, or hospital. A week was defined as 7 days.~The measured values presented are adjusted means" (NCT01634113)
Timeframe: 12 weeks
| Intervention | percentage of days (Mean) |
|---|---|
| Placebo Respimat | 53.151 |
| Tio R2.5 | 55.401 |
| Tio R5 | 50.654 |
Change from baseline in peak Forced expiratory volume in 1 second within the first 3 hours post dosing (FEV1 peak (0-3h)) measured at week 12 (NCT01634113)
Timeframe: 10 minutes before drug administration and 30 minutes, 1 hour (h), 2h and 3h after drug administration at baseline and week 12
| Intervention | Litres (Mean) |
|---|---|
| Placebo Respimat | 0.158 |
| Tio R2.5 | 0.130 |
| Tio R5 | 0.145 |
Change from baseline in individual FVC measurements at each timepoint after 12 weeks (NCT01634113)
Timeframe: Baseline and 12 weeks
| Intervention | Litres (Mean) | ||||
|---|---|---|---|---|---|
| Time: 0 hours | Time: 30 minutes | Time: 1 hour | Time: 2 hours | Time: 3 hours | |
| Placebo Respimat | 0.16 | 0.13 | 0.18 | 0.16 | 0.19 |
| Tio R2.5 | -0.03 | 0.04 | 0.06 | 0.02 | 0.04 |
| Tio R5 | -0.05 | 0.06 | 0.05 | -0.03 | -0.03 |
Change from baseline in maximum forced vital capacity (FVC) measured within the first 3 hours after administration of trial medication (FVC peak (0-3h)) after 12 weeks of treatment. (NCT01634113)
Timeframe: 10 minutes before drug administration and 30 minutes, 1 hour (h), 2h and 3h after drug administration at baseline and week 12
| Intervention | Litres (Mean) |
|---|---|
| Placebo Respimat | 0.210 |
| Tio R2.5 | 0.136 |
| Tio R5 | 0.060 |
Change from baseline in Trough (pre-dose) Forced expiratory volume in 1 second (FEV1) measured at week 12. (NCT01634113)
Timeframe: Baseline and 12 weeks
| Intervention | Litres (Mean) |
|---|---|
| Placebo Respimat | 0.060 |
| Tio R2.5 | 0.017 |
| Tio R5 | 0.085 |
Change from baseline of trough (pre-dose) forced vital capacity (FVC) measured 10 min before the administration of trial medication after 12 weeks of treatment. (NCT01634113)
Timeframe: Baseline and 12 weeks
| Intervention | Litres (Mean) |
|---|---|
| Placebo Respimat | 0.155 |
| Tio R2.5 | -0.027 |
| Tio R5 | -0.050 |
"Change from baseline in the weekly mean combined daytime asthma symptom score as assessed by the Paediatric Asthma Caregivers Diary (PACD) in the last week of the 12 week treatment period.~The PACD is a diary designed to evaluate daily asthma symptoms in children aged 2-5 years. The diary consists of three questions to be answered each morning, when the child wakes up, and seven questions to be answered each evening, right after the child goes to bed for the night. A week was defined as 7 days.~The combined daytime score is the average of scores from questions 4 - 7 in the diary which are questions regarding severity of cough, wheezing, trouble breathing and interference with activities, scores for each question range from 0 (best) to 5 (worst). The week 12 weekly mean is the mean of the responses for each day averaged over the 7 days in week 12, so combined daytime asthma symptom scores also range from 0 (best) to 5 (worst).~The measured values presented are adjusted means." (NCT01634113)
Timeframe: Baseline and 12 weeks
| Intervention | units on a scale (Mean) |
|---|---|
| Placebo Respimat | -0.456 |
| Tio R2.5 | -0.535 |
| Tio R5 | -0.504 |
Change from baseline of area under the curve (AUC) from 0 to 3 h for FEV1 (FEV1 AUC 0-3h) after 12 weeks of treatment. The AUC was calculated by using the trapezoidal rule divided by the observation time (3h). (NCT01634113)
Timeframe: 10 minutes before drug administration and 30 minutes, 1 hour (h), 2h and 3h after drug administration at baseline and week 12
| Intervention | Litres (Mean) |
|---|---|
| Placebo Respimat | 0.104 |
| Tio R2.5 | 0.072 |
| Tio R5 | 0.077 |
"Change from baseline in the number of puffs of rescue medication (salbutamol/albuterol) used during nighttime based on the weekly mean at weeks 24 and 48.~Measured values presented are actually adjusted means.~The number of participants analysed displays the number of participants included in the statistical model whereas the N's for each timepoint display the number of participants with available data at that timepoint." (NCT01634139)
Timeframe: Baseline and Week 24, Baseline and Week 48.
| Intervention | Number of puffs of rescue medication (Mean) | |
|---|---|---|
| Week 24 (N=122, 130, 130) | Week 48 (N=119, 122, 125) | |
| Placebo Respimat | -0.178 | -0.198 |
| Tio R2.5 | -0.274 | -0.298 |
| Tio R5 | -0.304 | -0.301 |
"Change from baseline in the number of puffs of rescue medication (salbutamol/albuterol) used during daytime based on the weekly mean at weeks 24 and 48.~Measured values presented are actually adjusted means~The number of participants analysed displays the number of participants included in the statistical model whereas the N's for each timepoint display the number of participants with available data at that timepoint." (NCT01634139)
Timeframe: Baseline and Week 24, Baseline and Week 48.
| Intervention | Number of puffs of rescue medication (Mean) | |
|---|---|---|
| Week 24 (N=121, 130, 133) | Week 48 (N=119, 123, 125) | |
| Placebo Respimat | -0.234 | -0.247 |
| Tio R2.5 | -0.350 | -0.372 |
| Tio R5 | -0.375 | -0.378 |
"Change from baseline in the number of puffs of rescue medication (salbutamol/albuterol) used per day (24 hour period) based on the weekly mean at weeks 24 and 48.~The measured values presented are actually adjusted means.~The number of participants analysed displays the number of participants included in the statistical model whereas the N's for each timepoint display the number of participants with available data at that timepoint." (NCT01634139)
Timeframe: Baseline and Week 24, Baseline and Week 48.
| Intervention | Number of puffs of rescue medication (Mean) | |
|---|---|---|
| Week 24 (N=122, 130, 133) | Week 48 (N=120, 123, 127) | |
| Placebo Respimat | -0.437 | -0.484 |
| Tio R2.5 | -0.603 | 0.638 |
| Tio R5 | 0.646 | 0.685 |
"Change from baseline in Trough (pre-dose) FVC measured at week 24 and 48.~Measured values presented are actually adjusted means.~The number of participants analysed displays the number of participants included in the statistical model whereas the N's for each timepoint display the number of participants with available data at that timepoint." (NCT01634139)
Timeframe: Baseline and Week 24, Baseline and Week 48
| Intervention | Litres (L) (Mean) | |
|---|---|---|
| Week 24 (N=126, 131, 134) | Week 48 (N=124, 130, 130) | |
| Placebo Respimat | 0.154 | 0.280 |
| Tio R2.5 | 0.246 | 0.341 |
| Tio R5 | 0.206 | 0.333 |
"Change from Baseline in Trough (pre-dose) Forced Expiratory Volume (FEV) in 1 second (FEV1) measured at week 24 and 48.~Measured values presented are actually adjusted means.~The number of participants analysed displays the number of participants included in the statistical model whereas the N's for each timepoint display the number of participants with available data at that timepoint." (NCT01634139)
Timeframe: Baseline and Week 24, Baseline and Week 48.
| Intervention | Litres (L) (Mean) | |
|---|---|---|
| Week 24 (N=126, 131, 134) | Week 48 (N=124, 130, 130) | |
| Placebo Respimat | 0.156 | 0.266 |
| Tio R2.5 | 0.272 | 0.337 |
| Tio R5 | 0.274 | 0.365 |
"Responders in PAQLQ(S) at weeks 24 and 48. Analysis was performed using the following categories and definitions: responder (change from trial baseline ≥0.5), no change (-0.5
Timeframe: Weeks 24 and 48.
| Intervention | Patients (Number) | |||||
|---|---|---|---|---|---|---|
| Responders at Week 24 | No Change at Week 24 | Worsening at Week 24 | Responders at Week 48 | No Change at Week 48 | Worsening at Week 48 | |
| Placebo Respimat | 67 | 58 | 6 | 89 | 39 | 3 |
| Tio R2.5 | 82 | 47 | 6 | 96 | 33 | 6 |
| Tio R5 | 73 | 56 | 6 | 92 | 42 | 1 |
"Change from baseline in the peak expiratory flow variability based on the weekly mean at week 24 and 48.~Measured values presented are actually adjusted means.~The number of participants analysed displays the number of participants included in the statistical model whereas the N's for each timepoint display the number of participants with available data at that timepoint." (NCT01634139)
Timeframe: Baseline and Week 24, Baseline and Week 48.
| Intervention | Percentage of PEF (Mean) | |
|---|---|---|
| Week 24 (N=121, 129, 128) | Week 48 (N=117, 120, 121) | |
| Placebo Respimat | -1.204 | -0.320 |
| Tio R2.5 | -0.942 | -0.048 |
| Tio R5 | -1.038 | -0.899 |
"Change from baseline in the evening (p.m.) peak expiratory flow based on the weekly mean at weeks 24 and 48.~Measured values presented are actually adjusted means.~The number of participants analysed displays the number of participants included in the statistical model whereas the N's for each timepoint display the number of participants with available data at that timepoint." (NCT01634139)
Timeframe: Baseline and Week 24, Baseline and Week 48.
| Intervention | Litres per min (L/min) (Mean) | |
|---|---|---|
| Week 24 (N= 121, 130, 133) | Week 48 (N=119, 123, 125) | |
| Placebo Respimat | 3.179 | 17.100 |
| Tio R2.5 | 15.539 | 15.219 |
| Tio R5 | 17.325 | 21.276 |
"Change from baseline in the morning (a.m.) peak expiratory flow based on the weekly mean at weeks 24 and 48.~Measured values presented are actually adjusted means.~The number of participants analysed displays the number of participants included in the statistical model whereas the N's for each timepoint display the number of participants with available data at that timepoint." (NCT01634139)
Timeframe: Baseline and Week 24, Baseline and Week 48.
| Intervention | Litres per min (L/min) (Mean) | |
|---|---|---|
| Week 24 (N=122, 130, 130) | Week 48 (N=119, 122, 125) | |
| Placebo Respimat | 14.153 | 20.824 |
| Tio R2.5 | 22.660 | 26.362 |
| Tio R5 | 21.646 | 29.598 |
"Standardised Paediatric Asthma Quality of Life Questionnaire (PAQLQ(S)) total score at weeks 24 and 48.~The PAQLQ(S) is 23 questions on a 7-point scale, ranging from 1 (worst control) to 7 (best control). Total Score is calculated as mean of all 23 questions.~The measured values presented are actually adjusted means.~The number of participants analysed displays the number of participants included in the statistical model whereas the N's for each timepoint display the number of participants with available data at that timepoint." (NCT01634139)
Timeframe: Weeks 24 and 48.
| Intervention | Units on a Scale (Mean) | |
|---|---|---|
| Week 24 (N= 126, 131, 134) | Week 48 (N=124, 130, 130) | |
| Placebo Respimat | 5.966 | 6.309 |
| Tio R2.5 | 6.142 | 6.288 |
| Tio R5 | 6.093 | 6.327 |
"PAQLQ(S) symptom domain score at weeks 24 and 48. The PAQLQ(S) is 23 questions on a 7-point scale, ranging from 1 (worst control) to 7 (best control). The individual domain score was calculated as the mean of the items in the domain.~The measured values presented are actually adjusted means.~The number of participants analysed displays the number of participants included in the statistical model whereas the N's for each timepoint display the number of participants with available data at that timepoint." (NCT01634139)
Timeframe: Weeks 24 and 48.
| Intervention | Units on a Scale (Mean) | |
|---|---|---|
| Week 24 (N=126, 131, 134) | Week 48 (N=124, 130, 130) | |
| Placebo Respimat | 5.840 | 6.195 |
| Tio R2.5 | 6.015 | 6.177 |
| Tio R5 | 5.967 | 6.199 |
"PAQLQ(S) emotional function domain score at weeks 24 and 48. The PAQLQ(S) is 23 questions on a 7-point scale, ranging from 1 (worst control) to 7 (best control). The individual domain score is calculated as the mean of the items in this domain.~The measured values presented are actually adjusted means.~The number of participants analysed displays the number of participants included in the statistical model whereas the N's for each timepoint display the number of participants with available data at that timepoint." (NCT01634139)
Timeframe: Weeks 24 and 48.
| Intervention | Units on a Scale (Mean) | |
|---|---|---|
| Week 24 (N=126, 131, 134) | Week 48 (N=124, 130, 130) | |
| Placebo Respimat | 6.157 | 6.481 |
| Tio R2.5 | 6.323 | 6.420 |
| Tio R5 | 6.298 | 6.491 |
"PAQLQ(S) activity limitation domain score at weeks 24 and 48. The PAQLQ(S) is 23 questions on a 7-point scale, ranging from 1 (worst control) to 7 (best control). The individual domain score is calculated as the mean of the items in this domain.~The measured values presented are actually adjusted means.~The number of participants analysed displays the number of participants included in the statistical model whereas the N's for each timepoint display the number of participants with available data at that timepoint." (NCT01634139)
Timeframe: Weeks 24 and 48.
| Intervention | Units on a Scale (Mean) | |
|---|---|---|
| Week 24 (N= 126, 131, 134) | Week 48 (N=124, 130, 130) | |
| Placebo Respimat | 5.898 | 6.249 |
| Tio R2.5 | 6.089 | 6.284 |
| Tio R5 | 6.023 | 6.319 |
"Change from baseline in Maximum forced vital capacity (FVC) measured within the first 3 hours after administration of trial medication (FVC peak(0-3h)) after 24 and 48 Weeks of treatment.~Measured values presented are actually adjusted means.~The number of participants analysed displays the number of participants included in the statistical model whereas the N's for each timepoint display the number of participants with available data at that timepoint." (NCT01634139)
Timeframe: Baseline and Week 24, Baseline and Week 48.
| Intervention | Litres (L) (Mean) | |
|---|---|---|
| Week 24 (N=124, 130, 134) | Week 48 (N=124, 130, 130) | |
| Placebo Respimat | 0.215 | 0.361 |
| Tio R2.5 | 0.325 | 0.430 |
| Tio R5 | 0.307 | 0.413 |
"FVC change from baseline to week 24 at each individual timepoint.~The measured values presented are actually adjusted means~The number of participants analysed displays the number of participants included in the statistical model whereas the N's for each timepoint display the number of participants with available data at that timepoint." (NCT01634139)
Timeframe: Baseline and 10 mins before drug administration and 30 mins, 1 hour (h), 2h, 3h after drug administration at Week 24
| Intervention | Litres (L) (Mean) | ||||
|---|---|---|---|---|---|
| 10 minutes pre-dose (Week 24) (N=124, 131, 134) | 30 minutes post-dose (Week 24) (N=124, 131, 134) | 1 hour post-dose (Week 24) (N=124, 131, 134) | 2 hours post-dose (Week 24) (N=124, 131, 134) | 3 hours post-dose (Week 24) (N=124, 131, 134) | |
| Placebo Respimat | 0.154 | 0.144 | 0.142 | 0.117 | 0.118 |
| Tio R2.5 | 0.246 | 0.222 | 0.252 | 0.230 | 0.233 |
| Tio R5 | 0.206 | 0.211 | 0.202 | 0.210 | 0.210 |
"FEV1 change from baseline to week 24 at each individual timepoint.~The measured values presented are actually adjusted means.~The number of participants analysed displays the number of participants included in the statistical model whereas the N's for each timepoint display the number of participants with available data at that timepoint." (NCT01634139)
Timeframe: Baseline and 10 mins before drug administration and 30 mins, 1 hour (h), 2h, 3h after drug administration at 24 weeks
| Intervention | Litres (L) (Mean) | ||||
|---|---|---|---|---|---|
| 10 minutes pre-dose (Week 24) (N=126, 131, 134) | 30 minutes post-dose (Week 24) (N=126, 131, 134) | 1 hour post-dose (Week 24) (N=126, 131, 134) | 2 hours post-dose (Week 24) (N=126, 131, 134) | 3 hours post-dose (Week 24) (N=126, 131, 134) | |
| Placebo Respimat | 0.156 | 0.156 | 0.165 | 0.144 | 0.147 |
| Tio R2.5 | 0.272 | 0.295 | 0.313 | 0.307 | 0.325 |
| Tio R5 | 0.274 | 0.307 | 0.312 | 0.312 | 0.322 |
"Change from baseline in morning (a.m.) FEV1 based on the weekly mean at week 24 and 48.~The measured values presented are actually adjusted means.~The number of participants analysed displays the number of participants included in the statistical model whereas the N's for each timepoint display the number of participants with available data at that timepoint." (NCT01634139)
Timeframe: Baseline and Week 24, Baseline and Week 48.
| Intervention | Litres (Mean) | |
|---|---|---|
| Week 24 (N=122, 130, 130) | Week 48 (N=119, 122, 125) | |
| Placebo Respimat | 0.191 | 0.236 |
| Tio R2.5 | 0.209 | 0.259 |
| Tio R5 | 0.126 | 0.221 |
"Change from baseline in nighttime awakenings based on the weekly mean at weeks 24 and 48.~Nighttime awakenings was assessed by the question Did you wake up during the night due to your asthma? from the e-diary. Scores range from 1 (did not wake up) to 5 (was awake all night).~Measured values presented are actually adjusted means.~The number of participants analysed displays the number of participants included in the statistical model whereas the N's for each timepoint display the number of participants with available data at that timepoint." (NCT01634139)
Timeframe: Baseline and Week 24, Baseline and Week 48.
| Intervention | Units on a scale (Mean) | |
|---|---|---|
| Week 24 (N=122, 130, 130) | Week 48 (N=119, 122, 125) | |
| Placebo Respimat | -0.070 | -0.101 |
| Tio R2.5 | -0.079 | -0.131 |
| Tio R5 | -0.144 | -0.127 |
"Change from baseline in morning asthma symptoms based on the weekly mean at weeks 24 and 48.~Morning asthma symptoms was assessed by the question how were your asthma symptoms this morning? from the e-diary. Scores range from 1 (no asthma symptoms) to 5 (very severe asthma symptoms).~Measured values presented are actually adjusted means.~The number of participants analysed displays the number of participants included in the statistical model whereas the N's for each timepoint display the number of participants with available data at that timepoint." (NCT01634139)
Timeframe: Baseline and Week 24, Baseline and Week 48.
| Intervention | Units on a scale (Mean) | |
|---|---|---|
| Week 24 (N=122, 130, 130) | Week 48 (N=119, 122, 125) | |
| Placebo Respimat | -0.138 | -0.177 |
| Tio R2.5 | -0.138 | -0.230 |
| Tio R5 | -0.220 | -0.221 |
"Change from baseline in daytime experiences of wheeze or cough based on the weekly mean at weeks 24 and 48.~Daytime experiences of wheeze or cough was assessed by the question did you experience wheeze or cough during the day? from the e-diary. Scores range from 1 (not at all) to 5 (all the time).~Measured values presented are actually adjusted means.~The number of participants analysed displays the number of participants included in the statistical model whereas the N's for each timepoint display the number of participants with available data at that timepoint." (NCT01634139)
Timeframe: Baseline and Week 24, Baseline and Week 48.
| Intervention | Units on a scale (Mean) | |
|---|---|---|
| Week 24 (N=121, 130, 133) | Week 48 (N=119, 123, 125) | |
| Placebo Respimat | -0.261 | -0.340 |
| Tio R2.5 | -0.307 | -0.337 |
| Tio R5 | -0.355 | -0.393 |
"Change from baseline in daytime experiences of shortness of breath based on the weekly mean at weeks 24 and 48.~Daytime experiences of shortness of breath was assessed by the question how much shortness of breath did you experience during the day from the e-diary. Scores range from 1 (none) to 5 (a very great deal).~Measured values presented are actually adjusted means.~The number of participants analysed displays the number of participants included in the statistical model whereas the N's for each timepoint display the number of participants with available data at that timepoint." (NCT01634139)
Timeframe: Baseline and Week 24, Baseline and Week 48.
| Intervention | Units on a scale (Mean) | |
|---|---|---|
| Week 24 (N=121, 130, 133) | Week 48 (N=119, 123, 125) | |
| Placebo Respimat | -0.134 | -0.219 |
| Tio R2.5 | -0.178 | -0.231 |
| Tio R5 | -0.240 | -0.253 |
"Change from baseline in daytime asthma symptoms based on the weekly mean at weeks 24 and 48.~Daytime asthma symptoms was assessed by the question how were your asthma symptoms during the day? from the e-diary. Scores range from 1 (no asthma symptoms) to 5 (very severe asthma symptoms).~Measured values presented are actually adjusted means.~The number of participants analysed displays the number of participants included in the statistical model whereas the N's for each timepoint display the number of participants with available data at that timepoint." (NCT01634139)
Timeframe: Baseline and Week 24, Baseline and Week 48.
| Intervention | Units on a scale (Mean) | |
|---|---|---|
| Week 24 (N=121, 130, 133) | Week 48 (N=119, 123, 125) | |
| Placebo Respimat | -0.204 | -0.261 |
| Tio R2.5 | -0.243 | -0.272 |
| Tio R5 | -0.263 | -0.312 |
"Change from baseline in daytime activity limitations based on the weekly mean at weeks 24 and 48.~Daytime activity limitations was assessed by the question how limited were you in your activities today because of your asthma? from the e-diary. Scores range from 1 (not limited) to 5 (totally limited).~Measured values presented are actually adjusted means.~The number of participants analysed displays the number of participants included in the statistical model whereas the N's for each timepoint display the number of participants with available data at that timepoint." (NCT01634139)
Timeframe: Baseline and Week 24, Baseline and Week 48.
| Intervention | Units on a scale (Mean) | |
|---|---|---|
| Week 24 (N=121, 130, 133) | Week 48 (N=119, 123, 125) | |
| Placebo Respimat | -0.181 | -0.227 |
| Tio R2.5 | -0.212 | -0.238 |
| Tio R5 | -0.240 | -0.259 |
"Change from baseline in asthma symptom-free days based on the weekly mean at weeks 24 and 48.~A day was considered as an asthma symptom-free day if there were no symptoms reported via the e-Diary (electronic diary) and no use of rescue medication reported via the eDiary during that day.~Measured values presented are actually adjusted means.~The number of participants analysed displays the number of participants included in the statistical model whereas the N's for each timepoint display the number of participants with available data at that timepoint." (NCT01634139)
Timeframe: Baseline and Week 24, Baseline and Week 48.
| Intervention | Days (Mean) | |
|---|---|---|
| Week 24 (N=122, 130, 133) | Week 48 (N=120, 123, 127) | |
| Placebo Respimat | 0.135 | 0.151 |
| Tio R2.5 | 0.176 | 0.170 |
| Tio R5 | 0.172 | 0.180 |
"Interviewer Administered Asthma Control Questionnaire (ACQ-IA) total score after 24 and 48 weeks of treatment.~The ACQ-IA is a scale containing 7 questions. Each question has a 7 point scale which ranges from 0 to 6. A score of 0 corresponds to no impairment and a score of 6 corresponds to maximum impairment. ACQ-IA total score is calculated as the mean of the responses to all 7 questions.~The measured values presented are actually adjusted means.~The number of participants analysed displays the number of participants included in the statistical model whereas the N's for each timepoint display the number of participants with available data at that timepoint." (NCT01634139)
Timeframe: Weeks 24 and 48.
| Intervention | Units on a Scale (Mean) | |
|---|---|---|
| Week 24 (N=126, 131, 134) | Week 48 (N=124, 130, 130) | |
| Placebo Respimat | 1.017 | 0.817 |
| Tio R2.5 | 0.897 | 0.752 |
| Tio R5 | 0.835 | 0.723 |
"Responder categories based on the ACQ-IA total score after 24 and 48 weeks of treatment. Analysis was performed using the following categories and definitions: responder (change from trial baseline ≤-0.5), no change (-0.5
Timeframe: Weeks 24 and 48
| Intervention | Patients (Number) | |||||
|---|---|---|---|---|---|---|
| Responders at Week 24 | No Change at Week 24 | Worsening at Week 24 | Responder at Week 48 | No Change at Week 48 | Worsening at Week 48 | |
| Placebo Respimat | 97 | 34 | 0 | 114 | 16 | 1 |
| Tio R2.5 | 108 | 27 | 0 | 118 | 14 | 3 |
| Tio R5 | 118 | 16 | 1 | 117 | 17 | 1 |
"Change from baseline of area under the curve (AUC) from 0 to 3 hours for FVC (Forced vital capacity) (FVC AUC (0-3h)) after 24 weeks of treatment. The AUC was calculated by using the trapezoidal rule divided by the observation time (3h).~Measured values presented are actually adjusted means.~The number of participants analysed displays the number of participants with available data at the timepoint of interest." (NCT01634139)
Timeframe: Baseline and 10 mins before drug administration and 30 mins, 1 hour (h), 2h, 3h after drug administration at 24 weeks
| Intervention | Litres (L) (Mean) |
|---|---|
| Placebo Respimat | 0.130 |
| Tio R2.5 | 0.235 |
| Tio R5 | 0.207 |
"Change from baseline in peak forced expiratory volume (FEV) in 1 second within the first 3 hours (h) post dosing (FEV1 peak(0-3h)) measured at week 24.~Measured values presented are actually adjusted means.~The number of participants analysed displays the number of participants with available data at the timepoint of interest." (NCT01634139)
Timeframe: Baseline and 24 Weeks.
| Intervention | Litres (L) (Mean) |
|---|---|
| Placebo Respimat | 0.225 |
| Tio R2.5 | 0.395 |
| Tio R5 | 0.389 |
"Change from baseline in peak forced expiratory volume (FEV) in 1 second within the first 3 hours (h) post dosing (FEV1 peak(0-3h)) measured at week 48.~Measured values presented are actually adjusted means.~The number of participants analysed displays the number of participants with available data at the timepoint of interest." (NCT01634139)
Timeframe: Baseline and Week 48.
| Intervention | Litres (L) (Mean) |
|---|---|
| Placebo Respimat | 0.351 |
| Tio R2.5 | 0.474 |
| Tio R5 | 0.477 |
"Change from baseline of area under the curve (AUC) from 0 to 3 hours for FEV1 (FEV1 AUC (0-3h)) after 24 weeks of treatment. The AUC was calculated by using the trapezoidal rule divided by the observation time (3h).~Measured values presented are actually adjusted means.~The number of participants analysed displays the number of participants with available data at the timepoint of interest." (NCT01634139)
Timeframe: Baseline and 10 mins before drug administration and 30 mins, 1 hour (h), 2h, 3h after drug administration at week 24
| Intervention | Litres (L) (Mean) |
|---|---|
| Placebo Respimat | 0.152 |
| Tio R2.5 | 0.306 |
| Tio R5 | 0.309 |
"Change from baseline in evening (p.m.) FEV1 based on the weekly mean at week 24 and 48.~Measured values presented are actually adjusted means.~The number of participants analysed displays the number of participants included in the statistical model whereas the N's for each timepoint display the number of participants with available data at that timepoint." (NCT01634139)
Timeframe: Baseline and Week 24, Baseline and Week 48.
| Intervention | Litres (L) (Mean) | |
|---|---|---|
| Week 24 (N=121, 129, 128) | Week 48 (N=119, 123, 125) | |
| Placebo Respimat | 0.167 | 0.202 |
| Tio R2.5 | 0.142 | 0.208 |
| Tio R5 | 0.092 | 0.159 |
"Responder categories based on the ACQ-IA total score after 12 weeks of treatment. Analysis was performed using the following categories and definitions: responder (change from trial baseline ≤-0.5), no change (-0.5
Timeframe: 12 weeks
| Intervention | Percentage of participants (Number) | ||
|---|---|---|---|
| Responder | No change | Worsening | |
| Placebo Respimat | 76.9 | 20.9 | 2.2 |
| Tio R2.5 | 79.4 | 18.4 | 2.2 |
| Tio R5 | 80.8 | 16.2 | 3.1 |
"Change from baseline in the morning (a.m.) peak expiratory flow based on the weekly mean at week 12.~Measured values presented are actually adjusted means." (NCT01634152)
Timeframe: Baseline and 12 weeks
| Intervention | L/min (Mean) |
|---|---|
| Placebo Respimat | 8.343 |
| Tio R2.5 | 13.119 |
| Tio R5 | 13.086 |
"Change from baseline in daytime asthma symptoms based on the weekly mean at week 12.~Daytime asthma symptoms was assessed by the question how were your asthma symptoms during the day? from the e-diary. Scores range from 1 (no asthma symptoms) to 5 (very severe asthma symptoms).~Measured values presented are actually adjusted means." (NCT01634152)
Timeframe: Baseline and 12 weeks
| Intervention | Units on a scale (Mean) |
|---|---|
| Placebo Respimat | -0.226 |
| Tio R2.5 | -0.262 |
| Tio R5 | -0.239 |
"Change from baseline in morning (a.m.) FEV1 based on the weekly mean at week 12.~Measured values presented are actually adjusted means." (NCT01634152)
Timeframe: Baseline and 12 weeks
| Intervention | Litres (Mean) |
|---|---|
| Placebo Respimat | 0.174 |
| Tio R2.5 | 0.142 |
| Tio R5 | 0.125 |
"Change from baseline of area under the curve (AUC) from 0 to 3 hours for FEV1 (FEV1 AUC (0-3h)) after 12 weeks of treatment. The AUC was calculated by using the trapezoidal rule divided by the observation time (3h).~Measured values presented are actually adjusted means." (NCT01634152)
Timeframe: Baseline and 10 mins before drug administration and 30 mins, 1 hour (h), 2h, 3h after drug administration at 12 weeks
| Intervention | Litres (Mean) |
|---|---|
| Placebo Respimat | 0.175 |
| Tio R2.5 | 0.206 |
| Tio R5 | 0.301 |
"Change from baseline in evening (p.m.) FEV1 based on the weekly mean at week 12.~Measured values presented are actually adjusted means." (NCT01634152)
Timeframe: Baseline and 12 weeks
| Intervention | Litres (Mean) |
|---|---|
| Placebo Respimat | 0.155 |
| Tio R2.5 | 0.104 |
| Tio R5 | 0.094 |
"Change from baseline in peak forced expiratory volume in 1 second within the first 3 hours post dosing (FEV1 peak(0-3h)) measured at week 12.~Measured values presented are actually adjusted means." (NCT01634152)
Timeframe: Baseline and 12 weeks
| Intervention | Litres (Mean) |
|---|---|
| Placebo Respimat | 0.252 |
| Tio R2.5 | 0.287 |
| Tio R5 | 0.391 |
"Change from baseline of area under the curve (AUC) from 0 to 3 hours for FVC (Forced vital capacity) (FVC AUC (0-3h)) after 12 weeks of treatment. The AUC was calculated by using the trapezoidal rule divided by the observation time (3h).~Measured values presented are actually adjusted means." (NCT01634152)
Timeframe: Baseline and 10 mins before drug administration and 30 mins, 1 hour (h), 2h, 3h after drug administration at 12 weeks
| Intervention | Litres (Mean) |
|---|---|
| Placebo Respimat | 0.145 |
| Tio R2.5 | 0.105 |
| Tio R5 | 0.182 |
"Change from baseline in Maximum forced vital capacity (FVC) measured within the first 3 hours after administration of trial medication (FVC peak(0-3h)) after 12 weeks of treatment.~The measured values presented are actually adjusted means." (NCT01634152)
Timeframe: Baseline and 12 weeks
| Intervention | Litres (Mean) |
|---|---|
| Placebo Respimat | 0.244 |
| Tio R2.5 | 0.201 |
| Tio R5 | 0.275 |
"Change from baseline in daytime experiences of shortness of breath based on the weekly mean at week 12.~Daytime experiences of shortness of breath was assessed by the question how much shortness of breath did you experience during the day from the e-diary. Scores range from 1 (none) to 5 (a very great deal).~Measured values presented are actually adjusted means." (NCT01634152)
Timeframe: Baseline and 12 weeks
| Intervention | Units on a scale (Mean) |
|---|---|
| Placebo Respimat | -0.204 |
| Tio R2.5 | -0.187 |
| Tio R5 | -0.287 |
"Change from baseline in the number of puffs of rescue medication (salbutamol/albuterol) used per day (24 hour period) based on the weekly mean at week 12.~The measured values presented are actually adjusted means." (NCT01634152)
Timeframe: Baseline and 12 weeks
| Intervention | Number of puffs of rescue medication (Mean) |
|---|---|
| Placebo Respimat | -0.570 |
| Tio R2.5 | -0.553 |
| Tio R5 | -0.660 |
"Change from baseline in the number of puffs of rescue medication (salbutamol/albuterol) used during the night-time based on the weekly mean at week 12.~Measured values presented are actually adjusted means" (NCT01634152)
Timeframe: Baseline and 12 weeks
| Intervention | Number of puffs of rescue medication (Mean) |
|---|---|
| Placebo Respimat | -0.285 |
| Tio R2.5 | -0.250 |
| Tio R5 | -0.310 |
"Change from baseline in the number of puffs of rescue medication (salbutamol/albuterol) used during the daytime based on the weekly mean at week 12.~Measured values presented are actually adjusted means." (NCT01634152)
Timeframe: Baseline and 12 weeks
| Intervention | Number of puffs of rescue medication (Mean) |
|---|---|
| Placebo Respimat | -0.279 |
| Tio R2.5 | -0.294 |
| Tio R5 | -0.365 |
"Change from baseline in Trough (pre-dose) FVC measured at week 12.~Measured values presented are actually adjusted means." (NCT01634152)
Timeframe: Baseline and 12 weeks
| Intervention | Litres (Mean) |
|---|---|
| Placebo Respimat | 0.141 |
| Tio R2.5 | 0.094 |
| Tio R5 | 0.150 |
"Change from baseline in Trough (pre-dose) Forced expiratory volume in 1 second (FEV1) measured at week 12.~Measured values presented are actually adjusted means." (NCT01634152)
Timeframe: Baseline and 12 weeks
| Intervention | Litres (Mean) |
|---|---|
| Placebo Respimat | 0.136 |
| Tio R2.5 | 0.154 |
| Tio R5 | 0.223 |
"Change from baseline in the peak expiratory flow variability based on the weekly mean at week 12.~Measured values presented are actually adjusted means." (NCT01634152)
Timeframe: Baseline and 12 weeks
| Intervention | Percentage of PEF (Mean) |
|---|---|
| Placebo Respimat | 0.150 |
| Tio R2.5 | -0.800 |
| Tio R5 | -0.352 |
"Forced expiratory volume in one second (FEV1) change from baseline at each individual timepoint.~The measured values presented are actually adjusted means." (NCT01634152)
Timeframe: Baseline and 10 mins before drug administration and 30 mins, 1 hour (h), 2h, 3h after drug administration at 12 weeks
| Intervention | Litres (Mean) | ||||
|---|---|---|---|---|---|
| 10 minutes pre-dose | 30 minutes post-dose | 1 hour post-dose | 2 hours post-dose | 3 hours post-dose | |
| Placebo Respimat | 0.136 | 0.166 | 0.177 | 0.191 | 0.168 |
| Tio R2.5 | 0.154 | 0.202 | 0.203 | 0.216 | 0.215 |
| Tio R5 | 0.223 | 0.285 | 0.300 | 0.324 | 0.308 |
"Change from baseline in the evening (p.m.) peak expiratory flow based on the weekly mean at week 12.~Measured values presented are actually adjusted means." (NCT01634152)
Timeframe: Baseline and 12 weeks
| Intervention | L/min (Mean) |
|---|---|
| Placebo Respimat | 7.892 |
| Tio R2.5 | 8.459 |
| Tio R5 | 3.785 |
"Change from baseline in Interviewer-Administered Asthma Control Questionnaire (ACQ-IA) total score measured at week 12.~The ACQ-IA is a scale containing 7 questions. Each question has a 7 point scale which ranges from 0 to 6. A score of 0 corresponds to no impairment and a score of 6 corresponds to maximum impairment. ACQ-IA total score is calculated as the mean of the responses to all 7 questions.~The measured values presented are actually adjusted means." (NCT01634152)
Timeframe: Baseline and 12 weeks
| Intervention | Units on a scale (Mean) |
|---|---|
| Placebo Respimat | 1.026 |
| Tio R2.5 | 1.046 |
| Tio R5 | 0.948 |
"FVC change from baseline at each individual timepoint.~The measured values presented are actually adjusted means." (NCT01634152)
Timeframe: Baseline and 10 mins before drug administration and 30 mins, 1 hour (h), 2h, 3h after drug administration at 12 weeks
| Intervention | Litres (Mean) | ||||
|---|---|---|---|---|---|
| 10 minutes pre-dose | 30 minutes post-dose | 1 hour post-dose | 2 hours post-dose | 3 hours post-dose | |
| Placebo Respimat | 0.141 | 0.130 | 0.146 | 0.159 | 0.132 |
| Tio R2.5 | 0.094 | 0.096 | 0.097 | 0.113 | 0.110 |
| Tio R5 | 0.150 | 0.164 | 0.181 | 0.199 | 0.176 |
"Change from baseline in daytime experiences of wheeze or cough based on the weekly mean at week 12.~Daytime experiences of wheeze or cough was assessed by the question did you experience wheeze or cough during the day? from the e-diary. Scores range from 1 (not at all) to 5 (all the time).~Measured values presented are actually adjusted means." (NCT01634152)
Timeframe: Baseline and 12 weeks
| Intervention | Units on a scale (Mean) |
|---|---|
| Placebo Respimat | -0.249 |
| Tio R2.5 | -0.263 |
| Tio R5 | -0.320 |
"Change from baseline in morning asthma symptoms based on the weekly mean at week 12.~Morning asthma symptoms was assessed by the question how were your asthma symptoms this morning? from the e-diary. Scores range from 1 (no asthma symptoms) to 5 (very severe asthma symptoms).~Measured values presented are actually adjusted means." (NCT01634152)
Timeframe: Baseline and 12 weeks
| Intervention | Units on a scale (Mean) |
|---|---|
| Placebo Respimat | -0.207 |
| Tio R2.5 | -0.213 |
| Tio R5 | -0.221 |
"Change from baseline in nighttime awakenings based on the weekly mean at week 12.~Nighttime awakenings was assessed by the question Did you wake up during the night due to your asthma? from the e-diary. Scores range from 1 (did not wake up) to 5 (was awake all night).~Measured values presented are actually adjusted means." (NCT01634152)
Timeframe: Baseline and 12 weeks
| Intervention | Units on a scale (Mean) |
|---|---|
| Placebo Respimat | -0.165 |
| Tio R2.5 | -0.166 |
| Tio R5 | -0.159 |
"Change from baseline in asthma symptom-free days based on the weekly mean at week 12.~A day was considered as an asthma symptom-free day if there were no symptoms reported via the e-Diary and no use of rescue medication reported via the eDiary during that day.~Measured values presented are actually adjusted means." (NCT01634152)
Timeframe: Baseline and 12 weeks
| Intervention | Days (Mean) |
|---|---|
| Placebo Respimat | 0.147 |
| Tio R2.5 | 0.130 |
| Tio R5 | 0.172 |
"Change from baseline in daytime activity limitations based on the weekly mean at week 12.~Daytime activity limitations was assessed by the question how limited were you in your activities today because of your asthma? from the e-diary. Scores range from 1 (not limited) to 5 (totally limited).~Measured values presented are actually adjusted means." (NCT01634152)
Timeframe: Baseline and 12 weeks
| Intervention | Units on a scale (Mean) |
|---|---|
| Placebo Respimat | -0.210 |
| Tio R2.5 | -0.203 |
| Tio R5 | -0.222 |
The health status was measured by the total COPD Assessment Test (CAT) score at baseline and at the end of the observation period after app. 3 months (visit 3). Therefore, the total CAT score at baseline and at Visit 3 was calculated by adding up the scores of the single questions of the CAT questionnaire. In the case of one or more missing items the total score was not determined for the specific visit. The health status is considered to be maintained or improved if the change in the total CAT score from baseline at Visit 3 is ≥0. (NCT01644734)
Timeframe: Baseline, 3 months
| Intervention | participants (Number) |
|---|---|
| Patients Treated With Spiriva HandiHaler | 972 |
The change represents the value at baseline minus the value after 3 months. The total CAT score ranges from 0 to 40 where 0 represents no symptoms and 40 very bad symptoms. Therefore, a positive value for the change in the total CAT score means an improvement. (NCT01644734)
Timeframe: Baseline, 3 months
| Intervention | units on a scale (Mean) |
|---|---|
| Patients Treated With Spiriva HandiHaler | 7.0 |
Total patient year exposure of COPD was calculated by aggregating the time to min(treatment stop +30, last contact) for on-treatment analysis, or time to last contact for on-study analysis. (NCT01662986)
Timeframe: start of treatment to the last timepoint with information of clinical adverse outcome available,Up to 2 years
| Intervention | Patient years (Number) |
|---|---|
| Placebo | 58.0 |
| Tiotropium Bromide (18 μg) | 60.2 |
Number of all-cause hospitalization per patient year outcome event occured during the study was analysed descriptively by calculating average occurrence (number of events per patient year drug exposure) by treatment group for on study period using the TS. (NCT01662986)
Timeframe: from first drug administration to the last timepoint with information of clinical adverse outcome available, Up to 2 years
| Intervention | hospitalizations per patient year (Number) |
|---|---|
| Placebo | 0.8 |
| Tiotropium Bromide (18 μg) | 0.6 |
Number of COPD exacerbation per patient year outcome event occured during the study was analysed descriptively by calculating average occurrence (number of events per patient year drug exposure) by treatment group for on study period using the TS. (NCT01662986)
Timeframe: start of treatment to the last timepoint with information of clinical adverse outcome available,Up to 2 years
| Intervention | exacerbations per patient year (Number) |
|---|---|
| Placebo | 1.3 |
| Tiotropium Bromide (18 μg) | 0.9 |
"Percentage (number) of patients with 30-day hospital readmission rates outcome events was analysed.~Days to hospital readmission were calculated as:Hospital readmission days = Readmission date - Date of hospital discharge + 1.~The 30-day hospital readmission analysis summarized the frequency of patients with hospital readmission and readmission days >1 and <31 days using the TS." (NCT01662986)
Timeframe: from date of hospital discharge prior to randomization upto readmission days >1 and <31 days
| Intervention | percentage of participants (Number) |
|---|---|
| Placebo | 5.1 |
| Tiotropium Bromide (18 μg) | 5.1 |
Change from baseline of trough Forced Vital Capacity (FVC) at 12 weeks on study drug. (NCT01662986)
Timeframe: baseline and 12 weeks
| Intervention | Litres (Mean) |
|---|---|
| Placebo | 0.090 |
| Tiotropium Bromide (18 μg) | 0.282 |
"Percentage (number) of patients with all-cause hospitalization outcome event occured during the study was analysed for the combined study.~All-cause hospitalization included all hospitalizations, except planned hospitalizations for elective procedures.~Hospitalizations occurring on the same day as discharge were not considered a separate admission." (NCT01662986)
Timeframe: from first drug administration to the last timepoint with information of clinical adverse outcome available, Up to 2 years
| Intervention | percentage of participants (Number) |
|---|---|
| Placebo | 26.9 |
| Tiotropium Bromide (18 μg) | 26.6 |
Percentage (number) of patients with adverse clinical event on study, which is defined as the combined endpoint of Chronic obstructive pulmonary disease (COPD) exacerbations per Boehringer Ingelheim (BI) definition, all-cause re-hospitalization, or all-cause mortality. (NCT01662986)
Timeframe: from first drug administration to the last timepoint with information of clinical adverse outcome available, Up to 2 years
| Intervention | percentage of participants (Number) |
|---|---|
| Placebo | 35.9 |
| Tiotropium Bromide (18 μg) | 46.2 |
"Change from baseline of trough forced expiratory volume in 1 second (FEV1) at 12 weeks on study drug.~Trough FEV1 is defined as the FEV1 measurement prior to the next dosing of study drug and approximately 24 hours after last inhalation of drug." (NCT01662986)
Timeframe: Baseline and 12 weeks
| Intervention | Litres (Mean) |
|---|---|
| Placebo | 0.124 |
| Tiotropium Bromide (18 μg) | 0.186 |
"Change from baseline of trough FEV1 (forced expiratory volume in 1 second) at 12 weeks on study drug.~Trough FEV1 is defined as the FEV1 measurement prior to the next dosing of study drug and approximately 24 hours after last inhalation of drug." (NCT01662986)
Timeframe: Baseline and week 12
| Intervention | Litres (Mean) |
|---|---|
| Placebo | 0.035 |
| Tiotropium Bromide (18 μg) | 0.185 |
"Time to event: Time to recovery based on EXACT-PRO total score. The percentage of observed patients recovered by end of study was reported.~Time to recovery was assessed with the EXACT-PRO questionnaire. EXACT-PRO total scores were transformed to smooth scores for determining time to recovery and all other endpoints related to the EXACT questionnaire. The day-2 score was transformed to the mean of the total scores recorded on Day 1, 2, and 3. Similarly, each subsequent day's score was transformed to the mean score using a rolling 3-day average.~Analysis based on Kaplan Meier estimate" (NCT01662986)
Timeframe: from first drug administration to the last timepoint with information of EXACT-PRO, Up to 2 years
| Intervention | Percentage of patients recovered (Number) |
|---|---|
| Placebo | 94.0 |
| Tiotropium Bromide (18 μg) | 88.0 |
"Percentage (number) of patients with next adverse clinical outcome event occured during the study, defined as the combined endpoint of Chronic obstructive pulmonary disease (COPD) exacerbations per Boehringer Ingelheim (BI) definition, all-cause re-hospitalization, or all-cause mortality.~Time to the next adverse clinical outcome event from the Two Twin Trials, present 205.478 (NCT01662986) and 205.477 (NCT01663987) was not analysed, only Kaplan Meier curve was plotted. So this endpoint has not been disclosed.~This endpoint was analysed using combined data, as specified in the analysis plan" (NCT01662986)
Timeframe: from first drug administration to the last timepoint with information of clinical adverse outcome available, Up to 2 years
| Intervention | Percentage of participants (Number) |
|---|---|
| Placebo | 47.4 |
| Tiotropium Bromide (18 μg) | 53.2 |
"Percentage (number) of patients with COPD exacerbation on study was analysed for the combined study.~A COPD exacerbation was defined as a complex of lower respiratory events/symptoms (increase or new onset) related to the underlying COPD with duration of three days or more, requiring a change in treatment where a complex of lower respiratory events/symptoms was defined as at least two of the following:~1) Shortness of breath; 2) Sputum production (volume) ; 3) Occurrence of purulent sputum; 4) Cough; 5) Wheezing; 6) Chest tightness.~Onset of exacerbation was defined by the onset of first recorded symptom.The end of exacerbation was decided by the investigator based on clinical judgment.~A required change in treatment included either prescription of antibiotics and/or systemic steroids; and/or a newly prescribed maintenance respiratory medication (i.e., bronchodilators including theophyllines and PDE4-inhibitors)." (NCT01662986)
Timeframe: from first drug administration to the last timepoint with information of clinical adverse outcome available, Up to 2 years
| Intervention | percentage of participants (Number) |
|---|---|
| Placebo | 44.9 |
| Tiotropium Bromide (18 μg) | 40.5 |
Total patient year exposure of all-cause hospitalization was calculated by aggregating the time to min(treatment stop +30, last contact) for on-treatment analysis, or time to last contact for on-study analysis. (NCT01662986)
Timeframe: from first drug administration to the last timepoint with information of clinical adverse outcome available, Up to 2 years
| Intervention | patient years (Number) |
|---|---|
| Placebo | 58.0 |
| Tiotropium Bromide (18 μg) | 60.2 |
Change from baseline of trough Forced Vital Capacity (FVC) at 12 weeks on study drug. (NCT01662986)
Timeframe: Baseline and week 12
| Intervention | Litres (Mean) |
|---|---|
| Placebo | -0.015 |
| Tiotropium Bromide (18 μg) | 0.278 |
"Percentage of patients with COPD exacerbation on study was analysed for the combined study.~A COPD exacerbation was defined as a complex of lower respiratory events/symptoms (increase or new onset) related to the underlying COPD with duration of three days or more, requiring a change in treatment where a complex of lower respiratory events/symptoms was defined as at least two of the following: 1) Shortness of breath; 2) Sputum production (volume); 3)Occurrence of purulent sputum; 4) Cough; 5) Wheezing; 6) Chest tightness. Onset of exacerbation was defined by the onset of first recorded symptom.The end of exacerbation was decided by the investigator based on clinical judgment.~A required change in treatment included either prescription of antibiotics and/or systemic steroids; and a newly prescribed maintenance respiratory medication (i.e. bronchodilators including theophyllines and PDE4-inhibitors).~This endpoint was analysed using combined data, as specified in the analysis plan." (NCT01663987)
Timeframe: from first drug administration to the last timepoint with information of clinical adverse outcome available, up to 2 years
| Intervention | Percentage of participants (Number) |
|---|---|
| Placebo | 44.9 |
| Tiotropium Bromide (18μg) | 40.5 |
"Number of all-cause hospitalization per patient year outcome event occured during the study was analysed descriptively by calculating average occurrence (number of events per patient year drug exposure) by treatment group for on study period using the TS.~This endpoint was analysed using combined data, as specified in the analysis plan." (NCT01663987)
Timeframe: From first drug administration to the last timepoint with information of clinical adverse outcome available, up to 2 years
| Intervention | Hospitalisation per patient year (Number) |
|---|---|
| Placebo | 0.8 |
| Tiotropium Bromide (18μg) | 0.6 |
"Time to event: Time to recovery based on EXACT-PRO total score. The percentage of observed patients recovered by end of study was reported.~Time to recovery was assessed with the EXACT-PRO questionnaire. EXACT-PRO total scores were transformed to smooth scores for determining time to recovery and all other endpoints related to the EXACT questionnaire. The day-2 score was transformed to the mean of the total scores recorded on Day 1, 2, and 3. Similarly, each subsequent day's score was transformed to the mean score using a rolling 3-day average.~Analysis based on Kaplan Meier estimate." (NCT01663987)
Timeframe: From first drug administration to the last timepoint with information of EXACT-PRO, up to 2 years
| Intervention | Percentage of patients recovered (Number) |
|---|---|
| Placebo | 94.0 |
| Tiotropium Bromide (18μg) | 88.0 |
"Percentage of patients with next adverse clinical outcome event occured during the study, defined as the combined endpoint of chronic obstructive pulmonary disease (COPD) exacerbations per Boehringer Ingelheim (BI) definition, all-cause re-hospitalization, or all-cause mortality.~Time to the next adverse clinical outcome event from the two twin trials, was defined as a primary endpoint but was not analysed numerically, so this endpoint is presented instead.~This endpoint was analysed using combined data, as specified in the analysis plan." (NCT01663987)
Timeframe: From first drug administration to the last timepoint with information of clinical adverse outcome available, up to 2 years
| Intervention | Percentage of perticipants (Number) |
|---|---|
| Placebo | 47.4 |
| Tiotropium Bromide (18μg) | 53.2 |
"Change from baseline of Trough FEV1 (forced expiratory volume in one second) at 12 weeks on study drug.~Trough FEV1 is defined as the FEV1 measurement prior to the next dosing of study drug and approximately 24 hours after last inhalation of drug.~This endpoint was analysed using combined data, as specified in the analysis plan." (NCT01663987)
Timeframe: Baseline and 12 weeks
| Intervention | Litres (Mean) |
|---|---|
| Placebo | 0.035 |
| Tiotropium Bromide (18μg) | 0.185 |
Change from baseline in trough forced expiratory volume in 1 second (FEV1) at 12 weeks on study medication. Trough FEV1 is defined as FEV1 measurement prior to the next dosing of study drug and approximately 24 hours after the last inhalation of drug. (NCT01663987)
Timeframe: Baseline and 12 weeks
| Intervention | Litres (Mean) |
|---|---|
| Placebo | -0.051 |
| Tiotropium Bromide (18μg) | 0.183 |
"Change from baseline of trough Forced Vital Capacity (FVC) at 12 weeks on study drug.~This endpoint was analysed using combined data, as specified in the analysis plan." (NCT01663987)
Timeframe: Baseline and 12 weeks
| Intervention | Litres (Mean) |
|---|---|
| Placebo | -0.015 |
| Tiotropium Bromide (18μg) | 0.278 |
Change from baseline of trough Forced Vital Capacity (FVC) at 12 weeks on study drug. (NCT01663987)
Timeframe: Baseline and 12 weeks
| Intervention | Litres (Mean) |
|---|---|
| Placebo | -0.117 |
| Tiotropium Bromide (18μg) | 0.274 |
"Number of COPD exacerbation per patient year outcome event occured during the study was analysed descriptively by calculating average occurrence (number of events per patient year drug exposure) by treatment group for on study period using the TS.~This endpoint was analysed using combined data, as specified in the analysis plan." (NCT01663987)
Timeframe: Start of treatment to the last timepoint with information of clinical adverse outcome available, up to 2 years
| Intervention | exacerbations per patient year (Number) |
|---|---|
| Placebo | 1.3 |
| Tiotropium Bromide (18μg) | 0.9 |
"Percentage of patients with 30-day hospital readmission rates outcome events was analysed.~Days to hospital readmission were calculated as:Hospital readmission days = Readmission date - Date of hospital discharge + 1.~The 30-day hospital readmission analysis summarized the frequency of patients with hospital readmission and readmission days >1 and <31 days using the TS.~This endpoint was analysed using combined data, as specified in the analysis plan." (NCT01663987)
Timeframe: from date of hospital discharge prior to randomization up to readmission days >1 and <31 days
| Intervention | Percentage of participants (Number) |
|---|---|
| Placebo | 5.1 |
| Tiotropium Bromide (18μg) | 5.1 |
Percentage of patients with adverse clinical event during on study, which is defined as the combined endpoint of chronic obstructive pulmonary disease (COPD) exacerbations per Boehringer Ingelheim (BI) definition, all-cause re-hospitalisation, or all cause mortality. (NCT01663987)
Timeframe: From first drug administration to the last timepoint with information of clinical adverse outcome available, up to 2 years
| Intervention | Percentage of participants (Number) |
|---|---|
| Placebo | 59.0 |
| Tiotropium Bromide (18μg) | 60.0 |
"Percentage of patients with all-cause hospitalization outcome event occured during the study was analysed for the combined study.~All-cause hospitalization included all hospitalizations, except planned hospitalizations for elective procedures. Hospitalizations occurring on the same day as discharge were not considered a separate admission.~This endpoint was analysed using combined data, as specified in the analysis plan." (NCT01663987)
Timeframe: from first drug administration to the last timepoint with information of clinical adverse outcome available, Up to 2 years
| Intervention | Percentage of participants (Number) |
|---|---|
| Placebo | 26.9 |
| Tiotropium Bromide (18μg) | 26.6 |
Trough Forced Vital Capacity (FVC) response at 12 weeks- defined as change from baseline. (NCT01694771)
Timeframe: baseline and 12 weeks
| Intervention | L (Least Squares Mean) |
|---|---|
| Olodaterol (5µg) and Tiotropium (18µg) | 0.276 |
| Placebo and Tiotropium (18µg) | 0.213 |
Peak FVC response at 12 weeks - defined as change from baseline. (NCT01694771)
Timeframe: baseline and 12 weeks
| Intervention | L (Least Squares Mean) |
|---|---|
| Olodaterol (5µg) and Tiotropium (18µg) | 0.586 |
| Placebo and Tiotropium (18µg) | 0.433 |
Peak FEV1 (Forced Expiratory Volume in 1 second) response at 12 Weeks - defined as changes from baseline (NCT01694771)
Timeframe: baseline and 12 weeks
| Intervention | L (Least Squares Mean) |
|---|---|
| Olodaterol (5µg) and Tiotropium (18µg) | 0.389 |
| Placebo and Tiotropium (18µg) | 0.270 |
Forced Vital Capacity (FVC) AUC0-3h response at 12 weeks - defined as change from baseline. (NCT01694771)
Timeframe: baseline and 12 weeks
| Intervention | L (Least Squares Mean) |
|---|---|
| Olodaterol (5µg) and Tiotropium (18µg) | 0.438 |
| Placebo and Tiotropium (18µg) | 0.292 |
FEV1 (Forced expiratory volume in 1 second) AUC0-3h (area under the curve) response at 12 weeks; defined as change from baseline to Week 12 (NCT01694771)
Timeframe: baseline and 12 weeks
| Intervention | Area Under the Curve (L) (Least Squares Mean) |
|---|---|
| Olodaterol (5µg) and Tiotropium (18µg) | 0.313 |
| Placebo and Tiotropium (18µg) | 0.196 |
Trough FEV1 (Forced expiratory volume in 1 second) response at 12 weeks; defined as change from baseline to Week 12 (NCT01694771)
Timeframe: baseline and 12 weeks
| Intervention | L (Least Squares Mean) |
|---|---|
| Olodaterol (5µg) and Tiotropium (18µg) | 0.195 |
| Placebo and Tiotropium (18µg) | 0.133 |
Rescue medication usage - the percentage of rescue free days. The percentage of rescue free days is defined as: number of rescue free days divided by total exposure, multiplied by 100%. The baseline for the number of rescue-free days was defined as the number of rescue-free days observed during the last week of the baseline period (i.e., the 7 days prior to administration of the first dose of randomized treatment). (NCT01694771)
Timeframe: over 12 weeks
| Intervention | percentage of days (Least Squares Mean) | |||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Week 1 | Week 2 | Week 3 | Week 4 | Week 5 | Week 6 | Week 7 | Week 8 | Week 9 | Week 10 | Week 11 | Week 12 | |
| Olodaterol (5µg) and Tiotropium (18µg) | 52.633 | 54.915 | 56.562 | 60.580 | 60.405 | 57.782 | 58.642 | 58.931 | 59.350 | 59.991 | 59.543 | 63.353 |
| Placebo and Tiotropium (18µg) | 48.606 | 50.774 | 50.262 | 55.577 | 52.614 | 50.547 | 50.727 | 51.618 | 51.399 | 52.535 | 50.584 | 54.894 |
Rescue medication usage - mean weekly rescue usage (total daily). The baseline for the rescue use was the mean of the observations during the last week of the baseline period. Administration of rescue medication could occur at any point during the trial as deemed necessary by the patient or the investigator. Open label albuterol MDI (100 μg per puff) was provided as rescue medication . Daily, between clinic visits, patients recorded the number of puffs of albuterol in a paper diary. (NCT01694771)
Timeframe: over 12 weeks
| Intervention | usage (total daily) number of puffs (Least Squares Mean) | |||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Week 1 | Week 2 | Week 3 | Week 4 | Week 5 | Week 6 | Week 7 | Week 8 | Week 9 | Week 10 | Week 11 | Week 12 | |
| Olodaterol (5µg) and Tiotropium (18µg) | 1.760 | 1.747 | 1.699 | 1.730 | 1.609 | 1.682 | 1.657 | 1.613 | 1.622 | 1.571 | 1.533 | 1.520 |
| Placebo and Tiotropium (18µg) | 2.028 | 2.073 | 2.094 | 2.057 | 2.037 | 2.047 | 2.053 | 2.042 | 2.056 | 2.050 | 2.020 | 1.998 |
Rescue medication usage - Mean weekly rescue usage during nighttime hours. Administration of rescue medication could occur at any point during the trial as deemed necessary by the patient or the investigator. Open label albuterol MDI (100 μg per puff) was provided as rescue medication by BI, and only the albuterol MDI provided by BI was allowed for rescue medication use. Daily, between clinic visits, patients recorded the number of puffs of albuterol in a paper diary. (NCT01694771)
Timeframe: over 12 weeks
| Intervention | percentage of days (Least Squares Mean) | |||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Week 1 | Week 2 | Week 3 | Week 4 | Week 5 | Week 6 | Week 7 | Week 8 | Week 9 | Week 10 | Week 11 | Week 12 | |
| Olodaterol (5µg) and Tiotropium (18µg) | 1.370 | 1.336 | 1.309 | 1.340 | 1.230 | 1.285 | 1.265 | 1.237 | 1.597 | 1.186 | 1.177 | 1.178 |
| Placebo and Tiotropium (18µg) | 1.617 | 1.620 | 1.654 | 1.640 | 1.581 | 1.596 | 1.600 | 1.587 | 1.225 | 1.600 | 1.581 | 1.571 |
Rescue medication usage - Mean weekly rescue usage during daytime hours. Administration of rescue medication could occur at any point during the trial as deemed necessary by the patient or the investigator. Open label albuterol MDI (100 μg per puff) was provided as rescue medication by BI, and only the albuterol MDI provided by BI was allowed for rescue medication use. Daily, between clinic visits, patients recorded the number of puffs of albuterol in a paper diary. (NCT01694771)
Timeframe: over 12 weeks
| Intervention | percentage of days (Least Squares Mean) | |||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Week 1 | Week 2 | Week 3 | Week 4 | Week 5 | Week 6 | Week 7 | Week 8 | Week 9 | Week 10 | Week 11 | Week 12 | |
| Olodaterol (5µg) and Tiotropium (18µg) | 0.392 | 0.415 | 0.394 | 0.393 | 0.383 | 0.404 | 0.402 | 0.385 | 0.404 | 0.390 | 0.360 | 0.346 |
| Placebo and Tiotropium (18µg) | 0.409 | 0.449 | 0.437 | 0.416 | 0.454 | 0.447 | 0.455 | 0.451 | 0.457 | 0.448 | 0.441 | 0.429 |
Peak FEV1 (Forced Expiratory Volume in 1 second) response at 12 Weeks - defined as change from baseline. All p-values for these measures are only descriptive. (NCT01696058)
Timeframe: baseline and 12 weeks
| Intervention | L (Least Squares Mean) |
|---|---|
| Olodaterol (5μg) and Tiotropium (18μg) | 0.371 |
| Placebo and Tiotropium (18μg) | 0.271 |
Peak FVC response at 12 weeks - defined as change from baseline. (NCT01696058)
Timeframe: baseline and 12 weeks
| Intervention | L (Least Squares Mean) |
|---|---|
| Olodaterol (5μg) and Tiotropium (18μg) | 0.562 |
| Placebo and Tiotropium (18μg) | 0.457 |
The Saint George Respiratory Questionnaire (SGRQ) is designed to measure health impairment in patients with asthma and chronic obstructive pulmonary disease (COPD). It is divided into two parts. Part I produces the Symptoms score (several scales), and Part II the Activity and Impacts scores [dichotomous (true/false) except last question (4-point Likert scale)]. A Total score is also produced with scores ranging from 0 to 100, with higher scores indicating more limitations. Since the SGRQ analysis is based on the combined data from both this study and protocol 1222.51 (NCT01694771), only combined SGRQ results will be included in the latest clinical trial report. Hence there will only be one SGRQ analysis from both studies, which will not appear in the first clinical trial report. For this same reason, another covariate - study - will also be included in the MMRM for SGRQ analysis. The combined data for this outcome measure was pre-specified in both protocols. (NCT01696058)
Timeframe: 12 weeks
| Intervention | units on a scale (total score) (Least Squares Mean) |
|---|---|
| Olodaterol (5μg) and Tiotropium (18μg) | 41.204 |
| Placebo and Tiotropium (18μg) | 43.059 |
Trough FEV1 (Forced expiratory volume in 1 second) response at 12 weeks; defined as change from baseline to Week 12 (NCT01696058)
Timeframe: baseline and 12 weeks
| Intervention | L (Least Squares Mean) |
|---|---|
| Olodaterol (5μg) and Tiotropium (18μg) | 0.175 |
| Placebo and Tiotropium (18μg) | 0.135 |
FEV1 (Forced expiratory volume in 1 second) AUC0-3h (area under the curve) response at 12 weeks; defined as change from baseline to Week 12. AUC was standardized by dividing by time unit. (NCT01696058)
Timeframe: baseline and 12 weeks
| Intervention | Area Under the Curve (L) (standardized) (Least Squares Mean) |
|---|---|
| Olodaterol (5μg) and Tiotropium (18μg) | 0.297 |
| Placebo and Tiotropium (18μg) | 0.191 |
Forced Vital Capacity (FVC) AUC0-3h response at 12 weeks - defined as change from baseline. AUC was standardized by dividing by time unit. (NCT01696058)
Timeframe: baseline and 12 Weeks
| Intervention | L (Least Squares Mean) |
|---|---|
| Olodaterol (5μg) and Tiotropium (18μg) | 0.424 |
| Placebo and Tiotropium (18μg) | 0.306 |
"Rescue medication usage - the percentage of rescue free days. The percentage of rescue free days is defined as: number of rescue free days divided by total exposure, multiplied by 100%. The baseline for the number of rescue-free days was defined as the number of rescue-free days observed during the last week of the baseline period (i.e., the 7 days prior to administration of the first dose of randomized treatment).~Results are from non-MMRM ANCOVA models by week with LOCF up to each week. Fixed effects include treatment and baseline.~Number of patients contributing to models: Tio+Placebo (559), Tio+Olo 5ug (552)" (NCT01696058)
Timeframe: over 12 weeks
| Intervention | percentage of days (Least Squares Mean) | |||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Week 1 | Week 2 | Week 3 | Week 4 | Week 5 | Week 6 | Week 7 | Week 8 | Week 9 | Week 10 | Week 11 | Week 12 | |
| Olodaterol (5μg) and Tiotropium (18μg) | 53.207 | 54.249 | 54.820 | 60.761 | 60.154 | 59.707 | 59.493 | 59.021 | 60.524 | 60.216 | 59.650 | 62.327 |
| Placebo and Tiotropium (18μg) | 48.583 | 48.640 | 49.865 | 55.969 | 51.840 | 49.001 | 50.164 | 51.017 | 51.273 | 51.634 | 51.604 | 55.090 |
Trough Forced Vital Capacity (FVC) response at 12 weeks- defined as change from baseline. (NCT01696058)
Timeframe: baseline and 12 weeks
| Intervention | L (Least Squares Mean) |
|---|---|
| Olodaterol (5μg) and Tiotropium (18μg) | 0.269 |
| Placebo and Tiotropium (18μg) | 0.235 |
"Rescue medication usage - Mean weekly rescue usage during daytime hours. Administration of rescue medication could occur at any point during the trial as deemed necessary by the patient or the investigator. Open label albuterol MDI (100 μg per puff) was provided as rescue medication by BI, and only the albuterol MDI provided by BI was allowed for rescue medication use. Daily, between clinic visits, patients recorded the number of puffs of albuterol in a paper diary.~Results are from non-MMRM ANCOVA models by week with LOCF up to each week. Fixed effects include treatment and baseline.~Number of patients contributing to models: Tio+Placebo (559), Tio+Olo 5ug (555)" (NCT01696058)
Timeframe: over 12 weeks
| Intervention | number of puffs (Least Squares Mean) | |||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Week 1 | Week 2 | Week 3 | Week 4 | Week 5 | Week 6 | Week 7 | Week 8 | Week 9 | Week 10 | Week 11 | Week 12 | |
| Olodaterol (5μg) and Tiotropium (18μg) | 0.406 | 0.421 | 0.407 | 0.408 | 0.375 | 0.378 | 0.403 | 0.417 | 0.396 | 0.392 | 0.383 | 0.393 |
| Placebo and Tiotropium (18μg) | 0.437 | 0.466 | 0.459 | 0.479 | 0.479 | 0.491 | 0.499 | 0.482 | 0.487 | 0.480 | 0.482 | 0.483 |
"Rescue medication usage - Mean weekly rescue usage during nighttime hours. Administration of rescue medication could occur at any point during the trial as deemed necessary by the patient or the investigator. Open label albuterol MDI (100 μg per puff) was provided as rescue medication by BI, and only the albuterol MDI provided by BI was allowed for rescue medication use. Daily, between clinic visits, patients recorded the number of puffs of albuterol in a paper diary.~Results are from non-MMRM ANCOVA models by week with LOCF up to each week. Fixed effects include treatment and baseline.~Number of patients contributing to models: Tio+Placebo (559), Tio+Olo 5ug (555)" (NCT01696058)
Timeframe: over 12 weeks
| Intervention | number of puffs (Least Squares Mean) | |||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Week 1 | Week 2 | Week 3 | Week 4 | Week 5 | Week 6 | Week 7 | Week 8 | Week 9 | Week 10 | Week 11 | Week 12 | |
| Olodaterol (5μg) and Tiotropium (18μg) | 1.222 | 1.232 | 1.229 | 1.239 | 1.177 | 1.148 | 1.139 | 1.173 | 1.125 | 1.108 | 1.104 | 1.143 |
| Placebo and Tiotropium (18μg) | 1.633 | 1.677 | 1.707 | 1.709 | 1.710 | 1.692 | 1.641 | 1.628 | 1.636 | 1.630 | 1.630 | 1.625 |
"Rescue medication usage - mean weekly rescue usage (total daily). The baseline for the rescue use was the mean of the observations during the last week of the baseline period. Administration of rescue medication could occur at any point during the trial as deemed necessary by the patient or the investigator. Open label albuterol metered dose inhaler (MDI) (100 μg per puff) was provided as rescue medication . Daily, between clinic visits, patients recorded the number of puffs of albuterol in a paper diary.~Results are from non-MMRM ANCOVA models by week with LOCF up to each week. Fixed effects include treatment and baseline.~Number of patients contributing to models: Tio+Placebo (559), Tio+Olo 5ug (555)" (NCT01696058)
Timeframe: over 12 weeks
| Intervention | usage (total daily) number of puffs (Least Squares Mean) | |||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Week 1 | Week 2 | Week 3 | Week 4 | Week 5 | Week 6 | Week 7 | Week 8 | Week 9 | Week 10 | Week 11 | Week 12 | |
| Olodaterol (5μg) and Tiotropium (18μg) | 1.627 | 1.652 | 1.635 | 1.647 | 1.551 | 1.523 | 1.540 | 1.586 | 1.519 | 1.499 | 1.484 | 1.535 |
| Placebo and Tiotropium (18μg) | 2.072 | 2.145 | 2.167 | 2.189 | 2.183 | 2.179 | 2.138 | 2.107 | 2.121 | 2.103 | 2.107 | 2.103 |
"Mixed Model Repeated Measure (MMRM) results. Response was defined as change from baseline. Means are adjusted for treatment, period, patient and study baseline.Measured following the respective dosing determined at the end of each 4 week period of randomised treatment. AUC0-24h calculated using the trapezoidal rule divided by the observation time (24 hours) to report in litres.~The values recorded at 11 hours 50 minutes and at 23 hours 50 minutes post dosing were assigned to 12 and 24 hours, respectively." (NCT01696071)
Timeframe: Baseline FEV1 taken at visit 2 prior to the first evening dose of randomised study medication. Then, 10 minutes (min) prior to dose to 30 min,1 hour (h),2h,3h,4h,11h50min,12h30min,13h,14h,15h,16h,18h,20h,22h and 23h,23h50min relative to dose after 4 weeks
| Intervention | Liters (Least Squares Mean) |
|---|---|
| Tio R2.5 BID | 0.219 |
| Tio R5 QD | 0.217 |
MMRM results. Response was defined as change from baseline. Means are adjusted for treatment, period, patient and study baseline. Measured following the respective dosing determined at the end of each 4 week period of randomised treatment. AUC0-12h calculated using the trapezoidal rule divided by the observation time (12 hours) to report in litres. (NCT01696071)
Timeframe: Baseline FEV1 taken at visit 2 prior to the first evening dose of randomised study medication. Then, 10 minutes(min) prior to dose to 30min,1hour(h),2h,3h,4h,11h50min,12h30min,13h,14h,15h,16h,18h,20h,22h and 23h,23h50min relative to dose after 4 weeks
| Intervention | Litres (Least Squares Mean) |
|---|---|
| Tio R2.5 BID | 0.182 |
| Tio R5 QD | 0.192 |
MMRM results. Response was defined as change from baseline. Means are adjusted for treatment, period, patient and study baseline. Measured following the respective dosing determined at the end of each 4 week period of randomised treatment. AUC12 -24h calculated using the trapezoidal rule divided by the observation time (12 hours) to report in litres. (NCT01696071)
Timeframe: Baseline FEV1 taken at visit 2 prior to the first evening dose of randomised study medication. Then, 10 minutes(min) prior to dose to 30min,1hour(h),2h,3h,4h,11h50min,12h30min,13h,14h,15h,16h,18h,20h,22h and 23h,23h50min relative to dose after 4 weeks
| Intervention | Litres (Least Squares Mean) |
|---|---|
| Tio R2.5 BID | 0.256 |
| Tio R5 QD | 0.243 |
"MMRM results. Response was defined as change from baseline. Means are adjusted for treatment, period, patient and study baseline.Measured following the respective dosing determined at the end of each 4 week period of randomised treatment. AUC0-24h calculated using the trapezoidal rule divided by the observation time (24 hours) to report in litres.~The values recorded at 11 hours 50 minutes and at 23 hours 50 minutes post dosing were assigned to 12 and 24 hours, respectively." (NCT01696071)
Timeframe: Baseline taken at visit 2 prior to the first evening dose of randomised study medication. Then, 10 minutes(min) prior to dose to 30min,1hour(h),2h,3h,4h,11h50min,12h30min,13h,14h,15h,16h,18h,20h,22h and 23h,23h50min relative to dose after 4 weeks
| Intervention | Litres (Least Squares Mean) |
|---|---|
| Tio R2.5 BID | 0.079 |
| Tio R5 QD | 0.075 |
MMRM results. Response was defined as change from baseline. Means are adjusted for treatment, period, patient and study baseline. Measured following the respective dosing determined at the end of each 4 week period of randomised treatment. AUC0-12h calculated using the trapezoidal rule divided by the observation time (12 hours) to report in litres. (NCT01696071)
Timeframe: Baseline taken at visit 2 prior to the first evening dose of randomised study medication. Then, 10 minutes(min) prior to dose to 30min,1hour(h),2h,3h,4h,11h50min,12h30min,13h,14h,15h,16h,18h,20h,22h and 23h,23h50min relative to dose after 4 weeks
| Intervention | Litres (Least Squares Mean) |
|---|---|
| Tio R2.5 BID | 0.056 |
| Tio R5 QD | 0.053 |
MMRM results. Response was defined as change from baseline. Means are adjusted for treatment, period, patient and study baseline.Measured following the respective dosing determined at the end of each 4 week period of randomised treatment. AUC12 -24h calculated using the trapezoidal rule divided by the observation time (12 hours) to report in litres. (NCT01696071)
Timeframe: Baseline taken at visit 2 prior to the first evening dose of randomised study medication. Then, 10 minutes(min) prior to dose to 30min,1hour(h),2h,3h,4h,11h50min,12h30min,13h,14h,15h,16h,18h,20h,22h and 23h,23h50min relative to dose after 4 weeks
| Intervention | Litres (Least Squares Mean) |
|---|---|
| Tio R2.5 BID | 0.102 |
| Tio R5 QD | 0.096 |
MMRM results. Response was defined as change from baseline. Means are adjusted for treatment, period, patient and study baseline.Measured following the respective dosing determined at the end of each 4 week period of randomised treatment. AUC0-24h calculated using the trapezoidal rule divided by the observation time (24 hours) to report in litres per minute. (NCT01696071)
Timeframe: Baseline taken at visit 2 prior to the first evening dose of randomised study medication. Then, 10 minutes(min) prior to dose to 30min,1hour(h),2h,3h,4h,11h50min,12h30min,13h,14h,15h,16h,18h,20h,22h and 23h,23h50min relative to dose after 4 weeks
| Intervention | Litres/min (Least Squares Mean) |
|---|---|
| Tio R2.5 BID | 42.788 |
| Tio R5 QD | 41.399 |
MMRM results. Response was defined as change from baseline. Means are adjusted for treatment, period, patient and study baseline.Measured following the respective dosing determined at the end of each 4 week period of randomised treatment. Peak FEV1 was defined as the highest FEV1 reading observed within the 24 hour period following inhalation of the last evening dose of study medication (FEV1 Peak0-24h). The values recorded at 11 hours 50 minutes and at 23 hours 50 minutes post dosing were assigned to 12 and 24 hours, respectively. (NCT01696071)
Timeframe: 10 minutes (min) prior to dose to 30 min,1 hour (h),2h,3h,4h,11h50min,12h30min,13h,14h,15h,16h,18h,20h,22h and 23h,23h50min relative to dose after 4 weeks.
| Intervention | Litres (Least Squares Mean) |
|---|---|
| Tio R2.5 BID | 0.465 |
| Tio R5 QD | 0.451 |
MMRM results. Response was defined as change from baseline. Means are adjusted for treatment, period, patient and study baseline.Measured following the respective dosing determined at the end of each 4 week period of randomised treatment. Peak FVC was defined as the highest FVC reading observed within the 24 hour period following inhalation of the last evening dose of study medication (FVC Peak0-24h). (NCT01696071)
Timeframe: Baseline taken at visit 2 prior to the first evening dose of randomised study medication. Then, 10 minutes(min) prior to dose to 30min,1hour(h),2h,3h,4h,11h50min,12h30min,13h,14h,15h,16h,18h,20h,22h and 23h,23h50min relative to dose after 4 weeks
| Intervention | Litres (Least Squares Mean) |
|---|---|
| Tio R2.5 BID | 0.328 |
| Tio R5 QD | 0.309 |
MMRM results. Response was defined as change from baseline. Means are adjusted for treatment, period, patient and study baseline.Measured following the respective dosing determined at the end of each 4 week period of randomised treatment. Trough FEV1 was defined as the FEV1 value just prior to the last evening dose of study medication. (NCT01696071)
Timeframe: 10 minutes (min) prior to dose after 4 weeks
| Intervention | Litres (Least Squares Mean) |
|---|---|
| Tio R2.5 BID | 0.203 |
| Tio R5 QD | 0.207 |
MMRM results. Response was defined as change from baseline. Means are adjusted for treatment, period, patient and study baseline.Measured following the respective dosing determined at the end of each 4 week period of randomised treatment. Trough FVC was defined as the FVC value just prior to the last evening dose of study medication. (NCT01696071)
Timeframe: Baseline taken at visit 2 prior to the first evening dose of randomised study medication. Then, 10 minutes(min) prior to dose after 4 weeks
| Intervention | Litres (Least Squares Mean) |
|---|---|
| Tio R2.5 BID | 0.077 |
| Tio R5 QD | 0.118 |
"Outcome data show are the number of participants with clinically relevant abnormalities reported as an adverse event (AE) related to the vital signs (pulse rate and blood pressure in supine position), clinical laboratory (routine blood chemistry, haematology, and urinalysis) tests and ECG (12-lead holter monitoring Electrocardiography). Relevant findings or worsening of baseline conditions were reported as adverse events.~There were no clinically relevant abnormalities reported as an AE related to the vital signs and ECG." (NCT01703845)
Timeframe: up to 6 weeks (3 weeks treatment and 3 weeks follow-up) post dose
| Intervention | participants (Number) | ||||
|---|---|---|---|---|---|
| AEs reported related to vital signs | AEs reported related to ECG | Haematuria | Blood creatine phosphokinase increased | Blood urine present | |
| Tiotropium + Olodaterol (2.5µg/5µg) | 0 | 0 | 1 | 0 | 0 |
| Tiotropium + Olodaterol (5µg/5µg) | 0 | 0 | 0 | 1 | 1 |
"Fraction eliminated in urine from the time point t1 (0 h) to time point t2 (4 h) at steady state (fet1-t2,ss).~Per Protocol there are no primary endpoints defined. Therefore this pharmacokinetic endpoint was selected for primary outcome measure type." (NCT01703845)
Timeframe: from 0 to 4 hours following drug administration on day 21
| Intervention | percentage of dose (Geometric Mean) |
|---|---|
| Tiotropium + Olodaterol (5µg/5µg) | 6.72 |
| Tiotropium + Olodaterol (2.5µg/5µg) | 4.89 |
"Amount of olodaterol that is eliminated in urine after multiple inhaled administration of tiotropium+olodaterol over the time interval 0 to 4 hours at steady state (Aet1-t2,ss).~Per Protocol there are no primary endpoints defined. Therefore this pharmacokinetic endpoint was selected for primary outcome measure type." (NCT01703845)
Timeframe: from 0 to 4 hours following drug administration on day 21
| Intervention | nanogram (ng) (Geometric Mean) |
|---|---|
| Tiotropium + Olodaterol (5µg/5µg) | 74.8 |
| Tiotropium + Olodaterol (2.5µg/5µg) | 50.0 |
"Amount of tiotropium that is eliminated in urine after multiple inhaled administration of tiotropium+olodaterol over the time interval 0 to 4 hours at steady state (Aet1-t2,ss).~Per Protocol there are no primary endpoints defined. Therefore this pharmacokinetic endpoint was selected for primary outcome measure type." (NCT01703845)
Timeframe: from 0 to 4 hours following drug administration on day 21
| Intervention | nanogram (ng) (Geometric Mean) |
|---|---|
| Tiotropium + Olodaterol (5µg/5µg) | 336 |
| Tiotropium + Olodaterol (2.5µg/5µg) | 122 |
"Area under the concentration-time curve of olodaterol after multiple inhaled administration of tiotropium+olodaterol in plasma over the time interval from 0 to the time of the last quantifiable data point at steady state (AUC0-tz,ss).~Per Protocol there are no primary endpoints defined. Therefore this pharmacokinetic endpoint was selected for primary outcome measure type." (NCT01703845)
Timeframe: 15 min pre-dose and 5, 10, 20, 40 min, 1, 2, 3, and 4 h following drug administration on day 21
| Intervention | pg*h/mL (Geometric Mean) |
|---|---|
| Tiotropium + Olodaterol (5µg/5µg) | 9.94 |
| Tiotropium + Olodaterol (2.5µg/5µg) | 6.85 |
"Area under the concentration-time curve of tiotropium after multiple inhaled administration of tiotropium+olodaterol in plasma over the time interval from 0 to the time of the last quantifiable data point at steady state (AUC0-tz,ss).~Per Protocol there are no primary endpoints defined. Therefore this pharmacokinetic endpoint was selected for primary outcome measure type." (NCT01703845)
Timeframe: 15 min pre-dose and 5, 10, 20, 40 min, 1, 2, 3, and 4 h following drug administration on day 21
| Intervention | pg*h/mL (Geometric Mean) |
|---|---|
| Tiotropium + Olodaterol (5µg/5µg) | 23.3 |
| Tiotropium + Olodaterol (2.5µg/5µg) | 7.99 |
"Area under the concentration-time curve of olodaterol in plasma after multiple inhaled administration of tiotropium+olodaterol over the time interval 0 to 4 hours at steady state (AUCt1-t2,ss).~Per Protocol there are no primary endpoints defined. Therefore this pharmacokinetic endpoint was selected for primary outcome measure type." (NCT01703845)
Timeframe: 15 min pre-dose and 5, 10, 20, 40 min, 1, 2, 3, and 4 h following drug administration on day 21
| Intervention | pg*h/mL (Geometric Mean) |
|---|---|
| Tiotropium + Olodaterol (5µg/5µg) | 9.94 |
| Tiotropium + Olodaterol (2.5µg/5µg) | 8.14 |
"Area under the concentration-time curve of tiotropium in plasma after multiple inhaled administration of tiotropium+olodaterol over the time interval 0 to 2 hours at steady state (AUCt1-t2,ss).~Per Protocol there are no primary endpoints defined. Therefore this pharmacokinetic endpoint was selected for primary outcome measure type." (NCT01703845)
Timeframe: 15 min pre-dose and 5, 10, 20, 40 min, 1 and 2 h following drug administration on day 21
| Intervention | pg*h/mL (Geometric Mean) |
|---|---|
| Tiotropium + Olodaterol (5µg/5µg) | 14.8 |
| Tiotropium + Olodaterol (2.5µg/5µg) | 7.00 |
"Renal clearance from the time point t1 (0 h) until the time point t2 (4 h) at steady state (CLR,t1-t2,ss).~Per Protocol there are no primary endpoints defined. Therefore this pharmacokinetic endpoint was selected for primary outcome measure type." (NCT01703845)
Timeframe: from 0 to 4 hours following drug administration on day 21
| Intervention | mL/min (Geometric Mean) |
|---|---|
| Tiotropium + Olodaterol (5µg/5µg) | 152 |
| Tiotropium + Olodaterol (2.5µg/5µg) | 148 |
"Renal clearance from the time point t1 (0 h) until the time point t2 (4 h) at steady state (CLR,t1-t2,ss).~Per Protocol there are no primary endpoints defined. Therefore this pharmacokinetic endpoint was selected for primary outcome measure type.~Plasma concentration of tiotropium could not be quantified up to 4 hours for Tiotropium + Olodaterol (2.5μg/5μg)." (NCT01703845)
Timeframe: from 0 to 4 hours following drug administration on day 21
| Intervention | mL/min (Geometric Mean) |
|---|---|
| Tiotropium + Olodaterol (5µg/5µg) | 292 |
"Maximum measured concentration of olodaterol after multiple inhaled administration of tiotropium+olodaterol in plasma at steady state (Cmax,ss).~Per Protocol there are no primary endpoints defined. Therefore this pharmacokinetic endpoint was selected for primary outcome measure type." (NCT01703845)
Timeframe: 15 minutes (min) pre-dose and 5, 10, 20, 40 min, 1, 2, 3, and 4 hours (h) following drug administration on day 21
| Intervention | picogram/milliliter (pg/mL) (Geometric Mean) |
|---|---|
| Tiotropium + Olodaterol (5µg/5µg) | 4.33 |
| Tiotropium + Olodaterol (2.5µg/5µg) | 2.82 |
"Maximum measured concentration of tiotropium after multiple inhaled administration of tiotropium+olodaterol in plasma at steady state (Cmax,ss).~Per Protocol there are no primary endpoints defined. Therefore this pharmacokinetic endpoint was selected for primary outcome measure type." (NCT01703845)
Timeframe: 15 minutes (min) pre-dose and 5, 10, 20, 40 min, 1, 2, 3, and 4 hours (h) following drug administration on day 21
| Intervention | picogram/milliliter (pg/mL) (Geometric Mean) |
|---|---|
| Tiotropium + Olodaterol (5µg/5µg) | 16.5 |
| Tiotropium + Olodaterol (2.5µg/5µg) | 6.49 |
"Fraction eliminated in urine from the time point t1 (0 h) to time point t2 (4 h) at steady state (fet1-t2,ss).~Per Protocol there are no primary endpoints defined. Therefore this pharmacokinetic endpoint was selected for primary outcome measure type." (NCT01703845)
Timeframe: from 0 to 4 hours following drug administration on day 21
| Intervention | percentage of dose (Geometric Mean) |
|---|---|
| Tiotropium + Olodaterol (5µg/5µg) | 1.50 |
| Tiotropium + Olodaterol (2.5µg/5µg) | 0.999 |
Outcome data show are the number of patients with an adverse event including the assessment based on physical examination. (NCT01703845)
Timeframe: up to 6 weeks (3 weeks treatment and 3 weeks follow-up) post dose
| Intervention | participants (Number) |
|---|---|
| Tiotropium + Olodaterol (5µg/5µg) | 4 |
| Tiotropium + Olodaterol (2.5µg/5µg) | 2 |
"Time from dosing to the maximum concentration of Olodaterol after multiple inhaled administration of tiotropium+olodaterol in plasma at steady state (tmax,ss).~Per Protocol there are no primary endpoints defined. Therefore this pharmacokinetic endpoint was selected for primary outcome measure type." (NCT01703845)
Timeframe: 15 min pre-dose and 5, 10, 20, 40 min, 1, 2, 3 and 4 hours (h) following drug administration on day 21
| Intervention | h (Median) |
|---|---|
| Tiotropium + Olodaterol (5µg/5µg) | 0.183 |
| Tiotropium + Olodaterol (2.5µg/5µg) | 0.217 |
"Time from dosing to the maximum concentration of tiotropium after multiple inhaled administration of tiotropium+olodaterol in plasma at steady state (tmax,ss).~Per Protocol there are no primary endpoints defined. Therefore this pharmacokinetic endpoint was selected for primary outcome measure type." (NCT01703845)
Timeframe: 15 min pre-dose and 5, 10, 20, 40 min, 1, 2, 3, 4 hours following drug administration on day 21
| Intervention | h (Median) |
|---|---|
| Tiotropium + Olodaterol (5µg/5µg) | 0.100 |
| Tiotropium + Olodaterol (2.5µg/5µg) | 0.100 |
Participants used a patient diary to report difficulties with handling the device. Thirteen difficulty categories were assessed. (NCT01727024)
Timeframe: 1 week
| Intervention | Participants (Number) | ||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Sometime vibration of drug was not heard | Anxiety | Placing capsule and inhaling drug | Capsule sticks to contact when hand is wet/moist | Requiring aspiration of drug more than once | Difficulty turning the device | Difficulty emptying the capsule in 1 aspiration | Difficulty using the device | Unable to place the capsule in the device | Patient reported to be unable to place the capsule | More difficulty handling this device than previous | Unpractical | Felt that capsule was out of place | |
| Indacaterol (QAB149) Breezhaler® | 1 | 0 | 1 | 1 | 1 | 0 | 1 | 0 | 1 | 0 | 0 | 0 | 1 |
| Tiotropium Respimat® | 0 | 1 | 0 | 0 | 0 | 1 | 0 | 1 | 0 | 1 | 1 | 1 | 0 |
The correct use of 2 drug delivery systems was measured. Participants were given written instructions prior to the first treatment at day one and a check list was used to report the proper handling of the devices. (NCT01727024)
Timeframe: day 7
| Intervention | Participants (Number) |
|---|---|
| Indacaterol (QAB149) Breezhaler® | 93 |
| Tiotropium Respimat® | 81 |
"Participants completed the FSI-10 questionnaire to assess their satisfaction with the devices.~The questionnaire contained 10 questions. each one with 5 possible answers in a Likert scale from 5 (a lot) to 1 (almost nothing). The total overall satisfaction score ranged from 0 - 50. Higher values indicated greater satisfaction" (NCT01727024)
Timeframe: day 7
| Intervention | score on a scale (Mean) |
|---|---|
| Indacaterol (QAB149) Breezhaler® | 46.0 |
| Tiotropium Respimat® | 44.4 |
Participants answered a single question to determine their device preference. (NCT01727024)
Timeframe: day 7
| Intervention | Participants (Number) | ||
|---|---|---|---|
| Breezhaler® | Respimat® | Indifferent | |
| Indacaterol (QAB149) Breezhaler® | 76 | 40 | 17 |
The correct use of 2 drug delivery systems was measured. Participants were given written instructions prior to the first treatment at day one and a check list was used to report the proper handling of the devices. (NCT01727024)
Timeframe: day 1
| Intervention | Participants (Number) |
|---|---|
| Indacaterol (QAB149) Breezhaler® | 55 |
| Tiotropium Respimat® | 49 |
sGaw is a measure of airways conductance and is intimately related to the diameter of the airways and consequently the level of bronchodilation. Plethysmography was performed to assess sGaw. The AUC was determined by using the trapezoidal rule and then dividing by the relevant time interval. A natural logarithmic transformation was applied and the data was analyzed by a mixed model including treatment, period and Baseline sGaw fitted as fixed effects and participants fitted as a random effect. Treatment ratios of all statistical comparisons were calculated by taking the anti-log of the difference between the Least Square (LS) means. (NCT01751113)
Timeframe: Day 28 of each treatment period (up to 35 days)
| Intervention | 1/kilopascal*second (1/kPa*s) (Geometric Mean) |
|---|---|
| Ado 50/250 µg BID+Tio 18 µg QD | 0.854 |
| Tio 18 µg QD | 0.737 |
| Ado 50/250 µg BID | 0.663 |
sRaw is a measure of airways resistance and is intimately related to the diameter of the airways and consequently the level of bronchodilation. Trough values were the values taken pre-dose. (NCT01751113)
Timeframe: Day 28 of each treatment period (up to 35 days)
| Intervention | kPa*s (Geometric Mean) |
|---|---|
| Ado 50/250 µg BID+Tio 18 µg QD | 1.391 |
| Tio 18 µg QD | 1.666 |
| Ado 50/250 µg BID | 1.732 |
FEV1 is a measure of lung function and the maximal amount of air that can be forcefully exhaled in one second. FVC is defined as the amount of air that can forcibly be blown out after a full inspiration. FEV1 and FVC data was obtained by spirometry measurements. Trough values were the values taken pre-dose. (NCT01751113)
Timeframe: Day 28 of each treatment period (up to 35 days)
| Intervention | Ratio of FEV1/FVC (Least Squares Mean) |
|---|---|
| Ado 50/250 µg BID+Tio 18 µg QD | 0.513 |
| Tio 18 µg QD | 0.481 |
| Ado 50/250 µg BID | 0.496 |
FEV1 is a measure of lung function and the maximal amount of air that can be forcefully exhaled in one second. FVC is defined as the amount of air that can forcibly be blown out after a full inspiration. FEV1 and FVC data was obtained by spirometry measurements. (NCT01751113)
Timeframe: Day 28 of each treatment period (up to 35 days)
| Intervention | Ratio of FEV1/FVC (Least Squares Mean) |
|---|---|
| Ado 50/250 µg BID+Tio 18 µg QD | 0.500 |
| Tio 18 µg BID | 0.472 |
| Ado 50/250 µg BID | 0.492 |
sRaw is a measure of airways resistance and is intimately related to the diameter of the airways and consequently the level of bronchodilation. Plethysmography was performed to assess sRaw. The AUC was determined by using the trapezoidal rule and then dividing by the relevant time interval. A natural logarithmic transformation was applied and the data was analyzed by a mixed model including treatment, period and Baseline sRaw fitted as fixed effects and participants fitted as a random effect. Treatment ratios of all statistical comparisons were calculated by taking the anti-log of the difference between the LS means. (NCT01751113)
Timeframe: Day 28 of each treatment period (up to 35 days)
| Intervention | kPa*s (Geometric Mean) |
|---|---|
| Ado 50/250 µg BID+Tio 18 µg QD | 1.181 |
| Tio 18 µg QD | 1.380 |
| Ado 50/250 µg BID | 1.525 |
sGaw is a measure of airways conductance and is intimately related to the diameter of the airways and consequently the level of bronchodilation. Trough values were the values taken pre-dose. (NCT01751113)
Timeframe: Day 28 of each treatment period (up to 35 days)
| Intervention | 1/kPa*s (Geometric Mean) |
|---|---|
| Ado 50/250 µg BID+Tio 18 µg QD | 0.720 |
| Tio 18 µg QD | 0.600 |
| Ado 50/250 µg BID | 0.577 |
Participants were given daily record cards for daily completion during the run-in, washout and treatment periods. Each morning, participants recorded the number of occasions in the last 24 hours when they had used their rescue medication (salbutamol) for symptomatic relief of COPD symptoms. (NCT01751113)
Timeframe: Day 28 of each treatment period (up to 35 days)
| Intervention | Number of occasions (Mean) | |
|---|---|---|
| Treatment, n=20, 18, 17 | Washout, n=15, 15, 11 | |
| Ado 50/250 µg BID | 0.2 | 0.4 |
| Ado 50/250 µg BID+Tio 18 µg QD | 0.2 | 0.4 |
| Tio 18 µg QD | 0.3 | 0.5 |
FEV1 is a measure of lung function and the maximal amount of air that can be forcefully exhaled in one second. FVC is defined as the amount of air that can forcibly be blown out after a full inspiration. FEV1 and FVC data was obtained by spirometry measurements. IC is defined as the maximum amount of air that can be inhaled into the lungs from the normal resting position after breathing out normally. Total lung capacity (TLC) is the maximum volume to which the lungs can be expanded with the greatest possible inspiratory effort; it is equal to the vital capacity (VC) plus the residual volume (RV). RV is defined as the volume of air remaining in the lungs. after a maximal exhalation. Thoracic gas volume at functional residual capacity (TGV) is defined as the volume of intrathoracic gas at the time the airway is occluded for the plethysmographic measurement at the end of a normal expiration. Trough values were the values taken pre-dose. (NCT01751113)
Timeframe: Day 28 of each treatment period (up to 35 days)
| Intervention | Liters (L) (Least Squares Mean) | |||||
|---|---|---|---|---|---|---|
| FEV1 | FVC | IC | RV | TLC | TGV | |
| Ado 50/250 µg BID | 1.706 | 3.439 | 2.395 | 3.123 | 6.525 | 4.129 |
| Ado 50/250 µg BID+Tio 18 µg QD | 1.823 | 3.575 | 2.460 | 3.021 | 6.511 | 4.053 |
| Tio 18 µg QD | 1.666 | 3.493 | 2.406 | 3.129 | 6.524 | 4.118 |
sRaw is a measure of airways resistance and is intimately related to the diameter of the airways and consequently the level of bronchodilation. Plethysmography was performed to assess sRaw. A natural logarithmic transformation was applied and the data was analysed by a mixed model including treatment, time, period, a treatment by time interaction and Baseline sRaw fitted as fixed effects and participant fitted as a random effect. (NCT01751113)
Timeframe: Day 28 of each treatment period (up to 35 days)
| Intervention | kPa*s (Geometric Mean) | |||
|---|---|---|---|---|
| 30 min | 75 min | 120 min | 240 min | |
| Ado 50/250 µg BID | 1.567 | 1.535 | 1.468 | 1.446 |
| Ado 50/250 µg BID+Tio 18 µg QD | 1.201 | 1.146 | 1.129 | 1.170 |
| Tio 18 µg QD | 1.419 | 1.348 | 1.300 | 1.334 |
sGaw is a measure of airways conductance and is intimately related to the diameter of the airways and consequently the level of bronchodilation. Plethysmography was performed to assess sGaws. A natural logarithmic transformation was applied and the data was analyzed by a mixed model including treatment, time, period, a treatment by time interaction and Baseline sGaw fitted as fixed effects and participant fitted as a random effect. (NCT01751113)
Timeframe: Day 28 of each treatment period (up to 35 days)
| Intervention | 1/kPa*s (Geometric Mean) | |||
|---|---|---|---|---|
| 30 min | 75 min | 120 min | 240 min | |
| Ado 50/250 µg BID | 0.639 | 0.652 | 0.680 | 0.690 |
| Ado 50/250 µg BID+Tio 18 µg QD | 0.833 | 0.873 | 0.885 | 0.855 |
| Tio 18 µg QD | 0.705 | 0.743 | 0.769 | 0.750 |
FEV1 is a measure of lung function and the maximal amount of air that can be forcefully exhaled in one second. FVC is defined as the amount of air that can forcibly be blown out after a full inspiration. FEV1 and FVC data was obtained by spirometry measurements. IC is defined as the maximum amount of air that can be inhaled into the lungs from the normal resting position after breathing out normally. Total lung capacity (TLC) is the maximum volume to which the lungs can be expanded with the greatest possible inspiratory effort; it is equal to the vital capacity (VC) plus the RV. RV is defined as the volume of air remaining in the lungs after a maximal exhalation. Thoracic gas volume at functional residual capacity (TGV) is defined as the volume of intrathoracic gas at the time the airway is occluded for the plethysmographic measurement at the end of a normal expiration. (NCT01751113)
Timeframe: Day 28 of each treatment period (up to 35 days)
| Intervention | Liters (L) (Least Squares Mean) | |||||
|---|---|---|---|---|---|---|
| FEV1 | FVC | IC | RV | TLC | TGV | |
| Ado 50/250 µg BID | 1.664 | 3.387 | 2.351 | 3.234 | 6.592 | 4.238 |
| Ado 50/250 µg BID+Tio 18 µg QD | 1.766 | 3.535 | 2.344 | 3.045 | 6.487 | 4.147 |
| Tio 18 µg QD | 1.605 | 3.430 | 2.351 | 3.275 | 6.588 | 4.239 |
The comparison of number of exacerbation between two detection methods EXACT and physician diagnosis: number of exacerbations detected by EXACT and number of exacerbations judged by physician. (NCT01762800)
Timeframe: 24 weeks
| Intervention | Number of exacerbations (Mean) | |
|---|---|---|
| EXACT | Physician's diagnosis | |
| SAL/FLU 50/250 µg BID | 0.7 | 0.1 |
| TIO 18 µg QD | 0.9 | 0.2 |
The randomized treatment could be switched to TRIPLE therapy in the case that chronic obstructive pulmonary disease (COPD) was not controlled by the randomized treatment. Participants on TRIPLE therapy received SAL/FLU 50/250 µg BID plus TIO 18 µg QD together. Continuation TRIPLE proportion is defined as [(number of subjects who switched to TRIPLE) - (number of subjects who stepped down)/ number of evaluable population]*100. Randomised treatment continuation proportion is calculated by a formula: (100 - switch proportion). (NCT01762800)
Timeframe: 24 weeks
| Intervention | Percentage of participants (Number) | |
|---|---|---|
| Randomised treatment | TRIPLE therapy | |
| SAL/FLU 50/250 µg BID | 66.67 | 32.35 |
| TIO 18 µg QD | 62.69 | 36.82 |
The E-RS total score is an 11-item patient questionnaire, which provides information specific to respiratory symptoms-severity of respiratory symptoms overall and severity of breathlessness, cough and sputum, and chest symptoms. The E-RS subscale scores for respiratory symptoms (RS)-breathlessness (RS-BRL), RS-cough and sputum (RS-CSP), and RS-chest symptoms (RS-CSY) are presented. Scores were assessed at Baseline, Week 1-4, Week 5-8, Week 9-12, Week 13-16, Week 17-20 and at Week 21-24. Daily EXACT total score is obtained as total score of 14 items from diary. Daily E-RS total score as 11 items and Daily E-RS subscale scores are subset of E-RS total score. Mean EXACT total score is mean value of daily EXACT total score within subject by every 4 weeks(Week1-4, Week5-8, Week9-12, Week13-16, Week17-20, Week21-24). Same calculation of mean values are applied to E-RS total and E-RS subscale scores. RS total scores range from 0 to 40, high value in score indicate worse outcome. (NCT01762800)
Timeframe: 24 weeks
| Intervention | Scores on a scale (Mean) | ||||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| RS-BRL; Baseline; n=135, 68, 125, 73 | RS-BRL; Week 1-4; n=131, 68, 121, 75 | RS-BRL; Week 5-8; n=126, 68, 115, 73 | RS-BRL; Week 9-12; n=122, 68, 116, 74 | RS-BRL; Week 13-16; n=121, 66, 116, 74 | RS-BRL; Week 17-20; n=118, 66, 114, 72 | RS-BRL; Week 21-24; n=93, 51, 94, 51 | RS-CSP; Baseline; n=135, 68, 124, 73 | RS-CSP; Week 1-4; n=131, 68, 121, 75 | RS-CSP; Week 5-8; n=126, 68, 116, 73 | RS-CSP; Week 9-12; n=122, 68, 116, 74 | RS-CSP; Week 13-16; n=121, 66, 116, 74 | RS-CSP; Week 17-20; n=119, 66, 114, 72 | RS-CSP; Week 21-24; n=93, 51, 94, 51 | RS-CSY; Baseline; n=135, 67, 125, 73 | RS-CSY; Week 1-4; n=131, 68, 121, 75 | RS-CSY; Week 5-8; n=126, 68, 116, 73 | RS-CSY; Week 9-12; n=122, 68, 116, 74 | RS-CSY; Week 13-16; n=121, 66, 116, 74 | RS-CSY; Week 17-20; n=119, 66, 114, 72 | RS-CSY; Week 21-24; n=93, 51, 94, 51 | |
| SAL/FLU 50/250 µg BID-Single | 3.36 | 3.06 | 3.08 | 3.08 | 2.80 | 2.82 | 2.79 | 2.29 | 2.12 | 2.03 | 2.06 | 1.98 | 2.06 | 1.82 | 1.77 | 1.58 | 1.65 | 1.54 | 1.46 | 1.48 | 1.38 |
| SAL/FLU 50/250 µg BID-TRIPLE | 5.81 | 6.28 | 5.96 | 5.87 | 5.81 | 5.56 | 4.94 | 2.73 | 2.90 | 2.83 | 2.81 | 2.74 | 2.43 | 2.27 | 2.93 | 3.21 | 3.05 | 3.12 | 3.11 | 2.81 | 2.61 |
| TIO 18 µg QD-Single | 3.41 | 3.36 | 3.18 | 2.98 | 3.04 | 3.04 | 2.95 | 2.23 | 2.13 | 2.13 | 2.11 | 2.09 | 2.09 | 1.99 | 1.84 | 1.69 | 1.70 | 1.60 | 1.70 | 1.72 | 1.64 |
| TIO 18 µg QD-TRIPLE | 5.62 | 6.59 | 5.38 | 5.52 | 5.11 | 4.94 | 4.71 | 2.81 | 3.05 | 2.74 | 2.77 | 2.49 | 2.40 | 2.34 | 2.92 | 3.59 | 2.99 | 3.01 | 2.66 | 2.55 | 2.53 |
"The E-RS total score is an 11-item patient questionnaire, which provides information specific to respiratory symptoms-severity of respiratory symptoms overall and severity of breathlessness, cough and sputum, and chest symptoms. Scores were assessed at Baseline, Week 1-4, Week 5-8, Week 9-12, Week 13-16, Week 17-20 and at Week 21-24. Daily EXACT total score is obtained as total score of 14 items from diary. Daily E-RS total score as 11 items and Daily E-RS subscale scores are subset of E-RS total score.~Mean EXACT total score is mean value of daily EXACT total score within subject by every 4 weeks(Week1-4, Week5-8, Week9-12, Week13-16, Week17-20, Week21-24). Same calculation of mean values are applied to E-RS total and E-RS subscale scores. Scores range from 0-100, high value in score indicate worse outcome." (NCT01762800)
Timeframe: Baseline and up to 24 weeks
| Intervention | Scores on a scale (Mean) | ||||||
|---|---|---|---|---|---|---|---|
| Baseline; n=135, 67, 124, 73 | Week 1-4; n=131, 68, 121, 75 | Week 5-8; n=126, 68, 115, 73 | Week 9-12; n=122, 68, 116, 74 | Week 13-16; n=121, 66, 116, 74 | Week 17-20; n=118, 66, 114, 72 | Week 21-24; n=93, 51, 94, 51 | |
| SAL/FLU 50/250 µg BID-Single | 7.42 | 6.76 | 6.75 | 6.69 | 6.23 | 6.33 | 5.99 |
| SAL/FLU 50/250 µg BID-TRIPLE | 11.43 | 12.39 | 11.86 | 11.79 | 11.66 | 10.80 | 9.82 |
| TIO 18 µg QD-Single | 7.51 | 7.18 | 6.99 | 6.70 | 6.82 | 6.85 | 6.58 |
| TIO 18 µg QD-TRIPLE | 11.36 | 13.23 | 11.11 | 11.30 | 10.26 | 9.89 | 9.59 |
"EXACT is a 14-item patient questionnaire used as a measure of respiratory symptoms (reported as units on a 0 [best health status] to 100 [worst possible status] scale). Scores were assessed at Baseline, Week 1-4, Week 5-8, Week 9-12, Week 13-16, Week 17-20 and Week 21-24. Daily EXACT total score is obtained as total score of 14 items from diary. Daily E-RS total score as 11 items and Daily E-RS subscale scores are subset of E-RS total score.~Mean EXACT total score is mean value of daily EXACT total score within subject by every 4 weeks(Week1-4, Week5-8, Week9-12, Week13-16, Week17-20, Week21-24). Same calculation of mean values are applied to E-RS total and E-RS subscale scores." (NCT01762800)
Timeframe: Baseline and up to 24 weeks
| Intervention | Scores on a scale (Mean) | ||||||
|---|---|---|---|---|---|---|---|
| Baseline; n=125, 66, 111, 71 | Week 1-4; n=120, 67, 109, 73 | Week 5-8; n=117, 63, 102, 69 | Week 9-12; n=109, 67, 101, 72 | Week 13-16; n=105, 65, 100, 71 | Week 17-20; n=107, 65, 97, 66 | Week 21-24; n=79, 51, 77, 46 | |
| SAL/FLU 50/250 µg BID-Single | 28.99 | 27.83 | 27.35 | 27.63 | 27.33 | 26.98 | 26.50 |
| SAL/FLU 50/250 µg BID-TRIPLE | 36.00 | 36.92 | 37.58 | 36.16 | 35.92 | 34.92 | 32.72 |
| TIO 18 µg QD-Single | 29.77 | 28.88 | 28.80 | 28.40 | 28.93 | 28.66 | 28.80 |
| TIO 18 µg QD-TRIPLE | 35.78 | 38.26 | 35.87 | 35.57 | 33.79 | 34.03 | 33.67 |
Participants evaluated treatment efficacy by using the following grades: significantly improved (SII), moderately improved (MOI), mildly improved (MII), no change (NC), mildly worse (MIW), moderately worse (MOW), and significantly worse (SIW). Treatment efficacy was assessed at Visit 3 (Week 4), Visit 4 (Week 8), Visit 5 (Week 8), Visit 6 (Week 12), Visit 7 (Week 16), and Visit 8 (Week 24). (NCT01762800)
Timeframe: Up to 24 weeks
| Intervention | Participants (Number) | ||||||||||||||||||||||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Visit 3; SII | Visit 3; MOI | Visit 3; MII | Visit 3; NC | Visit 3; MIW | Visit 3; MOW | Visit 3; SIW | Visit 4; SII | Visit 4; MOI | Visit 4; MII | Visit 4; NC | Visit 4; MIW | Visit 4; MOW | Visit 5; SII | Visit 5; MOI | Visit 5; MII | Visit 5; NC | Visit 5; MIW | Visit 5; MOW | Visit 5; SIW | Visit 6; SII | Visit 6; MOI | Visit 6; MII | Visit 6; NC | Visit 6; MIW | Visit 6; MOW | Visit 6; SIW | Visit 7; SII | Visit 7; MOI | Visit 7; MII | Visit 7; NC | Visit 7; MIW | Visit 7; MOW | Visit 8; SII | Visit 8; MOI | Visit 8; MII | Visit 8; NC | Visit 8; MIW | Visit 8; MOW | |
| SAL/FLU 50/250 µg BID-Single | 5 | 9 | 35 | 74 | 7 | 1 | 1 | 3 | 15 | 31 | 67 | 10 | 1 | 2 | 13 | 31 | 66 | 10 | 0 | 1 | 2 | 13 | 35 | 66 | 4 | 0 | 0 | 1 | 13 | 27 | 75 | 4 | 0 | 5 | 9 | 39 | 58 | 5 | 1 |
| SAL/FLU 50/250 µg BID-TRIPLE | 0 | 2 | 10 | 32 | 19 | 5 | 0 | 1 | 6 | 12 | 39 | 8 | 2 | 1 | 7 | 17 | 34 | 7 | 2 | 0 | 1 | 4 | 16 | 33 | 11 | 0 | 1 | 2 | 4 | 17 | 37 | 5 | 1 | 1 | 4 | 19 | 37 | 5 | 0 |
| TIO 18 µg QD-Single | 1 | 3 | 20 | 85 | 9 | 3 | 0 | 2 | 5 | 25 | 79 | 5 | 0 | 2 | 3 | 31 | 78 | 2 | 0 | 0 | 2 | 4 | 30 | 72 | 7 | 0 | 0 | 2 | 5 | 28 | 71 | 7 | 0 | 2 | 8 | 30 | 69 | 3 | 1 |
| TIO 18 µg QD-TRIPLE | 1 | 3 | 7 | 32 | 22 | 9 | 1 | 1 | 6 | 21 | 28 | 13 | 5 | 4 | 6 | 20 | 31 | 9 | 3 | 0 | 4 | 13 | 14 | 34 | 7 | 2 | 0 | 4 | 11 | 20 | 26 | 9 | 1 | 4 | 9 | 19 | 34 | 4 | 0 |
Physician evaluated treatment efficacy by using the following grades: significantly improved (SII), moderately improved (MOI), mildly improved (MII), no change (NC), mildly worse (MIW), moderately worse (MOW), and significantly worse (SIW). Treatment efficacy was assessed at Visit 3 (Week 4), Visit 4 (Week 8), Visit 5 (Week 8), Visit 6 (Week 12), Visit 7 (Week 16), and Visit 8 (Week 24). (NCT01762800)
Timeframe: 24 weeks
| Intervention | Participants (Number) | |||||||||||||||||||||||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Visit 3; SII | Visit 3; MOI | Visit 3; MII | Visit 3; NC | Visit 3; MIW | Visit 3; MOW | Visit 3; SIW | Visit 4; SII | Visit 4; MOI | Visit 4; MII | Visit 4; NC | Visit 4; MIW | Visit 4; MOW | Visit 4; SIW | Visit 5; SII | Visit 5; MOI | Visit 5; MII | Visit 5; NC | Visit 5; MIW | Visit 5; MOW | Visit 5; SIW | Visit 6; SII | Visit 6; MOI | Visit 6; MII | Visit 6; NC | Visit 6; MIW | Visit 6; MOW | Visit 6; SIW | Visit 7; SII | Visit 7; MOI | Visit 7; MII | Visit 7; NC | Visit 7; MIW | Visit 7; MOW | Visit 8; SII | Visit 8; MOI | Visit 8; MII | Visit 8; NC | Visit 8; MIW | Visit 8; MOW | |
| SAL/FLU 50/250 µg BID-Single | 6 | 11 | 40 | 67 | 7 | 0 | 1 | 3 | 14 | 28 | 74 | 6 | 1 | 1 | 1 | 12 | 29 | 73 | 7 | 0 | 1 | 2 | 10 | 31 | 74 | 3 | 0 | 0 | 0 | 13 | 25 | 79 | 3 | 0 | 2 | 7 | 36 | 70 | 1 | 1 |
| SAL/FLU 50/250 µg BID-TRIPLE | 0 | 1 | 12 | 31 | 16 | 8 | 0 | 1 | 3 | 13 | 33 | 12 | 6 | 0 | 2 | 6 | 14 | 35 | 10 | 1 | 0 | 1 | 1 | 18 | 33 | 11 | 1 | 1 | 1 | 2 | 18 | 38 | 5 | 2 | 1 | 4 | 19 | 39 | 2 | 1 |
| TIO 18 µg QD-Single | 1 | 5 | 21 | 83 | 7 | 3 | 1 | 2 | 8 | 23 | 79 | 4 | 0 | 0 | 2 | 4 | 22 | 83 | 5 | 0 | 0 | 2 | 3 | 28 | 72 | 10 | 0 | 0 | 2 | 5 | 23 | 77 | 5 | 1 | 3 | 7 | 27 | 71 | 4 | 1 |
| TIO 18 µg QD-TRIPLE | 1 | 4 | 3 | 32 | 23 | 12 | 0 | 0 | 9 | 18 | 27 | 12 | 8 | 0 | 4 | 8 | 19 | 29 | 10 | 3 | 0 | 2 | 11 | 17 | 32 | 9 | 3 | 0 | 3 | 12 | 12 | 35 | 8 | 1 | 3 | 9 | 13 | 40 | 5 | 0 |
FEV1 is defined as the volume of air forcefully expelled from the lungs in one second. Baseline was a value at Visit 2 (randomization). Change from Baseline was calculated as specific timepoint value minus Visit 2 value. FEV1 was assessed at Visit 2 (Baseline), Visit 3 (Week 4), Visit 4 (Week 8), Visit 5 (Week 8), Visit 6 (Week 12), Visit 7 (Week 16), and Visit 8 (Week 24). (NCT01762800)
Timeframe: Baseline (Visit 2) and up to 24 weeks
| Intervention | Liters (Mean) | |||||
|---|---|---|---|---|---|---|
| Visit 3; n=131, 68, 119, 75 | Visit 4; n=127, 68, 116, 74 | Visit 5; n=122, 68, 116, 72 | Visit 6; n=120, 66, 114, 74 | Visit 7; n=119, 66, 113, 71 | Visit 8; n=117, 66, 113, 70 | |
| SAL/FLU 50/250 µg BID-Single | 0.024 | 0.008 | -0.010 | -0.007 | -0.012 | -0.019 |
| SAL/FLU 50/250 µg BID-TRIPLE | -0.043 | -0.030 | -0.001 | 0.027 | 0.018 | 0.049 |
| TIO 18 µg QD-Single | 0.007 | -0.011 | -0.006 | 0.002 | -0.010 | -0.017 |
| TIO 18 µg QD-TRIPLE | -0.077 | -0.032 | 0.005 | 0.037 | 0.050 | 0.027 |
Participants were assessed for COPD symptoms by means of CAT at each Visit. This assessment was performed prior to the spirometry testing. A CAT total score of less than 10 represents best health status and greater than 15 represents worst health status. Baseline was the value at Visit 2 (randomization). Change from Baseline was calculated as specific timepoint value minus Visit 2 value. Scores were assessed at Visit 2 (Baseline), Visit 3 (Week 4), Visit 4 (Week 8), Visit 5 (Week 8), Visit 6 (Week 12), Visit 7 (Week 16), and Visit 8 (Week 24). Scores range from 0 to 40, high value in score indicate worse outcome. (NCT01762800)
Timeframe: Baseline and up to 24 weeks
| Intervention | Scores on a scale (Mean) | |||||
|---|---|---|---|---|---|---|
| Visit 3, n=132, 68, 121, 75 | Visit 4, n=127, 68, 116, 74 | Visit 5, n=123, 68, 116, 73 | Visit 6, n=120, 66, 115, 74 | Visit 7, n=120, 66, 113, 71 | Visit 8, n=117, 66, 113, 70 | |
| SAL/FLU 50/250 µg BID-Single | -1.6 | -1.7 | -1.6 | -2.3 | -2.0 | -2.4 |
| SAL/FLU 50/250 µg BID-TRIPLE | 0.1 | -0.2 | -0.8 | 0.0 | -0.8 | -1.0 |
| TIO 18 µg QD-Single | 0.1 | -0.3 | -0.7 | -0.7 | -0.8 | -1.4 |
| TIO 18 µg QD-TRIPLE | 2.1 | 1.6 | 0.8 | 0.0 | -0.6 | -0.5 |
The day of first switch to TRIPLE therapy (SAL/FLU 50/250 µg BID+TIO 18 µg QD) for the first switching participant in each arm. (NCT01762800)
Timeframe: 24 weeks
| Intervention | Days (Number) |
|---|---|
| TIO 18 µg QD | 5 |
| SAL/FLU 50/250 µg BID | 5 |
The day of detection of first exacerbation in any participant in each arm as diagnosed by physician. Exacerbation is defined primarily by physician's judgment. Date of randomisation will be start point and timing of exacerbation (first exacerbation if there are more than one) will be event. For subjects without exacerbation, last day of study or follow up period is regarded as censor. (NCT01762800)
Timeframe: 24 weeks
| Intervention | Days (Number) |
|---|---|
| SAL/FLU 50/250 µg BID-Single | 3 |
| SAL/FLU 50/250 µg BID-TRIPLE | 5 |
| TIO 18 µg QD-Single | 10 |
| TIO 18 µg QD-TRIPLE | 2 |
The EXAcerbations of Chronic pulmonary disease Tool (EXACT) is a 14-item patient-reported outcome (PRO) daily diary used to quantify and measure exacerbations of chronic obstructive pulmonary disease (COPD). Reported as units on a 0 [best health status] to 100 [worst possible status] scale). The day of detection of first exacerbation in any participant in each arm by EXACT. (NCT01762800)
Timeframe: 24 weeks
| Intervention | Days (Number) |
|---|---|
| SAL/FLU 50/250 µg BID-Single | 0 |
| SAL/FLU 50/250 µg BID-TRIPLE | 0 |
| TIO 18 µg QD-Single | 0 |
| TIO 18 µg QD-TRIPLE | 1 |
The percentage of participants who were withdrawn from the study. (NCT01762800)
Timeframe: 24 weeks
| Intervention | Percentage of participants (Number) |
|---|---|
| TIO 18 µg QD | 9 |
| SAL/FLU 50/250 µg BID | 10 |
The percentage of participants who required additional treatment to TRIPLE therapy is defined as number of participants who took additional medicine or therapy in TRIPLE therapy divided by number of participants who switch to TRIPLE therapy multiplied by 100. (NCT01762800)
Timeframe: 24 weeks
| Intervention | Percentage of participants (Number) |
|---|---|
| TIO 18 µg QD | 77.33 |
| SAL/FLU 50/250 µg BID | 72.06 |
Percentage of participants managed by TRIPLE therapy was calculated as [(number of participants who switched to TRIPLE therapy) - (number of participants who stepped down)/ number of evaluable population]*100 (NCT01762800)
Timeframe: 24 weeks
| Intervention | Percentage of participants (Number) |
|---|---|
| TIO 18 µg QD | 36.82 |
| SAL/FLU 50/250 µg BID | 32.35 |
FEV1 is defined as the volume of air forcefully expelled from the lungs in one second. At Screening (Visit 1) spirometric assessments were conducted before (Visit 1A) and 30 to 60 minutes after a bronchodilator challenge (400 µg of salbutamol) (Visit 1B). FEV1 during each visit are presented. FEV1 was assessed at Visit 1A (Screening), Visit 1B (Screening), Visit 2 (Baseline), Visit 3 (Week 4), Visit 4 (Week 8), Visit 5 (Week 8), Visit 6 (Week 12), Visit 7 (Week 16), and Visit 8 (Week 24). (NCT01762800)
Timeframe: Up to 24 weeks
| Intervention | Liters (Mean) | ||||||||
|---|---|---|---|---|---|---|---|---|---|
| Visit 1A; n=136, 68, 126, 75 | Visit 1B; n=136, 68, 126, 75 | Visit 2; n=136, 68, 126, 75 | Visit 3; n=131, 68, 119, 75 | Visit 4; n=127, 68, 116, 74 | Visit 5; n=122, 68, 116, 72 | Visit 6; n=120, 66, 114, 74 | Visit 7; n=119, 66, 113, 71 | Visit 8; n=117, 66, 113, 70 | |
| SAL/FLU 50/250 µg BID-Single | 1.687 | 1.764 | 1.695 | 1.731 | 1.713 | 1.718 | 1.716 | 1.710 | 1.694 |
| SAL/FLU 50/250 µg BID-TRIPLE | 1.401 | 1.471 | 1.385 | 1.342 | 1.355 | 1.384 | 1.413 | 1.404 | 1.435 |
| TIO 18 µg QD-Single | 1.675 | 1.754 | 1.681 | 1.710 | 1.703 | 1.708 | 1.712 | 1.694 | 1.688 |
| TIO 18 µg QD-TRIPLE | 1.349 | 1.429 | 1.362 | 1.285 | 1.336 | 1.376 | 1.405 | 1.423 | 1.390 |
The percentage of participants who stepped down from TRIPLE therapy to initial randomized treatment was calculated as number of participants who step-down from TRIPLE therapy divided by number of participants who switch to TRIPLE therapy and then multiplied by 100. (NCT01762800)
Timeframe: 24 weeks
| Intervention | Percentage of participants (Number) |
|---|---|
| TIO 18 µg QD | 1.33 |
| SAL/FLU 50/250 µg BID | 2.94 |
Switched to TRIPLE therapy is defined as: 1. Date of switch: when SAL/FLU or TIO was administered additionally to randomised treatment. 2. Date of randomisation was a start point and timing of switching (first switch if there are more than once) to TRIPLE was event. For participants without switching, last day of study or follow up period was regarded as censored. Percentage of participants who switched to TRIPLE therapy was calculated as: number of participants who switched to TRIPLE therapy divided by number of evaluable population and then multiplied by 100. (NCT01762800)
Timeframe: 24 weeks
| Intervention | Percentage of participants (Number) |
|---|---|
| TIO 18 µg QD | 37.31 |
| SAL/FLU 50/250 µg BID | 33.33 |
Each evening participants recorded the number of occasions in the last 24 hours when they used their salbutamol for symptomatic relief of COPD symptoms. The percentage of participants who used relief medication in the study are presented. (NCT01762800)
Timeframe: 24 weeks
| Intervention | Percentage of participants (Number) |
|---|---|
| SAL/FLU 50/250 µg BID-Single | 40.4 |
| SAL/FLU 50/250 µg BID-TRIPLE | 61.8 |
| TIO 18 µg QD-Single | 43.7 |
| TIO 18 µg QD-TRIPLE | 70.7 |
The randomized treatment could be switched to TRIPLE therapy in the case that chronic obstructive pulmonary disease (COPD) is not controlled by the randomized treatment. Participants on TRIPLE therapy received SAL/FLU 50/250 µg BID plus TIO 18 µg QD together. The percentage of participants who were able to remain on the randomized treatment was calculated by the following formula: 100 minus percentage of participants who switched over to TRIPLE therapy. (NCT01762800)
Timeframe: 24 weeks
| Intervention | Percentage of participants (Number) |
|---|---|
| TIO 18 µg QD | 62.69 |
| SAL/FLU 50/250 µg BID | 66.67 |
Participants were assessed for COPD symptoms by means of CAT at each Visit. This assessment was performed prior to the spirometry testing. A CAT total score of less than 10 represents best health status and greater than 15 represents worst health status. Scores were assessed at Visit 1 (Screening), Visit 2 (Baseline), Visit 3 (Week 4), Visit 4 (Week 8), Visit 5 (Week 8), Visit 6 (Week 12), Visit 7 (Week 16), and Visit 8 (Week 24). Scores range from 0 to 40, high value in score indicate worse outcome. (NCT01762800)
Timeframe: 24 weeks
| Intervention | Scores on a scale (Mean) | |||||||
|---|---|---|---|---|---|---|---|---|
| Visit 1, n=136, 68, 126, 75 | Visit 2, n=136, 68, 126, 75 | Visit 3, n=132, 68, 121, 75 | Visit 4, n=127, 68, 116, 74 | Visit 5, n=123, 68, 116, 73 | Visit 6, n=120, 66, 115, 74 | Visit 7, n=120, 66, 113, 71 | Visit 8, n=117, 66, 113, 70 | |
| SAL/FLU 50/250 µg BID-Single | 11.3 | 9.9 | 8.4 | 8.3 | 8.3 | 7.4 | 7.7 | 7.2 |
| SAL/FLU 50/250 µg BID-TRIPLE | 13.3 | 13.4 | 13.5 | 13.2 | 12.6 | 13.3 | 12.4 | 12.3 |
| TIO 18 µg QD-Single | 11.2 | 9.6 | 9.2 | 8.8 | 8.4 | 8.5 | 8.3 | 7.8 |
| TIO 18 µg QD-TRIPLE | 13.4 | 12.1 | 14.3 | 13.6 | 12.8 | 12.0 | 11.4 | 11.6 |
FEV1 is a measure of lung function and is defined as the maximal amount of air that can be forcefully exhaled in one second. The WM FEV1 was derived by calculating the area under the FEV1/time curve (AUC) using the trapezoidal rule, and then dividing the value by the time interval over which the AUC was calculated. The WM was calculated at Days 1, 84, and 168 using the 0-6-hour post-dose FEV1 measurements collected on that day, which included pre-dose (Day 1: 30 minutes [min] and 5 min prior to dosing; other serial visits: 23 and 24 hours after the previous morning dose) and post-dose at 15 min, 30 min, 1 hour, 3 hours, and 6 hours. Change from BL at a particular visit was calculated as the WM value at that visit minus the BL value. Analysis was performed using a repeated measures model with covariates of treatment, BL (mean of the two assessments made 30 min and 5 min pre-dose on Day 1), smoking status, center group, day, and day by BL and day by treatment interactions. (NCT01777334)
Timeframe: Baseline and Day 168
| Intervention | Liters (Least Squares Mean) |
|---|---|
| UMEC/VI 62.5/25 µg | 0.276 |
| TIO 18 µg | 0.170 |
FEV1 is a measure of lung function and is defined as the maximal amount of air that can be forcefully exhaled in one second. Trough FEV1 measurements were taken electronically by spirometry on Days 2, 28, 56, 84, 112, 140, 168, and 169. Baseline is defined as the mean of the assessments made 30 minutes (min) pre-dose and 5 min pre-dose on Treatment Day 1. Trough FEV1 is defined as the mean of the FEV1 values obtained at 23 and 24 hours (hr) after the previous morning's dosing (ie., trough FEV1 on Day 169 is the mean of the FEV1 values obtained 23 and 24 hr after the morning dosing on Day 168). Change from Baseline at a particular visit was calculated as the trough FEV1 value at that visit minus the Baseline value. Analysis was performed using a repeated measures model with covariates of treatment, Baseline (mean of the two assessmentsmade 30 min and 5 min pre-dose on Day 1), smoking status, center group, day, and day by Baseline and day by treatment interactions. (NCT01777334)
Timeframe: Baseline and Day 169
| Intervention | Liters (Least Squares Mean) |
|---|---|
| UMEC/VI 62.5/25 µg | 0.205 |
| TIO 18 µg | 0.093 |
Transition Dyspnea Index (TDI) captures changes from baseline. The TDI score is based on three domains with each domain scored from -3 (major deterioration) to +3 (major improvement), to give an overall score of -9 to +9, a negative score indicating a deterioration from baseline. A TDI focal score of 1 is considered to be a clinically significant improvement from baseline. BDI/TDI was used to assess dyspnea from several aspects, caused by daily activities. These were evaluated by the investigators in the study at the scheduled study visits. The indices were to be evaluated by the same investigator.as far as possible. (NCT01794780)
Timeframe: Baseline,3,6,9,12 months
| Intervention | Units on a scale (Mean) | ||||
|---|---|---|---|---|---|
| Baseline | 3 Month | 6 Month | 9 Month | 12 Month | |
| Indacaterol | 6.7 | 1.4 | 0.0 | 0.7 | 0.3 |
| Indacaterol +Tiotropium | 5.4 | 0.4 | -0.5 | 1.0 | 1.0 |
| LABA/ICS | 6.7 | 1.3 | 1.4 | 1.6 | 1.7 |
| LABA/ICS + Tiotropium | 6.2 | 1.1 | 0.9 | 0.9 | 1.0 |
| Oral Theophylline | 7.1 | 0.9 | 1.2 | 1.4 | 1.6 |
| Tiotropium Bromide | 6.6 | 1.2 | 1.0 | 0.9 | 1.0 |
The mMRC scale is scored from 0 (less severe) to 4 (severe). 0 Not troubled with breathlessness except with strenuous exercise; 1 Troubled by shortness of breath when hurrying on the level or walking up a slight hill; 2 Walks slower than people of the same age on the level because of breathlessness or has to stop for breath when walking at own pace on the level; 3 Stops for breath after walking about 100 yards or after a few minutes on the level; 4 Too breathless to leave the house or breathless when dressing or undressing. The modified Medical Research Council (mMRC) Dyspnea Scale , is a five-item instrument (part of the Borg scale) to assess a patient's degree of breathlessness in relation to physical activity. Participants will be required to read a brief description of an activity and then select a statement that best describes their experience with dyspnea at Visit 101. The mMRC was assessed by the investigators at the scheduled visits. (NCT01794780)
Timeframe: Baseline,3,6,9,12 months
| Intervention | Number of participants (Number) | ||||||||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Baseline scale item 0 | Baseline scale item 1 | Baseline scale item 2 | Baseline scale item 3 | Baseline scale item 4 | 3 month Scale item 0 | 3 month Scale item 1 | 3 month Scale item 2 | 3 month Scale item 3 | 3 month Scale item 4 | 6 month Scale item 0 | 6 month Scale item 1 | 6 month Scale item 2 | 6 month Scale item 3 | 6 month Scale item 4 | 9 month Scale item 0 | 9 month Scale item 1 | 9 month Scale item 2 | 9 month Scale item 3 | 9 month Scale item 4 | 12 month Scale item 0 | 12 month Scale item 1 | 12 month Scale item 2 | 12 month Scale item 3 | 12 month Scale item 4 | |
| Indacaterol | 4 | 11 | 14 | 3 | 0 | 3 | 9 | 7 | 1 | 0 | 2 | 5 | 8 | 1 | 0 | 3 | 5 | 4 | 1 | 0 | 1 | 5 | 2 | 2 | 0 |
| Indacaterol +Tiotropium | 1 | 4 | 1 | 3 | 0 | 0 | 4 | 3 | 0 | 0 | 0 | 1 | 4 | 1 | 0 | 0 | 1 | 2 | 0 | 0 | 0 | 2 | 1 | 0 | 0 |
| LABA/ICS | 161 | 435 | 327 | 154 | 19 | 101 | 364 | 203 | 67 | 6 | 96 | 290 | 138 | 54 | 5 | 116 | 256 | 131 | 42 | 4 | 150 | 275 | 127 | 41 | 9 |
| LABA/ICS + Tiotropium | 63 | 226 | 211 | 110 | 22 | 54 | 157 | 133 | 58 | 9 | 37 | 149 | 105 | 44 | 11 | 45 | 127 | 99 | 41 | 9 | 47 | 138 | 102 | 32 | 9 |
| Oral Theophylline | 31 | 66 | 34 | 19 | 4 | 20 | 52 | 26 | 11 | 1 | 15 | 43 | 20 | 4 | 0 | 20 | 40 | 19 | 5 | 1 | 20 | 52 | 12 | 4 | 1 |
| Tiotropium Bromide | 40 | 114 | 83 | 36 | 3 | 24 | 69 | 54 | 18 | 2 | 23 | 57 | 45 | 13 | 3 | 24 | 52 | 30 | 14 | 1 | 24 | 61 | 33 | 10 | 3 |
Forced expiratory volume in 1 second (FEV1) is the amount of air that can be exhaled in one second. A positive change from baseline in FEV1 indicates improvement in lung function. Pulmonary function tests were performed at study visits including FEV1, and Force Vital Capacity (FVC). These were performed 30 minutes before treatment and not more than 2 hours in advance after stopping the long-acting bronchodilators eight hours before visits. In order to reduce the variation between each test, the same instrument was used in the whole research process if condition allowed. (NCT01794780)
Timeframe: Baseline,12 months
| Intervention | Liters (Mean) |
|---|---|
| Indacaterol | 0.056 |
| Tiotropium Bromide | -0.036 |
| LABA/ICS | 0.056 |
| Indacaterol +Tiotropium | 0.030 |
| LABA/ICS + Tiotropium | -0.028 |
| Oral Theophylline | 0.046 |
Forced expiratory volume in 1 second (FEV1) is the amount of air that can be exhaled in one second. A positive change from baseline in FEV1 indicates improvement in lung function. Pulmonary function tests were performed at study visits including FEV1, and Force Vital Capacity (FVC). These were performed 30 minutes before treatment and not more than 2 hours in advance after stopping the Long-acting bronchodilators eight hours before visits. In order to reduce the variation between each test, the same instrument was used in the whole research process if condition allowed. (NCT01794780)
Timeframe: Baseline,3 months
| Intervention | Liters (Mean) |
|---|---|
| Indacaterol | -0.042 |
| Tiotropium | 0.006 |
| LABA/ICS | 0.033 |
| Indacaterol + Tiotropium | 0.022 |
| LABA/ICS + Tiotropium | 0.011 |
| Oral Theophylline | 0.012 |
Number of COPD exacerbations evaluated over 12 months. COPD exacerbation is defined as a new onset or worsening of at least 1 respiratory major symptoms (e.g. dyspnea, cough, sputum volume or sputum purulence) for at least 3 consecutive days, which results in recorded treatment change (antibiotics/steroids/oxygen therapy) OR recorded COPD related hospitalization/Emergency visit. COPD exacerbation is not considered as adverse event, and should only be recorded in COPD e-CRF. (NCT01794780)
Timeframe: Baseline,12 months
| Intervention | COPD Exacerbations/year (Mean) |
|---|---|
| Indacaterol | 1.1 |
| Tiotropium Bromide | 0.5 |
| Salmeterol/Fluticasone | 1.1 |
| Budesonide/ Formoterol | 0.4 |
| LABA/ICS | 0.9 |
| Indacaterol +Tiotropium | 4.1 |
| LABA/ICS + Tiotropium | 0.8 |
| Oral Theophylline | 1.0 |
The COPD assessment test (CAT) is a short instrument scale used to quantify the symptom burden of COPD and will be used to assess the health status of patients in this study. It consists of eight items, each presented as a semantic 6-point differential scale, providing a total score out of 40. A higher score indicates a worse health status. Scores of 0 - 10, 11 - 20, 21 - 30 and 31 - 40 represent a mild, moderate, severe or very severe clinical impact of COPD upon the patient. (NCT01794780)
Timeframe: Baseline,3,6,9,12 months
| Intervention | Score on a scale (Mean) | |||
|---|---|---|---|---|
| 3 Month | 6 Month | 9 Month | 12 Month | |
| Indacaterol | -1.9 | -1.9 | -4.4 | -5.1 |
| Indacaterol +Tiotropium | -1.9 | -2.7 | -9.0 | -7.7 |
| LABA/ICS | -2.3 | -2.7 | -3.5 | -4.1 |
| LABA/ICS + Tiotropium | -1.8 | -2.2 | -3.1 | -3.7 |
| Oral Theophylline | -1.8 | -2.5 | -3.1 | -2.4 |
| Tiotropium Bromide | -2.1 | -2.7 | -3.1 | -2.6 |
The overall satisfaction ranges from 1=very dissatisfied to 7=very satisfied. (NCT01810692)
Timeframe: day 1
| Intervention | units on a scale (Mean) |
|---|---|
| Spiriva Respimat | 5.96 |
| Hirobriz/Onbrez/Oslif Breezhaler | 5.90 |
All questions were answered on a 7-point scale ranging from 1= very dissatisfied to 7 = very satisfied).To calculate the domain scores, the sum of the items of the convenience domain was transformed to a 0- (least) to 100- (most) point scale which is scaled positively:higher scores represent higher levels of satisfaction. (NCT01810692)
Timeframe: day 1
| Intervention | units on a scale (Mean) |
|---|---|
| Spiriva Respimat | 78.62 |
| Hirobriz/Onbrez/Oslif Breezhaler | 81.93 |
Patient satisfaction with regard to the total score of the handling of the inhaled devices performed by means of a PASAPQ. All questions were answered on a 7-point scale ranging from 1= very dissatisfied to 7 = very satisfied).To calculate the total score, the sum of the 13 items of the two domains (performance and convenience) was transformed to a 0- (least) to 100- (most) point scale which is scaled positively:higher scores represent higher levels of satisfaction. (NCT01810692)
Timeframe: day 1
| Intervention | units on a scale (Mean) |
|---|---|
| Spiriva Respimat | 80.71 |
| Hirobriz/Onbrez/Oslif Breezhaler | 79.92 |
All questions were answered on a 7-point scale ranging from 1= very dissatisfied to 7 = very satisfied).To calculate the domain scores, the sum of the items of the performance domain was transformed to a 0- (least) to 100- (most) point scale which is scaled positively:higher scores represent higher levels of satisfaction. (NCT01810692)
Timeframe: day 1
| Intervention | units on a scale (Mean) |
|---|---|
| Spiriva Respimat | 82.50 |
| Hirobriz/Onbrez/Oslif Breezhaler | 78.20 |
Change from baseline in morning pre-dose trough forced expiratory volume in 1 second (FEV1) over 24 weeks. FEV1 was assessed at multiple time points post-baseline,and a modelbased average of all visits starting from Week 2 through week 24 inclusive was calculated. The change values reported in the table represent the change between the baseline and the average FEV1 post-baseline. (NCT01854645)
Timeframe: Baseline and Weeks 2 to 24
| Intervention | Liters (Least Squares Mean) |
|---|---|
| GFF MDI (PT003) | 0.150 |
| GP MDI (PT001) | 0.091 |
| FF MDI (PT005) | 0.086 |
| Spiriva® Handihaler® (Open-label) | 0.122 |
| Placebo | -0.007 |
Peak change from baseline in forced expiratory volume in 1 second (FEV1) within 2 hours post-dose (NCT01854645)
Timeframe: Baseline and at Week 24
| Intervention | Liters (Least Squares Mean) |
|---|---|
| GFF MDI (PT003) | 0.356 |
| GP MDI (PT001) | 0.223 |
| FF MDI (PT005) | 0.263 |
| Spiriva® Handihaler® (Open-label) | 0.259 |
| Placebo | 0.065 |
Change from baseline in average daily rescue Ventolin HFA use (NCT01854645)
Timeframe: Baseline and at Week 24
| Intervention | Puffs / Day (Least Squares Mean) |
|---|---|
| GFF MDI (PT003) | -0.8 |
| GP MDI (PT001) | -0.5 |
| FF MDI (PT005) | -0.8 |
| Spiriva® Handihaler® (Open-label) | -0.4 |
| Placebo | 0.3 |
Change from baseline in the SGRQ total score. The SGRQ is a disease-specific questionnaire, self-completed by participants, used to evaluate the effect of GFF MDI, FF MDI and GP MDI on health-related quality of life as compared to placebo in subjects with COPD. The scores range from 0 (minimum, best possible health status) to 100 (maximum, worst possible health status). The SGRQ contains 76 items grouped into three domains (symptoms, activity and impacts). Change from Baseline at a particular visit was calculated as the SGRQ total score at that visit minus Baseline. Change from Baseline in total score of -4 units or lower is considered as clinically meaningful improvement in quality of life. (NCT01854645)
Timeframe: Baseline and at Week 24
| Intervention | Scores on a scale (Least Squares Mean) |
|---|---|
| GFF MDI (PT003) | -3.1 |
| GP MDI (PT001) | -1.2 |
| FF MDI (PT005) | -2.4 |
| Spiriva® Handihaler® (Open-label) | -2.7 |
| Placebo | -0.8 |
Defined as the first time-point using the 5- and 15-minute post dose measurements where the difference in FEV1 from Placebo was statistically significant (NCT01854645)
Timeframe: Assessed for 5- and 15-minute post dose on Day 1
| Intervention | Liters (Least Squares Mean) | |
|---|---|---|
| 5 min post dose | 15 min post dose | |
| FF MDI (PT005) | 0.182 | 0.212 |
| GFF MDI (PT003) | 0.185 | 0.226 |
| GP MDI (PT001) | 0.042 | 0.101 |
| Placebo | -0.002 | 0.022 |
| Spiriva® Handihaler® (Open-label) | 0.048 | 0.117 |
Change from baseline in morning pre-dose trough forced expiratory volume in 1 second (FEV1) at Week 24 (NCT01854645)
Timeframe: Baseline and at Week 24
| Intervention | Liters (Least Squares Mean) |
|---|---|
| GFF MDI (PT003) | 0.126 |
| GP MDI (PT001) | 0.066 |
| FF MDI (PT005) | 0.062 |
| Spiriva® Handihaler® (Open-label) | 0.105 |
| Placebo | -0.024 |
FEV1 is a measure of lung function and is defined as the maximal amount of air that can be forcefully exhaled in 1 second. FEV1 assessments taken on 0 to 3 hour on Day 84 (pre-dose, 5 minutes (min), 15 min, 30 min, 1 hour, and 3 hour post-dose). Pre-dose was the reading obtained at 24 hours after the previous day's dose (Day 83 dose). BL is defined as mean of the values measured 23 hour and 24 hour after dosing prior to Day 1 (ie. after the last OL tiotropium dosing and prior to the randomized dose). Change from BL is defined as the post-BL value minus the BL value. Analysis performed using mixed model repeated measures with covariates of treatment, BL FEV1, center group, 24 hour subset flag, time, time by treatment interaction and time by BL interaction. Only those participants with data available at the specified time point were included in the analysis. (NCT01899742)
Timeframe: Baseline and Day 84
| Intervention | Liters (Least Squares Mean) |
|---|---|
| Umeclidinium/Vilanterol 62.5/25 µg | 0.164 |
| Tiotropium Bromide 18 µg | 0.091 |
FEV1 is a measure of lung function and is defined as the maximal amount of air that can be forcefully exhaled in 1 second. BL was the mean of the values measured 23 hour and 24 hour after dosing prior to Day 1 (ie. after the last open label [OL] tiotropium dosing and prior to the randomized dose). Change from BL is defined as the post-BL value minus the BL value. Trough FEV1 on Day 85 is defined as the mean of the FEV1 values obtained at 23 and 24 hours after dosing on Day 84 (at Week 12 + 1 day). Analysis performed using a mixed repeated measures model (MMRM) with covariates of treatment, BL, center group, 24 hour subset flag, Day, Day by BL and Day by treatment interactions. ITT Population is defined as participants who received at least one dose of randomized study medication in the treatment period. Only those participants with data available at the specified time point were included in the analysis. (NCT01899742)
Timeframe: Baseline (BL) and Day 85
| Intervention | Liters (Least Squares Mean) |
|---|---|
| Umeclidinium/Vilanterol 62.5/25 µg | 0.074 |
| Tiotropium Bromide 18 µg | -0.014 |
Inspiratory Capacity (IC) is the volume of air breathed in by a maximum inspiration at the end of a normal expiration. Whole body plethysmography (Bodybox) will be used to measure IC. (NCT01922271)
Timeframe: Day 1
| Intervention | Liters (Mean) | |||||
|---|---|---|---|---|---|---|
| -45 min (n=152, 150) | 30 min (n=150, 151) | 1hr (n=151, 149) | 1hr 30 min (n=151, 150) | 2hr 30 min (n=150, 149) | 3hr 30 min (n=150, 149) | |
| NVA237 | 2.169 | 2.433 | 2.455 | 2.472 | 2.467 | 2.479 |
| Tiotropium | 2.193 | 2.422 | 2.435 | 2.457 | 2.474 | 2.449 |
Total Lung Capacity (TLC) is the best vital capacity plus residual volume (RV). Whole body plethysmography (Bodybox) will be used to measure TLC. (NCT01922271)
Timeframe: Day 1
| Intervention | Liters (Mean) | |||||
|---|---|---|---|---|---|---|
| -45 min (n=152, 150) | 30 min (n=150, 151) | 1hr (n=151, 149) | 1hr 30 min (n=151, 149) | 2hr 30 min (n=150, 149) | 3hr 30 min (n=150, 148) | |
| NVA237 | 7.380 | 7.255 | 7.224 | 7.227 | 7.203 | 7.240 |
| Tiotropium | 7.335 | 7.274 | 7.161 | 7.165 | 7.149 | 7.149 |
Specific Airway Resistance (sRAW) indicates volume and resistance-dependent work of breathing needed in order to generate a reference flow rate of 1 L/s, measured by kPa*s. Whole body plethysmography (Bodybox) is used to measure SRaw. (NCT01922271)
Timeframe: Day 1
| Intervention | kilopascal (kPa) (Mean) | |||||
|---|---|---|---|---|---|---|
| -45 min (n=152, 150) | 30 min (n=150, 151) | 1 hr (n=151, 149) | 1 hr 30 min (n=151, 150) | 2 hr 30 min (n=150, 149) | 3 hr 30 min (n=150, 149) | |
| NVA237 | 4.203 | 2.904 | 2.656 | 2.632 | 2.643 | 2.779 |
| Tiotropium | 4.105 | 3.089 | 2.877 | 2.811 | 2.756 | 2.828 |
Residual Volume (RV) will be measured using whole body plethysmography (Bodybox). (NCT01922271)
Timeframe: Day 1
| Intervention | Liters (Mean) | |||||
|---|---|---|---|---|---|---|
| -45 min (n=152, 150) | 30 min (n=150, 151) | 1 hr (n=151, 149) | 1 hr 30 min (n=151, 149) | 2 h 30 min (n= 150, 149) | 3 h 30 min (n= 150, 148) | |
| NVA237 | 4.433 | 3.996 | 3.891 | 3.910 | 3.893 | 3.970 |
| Tiotropium | 4.344 | 4.035 | 3.913 | 3.903 | 3.861 | 3.895 |
Functional Resistance Capacity (FRCpleth) will be measured using whole body plethysmography (Bodybox). (NCT01922271)
Timeframe: Day 1
| Intervention | Liters (Mean) | |||||
|---|---|---|---|---|---|---|
| -45 min (n=152, 150) | 30 min (n=150, 151) | 1 hr (n=151, 149) | 1 hr 30 min (n=151, 149) | 2 h 30 min (n= 150, 149) | 3 h 30 min (n= 150, 148) | |
| NVA237 | 5.211 | 4.823 | 4.769 | 4.756 | 4.736 | 4.761 |
| Tiotropium | 5.142 | 4.852 | 4.725 | 4.714 | 4.676 | 4.704 |
Standardized Forced Expiratory Volume in One Second (FEV1) AUC0-2h will be measured via spirometry. The AUC will be calculated from the FEV1 measurements obtained at timepoints between 0 min and 2h using the trapezoidal rule and will be standardized (=divided) by the measurement time (i.e. 2h). (NCT01922271)
Timeframe: Day 1
| Intervention | liters per hour (Mean) |
|---|---|
| NVA237 | 1.490 |
| Tiotropium | 1.453 |
Forced expiratory volume in 1 second (FEV1) is the amount of air that can be exhaled in one second. FEV1 will be measured by spirometry. All spirometry calibrations and evaluations will follow the recommendations of the American Thoracic Society / European Respiratory Society guidelines for acceptability. (NCT01922271)
Timeframe: Day 1
| Intervention | liters per hour (Mean) |
|---|---|
| NVA237 | 1.433 |
| Tiotropium | 1.398 |
Percentage of subjects corresponding to each reason of non-adherence to once-daily long-acting bronchodilators in COPD patients are presented. (NCT01937390)
Timeframe: 13 months
| Intervention | Percentage of participants (Number) | |||||
|---|---|---|---|---|---|---|
| Felt good and decided not to take it | Financial reasons | Felt good and forgot to take it | Did not experience any significant improvement | Ran out of medicine | Unable to tolerate side effects | |
| LAMA/LABA Patients | 1.9 | 1.2 | 0.9 | 0.2 | 0.2 | 0.2 |
"Percentage of subjects experienced COPD exacerbations exactly n number of times during the study period is presented. Here, n represents the number of times each subject experienced COPD exacerbations." (NCT01937390)
Timeframe: 13 months
| Intervention | Percentage of participants (Number) | |||||||
|---|---|---|---|---|---|---|---|---|
| 1 Exacerbation | 2 Exacerbations | 3 Exacerbations | 4 Exacerbations | 5 Exacerbations | 6 Exacerbations | 7 Exacerbations | 9 Exacerbations | |
| LAMA/LABA Patients | 12.5 | 3.8 | 3.2 | 2.2 | 0.7 | 0.9 | 0.2 | 0.2 |
"Percentage of subjects hospitalized due to COPD exacerbations exactly n number of times during the study period is presented. Here, n represents the number of times each subject is hospitalized due to COPD exacerbations." (NCT01937390)
Timeframe: 13 months
| Intervention | Percentage of participants (Number) | |||
|---|---|---|---|---|
| 1 Exacerbation | 2 Exacerbations | 3 Exacerbations | 4 Exacerbations | |
| LAMA/LABA Patients | 1.7 | 0.7 | 0.3 | 0.5 |
"The Clinical COPD (Chronic Obstructive Pulmonary Disease) Questionnaire (CCQ) is a standardized, validated and reliable questionnaire (in local language) to assess the impact of treatment on health status in COPD patients. CCQ total score is calculated as the arithmetic average of 10 individual scores on a 7-point scale. CCQ total score varies from 0 (very good control) to 6 (extremely poor control). Mean change in CCQ total score from baseline at month 13 is presented along with its standard error. Change in CCQ total score is calculated for each subject as:~CCQ total score at month 13 - CCQ total score at baseline. Baseline is defined as the first assessment after enrolment (at Month 1)." (NCT01937390)
Timeframe: Baseline and 13 Month
| Intervention | Units on a scale (Mean) |
|---|---|
| LAMA/LABA Patients | -1.55 |
Mean and standard deviation of CCQ total score is presented at month 13. (NCT01937390)
Timeframe: 13 months
| Intervention | Units on a scale (Mean) |
|---|---|
| LAMA/LABA Patients | 2.03 |
Forced Expiratory Volume in 1 second (FEV1) Area Under the Curve (AUC) will measured via spirometry and calculated from 0 to 4 hours post-dose on day 1 of study treatment. (NCT01959516)
Timeframe: Day 1
| Intervention | Liters*hours (Least Squares Mean) |
|---|---|
| Glycopyronium From Sequence A to B and Sequence B to A | 1.7432 |
| Tiotropium From Sequence A to B and Sequence B to A | 1.7132 |
"Comparison of symptoms outcome between glycopyrronium QD versus tiotropium QD will be conducted via the PROMorning COPD Symptoms questionnaire. This questionnaire will be completed by participants at waking-up, pre-inhalation of study treatment (at home), and they will complete Part 2 of PRO-Morning COPD Symptoms questionnaire at site, 3hours post-inhalation of study treatment. The PRO-Morning COPD Symptoms Questionnaire is a self-administered patient reported outcome (PRO) instrument developed by the sponsor to evaluate patients' experience of early morning symptoms of COPD. The questionnaire consists of two parts : predose and postdose.~Each part has 6 questions and for each question a scale of 0 to 10 can be reached. For the predose and postdose part of the questionnaire you will have then each a total score of 0-60 by adding the sub-scores for each question, higher scores represent worse severity of COPD morning symptoms" (NCT01959516)
Timeframe: day 1 (baseline) and week 4
| Intervention | Scores on a scale (Least Squares Mean) | |
|---|---|---|
| 3h post-dose (Day 1) | 3h post-dose (Week 4) | |
| Glycopyronium From Sequence A to B and Sequence B to A | 9.7068 | 10.4641 |
| Tiotropium From Sequence A to B and Sequence B to A | 10.3974 | 10.3193 |
"This endpoint was evaluated based on the data from this individual trial and also based on the data from the combined dataset from this trial and the replicate study NCT02006732. The results for the combined dataset are included in the disclosure for NCT02006732 as specified in the analysis plan. The SGRQ ranges from 0 (no impairment of quality of life) to 100 (highest impairment of quality of life).~The adjusted mean (SE) are obtained from fitting a mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect; spatial power covariance structure for within-patient errors and Kenward-Roger approximation of denominator degrees of freedom." (NCT01964352)
Timeframe: 12 weeks treatment
| Intervention | units on a scale (Mean) |
|---|---|
| Placebo | 42.038 |
| Tiotropium 5 μg | 39.637 |
| Tiotropium 2.5 μg+ Olodaterol 5 μg | 37.916 |
| Tiotropium 5 μg + Olodaterol 5 μg | 37.144 |
Trough FVC was defined as the FVC value at the end of the dosing interval (24 hours). It was calculated as the mean of the 2 FVC measurements performed 23 h and at 23 h 50 min after inhalation of study medication at day 85. Trough FVC response was defined as trough FVC minus baseline FVC. The adjusted mean (SE) are obtained from fitting a mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect; spatial power covariance structure for within-patient errors and Kenward-Roger approximation of denominator degrees of freedom. (NCT01964352)
Timeframe: baseline and 12 weeks
| Intervention | L (Mean) |
|---|---|
| Placebo | 0.025 |
| Tiotropium 5 μg | 0.223 |
| Tiotropium 2.5 μg+ Olodaterol 5 μg | 0.233 |
| Tiotropium 5 μg + Olodaterol 5 μg | 0.244 |
Trough FEV1 was defined as the FEV1 value at the end of the dosing interval (24 hours). It was calculated as the mean of the 2 FEV1 measurements performed 23 h and at 23 h 50 min after inhalation of study medication at day 85. Trough FEV1 response was defines as trough FEV1 minus baseline FEV1. The adjusted mean (SE) are obtained from fitting a mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect; spatial power covariance structure for within-patient errors and Kenward-Roger approximation of denominator degrees of freedom. (NCT01964352)
Timeframe: baseline and 12 weeks
| Intervention | L (Mean) |
|---|---|
| Placebo | 0.001 |
| Tiotropium 5 μg | 0.135 |
| Tiotropium 2.5 μg+ Olodaterol 5 μg | 0.151 |
| Tiotropium 5 μg + Olodaterol 5 μg | 0.163 |
"This endpoint was evaluated based on the data from this individual trial and also based on the data from the combined dataset from this trial and the replicate study NCT02006732. The results for the combined dataset are included in the disclosure for NCT02006732 as specified in the analysis plan. Mahler Transitional Dyspnoea Index (TDI) focal score was performed to measure the effect of the treatment on patients' dyspnoea.(Rating scale of 3 components - change in functional impairment, change in magnitude of tasks, change in magnitude of efforts. Worst score = -9, best score = +9).~The adjusted mean (SE) are obtained from fitting an MMRM model including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect; spatial power covariance structure for within-patient errors and Kenward-Roger approximation of denominator degrees of freedom." (NCT01964352)
Timeframe: 12 weeks
| Intervention | Units on a scale (Mean) |
|---|---|
| Placebo | -0.113 |
| Tiotropium 5 μg | 1.332 |
| Tiotropium 2.5 μg+ Olodaterol 5 μg | 1.839 |
| Tiotropium 5 μg + Olodaterol 5 μg | 1.939 |
The adjusted mean (SE) are obtained from fitting a mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect; spatial power covariance structure for within-patient errors and Kenward-Roger approximation of denominator degrees of freedom. (NCT01964352)
Timeframe: baseline and 12 weeks
| Intervention | L (Mean) |
|---|---|
| Placebo | -0.011 |
| Tiotropium 5 μg | 0.286 |
| Tiotropium 2.5 μg+ Olodaterol 5 μg | 0.387 |
| Tiotropium 5 μg + Olodaterol 5 μg | 0.446 |
Forced expiratory volume in one second (FEV1) Area under the curve (AUC) 0-3h was calculated as the area under the FEV1-time curve from 0 to 3h post-dose using the trapezoidal rule, divided by the duration (3h) to report in litres. FEV1 AUC0-3h response was defined as FEV1 AUC0-3h minus baseline FEV1. The adjusted mean and standard error (SE) are obtained from fitting a mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect; spatial power covariance structure for within-patient errors and Kenward-Roger approximation of denominator degrees of freedom. (NCT01964352)
Timeframe: baseline and 12 weeks
| Intervention | L (Mean) |
|---|---|
| Placebo | -0.014 |
| Tiotropium 5 μg | 0.205 |
| Tiotropium 2.5 μg+ Olodaterol 5 μg | 0.285 |
| Tiotropium 5 μg + Olodaterol 5 μg | 0.316 |
"Change from patient baseline in Forced Expiratory Volume in one second (FEV1) Area Under the FEV1-time Curve from 0 to 12hours post-dose (AUC 0-12h) [L] after 6 weeks of treatment. Measured values presented are actually adjusted means.~The period baseline is defined as the pre-dose measurement taken at on the day 1 of each period. The patient baseline is defined as the mean of non-missing period baselines for each patient." (NCT01969721)
Timeframe: Baseline and 6 weeks.
| Intervention | Litres (Mean) |
|---|---|
| T+O 2.5/5 / F+S Placebo | 0.295 |
| T+O 5/5 / F+S Placebo | 0.317 |
| F+S 250/50 / T+O Placebo | 0.192 |
| F+S 500/50 / T+O Placebo | 0.188 |
Change from patient baseline in Forced Expiratory Volume in one second (FEV1) peak (0-3 hours) after 6 weeks of treatment. FEV1 peak (0-3 hours) was defined as the maximum FEV1 value measured within the first three hours post dosing. Measured values presented are actually adjusted means. (NCT01969721)
Timeframe: Baseline and 6 weeks.
| Intervention | Litres (Mean) |
|---|---|
| T+O 2.5/5 / F+S Placebo | 0.401 |
| T+O 5/5 / F+S Placebo | 0.432 |
| F+S 250/50 / T+O Placebo | 0.291 |
| F+S 500/50 / T+O Placebo | 0.285 |
"Change from patient baseline in Trough Forced Expiratory Volume in one second (FEV1) after 6 weeks of treatment. Trough FEV1 was defined as the mean of the 23h and 23h 50min (minutes) post-dose FEV1 measurements. Measured values presented are actually adjusted means.~The period baseline is defined as the pre-dose measurement taken at on the day 1 of each period. The patient baseline is defined as the mean of non-missing period baselines for each patient." (NCT01969721)
Timeframe: Baseline and 6 weeks.
| Intervention | Litres (Mean) |
|---|---|
| T+O 2.5/5 / F+S Placebo | 0.192 |
| T+O 5/5 / F+S Placebo | 0.197 |
| F+S 250/50 / T+O Placebo | 0.150 |
| F+S 500/50 / T+O Placebo | 0.139 |
"Change from patient baseline in Forced Expiratory Volume in one second (FEV1) Area Under the FEV1-time Curve from 0 to 24 hours post-dose (AUC 0-24h) [L] after 6 weeks of treatment.~Measured values presented are actually adjusted means. The period baseline is defined as the pre-dose measurement taken at on the day 1 of each period. The patient baseline is defined as the mean of non-missing period baselines for each patient." (NCT01969721)
Timeframe: Baseline and 6 weeks.
| Intervention | Litres (Mean) |
|---|---|
| T+O 2.5/5 / F+S Placebo | 0.228 |
| T+O 5/5 / F+S Placebo | 0.244 |
| F+S 250/50 / T+O Placebo | 0.162 |
| F+S 500/50 / T+O Placebo | 0.159 |
"Change from patient baseline in Forced Expiratory Volume in one second (FEV1) Area Under the FEV1-time Curve from 12 to 24 hours post-dose (AUC 12-24h) [L] after 6 weeks of treatment. Measured values presented are actually adjusted means.~The period baseline is defined as the pre-dose measurement taken at on the day 1 of each period. The patient baseline is defined as the mean of non-missing period baselines for each patient." (NCT01969721)
Timeframe: Baseline and 6 weeks.
| Intervention | Litres (Mean) |
|---|---|
| T+O 2.5/5 / F+S Placebo | 0.160 |
| T+O 5/5 / F+S Placebo | 0.172 |
| F+S 250/50 / T+O Placebo | 0.132 |
| F+S 500/50 / T+O Placebo | 0.129 |
The SGRQ is a disease-specific questionnaire, self-completed by participants, used to evaluate the effect of GFF MDI, FF MDI and GP MDI on health-related quality of life as compared to placebo in subjects with COPD. The scores range from 0 (best possible health status) to 100 (worst possible health status). The SGRQ contains 76 items grouped into three domains (symptoms, activity and impacts). Change from Baseline in total score of -4 units or lower is considered as clinically meaningful improvement in quality of life. SGRQ Total Score was assessed at multiple visits post-baseline, and a model-based average of all visits starting from Week 12 through week 52 inclusive was calculated. The change values reported in the table represent the change between the baseline and the average SGRQ Total Score post-baseline. (NCT01970878)
Timeframe: Baseline and Weeks 12 to 52
| Intervention | Scores on a scale (Least Squares Mean) |
|---|---|
| GFF MDI (PT003) | -3.3 |
| GP MDI (PT001) | -1.9 |
| FF MDI (PT005) | -2.4 |
| Spiriva® Handihaler® (Open-label) | -2.9 |
Subjects recorded in their diary the number of puffs of rescue Ventolin HFA taken on each study day. The subject's average daily number of puffs of rescue Ventolin HFA was calculated over the entire 52-week treatment period. Missing values were ignored in both the numerator and denominator. Diary data recorded during the last 7 days of the 10-14 day screening period were used to calculate the baseline average. Change in rescue Ventolin HFA use was calculated by subtracting the baseline average from the 52-week average. (NCT01970878)
Timeframe: Baseline through Week 52
| Intervention | Puffs per day (Least Squares Mean) |
|---|---|
| GFF MDI (PT003) | -0.9 |
| GP MDI (PT001) | -0.4 |
| FF MDI (PT005) | -0.7 |
| Spiriva® Handihaler® (Open-label) | -0.4 |
Change From Baseline in Morning Pre-Dose Trough FEV1 Over 52 Weeks as a Model-Based Average (ITT Population). FEV1 was assessed at multiple time points post-baseline, and a model-based average of all visits starting from Week 2 through week 52 inclusive was calculated. The change values reported in the table represent the change between the baseline and the average FEV1 post-baseline. (NCT01970878)
Timeframe: Baseline and Weeks 2 to 52
| Intervention | Liters (Least Squares Mean) |
|---|---|
| GFF MDI (PT003) | 0.133 |
| GP MDI (PT001) | 0.076 |
| FF MDI (PT005) | 0.068 |
| Spiriva® Handihaler® (Open-label) | 0.107 |
Peak change from Baseline FEV1 Over 52 Weeks is a Model-Based Average (ITT Population). Peak FEV1 was assessed at multiple visits post-baseline, and a model-based average of all visits starting from Week 2 through week 52 inclusive was calculated. The change values reported in the table represent the change between the baseline and the average Peak FEV1 post-baseline. (NCT01970878)
Timeframe: Baseline and Weeks 2 to 52
| Intervention | Liters (Least Squares Mean) |
|---|---|
| GFF MDI (PT003) | 0.363 |
| GP MDI (PT001) | 0.234 |
| FF MDI (PT005) | 0.275 |
| Spiriva® Handihaler® (Open-label) | 0.270 |
SAC TDI focal score over 52 Weeks as a Model-Based Average (ITT Population) The TDI is an instrument which measures the changes in the participant's dyspnea from Baseline. The scores in the TDI evaluate ratings for 3 different categories (functional impairment, magnitude of task in exertional capacity, and magnitude of effort). TDI scores ranged from -3 (major deterioration) to +3 (major improvement); total score = -9 to 9. (NCT01970878)
Timeframe: Baseline and Weeks 4 to 52
| Intervention | Scores on a scale (Least Squares Mean) |
|---|---|
| GFF MDI (PT003) | 0.5 |
| GP MDI (PT001) | 0.3 |
| FF MDI (PT005) | 0.3 |
| Spiriva® Handihaler® (Open-label) | 0.4 |
The adjusted mean (SE) are obtained from fitting a mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect; spatial power covariance structure for within-patient errors and Kenward-Roger approximation of denominator degrees of freedom. (NCT02006732)
Timeframe: baseline and 12 weeks
| Intervention | L (Mean) |
|---|---|
| Placebo | -0.018 |
| Tiotropium 5 μg | 0.266 |
| Tiotropium 2.5 μg+ Olodaterol 5 μg | 0.436 |
| Tiotropium 5 μg + Olodaterol 5 μg | 0.414 |
Forced expiratory volume in one second (FEV1) Area under the curve (AUC) 0-3h was calculated as the area under the FEV1-time curve from 0 to 3h post-dose using the trapezoidal rule, divided by the duration (3h) to report in litres. FEV1 AUC0-3h response was defined as FEV1 AUC0-3h minus baseline FEV1. The adjusted mean and standard error (SE) are obtained from fitting a mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect; spatial power covariance structure for within-patient errors and Kenward-Roger approximation of denominator degrees of freedom. (NCT02006732)
Timeframe: baseline and 12 weeks
| Intervention | L (Mean) |
|---|---|
| Placebo | -0.006 |
| Tiotropium 5 μg | 0.188 |
| Tiotropium 2.5 μg+ Olodaterol 5 μg | 0.279 |
| Tiotropium 5 μg + Olodaterol 5 μg | 0.293 |
"This endpoint was evaluated after combining the data from this and the replicate study NCT01964352 as specified in the analysis plan. Mahler Transitional Dyspnoea Index (TDI) focal score was performed to measure the effect of the treatment on patients' dyspnoea.(Rating scale of 3 components - change in functional impairment, change in magnitude of tasks, change in magnitude of efforts. Worst score = -9, best score = +9).~The adjusted mean (SE) are obtained from fitting an MMRM model including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect; spatial power covariance structure for within-patient errors and Kenward-Roger approximation of denominator degrees of freedom." (NCT02006732)
Timeframe: 12 weeks
| Intervention | Units on a scale (Mean) |
|---|---|
| Placebo | 0.111 |
| Tiotropium 5 μg | 1.140 |
| Tiotropium 2.5 μg+ Olodaterol 5 μg | 1.722 |
| Tiotropium 5 μg + Olodaterol 5 μg | 1.734 |
Trough FEV1 was defined as the FEV1 value at the end of the dosing interval (24 hours). It was calculated as the mean of the 2 FEV1 measurements performed 23 h and at 23 h 50 min after inhalation of study medication at day 85. Trough FEV1 response was defines as trough FEV1 minus baseline FEV1. The adjusted mean (SE) are obtained from fitting a mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect; spatial power covariance structure for within-patient errors and Kenward-Roger approximation of denominator degrees of freedom. (NCT02006732)
Timeframe: baseline and 12 weeks
| Intervention | L (Mean) |
|---|---|
| Placebo | -0.003 |
| Tiotropium 5 μg | 0.124 |
| Tiotropium 2.5 μg+ Olodaterol 5 μg | 0.166 |
| Tiotropium 5 μg + Olodaterol 5 μg | 0.163 |
"Mahler Transitional Dyspnoea Index (TDI) focal score was performed to measure the effect of the treatment on patients' dyspnoea.(Rating scale of 3 components - change in functional impairment, change in magnitude of tasks, change in magnitude of efforts. Worst score = -9, best score = +9).~The adjusted mean (SE) are obtained from fitting an MMRM model including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect; spatial power covariance structure for within-patient errors and Kenward-Roger approximation of denominator degrees of freedom." (NCT02006732)
Timeframe: 12 weeks
| Intervention | Units on a scale (Mean) |
|---|---|
| Placebo | 0.337 |
| Tiotropium 5 μg | 0.950 |
| Tiotropium 2.5 μg+ Olodaterol 5 μg | 1.599 |
| Tiotropium 5 μg + Olodaterol 5 μg | 1.531 |
"This endpoint was evaluated after combining the data from this and the replicate study NCT01964352 as specified in the analysis plan. The SGRQ ranges from 0 (no impairment of quality of life) to 100 (highest impairment of quality of life).~The adjusted mean (SE) are obtained from fitting a mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect; spatial power covariance structure for within-patient errors and Kenward-Roger approximation of denominator degrees of freedom." (NCT02006732)
Timeframe: 12 weeks treatment
| Intervention | units on a scale (Mean) |
|---|---|
| Placebo | 42.265 |
| Tiotropium 5 μg | 39.694 |
| Tiotropium 2.5 μg+ Olodaterol 5 μg | 38.419 |
| Tiotropium 5 μg + Olodaterol 5 μg | 37.597 |
Trough FVC was defined as the FVC value at the end of the dosing interval (24 hours). It was calculated as the mean of the 2 FVC measurements performed 23 h and at 23 h 50 min after inhalation of study medication at day 85. Trough FVC response was defined as trough FVC minus baseline FVC. The adjusted mean (SE) are obtained from fitting a mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect; spatial power covariance structure for within-patient errors and Kenward-Roger approximation of denominator degrees of freedom. (NCT02006732)
Timeframe: baseline and 12 weeks
| Intervention | L (Mean) |
|---|---|
| Placebo | -0.021 |
| Tiotropium 5 μg | 0.170 |
| Tiotropium 2.5 μg+ Olodaterol 5 μg | 0.284 |
| Tiotropium 5 μg + Olodaterol 5 μg | 0.231 |
"The SGRQ ranges from 0 (no impairment of quality of life) to 100 (highest impairment of quality of life).~The adjusted mean (SE) are obtained from fitting a mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment by test day interaction, baseline, and baseline by test day interaction; patient as a random effect; spatial power covariance structure for within-patient errors and Kenward-Roger approximation of denominator degrees of freedom." (NCT02006732)
Timeframe: 12 weeks treatment
| Intervention | units on a scale (Mean) |
|---|---|
| Placebo | 42.575 |
| Tiotropium 5 μg | 39.729 |
| Tiotropium 2.5 μg+ Olodaterol 5 μg | 38.909 |
| Tiotropium 5 μg + Olodaterol 5 μg | 38.011 |
Peak heart rate change from patient baseline over all post-dose time points (5min, 10min, 25min and 50min) (NCT02030535)
Timeframe: 40 min pre-dose and at 5 min, 10 min, 25 min and 50 min post-dose
| Intervention | bpm (Mean) |
|---|---|
| Placebo | -0.7 |
| Tio+Olo 5/5μg | -0.3 |
| Tiotropium 5μg + Olodaterol 5μg | -1.2 |
Peak PR change from patient baseline over all post-dose time points (5min, 10min, 25min and 50min) (NCT02030535)
Timeframe: 40 min pre-dose and at 5 min, 10 min, 25 min and 50 min post-dose
| Intervention | ms (Mean) |
|---|---|
| Placebo | 3.9 |
| Tio+Olo 5/5μg | 4.6 |
| Tiotropium 5μg + Olodaterol 5μg | 4.7 |
Peak QRS change from patient baseline over all post-dose time points (5min, 10min, 25min and 50min) (NCT02030535)
Timeframe: 40 min pre-dose and at 5 min, 10 min, 25 min and 50 min post-dose
| Intervention | ms (Mean) |
|---|---|
| Placebo | 0.6 |
| Tio+Olo 5/5μg | 0.9 |
| Tiotropium 5μg + Olodaterol 5μg | 1.0 |
Peak QT change from patient baseline over all post-dose time points (5min, 10min, 25min and 50min) (NCT02030535)
Timeframe: 40 min pre-dose and at 5 min, 10 min, 25 min and 50 min post-dose
| Intervention | ms (Mean) |
|---|---|
| Placebo | 12.4 |
| Tio+Olo 5/5μg | 11.5 |
| Tiotropium 5μg + Olodaterol 5μg | 13.4 |
Peak QTcF interval change from patient baseline over all post-dose time points (5min, 10min, 25min and 50min) (NCT02030535)
Timeframe: 40 min pre-dose and at 5 min, 10 min, 25 min and 50 min post-dose
| Intervention | ms (Mean) |
|---|---|
| Placebo | 5.2 |
| Tio+Olo 5/5μg | 5.7 |
| Tiotropium 5μg + Olodaterol 5μg | 5.7 |
Mean RR change from patient baseline over all post-dose time points (5min, 10min, 25min and 50min) (NCT02030535)
Timeframe: 40 min pre-dose and at 5 min, 10 min, 25 min and 50 min post-dose
| Intervention | ms (Mean) |
|---|---|
| Placebo | 40.4 |
| Tio+Olo 5/5μg | 29.3 |
| Tiotropium 5μg + Olodaterol 5μg | 39.5 |
QRS change from patient baseline at individual post-dose time points (NCT02030535)
Timeframe: 40 min pre-dose and at 5 min, 10 min, 25 min and 50 min post-dose
| Intervention | ms (Mean) | |||
|---|---|---|---|---|
| 5 min | 10 min | 25 min | 50 min | |
| Placebo | -0.3 | -0.3 | -0.3 | -0.4 |
| Tio+Olo 5/5μg | -0.2 | 0.1 | 0.1 | 0.2 |
| Tiotropium 5μg + Olodaterol 5μg | -0.0 | 0.1 | 0.0 | 0.2 |
QT change from patient baseline at individual post-dose time points (NCT02030535)
Timeframe: 40 min pre-dose and at 5 min, 10 min, 25 min and 50 min post-dose
| Intervention | ms (Mean) | |||
|---|---|---|---|---|
| 5 min | 10 min | 25 min | 50 min | |
| Placebo | 4.3 | 7.1 | 7.9 | 9.4 |
| Tio+Olo 5/5μg | 5.5 | 6.3 | 7.4 | 6.7 |
| Tiotropium 5μg + Olodaterol 5μg | 4.9 | 7.9 | 9.6 | 9.4 |
PR change from patient baseline at individual post-dose time points (NCT02030535)
Timeframe: 40 min pre-dose and at 5 min, 10 min, 25 min and 50 min post-dose
| Intervention | ms (Mean) | |||
|---|---|---|---|---|
| 5 min | 10 min | 25 min | 50 min | |
| Placebo | 0.1 | 0.1 | 0.1 | 2.2 |
| Tio+Olo 5/5μg | 1.2 | 2.5 | 0.8 | 1.9 |
| Tiotropium 5μg + Olodaterol 5μg | -0.2 | 1.4 | 1.9 | 2.7 |
Mean QTcF interval change from patient baseline over all post-dose time points (5min, 10min, 25min and 50min) (NCT02030535)
Timeframe: 40 min pre-dose and at 5 min, 10 min, 25 min and 50 min post-dose
| Intervention | ms (Mean) |
|---|---|
| Placebo | 1.3 |
| Tio+Olo 5/5μg | 2.2 |
| Tiotropium 5μg + Olodaterol 5μg | 1.9 |
"The response was defined as the change from patient baseline. Patient baseline was the average of the mean pre-dose values (period baseline) on each test day (Visit 2 (Day 1), Visit 3 (Day 22 (±7days)), and Visit 4 (Day 43±7days)).~For patients who did not complete all periods, patient baseline was the average of the available period baselines.~The means presented are the adjusted means." (NCT02030535)
Timeframe: 1 hour (h) and 10 min pre-dose and at 15 min, 30 min, 1 h, 2 h and 3 h post-dose
| Intervention | Litres (Mean) |
|---|---|
| Placebo | 0.014 |
| Tio+Olo 5/5μg | 0.233 |
| Tiotropium 5μg + Olodaterol 5μg | 0.266 |
RR change from patient baseline at individual post-dose time points (NCT02030535)
Timeframe: 40 min pre-dose and at 5 min, 10 min, 25 min and 50 min post-dose
| Intervention | ms (Mean) | |||
|---|---|---|---|---|
| 5 min | 10 min | 25 min | 50 min | |
| Placebo | 29.9 | 38.8 | 40.4 | 52.3 |
| Tio+Olo 5/5μg | 29.7 | 28.1 | 33.0 | 25.2 |
| Tiotropium 5μg + Olodaterol 5μg | 31.9 | 33.5 | 50.0 | 44.0 |
Peak RR change from patient baseline over all post-dose time points (5min, 10min, 25min and 50min) (NCT02030535)
Timeframe: 40 min pre-dose and at 5 min, 10 min, 25 min and 50 min post-dose
| Intervention | ms (Mean) |
|---|---|
| Placebo | 68.8 |
| Tio+Olo 5/5μg | 55.5 |
| Tiotropium 5μg + Olodaterol 5μg | 68.0 |
Heart rate change from patient baseline at individual post-dose time points (NCT02030535)
Timeframe: 40 min pre-dose and at 5 min, 10 min, 25 min and 50 min post-dose
| Intervention | bpm (Mean) | |||
|---|---|---|---|---|
| 5 min | 10 min | 25 min | 50 min | |
| Placebo | -2.3 | -2.7 | -3.1 | -4.1 |
| Tio+Olo 5/5μg | -2.5 | -2.4 | -2.6 | -2.4 |
| Tiotropium 5μg + Olodaterol 5μg | -2.9 | -3.1 | -4.5 | -3.9 |
QTcB change from patient baseline at individual post-dose time points (NCT02030535)
Timeframe: 40 min pre-dose and at 5 min, 10 min, 25 min and 50 min post-dose
| Intervention | ms (Mean) | |||
|---|---|---|---|---|
| 5 min | 10 min | 25 min | 50 min | |
| Placebo | -2.5 | -1.4 | -1.0 | -2.6 |
| Tio+Olo 5/5μg | -1.4 | -0.2 | 0.1 | 0.7 |
| Tiotropium 5μg + Olodaterol 5μg | -2.6 | -0.0 | -2.2 | -0.7 |
Peak QTcB (Heart Rate Corrected QT Interval (Using Bazett Adjustment))change from patient baseline over all post-dose time points (5min, 10min, 25min and 50min) (NCT02030535)
Timeframe: 40 min pre-dose and at 5 min, 10 min, 25 min and 50 min post-dose
| Intervention | ms (Mean) |
|---|---|
| Placebo | 3.0 |
| Tio+Olo 5/5μg | 4.2 |
| Tiotropium 5μg + Olodaterol 5μg | 3.5 |
Mean heart rate change from patient baseline over all post-dose time points (5min, 10min, 25min and 50min) (NCT02030535)
Timeframe: 40 min pre-dose and at 5 min, 10 min, 25 min and 50 min post-dose
| Intervention | bpm (Mean) |
|---|---|
| Placebo | -3.0 |
| Tio+Olo 5/5μg | -2.5 |
| Tiotropium 5μg + Olodaterol 5μg | -3.6 |
Mean PR change from patient baseline over all post-dose time points (5min, 10min, 25min and 50min) (NCT02030535)
Timeframe: 40 min pre-dose and at 5 min, 10 min, 25 min and 50 min post-dose
| Intervention | ms (Mean) |
|---|---|
| Placebo | 0.6 |
| Tio+Olo 5/5μg | 1.6 |
| Tiotropium 5μg + Olodaterol 5μg | 1.4 |
Mean QRS change from patient baseline over all post-dose time points (5min, 10min, 25min and 50min) (NCT02030535)
Timeframe: 40 min pre-dose and at 5 min, 10 min, 25 min and 50 min post-dose
| Intervention | ms (Mean) |
|---|---|
| Placebo | -0.3 |
| Tio+Olo 5/5μg | 0.1 |
| Tiotropium 5μg + Olodaterol 5μg | 0.1 |
Mean QT change from patient baseline over all post-dose time points (5min, 10min, 25min and 50min) (NCT02030535)
Timeframe: 40 min pre-dose and at 5 min, 10 min, 25 min and 50 min post-dose
| Intervention | ms (Mean) |
|---|---|
| Placebo | 7.2 |
| Tio+Olo 5/5μg | 6.5 |
| Tiotropium 5μg + Olodaterol 5μg | 7.9 |
Mean QTcB (Heart Rate Corrected QT Interval (Using Bazett Adjustment))change from patient baseline over all post-dose time points (5min, 10min, 25min and 50min) (NCT02030535)
Timeframe: 40 min pre-dose and at 5 min, 10 min, 25 min and 50 min post-dose
| Intervention | ms (Mean) |
|---|---|
| Placebo | -1.9 |
| Tio+Olo 5/5μg | -0.2 |
| Tiotropium 5μg + Olodaterol 5μg | -1.4 |
(NCT02059434)
Timeframe: Up to 36 hours after investigational product administration
| Intervention | Hours (Median) |
|---|---|
| LAS190792 5 µg (Part 1) | NA |
| LAS190792 20 µg (Part 1) | NA |
| LAS190792 50 µg (Part 1) | 0.25 |
| LAS190792 100 µg (Part 1) | 0.5 |
| LAS190792 200 µg (Part 1) | 0.375 |
| LAS190792 400 µg (Part 1) | 0.517 |
| LAS190792 100 µg (Part 2) | 0.5 |
| LAS190792 400 µg (Part 2) | 0.517 |
(NCT02059434)
Timeframe: Up to 36 hours after investigational product administration
| Intervention | pg/mL (Mean) |
|---|---|
| LAS190792 5 µg (Part 1) | NA |
| LAS190792 20 µg (Part 1) | NA |
| LAS190792 50 µg (Part 1) | 8.79 |
| LAS190792 100 µg (Part 1) | 19.5 |
| LAS190792 200 µg (Part 1) | 43.9 |
| LAS190792 400 µg (Part 1) | 59.7 |
| LAS190792 100 µg (Part 2) | 15.4 |
| LAS190792 400 µg (Part 2) | 56.2 |
Trough is defined as the mean of the FEV1 values obtained at 23 hours and at 24 hours after morning investigational product administration. (NCT02059434)
Timeframe: Day 2
| Intervention | Liters (Mean) |
|---|---|
| LAS190792 5 µg (Part 1) | -0.013 |
| LAS190792 20 µg (Part 1) | 0.161 |
| LAS190792 50 µg (Part 1) | 0.523 |
| LAS190792 100 µg (Part 1) | 0.536 |
| LAS190792 200 µg (Part 1) | 0.371 |
| LAS190792 400 µg (Part 1) | 0.599 |
| Placebo (Part 1) | 0.029 |
| LAS190792 100 µg (Part 2) | 1.369 |
| LAS190792 400 µg (Part 2) | 1.360 |
| Tiotropium 18 μg | 1.379 |
| Indacaterol 150 μg | 1.361 |
| Placebo (Part 2) | 1.338 |
(NCT02059434)
Timeframe: Up to 36 hours after investigational product administration
| Intervention | pg.h/mL (Mean) |
|---|---|
| LAS190792 5 µg (Part 1) | NA |
| LAS190792 20 µg (Part 1) | 0.106 |
| LAS190792 50 µg (Part 1) | 5.50 |
| LAS190792 100 µg (Part 1) | 20.1 |
| LAS190792 200 µg (Part 1) | 82.7 |
| LAS190792 400 µg (Part 1) | 122 |
| LAS190792 100 µg (Part 2) | 20.5 |
| LAS190792 400 µg (Part 2) | 127 |
Adverse events (AEs) are any unfavorable and unintended medical occurrence during the subject's participation in the study (including deterioration of a pre-existing medical condition, an abnormal value in a laboratory assessment, an ECG abnormality, a 12-lead 24-hour ECG-Holter abnormality, a blood pressure abnormal value, paradoxal bronchospasm or an abnormal finding in the physical examination) and will be coded using the current Medical Dictionary for Regulatory Activities (MedDRA). (NCT02059434)
Timeframe: 30 Days
| Intervention | Participants (Number) |
|---|---|
| LAS190792 5 µg (Part 1) | 2 |
| LAS190792 20 µg (Part 1) | 3 |
| LAS190792 50 µg (Part 1) | 2 |
| LAS190792 100 µg (Part 1) | 2 |
| LAS190792 200 µg (Part 1) | 2 |
| LAS190792 400 µg (Part 1) | 4 |
| Placebo (Part 1) | 3 |
| LAS190792 100 µg (Part 2) | 12 |
| LAS190792 400 µg (Part 2) | 12 |
| Tiotropium 18 μg | 14 |
| Indacaterol 150 μg | 21 |
| Placebo (Part 2) | 15 |
This composite outcome uses a hierarchical method to ascertain differences in asthma control. For each participant, treatments are first compared to see if they differ in terms of treatment failures. If one treatment results in no treatment failures and another treatment does, it is deemed the superior treatment and no further comparisons are made. If treatment superiority cannot be assigned by treatment failures, then they are compared by asthma control days (ACDs). If one treatment yields at least 31 annualized ACDs more than another, it is deemed the superior treatment. If treatment superiority still cannot be assigned by ACDs, then they are compared by percent predicted FEV1 at the end of a treatment period. If one treatment yields at least 5% greater FEV1 than another, it is deemed the superior treatment. If treatment superiority cannot be assigned by exacerbations, ACDs or FEV1, then that participant is classified as having no differential response. (NCT02066298)
Timeframe: End of 12-week treatment period
| Intervention | Participants (Count of Participants) | |||||
|---|---|---|---|---|---|---|
| Mometesone superior to placebo | Placebo superior to mometasone | Mometesone equal to placebo | Tiotropium superior to placebo | Placebo superior to tiotropium | Tiotropium equal to placebo | |
| Eosinophil High | 35 | 12 | 20 | 25 | 19 | 18 |
| Eosinophil Low | 74 | 56 | 46 | 80 | 52 | 49 |
Asthma Control Days (ACD) are based on patient completed electronic daily diaries, and are defined as: A day with no rescue albuterol use (pre-exercise albuterol will not be counted), no non-study asthma medications, no daytime asthma symptoms (shortness of breath, wheezing, chest tightness, phlegm/mucus rated as mild, moderate or severe, or cough rated as moderate or severe), no nighttime asthma symptoms, no unscheduled healthcare visits for asthma, and no PEF < 80% of predetermined baseline. Annualized ACD are calculated as the proportion of ACD during the treatment period multiplied by 365. (NCT02066298)
Timeframe: End of 12-week treatment period
| Intervention | days (Mean) |
|---|---|
| Placebo | 179 |
| Mometasone 220mcg BID | 186 |
| Tiotropium Respimat 5mcg QD | 176 |
Peak expiratory flow rate is a person's maximum speed of expiration. It measures the airflow through the bronchi and thus the degree of obstruction in the airways. (NCT02066298)
Timeframe: End of 12-week treatment period
| Intervention | liters per minute (Mean) |
|---|---|
| Placebo | 476 |
| Mometasone 220mcg BID | 485 |
| Tiotropium Respimat 5mcg QD | 497 |
"Treatment Failure includes:~Awakening from asthma three or more times in a two-week period or on two consecutive nights, or~Using albuterol for relief of symptoms four or more times/day for two or more consecutive days, or~Albuterol has been relieving symptoms for less than four hours after each treatment over a 12-hour period, or~Using albuterol for relief of symptoms daily for seven days, and this use exceeds two times the weekly use of albuterol in the baseline period, or~exercise induces unusual breathlessness" (NCT02066298)
Timeframe: End of 12-week treatment period
| Intervention | Participants (Count of Participants) |
|---|---|
| Placebo | 29 |
| Mometasone 220mcg BID | 29 |
| Tiotropium Respimat 5mcg QD | 35 |
FEV1, expressed as percent of predicted FEV1 based on age, sex, race, and height. (NCT02066298)
Timeframe: End of 12-week treatment period
| Intervention | percentage of predicted FEV1 (Mean) |
|---|---|
| Eosinophil Low - Placebo | 92 |
| Mometasone 220mcg BID | 94 |
| Tiotropium Respimat 5mcg QD | 95 |
"Asthma exacerbations are more severe episodes of acute worsening, defined by meeting one or more of the following:~FEV1 <50% of baseline on 2 consecutive measurements~FEV1 <40% of predicted on 2 consecutive measurements~Use of ≥ 16 puffs of as needed β-agonist per 24 hours for a period of 48 hours~Use of oral/parenteral corticosteroid due to asthma" (NCT02066298)
Timeframe: End of 12-week treatment period
| Intervention | Participants (Count of Participants) |
|---|---|
| Placebo | 1 |
| Mometasone 220mcg BID | 3 |
| Tiotropium Respimat 5mcg QD | 5 |
Average daily walking intensity measured by the activity monitor in the week prior to 12 weeks of treatment. The Movement Intensity (MI) is derived from the acceleration signals. Since seismic sensors measure gravitational acceleration (g) in static situations, the acceleration signal is expressed relative to g (1g = 9.81m/s2). To calculate movement intensity (MI) the gravitational acceleration in static situations was removed and the rotation vector of the three accelerometer signals was calculated. The MI gives an indication of the power of movements. (NCT02085161)
Timeframe: Week 12
| Intervention | Multiple of 9.8*(meters / (second^2)) (Least Squares Mean) |
|---|---|
| Placebo With Behavioural Modification (BM) | 0.20 |
| Tiotropium (Tio) 5 Micro-grams (μg) With BM | 0.20 |
| Tiotropium + Olodaterol (Olo) (5/5 μg) FDC With BM | 0.20 |
| Tio+Olo (5/5 μg) FDC With Exercise Training (ET) and BM | 0.20 |
One hour, Post-dose Forced Expiratory Volume in One Second (FEV1) after 8 weeks of treatment. (NCT02085161)
Timeframe: Week 8
| Intervention | Liter (Least Squares Mean) |
|---|---|
| Placebo With Behavioural Modification (BM) | 1.375 |
| Tiotropium (Tio) 5 Micro-grams (μg) With BM | 1.550 |
| Tiotropium + Olodaterol (Olo) (5/5 μg) FDC With BM | 1.731 |
| Tio+Olo (5/5 μg) FDC With Exercise Training (ET) and BM | 1.705 |
Average daily walking time measured by the activity monitor in the week prior to Week 12. (NCT02085161)
Timeframe: Week 12
| Intervention | Second (Least Squares Mean) |
|---|---|
| Placebo With Behavioural Modification (BM) | 4670.78 |
| Tiotropium (Tio) 5 Micro-grams (μg) With BM | 4145.85 |
| Tiotropium + Olodaterol (Olo) (5/5 μg) FDC With BM | 4831.85 |
| Tio+Olo (5/5 μg) FDC With Exercise Training (ET) and BM | 4338.80 |
Perceived difficulties as evaluated with FPI-SF. FPI-SF self-report questionnaire has 6 domains: Body care(5 items), Household maintenance(8 items), Physical exercise(5 items), Recreation(5 items), Spiritual activities(4 items) and Social interaction(5 items) with five possible answers on each item: Do with no difficulty - 3, Do with some difficulty - 2, Do with great difficulty - 1, don't do because of health reasons - 0, and don't do because choose not to - 0. Domain scores are expressed as mean values, with at least 6 non-missing items required for the household maintenance domain and at least 3 non-missing items for the other domains. Total score is the mean across the six domains. So total and domain scores range from 0 to 3, with higher scores indicating higher levels of functional activity within and across domains. Respondents engaged in many activities with no difficulty will score high on the FPI, while those who perform few activities with much difficulty will score low. (NCT02085161)
Timeframe: Week 12
| Intervention | Units on a scale (Least Squares Mean) |
|---|---|
| Placebo With Behavioural Modification (BM) | 2.191 |
| Tiotropium (Tio) 5 Micro-grams (μg) With BM | 2.207 |
| Tiotropium + Olodaterol (Olo) (5/5 μg) FDC With BM | 2.335 |
| Tio+Olo (5/5 μg) FDC With Exercise Training (ET) and BM | 2.268 |
One hour, Post-dose Forced Vital Capacity (FVC) after 8 weeks of treatment. (NCT02085161)
Timeframe: Week 8
| Intervention | Liter (Least Squares Mean) |
|---|---|
| Placebo With Behavioural Modification (BM) | 2.974 |
| Tiotropium (Tio) 5 Micro-grams (μg) With BM | 3.259 |
| Tiotropium + Olodaterol (Olo) (5/5 μg) FDC With BM | 3.504 |
| Tio+Olo (5/5 μg) FDC With Exercise Training (ET) and BM | 3.452 |
Endurance time during ESWT to symptom limitation at walking speed corresponding to 85% of maximum oxygen consumption (VO2 peak) after 12 weeks of pharmacological treatment and non-pharmacological intervention. The numerical value of endurance time in seconds was transformed in log10 scale to correct for skewness and then the ANCOVA was fitted to the log10-transformed data and the least square means and SE were obtained. To present the results in a way easier for interpretation, the least square mean from the ANCOVA fitted to the log10-transformed data were transformed back taking 10 to the power of the least square estimate to obtain the geometric mean and the corresponding SE was transformed using delta method to get the corresponding SE of the geometric mean. (NCT02085161)
Timeframe: Week 12
| Intervention | Second (Geometric Mean) |
|---|---|
| Placebo With Behavioural Modification (BM) | 243.30 |
| Tiotropium (Tio) 5 Micro-grams (μg) With BM | 255.67 |
| Tiotropium + Olodaterol (Olo) (5/5 μg) FDC With BM | 302.61 |
| Tio+Olo (5/5 μg) FDC With Exercise Training (ET) and BM | 324.21 |
Endurance time during ESWT to symptom limitation at walking speed corresponding to 85% of predicted maximum oxygen consumption (VO2 peak) after 8 weeks of pharmacological treatment and non-pharmacological intervention. The numerical value of endurance time in seconds was transformed in log10 scale to correct for skewness and then an analysis of covariance (ANCOVA) was fitted to the log10-transformed data and the least square means (LSMean) and standard error (SE) were obtained. To present the results in a way easier for interpretation, the least square mean from the ANCOVA fitted to the log10-transformed data were transformed back taking 10 to the power of the least square estimate to obtain the geometric mean and the corresponding SE was transformed using delta method to get the corresponding SE of the geometric mean. (NCT02085161)
Timeframe: Week 8
| Intervention | Second (Geometric Mean) |
|---|---|
| Placebo With Behavioural Modification (BM) | 244.07 |
| Tiotropium (Tio) 5 Micro-grams (μg) With BM | 254.18 |
| Tiotropium + Olodaterol (Olo) (5/5 μg) FDC With BM | 315.32 |
| Tio+Olo (5/5 μg) FDC With Exercise Training (ET) and BM | 355.73 |
Resting inspiratory capacity (IC) measured at 1.5 hours post dose after 8 weeks of treatment. (NCT02085161)
Timeframe: Week 8
| Intervention | Liter (Least Squares Mean) |
|---|---|
| Placebo With Behavioural Modification (BM) | 2.452 |
| Tiotropium (Tio) 5 Micro-grams (μg) With BM | 2.627 |
| Tiotropium + Olodaterol (Olo) (5/5 μg) FDC With BM | 2.755 |
| Tio+Olo (5/5 μg) FDC With Exercise Training (ET) and BM | 2.771 |
Forced Expiratory Volume in one second (FEV1) will be calculated as the volume of air forcibly exhaled in one second as measured by a spirometer. (NCT02125734)
Timeframe: week 4
| Intervention | Liters (Least Squares Mean) |
|---|---|
| QVA149 | 1.676 |
| Tiotropium | 1.595 |
The investigator preference for future treatment suggestion after experiencing both treatments was assessed at the end of treatment period 2 with the Investigator Preference Questionnaire (NCT02125734)
Timeframe: 8 weeks
| Intervention | Participants (Number) |
|---|---|
| QVA149 | 71 |
| Tiotropium | 16 |
Patient preference after experiencing both treatments. The patient's preference questionnaire was a two-choice question (preference for QVA149 OR Tiotropium. (NCT02125734)
Timeframe: 8 weeks
| Intervention | Participants (Number) |
|---|---|
| QVA149 | 59 |
| Tiotropium | 26 |
"General health of the patient as evaluated by the physician using the Physician´s Global Evaluation (PGE) score at the initial examination.~The PGE score consists of an 8-point-scale which extends from 1 (very bad) to 8 (excellent)." (NCT02173769)
Timeframe: Baseline
| Intervention | Percentage of participants (Number) | |||||||
|---|---|---|---|---|---|---|---|---|
| 1 (poor) | 2 | 3 | 4 | 5 | 6 | 7 | 8 (excellent) | |
| All Patients | 2.10 | 14.72 | 25.73 | 29.13 | 16.57 | 9.44 | 2.16 | 0.11 |
"Patient satisfaction with Spiriva Respimat plus Striverdi Respimat or Spiriva 18 Microgram plus Striverdi Respimat.~Patient´s satisfaction with study treatment and handling of the Respimat inhaler was assessed on a 7-point-ordinal scale extending from very satisfied (1) to very unsatisfied (7)." (NCT02173769)
Timeframe: 4-6 weeks
| Intervention | Percentage of participants (Number) | ||||||
|---|---|---|---|---|---|---|---|
| Very satisifed | Satisfied | Rather satisfied | Neither satisfied or dissatisfied | Rather dissatisfied | Dissatisfied | Very dissatisfied | |
| All Patients | 25.21 | 42.13 | 13.53 | 9.70 | 4.29 | 4.06 | 1.07 |
"Absolute changes in the PF-10 score.~The PF-10 score is a subscale of the quality of life questionnaire Short Form 36 (SF-36) and contains 10 questions concerning physical activity and capacity. The total score ranges from 0 to 100. A higher score indicates a better physical functioning." (NCT02173769)
Timeframe: 4-6 weeks
| Intervention | Units on a scale (Mean) |
|---|---|
| All Patients | 10.15 |
"Patient satisfaction with Spiriva Respimat plus Striverdi Respimat or Spiriva 18 Microgram plus Striverdi Respimat.~Patient´s satisfaction with study treatment and handling of the Respimat inhaler was assessed on a 7-point-ordinal scale extending from very satisfied (1) to very unsatisfied (7)." (NCT02173769)
Timeframe: 4-6 weeks
| Intervention | Percentage of participants (Number) | ||||||
|---|---|---|---|---|---|---|---|
| Very satisifed | Satisfied | Rather satisfied | Neither satisfied or dissatisfied | Rather dissatisfied | Dissatisfied | Very dissatisfied | |
| All Patients | 31.53 | 49.86 | 10.06 | 5.12 | 1.52 | 1.46 | 0.45 |
"Percentage of participants with therapeutic success defined as a 10-point increase in the physical activity assessed by patient´s questionnaire (PF-10) score between the initial examination and after 4-6 weeks.~The PF-10 score is a subscale of the quality of life questionnaire Short Form 36 (SF-36) and contains 10 questions concerning physical activity and capacity. The total score ranges from 0 to 100. A higher score indicates a better physical functioning." (NCT02173769)
Timeframe: Baseline and 4-6 weeks
| Intervention | Percentage of participants (Number) | |
|---|---|---|
| Therapy successful | Therapy not successful | |
| All Patients | 48.90 | 51.10 |
"General health of the patient as evaluated by the physician using the Physician´s Global Evaluation (PGE) score after 4-6 weeks.~The PGE score consists of an 8-point-scale which extends from 1 (very bad) to 8 (excellent)." (NCT02173769)
Timeframe: 4-6 weeks
| Intervention | Percentage of participants (Number) | |||||||
|---|---|---|---|---|---|---|---|---|
| 1 (poor) | 2 | 3 | 4 | 5 | 6 | 7 | 8 (excellent) | |
| All Patients | 0.96 | 5.48 | 13.67 | 22.60 | 25.08 | 22.09 | 8.25 | 1.86 |
"Patient satisfaction with Spiriva Respimat plus Striverdi Respimat or Spiriva 18 Microgram plus Striverdi Respimat.~Patient´s satisfaction with study treatment and handling of the Respimat inhaler was assessed on a 7-point-ordinal scale extending from very satisfied (1) to very unsatisfied (7)." (NCT02173769)
Timeframe: 4-6 weeks
| Intervention | Percentage of participants (Number) | ||||||
|---|---|---|---|---|---|---|---|
| Very satisifed | Satisfied | Rather satisfied | Neither satisfied or dissatisfied | Rather dissatisfied | Dissatisfied | Very dissatisfied | |
| All Patients | 31.44 | 49.32 | 11.25 | 5.06 | 1.57 | 0.96 | 0.39 |
FEV1 is a measure of lung function and is defined as the maximal amount of air that can be forcefully exhaled in one second. Trough FEV1 on Day 85 is defined as the mean of the FEV1 values obtained 23 and 24 hours after dosing on Day 84 (Week 12). Trough FEV1 measurements were taken electronically by spirometry on Days 2, 28, 56, 84 and 85. Baseline trough FEV1 is the mean of the two assessments made -30 and -5 minutes (min) pre-dose on Day 1. Change from baseline was calculated as the trough FEV1 value on Day 85 minus the BL value. Analysis performed using a repeated measures model with covariates of treatment, baseline FEV1, centre group, 24 hour subset flag, Day, Day by baseline and Day by treatment interactions. The least squares mean changes are presented here. (NCT02207829)
Timeframe: Baseline (BL) and Day 85
| Intervention | Liter (Least Squares Mean) |
|---|---|
| Umeclidinium 62.5 mcg+Placebo QD | 0.154 |
| Tiotropium 18 mcg+Placebo QD | 0.095 |
"Minimum concentration of the analyte in plasma at steady state over a uniform dosing interval (Cmin,ss).~The displayed values show gMeans and inter-subject variabilities calculated from descriptive statistics." (NCT02231177)
Timeframe: Within 30 min before drug administration and 0:02, 0:05, 0:10, 0:15, 0:20, 0:40, 1:00, 2:00, 4:00, 6:00, 8:00, 12:00, 24:00 hours after drug administration on Day 21 of the actual treatment period.
| Intervention | pg/mL (Geometric Mean) |
|---|---|
| Tiotropium+Olodaterol 5/10 μg | 2.95 |
| Tiotropium 5 µg | 2.89 |
"Fraction of Olodaterol eliminated in urine from 0 to 24 hours at steady state (fe(0-24,ss)).~The displayed values show gMeans and inter-subject variabilities calculated from descriptive statistics." (NCT02231177)
Timeframe: Within 30 min before drug administration and 0:02, 0:05, 0:10, 0:15, 0:20, 0:40, 1:00, 2:00, 4:00, 6:00, 8:00, 12:00, 24:00 hours after drug administration on Day 21 of the actual treatment period.
| Intervention | percentage of olodaterol dose (Geometric Mean) |
|---|---|
| Tiotropium+Olodaterol 5/10 μg | 3.62 |
| Olodaterol 10 µg | 3.57 |
"Fraction of Tiotropium eliminated in urine from 0 to 24 hours at steady state (fe(0-24,ss)).~The displayed values show gMeans and inter-subject variabilities calculated from descriptive statistics." (NCT02231177)
Timeframe: Within 30 min before drug administration and 0:02, 0:05, 0:10, 0:15, 0:20, 0:40, 1:00, 2:00, 4:00, 6:00, 8:00, 12:00, 24:00 hours after drug administration on Day 21 of the actual treatment period.
| Intervention | percentage of tiotropium dose (Geometric Mean) |
|---|---|
| Tiotropium+Olodaterol 5/10 μg | 18.2 |
| Tiotropium 5 µg | 18.6 |
Time from dosing to the maximum concentration of Olodaterol in plasma at steady state (tmax,ss). (NCT02231177)
Timeframe: Within 30 min before drug administration and 0:02, 0:05, 0:10, 0:15, 0:20, 0:40, 1:00, 2:00, 4:00, 6:00, 8:00, 12:00, 24:00 hours after drug administration on Day 21 of the actual treatment period.
| Intervention | h (Median) |
|---|---|
| Tiotropium+Olodaterol 5/10 μg | 0.25 |
| Olodaterol 10 µg | 0.25 |
Time from dosing to the maximum concentration of Tiotropium in plasma at steady state (tmax,ss). (NCT02231177)
Timeframe: Within 30 min before drug administration and 0:02, 0:05, 0:10, 0:15, 0:20, 0:40, 1:00, 2:00, 4:00, 6:00, 8:00, 12:00, 24:00 hours after drug administration on Day 21 of the actual treatment period.
| Intervention | h (Median) |
|---|---|
| Tiotropium+Olodaterol 5/10 μg | 0.083 |
| Tiotropium 5 µg | 0.083 |
Time from last dosing to the minimum concentration of the analyte in plasma at steady state over a uniform dosing interval (tmin,ss) (NCT02231177)
Timeframe: Within 30 min before drug administration and 0:02, 0:05, 0:10, 0:15, 0:20, 0:40, 1:00, 2:00, 4:00, 6:00, 8:00, 12:00, 24:00 hours after drug administration on Day 21 of the actual treatment period.
| Intervention | h (Median) |
|---|---|
| Tiotropium+Olodaterol 5/10 μg | 2.00 |
| Olodaterol 10 µg | 1.01 |
Time from last dosing to the minimum concentration of the analyte in plasma at steady state over a uniform dosing interval (tmin,ss) (NCT02231177)
Timeframe: Within 30 min before drug administration and 0:02, 0:05, 0:10, 0:15, 0:20, 0:40, 1:00, 2:00, 4:00, 6:00, 8:00, 12:00, 24:00 hours after drug administration on Day 21 of the actual treatment period.
| Intervention | h (Median) |
|---|---|
| Tiotropium+Olodaterol 5/10 μg | 6.00 |
| Tiotropium 5 µg | 8.00 |
"Concentration of the analyte in plasma at 0.333 hours (20 minutes) after the 8th, 14th and 21st dose, C(0.333_8), C(0.333_14,ss) and C(0.333_21,ss) respectively. As steady state was anticipated to be reached by day 14 at the latest, the index 'ss' was used for days 14 and 21.~The displayed values show gMeans and inter-subject variabilities calculated from descriptive statistics." (NCT02231177)
Timeframe: Within 30 min before drug administration and 0:02, 0:05, 0:10, 0:15, 0:20, 0:40, 1:00, 2:00, 4:00, 6:00, 8:00, 12:00, 24:00 hours after drug administration on Day 21 of the actual treatment period.
| Intervention | pg/mL (Geometric Mean) | ||
|---|---|---|---|
| C(0.333_8) (N=38, 34) | C(0.333_14,ss) (N=41, 38) | C(0.333_21,ss) (N=43, 40) | |
| Olodaterol 10 µg | 4.48 | 4.66 | 4.80 |
| Tiotropium+Olodaterol 5/10 μg | 5.09 | 5.13 | 5.23 |
"Concentration of the analyte in plasma at 0.333 hours (20 minutes) after the 8th, 14th and 21st dose, C(0.333_8), C(0.333_14,ss) and C(0.333_21,ss) respectively. As steady state was anticipated to be reached by day 14 at the latest, the index 'ss' was used for days 14 and 21.~The displayed values show gMeans and inter-subject variabilities calculated from descriptive statistics." (NCT02231177)
Timeframe: Within 30 min before drug administration and 0:02, 0:05, 0:10, 0:15, 0:20, 0:40, 1:00, 2:00, 4:00, 6:00, 8:00, 12:00, 24:00 hours after drug administration on Day 21 of the actual treatment period.
| Intervention | pg/mL (Geometric Mean) | ||
|---|---|---|---|
| C(0.333_8) (N=40, 38) | C(0.333_14,ss) (N=43, 40) | C(0.333_21,ss) (N=46, 44) | |
| Tiotropium 5 µg | 9.58 | 9.02 | 9.21 |
| Tiotropium+Olodaterol 5/10 μg | 8.90 | 9.08 | 8.34 |
"Mean change from baseline in forced expiratory volume in one second (FEV1). Pulmonary function test.~The baseline value was measured pre-dose on day 1 of the first treatment period." (NCT02231177)
Timeframe: 0:30 and 1:00 h after drug administration on the first day of each treatment period
| Intervention | L (Mean) | |
|---|---|---|
| 0:30 h after drug administration (N=47, 47, 47) | 1:00 h after drug administration (N=47, 46, 47) | |
| Olodaterol 10 µg | 0.292 | 0.357 |
| Tiotropium 5 µg | 0.271 | 0.284 |
| Tiotropium+Olodaterol 5/10 μg | 0.275 | 0.335 |
"Mean change from baseline in forced vital capacity (FVC). Pulmonary function test.~The baseline value was measured pre-dose on day 1 of the first treatment period." (NCT02231177)
Timeframe: 0:30 and 1:00 h after drug administration on the first day of each treatment period
| Intervention | L (Mean) | |
|---|---|---|
| 0:30 h after drug administration (N=47, 47, 47) | 1:00 h after drug administration (N=47, 46, 47) | |
| Olodaterol 10 µg | 0.450 | 0.522 |
| Tiotropium 5 µg | 0.436 | 0.470 |
| Tiotropium+Olodaterol 5/10 μg | 0.485 | 0.547 |
"Amount of Olodaterol that was eliminated in urine at steady state from time point 0 to 24 h post-inhalation (Ae(0-24h,ss)).~The displayed values show adjusted gMeans and intra-subject variabilities calculated from the statistical model (ANOVA)." (NCT02231177)
Timeframe: Intervals 0-4, 4-8, 8-12 and 12-24 hours on Day 21 of the actual treatment period.
| Intervention | ng (Geometric Mean) |
|---|---|
| Tiotropium+Olodaterol 5/10 μg | 360.98 |
| Olodaterol 10 µg | 344.17 |
"Amount of Tiotropium that was eliminated in urine at steady state from time point 0 to 24 h post-inhalation (Ae(0-24h,ss)).~The displayed values show adjusted gMeans and intra-subject variabilities calculated from the statistical model (ANOVA)." (NCT02231177)
Timeframe: Intervals 0-4, 4-8, 8-12 and 12-24 hours on Day 21 of the actual treatment period.
| Intervention | ng (Geometric Mean) |
|---|---|
| Tiotropium+Olodaterol 5/10 μg | 900.57 |
| Tiotropium 5 µg | 918.63 |
"Area under the concentration time curve of Olodaterol in plasma over the time interval t1=0 to t2=1 hour at steady state (AUC(0-1h,ss)).~As plasma concentrations were not expected to be quantifiable over the complete dosing interval in all patients, t2 was defined as the time-point where at least 2/3 of the patients reveal quantifiable plasma concentrations of Olodaterol. Based on the given definition AUC(0-1h,ss) was selected as primary endpoint.~The displayed values show adjusted gMeans and intra-subject variabilities calculated from the statistical model (ANOVA)." (NCT02231177)
Timeframe: Within 30 min before drug administration and 0:02, 0:05, 0:10, 0:15, 0:20, 0:40, 1:00, 2:00, 4:00, 6:00, 8:00, 12:00, 24:00 hours after drug administration on Day 21 of the actual treatment period.
| Intervention | pg*h/mL (Geometric Mean) |
|---|---|
| Tiotropium+Olodaterol 5/10 μg | 4.67 |
| Olodaterol 10 µg | 4.15 |
"Area under the concentration time curve of Olodaterol in plasma over the time interval 0 to 2 hours at steady state (AUC(0-2h,ss)).~The displayed values show adjusted gMeans and intra-subject variabilities calculated from the statistical model (ANOVA)." (NCT02231177)
Timeframe: Within 30 min before drug administration and 0:02, 0:05, 0:10, 0:15, 0:20, 0:40, 1:00, 2:00, 4:00, 6:00, 8:00, 12:00, 24:00 hours after drug administration on Day 21 of the actual treatment period.
| Intervention | pg*h/mL (Geometric Mean) |
|---|---|
| Tiotropium+Olodaterol 5/10 μg | 8.52 |
| Olodaterol 10 µg | 8.36 |
"Area under the concentration time curve of Tiotropium in plasma over the time interval t1=0 to t2=4 h at steady state (AUC(0-4h,ss)).~The displayed values show adjusted gMeans and intra-subject variabilities calculated from the statistical model (ANOVA)." (NCT02231177)
Timeframe: Within 30 min before drug administration and 0:02, 0:05, 0:10, 0:15, 0:20, 0:40, 1:00, 2:00, 4:00, 6:00, 8:00, 12:00, 24:00 hours after drug administration on Day 21 of the actual treatment period.
| Intervention | pg*h/mL (Geometric Mean) |
|---|---|
| Tiotropium+Olodaterol 5/10 μg | 21.92 |
| Tiotropium 5 µg | 24.00 |
"Area under the concentration time curve of Tiotropium in plasma over the time interval t1=0 to t2=6 h at steady state (AUC(0-6h,ss)).~As plasma concentrations were not expected to be quantifiable over the complete dosing interval in all patients, t2 was defined as the time-point where at least 2/3 of the patients reveal quantifiable plasma concentrations of Tiotropium. Based on the given definition AUC(0-6h,ss) was selected as secondary endpoint.~The displayed values show adjusted gMeans and intra-subject variabilities calculated from the statistical model (ANOVA)." (NCT02231177)
Timeframe: Within 30 min before drug administration and 0:02, 0:05, 0:10, 0:15, 0:20, 0:40, 1:00, 2:00, 4:00, 6:00, 8:00, 12:00, 24:00 hours after drug administration on Day 21 of the actual treatment period.
| Intervention | pg*h/mL (Geometric Mean) |
|---|---|
| Tiotropium+Olodaterol 5/10 μg | 29.97 |
| Tiotropium 5 µg | 33.24 |
"Area under the plasma concentration-time curve at steady state over the time interval from 0 to the time of the last quantifiable data point (AUC(0-tz)) for Olodaterol.~The displayed values show adjusted gMeans and intra-subject variabilities calculated from the statistical model (ANOVA)." (NCT02231177)
Timeframe: Within 30 min before drug administration and 0:02, 0:05, 0:10, 0:15, 0:20, 0:40, 1:00, 2:00, 4:00, 6:00, 8:00, 12:00, 24:00 hours after drug administration on Day 21 of the actual treatment period.
| Intervention | pg*h/mL (Geometric Mean) |
|---|---|
| Tiotropium+Olodaterol 5/10 μg | 12.20 |
| Olodaterol 10 µg | 9.25 |
"Area under the plasma concentration-time curve at steady state over the time interval from 0 to the time of the last quantifiable data point (AUC(0-tz)) for Tiotropium.~The displayed values show adjusted gMeans and intra-subject variabilities calculated from the statistical model (ANOVA)." (NCT02231177)
Timeframe: Within 30 min before drug administration and 0:02, 0:05, 0:10, 0:15, 0:20, 0:40, 1:00, 2:00, 4:00, 6:00, 8:00, 12:00, 24:00 hours after drug administration on Day 21 of the actual treatment period.
| Intervention | pg*h/mL (Geometric Mean) |
|---|---|
| Tiotropium+Olodaterol 5/10 μg | 32.67 |
| Tiotropium 5 µg | 32.91 |
Clinically relevant abnormalities in vital signs (blood pressure and pulse rate), physical examination, blood chemistry, haematology, urinanalysis and ECG. New abnormal findings or worsening of baseline conditions were reported as Adverse Events. Any adverse events which occurred within 14 days following the last drug administration were assigned to the last study treatment administered. (NCT02231177)
Timeframe: From drug administration until 14 days following the last drug administration
| Intervention | participants (Number) |
|---|---|
| Tiotropium+Olodaterol 5/10 μg | 0 |
| Olodaterol 10 µg | 0 |
| Tiotropium 5 µg | 0 |
"Maximum measured concentration of Olodaterol in plasma at steady state (Cmax,ss).~The displayed values show adjusted gMeans and intra-subject variabilities calculated from the statistical model (ANOVA)." (NCT02231177)
Timeframe: Within 30 min before drug administration and 0:02, 0:05, 0:10, 0:15, 0:20, 0:40, 1:00, 2:00, 4:00, 6:00, 8:00, 12:00, 24:00 hours after drug administration on Day 21 of the actual treatment period.
| Intervention | pg/mL (Geometric Mean) |
|---|---|
| Tiotropium+Olodaterol 5/10 μg | 5.87 |
| Olodaterol 10 µg | 5.28 |
"Maximum measured concentration of Tiotropium in plasma at steady state (Cmax,ss).~The displayed values show adjusted gMeans and intra-subject variabilities calculated from the statistical model (ANOVA)." (NCT02231177)
Timeframe: Within 30 min before drug administration and 0:02, 0:05, 0:10, 0:15, 0:20, 0:40, 1:00, 2:00, 4:00, 6:00, 8:00, 12:00, 24:00 hours after drug administration on Day 21 of the actual treatment period.
| Intervention | pg/mL (Geometric Mean) |
|---|---|
| Tiotropium+Olodaterol 5/10 μg | 15.55 |
| Tiotropium 5 µg | 16.15 |
"Minimum concentration of the analyte in plasma at steady state over a uniform dosing interval (Cmin,ss).~The displayed values show gMeans and inter-subject variabilities calculated from descriptive statistics." (NCT02231177)
Timeframe: Within 30 min before drug administration and 0:02, 0:05, 0:10, 0:15, 0:20, 0:40, 1:00, 2:00, 4:00, 6:00, 8:00, 12:00, 24:00 hours after drug administration on Day 21 of the actual treatment period.
| Intervention | pg/mL (Geometric Mean) |
|---|---|
| Tiotropium+Olodaterol 5/10 μg | 2.30 |
| Olodaterol 10 µg | 2.26 |
BL FEV1 was the mean of the 2 assessments made 30 and 5 min PD on Day 1. WM FEV1 derived by calculating the area under the FEV1/time curve (AUC) using the trapezoidal rule, and then dividing the value by the time interval over which the AUC was calculated. The WM was calculated at Days 1 and 84 using the 0-6 hr post-dose FEV1 measurements collected on that day, which included PD FEV1 (taken 30 and 5 min prior to dosing on Day 1 and the 30 and 5 min reading prior to dosing on Day 84) and post-dose FEV1 measurements at 1, 3 and 6 hr post-dose.WM change from BL was the WM at at the visit minus the BL value. Analysis was performed using a RM model with covariates of trt, BL FEV1 (mean of values measured at 30 and 5 min PD on Day 1) center group, day, day by BL and day by trt interaction, where day was nominal. Only par with data available at the specified TP were analyzed but all par w/o missing covariate information and with >=1 post-BL measurement were included in the analysis. (NCT02257385)
Timeframe: Baseline and Day 84
| Intervention | Liters (Least Squares Mean) |
|---|---|
| Umeclidinium/Vilanterol 62.5/25 µg | 0.235 |
| Indacaterol 150 µg + Tiotropium Bromide 18 µg | 0.258 |
FEV1 is a measure of lung function and is defined as the maximal amount of air that can be forcefully exhaled in 1 second. BL was the mean of the 2 assessments made 30 and 5 minutes (min) pre-dose (PD) on Day 1. Trough FEV1 measurements were taken electronically by spirometry on Days 2, 28, 56, 84 and 85. Trough FEV1 on Day 85 is defined as the mean of the FEV1 values obtained at 23 and 24 hours (hr) after dosing on Day 84 (at Week 12 + 1 day). Analysis was performed using mixed model repeated measures (RM) with covariates of trt, BL FEV1 (mean of values measured at 30 and 5 min PD on Day 1), center group, day, day by BL interaction and day by trt interaction, where day was nominal. (NCT02257385)
Timeframe: Baseline (BL) and Day 85
| Intervention | Liters (Least Squares Mean) |
|---|---|
| Umeclidinium/Vilanterol 62.5/25 µg | 0.172 |
| Indacaterol 150 µg + Tiotropium Bromide 18 µg | 0.171 |
"All deaths and any other findings suggestive of a potential MACE (including clinically relevant information and SAEs, and all PTs form the SMQs myocardial infarction, other ischemic heart disease, central nervous system hemorrhages and cerebrovascular conditions) were sent to an adjudication committee for review and categorized as CV death, nonfatal MI, and nonfatal stroke. The MACE score was defined as the total number of subjects with CV deaths, nonfatal MIs, and nonfatal strokes. These events were collected from the first date of study medication until the date of last contact." (NCT02276222)
Timeframe: Up to 48 Weeks
| Intervention | percentage of participants (Number) | |||
|---|---|---|---|---|
| MACE score | cardiovascular death | non-fatal myocardial infarction | non-fatal stroke | |
| Spiriva 18 mcg QD Handihaler | 1.7 | 0.4 | 1.1 | 0.2 |
| SUN-101 50 mcg BID eFlow (CS) Nebulizer | 0.5 | 0.2 | 0.3 | 0 |
"All deaths and any other findings suggestive of a potential MACE (including clinically relevant information and SAEs, and all PTs form the SMQs myocardial infarction, other ischemic heart disease, central nervous system hemorrhages and cerebrovascular conditions) were sent to an adjudication committee for review and categorized as CV death, nonfatal MI, and nonfatal stroke. The MACE score was defined as the total number of subjects with CV deaths, nonfatal MIs, and nonfatal strokes. These events were collected from the first date of study medication until the date of last contact." (NCT02276222)
Timeframe: Up to Week 48
| Intervention | participants (Number) | |||
|---|---|---|---|---|
| MACE score | cardiovascular death | non-fatal myocardial infarction | non-fatal stroke | |
| Spiriva 18 mcg QD Handihaler | 8 | 2 | 5 | 1 |
| SUN-101 50 mcg BID eFlow (CS) Nebulizer | 3 | 1 | 2 | 0 |
"All deaths and any other findings suggestive of a potential MACE (including clinically relevant information and SAEs, and all PTs form the SMQs myocardial infarction, other ischemic heart disease, central nervous system hemorrhages and cerebrovascular conditions) were sent to an adjudication committee for review and categorized as CV death, nonfatal MI, and nonfatal stroke. The MACE score was defined as the total number of subjects with CV deaths, nonfatal MIs, and nonfatal strokes. These events were collected from the first date of study medication until the date of last contact." (NCT02276222)
Timeframe: up to week 48
| Intervention | event per 1000 person years (Number) | |||
|---|---|---|---|---|
| MACE score | cardiovascular death | non-fatal myocardial infarction | non-fatal stroke | |
| Spiriva 18 mcg QD Handihaler | 20.3 | 5.1 | 12.7 | 2.5 |
| SUN-101 50 mcg BID eFlow (CS) Nebulizer | 6.4 | 2.1 | 4.3 | 0 |
A TEAE is any adverse event (AE) that occurred on or after the first dose of study medication, any AE with a missing start date and a stop date on or after the first dose of study medication, or any AE with both a missing start and stop date. (NCT02276222)
Timeframe: Up to Week 48
| Intervention | percentage of participants (Number) |
|---|---|
| SUN-101 50 mcg BID eFlow (CS) Nebulizer | 69.4 |
| Spiriva 18 mcg QD Handihaler | 67.0 |
A TEAE is any adverse event (AE) that occurred on or after the first dose of study medication, any AE with a missing start date and a stop date on or after the first dose of study medication, or any AE with both a missing start and stop date. (NCT02276222)
Timeframe: Up to 48 Weeks
| Intervention | percentage of participants (Number) |
|---|---|
| SUN-101 50 mcg BID eFlow (CS) Nebulizer | 10.0 |
| Spiriva 18 mcg QD Handihaler | 2.8 |
A treatment emergent serious adverse event (SAE) is any SAE that occurred on or after the first dose of study medication, any SAE with a missing start date and a stop date on or after the first dose of study medication, or any SAE with both a missing start and stop date. (NCT02276222)
Timeframe: Up to Week 48
| Intervention | participants (Number) |
|---|---|
| SUN-101 50 mcg BID eFlow (CS) Nebulizer | 76 |
| Spiriva 18 mcg QD Handihaler | 49 |
A TEAE is any adverse event (AE) that occurred on or after the first dose of study medication, any AE with a missing start date and a stop date on or after the first dose of study medication, or any AE with both a missing start and stop date. (NCT02276222)
Timeframe: Up to Week 48
| Intervention | participants (Number) |
|---|---|
| SUN-101 50 mcg BID eFlow (CS) Nebulizer | 430 |
| Spiriva 18 mcg QD Handihaler | 312 |
A TEAE is any adverse event (AE) that occurred on or after the first dose of study medication, any AE with a missing start date and a stop date on or after the first dose of study medication, or any AE with both a missing start and stop date. (NCT02276222)
Timeframe: Up to Week 48
| Intervention | participants (Number) |
|---|---|
| SUN-101 50 mcg BID eFlow (CS) Nebulizer | 62 |
| Spiriva 18 mcg QD Handihaler | 13 |
"Spirometry was performed according to internationally accepted standards. Trough FEV1 was defined as the average of the FEV1 values collected at the end of the dosing interval at each clinic visit. The mean change from baseline in trough FEV1 over the 48 week treatment period is calculated by averaging the trough FEV1 changes from baseline across all study visits while subjects are taking randomized treatment.~Values affected by other medication use were to be set to missing." (NCT02276222)
Timeframe: Up to Week 48
| Intervention | liters (Least Squares Mean) |
|---|---|
| SUN-101 50 mcg BID eFlow (CS) Nebulizer | 0.1016 |
| Spiriva 18 mcg QD Handihaler | 0.0931 |
A treatment emergent serious adverse event (SAE) is any SAE that occurred on or after the first dose of study medication, any SAE with a missing start date and a stop date on or after the first dose of study medication, or any SAE with both a missing start and stop date. (NCT02276222)
Timeframe: Up to Week 48
| Intervention | percentage of participants (Number) |
|---|---|
| SUN-101 50 mcg BID eFlow (CS) Nebulizer | 12.3 |
| Spiriva 18 mcg QD Handihaler | 10.5 |
Key secondary endpoint: Number of patients with at least one moderate to severe COPD exacerbation during the actual treatment period per treatment. The actual treatment period was defined as the interval from first in-take of study medication until 1 day after last in-take of study medication. The median was not estimated due to less than 50% of patients having an event. Hence the number of patients with at least one moderate to severe COPD exacerbation is presented. (NCT02296138)
Timeframe: From first in-take of study medication until 1 day after last in-take of study medication, up to 361 days
| Intervention | Number of patients (Number) |
|---|---|
| Tiotropium 5 Microgram (μg) | 1777 |
| Tiotropium (5 μg) + Olodaterol (5 μg) | 1746 |
Annualised rate of exacerbations leading to hospitalisation during the actual treatment period was calculated per treatment per patient-year. The actual treatment period was defined as the interval from first in-take of study medication until 1 day after last in-take of study medication. (NCT02296138)
Timeframe: From first in-take of study medication until 1 day after last in-take of study medication, up to 361 days
| Intervention | Rate per patient-year (Least Squares Mean) |
|---|---|
| Tiotropium 5 Microgram (μg) | 0.20 |
| Tiotropium (5 μg) + Olodaterol (5 μg) | 0.18 |
Annualised rate of moderate to severe COPD exacerbations during the actual treatment period was calculated per treatment per patient-year. The actual treatment period was defined as the interval from first in-take of study medication until 1 day after last in-take of study medication. Least Squares Means are actually exponentiated. (NCT02296138)
Timeframe: From first in-take of study medication until 1 day after last in-take of study medication, up to 361 days
| Intervention | Rate per patient-year (Least Squares Mean) |
|---|---|
| Tiotropium 5 Microgram (μg) | 0.97 |
| Tiotropium (5 μg) + Olodaterol (5 μg) | 0.90 |
Number of patients with all-cause mortality occurring during the actual treatment period per treatment. The actual treatment period was defined as the interval from first in-take of study medication until 1 day after last in-take of study medication. The median was not estimated due to less than 50% of patients having an event. Hence the number of patients with all-cause mortality is presented. (NCT02296138)
Timeframe: From first in-take of study medication until 1 day after last in-take of study medication, up to 361 days
| Intervention | Number of patients (Number) |
|---|---|
| Tiotropium 5 Microgram (μg) | 32 |
| Tiotropium (5 μg) + Olodaterol (5 μg) | 36 |
Number of patients with at least one COPD exacerbation leading to hospitalisation during the actual treatment period per treatment. The actual treatment period was defined as the interval from first in-take of study medication until 1 day after last in-take of study medication. The median was not estimated due to less than 50% of patients having an event. Hence the number of patients with at least one moderate to severe COPD exacerbation leading to hospitalisation is presented. (NCT02296138)
Timeframe: From first in-take of study medication until 1 day after last in-take of study medication, up to 361 days
| Intervention | Number of patients (Number) |
|---|---|
| Tiotropium 5 Microgram (μg) | 469 |
| Tiotropium (5 μg) + Olodaterol (5 μg) | 450 |
Mean sleeping oxygen saturation (%) (NCT02331940)
Timeframe: 6 months after treatment initiation
| Intervention | percentage of Oxygen Saturation (Mean) |
|---|---|
| Handihaler | 94.4 |
| Respimat | 94.4 |
Sleepiness - Epworth Sleepiness Scale (ESS) score (range 0-24, higher values indicate worse outcome, >10 indicates sleepiness, >16 excessive sleepiness) (NCT02331940)
Timeframe: 6 months after treatment initiation
| Intervention | units on a scale (Mean) |
|---|---|
| Handihaler | 6.5 |
| Respimat | 6.1 |
Number of patients needed hospitalization (NCT02331940)
Timeframe: 6 months after treatment initiation
| Intervention | participants (Number) |
|---|---|
| Handihaler | 0 |
| Respimat | 0 |
"Sleep quality, meaning the architecture of sleep (amount of the different sleep stages across the sleep episode),consists of sleep efficiency (%) (total sleep time - TST divided by the total time in bed and multiplied by 100), REM (%TST) (rapid eye movement sleep divided by TST and multiplied by 100) and NREM (%TST) (non-rapid eye movement sleep divided by TST and multiplied by 100).~NORMAL RANGES Sleep efficiency: Normal is approximately 85 to 90% or higher. NREM (%TST): 75-80% REM (%TST) normally occupies about 20-25% of sleep time." (NCT02331940)
Timeframe: 6 months after treatment initiation
| Intervention | percentage of time (Mean) | ||
|---|---|---|---|
| sleep efficiency (%) | NREM (%TST) | REM (%TST) | |
| Handihaler | 73.2 | 87.3 | 12.7 |
| Respimat | 79.1 | 85.3 | 14.7 |
Normalized FEV1 AUC0-12 (NCT02347072)
Timeframe: Pre dose, 15 and 30 minutes, 1, 2, 4, 8, and 12 hours post the morning dose on Day 29
| Intervention | Liters (Least Squares Mean) |
|---|---|
| GFF MDI | 0.226 |
| Spiriva Respimat | 0.178 |
| Placebo | -0.026 |
Normalized FEV1 AUC12-24 (NCT02347072)
Timeframe: Pre dose, 15 and 30 minutes, 1, 2, 4, 8, and 12 hours post the evening dose on Day 29
| Intervention | Liters (Least Squares Mean) |
|---|---|
| GFF MDI | 0.159 |
| Spiriva Respimat | 0.039 |
| Placebo | -0.118 |
Normalized Forced Expiratory Volume in 1 second (FEV1) Area Under the Curve (AUC) 0-24 (NCT02347072)
Timeframe: Pre dose, 15 and 30 minutes, 1, 2, 4, 8, 12, 12.25, 12.5, 13, 14, 16, 22, and 24 hours post the morning dose on Day 29
| Intervention | Liters (Least Squares Mean) |
|---|---|
| GFF MDI | 0.192 |
| Spiriva Respimat | 0.112 |
| Placebo | -0.072 |
Morning Pre-Dose Trough FEV1 on Day 30 (NCT02347072)
Timeframe: Day 30
| Intervention | Liters (Least Squares Mean) |
|---|---|
| GFF MDI | 0.129 |
| Spiriva Respimat | 0.072 |
| Placebo | -0.073 |
Peak Change From Baseline in FEV1 Evening (NCT02347072)
Timeframe: Baseline and Day 29
| Intervention | Liters (Least Squares Mean) |
|---|---|
| GFF MDI | 0.395 |
| Spiriva Respimat | 0.230 |
| Placebo | 0.058 |
Peak Change From Baseline in FEV1 Morning (NCT02347072)
Timeframe: Baseline and Day 29
| Intervention | Liters (Least Squares Mean) |
|---|---|
| GFF MDI | 0.406 |
| Spiriva Respimat | 0.325 |
| Placebo | 0.129 |
Peak Change From Baseline in IC Evening (NCT02347072)
Timeframe: Baseline and Day 29
| Intervention | Liters (Least Squares Mean) |
|---|---|
| GFF MDI | 0.421 |
| Spiriva Respimat | 0.297 |
| Placebo | 0.109 |
Peak Change From Baseline in IC Morning (NCT02347072)
Timeframe: Baseline and Day 29
| Intervention | Liters (Least Squares Mean) |
|---|---|
| GFF MDI | 0.454 |
| Spiriva Respimat | 0.374 |
| Placebo | 0.206 |
Morning Pre-Dose Trough FEV1 on Day 29 (NCT02347072)
Timeframe: Day 29
| Intervention | Liters (Least Squares Mean) |
|---|---|
| GFF MDI | 0.140 |
| Spiriva Respimat | 0.097 |
| Placebo | -0.020 |
Time to maximum concentration of fluticasone (NCT02441114)
Timeframe: Period 1 (day 1), 2 (day 15), and 3 (day 29) at 0 to 24 h post-dose
| Intervention | h (Median) | ||
|---|---|---|---|
| Period 1 | Period 2 | Period 3 | |
| Inhalation of HCP0910 and HGP1011 | 0.76 | 0.50 | 0.88 |
Area under the concentration of fluticasone versus time curve from the time of dosing to the last measurable concentration (NCT02441114)
Timeframe: Period 1 (day 1), 2 (day 15), and 3 (day 29) at 0 to 24 h post-dose
| Intervention | h*pg/mL (Mean) | ||
|---|---|---|---|
| Period 1 | Period 2 | Period 3 | |
| Inhalation of HCP0910 and HGP1011 | 686.98 | 1247.63 | 1769.58 |
Maximum observed concentration of fluticasone (NCT02441114)
Timeframe: Period 1 (day 1), 2 (day 15), and 3 (day 29) at 0 to 24 h post-dose
| Intervention | pg/mL (Mean) | ||
|---|---|---|---|
| Period 1 | Period 2 | Period 3 | |
| Inhalation of HCP0910 and HGP1011 | 95.70 | 173.56 | 246.77 |
Percentage of patients with ADRs are presented. There was no primary outcome for effectiveness as the primary objective of the surveillance is the evaluation of safety. (NCT02489981)
Timeframe: Week 52
| Intervention | Percentage of participants (Number) |
|---|---|
| Spiriva® Respimat® | 5.59 |
"The effectiveness was determined based on the change of asthma control status from baseline at Week 52 which is the secondary endpoint in the surveillance. The asthma control status was rated on a 3-point scale of well controlled, insufficiently controlled and poorly controlled based on asthma symptoms (in the daytime or at night), use of reliever and limitation of activities including exercise (based on Asthma prevention and management guideline).~Well-controlled=WC, Insufficiently-controlled=IC, Poorly-controlled=PC, Unknown=Unk, Missing=Miss, Baseline=BL, Week 52=W52" (NCT02489981)
Timeframe: Baseline and Week 52
| Intervention | Percentage of participants (Number) | ||||||||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| WC_BL & WC_52 | IC_BL & WC_52 | PC_BL & WC_52 | Unk_BL & WC_52 | Miss_BL & WC_52 | WC_BL & IC_52 | IC_BL & IC_52 | PC_BL & IC_52 | Unk_BL & IC_52 | Miss_BL & IC_52 | WC_BL & PC_52 | IC_BL & PC_52 | PC_BL & PC_52 | Unk_BL & PC_52 | Miss_BL & PC_52 | WC_BL & Unk_52 | IC_BL & Unk_52 | PC_BL & Unk_52 | Unk_BL & Unk_52 | Miss_BL & Unk_52 | WC_BL & Miss_52 | IC_BL & Miss_52 | PC_BL & Miss_52 | Unk_BL & Miss_52 | Miss_BL & Miss_52 | |
| Spiriva® Respimat® | 66.67 | 58.12 | 35.14 | 50.00 | 0.00 | 0.00 | 17.95 | 22.52 | 25.00 | 25.00 | 0.00 | 4.27 | 17.12 | 0.00 | 0.00 | 0.00 | 2.56 | 0.90 | 25.00 | 0.00 | 33.33 | 17.09 | 24.32 | 0.00 | 75.00 |
To assess the safety and tolerability of TD-4208 by assessing the frequency and severity of Treatment Emergent Adverse Events (TEAE) (NCT02518139)
Timeframe: Baseline to Day 365
| Intervention | Participants (Count of Participants) | ||
|---|---|---|---|
| Adverse Event (AE) | Moderate or Severe AE | Serious AE | |
| TD-4208-1 | 272 | 226 | 58 |
| TD-4208-2 | 242 | 174 | 43 |
| Tiotropium | 275 | 210 | 58 |
Total score of COPD Assessment Test (CAT) will be measured at week 12. This questionnaire is completed by the patient. The score ranges from 0-40 where higher scores represent worse health status. Mild: Score = 0 - 10, Moderate: Score = 11 - 20, Severe: Score = 21 - 30, Very Severe: Score = 31 - 40. The CAT total score was the sum of 8 item scores (each ranging from 0 to 5). If 1 or 2 items were missing, they were replaced with the mean of the completed items. If 3 or more items were missing, the CAT total score was set missing (NCT02566031)
Timeframe: Week 12
| Intervention | Number of participants (Number) | ||||
|---|---|---|---|---|---|
| Mild | Moderate | Severe | Very severe | Missing | |
| Indacaterol and Glycopyrronium (QVA149) | 62 | 92 | 15 | 0 | 8 |
| Tiotropium | 54 | 101 | 22 | 1 | 6 |
Spirometry was performed according to internationally accepted standards. Trough FEV1 is defined as the mean of 45 minute and 15 minute pre-dose values. (NCT02566031)
Timeframe: Week 12
| Intervention | Liters (Mean) |
|---|---|
| Indacaterol and Glycopyrronium (QVA149) | 0.0668 |
| Tiotropium | 0.0090 |
A trained assessor interviewed the patient and graded the degree of impairment due to dyspnea (difficulty breathing). TDI focal score is based on three domains: functional impairment, magnitude of task and magnitude of effort and captures changes from baseline. TDI captures changes from baseline, each domain is scored from -3=major deterioration to 3=major improvement to give an overall TDI focal score of -9 to 9. Higher numbers indicate a better score. (NCT02566031)
Timeframe: Week 12
| Intervention | Score (Mean) |
|---|---|
| Indacaterol and Glycopyrronium (QVA149) | 0.77 |
| Tiotropium | 0.61 |
The total number of puffs of rescue medication used over the last 24 hours will be recorded in the patient diary in the morning. The total number of puffs of rescue medication per day over the full 12 weeks will be calculated and divided by the total number of days with non-missing rescue medication data to derive the mean daily number of puffs of rescue medication taken for the patient. The mean daily number of puffs of rescue medication used over 12 weeks will be summarized by treatments (NCT02566031)
Timeframe: Week 12
| Intervention | Puffs/day (Mean) |
|---|---|
| Indacaterol and Glycopyrronium (QVA149) | 1.7 |
| Tiotropium | 1.8 |
Spirometry was performed according to internationally accepted standards. Trough FEV1 was defined as the mean of 45 minute and 15 minute pre-dose values. (NCT02566031)
Timeframe: mean of 45 min and 15 min pre-dose week 4
| Intervention | Liters (Mean) | |
|---|---|---|
| -45min | -15min | |
| Indacaterol and Glycopyrronium (QVA149) | 0.087 | 0.077 |
| Tiotropium | 0.026 | 0.024 |
Elimination half-life (t½λz) for AZD8871 on Day 1 of each treatment period. t½λz was generally calculated over a period of less than 3 times the resultant half-life (NCT02573155)
Timeframe: Predose, and 5 min, 15 min, 30 min, and 45 min, at 1 h, 2 h, 3 h, 4 h, 6 h, 8 h, 12 h (Day 1), 24 h and 36 h (Day 2) post-dose
| Intervention | Hours (Mean) |
|---|---|
| AZD8871 50 μg (Part 1) | 9.439 |
| AZD8871 200 μg (Part 1) | 23.10 |
| AZD8871 400 μg (Part 1) | 20.81 |
| AZD8871 900 μg (Part 1) | 18.86 |
| AZD8871 1800 μg (Part 1) | 19.29 |
| AZD8871 2100 μg (Part 1) | 15.96 |
| AZD8871 400 μg (Part 2) | 14.20 |
| AZD8871 1800 μg (Part 2) | 12.89 |
"Blood pressure (BP) measurements (diastolic [DBP] and systolic BP [SBP]) taken after ~5 minutes rest in supine position, at screening, baseline (≤1 hour before IP administration), 10 and 30 minutes, 1, 2, 3, 4, 8, 12 hours (Day 1) and 24 and 36 hours (Day 2) after IP administration. Normal BP at screening: SBP 100-140 mmHg (subjects aged ≤59 years) and 100-150 mmHg (subjects aged ≥60 years), and DBP 40-90 mmHg.~Criteria for notable changes in BP:~High SBP: (≥180 and increase over baseline (predose) ≥20) or (≥200 and baseline <200) Low SBP: (≤ 90 and decrease over baseline ≥20) or (≤75 and baseline >75) High DBP: (≥105 and increase over baseline ≥15) or (≥115 and baseline <115) Low DBP: (≤50 and decrease over baseline ≥15) or (≤40 and baseline >40) All out of range values were flagged to the principal investigator who assessed clinical relevance based on medical criteria at individual subject level. Clinically relevant findings were assessed until considered non-clinically relevant." (NCT02573155)
Timeframe: From the time of informed consent up to 36 hours after last dose of IP.
| Intervention | Participants (Count of Participants) |
|---|---|
| AZD8871 50 μg (Part 1) | 0 |
| AZD8871 200 μg (Part 1) | 0 |
| AZD8871 400 μg (Part 1) | 0 |
| AZD8871 900 μg (Part 1) | 0 |
| AZD8871 1800 μg (Part 1) | 0 |
| AZD8871 2100 μg (Part 1) | 0 |
| Placebo (Part 1) | 0 |
| AZD8871 400 μg (Part 2) | 0 |
| AZD8871 1800 μg (Part 2) | 0 |
| Indacaterol 150 μg (Part 2) | 0 |
| Tiotropium 18 μg (Part 2) | 0 |
| Placebo (Part 2) | 0 |
"A composite of clinically relevant abnormalities in clinical biochemistry, hematology and urinalysis laboratory evaluations. Laboratory tests (haematology, blood chemistry, and urinalysis) were performed at screening, at Day -1 (Part 1 only), at 24 hours (Day 2) and at follow-up (7 [±2] days) after IP administration. Coagulation was only performed at screening; TSH, T4 only at screening, at Day-1 and at follow-up.~Abnormal findings were flagged to the principal investigator who assessed clinical relevance based on medical criteria at individual subject level. Clinically relevant findings were assessed until the abnormality was considered non-clinically relevant." (NCT02573155)
Timeframe: From the time of informed consent up to 7 days after the last dose of IP.
| Intervention | Participants (Count of Participants) |
|---|---|
| AZD8871 50 μg (Part 1) | 0 |
| AZD8871 200 μg (Part 1) | 0 |
| AZD8871 400 μg (Part 1) | 0 |
| AZD8871 900 μg (Part 1) | 0 |
| AZD8871 1800 μg (Part 1) | 0 |
| AZD8871 2100 μg (Part 1) | 0 |
| Placebo (Part 1) | 0 |
| AZD8871 400 μg (Part 2) | 0 |
| AZD8871 1800 μg (Part 2) | 0 |
| Indacaterol 150 μg (Part 2) | 0 |
| Tiotropium 18 μg (Part 2) | 0 |
| Placebo (Part 2) | 0 |
"HR, QTcF and other ECG abnormalities were assessed by local digital 12-lead ECG performed in triplicate at the time points indicated:~ECG (Parts 1 and 2) was assessed at Screening, Day 1 baseline, 10 min, 30 min, 1 hour (h), 2 h, 3 h, 4 h, 8 h, 12 h, 24 h, 36 h after dosing.~Telemetry (Part 1), assessed with at least 2 lead real time display, was recorded at Day -1 (4-6 hours continuous recording, at the time this was more convenient for the logistics of the unit) and on Day 1 from the time of the IP administration up to at least 24 hours, but if advised by the Investigator or designee, then up to 36 hours after IP administration.~Abnormal findings were flagged to the principal investigator who assessed clinical relevance based on medical criteria at individual subject level. Clinically relevant findings were assessed until the abnormality was considered non-clinically relevant." (NCT02573155)
Timeframe: From the time of informed consent up to 36 hours after last dose of IP.
| Intervention | Participants (Count of Participants) |
|---|---|
| AZD8871 50 μg (Part 1) | 0 |
| AZD8871 200 μg (Part 1) | 0 |
| AZD8871 400 μg (Part 1) | 0 |
| AZD8871 900 μg (Part 1) | 0 |
| AZD8871 1800 μg (Part 1) | 0 |
| AZD8871 2100 μg (Part 1) | 0 |
| Placebo (Part 1) | 0 |
| AZD8871 400 μg (Part 2) | 0 |
| AZD8871 1800 μg (Part 2) | 0 |
| Indacaterol 150 μg (Part 2) | 0 |
| Tiotropium 18 μg (Part 2) | 0 |
| Placebo (Part 2) | 0 |
An adverse event is the development of an undesirable medical condition, or the deterioration of a pre-existing medical condition, following or during exposure to a pharmaceutical product, whether or not considered causally related to the product. An undesirable medical condition can be symptoms, signs, or the abnormal results of laboratory parameters (haematology, blood chemistry, urinalysis, physical examination, 12-lead ECGs and telemetry, and vital signs). AEs were coded using the Medical Dictionary for Regulatory Activities (MedDRA) version 18.1. (NCT02573155)
Timeframe: From the time of informed consent up to 14 (±2) days after the last dose of investigational product. Unresolved AEs were followed up by the investigator for as long as medically indicated.
| Intervention | Participants (Count of Participants) |
|---|---|
| AZD8871 50 μg (Part 1) | 5 |
| AZD8871 200 μg (Part 1) | 5 |
| AZD8871 400 μg (Part 1) | 3 |
| AZD8871 900 μg (Part 1) | 3 |
| AZD8871 1800 μg (Part 1) | 3 |
| AZD8871 2100 μg (Part 1) | 2 |
| Placebo (Part 1) | 7 |
| AZD8871 400 μg (Part 2) | 18 |
| AZD8871 1800 μg (Part 2) | 7 |
| Indacaterol 150 μg (Part 2) | 12 |
| Tiotropium 18 μg (Part 2) | 11 |
| Placebo (Part 2) | 11 |
tmax (time to reach maximum concentration) of AZD8871 on Day 1 of each treatment period. (NCT02573155)
Timeframe: Pre-dose, and 5 min, 15 min, 30 min, 45 min, 1 h, 2 h, 3 h, 4 h, 6 h, 8 h, 12 h (Day 1), 24 h, and 36 h (Day 2) post-dose
| Intervention | Hours (Median) |
|---|---|
| AZD8871 50 μg (Part 1) | 0.88 |
| AZD8871 200 μg (Part 1) | 0.86 |
| AZD8871 400 μg (Part 1) | 1.00 |
| AZD8871 900 μg (Part 1) | 1.00 |
| AZD8871 1800 μg (Part 1) | 1.49 |
| AZD8871 2100 μg (Part 1) | 1.02 |
| AZD8871 400 μg (Part 2) | 1.00 |
| AZD8871 1800 μg (Part 2) | 2.00 |
AUC (area under the concentration-time curve from time 0 to infinity) of AZD8871 on Day 1 of each treatment period (NCT02573155)
Timeframe: Predose, and 5 min, 15 min, 30 min, and 45 min, at 1 h, 2 h, 3 h, 4 h, 6 h, 8 h, 12 h (Day 1), 24 h and 36 h (Day 2) post-dose
| Intervention | pg*h/mL (Geometric Mean) |
|---|---|
| AZD8871 50 μg (Part 1) | 123.1 |
| AZD8871 200 μg (Part 1) | 774.5 |
| AZD8871 400 μg (Part 1) | 1671 |
| AZD8871 900 μg (Part 1) | 3831 |
| AZD8871 1800 μg (Part 1) | 6941 |
| AZD8871 2100 μg (Part 1) | 7164 |
| AZD8871 400 μg (Part 2) | 1459 |
| AZD8871 1800 μg (Part 2) | 6769 |
AUC(0-24) (area under the concentration-time curve from zero to 24h) of AZD8871 on Day 1 of each treatment period. (NCT02573155)
Timeframe: Pre-dose, and 5 min, 15 min, 30 min, 45 min, 1 h, 2 h, 3 h, 4 h, 6 h, 8 h, 12 h (Day 1), 24 h, and 36 h (Day 2) post-dose
| Intervention | pg*h/mL (Geometric Mean) |
|---|---|
| AZD8871 50 μg (Part 1) | 118.9 |
| AZD8871 200 μg (Part 1) | 567.9 |
| AZD8871 400 μg (Part 1) | 1265 |
| AZD8871 900 μg (Part 1) | 3020 |
| AZD8871 1800 μg (Part 1) | 5587 |
| AZD8871 2100 μg (Part 1) | 5922 |
| AZD8871 400 μg (Part 2) | 1195 |
| AZD8871 1800 μg (Part 2) | 5659 |
AUC(0-t) (area under the concentration-time curve from time zero to time of the last quantifiable measurable concentration) of AZD8871 on Day 1 of each treatment period. (NCT02573155)
Timeframe: Pre-dose, and 5 min, 15 min, 30 min, 45 min, 1 h, 2 h, 3 h, 4 h, 6 h, 8 h, 12 h (Day 1), 24 h, and 36 h (Day 2) post-dose
| Intervention | pg*h/mL (Geometric Mean) |
|---|---|
| AZD8871 50 μg (Part 1) | 110 |
| AZD8871 200 μg (Part 1) | 631.3 |
| AZD8871 400 μg (Part 1) | 1397 |
| AZD8871 900 μg (Part 1) | 3299 |
| AZD8871 1800 μg (Part 1) | 6055 |
| AZD8871 2100 μg (Part 1) | 6418 |
| AZD8871 400 μg (Part 2) | 1239 |
| AZD8871 1800 μg (Part 2) | 6159 |
Pharmacodynamics of AZD8871 before (-45 min and -15 min pre-dose) and after single dosing of AZD8871 Forced expiratory volume in 1 second (FEV1) on Day 2 (defined as the average of the values 23:00 and 24:00 hours after the morning dose of investigational product) (NCT02573155)
Timeframe: Baseline (Day 1) to 36 hours post-dose (Day 2)
| Intervention | Liters (Mean) |
|---|---|
| AZD8871 50 μg (Part 1) | -0.0375 |
| AZD8871 200 μg (Part 1) | 0.2183 |
| AZD8871 400 μg (Part 1) | 0.2883 |
| AZD8871 900 μg (Part 1) | 0.1858 |
| AZD8871 1800 μg (Part 1) | 0.3275 |
| AZD8871 2100 μg (Part 1) | 0.4630 |
| Placebo (Part 1) | -0.0600 |
| AZD8871 400 μg (Part 2) | 0.0738 |
| AZD8871 1800 μg (Part 2) | 0.1731 |
| Indacaterol 150 μg (Part 2) | 0.1036 |
| Tiotropium 18 μg (Part 2) | 0.1055 |
| Placebo (Part 2) | -0.0294 |
Cmax (maximum observed plasma drug concentrations) of AZD8871 on Day 1 of each treatment period. (NCT02573155)
Timeframe: Pre-dose, and 5 min, 15 min, 30 min, 45 min, 1 h, 2 h, 3 h, 4 h, 6 h, 8 h, 12 h (Day 1), 24 h, and 36 h (Day 2) post-dose
| Intervention | pg/mL (Geometric Mean) |
|---|---|
| AZD8871 50 μg (Part 1) | 34.77 |
| AZD8871 200 μg (Part 1) | 174.1 |
| AZD8871 400 μg (Part 1) | 313.4 |
| AZD8871 900 μg (Part 1) | 797.3 |
| AZD8871 1800 μg (Part 1) | 1351 |
| AZD8871 2100 μg (Part 1) | 1243 |
| AZD8871 400 μg (Part 2) | 199.3 |
| AZD8871 1800 μg (Part 2) | 810.8 |
Transitional Dyspnea Index (TDI) score presents the degree of impairment due to dyspnea. The lower the score the worse the severity of dyspnea. The Baseline Dyspnea Index (BDI) / TDI is an instrument used to assess a participant's level of dyspnea. The BDI and TDI each have three domains: functional impairment, magnitude of task and magnitude of effort. BDI domains were rated from 0 (severe) to 4 (unimpaired) and rates summed for baseline focal score ranged from 0 to 12; lower scores mean worse severity. TDI domains were rated from -3 (major deterioration) to 3 (major improvement) and rates summed for transition focal score ranged from -9 to 9; negative scores indicate deterioration. A TDI focal score of ≥1 was defined as a clinically important improvement from baseline. (NCT02603393)
Timeframe: 12 weeks
| Intervention | Score on a scale (Least Squares Mean) |
|---|---|
| QVA149 | 1.177 |
| Tiotropium + Salmeterol/Fluticasone | 1.418 |
COPD exacerbations starting between first dose and one day after last treatment are included. COPD exacerbations that occurred within 7 days of each other are collapsed as one event. (NCT02603393)
Timeframe: 26 weeks
| Intervention | COPD Exacerbations/year (Number) |
|---|---|
| QVA149 | 0.001 |
| Tiotropium + Salmeterol/Fluticasone | 0.001 |
COPD exacerbations starting between first dose and one day after last treatment are included. COPD exacerbations that occurred within 7 days of each other are collapsed as one event (NCT02603393)
Timeframe: 26 weeks
| Intervention | COPD Exacerbations/year (Number) |
|---|---|
| QVA149 | 0.47 |
| Tiotropium + Salmeterol/Fluticasone | 0.44 |
Change from baseline in mean daily number of puffs of rescue medication (number of puffs taken in the previous 12 hours) over 26 weeks of treatment. (NCT02603393)
Timeframe: Baseline, 26 weeks
| Intervention | Number of puffs per day (Least Squares Mean) |
|---|---|
| QVA149 | -0.307 |
| Tiotropium + Salmeterol/Fluticasone | -0.484 |
Change from baseline in forced vital capacity following 26 weeks of treatment. Trough FVC is defined as the average of the pre-dose FVC measurements at -45 min and -15 min prior to dosing at each visit except Day 182 which is the average of the post-dose FVC measurements at 23h15min and 23h45min after dosing at Day 181. Baseline is considered the Day 1 average of pre-dose measurements. (NCT02603393)
Timeframe: Baseline, 26 weeks
| Intervention | Liters (Least Squares Mean) |
|---|---|
| QVA149 | -0.030 |
| Tiotropium + Salmeterol/Fluticasone | -0.048 |
Mean change from baseline in post-dose trough forced expiratory volume in 1 second (FEV1) following 26 weeks of treatment. Trough FEV1 is defined as the mean of the two FEV1 values measured at 23 hr 15 min and 23 hr 45 min after the morning dose taken at site on Day 181. Baseline FEV1 is defined as the average of the pre-dose FEV1 measured at -45 min and -15 min at Day 1. (NCT02603393)
Timeframe: Baseline, 26 weeks
| Intervention | Liters (Least Squares Mean) |
|---|---|
| QVA149 | -0.029 |
| Tiotropium + Salmeterol/Fluticasone | -0.003 |
Trough FEV1 is defined as the average of the pre-dose FEV1 measurements at -45 min and -15 min prior to dosing at each visit except Day 182 which is the average of the post-dose FEV1 measurements at 23h15min and 23h45min after dosing at Day 181. Baseline FEV1 is considered the Day 1 average of pre-dose measurements. (NCT02603393)
Timeframe: 26 weeks
| Intervention | Liters (Least Squares Mean) |
|---|---|
| QVA149 | -0.029 |
| Tiotropium + Salmeterol/Fluticasone | -0.003 |
"The St. George Respiratory Questionnaire C (SGRQ-C) is used to provide the health status measurements in this study. Baseline SGRQ-C is defined as the assessment taken right before the first dose of the double-blind drug on Day 1. Higher values correspond to greater impairment of health status. The SGRQ contains 50 items divided into 2 parts covering 3 aspects of health related to COPD: Part I covers Symptoms and is concerned with respiratory symptoms, their frequency and severity; Part II covers Activity and is concerned with activities that cause or are limited by breathlessness; Part II is also concerned with Impacts, which covers a range of aspects concerned with social functioning and psychological disturbances resulting from airways disease. A score was calculated for each of these 3 subscales and a Total score was calculated. In each case the lowest possible value is zero and the highest 100. Higher values correspond to greater impairment of health status." (NCT02603393)
Timeframe: Baseline, 12 weeks
| Intervention | Score on a scale (Least Squares Mean) |
|---|---|
| QVA149 | -0.7 |
| Tiotropium + Salmeterol/Fluticasone | -2.5 |
"The St. George Respiratory Questionnaire C (SGRQ-C) is used to provide the health status measurements in this study. Baseline SGRQ-C is defined as the assessment taken right before the first dose of the double-blind drug on Day 1. Higher values correspond to greater impairment of health status. The SGRQ contains 50 items divided into 2 parts covering 3 aspects of health related to COPD: Part I covers Symptoms and is concerned with respiratory symptoms, their frequency and severity; Part II covers Activity and is concerned with activities that cause or are limited by breathlessness; Part II is also concerned with Impacts, which covers a range of aspects concerned with social functioning and psychological disturbances resulting from airways disease. A score was calculated for each of these 3 subscales and a Total score was calculated. In each case the lowest possible value is zero and the highest 100. Higher values correspond to greater impairment of health status." (NCT02603393)
Timeframe: Baseline, 26 weeks
| Intervention | Score on a scale (Least Squares Mean) |
|---|---|
| QVA149 | -1.0 |
| Tiotropium + Salmeterol/Fluticasone | -2.5 |
Transitional Dyspnea Index (TDI) score presents the degree of impairment due to dyspnea. The lower the score the worse the severity of dyspnea. The Baseline Dyspnea Index (BDI) / TDI is an instrument used to assess a participant's level of dyspnea. The BDI and TDI each have three domains: functional impairment, magnitude of task and magnitude of effort. BDI domains were rated from 0 (severe) to 4 (unimpaired) and rates summed for baseline focal score ranged from 0 to 12; lower scores mean worse severity. TDI domains were rated from -3 (major deterioration) to 3 (major improvement) and rates summed for transition focal score ranged from -9 to 9; negative scores indicate deterioration. A TDI focal score of ≥1 was defined as a clinically important improvement from baseline. (NCT02603393)
Timeframe: 26 weeks
| Intervention | Score on a scale (Least Squares Mean) |
|---|---|
| QVA149 | 1.382 |
| Tiotropium + Salmeterol/Fluticasone | 1.671 |
Moderate or severe COPD exacerbations starting between first dose and one day after last treatment are included. COPD exacerbations that occurred within 7 days of each other are collapsed as one event. (NCT02603393)
Timeframe: 26 weeks
| Intervention | COPD exacerbations/year (Number) |
|---|---|
| QVA149 | 0.52 |
| Tiotropium + Salmeterol/Fluticasone | 0.48 |
At day 43 adjusted mean (standard error) of inspiratory capacity [Litre] treatment comparisons after 6 weeks of each treatment for subgroup of GOLD stage I/II. Adjusted mean was entered instead of mean in statistical analysis. (NCT02629965)
Timeframe: Day 43, 60 minutes post-dose after 6 weeks of each treatment
| Intervention | Litre (L) (Mean) |
|---|---|
| Tiotropium 5 μg | 2.023 |
| Tiotropium + Olodaterol 5/5 μg | 2.106 |
At day 43 adjusted mean (SE) of average daily duration [minute] of ≥ 3 METs treatment comparisons measured by the activity monitor in 2 weeks prior to Week 6 of each treatment. Adjusted mean was entered instead of mean in statistical analysis. (NCT02629965)
Timeframe: 2 weeks prior to Week 6 per treatment
| Intervention | minute (Mean) |
|---|---|
| Tiotropium 5 μg | 44.662 |
| Tiotropium + Olodaterol 5/5 μg | 45.601 |
At day 43 adjusted mean (SE) of 30 minute post-dose forced expiratory volume in one second (FEV1) [Litre] treatment comparisons after 6 weeks of each treatment. Adjusted mean was entered instead of mean in statistical analysis. (NCT02629965)
Timeframe: Day 43, 30 minutes post-dose after 6 weeks of each treatment
| Intervention | Litre (L) (Mean) |
|---|---|
| Tiotropium 5 μg | 1.169 |
| Tiotropium + Olodaterol 5/5 μg | 1.275 |
At day 43 adjusted mean (SE) of 30 minute post-dose forced vital capacity (FVC) [Litre] treatment comparisons after 6 weeks of each treatment. Adjusted mean was entered instead of mean in statistical analysis. (NCT02629965)
Timeframe: Day 43, 30 minutes post-dose after 6 weeks of each treatment
| Intervention | Litre (L) (Mean) |
|---|---|
| Tiotropium 5 μg | 2.857 |
| Tiotropium + Olodaterol 5/5 μg | 3.020 |
At day 43 adjusted mean (SE) of average daily duration [minute] of ≥ 2 METs treatment comparison measured by the activity monitor in 2 weeks prior to Week 6 of each treatment. Adjusted mean was entered instead of mean in statistical analysis. (NCT02629965)
Timeframe: 2 weeks prior to Week 6 per treatment
| Intervention | minute (Mean) |
|---|---|
| Tiotropium 5 μg | 171.935 |
| Tiotropium + Olodaterol 5/5 μg | 174.192 |
At day 43 inspiratory capacity at rest measured at 60 minutes post-dose, after 6 weeks of each treatment. Adjusted mean was entered instead of mean in statistical analysis. (NCT02629965)
Timeframe: Day 43, 60 minutes post-dose after 6 weeks of each treatment
| Intervention | Litre (L) (Mean) |
|---|---|
| Tiotropium 5 μg | 1.875 |
| Tiotropium + Olodaterol 5/5 μg | 1.990 |
6-minute walk distance [Meter] treatment comparisons after 6 weeks of each treatment. Adjusted mean was entered instead of mean in statistical analysis. (NCT02629965)
Timeframe: Day 43, 60 minutes post-dose after 6 weeks of each treatment
| Intervention | Meter (m) (Mean) |
|---|---|
| Tiotropium 5 μg | 307.356 |
| Tiotropium + Olodaterol 5/5 μg | 311.524 |
At day 43 adjusted mean (SE) of 60 minute post-dose slow vital capacity [Litre] treatment comparisons after 6 weeks of each treatment. Adjusted mean was entered instead of mean in statistical analysis. (NCT02629965)
Timeframe: Day 43, 60 minutes post-dose after 6 weeks of each treatment
| Intervention | Litre (L) (Mean) |
|---|---|
| Tiotropium 5 μg | 2.962 |
| Tiotropium + Olodaterol 5/5 μg | 3.096 |
At day 43 adjusted mean (standard error) of inspiratory capacity [Litre] test comparisons after 6 weeks of each test for 6MWT in-completer at baseline period. Adjusted mean was entered instead of mean in statistical analysis. (NCT02629965)
Timeframe: Day 43, 60 minutes post-dose after 6 weeks of each treatment
| Intervention | Litre (L) (Mean) |
|---|---|
| Tiotropium 5 μg | 1.744 |
| Tiotropium + Olodaterol 5/5 μg | 1.830 |
At day 43 adjusted mean (standard error) of inspiratory capacity [Litre] test comparisons after 6 weeks of each treatment for 6MWT completer at treatment period. Adjusted mean was entered instead of mean in statistical analysis. (NCT02629965)
Timeframe: Day 43, 60 minutes post-dose after 6 weeks of each treatment
| Intervention | Litre (L) (Mean) |
|---|---|
| Tiotropium 5 μg | 1.940 |
| Tiotropium + Olodaterol 5/5 μg | 2.072 |
At day 43 adjusted mean (standard error) of inspiratory capacity [Litre] test comparisons after 6 weeks of each treatment for 6MWT completer at baseline period. Adjusted mean was entered instead of mean in statistical analysis. (NCT02629965)
Timeframe: Day 43, 60 minutes post-dose after 6 weeks of each treatment
| Intervention | Litre (L) (Mean) |
|---|---|
| Tiotropium 5 μg | 1.925 |
| Tiotropium + Olodaterol 5/5 μg | 2.053 |
At day 43 adjusted mean (standard error) of inspiratory capacity [Litre] treatment comparisons after 6 weeks of each treatment for subgroup of GOLD stage III/IV. Adjusted mean was entered instead of mean in statistical analysis. (NCT02629965)
Timeframe: Day 43, 60 minutes post-dose after 6 weeks of each treatment
| Intervention | Litre (L) (Mean) |
|---|---|
| Tiotropium 5 μg | 1.697 |
| Tiotropium + Olodaterol 5/5 μg | 1.849 |
At day 43 adjusted mean (standard error) of inspiratory capacity [Litre] test comparisons after 6 weeks of each treatment for 6MWT in-completer at treatment period. Adjusted mean was entered instead of mean in statistical analysis. (NCT02629965)
Timeframe: Day 43, 60 minutes post-dose after 6 weeks of each treatment
| Intervention | Litre (L) (Mean) |
|---|---|
| Tiotropium 5 μg | 1.738 |
| Tiotropium + Olodaterol 5/5 μg | 1.820 |
At day 43 adjusted mean (SE) of average number of step per day [step/day] treatment comparisons in measured by the activity monitor in 2 weeks prior to Week 6 of each treatment. Adjusted mean was entered instead of mean in statistical analysis. (NCT02629965)
Timeframe: 2 weeks prior to Week 6 per treatment
| Intervention | step/day (Mean) |
|---|---|
| Tiotropium 5 μg | 3550.400 |
| Tiotropium + Olodaterol 5/5 μg | 3559.901 |
At day 43 adjusted mean (SE) of average daily duration [minute] of ≥ 4 METs treatment comparisons measured by the activity monitor in the 2 weeks prior to week 6 of each treatment. Adjusted mean was entered instead of mean in statistical analysis. (NCT02629965)
Timeframe: 2 weeks prior to Week 6 per treatment
| Intervention | minute (Mean) |
|---|---|
| Tiotropium 5 μg | 10.206 |
| Tiotropium + Olodaterol 5/5 μg | 9.914 |
At day 43 adjusted mean (SE) of average daily active strength [METs x minute] of >=3 METs treatment comparisons measured by the activity monitor in 2 weeks prior to Week 6 of each treatment. Adjusted mean was entered instead of mean in statistical analysis. (NCT02629965)
Timeframe: 2 weeks prior to Week 6 per treatment
| Intervention | Metabolic equivalents * minutes (Mean) |
|---|---|
| Tiotropium 5 μg | 148.647 |
| Tiotropium + Olodaterol 5/5 μg | 151.067 |
"This outcome measure presents trough FVC after 28 days of treatment (measurement on Day 29).~The FVC measurement at Visit 4, which was 24 hours after the last open-label run-in treatment intake and 15 minutes before the first double-blind study drug intake was the baseline measurement for FVC." (NCT02683109)
Timeframe: Day 29
| Intervention | Liter (Mean) |
|---|---|
| T+O 5/5 | 3.126 |
| T 5/O 5 | 3.121 |
"This outcome measure presents FEV1 after 28 days of treatment (measurement on Day 29). Trough FEV1 was defined as the FEV1 value at the end of the dosing interval (24 hours), and was measured at 24 hours (+/- 10 minutes) after trial medication administration at Visit 5.~The FEV1 measurement at Visit 4, which was 24 hours after the last open-label run-in treatment intake and 15 minutes before the first double-blind study drug intake was the baseline measurement." (NCT02683109)
Timeframe: Day 29
| Intervention | Liter (Mean) |
|---|---|
| T+O 5/5 | 1.422 |
| T 5/O 5 | 1.399 |
"This outcome measure presents COPD assessment test score on Day 28. The COPD Assessment Test™ is a short 8-item questionnaire for assessment and monitoring of COPD health status in routine practice. Its scale is 0-40 (high score = poor health).~The CAT measurement on Visit 4 prior to the first dose of double-blind study drug was the baseline for CAT." (NCT02683109)
Timeframe: Day 28
| Intervention | Score on scale (Mean) |
|---|---|
| T+O 5/5 | 15.423 |
| T 5/O 5 | 15.750 |
After treatment period the lung function parameters FEV1 (NCT02683668)
Timeframe: 14 days
| Intervention | liters (Mean) |
|---|---|
| Handihaler-Tiotropium 18 mcg Untrained | 1.575 |
| Handihaler-Tiotropium 18 mcg Trained | 1.571 |
| Respimat-Tiotropium 5 mcg Trained | 1.651 |
After treatment Impulse Oscillometry parameter. Sacin is a gas exchange measures, assessing convectional ventilation heterogeneity in pre acinar/acinar airways. (NCT02683668)
Timeframe: 14 days
| Intervention | kPals (Mean) |
|---|---|
| Handihaler-Tiotropium 18 mcg Untrained | 0.333 |
| Handihaler-Tiotropium 18 mcg Trained | 0.339 |
| Respimat-Tiotropium 5 mcg Trained | 0.345 |
Peripheral airways resistance measured by impulse oscillometry (IOS). Specific frequencies relate to different levels: a frequency of 5 hertz (Hz) provides values for total airway resistance (R5) and reactance (X5); a 20Hz frequency gives a value for central or large airway resistance (R20); and if one subtracts the value of central airway resistance from that for total airway resistance (i.e. R5-R20), this provides a measure of peripheral or small airways resistance. (NCT02683668)
Timeframe: 6 months
| Intervention | kPa/l/s (Mean) |
|---|---|
| Handihaler-Tiotropium 18 mcg Untrained | 0.608 |
| Handihaler-Tiotropium 18 mcg Trained | 0.589 |
| Respimat-Tiotropium 5 mcg Trained | 0.497 |
After the treatment period the MBW parameters. Scond is a gas exchange measures, assessing convectional ventilation heterogeneity in peripheral conducting airways. (NCT02683668)
Timeframe: 14 days
| Intervention | kPals (Mean) |
|---|---|
| Handihaler-Tiotropium 18 mcg Untrained | 0.047 |
| Handihaler-Tiotropium 18 mcg Trained | 0.042 |
| Respimat-Tiotropium 5 mcg Trained | 0.036 |
"To assess the bronchodilatory effect by evaluating the mean changes from baseline in FEV1 in morning pre-dose (trough) of AB/FF 400/12 µg compared to FF 12 μg after administration of oral inhalation powder BID via DPI to participants with COPD.~Morning pre-dose (trough) FEV1 was defined as the average of the corresponding -30 minute and 0 minute before the morning study medication at Week 24. If one time-point was missing then the available one would be used as morning pre-dose." (NCT02796677)
Timeframe: At baseline morning predose and Week 24
| Intervention | Litres (Least Squares Mean) |
|---|---|
| AB/FF 400/12 μg | 0.080 |
| AB 400 μg | 0.066 |
| FF 12 μg | 0.025 |
| TIO 18 μg | 0.060 |
"SGRQ was a A standardized self-completed tool used to measure impaired health and perceived well-being (quality of life) in respiratory diseases. The questionnaire contained 50 items divided into 3 (symptoms, activity and impacts) dimensions. Each of the three dimensions of the questionnaire is scored separately in the range from 0 to 100%, zero score indicating no impairment of life quality. A summary score utilizing responses to all items is the total SGRQ score which also ranges from 0 to 100%. The SGRQ scores are calculated using weights attached to each item of the questionnaire which provides an estimate of the distress associated with the symptoms or state described in each item. Higher scores indicate poorer health. A decrease of at least 4 units in the SGRQ total score has been established as the criterion for minimal meaningful improvement. SGRQ responders will be those with a decrease in SGRQ total score of at least 4 units from baseline." (NCT02796677)
Timeframe: At baseline and Week 24
| Intervention | Participants (Count of Participants) | |
|---|---|---|
| Number of responders -Yes | Number of responders- NO | |
| AB 400 μg | 188 | 195 |
| AB/FF 400/12 μg | 130 | 140 |
| FF 12 μg | 128 | 130 |
| TIO 18 μg | 197 | 192 |
To assess the bronchodilatory effect by evaluating the mean changes from baseline in nAUC0-3/3h FEV1 of AB/FF 400/12 µg compared to AB 400 μg and and FF 12 μg after administration of oral inhalation powder BID via DPI to participants with COPD. (NCT02796677)
Timeframe: At Day 1 and Day 169
| Intervention | Litres (Least Squares Mean) |
|---|---|
| AB/FF 400/12 μg | 0.237 |
| AB 400 μg | 0.162 |
| FF 12 μg | 0.149 |
| TIO 18 μg | 0.151 |
To assess the non-inferior bronchodilatory effect by evaluating the mean changes from baseline in FEV1 in morning pre-dose (trough)of AB 400 µg compared to TIO 18 μg after administration of oral inhalation powder BID via DPI to participants with COPD. (NCT02796677)
Timeframe: At baseline morning predose and Week 24
| Intervention | Litres (Least Squares Mean) |
|---|---|
| AB 400 μg | 0.064 |
| TIO 18 μg | 0.057 |
"To assess the bronchodilatory effect by evaluating the mean changes from baseline in FEV1 at 1 hour post-dose of AB/FF 400/12 µg compared to AB 400 μg after administration of oral inhalation powder BID via DIP to participants with COPD.~Baseline was defined as the average of the two FEV1 values measured just prior to the administration of the first dose of investigational product (IP) at randomization Visit. If one of the two was missing, then the available one would be used as baseline value." (NCT02796677)
Timeframe: At baseline 1-hour postdose and Week 24
| Intervention | Litres (Least Squares Mean) |
|---|---|
| AB/FF 400/12 μg | 0.253 |
| AB 400 μg | 0.169 |
| FF 12 μg | 0.168 |
| TIO 18 μg | 0.161 |
Tissue saturation of hemoglobin plus myoglobin with oxygen is measured by spatially resolved near-infrared spectroscopy from the vastus lateralis muscle during constant work rate (CWR) cycling exercise at the time of the shortest duration of each intervention arm (isotime). A greater muscle oxygen saturation at isotime would reflect a beneficial response to the intervention. (NCT02845752)
Timeframe: Baseline and day 7 of each treatment period
| Intervention | % of O2 saturated hemoglobin+myoglobin (Median) |
|---|---|
| Stiolto Respimat | 54.5 |
| Placebo Respimat | 53.4 |
Pulmonary oxygen uptake (VO2) measured during constant work rate (CWR) cycling exercise at the time of the shortest duration of each intervention arm (isotime). A lesser VO2 would reflect a beneficial response to the intervention. (NCT02845752)
Timeframe: Baseline and day 7 of each treatment period
| Intervention | Liters/minute (Median) |
|---|---|
| Stiolto Respimat | 1.279 |
| Placebo Respimat | 1.219 |
Minute ventilation (VE) measured during constant work rate (CWR) cycling exercise at the time of the shortest duration of each intervention arm (isotime). A lesser VE would reflect a beneficial response to the intervention. (NCT02845752)
Timeframe: Baseline and day 7 of each treatment period
| Intervention | Liters/minute (Median) |
|---|---|
| Stiolto Respimat | 50.20 |
| Placebo Respimat | 45.25 |
Constant work rate (CWR) exercise causes muscle fatigue (MF) and reduces muscle activation (activation fatigue; AF). The relationship between muscle activity (using EMG) and power is measured at baseline (unfatigued condition). Fatigue is measured by the difference between pre-CWR and post-CWR maximal voluntary isokinetic power i.e. how much maximal voluntary isokinetic power declines during CWR. The fraction of the total fall in voluntary isokinetic power (total fatigue) that is ascribed to reduced muscle activity is then calculated from the reduction in EMG activity. The remainder is ascribed to muscle fatigue (MF) and expressed as a percentage of total fatigue. This measurement was made at peak exercise. A smaller value (%) of MF would be associated with a beneficial response to the intervention. (NCT02845752)
Timeframe: Baseline and day 7 of each treatment period
| Intervention | percentage of total fatigue (Median) |
|---|---|
| Stiolto Respimat | 20.9 |
| Placebo Respimat | 25.4 |
Percentage of arterial hemoglobin that is saturated with oxygen, measured using pulse oximetry during constant work rate (CWR) cycling exercise at the time of the shortest duration of each intervention arm (isotime). A greater pulse oximeter oxygen saturation would reflect a beneficial response to the intervention. (NCT02845752)
Timeframe: Baseline and day 7 of each treatment period
| Intervention | percent of hemoglobin saturated with O2 (Median) |
|---|---|
| Stiolto Respimat | 99.0 |
| Placebo Respimat | 98.5 |
The duration in seconds for which constant work rate (CWR) cycling exercise could be tolerated prior to voluntary termination of exercise. (NCT02845752)
Timeframe: Baseline and day 7 of each treatment period
| Intervention | seconds (Median) |
|---|---|
| Stiolto Respimat | 297 |
| Placebo Respimat | 274 |
"Constant work rate (CWR) exercise causes fatigue and reduces muscle activation. The relationship between muscle activation and power is measured at baseline (unfatigued condition). Fatigue is measured by the difference between pre-CWR and post-CWR maximal voluntary isokinetic power i.e. how much maximal voluntary isokinetic power declines during CWR. The fraction of fatigue that is ascribed to reduced muscle activity is then calculated. The magnitude of activation fatigue is measured in EMG activity and expressed in watts at the time of the shortest exercise duration in either study arm, which is termed isotime. A smaller value (in watts) of activation fatigue means that the intervention was associated with a less reduction in EMG activity after a given CWR exercise duration (i.e. at isotime)." (NCT02845752)
Timeframe: Baseline and day 7 of each treatment period
| Intervention | watts (Median) |
|---|---|
| Stiolto Respimat | 58 |
| Placebo Respimat | 50 |
Inspiratory capacity (IC) measured during constant work rate (CWR) cycling exercise at the time of the shortest duration of each intervention arm (isotime). A greater IC would reflect a beneficial response to the intervention. (NCT02845752)
Timeframe: Baseline and day 7 of each treatment period
| Intervention | Liters (Median) |
|---|---|
| Stiolto Respimat | 1.91 |
| Placebo Respimat | 1.88 |
Borg rating of perceived shortness of breath (dyspnea) were measured on a category-ratio scale from 0 to 10 (CR-10) during constant work rate (CWR) cycling exercise at the time of the shortest duration of each intervention arm (isotime). A lower CR-10 score for dyspnea at isotime would reflect a beneficial response to the intervention. (NCT02845752)
Timeframe: Baseline and day 7 of each treatment period
| Intervention | scores on a scale (Median) |
|---|---|
| Stiolto Respimat | 3 |
| Placebo Respimat | 2.5 |
This outcome describes the the effect of the intervention on forced expiratory volume in 1 second (FEV1) during resting spirometry. A greater FEV1 would reflect a positive benefit of the intervention. (NCT02845752)
Timeframe: Baseline and day 7 of each treatment period
| Intervention | Liters (Median) |
|---|---|
| Stiolto Respimat | 1.81 |
| Placebo Respimat | 1.72 |
"Constant work rate (CWR) exercise causes fatigue. Fatigue is measured by the difference between pre-CWR and post-CWR maximal voluntary isokinetic power i.e. how much maximal voluntary isokinetic power declines during CWR. The magnitude of fatigue is measured in watts at the time of the shortest exercise duration in either study arm, which is termed isotime. A smaller value (in watts) of performance fatigue means that the intervention was associated with less fatigue after a given CWR exercise duration (i.e. at isotime)." (NCT02845752)
Timeframe: Baseline and day 7 of each treatment period
| Intervention | watts (Median) |
|---|---|
| Stiolto Respimat | 75 |
| Placebo Respimat | 77 |
Tissue saturation of hemoglobin with oxygen is measured by spatially resolved near-infrared spectroscopy from the frontal lobe during constant work rate (CWR) cycling exercise at the time of the shortest duration of each intervention arm (isotime). A greater frontal lobe oxygen saturation at isotime would reflect a beneficial response to the intervention. (NCT02845752)
Timeframe: Baseline and day 7 of each treatment period
| Intervention | Percent of hemoglobin saturated with O2 (Median) |
|---|---|
| Stiolto Respimat | 62.5 |
| Placebo Respimat | 62.8 |
Borg rating of perceived tiredness on the legs (leg fatigue) were measured on a category-ratio scale from 0 to 10 (CR-10) during constant work rate (CWR) cycling exercise at the time of the shortest duration of each intervention arm (isotime). A lower CR-10 score for leg fatigue at isotime would reflect a beneficial response to the intervention. (NCT02845752)
Timeframe: Baseline and day 7 of each treatment period
| Intervention | scores on a scale (Median) |
|---|---|
| Stiolto Respimat | 3 |
| Placebo Respimat | 2.5 |
Inspiratory reserve volume (IRV) measured during CWR cycling exercise at the time of the shortest duration of each intervention arm (isotime). A greater IRV would reflect a beneficial response to intervention. (NCT02845752)
Timeframe: Baseline and day 7 of each treatment period
| Intervention | Liters (Median) |
|---|---|
| Stiolto Respimat | 0.54 |
| Placebo Respimat | 0.46 |
Forced Vital Capacity (FVC) is a standard measurement for the assessment of lung function. The best of 3 efforts was defined as the highest FVC, each obtained on any of 3 manoeuvres meeting the American Thoracic Society (ATS) criteria (to a maximum of 5 attempts). Measure type is actually Adjusted Mean Change from Baseline. (NCT02853123)
Timeframe: Baseline and week 6
| Intervention | Litre (L) (Least Squares Mean) |
|---|---|
| Tiotropium 5 Microgram (μg) | 0.258 |
| Tiotropium + Olodaterol 5/5 μg | 0.459 |
CRQ-SAS was questionnaire to assess patients' perception of COPD and measures the impact of COPD on their life. This version was derived from the original CRQ tool & therefore, is scored on 7-point Likert-type scale (1: maximum impairment to 7: no impairment) for each 4 domains covering: dyspnea, fatigue, emotional function & mastery. The CRQ-SAS refers to the CRQ-Self-administered standardized format & contains 20 questions. The first part of the questionnaire contains 5 standardized dyspnea questions and the patients must indicate how much shortness of breath they have experienced while performing each of these 5 activities. The scores for each question of each domain were added together and divided by the number of questions answered in each domain. The higher scores indicate better health-related quality of life in the respective domain. Measure type is actually Adjusted Mean Change from Baseline. (NCT02853123)
Timeframe: Baseline and week 6
| Intervention | Unit on Scale (Least Squares Mean) |
|---|---|
| Tiotropium 5 Microgram (μg) | 0.325 |
| Tiotropium + Olodaterol 5/5 μg | 0.415 |
Inspiratory Capacity (IC) is a standard measurement for the assessment of lung function. IC measurements were performed at the end of the 3min Constant Speed Shuttle Test (CSST). Measure type is actually Adjusted Mean Change from Baseline. (NCT02853123)
Timeframe: Baseline and week 6
| Intervention | Litre (L) (Least Squares Mean) |
|---|---|
| Tiotropium 5 Microgram (μg) | 0.256 |
| Tiotropium + Olodaterol 5/5 μg | 0.322 |
CRQ-SAI refers to the CRQ-Self-administered individualized format as it contains a dyspnea domain that is individualized to each patient. This version was derived from the original CRQ tool & therefore, is scored on 7-point Likert-type scale (1: maximum impairment to 7: no impairment) for each 4 domains covering: dyspnea, fatigue, emotional function & mastery. Dyspnea items may be selected from list of 26 suggested items or written in by the patients. The patients are asked to select up to 5 activities associated with breathlessness that they perform frequently and are most important to them. The scores for each question of each domain were added together and divided by the number of questions answered in each domain. The higher scores indicate better health-related quality of life in the respective domain. Measure type is actually Adjusted Mean Change from Baseline. (NCT02853123)
Timeframe: Baseline and week 6
| Intervention | Unit on Scale (Least Squares Mean) |
|---|---|
| Tiotropium 5 Microgram (μg) | 0.640 |
| Tiotropium + Olodaterol 5/5 μg | 0.610 |
Inspiratory Capacity (IC) is a standard measurement for the assessment of lung function. IC measurements were performed prior to the 3min Constant Speed Shuttle Test (CSST) (at rest). Measure type is actually Adjusted Mean Change from Baseline. (NCT02853123)
Timeframe: Baseline and week 6
| Intervention | Litre (L) (Least Squares Mean) |
|---|---|
| Tiotropium 5 Microgram (μg) | 0.279 |
| Tiotropium + Olodaterol 5/5 μg | 0.464 |
At 1, 2 and 2.5 min during exercise, patients were asked to estimate the intensity of breathing discomfort that they were experiencing by matching their subjective estimate to descriptive phrases that best described the intensity of each sensation using the Modified Borg Scale (MBS-S). At 3 min or end of exercise (if 3 min not achieved), patients were asked to estimate the intensity of breathing discomfort that they were experiencing by matching their subjective estimate to descriptive phrases that best described the intensity of each sensation using the Modified Borg Scale (MBS-S). The modified Borg scale is 10-point subjective scoring system, in which a patient rates effort of exertion while performing a particular activity. The scale is 0 to 10, the higher the score, the greater the perceived difficulty. Measure type is actually Adjusted Mean Change from Baseline. (NCT02853123)
Timeframe: Baseline and week 6
| Intervention | Unit on Scale (Least Squares Mean) | ||
|---|---|---|---|
| 1 min | 2 min | 2.5 min | |
| Tiotropium + Olodaterol 5/5 μg | -0.793 | -1.079 | -1.164 |
| Tiotropium 5 Microgram (μg) | -0.685 | -0.839 | -0.846 |
At 3 min or end of exercise (if 3 min not achieved), patients were asked to estimate the intensity of breathing discomfort that they were experiencing by matching their subjective estimate to descriptive phrases that best described the intensity of each sensation using the Modified Borg Scale (MBS-S). The modified Borg scale is 10-point subjective scoring system, in which a patient rates effort of exertion while performing a particular activity. The scale is 0 to 10, the higher the score, the greater the perceived difficulty. Measure type is actually Adjusted Mean Change from Baseline. (NCT02853123)
Timeframe: Baseline and week 6
| Intervention | Unit on Scale (Least Squares Mean) |
|---|---|
| Tiotropium 5 Microgram (μg) | -0.968 |
| Tiotropium + Olodaterol 5/5 μg | -1.325 |
Forced Expiratory Volume in 1st second (FEV1) is a standard measurement for the assessment of lung function. The best of 3 efforts was defined as the highest FEV1, each obtained on any of 3 manoeuvres meeting the American Thoracic Society (ATS) criteria (to a maximum of 5 attempts). Measure type is actually Adjusted Mean Change from Baseline. (NCT02853123)
Timeframe: Baseline and week 6
| Intervention | Litre (L) (Least Squares Mean) |
|---|---|
| Tiotropium 5 Microgram (μg) | 0.163 |
| Tiotropium + Olodaterol 5/5 μg | 0.318 |
"FEV1 is the maximum amount of air that can be forcefully exhaled in one second. It assesses the degree of airway obstruction in a routine test called spirometry, via a spirometer. FEVI was measured before the administration of Vahelva® Respimat® (pre-dose FEV1) at baseline and at Week 52 (±2 weeks). Pre-dose percent predicted FEV1 was calculated by converting the spirometer reading to a percentage of what would be predicted as normal FEV1 based on a several personal factors (e.g. sex, age, etc.).~Change from baseline in pre-dose percent predicted Forced Expiratory Volume in one second (FEV1) to Week 52 was calculated as: pre-dose percent predicted FEV1 value at Week 52 (±2 weeks) - pre-dose percent predicted FEV1 value at baseline." (NCT02864407)
Timeframe: At baseline (30 days before baseline visit (Visit 1)) and Week 52 (±2 weeks).
| Intervention | percentage of predicted FEV1 (Mean) |
|---|---|
| Vahelva® Respimat® (Tiotropium + Olodaterol Fixed Dose Combination) | 4.83 |
"FEV1 is the maximum amount of air that can be forcefully exhaled in one second. It assesses the degree of airway obstruction in a routine test called spirometry, via a spirometer. FEVI was measured before the administration of Vahelva® Respimat® (pre-dose FEV1) at baseline and at Week 52 (±2 weeks). Pre-dose percent predicted FEV1 was calculated by converting the spirometer reading to a percentage of what would be predicted as normal FEV1 based on a several personal factors (e.g. sex, age, etc.).~Change from baseline in pre-dose percent predicted Forced Expiratory Volume in one second (FEV1) to Week 52 was calculated as: pre-dose percent predicted FEV1 value at Week 52 (±2 weeks) - pre-dose percent predicted FEV1 value at baseline." (NCT02864407)
Timeframe: At baseline (30 days before baseline visit (Visit 1)) and Week 52 (±2 weeks).
| Intervention | percentage of predicted FEV1 (Mean) |
|---|---|
| Vahelva® Respimat® (Tiotropium + Olodaterol Fixed Dose Combination) | 4.91 |
"FEV1 is the maximum amount of air that can be forcefully exhaled in one second. It assesses the degree of airway obstruction in a routine test called spirometry, via a spirometer. FEVI was measured before the administration of Vahelva® Respimat® (pre-dose FEV1) at baseline and at Week 24 (±2 weeks). Pre-dose percent predicted FEV1 was calculated by converting the spirometer reading to a percentage of what would be predicted as normal FEV1 based on a several personal factors (e.g. sex, age, etc.).~Change from baseline in pre-dose percent predicted Forced Expiratory Volume in one second (FEV1) to Week 24 was calculated as: pre-dose percent predicted FEV1 value at Week 24 (±2 weeks) - pre-dose percent predicted FEV1 value at baseline." (NCT02864407)
Timeframe: At baseline (30 days before baseline visit (Visit 1)) and Week 24 (±2 weeks).
| Intervention | percentage of predicted FEV1 (Mean) |
|---|---|
| Vahelva® Respimat® (Tiotropium + Olodaterol Fixed Dose Combination) | 6.13 |
"FEV1 is the maximum amount of air that can be forcefully exhaled in one second. It assesses the degree of airway obstruction in a routine test called spirometry, via a spirometer. FEVI was measured before the administration of Vahelva® Respimat® (pre-dose FEV1) at baseline and at Week 24 (±2 weeks). Pre-dose percent predicted FEV1 was calculated by converting the spirometer reading to a percentage of what would be predicted as normal FEV1 based on a several personal factors (e.g. sex, age, etc.).~Change from baseline in pre-dose percent predicted FEV1 to Week 24 was calculated as: pre-dose percent predicted FEV1 value at Week 24 (±2 weeks) - pre-dose percent predicted FEV1 value at baseline." (NCT02864407)
Timeframe: At baseline (30 days before baseline visit (Visit 1)) and Week 24 (±2 weeks).
| Intervention | percentage of predicted FEV1 (Mean) |
|---|---|
| Vahelva® Respimat® (Tiotropium + Olodaterol Fixed Dose Combination) | 5.41 |
"FEV1 is the maximum amount of air that can be forcefully exhaled in one second. FEVI was measured via a spirometer after the administration of the bronchodilator (Vahelva® Respimat®) at baseline and at Week 52 (±2 weeks). Post bronchodilator percent predicted FEV1 was calculated by converting the spirometer reading to a percentage of what would be predicted as normal FEV1 based on a several personal factors (e.g. sex, age, etc.).~Change from baseline in post bronchodilator percent predicted FEV1 to Week 52 was calculated as: post bronchodilator percent predicted FEV1 value at Week 52 (±2 weeks) - post bronchodilator percent predicted FEV1 value at baseline." (NCT02864407)
Timeframe: At baseline and Week 52 (±2 weeks).
| Intervention | percentage of predicted FEV1 (Mean) |
|---|---|
| Vahelva® Respimat® (Tiotropium + Olodaterol Fixed Dose Combination) | 4.36 |
"FEV1 is the maximum amount of air that can be forcefully exhaled in one second. FEVI was measured via a spirometer after the administration of the bronchodilator (Vahelva® Respimat®) at baseline and at Week 52 (±2 weeks). Post bronchodilator percent predicted FEV1 was calculated by converting the spirometer reading to a percentage of what would be predicted as normal FEV1 based on a several personal factors (e.g. sex, age, etc.).~Change from baseline in post bronchodilator percent predicted FEV1 to Week 52 was calculated as: post bronchodilator percent predicted FEV1 value at Week 52 (±2 weeks) - post bronchodilator percent predicted FEV1 value at baseline." (NCT02864407)
Timeframe: At baseline and Week 52 (±2 weeks).
| Intervention | percentage of predicted FEV1 (Mean) |
|---|---|
| Vahelva® Respimat® (Tiotropium + Olodaterol Fixed Dose Combination) | 4.52 |
"Overall evaluation (Improved, unchanged, aggravated or unassessable) by investigator was based on overall clinical assessment including change from baseline in effectiveness assessment (pre-dose percent predicted Forced Expiratory Volume in one second (FEV1), post bronchodilator percent predicted Forced Expiratory Volume in one second (FEV1), Transition dyspnea index (TDI)) after 24 weeks or 52 weeks of treatment. 'Improved' was assessed as Effective, 'Unchanged, Aggravated' were assessed as Invalid." (NCT02864407)
Timeframe: At baseline and at Week 24 (±2 weeks) or at Week 52 (±2 weeks).
| Intervention | percentage of participants (Number) |
|---|---|
| Vahelva® Respimat® (Tiotropium + Olodaterol Fixed Dose Combination) | 70.80 |
"An adverse event (AE) was defined as any untoward medical occurrence in a patient or clinical investigation subject administered a medicinal product and which does not necessarily have a causal relationship with this treatment. An adverse event could therefore be any unfavourable and unintended sign (e.g. an abnormal laboratory finding), symptom, or disease temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product.~An adverse event was assessed as unexpected if not listed in Local Product Information (LPI) and Company Core Data Sheet (CCDS).~Percentage of subjects with any Adverse Event, unexpected Adverse Event, unexpected Serious Adverse Event, Adverse Event leading to discontinuation is reported. Percentages were rounded to two decimal places." (NCT02864407)
Timeframe: From the signing date on Informed Consent Form (ICF) to 28 days after last administration date of Vahelva® Respimat®, up to 52 (±2) weeks+ 28 days.
| Intervention | percentage of participants (Number) | |||
|---|---|---|---|---|
| Any Adverse Event | Unexpected Adverse Event | Unexpected Serious Adverse Event | Adverse Event leading to discontinuation | |
| Vahelva® Respimat® (Tiotropium + Olodaterol Fixed Dose Combination) | 19.90 | 13.65 | 3.48 | 2.29 |
Transition dyspnea index (TDI) is a validated, interviewer-administered questionnaire that measures changes in dyspnea severity from the baseline. TDI consists of 3 individual components: functional impairment, magnitude of task, and magnitude of effort. Each component was rated by 7 grades from -3 (major deterioration) to +3 (major improvement), and were sum up to form a TDI focal score from -9 to +9, with higher scores indicating better outcomes. (NCT02864407)
Timeframe: At Week 24 (±2 weeks).
| Intervention | units on a scale (Mean) |
|---|---|
| Vahelva® Respimat® (Tiotropium + Olodaterol Fixed Dose Combination) | -0.18 |
"Overall evaluation (Improved, unchanged or aggravated) by investigator was based on overall clinical assessment including change from baseline in effectiveness assessment (pre-dose percent predicted Forced Expiratory Volume in one second (FEV1), post bronchodilator percent predicted Forced Expiratory Volume in one second (FEV1), Transition dyspnea index (TDI)) after 24 weeks or 52 weeks of treatment. 'Improved' was assessed as Effective, 'Unchanged, Aggravated' were assessed as Invalid." (NCT02864407)
Timeframe: At baseline and at Week 24 (±2 weeks) or at Week 52 (±2 weeks).
| Intervention | percentage of participants (Number) |
|---|---|
| Vahelva® Respimat® (Tiotropium + Olodaterol Fixed Dose Combination) | 65.84 |
Transition dyspnea index (TDI) is a validated, interviewer-administered questionnaire that measures changes in dyspnea severity from the baseline. TDI consists of 3 individual components: functional impairment, magnitude of task, and magnitude of effort. Each component was rated by 7 grades from -3 (major deterioration) to +3 (major improvement), and were sum up to form a TDI focal score from -9 to +9, with higher scores indicating better outcomes. (NCT02864407)
Timeframe: At Week 24 (±2 weeks).
| Intervention | units on a scale (Mean) |
|---|---|
| Vahelva® Respimat® (Tiotropium + Olodaterol Fixed Dose Combination) | -0.31 |
"An adverse event (AE) was defined as any untoward medical occurrence in a patient or clinical investigation subject administered a medicinal product and which does not necessarily have a causal relationship with this treatment. An adverse event could therefore be any unfavourable and unintended sign (e.g. an abnormal laboratory finding), symptom, or disease temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product.~Percentage of participants with any AE is reported. Percentages were rounded to two decimal places." (NCT02864407)
Timeframe: From the signing date on Informed Consent Form (ICF) to 28 days after last administration date of Vahelva® Respimat®, up to 52 (±2) weeks+ 28 days.
| Intervention | percentage of partcipants (Number) |
|---|---|
| Vahelva® Respimat® (Tiotropium + Olodaterol Fixed Dose Combination) | 22.88 |
Transition dyspnea index (TDI) is a validated, interviewer-administered questionnaire that measures changes in dyspnea severity from the baseline. TDI consists of 3 individual components: functional impairment, magnitude of task, and magnitude of effort. Each component was rated by 7 grades from -3 (major deterioration) to +3 (major improvement), and were sum up to form a TDI focal score from -9 to +9, with higher scores indicating better outcomes. (NCT02864407)
Timeframe: At Week 52 (±2 weeks).
| Intervention | units on a scale (Mean) |
|---|---|
| Vahelva® Respimat® (Tiotropium + Olodaterol Fixed Dose Combination) | -0.39 |
Transition dyspnea index (TDI) is a validated, interviewer-administered questionnaire that measures changes in dyspnea severity from the baseline. TDI consists of 3 individual components: functional impairment, magnitude of task, and magnitude of effort. Each component was rated by 7 grades from -3 (major deterioration) to +3 (major improvement), and were sum up to form a TDI focal score from -9 to +9, with higher scores indicating better outcomes. (NCT02864407)
Timeframe: At Week 52 (±2 weeks).
| Intervention | units on a scale (Mean) |
|---|---|
| Vahelva® Respimat® (Tiotropium + Olodaterol Fixed Dose Combination) | -0.44 |
"An adverse drug reaction (ADR) was defined as a response to a medicinal product which is noxious and unintended. Response in this context means that a causal relationship between a medicinal product and an adverse event is at least a reasonable possibility. Adverse reactions may arise from use of the product within or outside the terms of the marketing authorization or from occupational exposure. Conditions of use outside the marketing authorization include off label use, overdose, misuse, abuse and medication errors. Investigator was primarily responsible to assess ADR relatedness.~An ADR was assessed as unexpected if not listed in Local Product Information (LPI) and Company Core Data Sheet (CCDS).~Percentage of subjects with any Adverse Drug Reaction, serious Adverse Drug Reaction, unexpected Adverse Drug Reaction, unexpected Serious Adverse Drug Reaction, Adverse Drug Reaction leading to discontinuation is reported. Percentages were rounded to two decimal places." (NCT02864407)
Timeframe: From the signing date on Informed Consent Form (ICF) to 28 days after last administration date of Vahelva® Respimat®, up to 52 (±2) weeks+ 28 days.
| Intervention | percentage of participants (Number) | ||||
|---|---|---|---|---|---|
| Any Adverse Drug Reaction | Serious Adverse Drug Reaction | Unexpected Adverse Drug Reaction | Unexpected Serious Adverse Drug Reaction | Adverse Drug Reaction leading to discontinuation | |
| Vahelva® Respimat® (Tiotropium + Olodaterol Fixed Dose Combination) | 2.87 | 0.16 | 1.16 | 0.13 | 1.32 |
"FEV1 is the maximum amount of air that can be forcefully exhaled in one second. FEVI was measured via a spirometer after the administration of the bronchodilator (Vahelva® Respimat®) at baseline and at Week 24 (±2 weeks). Post bronchodilator percent predicted FEV1 was calculated by converting the spirometer reading to a percentage of what would be predicted as normal FEV1 based on a several personal factors (e.g. sex, age, etc.).~Change from baseline in post bronchodilator percent predicted FEV1 to Week 24 was calculated as: post bronchodilator percent predicted FEV1 value at Week 24 (±2 weeks) - post bronchodilator percent predicted FEV1 value at baseline." (NCT02864407)
Timeframe: At baseline and Week 24 (±2 weeks).
| Intervention | percentage of predicted FEV1 (Mean) |
|---|---|
| Vahelva® Respimat® (Tiotropium + Olodaterol Fixed Dose Combination) | 3.80 |
"FEV1 is the maximum amount of air that can be forcefully exhaled in one second. FEVI was measured via a spirometer after the administration of the bronchodilator (Vahelva® Respimat®) at baseline and at Week 24 (±2 weeks). Post bronchodilator percent predicted FEV1 was calculated by converting the spirometer reading to a percentage of what would be predicted as normal FEV1 based on a several personal factors (e.g. sex, age, etc.).~Change from baseline in post bronchodilator percent predicted FEV1 to Week 24 was calculated as: post bronchodilator percent predicted FEV1 value at Week 24 (±2 weeks) - post bronchodilator percent predicted FEV1 value at baseline." (NCT02864407)
Timeframe: At baseline and Week 24 (±2 weeks).
| Intervention | percentage of predicted FEV1 (Mean) |
|---|---|
| Vahelva® Respimat® (Tiotropium + Olodaterol Fixed Dose Combination) | 5.19 |
"Cmax, maximum measured concentration of olodaterol in plasma after single inhaled administration of tiotropium+olodaterol FDC 5 mg/5 mg is presented as unadjusted geometric mean (gMean) and geometric coefficient of variation (gCV) (%).~detailed sampling time points: 0:05 (hours:minutes) before drug administration and 0:02, 0:05, 0:07, 0:10, 0:20, 0:30, 0:40, 1:00, 2:00, 3:00, 4:00, 6:00, 143:45, 144:20, 311:45, 312:20, 407:45, 408:20, 431:45, 432:20, 455:45, 456:20(hours:minutes) after drug administration." (NCT02969317)
Timeframe: Day 1, 7, 14, 18, 19 and 20
| Intervention | Picograms per millilitre [pg/mL] (Geometric Mean) |
|---|---|
| Tiotropium+Olodaterol FDC 5 mg/5 mg | 1.26 |
AUCτ,ss, area under the concentration-time curve of Tiotropium in plasma at steady state over a uniform dosing interval τ at steady state after multiple dosing at Visit 4 is presented as unadjusted geometric mean (gMean) and geometric coefficient of variation (gCV) (%). (NCT02969317)
Timeframe: Day 21: 0:15 (hours:minutes) before drug administration and 0:02, 0:05, 0:07, 0:10, 0:20, 0:30, 0:40, 1:00, 2:00, 3:00, 4:00, 6:00, 12:00, 24:00 (hours:minutes) after drug administration
| Intervention | Picograms*hour per millilitre [pg*h/mL] (Geometric Mean) |
|---|---|
| Tiotropium+Olodaterol FDC 5 mg/5 mg | 54.8 |
AUCτ,ss, area under the concentration-time curve of olodaterol in plasma at steady state over a uniform dosing interval τ at steady state after multiple dosing at Day 21 is presented as unadjusted geometric mean (gMean) and geometric coefficient of variation (gCV) (%). (NCT02969317)
Timeframe: Day 21: 0:15 (hours:minutes) before drug administration and 0:02, 0:05, 0:07, 0:10, 0:20, 0:30, 0:40, 1:00, 2:00, 3:00, 4:00, 6:00, 12:00, 24:00 (hours:minutes) after drug administration
| Intervention | Picograms*hour per millilitre [pg*h/mL] (Geometric Mean) |
|---|---|
| Tiotropium+Olodaterol FDC 5 mg/5 mg | 25.5 |
AUC0-6,ss, area under the concentration time curve of Tiotropium in plasma over the time interval from 0 to 6 hours at steady state after multiple dosing at Visit 4 of tiotropium+olodaterol FDC 5 mg/5 mg is presented as unadjusted geometric mean (gMean) and geometric coefficient of variation (gCV) (%). (NCT02969317)
Timeframe: Day 21:0:15 (hours:minutes) before drug administration and 0:02, 0:05, 0:07, 0:10, 0:20, 0:30, 0:40, 1:00, 2:00, 3:00, 4:00, 6:00 (hours:minutes) after drug administration
| Intervention | Picograms*hour per millilitre [pg*h/mL] (Geometric Mean) |
|---|---|
| Tiotropium+Olodaterol FDC 5 mg/5 mg | 22.0 |
AUC0-6,ss, area under the concentration time curve of olodaterol in plasma over the time interval from 0 to 6 hours at steady state after multiple dosing at Day 21 of tiotropium+olodaterol FDC 5 mg/5 mg is presented as unadjusted geometric mean (gMean) and geometric coefficient of variation (gCV) (%). (NCT02969317)
Timeframe: Day 21: 0:15 (hours:minutes) before drug administration and 0:02, 0:05, 0:07, 0:10, 0:20, 0:30, 0:40, 1:00, 2:00, 3:00, 4:00, 6:00 (hours:minutes) after drug administration
| Intervention | Picograms*hour per millilitre [pg*h/mL] (Geometric Mean) |
|---|---|
| Tiotropium+Olodaterol FDC 5 mg/5 mg | 7.54 |
Accumulation ratios in plasma of Tiotropium (RA,Cmax =Cmax,ss/Cmax) after multiple dosing at Visit 4 is presented as unadjusted geometric mean (gMean) and geometric coefficient of variation (gCV) (%). (NCT02969317)
Timeframe: Day 1, 7, 14, 18, 19, 20 and 21
| Intervention | ratio (Geometric Mean) |
|---|---|
| Tiotropium+Olodaterol FDC 5 mg/5 mg | 1.29 |
Accumulation ratios in plasma of olodaterol (RA,Cmax =Cmax,ss/Cmax) after multiple dosing at Day 21 is presented as unadjusted geometric mean (gMean) and geometric coefficient of variation (gCV) (%). (NCT02969317)
Timeframe: Day 1 and Day 21
| Intervention | Ratio (Geometric Mean) |
|---|---|
| Tiotropium+Olodaterol FDC 5 mg/5 mg | 1.58 |
Tmax,ss,time from dosing to the maximum concentration of olodaterol in plasma at steady state after multiple dosing at Day 21 of tiotropium+olodaterol FDC 5 mg/5 mg is presented as unadjusted geometric mean (gMean) and geometric coefficient of variation (gCV) (%). (NCT02969317)
Timeframe: Day 21: 0:15 (hours:minutes) before drug administration and 0:02, 0:05, 0:07, 0:10, 0:20, 0:30, 0:40, 1:00, 2:00, 3:00, 4:00, 6:00, 12:00, 24:00 (hours:minutes) after drug administration
| Intervention | Hour [h] (Median) |
|---|---|
| Tiotropium+Olodaterol FDC 5 mg/5 mg | 2.00 |
"Tmax, time from dosing to the maximum concentration of Tiotropium in plasma after single inhaled administration of tiotropium+olodaterol FDC 5 mg/5 mgis presented as unadjusted geometric mean (gMean) and geometric coefficient of variation (gCV) (%).~Detailed sampling time points:0:05 (hours:minutes) before drug administration and 0:02, 0:05, 0:07, 0:10, 0:20, 0:30, 0:40, 1:00, 2:00, 3:00, 4:00, 6:00, 143:45, 144:20, 311:45, 312:20, 407:45, 408:20, 431:45, 432:20, 455:45, 456:20 (hours:minutes) after drug administration" (NCT02969317)
Timeframe: Day 1, 7, 14, 18, 19, 20
| Intervention | Hour [h] (Median) |
|---|---|
| Tiotropium+Olodaterol FDC 5 mg/5 mg | 0.167 |
Tmax,ss,time from dosing to the maximum concentration of Tiotropium in plasma at steady state after multiple dosing at Visit 4 of tiotropium+olodaterol FDC 5 mg/5 mg is presented as unadjusted geometric mean (gMean) and geometric coefficient of variation (gCV) (%). (NCT02969317)
Timeframe: Day 21: 0:15 (hours:minutes) before drug administration and 0:02, 0:05, 0:07, 0:10, 0:20, 0:30, 0:40, 1:00, 2:00, 3:00, 4:00, 6:00, 12:00, 24:00 (hours:minutes) after drug administration
| Intervention | Hour [h] (Median) |
|---|---|
| Tiotropium+Olodaterol FDC 5 mg/5 mg | 0.0830 |
Cmax,ss, maximum measured concentration of olodaterol in plasma at steady state of olodaterol after multiple dosing at Visit 4 (day 21) of tiotropium+olodaterol FDC 5 mg/5 mg is presented as unadjusted geometric mean (gMean) and geometric coefficient of variation (gCV) (%). (NCT02969317)
Timeframe: Day 21: 0:15 (hours:minutes) before drug administration and 0:02, 0:05, 0:07, 0:10, 0:20, 0:30, 0:40, 1:00, 2:00, 3:00, 4:00, 6:00, 12:00, 24:00 (hours:minutes) after drug administration
| Intervention | Picograms per millilitre [pg/mL] (Geometric Mean) |
|---|---|
| Tiotropium+Olodaterol FDC 5 mg/5 mg | 2.00 |
"Cmax, maximum measured concentration of Tiotropium in plasma after single inhaled administration of tiotropium+olodaterol FDC 5 mg/5 mg is presented as unadjusted geometric mean (gMean) and geometric coefficient of variation (gCV) (%).~Detailed sampling time points:0:05 (hours:minutes) before drug administration and 0:02, 0:05, 0:07, 0:10, 0:20, 0:30, 0:40, 1:00, 2:00, 3:00, 4:00, 6:00, 143:45, 144:20, 311:45, 312:20, 407:45, 408:20, 431:45, 432:20, 455:45, 456:20 (hours:minutes) after drug administration" (NCT02969317)
Timeframe: Day 1, 7, 14, 18, 19, 20
| Intervention | Picograms per millilitre [pg/mL] (Geometric Mean) |
|---|---|
| Tiotropium+Olodaterol FDC 5 mg/5 mg | 6.12 |
Cmax,ss, maximum measured concentration of olodaterol in plasma at steady state of Tiotropium after multiple dosing at Visit 4 of tiotropium+olodaterol FDC 5 mg/5 mg is presented as unadjusted geometric mean (gMean) and geometric coefficient of variation (gCV) (%). (NCT02969317)
Timeframe: Day 21: 0:15 (hours:minutes) before drug administration and 0:02, 0:05, 0:07, 0:10, 0:20, 0:30, 0:40, 1:00, 2:00, 3:00, 4:00, 6:00, 12:00, 24:00 (hours:minutes) after drug administration
| Intervention | Picograms per millilitre [pg/mL] (Geometric Mean) |
|---|---|
| Tiotropium+Olodaterol FDC 5 mg/5 mg | 7.65 |
Cpre,ss, pre-dose concentration of olodaterol in plasma at steady state after multiple dosing at Day 21 of tiotropium+olodaterol FDC 5 mg/5 mg is presented as unadjusted geometric mean (gMean) and geometric coefficient of variation (gCV) (%). (NCT02969317)
Timeframe: Day 21: 0:15 (hours:minutes) before drug administration and 0:02, 0:05, 0:07, 0:10, 0:20, 0:30, 0:40, 1:00, 2:00, 3:00, 4:00, 6:00, 12:00, 24:00 (hours:minutes) after drug administration
| Intervention | Picograms per millilitre [pg/mL] (Geometric Mean) |
|---|---|
| Tiotropium+Olodaterol FDC 5 mg/5 mg | 0.788 |
Cpre,ss, pre-dose concentration of Tiotropium in plasma at steady state after multiple dosing at Visit 4 of tiotropium+olodaterol FDC 5 mg/5 mg is presented as unadjusted geometric mean (gMean) and geometric coefficient of variation (gCV) (%). (NCT02969317)
Timeframe: Day 21: 0:15 (hours:minutes) before drug administration and 0:02, 0:05, 0:07, 0:10, 0:20, 0:30, 0:40, 1:00, 2:00, 3:00, 4:00, 6:00, 12:00, 24:00 (hours:minutes) after drug administration
| Intervention | Picograms per millilitre [pg/mL] (Geometric Mean) |
|---|---|
| Tiotropium+Olodaterol FDC 5 mg/5 mg | 1.90 |
"Tmax, time from dosing to the maximum concentration of olodaterol in plasma after single inhaled administration of tiotropium+olodaterol FDC 5 mg/5 mg is presented as unadjusted geometric mean (gMean) and geometric coefficient of variation (gCV) (%).~detailed sampling time points: 0:05 (hours:minutes) before drug administration and 0:02, 0:05, 0:07, 0:10, 0:20, 0:30, 0:40, 1:00, 2:00, 3:00, 4:00, 6:00, 143:45, 144:20, 311:45, 312:20, 407:45, 408:20, 431:45, 432:20, 455:45, 456:20(hours:minutes) after drug administration." (NCT02969317)
Timeframe: Day 1, 7, 14, 18, 19 and 20
| Intervention | Hour [h] (Median) |
|---|---|
| Tiotropium+Olodaterol FDC 5 mg/5 mg | 0.167 |
Average FEV1 AUC over 12 hours on Day 1 (NCT03028142)
Timeframe: Day 1
| Intervention | Liters*hour (Mean) |
|---|---|
| Lower Dose Nebulised Treatment | 3.058 |
| Higher Dose Nebulised Treatment | 3.094 |
| Placebo | 2.510 |
Average FEV1 area under the curve (AUC) over 12 hours on the third day of dosing (NCT03028142)
Timeframe: Day 3
| Intervention | Liters*hour (Mean) |
|---|---|
| Lower Dose Nebulised Treatment | 3.804 |
| Higher Dose Nebulised Treatment | 3.967 |
| Placebo | 3.197 |
Peak FEV1 over 4 hours on Day 1 (NCT03028142)
Timeframe: Day 1
| Intervention | Liters (Mean) |
|---|---|
| Lower Dose Nebulised Treatment | 0.383 |
| Higher Dose Nebulised Treatment | 0.432 |
| Placebo | 0.337 |
Peak forced expired volume in 1 second (FEV1) over 4 hours on the third day of dosing (NCT03028142)
Timeframe: Day 3
| Intervention | Liters (Mean) |
|---|---|
| Lower Dose Nebulised Treatment | 0.477 |
| Higher Dose Nebulised Treatment | 0.500 |
| Placebo | 0.373 |
Change from Baseline in Functional Residual Capacity Body Plethysmography (FRCpleth) % predicted is presented. Functional residual capacity, percent predicted is a lung volume at the end of normal expiration assessed/measured by body plethysmography and compared to predicted capacity for such subject, if nonsmoker and without a disease which could compromise their ventilator function, to give a percentage predicted. (NCT03055988)
Timeframe: Baseline and 6 weeks
| Intervention | Percentage of FRCpleth (%) (Least Squares Mean) |
|---|---|
| Fluticasone Propionate + Salmeterol FDC (F+S 1000/100) | -10.211 |
| Tiotropium + Olodaterol FDC (T+O 5/5) | -18.168 |
"LVEDVI is normalised left ventricular end diastolic volume, divided by body surface area.~Baseline was defined as the value obtained during the assessment performed in a week prior to Visit 2 (Day 1). The change from baseline was calculated as the value obtained in a week prior to Visits 3 and 4 (end of each treatment periods) minus the baseline value." (NCT03055988)
Timeframe: Baseline and 6 weeks
| Intervention | Millilitre/ meter^2 (mL/m^2) (Least Squares Mean) |
|---|---|
| Fluticasone Propionate + Salmeterol FDC (F+S 1000/100) | 2.855 |
| Tiotropium + Olodaterol FDC (T+O 5/5) | 2.317 |
Change from baseline in pulse pressure is presented. (NCT03055988)
Timeframe: Baseline and 6 weeks
| Intervention | mmHg (Least Squares Mean) |
|---|---|
| Fluticasone Propionate + Salmeterol FDC (F+S 1000/100) | 0.170 |
| Tiotropium + Olodaterol FDC (T+O 5/5) | 0.579 |
Change from baseline in aortic distensibility is presented. Aortic distensibility measurements as measure of arterial stiffness were derived from cine images acquired at end-expiration in planes perpendicular to the thoracic aorta at the level of the pulmonary artery (ascending and descending section of thoracic aorta), abdominal aorta, and perpendicularly to the main, right, and left pulmonary arteries. (NCT03055988)
Timeframe: Baseline and 6 weeks
| Intervention | Percentage/millimeter of mercury(%/mmHg) (Least Squares Mean) |
|---|---|
| Fluticasone Propionate + Salmeterol FDC (F+S 1000/100) | -0.006 |
| Tiotropium + Olodaterol FDC (T+O 5/5) | -0.005 |
Change from baseline in pulmonary artery pulsatility (PAP) is presented. Pulmonary artery pulsatility measurements as measure of arterial stiffness were derived from cine images acquired at end-expiration in planes perpendicular to the thoracic aorta at the level of the pulmonary artery (ascending and descending section of thoracic aorta), abdominal aorta, and perpendicularly to the main, right, and left pulmonary arteries. (NCT03055988)
Timeframe: Baseline and 6 weeks
| Intervention | Percentage of PAP (%) (Least Squares Mean) |
|---|---|
| Fluticasone Propionate + Salmeterol FDC (F+S 1000/100) | -0.175 |
| Tiotropium + Olodaterol FDC (T+O 5/5) | 1.105 |
Change from baseline in central systolic pressure is presented. (NCT03055988)
Timeframe: Baseline and 6 weeks
| Intervention | mmHg (Least Squares Mean) |
|---|---|
| Fluticasone Propionate + Salmeterol FDC (F+S 1000/100) | 0.202 |
| Tiotropium + Olodaterol FDC (T+O 5/5) | 2.271 |
Change from baseline in aortic augmentation index is presented. Augmentation index was derived from brachial pulse wave separation analysis as augmentation pressure (pressure difference between the reflection wave to the ejection wave) divided by central pulse pressure (at the central aortic site) multiplied by 100. (NCT03055988)
Timeframe: Baseline and 6 weeks
| Intervention | Percentage of index (%) (Least Squares Mean) |
|---|---|
| Fluticasone Propionate + Salmeterol FDC (F+S 1000/100) | 1.723 |
| Tiotropium + Olodaterol FDC (T+O 5/5) | 1.404 |
Change from baseline in 1.5 hour post dose Forced Vital Capacity (FVC) is presented. (NCT03055988)
Timeframe: Baseline and 6 weeks
| Intervention | Litre (L) (Least Squares Mean) |
|---|---|
| Fluticasone Propionate + Salmeterol FDC (F+S 1000/100) | 0.159 |
| Tiotropium + Olodaterol FDC (T+O 5/5) | 0.445 |
Change from baseline in 1.5 hour post dose Forced Expiratory Volume in 1st second (FEV1) is presented. (NCT03055988)
Timeframe: Baseline and 6 weeks
| Intervention | Litre (L) (Least Squares Mean) |
|---|---|
| Fluticasone Propionate + Salmeterol FDC (F+S 1000/100) | 0.158 |
| Tiotropium + Olodaterol FDC (T+O 5/5) | 0.339 |
"Change from baseline in IC at treatment Visit 3 (Week 3) and treatment Visit 4 (Week 6). Spirometry was used to measure IC and was performed according to internationally accepted standards.~Definitions:~Baseline: value of the measurement recorded at 45 mins pre-dose at Visit 2 (Week 0); IC=Inspiratory capacity;" (NCT03084796)
Timeframe: Baseline, Week 3, Week 6
| Intervention | Litres (Least Squares Mean) | |
|---|---|---|
| Week 3 | Week 6 | |
| Treatment A | 0.156 | 0.045 |
| Treatment B | 0.137 | 0.090 |
| Treatment C | 0.106 | 0.136 |
| Treatment D | 0.140 | 0.105 |
| Treatment E | 0.047 | 0.025 |
| Treatment F | 0.090 | 0.099 |
"Change from baseline in FEV1 at treatment visit 3 (Week 3) and treatment visit 4 (Week 6) of treatment. Spirometry, used to measure FEV1, was performed according to internationally accepted standards.~Definitions:~Baseline=Baseline value was the average of the pre-dose measurements (at 45 mins and 15 mins pre-dose), at Visit 2 (Week 0); FEV1=Forced expiratory volume in the 1st second;" (NCT03084796)
Timeframe: Baseline, Week 3, Week 6
| Intervention | Litres (Least Squares Mean) | |
|---|---|---|
| Week 3 | Week 6 | |
| Treatment A | 0.059 | 0.020 |
| Treatment B | 0.080 | 0.088 |
| Treatment C | 0.122 | 0.107 |
| Treatment D | 0.111 | 0.130 |
| Treatment E | 0.000 | -0.012 |
| Treatment F | 0.122 | 0.112 |
"Evaluate the number of rescue medication-free days compared with baseline. Results are shown as percentage (%) of rescue medication-free days; an increased value indicates improvement from baseline.~Definitions:~Baseline=Data recorded during the run-in period (a 2-week period prior to randomization to study treatment and study drug intake); Inter-visit period 1=Starts at randomization to treatment (Visit 2, Week 0) and runs to the day before the subject returns to the clinic (Visit 3, Week 3); Inter-visit period 2=Starts when the subject returns to the clinic (Visit 3, Week 3) and runs to the end of the randomized treatment period (Visit 4, Week 6); Entire Treatment period=From day of randomization to drug intake to the end of the randomized treatment period (Visit 4, Week 6); Randomization=Randomization to study drug treatment (Visit 2, Week 0)." (NCT03084796)
Timeframe: Baseline, Inter-visit period 1, Inter-visit period 2, Entire treatment period
| Intervention | % of of rescue medication-free days (Least Squares Mean) | ||
|---|---|---|---|
| Inter-visit period 1 | Inter-visit period 2 | Entire treatment period | |
| Treatment A | 16.78 | 13.83 | 15.30 |
| Treatment B | 15.67 | 15.51 | 15.59 |
| Treatment C | 15.55 | 14.03 | 14.79 |
| Treatment D | 18.19 | 18.15 | 18.17 |
| Treatment E | 8.90 | 7.07 | 7.98 |
| Treatment F | 13.51 | 11.27 | 12.39 |
"Change from baseline in FEV1 AUC(0-12h), normalized by time, on Day 1.~Spirometry, used to measure FEV1, was performed according to internationally accepted standards. The AUC for FEV1 on Day 1 of treatment was calculated by using the linear trapezoidal rule, based on the changes in FEV1 from the baseline values, and divided by the observation time (12 hours).~Definitions:~AUC=Area under the curve; Baseline=Baseline value was the average of the pre-dose measurements (at 45 mins and 15 mins pre-dose), at Visit 2 (Week 0); Day 1=Day of the first dose of randomized study drug at Visit 2 (Week 0); FEV1=Forced expiratory volume in the 1st second; FEV1 AUC(0-12h)=Mean FEV1 after inhalation, measured at prespecified times for up to 12-h observation period (0-12 h), normalized by time;" (NCT03084796)
Timeframe: Baseline, Day 1
| Intervention | Litres (Least Squares Mean) |
|---|---|
| Treatment A | 0.067 |
| Treatment B | 0.086 |
| Treatment C | 0.135 |
| Treatment D | 0.149 |
| Treatment E | 0.009 |
| Treatment F | 0.192 |
"Change from baseline in FEV1 AUC(0-12h), normalized by time, at the end of treatment (Week 6).~Spirometry, used to measure FEV1, was performed according to internationally accepted standards. The AUC for FEV1 at Week 6 of treatment was calculated by using the linear trapezoidal rule, based on the changes in FEV1 from the baseline values, and divided by the observation time (12 hours).~Definitions:~AUC=Area under the curve; Baseline=Baseline value was the average of the pre-dose measurements (at 45 mins and 15 mins pre-dose), at Visit 2 (Week 0); FEV1=Forced expiratory volume in the 1st second; FEV1 AUC(0-12h)=Mean FEV1 after inhalation, measured at prespecified times for up to 12-h observation period (0-12 h), normalized by time;" (NCT03084796)
Timeframe: Baseline, Week 6
| Intervention | Litres (Least Squares Mean) |
|---|---|
| Treatment A | 0.070 |
| Treatment B | 0.118 |
| Treatment C | 0.153 |
| Treatment D | 0.147 |
| Treatment E | 0.002 |
| Treatment F | 0.213 |
"Change from baseline in FVC AUC(0-12h), normalized by time, on Day 1 and at the end of treatment (Week 6).~Spirometry, used to measure FVC, was performed according to internationally accepted standards. The AUC for FVC was calculated by using the linear trapezoidal rule, based on the changes in FVC from the baseline values, and divided by the observation time (4 hours).~Definitions:~AUC=Area under the curve; Baseline=Baseline value was the average of the pre-dose measurements (at 45 mins and 15 mins pre-dose), at Visit 2 (Week 0); Day 1=Day of the first dose of randomized study drug at Visit 2 (Week 0); FVC=Forced Vital Capacity; FVC AUC(0-12h)=Mean FVC after inhalation, measured at prespecified times for up to 12-h observation period (0-12 h), normalized by time;" (NCT03084796)
Timeframe: Baseline, Day 1, Week 6
| Intervention | Litres (Least Squares Mean) | |
|---|---|---|
| Day 1 | Week 6 | |
| Treatment A | 0.086 | 0.084 |
| Treatment B | 0.133 | 0.145 |
| Treatment C | 0.195 | 0.190 |
| Treatment D | 0.220 | 0.184 |
| Treatment E | 0.011 | -0.029 |
| Treatment F | 0.305 | 0.298 |
"Change from baseline in FEV1 peak(0-4h) (L) on Day 1 and at Week 6.~Peak FEV1 is defined as the maximum FEV1 observed in the first 4 hours after dose of study medication.~Definitions:~Baseline=Baseline value was the average of the pre-dose measurements (at 45 mins and 15 mins pre-dose), at Visit 2 (Week 0); Day 1=Day of the first dose of randomized study drug at Visit 2 (Week 0); FEV1=Forced expiratory volume in the 1st second; Peak(0-4h)=Maximum FEV1 between 0 and 4 h." (NCT03084796)
Timeframe: Baseline, Day 1, Week 6
| Intervention | Litres (Least Squares Mean) | |
|---|---|---|
| Day 1 | Week 6 | |
| Treatment A | 0.197 | 0.212 |
| Treatment B | 0.211 | 0.255 |
| Treatment C | 0.260 | 0.305 |
| Treatment D | 0.288 | 0.301 |
| Treatment E | 0.136 | 0.143 |
| Treatment F | 0.299 | 0.356 |
"Vital signs -- Systolic blood pressure (SBP), Diastolic blood pressure (DBP) were measured at prespecified times, using a 12-Lead single ECGs were recorded at all study visits (pre-dose at V1 (Week -2) and V3 (Week 3), as well as at pre-dose and 1.5 hours post-dose at Visit 2 (Week 0) and Visit 4 (Week 6).~Results are shown by treatment group, as change from baseline (in mmHg) for representative timepoints.~Definitions:~Baseline=Values recorded pre-dose (Visit 2, Week 0); Day 1=Day of the first dose of randomized study drug (Visit 2, Week 0);" (NCT03084796)
Timeframe: Baseline, Day 1, Week 6
| Intervention | mmHg (Mean) | |||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| SBP, Day 1, 30 min post dose | DBP, Day 1, 30 min post dose | SBP, Day 1, 1,5 h post dose | DBP, Day 1, 1,5 h post dose | SBP, Day 1, 11 h post dose | DBP, Day 1, 11 h post dose | SBP, Week 6, pre-dose | DBP, Week 6, pre-dose | SBP, Week 6, 30 min post dose | DBP, Week 6, 30 min post dose | SBP, Week 6, 1,5 h post dose | DBP, Week 6, 1,5 h post dose | SBP, Week 6, 11 h post dose | DBP, Week 6, 11 h post dose | |
| Treatment A | -1.4 | -0.7 | 0.3 | -0.7 | 1.1 | -0.9 | 0.4 | 0.4 | -1.6 | -0.7 | -1.3 | -1.0 | 0.2 | -0.9 |
| Treatment B | -0.4 | -0.6 | -1.1 | -1.8 | 2.0 | 0.3 | 0.8 | 0.5 | -0.9 | -0.9 | -0.6 | -2.7 | 1.5 | -2.0 |
| Treatment C | -2.0 | -2.1 | -0.6 | -1.7 | -0.0 | -1.6 | 0.4 | -0.3 | -0.5 | -1.5 | -0.5 | -2.0 | 0.5 | -2.3 |
| Treatment D | -1.9 | -1.4 | -1.8 | -1.6 | 1.7 | -1.4 | -1.0 | -1.0 | -2.5 | -2.0 | -2.3 | -2.3 | 2.2 | -1.4 |
| Treatment E | -0.9 | -0.8 | 0.2 | -1.7 | 1.9 | -1.0 | 1.6 | 0.0 | 0.5 | -0.8 | 0.1 | -1.1 | 3.2 | -1.0 |
| Treatment F | -1.2 | 0.1 | -1.5 | -1.5 | 0.9 | -1.2 | 1.3 | -0.2 | 0.1 | -1.2 | 0.5 | -0.6 | 2.0 | -0.7 |
"24-hour Holter ECG - Prolonged QTcF - Change from baseline.~Subjects had a 24-h Holter recording before and 24 h after the 1st dose of study drug (Visit 2) and for 24 h before the last dose of study drug (Visit 4). The time-matched values recorded during the 24 h before the 1st dose of study drug on Visit 2 and served as the baseline for the Holter-extracted ECG parameters. The time-averaged baseline score is the average of the Day -1 scores at +5 min, +55 min, and at +2.5 h.~Results are presented as the number of subjects who had a change from baseline in QTcF of: > 30 msec, > 60 msec, and no prolongation (by > 30 msec or > 60 msec)." (NCT03084796)
Timeframe: Baseline, Day 1, Week 6
| Intervention | Participants (Count of Participants) | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| QTcF, Any post dose time point72488794 | QTcF, Any post dose time point72488795 | QTcF, Any post dose time point72488796 | QTcF, Any post dose time point72488797 | QTcF, Any post dose time point72488798 | QTcF, Any post dose time point72488793 | QTcF, Day 1, 5 min post dose72488793 | QTcF, Day 1, 5 min post dose72488795 | QTcF, Day 1, 5 min post dose72488796 | QTcF, Day 1, 5 min post dose72488797 | QTcF, Day 1, 5 min post dose72488798 | QTcF, Day 1, 5 min post dose72488794 | QTcF, Day 1, 55 min post dose72488793 | QTcF, Day 1, 55 min post dose72488794 | QTcF, Day 1, 55 min post dose72488796 | QTcF, Day 1, 55 min post dose72488797 | QTcF, Day 1, 55 min post dose72488798 | QTcF, Day 1, 55 min post dose72488795 | QTcF, Day 1, 2.5 h post dose72488793 | QTcF, Day 1, 2.5 h post dose72488795 | QTcF, Day 1, 2.5 h post dose72488796 | QTcF, Day 1, 2.5 h post dose72488797 | QTcF, Day 1, 2.5 h post dose72488798 | QTcF, Day 1, 2.5 h post dose72488794 | QTcF, Day before Week 6, 5 min post dose72488793 | QTcF, Day before Week 6, 5 min post dose72488794 | QTcF, Day before Week 6, 5 min post dose72488795 | QTcF, Day before Week 6, 5 min post dose72488796 | QTcF, Day before Week 6, 5 min post dose72488797 | QTcF, Day before Week 6, 5 min post dose72488798 | QTcF, Day before Week 6, 55 min post dose72488793 | QTcF, Day before Week 6, 55 min post dose72488794 | QTcF, Day before Week 6, 55 min post dose72488796 | QTcF, Day before Week 6, 55 min post dose72488797 | QTcF, Day before Week 6, 55 min post dose72488798 | QTcF, Day before Week 6, 55 min post dose72488795 | QTcF, Day before Week 6, 2.5 h post dose72488794 | QTcF, Day before Week 6, 2.5 h post dose72488796 | QTcF, Day before Week 6, 2.5 h post dose72488797 | QTcF, Day before Week 6, 2.5 h post dose72488798 | QTcF, Day before Week 6, 2.5 h post dose72488793 | QTcF, Day before Week 6, 2.5 h post dose72488795 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Change from baseline: > 60 msec | No change from baseline (> 30 msec or > 60 msec) | Change from baseline: > 30 msec | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Treatment A | 19 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Treatment B | 20 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Treatment C | 21 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Treatment D | 20 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Treatment E | 16 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Treatment F | 18 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Treatment A | 0 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Treatment B | 1 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Treatment C | 0 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Treatment D | 2 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Treatment E | 2 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Treatment F | 1 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Treatment A | 102 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Treatment B | 102 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Treatment C | 100 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Treatment D | 101 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Treatment E | 103 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Treatment F | 104 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Treatment A | 2 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Treatment B | 4 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Treatment C | 9 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Treatment E | 3 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Treatment F | 4 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Treatment D | 0 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Treatment E | 0 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Treatment A | 119 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Treatment B | 119 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Treatment C | 112 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Treatment D | 121 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Treatment E | 118 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Treatment F | 119 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Treatment A | 8 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Treatment C | 5 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Treatment D | 6 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Treatment E | 4 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Treatment F | 5 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Treatment A | 113 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Treatment C | 116 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Treatment D | 116 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Treatment E | 116 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Treatment F | 118 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Treatment A | 5 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Treatment B | 12 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Treatment C | 6 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Treatment D | 5 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Treatment E | 6 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Treatment F | 8 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Treatment B | 0 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Treatment D | 1 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Treatment E | 1 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Treatment F | 0 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Treatment A | 116 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Treatment B | 111 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Treatment C | 115 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Treatment D | 117 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Treatment E | 114 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Treatment F | 115 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Treatment B | 3 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Treatment D | 3 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Treatment F | 3 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Treatment C | 121 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Treatment D | 120 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Treatment E | 121 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Treatment F | 120 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Treatment C | 7 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Treatment D | 7 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Treatment B | 123 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Treatment C | 114 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Treatment A | 6 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Treatment B | 6 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Treatment C | 3 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Treatment F | 7 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Treatment A | 115 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Treatment B | 117 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Treatment C | 118 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Treatment F | 116 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
"Evaluate the change from baseline in average use of rescue medication (number of puffs/day) during the inter-visit periods and the entire treatment period.~Results are shown as number of puffs/day; a decrease (implies improvement) from baseline in average use of rescue medication.~Definitions:~Baseline=Data recorded during the run-in period (a 2-week period prior to randomization to study treatment and study drug intake); Inter-visit period 1=Starts at randomization to treatment (Visit 2, Week 0) and runs to the day before the subject returns to the clinic (Visit 3 (Week 3); Inter-visit period 2=Starts when the subject returns to the clinic (Visit 3, Week 3) and runs to the end of the randomized treatment period (Visit 4, Week 6); Entire Treatment period=From day of randomization to drug intake to the end of the randomized treatment period (Visit 4, Week 6); Randomization=Randomization to study drug treatment (Visit 2, Week 0);" (NCT03084796)
Timeframe: Baseline, Inter-visit period 1, Inter-visit period 2, Entire treatment period
| Intervention | Number of puffs/day (Least Squares Mean) | ||
|---|---|---|---|
| Inter-visit period 1 | Inter-visit period 2 | Entire treatment period | |
| Treatment A | -0.72 | -0.59 | -0.66 |
| Treatment B | -0.58 | -0.50 | -0.54 |
| Treatment C | -0.53 | -0.51 | -0.52 |
| Treatment D | -0.71 | -0.69 | -0.70 |
| Treatment E | -0.30 | -0.17 | -0.23 |
| Treatment F | -0.52 | -0.40 | -0.46 |
"Change from baseline in average EXACT-Respiratory Symptom (E-RS) total score during inter-visit periods and the entire treatment period~E-RS in COPD uses 11 respiratory symptom items from the 14-item EXAcerbations of COPD tool (EXACT). E-RS total score quantifies respiratory symptom severity on a scale ranging from 0 to 40. Higher E-RS total scores indicate more severe symptoms and a declining total score indicates health improvement. E-RS questionnaire was completed by the patient each evening (e-diary).~Definitions:~For details on baseline, inter-visit periods, and the entire treatment period, please refer to outcome measure #15." (NCT03084796)
Timeframe: Baseline, Inter-visit period 1, Inter-visit period 2, Entire treatment period
| Intervention | score on a scale (Least Squares Mean) | ||
|---|---|---|---|
| Inter-visit period 1 | Inter-visit period 2 | Entire treatment period | |
| Treatment A | -1.681 | -2.030 | -1.855 |
| Treatment B | -1.539 | -1.840 | -1.689 |
| Treatment C | -1.941 | -2.147 | -2.044 |
| Treatment D | -1.663 | -2.077 | -1.870 |
| Treatment E | -0.714 | -0.681 | -0.698 |
| Treatment F | -1.280 | -1.505 | -1.393 |
"24-hour Holter ECG - Prolonged QTcF - Male subjects.~Subjects had a 24-h Holter recording before and 24 h after the 1st dose of study drug (Visit 2) and for 24 h before the last dose of study drug (Visit 4). The time-matched values recorded during the 24 h before the 1st dose of study drug on Visit 2 and served as the baseline for the Holter-extracted ECG parameters. The time-averaged baseline score is the average of the Day -1 scores at +5 min, +55 min, and at +2.5 h." (NCT03084796)
Timeframe: Baseline, Day 1, Week 6
| Intervention | Participants (Count of Participants) | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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| QTcF, Day -1, 5 min72488794 | QTcF, Day -1, 5 min72488798 | QTcF, Day -1, 5 min72488797 | QTcF, Day -1, 5 min72488793 | QTcF, Day -1, 5 min72488795 | QTcF, Day -1, 5 min72488796 | QTcF, Day -1, 55 min72488793 | QTcF, Day -1, 55 min72488794 | QTcF, Day -1, 55 min72488795 | QTcF, Day -1, 55 min72488798 | QTcF, Day -1, 55 min72488797 | QTcF, Day -1, 55 min72488796 | QTcF, Day -1, 2.5 h72488794 | QTcF, Day -1, 2.5 h72488797 | QTcF, Day -1, 2.5 h72488798 | QTcF, Day -1, 2.5 h72488793 | QTcF, Day -1, 2.5 h72488795 | QTcF, Day -1, 2.5 h72488796 | QTcF, Any post dose time point72488793 | QTcF, Any post dose time point72488794 | QTcF, Any post dose time point72488797 | QTcF, Any post dose time point72488798 | QTcF, Any post dose time point72488795 | QTcF, Any post dose time point72488796 | QTcF, Day 1, 5 min post dose72488794 | QTcF, Day 1, 5 min post dose72488797 | QTcF, Day 1, 5 min post dose72488798 | QTcF, Day 1, 5 min post dose72488793 | QTcF, Day 1, 5 min post dose72488795 | QTcF, Day 1, 5 min post dose72488796 | QTcF, Day 1, 55 min post dose72488795 | QTcF, Day 1, 55 min post dose72488797 | QTcF, Day 1, 55 min post dose72488798 | QTcF, Day 1, 55 min post dose72488793 | QTcF, Day 1, 55 min post dose72488794 | QTcF, Day 1, 55 min post dose72488796 | QTcF, Day 1, 2.5 h post dose72488794 | QTcF, Day 1, 2.5 h post dose72488798 | QTcF, Day 1, 2.5 h post dose72488797 | QTcF, Day 1, 2.5 h post dose72488793 | QTcF, Day 1, 2.5 h post dose72488795 | QTcF, Day 1, 2.5 h post dose72488796 | QTcF, Day before Week 6, 5 min post dose72488794 | QTcF, Day before Week 6, 5 min post dose72488797 | QTcF, Day before Week 6, 5 min post dose72488798 | QTcF, Day before Week 6, 5 min post dose72488793 | QTcF, Day before Week 6, 5 min post dose72488795 | QTcF, Day before Week 6, 5 min post dose72488796 | QTcF, Day before Week 6, 55 min post dose72488793 | QTcF, Day before Week 6, 55 min post dose72488798 | QTcF, Day before Week 6, 55 min post dose72488794 | QTcF, Day before Week 6, 55 min post dose72488795 | QTcF, Day before Week 6, 55 min post dose72488796 | QTcF, Day before Week 6, 55 min post dose72488797 | QTcF, Day before Week 6, 2.5 h post dose72488793 | QTcF, Day before Week 6, 2.5 h post dose72488794 | QTcF, Day before Week 6, 2.5 h post dose72488797 | QTcF, Day before Week 6, 2.5 h post dose72488798 | QTcF, Day before Week 6, 2.5 h post dose72488795 | QTcF, Day before Week 6, 2.5 h post dose72488796 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Actual value > 450 msec | Actual value > 480 msec | Actual value > 500 msec | No prolongation (> 450 msec or > 480 msec or > 500 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Treatment F | 1 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Treatment B | 55 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Treatment C | 54 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Treatment F | 65 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Treatment C | 1 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Treatment A | 62 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Treatment C | 53 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Treatment E | 68 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Treatment F | 63 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Treatment B | 1 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Treatment E | 1 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Treatment B | 54 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Treatment E | 66 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Treatment F | 66 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Treatment B | 4 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Treatment C | 6 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Treatment D | 4 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Treatment E | 2 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Treatment F | 5 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Treatment E | 0 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Treatment F | 3 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Treatment B | 0 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Treatment F | 0 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Treatment B | 51 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Treatment C | 47 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Treatment D | 54 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Treatment E | 67 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Treatment F | 58 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Treatment B | 2 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Treatment C | 0 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Treatment C | 51 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Treatment F | 61 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Treatment C | 3 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Treatment A | 1 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Treatment B | 53 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Treatment C | 50 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Treatment A | 3 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Treatment B | 3 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Treatment F | 4 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Treatment A | 59 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Treatment B | 52 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Treatment F | 62 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Treatment D | 3 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Treatment F | 2 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Treatment A | 0 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Treatment A | 60 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Treatment D | 55 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Treatment A | 2 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Treatment C | 2 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Treatment D | 2 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Treatment D | 0 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Treatment A | 61 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Treatment C | 52 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Treatment D | 56 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Treatment E | 69 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Treatment D | 1 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Treatment D | 57 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
"Change from baseline in FEV1 AUC(0-4h), normalized by time on Day 1 of treatment (Week 0).~Spirometry, used to measure FEV1, was performed according to internationally accepted standards. The AUC for FEV1 on Day 1 and at Week 6 of treatment was calculated by using the linear trapezoidal rule, based on the changes in FEV1 from the baseline values, and divided by the observation time (4 hours).~Definitions:~AUC=Area under the curve; Baseline=Baseline value was the average of the pre-dose measurements (at 45 mins and 15 mins pre-dose), at Visit 2 (Week 0); Day 1=Day of the first dose of randomized study drug at Visit 2 (Week 0); FEV1=Forced expiratory volume in the 1st second; FEV1 AUC(0-4h)=Mean FEV1 after inhalation, measured at prespecified times for up to 4-h observation period (0-4h), normalized by time;" (NCT03084796)
Timeframe: Baseline, Day 1, Week 6
| Intervention | Litres (Least Squares Mean) | |
|---|---|---|
| Day 1 | Week 6 | |
| Treatment A | 0.101 | 0.116 |
| Treatment B | 0.115 | 0.157 |
| Treatment C | 0.173 | 0.198 |
| Treatment D | 0.190 | 0.204 |
| Treatment E | 0.030 | 0.024 |
| Treatment F | 0.194 | 0.253 |
"24-hour Holter ECG - Prolonged QTcF - Female subjects.~Subjects had a 24-h Holter recording before and 24 h after the 1st dose of study drug (Visit 2) and for 24 h before the last dose of study drug (Visit 4). The time-matched values recorded during the 24 h before the 1st dose of study drug on Visit 2 and served as the baseline for the Holter-extracted ECG parameters. The time-averaged baseline score is the average of the Day -1 scores at +5 min, +55 min, and at +2.5 h." (NCT03084796)
Timeframe: Baseline, Day 1, Week 6
| Intervention | Participants (Count of Participants) | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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| QTcF, Day -1, 5 min72488795 | QTcF, Day -1, 5 min72488798 | QTcF, Day -1, 5 min72488793 | QTcF, Day -1, 5 min72488794 | QTcF, Day -1, 5 min72488796 | QTcF, Day -1, 5 min72488797 | QTcF, Day -1, 55 min72488795 | QTcF, Day -1, 55 min72488797 | QTcF, Day -1, 55 min72488798 | QTcF, Day -1, 55 min72488793 | QTcF, Day -1, 55 min72488794 | QTcF, Day -1, 55 min72488796 | QTcF, Day -1, 2.5 h72488794 | QTcF, Day -1, 2.5 h72488797 | QTcF, Day -1, 2.5 h72488795 | QTcF, Day -1, 2.5 h72488793 | QTcF, Day -1, 2.5 h72488796 | QTcF, Day -1, 2.5 h72488798 | QTcF, Any post dose time point72488794 | QTcF, Any post dose time point72488795 | QTcF, Any post dose time point72488797 | QTcF, Any post dose time point72488798 | QTcF, Any post dose time point72488793 | QTcF, Any post dose time point72488796 | QTcF, Day 1, 5 min post dose72488798 | QTcF, Day 1, 5 min post dose72488795 | QTcF, Day 1, 5 min post dose72488793 | QTcF, Day 1, 5 min post dose72488794 | QTcF, Day 1, 5 min post dose72488796 | QTcF, Day 1, 5 min post dose72488797 | QTcF, Day 1, 55 min post dose72488793 | QTcF, Day 1, 55 min post dose72488798 | QTcF, Day 1, 55 min post dose72488797 | QTcF, Day 1, 55 min post dose72488794 | QTcF, Day 1, 55 min post dose72488795 | QTcF, Day 1, 55 min post dose72488796 | QTcF, Day 1, 2.5 h post dose72488795 | QTcF, Day 1, 2.5 h post dose72488793 | QTcF, Day 1, 2.5 h post dose72488794 | QTcF, Day 1, 2.5 h post dose72488796 | QTcF, Day 1, 2.5 h post dose72488797 | QTcF, Day 1, 2.5 h post dose72488798 | QTcF, Day before Week 6, 5 min post dose72488798 | QTcF, Day before Week 6, 5 min post dose72488793 | QTcF, Day before Week 6, 5 min post dose72488794 | QTcF, Day before Week 6, 5 min post dose72488795 | QTcF, Day before Week 6, 5 min post dose72488796 | QTcF, Day before Week 6, 5 min post dose72488797 | QTcF, Day before Week 6, 55 min post dose72488798 | QTcF, Day before Week 6, 55 min post dose72488793 | QTcF, Day before Week 6, 55 min post dose72488794 | QTcF, Day before Week 6, 55 min post dose72488795 | QTcF, Day before Week 6, 55 min post dose72488796 | QTcF, Day before Week 6, 55 min post dose72488797 | QTcF, Day before Week 6, 2.5 h post dose72488798 | QTcF, Day before Week 6, 2.5 h post dose72488793 | QTcF, Day before Week 6, 2.5 h post dose72488794 | QTcF, Day before Week 6, 2.5 h post dose72488795 | QTcF, Day before Week 6, 2.5 h post dose72488796 | QTcF, Day before Week 6, 2.5 h post dose72488797 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Actual value > 470 msec | Actual value > 500 msec | No prolongation (> 470 msec or > 500 msec) | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Treatment B | 64 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Treatment C | 67 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Treatment E | 0 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Treatment A | 3 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Treatment F | 1 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Treatment A | 55 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Treatment F | 0 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Treatment F | 57 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Treatment A | 2 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Treatment B | 3 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Treatment A | 56 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Treatment B | 65 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Treatment C | 0 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Treatment F | 56 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Treatment A | 1 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Treatment A | 57 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Treatment B | 2 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Treatment A | 0 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Treatment B | 0 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Treatment D | 0 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Treatment A | 58 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Treatment B | 66 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Treatment D | 65 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Treatment E | 52 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Treatment B | 1 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Treatment D | 1 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Treatment B | 67 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Treatment D | 64 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
"Number of subjects achieving TDI focal score ≥1, at treatment visit 3 (Week 3) and at treatment visit 4 (Week 6).~TDI is a validated, interviewer-administered questionnaire that measures changes in dyspnea severity from the baseline established by the BDI questionnaire. TDI consists of the same 24 items and 3 domains as the BDI, with the same 2-week recall period. Each category is rated by 7 grades ranging from -3 (major deterioration) to +3 (major improvement); total score ranging from -9 to +9, with higher scores indicating better outcomes. The minimal clinically important differences (MCID) is considered a change of ≥1 unit. The same investigator or designee interviewed the subject for the BDI and TDI during the study period. A TDI focal score of ≥1 is considered as clinically important.~Definitions:~Baseline=The BDI focal score value at Visit 2 (Week 0); BDI=Baseline Dyspnea Index; MCID=Minimal Clinically Important Differences; TDI=Transition Dyspnea Index;" (NCT03084796)
Timeframe: Baseline, Week 3, Week 6
| Intervention | Participants (Count of Participants) | |
|---|---|---|
| Week 3 Focal Score ≥ 1 | Week 6 Focal Score ≥ 1 | |
| Treatment A | 70 | 74 |
| Treatment B | 78 | 83 |
| Treatment C | 75 | 82 |
| Treatment D | 84 | 91 |
| Treatment E | 67 | 55 |
| Treatment F | 74 | 80 |
"Transitional Dyspnea Index (TDI) focal score at treatment visit 3 (Week 3) and treatment visit 4 (Week 6).~TDI is a validated, interviewer-administered questionnaire that measures changes in dyspnea severity from the baseline established by the BDI questionnaire. TDI consists of the same 24 items and 3 domains as the BDI, with the same 2-week recall period. Each category is rated by 7 grades ranging from -3 (major deterioration) to +3 (major improvement), with a total score ranging from -9 to +9, with higher scores indicating better outcomes. The minimal clinically important differences (MCID) is considered a change of ≥1 unit. The same investigator or designee interviewed the subject for the BDI and TDI during the study period. A TDI focal score of ≥1 is considered as clinically important.~Definitions:~Baseline=The BDI focal score value at Visit 2 (Week 0); BDI=Baseline Dyspnea Index; MCID=Minimal Clinically Important Differences; TDI=Transition Dyspnea Index;" (NCT03084796)
Timeframe: Baseline, Week 3, Week 6
| Intervention | score on a scale (Least Squares Mean) | |
|---|---|---|
| Week 3 | Week 6 | |
| Treatment A | 1.29 | 1.65 |
| Treatment B | 1.55 | 2.02 |
| Treatment C | 1.54 | 2.05 |
| Treatment D | 1.94 | 2.55 |
| Treatment E | 1.14 | 1.03 |
| Treatment F | 1.66 | 2.11 |
"Change from baseline in 24-Hour Holter electrocardiogram (ECG) parameters - QRS Interval~Subjects had a 24-h Holter recording before and 24 h after the 1st dose of study drug (Visit 2) and for 24 h before the last dose of study drug (Visit 4). The time-matched values were recorded during the 24 h before the 1st dose of study drug on Visit 2 and served as the baseline for the Holter-extracted ECG parameters. The time-averaged baseline score is the average of the Day -1 scores at +5 min, +55 min, and at +2.5 h." (NCT03084796)
Timeframe: Baseline, Day 1, Week 6
| Intervention | msec (Mean) | |||||
|---|---|---|---|---|---|---|
| QRS Interval, Day 1, 5 min post dose | QRS Interval, Day 1, 55 min post dose | QRS Interval, Day 1, 2.5 h post dose | QRS Interval, Day before Week 6, 5 min post dose | QRS Interval, Day before Week 6, 55 min post dose | QRS Interval, Day before Week 6, 2.5 h post dose | |
| Treatment A | 1.18 | 0.97 | 1.38 | 0.61 | 1.12 | 1.49 |
| Treatment B | 0.05 | 1.19 | 2.40 | -1.76 | -0.09 | 0.74 |
| Treatment C | 1.50 | 1.21 | 1.80 | 0.43 | 0.85 | 0.30 |
| Treatment D | 1.99 | 1.56 | 1.50 | 2.00 | 2.38 | 2.18 |
| Treatment E | 0.45 | 0.14 | 0.64 | 0.45 | 0.77 | 1.14 |
| Treatment F | 1.50 | 1.70 | 0.86 | 0.69 | 0.42 | 1.35 |
"Change from baseline in 24-Hour Holter electrocardiogram (ECG) parameters - PR Interval~Subjects had a 24-h Holter recording before and 24 h after the 1st dose of study drug (Visit 2) and for 24 h before the last dose of study drug (Visit 4). The time-matched values were recorded during the 24 h before the 1st dose of study drug on Visit 2 and served as the baseline for the Holter-extracted ECG parameters. The time-averaged baseline score is the average of the Day -1 scores at +5 min, +55 min, and at +2.5 h." (NCT03084796)
Timeframe: Baseline, Day 1, Week 6
| Intervention | msec (Mean) | |||||
|---|---|---|---|---|---|---|
| PR Interval, Day 1, 5 min post dose | PR Interval, Day 1, 55 min post dose | PR Interval, Day 1, 2.5 h post dose | PR Interval, Day before Week 6, 5 min post dose | PR Interval, Day before Week 6, 55 min post dose | PR Interval, Day before Week 6, 2.5 h post dose | |
| Treatment A | 7.24 | 7.20 | 8.48 | 0.44 | 0.88 | 2.50 |
| Treatment B | 6.53 | 6.89 | 9.38 | 1.36 | 2.37 | 3.01 |
| Treatment C | 6.08 | 8.21 | 7.58 | -0.11 | 1.91 | 0.16 |
| Treatment D | 6.71 | 6.77 | 6.16 | 3.88 | 0.82 | 0.84 |
| Treatment E | 3.06 | 4.38 | 5.84 | -1.36 | -1.13 | -1.22 |
| Treatment F | 4.90 | 4.77 | 4.25 | 0.82 | -1.66 | -1.94 |
"Change from baseline in 24-Hour Holter electrocardiogram (ECG) parameters - Heart rate (HR)~Subjects had a 24-h Holter recording before and 24 h after the 1st dose of study drug (Visit 2) and for 24 h before the last dose of study drug (Visit 4). The time-matched values recorded during the 24 h before the 1st dose of study drug on Visit 2 and served as the baseline for the Holter-extracted ECG parameters. The time-averaged baseline score is the average of the Day -1 scores at +5m, +55m, and at +2.5 h." (NCT03084796)
Timeframe: Baseline, Day 1, Week 6
| Intervention | bpm (Mean) | |||||
|---|---|---|---|---|---|---|
| HR, Day 1, 5 min post dose | HR, Day 1, 55 min post dose | HR, Day 1, 2.5 h post dose | HR, Day before Week 6, 5 min post dose | HR, Day before Week 6, 55 min post dose | HR, Day before Week 6, 2.5 h post dose | |
| Treatment A | -8.85 | -7.19 | -7.57 | -1.72 | -1.52 | -2.30 |
| Treatment B | -6.62 | -8.29 | -6.75 | -1.06 | 0.41 | -0.01 |
| Treatment C | -7.78 | -8.28 | -9.20 | -1.61 | -1.10 | -1.13 |
| Treatment D | -7.64 | -9.59 | -7.46 | -1.85 | -1.40 | -0.73 |
| Treatment E | -4.84 | -7.44 | -6.12 | 3.92 | 1.12 | 2.49 |
| Treatment F | -5.54 | -7.19 | -8.96 | 1.70 | 1.22 | -1.47 |
"Change from baseline in 24-Hour Holter electrocardiogram (ECG) parameters - Fridericia-corrected QT interval (QTcF).~Subjects had a 24-h Holter recording before and 24 h after the 1st dose of study drug (Visit 2) and for 24 h before the last dose of study drug (Visit 4). The time-matched values recorded during the 24 h before the 1st dose of study drug on Visit 2 and served as the baseline for the Holter-extracted ECG parameters. The time-averaged baseline score is the average of the Day -1 scores at +5 min, +55 min, and at +2.5 h." (NCT03084796)
Timeframe: Baseline, Day 1, Week 6
| Intervention | msec (Mean) | |||||
|---|---|---|---|---|---|---|
| QTcF, Day 1, 5 min post dose | QTcF, Day 1, 55 min post dose | QTcF, Day 1, 2.5 h post dose | QTcF, Day before Week 6, 5 min post dose | QTcF, Day before Week 6, 55 min post dose | QTcF, Day before Week 6, 2.5 h post dose | |
| Treatment A | 3.62 | 8.37 | 7.15 | 1.61 | 2.38 | 4.13 |
| Treatment B | 5.37 | 5.41 | 8.65 | 1.14 | 0.09 | 0.85 |
| Treatment C | 6.81 | 6.72 | 7.20 | -0.60 | 1.41 | -0.97 |
| Treatment D | 6.25 | 9.90 | 5.45 | 1.67 | 4.15 | 1.73 |
| Treatment E | 3.59 | 6.04 | 4.81 | -3.56 | 1.02 | 0.14 |
| Treatment F | 5.56 | 5.43 | 6.77 | 1.41 | 3.19 | 2.50 |
Time to onset of action is defined as the time (in minutes) from receiving the study drug on Day 1, until the FEV1 change from baseline is ≥100 mL. (NCT03084796)
Timeframe: Day 1
| Intervention | minutes (Mean) |
|---|---|
| Treatment A | 45.1 |
| Treatment B | 32.6 |
| Treatment C | 29.5 |
| Treatment D | 27.3 |
| Treatment E | 240.1 |
| Treatment F | 28.1 |
Number of patients achieving onset of action was defined as a change from baseline in post-dose FEV1 ≥100 mL on Day 1. These are the patients who contributed to the results, reported as median and 95% CI for 'time to onset of action' presented in Outcome Measure 8, above. (NCT03084796)
Timeframe: Day 1
| Intervention | Participants (Count of Participants) |
|---|---|
| Treatment A | 90 |
| Treatment B | 103 |
| Treatment C | 103 |
| Treatment D | 110 |
| Treatment E | 74 |
| Treatment F | 113 |
"Change from baseline in FVC AUC(0-4h), normalized by time, on Day 1 and at the end of treatment (Week 6).~Spirometry, used to measure FVC, was performed according to internationally accepted standards. The AUC for FVC was calculated by using the linear trapezoidal rule, based on the changes in FVC from the baseline values, and divided by the observation time (4 hours).~Definitions:~AUC=Area under the curve; Baseline=Baseline value was the average of the pre-dose measurements (at 45 mins and 15 mins pre-dose), at Visit 2 (Week 0); Day 1=Day of the first dose of randomized study drug at Visit 2 (Week 0); FVC=Forced Vital Capacity; FVC AUC(0-4)=Mean FVC after inhalation, measured at prespecified times for up to 4-h observation period (0-4 h), normalized by time;" (NCT03084796)
Timeframe: Baseline, Day 1, Week 6
| Intervention | Litres (Least Squares Mean) | |
|---|---|---|
| Day 1 | Week 6 | |
| Treatment A | 0.133 | 0.149 |
| Treatment B | 0.192 | 0.203 |
| Treatment C | 0.244 | 0.248 |
| Treatment D | 0.273 | 0.253 |
| Treatment E | 0.036 | 0.000 |
| Treatment F | 0.311 | 0.353 |
"Change from baseline in FVC peak(0-4h) (L) on Day 1 and at the end of treatment at Week 6. Peak FEV1 is defined as the maximum FEV1 observed in the first 4 hours after dose of study medication.~Definitions:~Baseline=Baseline value was the average of the pre-dose measurements (at 45 mins and 15 mins pre-dose), at Visit 2 (Week 0); Day 1=Day of the first dose of randomized study drug at Visit 2 (Week 0); FVC=Forced Vital Capacity; Peak(0-4h)=Maximum FEV1 between 0 and 4 h." (NCT03084796)
Timeframe: Baseline, Day 1, Week 6
| Intervention | Litres (Least Squares Mean) | |
|---|---|---|
| Day 1 | Week 6 | |
| Treatment A | 0.293 | 0.322 |
| Treatment B | 0.372 | 0.379 |
| Treatment C | 0.414 | 0.431 |
| Treatment D | 0.455 | 0.427 |
| Treatment E | 0.213 | 0.182 |
| Treatment F | 0.491 | 0.530 |
(NCT03095456)
Timeframe: Baseline and Day 29
| Intervention | mL (Least Squares Mean) |
|---|---|
| Revefenacin | 125.4 |
| Spiriva Handihaler® | 55.8 |
(NCT03095456)
Timeframe: 1 Month
| Intervention | puffs per day (Least Squares Mean) |
|---|---|
| Revefenacin | 3.4 |
| Spiriva Handihaler® | 2.9 |
(NCT03095456)
Timeframe: Baseline and Day 29
| Intervention | mL (Least Squares Mean) |
|---|---|
| Revefenacin | 71.4 |
| Spiriva Handihaler® | 84.1 |
(NCT03095456)
Timeframe: Baseline and Day 29 (0-4 hours)
| Intervention | mL (Least Squares Mean) |
|---|---|
| Revefenacin | 354.2 |
| Spiriva Handihaler® | 340.1 |
(NCT03095456)
Timeframe: Baseline and Day 29 (0-4 hours)
| Intervention | mL (Least Squares Mean) |
|---|---|
| Revefenacin | 174.2 |
| Spiriva Handihaler® | 197.7 |
FEV1 = forced expiratory volume at one second (NCT03095456)
Timeframe: Baseline and Day 29
| Intervention | mL (Least Squares Mean) |
|---|---|
| Revefenacin | 63.0 |
| Spiriva Handihaler® | 47.3 |
"Participants were asked to demonstrate use of their prescribed DPI at Visit 1 and any error made by the participant was recorded by the HCP in the checklist. Checklist of instructions for correct use were based on the steps for correct use listed in PILs for the respective DPI. The errors made during demonstration by participants were defined as critical, when the participant received a lesser/no dose. The percentage of participants making at least one critical error in either one or both devices (where applicable) is presented. The aim of the analysis was to compare percentage of participants making at least one critical error with Ellipta and Ellipta+LAMA versus Turbuhaler and Turbuhaler+LAMA and Diskus and Diskus+LAMA; hence, the arms were combined as pre-specified in the protocol and RAP." (NCT03114969)
Timeframe: Day 1
| Intervention | Percentage of participants (Number) |
|---|---|
| Relvar Ellipta+[Relvar Ellipta+LAMA] | 16 |
| Symbicort Turbuhaler+[Symbicort Turbuhaler+LAMA] | 47 |
| Seretide Diskus+[Seretide Diskus+LAMA] | 36 |
"Participants were asked to demonstrate use of their prescribed DPI at Visit 2 within 6 weeks after they were retrained on the correct use of inhalers. Any error made by the participant was recorded by the HCP in the checklist. Checklist of instructions for correct use were based on the steps for correct use listed in PILs for the respective DPI. The errors made during demonstration by participants were defined as critical, when the participant received a lesser/no dose. The percentage of participants making at least one critical error in either one or both devices (where applicable) is presented." (NCT03114969)
Timeframe: Week 6
| Intervention | Percentage of participants (Number) |
|---|---|
| Relvar Ellipta | 0 |
| Relvar Ellipta+LAMA | 8 |
"Participants were asked to demonstrate use of their prescribed DPI at Visit 2 within 6 weeks after they were retrained on the correct use of inhalers. Any error made by the participant was recorded by the HCP in the checklist. Checklist of instructions for correct use were based on the steps for correct use listed in PILs for the respective DPI. The errors made during demonstration by participants were defined as critical, when the participant received a lesser/no dose. The percentage of participants making at least one critical error in either one or both devices (where applicable) is presented. The aim of the analysis was to compare percentage of participants making at least one critical error with Ellipta versus all ICS/LABA+LAMA DPIs; hence, the arms were combined as pre-specified in the protocol and RAP." (NCT03114969)
Timeframe: Week 6
| Intervention | Percentage of participants (Number) |
|---|---|
| Relvar Ellipta | 0 |
| [Relvar Ellipta+LAMA]+[Symb Turb+LAMA]+[Seretide Diskus+LAMA] | 13 |
"Participants were asked to demonstrate use of their prescribed DPI at Visit 2 within 6 weeks after they were retrained on the correct use of inhalers. Any error made by the participant was recorded by the HCP in the checklist. Checklist of instructions for correct use were based on the steps for correct use listed in PILs for the respective DPI. The errors during demonstration by participants were defined as critical, when the participant received a lesser/no dose. The percentage of participants making at least one critical error in the primary DPI is presented. The aim of the analysis was to compare percentage of participants making at least one critical error with Ellipta and Ellipta+LAMA versus Turbuhaler and Turbuhaler+LAMA and Diskus and Diskus+LAMA; hence, the arms were combined as pre-specified in the protocol and RAP." (NCT03114969)
Timeframe: Week 6
| Intervention | Percentage of participants (Number) |
|---|---|
| Relvar Ellipta+[Relvar Ellipta+LAMA] | 3 |
| Symbicort Turbuhaler+[Symbicort Turbuhaler+LAMA] | 7 |
| Seretide Diskus+[Seretide Diskus+LAMA] | 12 |
"Participants were asked to demonstrate use of their prescribed DPI at Visit 2 within 6 weeks after they were retrained on the correct use of inhalers. Any error made by the participant was recorded by the HCP in the checklist. Checklist of instructions for correct use were based on the steps for correct use listed in PILs for the respective DPI. The errors made during demonstration by participants were defined as critical, when the participant received a lesser/no dose. The percentage of participants making at least one critical error in the primary DPI is presented. The aim of the analysis was to compare percentage of participants making at least one critical error with Ellipta versus all ICS/LABA+LAMA DPIs; hence, the arms were combined as pre-specified in the protocol and RAP." (NCT03114969)
Timeframe: Week 6
| Intervention | Percentage of participants (Number) |
|---|---|
| [Relvar Ellipta+LAMA]+[Symb Turb+LAMA]+[Seretide Diskus+LAMA] | 8 |
| Relvar Ellipta | 0 |
"Participants were asked to demonstrate use of their prescribed DPI at Visit 1 and any error made by the participant was recorded by the health care practitioner (HCP) in the checklist. Checklist of instructions for correct use were based on the steps for correct use listed in patient instruction leaflets (PILs) for the respective DPI. The errors made during demonstration by participants were defined as critical, when the participant received a lesser/no dose. The percentage of participants making at least one critical error in the primary DPI is presented. The analysis was performed on the Intent to Treat (ITT) Population which comprised of all enrolled participants who demonstrated use of their primary DPI." (NCT03114969)
Timeframe: Day 1
| Intervention | Percentage of participants (Number) |
|---|---|
| Relvar Ellipta | 10 |
| Symbicort Turbuhaler | 40 |
| Seretide Diskus | 26 |
| Spiriva Handihaler | 34 |
| Incruse/Anoro Ellipta | 10 |
| Ultibro/Seebri Breezhaler | 33 |
| Relvar Ellipta+LAMA | 12 |
| Symbicort Turbuhaler+LAMA | 38 |
| Seretide Diskus+LAMA | 26 |
"Participants were asked to demonstrate use of their prescribed DPI at Visit 2 within 6 weeks after they were retrained on the correct use of inhalers. Any error made by the participant was recorded by the HCP in the checklist. Checklist of instructions for correct use were based on the steps listed in PILs for the respective DPI. The errors were defined as critical, when the participant received a lesser/no dose and non-critical when the dose may not be affected, but the participant has demonstrated improper use of their DPI, as per PIL. Overall errors is the combination of critical and non-critical errors. The percentage of participants making at least one overall error in primary DPI is presented. The aim of the analysis was to compare percentage of participants making at least one overall error with Ellipta versus all ICS/LABA+LAMA DPIs; hence, the arms were combined as pre-specified in the protocol and RAP." (NCT03114969)
Timeframe: Week 6
| Intervention | Percentage of participants (Number) |
|---|---|
| [Relvar Ellipta+LAMA]+[Symb Turb+LAMA]+[Seretide Diskus+LAMA] | 19 |
| Relvar Ellipta | 12 |
"Participants were asked to demonstrate use of their prescribed DPI at Visit 1 and any error made by the participant was recorded by the HCP in the checklist. Checklist of instructions for correct use were based on the steps for correct use listed in PILs for the respective DPI. The errors made during demonstration by participants were defined as critical, when the participant received a lesser/no dose. The percentage of participants making at least one critical error in either one or both devices (where applicable) is presented." (NCT03114969)
Timeframe: Day 1
| Intervention | Percentage of participants (Number) |
|---|---|
| Relvar Ellipta | 10 |
| Relvar Ellipta+LAMA | 22 |
"Participants were asked to demonstrate use of their prescribed DPI at Visit 1 and any error made by the participant was recorded by the HCP in the checklist. Checklist of instructions for correct use were based on the steps for correct use listed in PILs for the respective DPI. The errors made during demonstration by participants were defined as critical, when the participant received a lesser/no dose. The percentage of participants making at least one critical error in either one or both devices (where applicable) is presented. The aim of the analysis was to compare percentage of participants making at least one critical error with Ellipta versus all ICS/LABA+LAMA DPIs; hence, the arms were combined as pre-specified in the protocol and RAP." (NCT03114969)
Timeframe: Day 1
| Intervention | Percentage of participants (Number) |
|---|---|
| Relvar Ellipta | 10 |
| [Relvar Ellipta+LAMA]+[Symb Turb+LAMA]+[Seretide Diskus+LAMA] | 41 |
"Participants were asked to demonstrate use of their prescribed DPI at Visit 1 and any error made by the participant was recorded by the HCP in the checklist. Checklist of instructions for correct use were based on the steps for correct use listed in PILs for the respective DPI. The errors made during demonstration by participants were defined as critical, when the participant received a lesser/no dose. The percentage of participants making at least one critical error in the primary DPI is presented. The aim of the analysis was to compare percentage of participants making at least one critical error with Ellipta versus all ICS/LABA+LAMA DPIs; hence, the arms were combined as pre-specified in the protocol and reporting and analysis plan (RAP)." (NCT03114969)
Timeframe: Day 1
| Intervention | Percentage of participants (Number) |
|---|---|
| [Relvar Ellipta+LAMA]+[Symb Turb+LAMA]+[Seretide Diskus+LAMA] | 25 |
| Relvar Ellipta | 10 |
"Participants were asked to demonstrate use of their prescribed DPI at Visit 1 and any error made by the participant was recorded by the HCP in the checklist. Checklist of instructions for correct use were based on the steps for correct use listed in PILs for the respective DPI. The errors made during demonstration by participants were defined as critical, when the participant received a lesser/no dose and non-critical when the dose may not be affected, but the participant has demonstrated improper use of their DPI, as per the PIL. Overall errors is the combination of critical and non-critical errors. The percentage of participants with at least one overall error in the primary DPI is presented." (NCT03114969)
Timeframe: Day 1
| Intervention | Percentage of participants (Number) |
|---|---|
| Relvar Ellipta | 34 |
| Symbicort Turbuhaler | 64 |
| Seretide Diskus | 60 |
| Spiriva Handihaler | 74 |
| Incruse/Anoro Ellipta | 37 |
| Ultibro/Seebri Breezhaler | 55 |
| Relvar Ellipta+LAMA | 34 |
| Symbicort Turbuhaler+LAMA | 70 |
| Seretide Diskus+LAMA | 66 |
"Participants were asked to demonstrate use of their prescribed DPI at Visit 2 within 6 weeks after they were retrained on the correct use of inhalers. Any error made by the participant was recorded by the HCP in the checklist. Checklist of instructions for correct use were based on the steps listed in PILs for the respective DPI. The errors were defined as critical, when the participant received a lesser/no dose and non-critical when the dose may not be affected, but the participant has demonstrated improper use of their DPI, as per PIL. Overall errors is the combination of critical and non-critical errors. The percentage of participants making at least one overall error in primary DPI is presented. The aim of the analysis was to compare percentage of participants making at least one overall error with Ellipta and Ellipta+LAMA versus Turbuhaler and Turbuhaler+LAMA and Diskus and Diskus+LAMA; hence, the arms were combined as pre-specified in the protocol and RAP.~." (NCT03114969)
Timeframe: Week 6
| Intervention | Percentage of participants (Number) |
|---|---|
| Relvar Ellipta+[Relvar Ellipta+LAMA] | 13 |
| Symbicort Turbuhaler+[Symbicort Turbuhaler+LAMA] | 25 |
| Seretide Diskus+[Seretide Diskus+LAMA] | 27 |
Participants were asked to demonstrate use of their prescribed DPI at Visit 2 within 6 weeks after they were retrained on correct use of inhalers. Any error made by the participant was recorded by HCP in the checklist. Checklist of instructions for correct use were based on steps for correct use listed in PILs for the respective DPI. Errors made during demonstration by participants were defined as critical, when the participant received a lesser/no dose and non-critical when the dose may not be affected, but the participant has demonstrated improper use of their DPI, as per PIL. Overall errors is the combination of critical and non-critical errors. Percentage of participants making at least one overall error in either one or both devices (where applicable) is presented. The aim of the analysis was to compare percentage of participants making at least one overall error with Ellipta versus all ICS/LABA+LAMA DPIs; hence, the arms were combined as pre-specified in the protocol and RAP. (NCT03114969)
Timeframe: Week 6
| Intervention | Percentage of participants (Number) |
|---|---|
| Relvar Ellipta | 12 |
| [Relvar Ellipta+LAMA]+[Symb Turb+LAMA]+[Seretide Diskus+LAMA] | 29 |
"Participants were asked to demonstrate use of their prescribed DPI at Visit 2 within 6 weeks after they were retrained on the correct use of inhalers. Any error made by the participant was recorded by the HCP in the checklist. Checklist of instructions for correct use were based on the steps for correct use listed in PILs for the respective DPI. The errors made during demonstration by participants were defined as critical, when the participant received a lesser/no dose and non-critical when the dose may not be affected, but the participant has demonstrated improper use of their DPI, as per the PIL. Overall errors is the combination of critical and non-critical errors. The percentage of participants making at least one overall error in either one or both devices (where applicable) is presented." (NCT03114969)
Timeframe: Week 6
| Intervention | Percentage of participants (Number) |
|---|---|
| Relvar Ellipta | 12 |
| Relvar Ellipta+LAMA | 16 |
"Participants were asked to demonstrate use of their prescribed DPI at Visit 1 and any error made by the participant was recorded by the HCP in the checklist. Checklist of instructions for correct use were based on the steps for correct use listed in PILs for the respective DPI. The errors made during demonstration by participants were defined as critical, when the participant received a lesser/no dose. The percentage of participants making at least one critical error in the primary DPI is presented. The aim of the analysis was to compare percentage of participants making at least one critical error with Ellipta and Ellipta+LAMA versus Turbuhaler and Turbuhaler+LAMA and Diskus and Diskus+LAMA; hence, the arms were combined as pre-specified in the protocol and RAP." (NCT03114969)
Timeframe: Day 1
| Intervention | Percentage of participants (Number) |
|---|---|
| Relvar Ellipta+[Relvar Ellipta+LAMA] | 11 |
| Symbicort Turbuhaler+[Symbicort Turbuhaler+LAMA] | 39 |
| Seretide Diskus+[Seretide Diskus+LAMA] | 26 |
"Participants were asked to demonstrate use of their prescribed DPI at Visit 2 within 6 weeks after they were retrained on the correct use of inhalers. Any error made by the participant was recorded by the HCP in the checklist. Checklist of instructions for correct use were based on the steps for correct use listed in PILs for the respective DPI. The errors made during demonstration by participants were defined as critical, when the participant received a lesser/no dose and non-critical when the dose may not be affected, but the participant has demonstrated improper use of their DPI, as per the PIL. Overall errors is the combination of critical and non-critical errors. The aim of the analysis was to compare percentage of participants making at least one overall error with Ellipta and Ellipta+LAMA versus Turbuhaler and Turbuhaler+LAMA and Diskus and Diskus+LAMA; hence, the arms were combined as pre-specified in the protocol and RAP." (NCT03114969)
Timeframe: Week 6
| Intervention | Percentage of participants (Number) |
|---|---|
| Relvar Ellipta+[Relvar Ellipta+LAMA] | 14 |
| Symbicort Turbuhaler+[Symbicort Turbuhaler+LAMA] | 33 |
| Seretide Diskus+[Seretide Diskus+LAMA] | 34 |
"Participants were asked to demonstrate use of their prescribed DPI at Visit 2 within 6 weeks after they were retrained on the correct use of inhalers. Any error made by the participant was recorded by the HCP in the checklist. Checklist of instructions for correct use were based on the steps for correct use listed in PILs for the respective DPI. The errors made during demonstration by participants were defined as critical, when the participant received a lesser/no dose and non-critical when the dose may not be affected, but the participant has demonstrated improper use of their DPI, as per the PIL. Overall errors is the combination of critical and non-critical errors. The percentage of participants making at least one overall error in the primary DPI is presented." (NCT03114969)
Timeframe: Week 6
| Intervention | Percentage of participants (Number) |
|---|---|
| Relvar Ellipta | 12 |
| Symbicort Turbuhaler | 35 |
| Seretide Diskus | 27 |
| Spiriva Handihaler | 36 |
| Incruse/Anoro Ellipta | 8 |
| Ultibro/Seebri Breezhaler | 32 |
| Relvar Ellipta+LAMA | 14 |
| Symbicort Turbuhaler+LAMA | 14 |
| Seretide Diskus+LAMA | 28 |
"Participants were asked to demonstrate use of their prescribed DPI at Visit 2 within 6 weeks after they were retrained on the correct use of inhalers. Any error made by the participant was recorded by the HCP in the checklist. Checklist of instructions for correct use were based on the steps for correct use listed in PILs for the respective DPI. The errors made during demonstration by participants were defined as critical, when the participant received a lesser/no dose. The percentage of participants making at least one critical error in either one or both devices (where applicable) is presented. The aim of the analysis was to compare percentage of participants making at least one critical error with Ellipta and Ellipta+LAMA versus Turbuhaler and Turbuhaler+LAMA and Diskus and Diskus+LAMA; hence, the arms were combined as pre-specified in the protocol and RAP." (NCT03114969)
Timeframe: Week 6
| Intervention | Percentage of participants (Number) |
|---|---|
| Relvar Ellipta+[Relvar Ellipta+LAMA] | 4 |
| Symbicort Turbuhaler+[Symbicort Turbuhaler+LAMA] | 11 |
| Seretide Diskus+[Seretide Diskus+LAMA] | 13 |
"Participants were asked to demonstrate use of their prescribed DPI at Visit 2 within 6 weeks after they were retrained on the correct use of inhalers. Any error made by the participant was recorded by the HCP in the checklist. Checklist of instructions for correct use were based on the steps for correct use listed in PILs for the respective DPI. The errors made during demonstration by participants were defined as critical, when the participant received a lesser/no dose. The percentage of participants making at least one critical error in the primary DPI is presented." (NCT03114969)
Timeframe: Week 6
| Intervention | Percentage of participants (Number) |
|---|---|
| Relvar Ellipta | 0 |
| Symbicort Turbuhaler | 8 |
| Seretide Diskus | 11 |
| Spiriva Handihaler | 21 |
| Incruse/Anoro Ellipta | 0 |
| Ultibro/Seebri Breezhaler | 17 |
| Relvar Ellipta+LAMA | 6 |
| Symbicort Turbuhaler+LAMA | 6 |
| Seretide Diskus+LAMA | 13 |
"Participants were asked to demonstrate use of their prescribed DPI at Visit 1 and any error made by the participant was recorded by the HCP in the checklist. Checklist of instructions for correct use were based on the steps for correct use listed in PILs for the respective DPI. The errors made during demonstration by participants were defined as critical, when the participant received a lesser/no dose and non-critical when the dose may not be affected, but the participant has demonstrated improper use of their DPI, as per the PIL. Overall errors is the combination of critical and non-critical errors. The percentage of participants with at least one overall error in primary DPI is presented. The aim of the analysis was to compare percentage of participants making at least one overall error with Ellipta versus all ICS/LABA+LAMA DPIs; hence, the arms were combined as pre-specified in the protocol and RAP." (NCT03114969)
Timeframe: Day 1
| Intervention | Percentage of participants (Number) |
|---|---|
| [Relvar Ellipta+LAMA]+[Symb Turb+LAMA]+[Seretide Diskus+LAMA] | 57 |
| Relvar Ellipta | 34 |
"Participants were asked to demonstrate use of their prescribed DPI at Visit 1 and any error made by the participant was recorded by the HCP in the checklist. Checklist of instructions for correct use were based on the steps for correct use listed in PILs for the respective DPI. The errors made during demonstration by participants were defined as critical, when the participant received a lesser/no dose and non-critical when the dose may not be affected, but the participant has demonstrated improper use of their DPI, as per the PIL. Overall errors is the combination of critical and non-critical errors. The percentage of participants with at least one overall error in primary DPI is presented. The aim of the analysis was to compare percentage of participants making at least one overall error with Ellipta and Ellipta+LAMA versus Turbuhaler and Turbuhaler+LAMA and Diskus and Diskus+LAMA; hence, the arms were combined as pre-specified in the protocol and RAP." (NCT03114969)
Timeframe: Day 1
| Intervention | Percentage of participants (Number) |
|---|---|
| Relvar Ellipta+[Relvar Ellipta+LAMA] | 34 |
| Symbicort Turbuhaler+[Symbicort Turbuhaler+LAMA] | 67 |
| Seretide Diskus+[Seretide Diskus+LAMA] | 63 |
"Participants were asked to demonstrate use of their prescribed DPI at Visit 1 and any error made by the participant was recorded by HCP in the checklist. Checklist of instructions for correct use were based on the steps for correct use listed in PILs for the respective DPI. Errors made during demonstration by participants were defined as critical, when the participant received a lesser/no dose and non-critical when the dose may not be affected, but the participant has demonstrated improper use of their DPI, as per the PIL. Overall errors is the combination of critical and non-critical errors. Percentage of participants making at least one overall error in either one or both devices (where applicable) is presented. The aim of the analysis was to compare percentage of participants making at least one overall error with Ellipta versus all ICS/LABA+LAMA DPIs; hence, the arms were combined as pre-specified in the protocol and RAP." (NCT03114969)
Timeframe: Day 1
| Intervention | Percentage of participants (Number) |
|---|---|
| Relvar Ellipta | 34 |
| [Relvar Ellipta+LAMA]+[Symb Turb+LAMA]+[Seretide Diskus+LAMA] | 71 |
"Participants were asked to demonstrate use of their prescribed DPI at Visit 1 and any error made by the participant was recorded by the HCP in the checklist. Checklist of instructions for correct use were based on the steps for correct use listed in PILs for the respective DPI. The errors made during demonstration by participants were defined as critical, when the participant received a lesser/no dose and non-critical when the dose may not be affected, but the participant has demonstrated improper use of their DPI, as per the PIL. Overall errors is the combination of critical and non-critical errors. The percentage of participants making at least one overall error in either one or both devices (where applicable) is presented." (NCT03114969)
Timeframe: Day 1
| Intervention | Percentage of participants (Number) |
|---|---|
| Relvar Ellipta | 34 |
| Relvar Ellipta+LAMA | 46 |
"Participants were asked to demonstrate use of their prescribed DPI at Visit 1 and any error made by the participant was recorded by the HCP in the checklist. Checklist of instructions for correct use were based on the steps for correct use listed in PILs for the respective DPI. Errors made during demonstration by participants were defined as critical, when the participant received a lesser/no dose and non-critical when the dose may not be affected, but the participant has demonstrated improper use of their DPI, as per the PIL. Overall errors is the combination of critical and non-critical errors. Percentage of participants making at least one overall error in either one or both devices (where applicable) is presented.The aim of the analysis was to compare percentage of participants making at least one overall error with Ellipta and Ellipta+LAMA versus Turbuhaler and Turbuhaler+LAMA and Diskus and Diskus+LAMA; hence, the arms were combined as pre-specified in the protocol and RAP." (NCT03114969)
Timeframe: Day 1
| Intervention | Percentage of participants (Number) |
|---|---|
| Relvar Ellipta+[Relvar Ellipta+LAMA] | 40 |
| Symbicort Turbuhaler+[Symbicort Turbuhaler+LAMA] | 72 |
| Seretide Diskus+[Seretide Diskus+LAMA] | 74 |
Descriptive statistics for tiotropium plasma PK parameter - Area under the plasma concentration-time curve over the dosing interval (AUC0-tau) on Day 1 (NCT03118765)
Timeframe: Day 1
| Intervention | pg*h/mL (Mean) |
|---|---|
| GSP304 10 μg | 10.65 |
| GSP304 20 μg | 22.94 |
| GSP304 40 μg | 52.11 |
| SPIRIVA RESPIMAT 5 μg | 22.64 |
Descriptive statistics for tiotropium urine PK parameter - Amount (Aetau) of Tiotropium Excreted in Urine Over the Dosing Interval on Day 21 (NCT03118765)
Timeframe: Day 21
| Intervention | pg (Mean) |
|---|---|
| GSP304 10 μg | 375400 |
| GSP304 20 μg | 647100 |
| GSP304 40 μg | 1611000 |
| SPIRIVA RESPIMAT 5 μg | 775500 |
Descriptive statistics for tiotropium urine PK parameter - Amount (Aetau) of tiotropium excreted in urine over the dosing interval on Day 1 (NCT03118765)
Timeframe: Day 1
| Intervention | pg (Mean) |
|---|---|
| GSP304 10 μg | 138600 |
| GSP304 20 μg | 336100 |
| GSP304 40 μg | 602900 |
| SPIRIVA RESPIMAT 5 μg | 247400 |
Descriptive statistics for tiotropium plasma PK parameter-Accumulation ratio Rac(cmax). Rac(Cmax) was calculated as CmaxSS/Cmax. (NCT03118765)
Timeframe: Day 21
| Intervention | ratio (Mean) |
|---|---|
| GSP304 10 μg | 2.063 |
| GSP304 20 μg | 3.492 |
| GSP304 40 μg | 2.622 |
| SPIRIVA RESPIMAT 5 μg | 2.835 |
Descriptive statistics for tiotropium plasma PK parameter-Accumulation ratio Rac(auc). Rac(auc) was calculated as AUC0-tauSS/AUC0-tau. (NCT03118765)
Timeframe: Day 21
| Intervention | ratio (Mean) |
|---|---|
| GSP304 10 μg | 2.966 |
| GSP304 20 μg | 5.328 |
| GSP304 40 μg | 3.667 |
| SPIRIVA RESPIMAT 5 μg | 3.699 |
Descriptive statistics for tiotropium plasma PK parameter - Average concentration during a dosing interval at steady state (CavSS) on day 21 (NCT03118765)
Timeframe: Day 21
| Intervention | pg/mL (Mean) |
|---|---|
| GSP304 10 μg | 1.120 |
| GSP304 20 μg | 2.436 |
| GSP304 40 μg | 6.273 |
| SPIRIVA RESPIMAT 5 μg | 2.725 |
The PK endpoint in plasma to assess the relative bioavailability was peak concentrations of tiotropium during the dosing interval at steady-state (CmaxSS) (NCT03118765)
Timeframe: Plasma concentrations on day 21 according to the below schedule: Pre-dose (0 hour), and at 2, 4, 6, 10, 15, 30, and 45, 60, 75, and 90 minutes post-dose, as well as 2, 4, 6, 8, 12, 16, 20 and 24 hours post-dose.
| Intervention | pg/mL (Mean) |
|---|---|
| GSP304 10 μg | 4.10 |
| GSP304 20 μg | 8.00 |
| GSP304 40 μg | 21.80 |
| SPIRIVA RESPIMAT 5 μg | 14.00 |
Descriptive statistics for tiotropium plasma PK parameter - Time of peak drug concentration over the dosing interval (tmax) on Day 1 (NCT03118765)
Timeframe: Day 1
| Intervention | hour (Median) |
|---|---|
| GSP304 10 μg | 0.067 |
| GSP304 20 μg | 0.100 |
| GSP304 40 μg | 0.108 |
| SPIRIVA RESPIMAT 5 μg | 0.100 |
Descriptive statistics for tiotropium plasma PK parameter - Time of peak drug concentration over the dosing interval (tmax) on Day 21 (NCT03118765)
Timeframe: Day 21
| Intervention | hour (Median) |
|---|---|
| GSP304 10 μg | 0.075 |
| GSP304 20 μg | 0.150 |
| GSP304 40 μg | 0.108 |
| SPIRIVA RESPIMAT 5 μg | 0.100 |
Descriptive statistics for tiotropium urine PK parameter - Fraction of dose (Fe) of tiotropium excreted in urine over the dosing interval on Day 1 (NCT03118765)
Timeframe: Day 1
| Intervention | percentage of dose (Mean) |
|---|---|
| GSP304 10 μg | 1.386 |
| GSP304 20 μg | 1.681 |
| GSP304 40 μg | 1.507 |
| SPIRIVA RESPIMAT 5 μg | 4.948 |
Least Square Mean (SE) change from baseline in time-normalized area under the curve for FEV1 Measured Over 12 Hours on Day 21. (NCT03118765)
Timeframe: Day 21(Pre-dose FEV1 at -45 mins and 15 mins prior to dosing on Day 21. On Day 21, FEV1 at post-dose at 5 mins ±3, 15 mins ±2, 30 mins ±5, 60 mins, 90 mins, and 2 hours; and post-dose at 4, 6, 8, 10, 12 hours after the morning dose).
| Intervention | Litre (Least Squares Mean) |
|---|---|
| GSP304 10 μg | 0.23 |
| GSP304 20 μg | 0.17 |
| GSP304 40 μg | 0.15 |
| Placebo | 0.08 |
| SPIRIVA RESPIMAT 5 μg | 0.23 |
Least Square Mean (SE) change from baseline in time-normalized area under the curve for FEV1 measured over 12 hours on Day 1. (NCT03118765)
Timeframe: Day 1 (Pre-dose FEV1 at -45 mins and 15 mins prior to dosing on Day 1. On Day 1 FEV1 at post-dose at 5 mins ±3, 15 mins ±2, 30 mins ±5, 60 mins, 90 mins, and 2 hours; and post-dose at 4, 6, 8, 10, 12 hours after the morning dose).
| Intervention | Litre (Least Squares Mean) |
|---|---|
| GSP304 10 μg | 0.22 |
| GSP304 20 μg | 0.24 |
| GSP304 40 μg | 0.24 |
| Placebo | 0.10 |
| SPIRIVA RESPIMAT 5 μg | 0.26 |
The least square mean change from baseline to peak FEV1 within 12 hours postdose on Day 21. Change from baseline in peak FEV1 within 12 hours postdose on Day 21 was derived from the serial readings taken through 12 hours postdose and calculating the change from baseline. (NCT03118765)
Timeframe: Day 21(Pre-dose FEV1 at -45 mins and 15 mins prior to dosing on Day 21. On Day 21, FEV1 at post-dose at 5 mins ±3, 15 mins ±2, 30 mins ±5, 60 mins, 90 mins, and 2 hours; and post-dose at 4, 6, 8, 10, 12 hours after the morning dose).
| Intervention | Litre (Least Squares Mean) |
|---|---|
| GSP304 10 μg | 0.37 |
| GSP304 20 μg | 0.34 |
| GSP304 40 μg | 0.31 |
| Placebo | 0.20 |
| SPIRIVA RESPIMAT 5 μg | 0.37 |
Descriptive statistics for tiotropium plasma PK parameters - (Cmax) on Day 1 (NCT03118765)
Timeframe: Day 1
| Intervention | pg/mL (Mean) |
|---|---|
| GSP304 10 μg | 2.632 |
| GSP304 20 μg | 7.119 |
| GSP304 40 μg | 14.06 |
| SPIRIVA RESPIMAT 5 μg | 10.25 |
Least Square Mean change from baseline in forced vital capacity (FVC) to end of Day 1. (NCT03118765)
Timeframe: Day 1 (Pre-dose FVC at -45 mins and 15 mins prior to dosing on Day 1. Postdose timing were relative to the end of dosing.The window for 1 hour spirometry and thereafter was ±5 minutes).
| Intervention | Litre (Least Squares Mean) |
|---|---|
| GSP304 10 μg | 0.21 |
| GSP304 20 μg | 0.21 |
| GSP304 40 μg | 0.18 |
| Placebo | 0.13 |
| SPIRIVA RESPIMAT 5 μg | 0.16 |
The PK endpoint in plasma to assess the relative bioavailability was area under the plasma concentration-time curve of tiotropium over the dosing interval at steady state (AUC0-tauSS) (NCT03118765)
Timeframe: Plasma concentrations on day 21 according to the below schedule: Pre-dose (0 hour), and at 2, 4, 6, 10, 15, 30, and 45, 60, 75, and 90 minutes post-dose, as well as 2, 4, 6, 8, 12, 16, 20 and 24 hours post-dose.
| Intervention | h*pg/mL (Mean) |
|---|---|
| GSP304 10 μg | 22.90 |
| GSP304 20 μg | 49.10 |
| GSP304 40 μg | 122.00 |
| SPIRIVA RESPIMAT 5 μg | 57.70 |
The least square mean change from baseline to peak FEV1 within 12 hours postdose on Day 1. Change from baseline in peak FEV1 within 12 hours postdose on Day 1 was derived from the serial readings taken through 12 hours postdose and calculating the change from baseline. (NCT03118765)
Timeframe: Day 1 (Pre-dose FEV1 at -45 mins and 15 mins prior to dosing on Day 1. On Day 1 FEV1 at post-dose at 5 mins ±3, 15 mins ±2, 30 mins ±5, 60 mins, 90 mins, and 2 hours; and post-dose at 4, 6, 8, 10, 12 hours after the morning dose).
| Intervention | Litre (Least Squares Mean) |
|---|---|
| GSP304 10 μg | 0.34 |
| GSP304 20 μg | 0.38 |
| GSP304 40 μg | 0.33 |
| Placebo | 0.21 |
| SPIRIVA RESPIMAT 5 μg | 0.38 |
Least Square Mean change from baseline in forced vital capacity (FVC) to end of Day 21 (NCT03118765)
Timeframe: Day 21 (Pre-dose FVC at -45 mins and 15 mins prior to dosing on Day 21. Postdose timing were relative to the end of dosing. The window for 1 hour spirometry and thereafter was ±5 minutes).
| Intervention | Litre (Least Squares Mean) |
|---|---|
| GSP304 10 μg | 0.16 |
| GSP304 20 μg | 0.10 |
| GSP304 40 μg | 0.11 |
| Placebo | 0.11 |
| SPIRIVA RESPIMAT 5 μg | 0.16 |
Change from baseline (Day 1) at Day 21 (Week 3) in trough FEV1 response at approximately 24 hours after the last dose (average of 23 hours 15 minutes and 23 hours 45 minutes postdose measurements), in comparison with placebo. (NCT03118765)
Timeframe: 21 days (Pre- dose trough FEV1 is mean FEV1 at -45 mins and -15 mins pre-morning dose at Day 1. Trough FEV1 is mean FEV1 obtained 23 hrs 15 mins and 23 hrs 45 mins post-morning dose of day 21).
| Intervention | L (Mean) |
|---|---|
| GSP304 10 μg | 0.14 |
| GSP304 20 μg | 0.10 |
| GSP304 40 μg | 0.09 |
| Placebo | 0.08 |
| SPIRIVA RESPIMAT 5 μg | 0.14 |
Descriptive statistics for tiotropium urine PK parameter-Fraction of Dose (Fe) of Tiotropium Excreted in Urine Over the Dosing Interval on Day 21 (NCT03118765)
Timeframe: Day 21
| Intervention | percentage of dose (Mean) |
|---|---|
| GSP304 10 μg | 3.754 |
| GSP304 20 μg | 3.236 |
| GSP304 40 μg | 4.026 |
| SPIRIVA RESPIMAT 5 μg | 15.51 |
To show clinical bioequivalence in the efficacy of the test product as a single dose versus reference product based on the baseline adjusted mean change in forced expiratory volume in the first second (FEV1) area under the curve from time zero to 24 hours post dose (AUC0-24h) on day 1 zero to 24 hours post-dose (AUC0-24h). Baseline was defined as the average of the FEV1 values recorded at approximately 30 minutes and 15 minutes before dosing with study medication. (NCT03137992)
Timeframe: 0-24 hours after dosing on Day 1 of visits 2-4 over a period of approximately 6 weeks
| Intervention | L*hour (Least Squares Mean) |
|---|---|
| Test Product (Tiotropium Bromide Inhalation Powder) | 2.5644 |
| Reference Product (Spiriva®) | 2.7370 |
This measure is to demonstrate that test product as a single dose and reference product are superior to placebo based on the baseline adjusted mean change in forced expiratory volume in the first second (FEV1) area under the curve from time zero to 24 hours post dose (AUC0-24h) on day 1 zero to 24 hours post-dose (AUC0-24h). Baseline was defined as the average of the FEV1 values recorded at approximately 30 minutes and 15 minutes before dosing with study medication. (NCT03137992)
Timeframe: 0-24 hours after dosing on Day 1 of visits 2-4 over a period of approximately 6 weeks
| Intervention | L*hour (Least Squares Mean) |
|---|---|
| Test Product (Tiotropium Bromide Inhalation Powder) | 2.90 |
| Reference Product (Spiriva®) | 3.03 |
| Placebo | -0.40 |
FEV1 is the amount of air which can be forcibly exhaled from the lungs in the first second of a forced exhalation, measured through spirometry testing. Trough FEV1 is the mean of two FEV1 values measures taken 15 minutes (min) and 45 min prior to evening dose. (NCT03158311)
Timeframe: Baseline, Week 8, Week 16 and Week 24
| Intervention | Litre (L) (Least Squares Mean) | ||
|---|---|---|---|
| Week 8 | Week 16 | Week 24 | |
| QVM149 150/50/160 μg | 0.309 | 0.319 | 0.334 |
| QVM149 150/50/80 μg | 0.246 | 0.251 | 0.248 |
| Salmeterol/Fluticasone 50/500 μg Plus Tiotropium 5 μg | 0.243 | 0.253 | 0.238 |
FVC is the total volume of air exhaled during a expiratory maneuvre. It was assessed by performing a spirometry assessment. (NCT03158311)
Timeframe: Baseline, Week 8, Week 16 and Week 24
| Intervention | Litre (L) (Least Squares Mean) | ||
|---|---|---|---|
| Week 8 | Week 16 | Week 24 | |
| QVM149 150/50/160 μg | 0.272 | 0.275 | 0.280 |
| QVM149 150/50/80 μg | 0.216 | 0.221 | 0.214 |
| Salmeterol/Fluticasone 50/500 μg Plus Tiotropium 5 μg | 0.219 | 0.217 | 0.186 |
Forced expiratory flow during the mid (25 - 75%) portion of the FVC. It was assessed by performing spirometric assessment. (NCT03158311)
Timeframe: Baseline, Week 8, Week 16 and Week 24
| Intervention | Litres/second (L/s) (Least Squares Mean) | ||
|---|---|---|---|
| Week 8 | Week 16 | Week 24 | |
| QVM149 150/50/160 μg | 0.332 | 0.355 | 0.375 |
| QVM149 150/50/80 μg | 0.290 | 0.291 | 0.290 |
| Salmeterol/Fluticasone 50/500 μg Plus Tiotropium 5 μg | 0.270 | 0.297 | 0.286 |
The ACQ-7 measured asthma symptom control and consists of 7 items: 5 on symptom assessment, 1 on rescue medication use and 1 on airway calibre (FEV1 % predicted). All seven items are scored on a 7-point Likert scale, with 0 indicating total control and 6 indicating poor control. The questions are equally weighted and the total score is the mean of the seven items. Higher score indicates worst symptoms. The first 6 questions of the ACQ-7 were completed by the participant while the last question was completed by the study investigator using data from the Master Scope spirometer. A negative change from baseline indicates improvement in lung function. (NCT03158311)
Timeframe: Baseline, Week 16 and Week 24
| Intervention | Score on a scale (Least Squares Mean) | |
|---|---|---|
| Week 16 | Week 24 | |
| QVM149 150/50/160 μg | -1.098 | -1.172 |
| QVM149 150/50/80 μg | -1.043 | -1.080 |
| Salmeterol/Fluticasone 50/500 μg Plus Tiotropium 5 μg | -1.020 | -1.048 |
The ACQ-7 measured asthma symptom control and consists of 7 items: 5 on symptom assessment, 1 on rescue medication use and 1 on airway calibre (FEV1 % predicted). All seven items are scored on a 7-point Likert scale, with 0 indicating total control and 6 indicating poor control. The questions are equally weighted and the total score is the mean of the seven items. Higher score indicates worst symptoms. The first 6 questions of the ACQ-7 were completed by the participant while the last question was completed by the study investigator using data from the Master Scope spirometer. A negative change from baseline indicates improvement in lung function. Decrease of ACQ-7 score of at least 0.5 from baseline was considered clinically meaningful. (NCT03158311)
Timeframe: Baseline and Week 24
| Intervention | Participants (Count of Participants) |
|---|---|
| QVM149 150/50/80 μg | 393 |
| QVM149 150/50/160 μg | 387 |
| Salmeterol/Fluticasone 50/500 μg Plus Tiotropium 5 μg | 375 |
The AQLQ is a 32-item asthma specific questionnaire designed to measure functional impairments that are most important to patients with asthma, with a recall time of two weeks and each question to be answered on a 7-point scale, where 1=totally limited/problems all the time and 7= not at all limited/no problems. It consists of 4 domains: symptoms, activity limitation, emotional function and environmental stimuli. The overall score is calculated as the mean of 32 items. Higher AQLQ scores indicate better health-related quality of life. An improvement of 0.5 points in AQLQ score is considered to be the minimally clinically important difference in asthma. (NCT03158311)
Timeframe: Baseline and Week 24
| Intervention | Participants (Count of Participants) |
|---|---|
| QVM149 150/50/80 μg | 318 |
| QVM149 150/50/160 μg | 333 |
| Salmeterol/Fluticasone 50/500 μg Plus Tiotropium 5 μg | 299 |
The AQLQ is a 32-item asthma specific questionnaire designed to measure functional impairments that are most important to patients with asthma, with a recall time of two weeks and each question to be answered on a 7-point scale, where 1=totally limited/problems all the time and 7= not at all limited/no problems. It consists of 4 domains: symptoms, activity limitation, emotional funtion, and emotional stimuli. The overall score is calculated as the mean of 32 items. Higher AQLQ scores indicate better health-related quality of life. (NCT03158311)
Timeframe: Baseline and Week 24
| Intervention | Score on a scale (Least Squares Mean) |
|---|---|
| QVM149 150/50/80 μg | 0.715 |
| QVM149 150/50/160 μg | 0.827 |
| Salmeterol/Fluticasone 50/500 μg Plus Tiotropium 5 μg | 0.753 |
The AQLQ is a 32-item asthma specific questionnaire designed to measure functional impairments that are most important to patients with asthma, with a recall time of two weeks and each question to be answered on a 7-point scale, where 1=totally limited/problems all the time and 7= not at all limited/no problems. It consists of 4 domains: symptoms, activity limitation, emotional function and environmental stimuli. The overall score is calculated as the mean of 32 items. Higher AQLQ scores indicate better health-related quality of life. (NCT03158311)
Timeframe: Baseline and Week 16
| Intervention | Score on a scale (Least Squares Mean) |
|---|---|
| QVM149 150/50/80 μg | 0.690 |
| QVM149 150/50/160 μg | 0.755 |
| Salmeterol/Fluticasone 50/500 μg Plus Tiotropium 5 μg | 0.673 |
"Number of participants with suspected adverse drug reactions (ADRs) is presented.~An Adverse Event (AE) was considered to be ADR if either the physician who reported the AE or the sponsor assessed its causal relationship as related." (NCT03188120)
Timeframe: From first drug administration until 30 days after last drug administration; up to 337 days
| Intervention | Participants (Count of Participants) |
|---|---|
| Spiriva Respimat Group | 5 |
"The change from baseline in asthma control status at week 12 using Asthma prevention and management guideline is presented.~Well controlled is a better outcome compared to Insufficiently controlled and Poorly controlled outcomes.~Abbreviations used:~Baseline (BL), Week 12 (W12), Well-controlled (WC), Insufficiently controlled (IC), Poorly controlled (PC), Unknown (UNK), Missing (MIS); If a patient was well-controlled at baseline and maintained the state until Week 12, the effectiveness was assessed as no change. If a patient insufficiently controlled or poorly controlled at baseline became well-controlled at Week 12, or if a patient was poorly controlled at baseline and became insufficiently controlled at Week 12, Spiriva Respimat was assessed as effective (or the patient assessed as a responder). If the disease condition did not improve in a patient at Week 12 from baseline, Spiriva Respimat was assessed as ineffective (or the patient assessed as a non-responder)." (NCT03188120)
Timeframe: baseline and 12 weeks
| Intervention | participants (Number) | ||||||||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| BL- WC W12-WC | BL-WC W12-IC | BL-WC W12-PC | BL-WC W12-UNK | BL-WC W12-MIS | BL-IC W12-WC | BL-IC W12-IC | BL-IC W12-PC | BL-IC W12-UNK | BL-IC W12-MIS | BL-PC W12-WC | BL-PC W12-IC | BL-PC W12-PC | BL-PC W12-UNK | BL-PC W12-MIS | BL-UNK W12-WC | BL-UNK W12-IC | BL-UNK W12-PC | BL-UNK W12-UNK | BL-UNK W12-MIS | BL-MIS W12-WC | BL-MIS W12-IC | BL-MIS W12-PC | BL-MIS W12-UNK | BL-MIS W12-MIS | |
| Spiriva Respimat Group | 9 | 0 | 0 | 0 | 0 | 68 | 39 | 0 | 0 | 6 | 11 | 10 | 6 | 0 | 0 | 3 | 1 | 0 | 4 | 1 | 0 | 1 | 0 | 0 | 0 |
The COPD Assessment Test (CAT) is a patient-completed instrument that can quantify the impact of COPD on the patient's health. The CAT is a validated, short (8-item) and simple patient completed questionnaire. The CAT has a scoring range of 0-40 and a difference or change of 2 or more units over 2 to 3 months in a patient suggests a clinically significant difference or change in health status. A score of >30 indicates that COPD has a very high impact on daily life, a score of >20 indicates a high impact, 10-20 is medium impact, <10 is low impact, and 5 is the upper limit for healthy non-smokers. A higher score would represent a poor outcome for this test. (NCT03219866)
Timeframe: 90 Days
| Intervention | score on a scale (Mean) |
|---|---|
| Nebulizers | 19.2 |
| Dry Powder Inhaler | 16.5 |
The Modified Medical Research Council Dyspnea Scale, or MMRC, uses a simple grading system to assess a patient's level of dyspnea -- shortness of breath. The scale goes from 0-4 with a 0 = I only get breathless with strenuous exercise, 1 = I get short of breath when hurrying on level ground or walking up a slight hill, 2 = On level ground, I walk slower than people of the same age because of breathlessness or have to stop for breath when walking at my own pace, 3 = I stop for breath after walking about 100 yards or after a few minutes on level ground, and 4 = I am too breathless to leave the house or I am breathless when dressing. 4 would represent the worst outcome. (NCT03219866)
Timeframe: 90 Days
| Intervention | score on a scale (Mean) |
|---|---|
| Nebulizers | 2.1 |
| Dry Powder Inhaler | 1.6 |
Compare the number of unscheduled clinic or ER visits between the two arms after 90 days of using each device (NCT03219866)
Timeframe: 90 Days
| Intervention | number of visits (Number) |
|---|---|
| Nebulizers | 4 |
| Dry Powder Inhaler | 4 |
Compare the number of hospital readmissions between the two arms after 30 days of using each device. (NCT03219866)
Timeframe: 30 Days
| Intervention | number of readmissions (Number) |
|---|---|
| Nebulizers | 1 |
| Dry Powder Inhaler | 3 |
Compare the number of hospital readmissions between the two arms after 90 days of using each device. (NCT03219866)
Timeframe: 90 Days
| Intervention | number of readmissions (Number) |
|---|---|
| Nebulizers | 2 |
| Dry Powder Inhaler | 4 |
(NCT03219866)
Timeframe: 90 days
| Intervention | Participants (Count of Participants) |
|---|---|
| Nebulizers | 1 |
| Dry Powder Inhaler | 1 |
Scores range from 0 to 100, with higher scores indicating more limitations - Symptoms component (frequency & severity) with a 1, 3 or 12-month recall (best performance with 3- and 12-month recall); Part 2: Activities that cause or are limited by breathlessness; Impact components (social functioning, psychological disturbances resulting from airways disease) refer to current state as the recall (NCT03219866)
Timeframe: 90 Days
| Intervention | score on a scale (Mean) |
|---|---|
| Nebulizers | 49.3 |
| Dry Powder Inhaler | 43.7 |
Pulmonary inspiratory force (PIF) from hospital baseline between the two arms for the duration of the 90 day study. (NCT03219866)
Timeframe: Baseline and 90 days
| Intervention | cmH2O (Mean) |
|---|---|
| Nebulizers | 73.9 |
| Dry Powder Inhaler | 74.2 |
Pulmonary inspiratory force (PIF) from hospital baseline between the two arms for the duration of the 90 day study. (NCT03219866)
Timeframe: Baseline and 90 days
| Intervention | cmH2O (Mean) |
|---|---|
| Nebulizers | 43.7 |
| Dry Powder Inhaler | 46.5 |
"Forced Expiratory Volume in one second (FEV1) Area under the Curve from 0 to 12 hours (AUC0-12) response (change from baseline) [L] after 12 weeks of treatment.~FEV1 AUC0-12 was calculated as the area under the FEV1-time curve from 0-12 hours post-dose using the trapezoidal rule, divided by the duration (12 hours) and reported in liters. FEV1 AUC0-12 response (change from baseline) was defined as FEV1 AUC0-12 minus baseline FEV1." (NCT03240575)
Timeframe: 1 hours (h) and 10 minutes (min) before first dose at day1 of weeks 1 for baseline. 10 min before and 30 min, 1 h, 2h, 3h, 4h, 6h, 8h, 10h, 11h 50min post morning dose at week 12.
| Intervention | Litre*hours (L*h) (Mean) |
|---|---|
| Tiotropium+Olodaterol (5μg/5μg) - Main Study | 0.237 |
| Fluticasone Propionate+Salmeterol (500μg/100μg) - Main Study | 0.147 |
| Tiotropium+Olodaterol (5μg/5μg) - DH-study | NA |
| Fluticasone Propionate+Salmeterol (500μg/100μg) - DH-study | NA |
Forced Expiratory Volume in one second (FEV1) Area under the Curve from 0 to 24 hours (AUC0-24) response (change from baseline) [L] after 12 weeks of treatment. FEV1 AUC0-24 was calculated as the area under the FEV1-time curve from 0-24 hours post-dose using the trapezoidal rule, divided by the duration (24 hours) and reported in liters. FEV1 AUC0-24 response (change from baseline) was defined as FEV1 AUC0-24 mius baseline FEV1. (NCT03240575)
Timeframe: 1 hours (h) and 10 minutes (min) before first dose at day1 of weeks 1 for baseline.10 min before and 30 min, 1 h, 2h, 3h, 4h, 6h, 8h, 10h, 11h 50min, 12h 30 min, 13h, 14h, 22h, 23h, and 24h post morning dose at week 12.
| Intervention | Litre*hours (L*h) (Mean) |
|---|---|
| Tiotropium+Olodaterol (5μg/5μg) - Main Study | 0.174 |
| Fluticasone Propionate+Salmeterol (500μg/100μg) - Main Study | 0.122 |
| Tiotropium+Olodaterol (5μg/5μg) - DH-study | NA |
| Fluticasone Propionate+Salmeterol (500μg/100μg) - DH-study | NA |
Peak 0-3 hours Forced Expiratory Volume in one second (FEV1) response (change from baseline) [L] after 12 weeks treatment. Peak 0-3h was defined as the maximum value measured within the first three hours post doing. (NCT03240575)
Timeframe: 30 minutes, 1 h, 2h and 3h post dose at baseline and week 12.
| Intervention | Litre (L) (Mean) |
|---|---|
| Tiotropium+Olodaterol (5μg/5μg) - Main Study | 0.341 |
| Fluticasone Propionate+Salmeterol (500μg/100μg) - Main Study | 0.243 |
| Tiotropium+Olodaterol (5μg/5μg) - DH-study | NA |
| Fluticasone Propionate+Salmeterol (500μg/100μg) - DH-study | NA |
Trough Forced Expiratory Volume in one second (FEV1) response (change from baseline) [L] after 12 weeks treatment. Trough FEV1 was defined as the mean of the FEV1 value measured at 23 hours and at 24 hours after the trial medication administration. Through FEV1 response (change from baseline) was defined as trough FEV1 minus baseline FEV1. (NCT03240575)
Timeframe: At 23 h and 24 h post dose at baseline and at 23h and 24 h post dose at week 12.
| Intervention | Litre (L) (Mean) |
|---|---|
| Tiotropium+Olodaterol (5μg/5μg) - Main Study | 0.118 |
| Fluticasone Propionate+Salmeterol (500μg/100μg) - Main Study | 0.114 |
| Tiotropium+Olodaterol (5μg/5μg) - DH-study | NA |
| Fluticasone Propionate+Salmeterol (500μg/100μg) - DH-study | NA |
Rate of moderate to severe Asthma exacerbations (A deterioration of asthma requiring a new or increased dose of ICS for at least 3 days) or severe Asthma exacerbation (Use of systemic corticosteroids (tablets, suspension, or injection) for at least 3 days OR a hospitalization or ER visit because of asthma) (NCT03358147)
Timeframe: over 24 Weeks (timepoints of 4, 12 & 20 weeks)
| Intervention | Events per year (Mean) |
|---|---|
| GP MDI 28.8 μg | 0.43 |
| GP MDI 14.4 μg | 0.44 |
| GP MDI 7.2 μg | 0.41 |
| Placebo MDI | 0.55 |
| Spiriva Respimat 2.5 μg | 0.50 |
(NCT03358147)
Timeframe: Week 24
| Intervention | Liter (Least Squares Mean) |
|---|---|
| GP MDI 28.8 μg | 0.142 |
| GP MDI 14.4 μg | 0.108 |
| GP MDI 7.2 μg | 0.142 |
| Placebo MDI | 0.129 |
| Spiriva Respimat 2.5 μg | 0.150 |
Change from baseline in forced expiratory volume in 1 second (FEV1) area under the curve from 0 to 4 hours (AUC0-4)AUC was normalized for length of follow up (e.g. typically 4 hours). (NCT03358147)
Timeframe: Week 24
| Intervention | Liter (Least Squares Mean) |
|---|---|
| GP MDI 28.8 μg | 0.294 |
| GP MDI 14.4 μg | 0.284 |
| GP MDI 7.2 μg | 0.308 |
| Placebo MDI | 0.240 |
| Spiriva Respimat 2.5 μg | 0.347 |
AQLQ +12 - Asthma Quality of Life Questionnaire The AQLQ +12 is a 32-item validated subject-administered questionnaire that was developed to measure the functional problems (physical, emotional, social and occupational) that are most troublesome to adults (≥18 years of age) and adolescents (12 to 17 years of age) with asthma. The 32 questions in the AQLQ +12 are in 4 domains (symptoms, activity limitation, emotional function, and environmental stimuli). All 4 domains contain standard specific questions relating to each domain. Subjects are asked to think about how they have been during the previous 2 weeks. Responses to each of the 32 questions are on a 7-point scale (7=no impairment to 1=severe impairment). The overall AQLQ +12 score is the mean of all 32 responses. Overall scores range from 1=severe impairment to 7=no impairment. (NCT03358147)
Timeframe: Week 24
| Intervention | Scores on a scale (Least Squares Mean) |
|---|---|
| GP MDI 28.8 μg | 0.89 |
| GP MDI 14.4 μg | 0.90 |
| GP MDI 7.2 μg | 1.02 |
| Placebo MDI | 0.96 |
| Spiriva Respimat 2.5 μg | 1.04 |
ACQ-7: The ACQ, comprising 7 questions, is completed in the clinic and requires subjects to recall their experiences during the previous week (7 days) prior to the study visit. The ACQ-5 measures 5 symptoms (woken at night by symptoms, wake in the morning with symptoms, limitation of daily activities, shortness of breath, and wheeze); the ACQ-6 is these symptom measurements plus daily rescue medication use as recalled by the subject; and the ACQ 7 is the ACQ 6 plus airway caliber as measured by pre-bronchodilator FEV1 percent predicted. Each question is scored on a 7-point scale (generally, 0=no impairment, 6=maximum impairment), the questions are equally weighted, and the ACQ score is the mean of the item responses and therefore ranges from 0 (totally controlled) to 6 (severely uncontrolled. (NCT03358147)
Timeframe: Week 24
| Intervention | Scores on a scale (Least Squares Mean) |
|---|---|
| GP MDI 28.8 μg | -0.78 |
| GP MDI 14.4 μg | -0.73 |
| GP MDI 7.2 μg | -0.90 |
| Placebo MDI | -0.80 |
| Spiriva Respimat 2.5 μg | -0.90 |
ACQ-5:The ACQ-5 measures 5 symptoms (woken at night by symptoms, wake in the morning with symptoms, limitation of daily activities, shortness of breath, and wheeze). Each question is scored on a 7-point scale (generally, 0=no impairment, 6=maximum impairment), the questions are equally weighted, and the ACQ score is the mean of the item responses and therefore ranges from 0 (totally controlled) to 6 (severely uncontrolled). (NCT03358147)
Timeframe: Week 24
| Intervention | Scores on a scale (Least Squares Mean) |
|---|---|
| GP MDI 28.8 μg | -0.87 |
| GP MDI 14.4 μg | -0.80 |
| GP MDI 7.2 μg | -1.02 |
| Placebo MDI | -0.93 |
| Spiriva Respimat 2.5 μg | -1.03 |
The number of the first occurences of the hospitalization for community-acquired pneumonia (serious pneumonia)associated with LABA-TIO relative to LABA-ICS in patients with COPD, with one-year follow-up, from the as-treated analysis and from the time-dependent on-treatment analysis based on current exposure is presented. On-treatment exposure was based on analysis of current use during the entire 1-year follow-up, allowing patients to switch treatments. (NCT03376295)
Timeframe: 12 years
| Intervention | Hospitalizations (Number) | |
|---|---|---|
| As-treated analysis | On-treatment exposure | |
| LABA-ICS | 41 | 143 |
| LABA-TIO | 32 | 49 |
Incidence rates and rate ratios of the moderate or severe exacerbation associated with LABA-TIO relative to LABA-ICS in patients with COPD, with one-year follow-up, from the as-treated analysis, estimated. (NCT03376295)
Timeframe: 12 years
| Intervention | Events per participant-year (Number) | |
|---|---|---|
| Moderate/severe exacerbation | Severe exacerbation | |
| LABA-ICS | 0.83 | 0.13 |
| LABA-TIO | 0.91 | 0.11 |
The number of observed patients with first COPD exacerbation after cohort entry was reported. The event of time to first COPD exacerbation to occur after cohort entry was defined as a hospitalization for COPD (severe exacerbation) or the prescription of an oral corticosteroid, namely prednisolone (moderate exacerbation) to occur after cohort entry with one-year follow-up, from the as-treated analysis. (NCT03376295)
Timeframe: 12 Years
| Intervention | Participants (Count of Participants) | |
|---|---|---|
| Moderate/severe exacerbation | Severe exacerbation | |
| LABA-ICS | 344 | 55 |
| LABA-TIO | 412 | 60 |
FEV1 is a measure of lung function and is defined as the maximal amount of air that can be forcefully exhaled in one second. Trough FEV1 on Day 28 was defined as the average of the two pre-dose FEV1 measurements recorded before the morning dose of randomized study medication on Day 28. Change from Baseline in trough FEV1 on Day 28 was calculated by subtracting Baseline FEV1 value from the trough FEV1 value on Day 28. Baseline FEV1 was defined as the mean of the two assessments made at 30 and 5 minutes pre-dose on Day 1. (NCT03474081)
Timeframe: Baseline (Day 1 [Pre-dose at 30 minutes and 5 minutes]) and Day 28
| Intervention | Liters (Least Squares Mean) |
|---|---|
| Fluticasone Furoate/Umeclidinium/Vilanterol 100/62.5/25 mcg | 0.115 |
| Tiotropium 18 mcg | -0.007 |
SBP and DBP were assessed in the sitting position after approximately 5 minutes rest. Change from Baseline was calculated by subtracting Baseline value from the post-dose visit value. Baseline was defined as the latest pre-first-dose assessment with a non-missing value, including those from unscheduled visits. (NCT03474081)
Timeframe: Baseline (Day 1, Pre-dose) and Day 84
| Intervention | Millimeters of mercury (Mean) | |
|---|---|---|
| SBP | DBP | |
| Fluticasone Furoate/Umeclidinium/Vilanterol 100/62.5/25 mcg | -0.3 | -0.3 |
| Tiotropium 18 mcg | -0.1 | -0.7 |
Pulse rate was assessed in the sitting position after approximately 5 minutes rest. Change from Baseline was calculated by subtracting Baseline value from the post-dose visit value. Baseline was defined as the latest pre-first-dose assessment with a non-missing value, including those from unscheduled visits. (NCT03474081)
Timeframe: Baseline (Day 1, Pre-dose) and Day 84
| Intervention | Beats per minute (Mean) |
|---|---|
| Fluticasone Furoate/Umeclidinium/Vilanterol 100/62.5/25 mcg | 0.2 |
| Tiotropium 18 mcg | 0.8 |
FEV1 is a measure of lung function and is defined as the maximal amount of air that can be forcefully exhaled in one second. Trough FEV1 on Day 85 was defined as the mean of the two planned spirometry FEV1 measurements. Change from Baseline in trough FEV1 on Day 85 was calculated by subtracting Baseline FEV1 value from the trough FEV1 value on Day 85. Baseline FEV1 was defined as the mean of the two assessments made at 30 and 5 minutes pre-dose on Day 1. (NCT03474081)
Timeframe: Baseline (Day 1 [Pre-dose at 30 minutes and 5 minutes]) and Day 85
| Intervention | Liters (Least Squares Mean) |
|---|---|
| Fluticasone Furoate/Umeclidinium/Vilanterol 100/62.5/25 mcg | 0.115 |
| Tiotropium 18 mcg | 0.020 |
An AE is any untoward medical occurrence in a clinical study participant, temporally associated with the use of a study treatment, whether or not considered related to the study treatment. Any untoward event resulting in death, life threatening, requires hospitalization or prolongation of existing hospitalization, results in disability/incapacity, congenital anomaly/birth defect or any other important medical event according to medical or scientific judgement was categorized as SAE. (NCT03474081)
Timeframe: Up to Day 95
| Intervention | Participants (Count of Participants) | |
|---|---|---|
| Non-SAEs | SAEs | |
| Fluticasone Furoate/Umeclidinium/Vilanterol 100/62.5/25 mcg | 31 | 13 |
| Tiotropium 18 mcg | 29 | 11 |
FEV1 is a measure of lung function and is defined as the maximal amount of air that can be forcefully exhaled in one second. Trough FEV1 on Day 84 was defined as the average of the two pre-dose FEV1 measurements recorded before the morning dose of randomized study medication on Day 84. Change from Baseline in trough FEV1 on Day 84 was calculated by subtracting Baseline FEV1 value from the trough FEV1 value on Day 84. Baseline FEV1 was defined as the mean of the two assessments made at 30 and 5 minutes pre-dose on Day 1. (NCT03474081)
Timeframe: Baseline (Day 1 [Pre-dose at 30 minutes and 5 minutes]) and Day 84
| Intervention | Liters (Least Squares Mean) |
|---|---|
| Fluticasone Furoate/Umeclidinium/Vilanterol 100/62.5/25 mcg | 0.105 |
| Tiotropium 18 mcg | 0.018 |
FEV1 is an important measure of pulmonary function and is the maximum amount of air that can be forced out in one second after taking a deep breath. FEV1 was measured using spirometry. Serial FEV1 assessments were performed at multiple time points (-30 and -5 minutes pre-dose, and 5 minutes, 15 minutes, 30 minutes, 1 hour, 3 hours, 6 hours, 12 hours, 15 hours, 21 hours, 23 hours and 24 hours post-dose) over 24-hour period on Day 1. Weighted mean change from Baseline on Day 1 was calculated by subtracting weighted mean FEV1 on Day 1 from Baseline FEV1, where Baseline FEV1 is the average of the two FEV1 measurements made at 30 minutes and 5 minutes pre-dose on Day 1. The weighted mean was derived by calculating the area under the FEV1 time curve (AUC) over the actual time of assessment relative to the time of dosing (over 24-hour period) using the trapezoidal rule, and then dividing the value by the time interval (24-hour) over which the AUC was calculated. (NCT03478683)
Timeframe: Baseline and Day 1
| Intervention | Liters (Least Squares Mean) |
|---|---|
| Fluticasone Furoate/Umeclidinium/Vilanterol 100/62.5/25 mcg | 0.054 |
| Budesonide/Formoterol 320/9 mcg Plus Tiotropium 18 mcg | 0.063 |
FEV1 is an important measure of pulmonary function and is the maximum amount of air that can be forced out in one second after taking a deep breath. FEV1 was measured using spirometry. For Day 2 and Day 85, trough FEV1 was defined as the mean of the 23-hour and 24-hour serial spirometry FEV1 measurements. For Day 28 and Day 84, trough FEV1 was defined as the average of the pre-dose FEV1 measurements recorded before the morning dose of randomized study treatment. Change from Baseline in trough FEV1 was calculated by subtracting post-dose trough FEV1 value from Baseline FEV1, where Baseline FEV1 is the average of the two FEV1 measurements made at 30 minutes and 5 minutes pre-dose on Day 1. The treatment effect to be estimated for trough FEV1 was hypothetical effect if all participants stayed on their randomized study treatment. Only on treatment data was included in analysis. (NCT03478683)
Timeframe: Baseline, Days 2, 28, 84 and 85
| Intervention | Liters (Least Squares Mean) | |||
|---|---|---|---|---|
| Day 2, n=358,359 | Day 28, n=355,353 | Day 84, n=344,340 | Day 85, n=341,337 | |
| Budesonide/Formoterol 320/9 mcg Plus Tiotropium 18 mcg | 0.018 | -0.015 | -0.018 | -0.012 |
| Fluticasone Furoate/Umeclidinium/Vilanterol 100/62.5/25 mcg | 0.008 | 0.046 | 0.040 | 0.026 |
FEV1 is an important measure of pulmonary function and is the maximum amount of air that can be forced out in one second after taking a deep breath. FEV1 was measured using spirometry. Serial FEV1 assessments were performed at multiple time points (-30 and -5 minutes pre-dose, and 5 minutes, 15 minutes, 30 minutes, 1 hour, 3 hours, 6 hours, 12 hours, 15 hours, 21 hours, 23 hours and 24 hours post-dose) over 24-hour period at Week 12. Weighted mean change from Baseline at week 12 was calculated by subtracting weighted mean FEV1 at week 12 from Baseline FEV1, where Baseline FEV1 is the average of the two FEV1 measurements made at 30 minutes and 5 minutes pre-dose on Day 1. The weighted mean was derived by calculating the area under the FEV1 time curve (AUC) over the actual time of assessment relative to the time of dosing (over 24-hour period) using the trapezoidal rule, and then dividing the value by the time interval (24-hour) over which the AUC was calculated. (NCT03478683)
Timeframe: Baseline and Week 12
| Intervention | Liters (Least Squares Mean) |
|---|---|
| Fluticasone Furoate/Umeclidinium/Vilanterol 100/62.5/25 mcg | 0.045 |
| Budesonide/Formoterol 320/9 mcg Plus Tiotropium 18 mcg | 0.030 |
FEV1 is an important measure of pulmonary function and is the maximum amount of air that can be forced out in one second after taking a deep breath. FEV1 was measured using spirometry. Serial FEV1 assessments were performed at multiple time points (-30 and -5 minutes pre-dose, and 5 minutes, 15 minutes, 30 minutes, 1 hour, 3 hours, 6 hours, 12 hours, 15 hours, 21 hours, 23 hours and 24 hours post-dose) over 24-hour period at Week 12. Weighted mean change from Baseline at week 12 was calculated by subtracting weighted mean FEV1 at week 12 from Baseline FEV1, where Baseline FEV1 is the average of the two FEV1 measurements made at 30 minutes and 5 minutes pre-dose on Day 1. The weighted mean was derived by calculating the area under the FEV1 time curve (AUC) over the actual time of assessment relative to the time of dosing (over 24-hour period) using the trapezoidal rule, and then dividing the value by the time interval (24-hour) over which the AUC was calculated. (NCT03478683)
Timeframe: Baseline and Week 12
| Intervention | Liters (Least Squares Mean) |
|---|---|
| Fluticasone Furoate/Umeclidinium/Vilanterol 100/62.5/25 mcg | 0.046 |
| Budesonide/Formoterol 320/9 mcg Plus Tiotropium 18 mcg | 0.032 |
FEV1 is an important measure of pulmonary function and is the maximum amount of air that can be forced out in one second after taking a deep breath. FEV1 was measured using spirometry. Serial FEV1 assessments were performed at multiple time points (-30 and -5 minutes pre-dose, and 5 minutes, 15 minutes, 30 minutes, 1 hour, 3 hours, 6 hours, 12 hours, 15 hours, 21 hours, 23 hours and 24 hours post-dose) over 24-hour period at Week 12. Weighted mean change from Baseline at week 12 was calculated by subtracting weighted mean FEV1 at week 12 from Baseline FEV1, where Baseline FEV1 is the average of the two FEV1 measurements made at 30 minutes and 5 minutes pre-dose on Day 1. The weighted mean was derived by calculating the area under the FEV1 time curve (AUC) over the actual time of assessment relative to the time of dosing (over 24-hour period) using the trapezoidal rule, and then dividing the value by the time interval (24-hour) over which the AUC was calculated. (NCT03478696)
Timeframe: Baseline and Week 12
| Intervention | Liters (Least Squares Mean) |
|---|---|
| Fluticasone Furoate/Umeclidinium/Vilanterol 100/62.5/25 mcg | 0.039 |
| Budesonide/Formoterol 320/9 mcg Plus Tiotropium 18 mcg | 0.029 |
FEV1 is an important measure of pulmonary function and is the maximum amount of air that can be forced out in one second after taking a deep breath. FEV1 was measured using spirometry. Serial FEV1 assessments were performed at multiple time points (-30 and -5 minutes pre-dose, and 5 minutes, 15 minutes, 30 minutes, 1 hour, 3 hours, 6 hours, 12 hours, 15 hours, 21 hours, 23 hours and 24 hours post-dose) over 24-hour period on Day 1. Weighted mean change from Baseline on Day 1 was calculated by subtracting weighted mean FEV1 on Day 1 from Baseline FEV1, where Baseline FEV1 is the average of the two FEV1 measurements made at 30 minutes and 5 minutes pre-dose on Day 1. The weighted mean was derived by calculating the area under the FEV1 time curve (AUC) over the actual time of assessment relative to the time of dosing (over 24-hour period) using the trapezoidal rule, and then dividing the value by the time interval (24-hour) over which the AUC was calculated. (NCT03478696)
Timeframe: Baseline and Day 1
| Intervention | Liters (Least Squares Mean) |
|---|---|
| Fluticasone Furoate/Umeclidinium/Vilanterol 100/62.5/25 mcg | 0.045 |
| Budesonide/Formoterol 320/9 mcg Plus Tiotropium 18 mcg | 0.041 |
FEV1 is an important measure of pulmonary function and is the maximum amount of air that can be forced out in one second after taking a deep breath. FEV1 was measured using spirometry. For Day 2 and Day 85, trough FEV1 was defined as the mean of the 23-hour and 24-hour serial spirometry FEV1 measurements. For Day 28 and Day 84, trough FEV1 was defined as the average of the pre-dose FEV1 measurements recorded before the morning dose of randomized study treatment. Change from Baseline in trough FEV1 was calculated by subtracting post-dose trough FEV1 value from Baseline FEV1, where Baseline FEV1 is the average of the two FEV1 measurements made at 30 minutes and 5 minutes pre-dose on Day 1. The treatment effect to be estimated for trough FEV1 was hypothetical effect if all participants stayed on their randomized study treatment. Only on treatment data was included in analysis. (NCT03478696)
Timeframe: Baseline, Days 2, 28, 84 and 85
| Intervention | Liters (Least Squares Mean) | |||
|---|---|---|---|---|
| Day 2, n=355,341 | Day 28, n=353,354 | Day 84, n=346,343 | Day 85, n=343,342 | |
| Budesonide/Formoterol 320/9 mcg Plus Tiotropium 18 mcg | -0.010 | -0.019 | -0.030 | -0.022 |
| Fluticasone Furoate/Umeclidinium/Vilanterol 100/62.5/25 mcg | 0.015 | 0.044 | 0.024 | 0.029 |
FEV1 is an important measure of pulmonary function and is the maximum amount of air that can be forced out in one second after taking a deep breath. FEV1 was measured using spirometry. Serial FEV1 assessments were performed at multiple time points (-30 and -5 minutes pre-dose, and 5 minutes, 15 minutes, 30 minutes, 1 hour, 3 hours, 6 hours, 12 hours, 15 hours, 21 hours, 23 hours and 24 hours post-dose) over 24-hour period at Week 12. Weighted mean change from Baseline at week 12 was calculated by subtracting weighted mean FEV1 at week 12 from Baseline FEV1, where Baseline FEV1 is the average of the two FEV1 measurements made at 30 minutes and 5 minutes pre-dose on Day 1. The weighted mean was derived by calculating the area under the FEV1 time curve (AUC) over the actual time of assessment relative to the time of dosing (over 24-hour period) using the trapezoidal rule, and then dividing the value by the time interval (24-hour) over which the AUC was calculated. (NCT03478696)
Timeframe: Baseline and Week 12
| Intervention | Liters (Least Squares Mean) |
|---|---|
| Fluticasone Furoate/Umeclidinium/Vilanterol 100/62.5/25 mcg | 0.040 |
| Budesonide/Formoterol 320/9 mcg Plus Tiotropium 18 mcg | 0.023 |
Time to >10% increase in FEV1 from pre-first dose, censored at 2 hours (NCT03673670)
Timeframe: Change from pre-dose to the following timepoints: 5, 15 and 30 minutes and 1, 1.5, 2 hours on Day 1 (after the morning dose)
| Intervention | minutes (Median) |
|---|---|
| 1.5 mg RPL554 and Tiotropium/Olodaterol | 10.0 |
| 6 mg RPL554 and Tiotropium/Olodaterol | 6.0 |
| Placebo and Tiotropium/Olodaterol | 11.0 |
Change from baseline to morning trough FEV1 on Day 4 (NCT03673670)
Timeframe: Change from pre-dose on Day 1 to pre-dose on Day 4
| Intervention | Liters (Mean) |
|---|---|
| 1.5 mg RPL554 and Tiotropium/Olodaterol | 0.186 |
| 6 mg RPL554 and Tiotropium/Olodaterol | 0.178 |
| Placebo and Tiotropium/Olodaterol | 0.150 |
Change from baseline FEV1 to peak FEV1 in the 4 hours post-dose after the morning dose on Day 1 (NCT03673670)
Timeframe: Change from pre-dose to each of the following timepoints: 5, 15 and 30 minutes and 1, 1.5, 2, 4 hours on Day 1 (after the morning dose), with the maximum change reported
| Intervention | Liters (Mean) |
|---|---|
| 1.5 mg RPL554 and Tiotropium/Olodaterol | 0.490 |
| 6 mg RPL554 and Tiotropium/Olodaterol | 0.467 |
| Placebo and Tiotropium/Olodaterol | 0.445 |
Change from baseline FEV1 to peak FEV1 (measured as the greatest value in the 4 hours post-dose after the morning dose) on Day 3 (NCT03673670)
Timeframe: Change from pre-dose at 5, 15 and 30 minutes and 1, 1.5, 2 & 4 hours on Day 3
| Intervention | Liters (Mean) |
|---|---|
| 1.5 mg RPL554 and Tiotropium/Olodaterol | 0.565 |
| 6 mg RPL554 and Tiotropium/Olodaterol | 0.506 |
| Placebo and Tiotropium/Olodaterol | 0.519 |
Change in specific airway conductance during treatment (NCT03673670)
Timeframe: Change from pre-dose to 1.25 hours on Day 1 (after the morning dose)
| Intervention | 1/kPa*sec (Mean) |
|---|---|
| 1.5 mg RPL554 and Tiotropium/Olodaterol on Day 1 | 0.064 |
| 6 mg RPL554 and Tiotropium/Olodaterol on Day 1 | 0.042 |
| Placebo and Tiotropium/Olodaterol on Day 1 | 0.043 |
Change from baseline FEV1 to AUC FEV1 over 4 hours post-dose after the morning dose on Day 3. The endpoint is measured as AUC/interval length (average) and measured in liters. (Note: Endpoint is AUC/interval length (average) so the units are in liters.) (NCT03673670)
Timeframe: Change from pre-dose to each of the following timepoints: 5, 15 and 30 minutes and 1, 1.5, 2, 4 hours on Day 3 (after the morning dose)
| Intervention | Liters (Mean) |
|---|---|
| 1.5 mg RPL554 and Tiotropium/Olodaterol | 0.429 |
| 6 mg RPL554 and Tiotropium/Olodaterol | 0.390 |
| Placebo and Tiotropium/Olodaterol | 0.377 |
Change from baseline FEV1 to peak FEV1 in the 4 hours post-dose after the evening dose on Day 3 (NCT03673670)
Timeframe: Change from pre-dose to each of the ollowing timepoints: 5, 15 and 30 minutes and 1, 1.5, 2, 4 hours on Day 3 (after the evening dose), with the maximum change reported
| Intervention | Liters (Mean) |
|---|---|
| 1.5 mg RPL554 and Tiotropium/Olodaterol | 0.453 |
| 6 mg RPL554 and Tiotropium/Olodaterol | 0.405 |
| Placebo and Tiotropium/Olodaterol | 0.324 |
Change in functional residual capacity during treatment (NCT03673670)
Timeframe: Change from pre-dose on Day 1 to the following timepoints: pre-dose, 1.25, 8.25 and 12.25 hours on Day 3 (after the morning dose)
| Intervention | Liters (Mean) | |||
|---|---|---|---|---|
| 1.25 hours | 8.25 hours | 12.25 hours | Pre-dose on Day 3 | |
| 1.5 mg RPL554 and Tiotropium/Oldaterol on Day 3 | -0.490 | -0.420 | -0.255 | -0.278 |
| 6 mg RPL554 and Tiotropium/Oldaterol on Day 3 | -0.408 | -0.405 | -0.155 | -0.206 |
| Placebo and Tiotropium/Oldaterol on Day 3 | -0.382 | -0.355 | -0.075 | -0.163 |
Change in residual volume during treatment (NCT03673670)
Timeframe: Change from pre-dose on Day 1 to the following timepoints: pre-dose, 1.25, 8.25 and 12.25 hours on Day 3 (after the morning dose)
| Intervention | Liters (Mean) | |||
|---|---|---|---|---|
| Pre-dose Day 3 | 1.25 hours | 8.25 hours | 12.25 hours | |
| 1.5 mg RPL554 and Tiotropium/Olodaterol on Day 3 | -0.323 | -0.648 | -0.526 | -0.353 |
| 6 mg RPL554 and Tiotropium/Olodaterol on Day 3 | -0.313 | -0.510 | -0.481 | -0.236 |
| Placebo and Tiotropium/Olodaterol on Day 3 | -0.184 | -0.510 | -0.471 | -0.094 |
Change in residual volume during treatment (NCT03673670)
Timeframe: Change from pre-dose to 1.25 hours on Day 1 (after the morning dose)
| Intervention | Liters (Mean) |
|---|---|
| 1.5 mg RPL554 and Tiotropium/Olodaterol on Day 1 | -0.469 |
| 6 mg RPL554 and Tiotropium/Olodaterol on Day 1 | -0.408 |
| Placebo and Tiotropium/Olodaterol on Day 1 | -0.377 |
Change in functional residual capacity during treatment (NCT03673670)
Timeframe: Change from pre-dose to 1.25 hours on Day 1 (after the morning dose)
| Intervention | Liters (Mean) |
|---|---|
| 1.5 mg RPL554 and Tiotropium/Olodaterol on Day 1 | -0.344 |
| 6 mg RPL554 and Tiotropium/Olodaterol on Day 1 | -0.294 |
| Placebo and Tiotropium/Olodaterol on Day 1 | -0.277 |
Change in specific airway conductance during treatment (NCT03673670)
Timeframe: Change from pre-dose on Day 1 to the following timepoints: pre-dose, 1.25, 8.25 and 12.25 hours on Day 3 (after the morning dose)
| Intervention | 1/kPa*sec (Mean) | |||
|---|---|---|---|---|
| Pre-dose Day 3 | 1.25 hours | 8.25 hours | 12.25 hours | |
| 1.5 mg RPL554 and Tiotropium/Olodaterol on Day 3 | 0.021 | 0.064 | 0.059 | 0.029 |
| 6 mg RPL554 and Tiotropium/Olodaterol on Day 3 | 0.046 | 0.050 | 0.048 | 0.032 |
| Placebo and Tiotropium/Olodaterol on Day 3 | 0.016 | 0.049 | 0.037 | 0.021 |
Change from baseline in AUC over 12 hours post-dose after the morning dose on Day 3. The endpoint is measured as AUC/interval length (average) and measured in liters (Note: Endpoint is AUC/interval length (average) so the units are in liters.) (NCT03673670)
Timeframe: Change from pre-dose to each of the following timepoints: 5, 15 and 30 minutes and 1, 1.5, 2, 4, 6, 8, 12 hours on Day 3 (after the morning dose)
| Intervention | Liters (Mean) |
|---|---|
| 1.5 mg RPL554 and Tiotropium/Olodaterol | 0.390 |
| 6 mg RPL554 and Tiotropium/Olodaterol | 0.347 |
| Placebo and Tiotropium/Olodaterol | 0.337 |
Change from baseline FEV1 to AUC FEV1 over 12 hours post-dose after the morning dose on Day 1. The endpoint is measured as AUC/interval length (average) and measured in liters (Note: Endpoint is AUC/interval length (average) so the units are in liters.) (NCT03673670)
Timeframe: Change from pre-dose to each of the following timepoints: 5, 15 and 30 minutes and 1, 1.5, 2, 4, 6, 8, 12 hours on Day 1 (after the morning dose)
| Intervention | Liters (Mean) |
|---|---|
| 1.5 mg RPL554 and Tiotropium/Olodaterol | 0.333 |
| 6 mg RPL554 and Tiotropium/Olodaterol | 0.308 |
| Placebo and Tiotropium/Olodaterol | 0.303 |
The number of participants who had Cardiac failure on the index date or in the year prior to the index date. (NCT03692676)
Timeframe: On the index date or in the year prior to the index date
| Intervention | Patients with cardiac failures (Number) |
|---|---|
| Spiriva Respimat | NA |
| Leukotriene Receptor Antagonist (LTRA) | 9 |
| ICS/LABA Fixed Dose Combination (Switchers) | 49 |
| ICS Dose Increase of ICS/LABA Fixed Dose Combination User | 12 |
The number of participants who had Cardiac arrhythmias on the index date or in the year prior to the index date. (NCT03692676)
Timeframe: On the index date or in the year prior to the index date
| Intervention | Participants (Count of Participants) |
|---|---|
| Spiriva Respimat | 11 |
| Leukotriene Receptor Antagonist (LTRA) | 17 |
| ICS/LABA Fixed Dose Combination (Switchers) | 102 |
| ICS Dose Increase of ICS/LABA Fixed Dose Combination User | 16 |
An adverse event (AE) was defined as any undesirable experience occurring to a patient, or worsening in a patient, whether considered related to the study medication or not. All AEs which started after the first dose of study treatment or started prior to first dose of study treatment and worsened, based on the Investigator's assessment of severity, on or after first dose of study treatment were considered to be treatment-emergent. A serious adverse event is any adverse experience that: results in death; is life-threatening; requires inpatient hospitalization or prolongation of existing hospitalization; results in persistent or significant disability/incapacity; is a congenital anomaly/birth defect; or other important medical events. (NCT03937479)
Timeframe: TEAEs were collected from the first dose of study treatment up to 1 week after the final study visit at Week 4, approximately 5 weeks.
| Intervention | Participants (Count of Participants) | ||||||
|---|---|---|---|---|---|---|---|
| Any TEAE | Any TEAE leading to drug discontinuation | Any drug-related TEAE | Any serious TEAE | Any serious drug-related TEAE | Any serious TEAE leading drug discontinuation | Any TEAE leading to death | |
| Placebo | 17 | 1 | 4 | 0 | 0 | 0 | 0 |
| RPL554 0.375 mg | 12 | 2 | 1 | 0 | 0 | 0 | 0 |
| RPL554 0.75 mg | 15 | 3 | 3 | 1 | 0 | 1 | 0 |
| RPL554 1.5 mg | 14 | 0 | 2 | 0 | 0 | 0 | 0 |
| RPL554 3.0 mg | 18 | 0 | 2 | 2 | 0 | 0 | 0 |
"The PGAC is a single question assessment to determine whether patients noticed a change in their breathing since the start of the study. Patients were asked to respond to a PGAC question asking, Compared with prior to the study start, how do you feel your breathing is? on a scale of '1=much worse' to '5=much better', with '3=no change'. Higher scores indicate better outcome." (NCT03937479)
Timeframe: Weeks 2 and 4
| Intervention | units on a scale (Least Squares Mean) | |
|---|---|---|
| Week 2 | Week 4 | |
| Placebo | 3.427 | 3.506 |
| RPL554 0.375 mg | 3.512 | 3.553 |
| RPL554 0.75 mg | 3.522 | 3.543 |
| RPL554 1.5 mg | 3.456 | 3.536 |
| RPL554 3.0 mg | 3.523 | 3.577 |
Use of rescue medication (albuterol) per visit was calculated as the LS mean use daily over total number of days between previous visit (inclusive) and the following visit. Baseline use was the mean over the last 7 days of the run-in phase (calculated as the sum of puffs taken, divided by number of days data has been recorded). (NCT03937479)
Timeframe: Baseline and Weeks 1, 2, 3 and 4
| Intervention | number of rescue medication puffs (Least Squares Mean) | |||
|---|---|---|---|---|
| Week 1 | Week 2 | Week 3 | Week 4 | |
| Placebo | -0.556 | -0.544 | -0.504 | -0.671 |
| RPL554 0.375 mg | -0.510 | -0.325 | -0.302 | -0.412 |
| RPL554 0.75 mg | -0.580 | -0.360 | -0.139 | -0.510 |
| RPL554 1.5 mg | -0.539 | -0.388 | -0.647 | -0.784 |
| RPL554 3.0 mg | -0.629 | -0.379 | -0.558 | -0.506 |
The E-RS scale consists of 11 questions, with 3 sub-domains of: breathlessness, cough and sputum, and chest symptoms. The E-RS sub-domain score was calculated as the sum from the relevant questions. The E-RS:COPD scale has a scoring range of 0 to 40. Higher scores indicates severe respiratory symptoms. Baseline was the mean over the 7 days prior to first intake of study treatment. Scores were derived weekly as the mean over 7 days prior to the visit, using only days where data was recorded. The E-RS:COPD was measured by daily electronic diary (e-diary). (NCT03937479)
Timeframe: Baseline and Weeks 1, 2, 3 and 4
| Intervention | units on a scale (Least Squares Mean) | |||
|---|---|---|---|---|
| Week 1 | Week 2 | Week 3 | Week 4 | |
| Placebo | -0.319 | -0.102 | -0.287 | -0.228 |
| RPL554 0.375 mg | -0.978 | -0.873 | -0.950 | -1.690 |
| RPL554 0.75 mg | -0.669 | -0.471 | -0.338 | -0.593 |
| RPL554 1.5 mg | -0.617 | -0.597 | -1.091 | -1.226 |
| RPL554 3.0 mg | -1.142 | -0.598 | -1.097 | -1.071 |
Patients completed the SGRQ-C consisting of 40 items each weighted from 0 to a possible maximum of 100. Items 1-7 produced the symptoms score, 9-12 the activity score, and items 8, 10, 11, 13 and 14 the impacts score. Each component sub-score was calculated as a percentage of the summed weights of each item out of the sum of the maximum possible weight for that component (range 0-100). The total score was calculated by summing the weights to all positive responses in each component, where a positive item indicated the presence of symptoms, expressed as a percentage (range 0-100). Higher scores indicated a worse outcome. The SGRQ-C was measured at Week 2 and 4 visits. (NCT03937479)
Timeframe: Baseline, Weeks 2 and 4
| Intervention | units on a scale (Least Squares Mean) | |
|---|---|---|
| Week 2 | Week 4 | |
| Placebo | -0.249 | -0.116 |
| RPL554 0.375 mg | -1.808 | -4.387 |
| RPL554 0.75 mg | -1.132 | -2.400 |
| RPL554 1.5 mg | -3.465 | -4.870 |
| RPL554 3.0 mg | -3.618 | -4.163 |
Forced spirometry maneuvers including the FEV1 were used to assess pulmonary function. Baseline FEV1 was defined as the value of FEV1 assessed 30 minutes before first administration and average AUC0-3h FEV1 was defined as area under the curve over 3 hours of the FEV1, divided by 3 hours. Spirometry assessments were performed in accordance with ATS/ERS guidelines. (NCT03937479)
Timeframe: Baseline (30 minutes before first administration on Day 1); 30 minutes and 1, 2, and 3 hours post-dose on Day 1 and Weeks 1, 2, 3 and 4
| Intervention | liters (Least Squares Mean) | ||||
|---|---|---|---|---|---|
| Day 1 | Week 1 | Week 2 | Week 3 | Week 4 | |
| Placebo | 0.0654 | 0.0246 | 0.0304 | 0.0294 | 0.0369 |
| RPL554 0.375 mg | 0.1533 | 0.1118 | 0.1154 | 0.1156 | 0.1095 |
| RPL554 0.75 mg | 0.1614 | 0.1301 | 0.1309 | 0.1243 | 0.1305 |
| RPL554 1.5 mg | 0.1810 | 0.1308 | 0.1433 | 0.1444 | 0.1394 |
| RPL554 3.0 mg | 0.2017 | 0.1526 | 0.1651 | 0.1385 | 0.1626 |
Blood samples were taken to determine steady-state plasma concentrations of RPL554 following 14 days of treatment with RPL554. (NCT03937479)
Timeframe: Pre-dose at Week 2
| Intervention | pg/mL (Mean) |
|---|---|
| RPL554 0.375 mg | 37.3 |
| RPL554 0.75 mg | 53.7 |
| RPL554 1.5 mg | 107.9 |
| RPL554 3.0 mg | 170.6 |
| Placebo | NA |
Forced spirometry maneuvers including the FEV1 were used to assess pulmonary function. Baseline FEV1 was defined as the value of FEV1 assessed 30 minutes before first administration and peak FEV1 was defined as the maximum value in the 3 hours after dosing. Spirometry assessments were performed in accordance with American Thoracic Society (ATS)/European Respiratory Society (ERS) guidelines. (NCT03937479)
Timeframe: Baseline and Week 4
| Intervention | liters (Least Squares Mean) |
|---|---|
| RPL554 0.375 mg | 0.1963 |
| RPL554 0.75 mg | 0.2100 |
| RPL554 1.5 mg | 0.2260 |
| RPL554 3.0 mg | 0.2431 |
| Placebo | 0.1188 |
Forced spirometry maneuvers including the FEV1 were used to assess pulmonary function. Baseline FEV1 was defined as the value of FEV1 assessed 30 minutes before first administration and average AUC0-12h FEV1 was defined as area under the curve over 12 hours of the FEV1, divided by 12 hours. Spirometry assessments were performed in accordance with ATS/ERS guidelines. (NCT03937479)
Timeframe: Baseline (30 minutes before first administration on Day 1); 30 minutes and 1, 2, 3, 4, 6, 8 and 12 hours post-dose on Day 1 and at Week 4
| Intervention | liters (Least Squares Mean) | |
|---|---|---|
| Day 1 | Week 4 | |
| Placebo | 0.0282 | 0.0096 |
| RPL554 0.375 mg | 0.0795 | 0.0359 |
| RPL554 0.75 mg | 0.0909 | 0.0630 |
| RPL554 1.5 mg | 0.1020 | 0.0640 |
| RPL554 3.0 mg | 0.1374 | 0.0969 |
The TDI is a questionnaire that focussed on 3 sub-domains: functional impairment, magnitude of task and magnitude of effort. Sub-domain score was calculated as the sum from the related questions. Total score was calculated as the sum of the sub-domain scores. The TDI measures the change in dyspnea severity from the baseline as measured by the baseline dyspnea index. It was rated by 7 grades ranging from -3 (major deterioration) to +3 (major improvement). Higher scores indicate better outcome. (NCT03937479)
Timeframe: Weeks 2 and 4
| Intervention | units on a scale (Least Squares Mean) | |
|---|---|---|
| Week 2 | Week 4 | |
| Placebo | 1.421 | 1.766 |
| RPL554 0.375 mg | 1.682 | 2.089 |
| RPL554 0.75 mg | 1.285 | 1.484 |
| RPL554 1.5 mg | 1.582 | 2.055 |
| RPL554 3.0 mg | 1.589 | 2.063 |
Forced spirometry maneuvers including the FEV1 were used to assess pulmonary function. Baseline FEV1 was defined as the value of FEV1 assessed 30 minutes before first administration and morning trough FEV1 was defined as the last pre-dose value. Spirometry assessments were performed in accordance with ATS/ERS guidelines. (NCT03937479)
Timeframe: Baseline (30 minutes before first administration on Day 1) and morning pre-dose on Weeks 1, 2, 3 and 4
| Intervention | liters (Least Squares Mean) | |||
|---|---|---|---|---|
| Week 1 | Week 2 | Week 3 | Week 4 | |
| Placebo | -0.0520 | -0.0377 | -0.0533 | -0.0218 |
| RPL554 0.375 mg | -0.0088 | -0.0278 | -0.0385 | -0.0201 |
| RPL554 0.75 mg | -0.0354 | -0.0696 | -0.0630 | -0.0348 |
| RPL554 1.5 mg | -0.0451 | -0.0070 | -0.0413 | -0.0141 |
| RPL554 3.0 mg | -0.0216 | 0.0136 | -0.0232 | 0.0054 |
Blood samples were taken to determine steady-state plasma concentrations of tiotropium prior to and following 14 days of treatment with RPL554. (NCT03937479)
Timeframe: Pre-dose on Day 1 and Week 2
| Intervention | picogram per milliliter (pg/mL) (Mean) | |
|---|---|---|
| Day 1 | Week 2 | |
| Placebo | 2.4 | 2.2 |
| RPL554 0.375 mg | 2.8 | 2.2 |
| RPL554 0.75 mg | 2.1 | 2.3 |
| RPL554 1.5 mg | 1.9 | 1.9 |
| RPL554 3.0 mg | 2.4 | 2.0 |
Forced spirometry maneuvers including the FVC were used to assess pulmonary function. Baseline FVC was defined as the value of FVC assessed 30 minutes before first administration and morning trough FVC was defined as the last pre-dose value. Spirometry assessments were performed in accordance with ATS/ERS guidelines. (NCT03937479)
Timeframe: Baseline (30 minutes before first administration on Day 1) and morning pre-dose on Weeks 1, 2, 3 and 4
| Intervention | liters (Least Squares Mean) | |||
|---|---|---|---|---|
| Week 1 | Week 2 | Week 3 | Week 4 | |
| Placebo | -0.0617 | -0.0614 | -0.0969 | -0.0198 |
| RPL554 0.375 mg | -0.0159 | -0.0647 | -0.0966 | -0.0390 |
| RPL554 0.75 mg | -0.0650 | -0.0744 | -0.0936 | -0.0347 |
| RPL554 1.5 mg | -0.0887 | -0.0458 | -0.0857 | -0.0570 |
| RPL554 3.0 mg | -0.0624 | -0.0045 | -0.0690 | -0.0217 |
Forced spirometry maneuvers including the FVC were used to assess pulmonary function. Baseline FVC was defined as the value of FVC assessed 30 minutes before first administration and average AUC0-3h FVC was defined as area under the curve over 3 hours of the FVC, divided by 3 hours. Spirometry assessments were performed in accordance with ATS/ERS guidelines. (NCT03937479)
Timeframe: Baseline (30 minutes before first administration on Day 1); 30 minutes and 1, 2, and 3 hours post-dose on Day 1 and Weeks 1, 2, 3 and 4
| Intervention | liters (Least Squares Mean) | ||||
|---|---|---|---|---|---|
| Day 1 | Week 1 | Week 2 | Week 3 | Week 4 | |
| Placebo | 0.0864 | 0.0323 | 0.0217 | 0.0252 | 0.0382 |
| RPL554 0.375 mg | 0.2165 | 0.1460 | 0.1362 | 0.1431 | 0.1350 |
| RPL554 0.75 mg | 0.2397 | 0.1890 | 0.2010 | 0.1860 | 0.1928 |
| RPL554 1.5 mg | 0.2519 | 0.1691 | 0.1783 | 0.1798 | 0.1623 |
| RPL554 3.0 mg | 0.2715 | 0.2039 | 0.2104 | 0.1739 | 0.2134 |
Forced spirometry maneuvers including the FVC were used to assess pulmonary function. Baseline FVC was defined as the value of FVC assessed 30 minutes before first administration and average AUC0-12h FVC was defined as area under the curve over 12 hours of the FVC, divided by 12 hours. Spirometry assessments were performed in accordance with ATS/ERS guidelines. (NCT03937479)
Timeframe: Baseline (30 minutes before first administration on Day 1); 30 minutes and 1, 2, 3, 4, 6, 8 and 12 hours post-dose on Day 1 and at Week 4
| Intervention | liters (Least Squares Mean) | |
|---|---|---|
| Day 1 | Week 4 | |
| Placebo | 0.0344 | -0.0030 |
| RPL554 0.375 mg | 0.0838 | 0.0152 |
| RPL554 0.75 mg | 0.1294 | 0.0838 |
| RPL554 1.5 mg | 0.1187 | 0.0438 |
| RPL554 3.0 mg | 0.1514 | 0.0982 |
Forced spirometry maneuvers including the FVC were used to assess pulmonary function. Baseline FVC was defined as the value of FVC assessed 30 minutes before first administration and peak FVC was defined as the maximum value in the 3 hours after dosing. Spirometry assessments were performed in accordance with ATS/ERS guidelines. (NCT03937479)
Timeframe: Baseline (30 minutes before first administration on Day 1); 30 minutes post-dose on Day 1 and Weeks 1, 2, 3 and 4
| Intervention | liters (Least Squares Mean) | ||||
|---|---|---|---|---|---|
| Day 1 | Week 1 | Week 2 | Week 3 | Week 4 | |
| Placebo | 0.2241 | 0.1717 | 0.1524 | 0.1626 | 0.1736 |
| RPL554 0.375 mg | 0.3463 | 0.2839 | 0.2597 | 0.2744 | 0.2706 |
| RPL554 0.75 mg | 0.3775 | 0.3199 | 0.3282 | 0.3177 | 0.3198 |
| RPL554 1.5 mg | 0.3852 | 0.3065 | 0.3070 | 0.3176 | 0.2951 |
| RPL554 3.0 mg | 0.4035 | 0.3545 | 0.3343 | 0.3008 | 0.3414 |
Forced spirometry maneuvers including the FEV1 were used to assess pulmonary function. Baseline FEV1 was defined as the value of FEV1 assessed 30 minutes before first administration and peak FEV1 was defined as the maximum value in the 3 hours after dosing. Spirometry assessments were performed in accordance with ATS/ERS guidelines. (NCT03937479)
Timeframe: Baseline (30 minutes before first administration on Day 1); 30 minutes post-dose on Day 1 and Weeks 1, 2 and 3
| Intervention | liters (Least Squares Mean) | |||
|---|---|---|---|---|
| Day 1 | Week 1 | Week 2 | Week 3 | |
| Placebo | 0.1469 | 0.1041 | 0.1098 | 0.1072 |
| RPL554 0.375 mg | 0.2353 | 0.1860 | 0.1963 | 0.1987 |
| RPL554 0.75 mg | 0.2426 | 0.2026 | 0.2121 | 0.2006 |
| RPL554 1.5 mg | 0.2610 | 0.2116 | 0.2191 | 0.2277 |
| RPL554 3.0 mg | 0.2852 | 0.2353 | 0.2421 | 0.2197 |
"The overall satisfaction question score in the Patient satisfaction and preference questionnaire (PASAPQ) at week 4 and 8 is reported (after 4 weeks of treatment). In Part I of the questionnaire PASAPQ: the Question 14 (Q14) asked for the overall satisfaction with the device used in the study. Q14 had Likert-type response options of 1 (very dissatisfied) to 7 (very satisfied) and was then transformed to a 0 (least) to 100 (most) point scale (if a patient scored x, the transfer to 0-100 scale was x/7*100). Mixed-effects Model for Repeated Measures (MMRM) was used to analyze the overall satisfaction question score, with treatment and period as fixed effects, and patient as a random effect." (NCT03964207)
Timeframe: At the end of 4 weeks of treatment
| Intervention | Score on a scale (Mean) |
|---|---|
| (T1): 5μg Tiotropium Respimat® | 82.56 |
| (T2): 18μg Tiotropium Handihaler® | 87.24 |
The score on the performance domain of the Patient satisfaction and preference questionnaire (PASAPQ) after 4 weeks of treatment is reported. The performance domain score is the sum of 7 questions (Q) within the domain (Q1, Q2, Q3, Q4, Q5, Q10 and Q11), the range for each question went from 1 to 7 the higher the better. The score was then transformed to a 0 (least) to 100 (most) point scale following ((Q1+Q2+Q3+Q4+Q5+Q10+Q11)/49)*100, the higher the better performance. The performance domain of PASAPQ) was analysed using Mixed-effects Model for Repeated Measures (MMRM), with treatment and period as fixed effects, and patient as a random effect. Compound symmetry was used as a covariance structure for within-patient variation. (NCT03964207)
Timeframe: After 4 weeks of treatment (at week 4 and week 8)
| Intervention | Scores on a scale (Mean) |
|---|---|
| (T1): 5μg Tiotropium Respimat® | 79.830 |
| (T2): 18μg Tiotropium Handihaler® | 85.112 |
The total score on the Patient satisfaction and preference questionnaire (PASAPQ) after 4 weeks of treatment is reported. The Total score is the sum of 13 questions (Q1-Q13) and then transformed to a 0 (least) to 100 (most) point scale. This continuous secondary endpoint was analyzed using a similar MMRM model as for the primary endpoint. (NCT03964207)
Timeframe: After 4 weeks of treatment (at week 4 and week 8)
| Intervention | Scores on a scale (Mean) |
|---|---|
| (T1): 5μg Tiotropium Respimat® | 81.51 |
| (T2): 18μg Tiotropium Handihaler® | 85.69 |
"The percentage of patients indicating preference in the Patient satisfaction and preference questionnaire (PASAPQ) at week 8 is reported. The questionnaire PASAPQ is a two part questionnaire, in Part II of the PASAPQ the stand-alone question 15 (Q15) was asked for a response to indicate the preference for the trial device, it had three possible answers: I prefer Respimat, I prefer Handihaler, No answer to this question and no preference. Chi-squared test was used to analyze proportion of patients indicating preference in the Patient satisfaction and preference questionnaire (PASAPQ) at week 8." (NCT03964207)
Timeframe: At Week 8.
| Intervention | Percentage (Number) | |||
|---|---|---|---|---|
| I prefer Respimat | I prefer Handihaler | No preference | No answer to this question | |
| Tiotropium (T1 or T2) | 50.7 | 37.7 | 5.8 | 5.8 |
The score on willingness to continue in the Patient satisfaction and preference questionnaire (PASAPQ) at week 8 is reported. The PASAPQ is a two part questionnaire, in Part I of the questionnaire PASAPQ the Question 16 (Q16) asked for a response between 0 and 100 with 0 indicating not willing to continue using the trial device and 100 indicating definitely willingness to continue. Mixed-effects Model for Repeated Measures (MMRM) was used to analyze the score on willingness to continue, with treatment and period as fixed effects, and patient as a random effect. (NCT03964207)
Timeframe: At Week 8.
| Intervention | Scores on a scale (Mean) |
|---|---|
| (T1): 5μg Tiotropium Respimat® | 82.9 |
| (T2): 18μg Tiotropium Handihaler® | 87.3 |
Exacerbation rate per 100 person-years. Follow-up period was from index date (date of the first prescription for Tiotropium Respimat® 1.25 mcg in Tio group; date of the first prescription from low to medium/high does or medium to high does or additional high-does of Inhaled Corticosteroid (ICS)/long-acting beta-agonists (LABA) for NonTio group). (NCT03964220)
Timeframe: At 6 month and 1 year of follow-up
| Intervention | Events per 100 person-years (Number) | |
|---|---|---|
| At 6 months of follow-up | At 1 year of follow-up | |
| Inhaled Corticosteroid/Long-acting Beta-agonist (NonTio Group) | 116.07 | 57.24 |
| Tiotropium Respimat® (Tio Group) | 41.40 | 15.65 |
Follow-up period was from index date (date of the first prescription for Tiotropium Respimat® 1.25 mcg in Tio group; date of the first prescription from low to medium/high does or medium to high does or additional high-does of Inhaled Corticosteroid (ICS)/long-acting beta-agonists (LABA) for NonTio group) and up to 3 years of study period. (NCT03964220)
Timeframe: During follow-up period, From baseline until end of follow-up, up to 3 years
| Intervention | Events per 100 person-years (Number) | |||||
|---|---|---|---|---|---|---|
| Hospitalization (all cause) | Hospitalization (asthma related) | Emergency room (ER) visit (all cause) | ER visit (asthma related) | Outpatient (OP) visit (all cause) | OP visit (asthma related) | |
| Inhaled Corticosteroid/Long-acting Beta-agonist (NonTio Group) | 46.51 | 20.27 | 84.67 | 47.70 | 232.55 | 158.61 |
| Tiotropium Respimat® (Tio Group) | 23.97 | 4.89 | 45.00 | 12.23 | 206.92 | 133.06 |
Exacerbations will be defined as either a hospitalization with a primary diagnosis of asthma, an emergency room (ER) visit with a primary diagnosis of asthma, an asthma exacerbation diagnosis recorded. (NCT03964220)
Timeframe: From baseline until end of follow-up, up to 3 years
| Intervention | Days (Mean) |
|---|---|
| Tiotropium Respimat® (Tio Group) | 340.656 |
| Inhaled Corticosteroid/Long-acting Beta-agonist (NonTio Group) | 123.151 |
Follow-up period was from index date (date of the first prescription for Tiotropium Respimat® 1.25 mcg in Tio group; date of the first prescription from low to medium/high does or medium to high does or additional high-does of Inhaled Corticosteroid (ICS)/long-acting beta-agonists (LABA) for NonTio group) and up to 3 years of study period. FEV1 score range from 0 to 100. Higher FEV1 score suggests normal lung function, while lower for dangerous. Only the descriptive statistics of FEV1 score were reported other than change of FEV1 score from baseline due to lack of enough data points. (NCT03964220)
Timeframe: From baseline until end of follow-up, up to 3 years
| Intervention | Score on a scale (Mean) |
|---|---|
| Tiotropium Respimat® (Tio Group) | 77.77 |
| Inhaled Corticosteroid/Long-acting Beta-agonist (NonTio Group) | 85.69 |
Follow-up period was from index date (date of the first prescription for Tiotropium Respimat® 1.25 mcg in Tio group; date of the first prescription from low to medium/high does or medium to high does or additional high-does of Inhaled Corticosteroid (ICS)/long-acting beta-agonists (LABA) for NonTio group) and up to 3 years of study period. ACT score is based on a range of 5 to 25. Higher score indicates better asthma control. A score of 19 or less may be a sign that asthma symptoms not under control. Only the descriptive statistics of ACT score were reported other than change of ACT score from baseline due to lack of enough data points. (NCT03964220)
Timeframe: From baseline until end of follow-up, up to 3 years
| Intervention | Score on a scale (Mean) |
|---|---|
| Tiotropium Respimat® (Tio Group) | 15.65 |
| Inhaled Corticosteroid/Long-acting Beta-agonist (NonTio Group) | 16.16 |
The primary outcome of interest was discontinuation of index treatment (Olodaterol/Tiotropium Bromide or Umeclidinium/Vilanterol), defined as persistence, (i.e. no refill Claim within 60 days [not including treatment Switch, nor death] after end of supply) during follow-up. Persistence was assessed by calculating rates of discontinuation in the matched cohorts using a 60-day allowable gap. Rates of discontinuation are reported as the number of events divided by the number of Person-years at risk. Addition of another treatment to index treatment did not count as discontinuation. (NCT03979807)
Timeframe: From first day after the cohort entry date to the earliest occurence of the outcome (discontinuation or refills), or any censoring criteria (365 days of follow-up without discontinuation, death, disenrollment end of data).
| Intervention | Events per 1000 person-years (Number) |
|---|---|
| Olodaterol/Tiotropium Bromide - Matched Cohort | 1826.00 |
| Umeclidinium/Vilanterol - Matched Cohort | 1647.03 |
"Change from baseline in pulmonary function after Long-Acting Beta-Agonist (LABA)+Long-Acting Muscarinic Antagonist (LAMA) (Tiotropium+Olodaterol or other LABA+LAMA therapy) or LAMA initiation evaluating by post-bronchodilator Forced Volume Vital Capacity (Post-FVC) at 12 months after index date was reported.~Spirometry was the most common tool to evaluate the lung function of patients with respiratory disease. Among the results of spirometry, post-bronchodilator Forced Volume Vital Capacity was used for assisting in the diagnosis, determining disease severity, and following up the prognosis." (NCT04011475)
Timeframe: At index date (Baseline) and at 12 months after index date.
| Intervention | milliliter (Mean) |
|---|---|
| Tiotropium+Olodaterol (Group A) | -74.0 |
| Other Long-Acting Beta-Agonist (LABA)+Long-Acting Muscarinic Antagonist (LAMA) (Group B) | 134.5 |
| Long-Acting Muscarinic Antagonist (LAMA) (Group C) | 63.7 |
Incidence of patients escalating therapy, from single/dual to dual/triple therapy such as receiving Long-Acting Muscarinic Antagonist (LAMA) escalated to dual therapy or receiving LABA+LAMA (Tiotropium+Olodaterol) escalated to triple therapy(LABA+LAMA+inhaled corticosteroids (ICS)), within 1 year after the index date was reported. (NCT04011475)
Timeframe: Up to 1 year after the index date (Baseline).
| Intervention | Participants (Count of Participants) |
|---|---|
| Tiotropium+Olodaterol (Group A) | 10 |
| Other Long-Acting Beta-Agonist (LABA)+Long-Acting Muscarinic Antagonist (LAMA) (Group B) | 17 |
| Long-Acting Muscarinic Antagonist (LAMA) (Group C) | 19 |
Number of participants with moderate-to-severe acute exacerbation within 1 year after the index date was reported. (NCT04011475)
Timeframe: Up to 1 year after the index date (Baseline).
| Intervention | Participants (Count of Participants) |
|---|---|
| Tiotropium+Olodaterol (Group A) | 20 |
| Other Long-Acting Beta-Agonist (LABA)+Long-Acting Muscarinic Antagonist (LAMA) (Group B) | 22 |
| Long-Acting Muscarinic Antagonist (LAMA) (Group C) | 9 |
Percentage of patients receiving dual therapy (Tiotropium+Olodaterol or other Long-Acting Beta-Agonist (LABA)+Long-Acting Muscarinic Antagonist (LAMA) therapy) escalated to triple therapy (LABA+LAMA + inhaled corticosteroids (ICS)) or LAMA escalated to dual therapy (LABA + LAMA) was reported. (NCT04011475)
Timeframe: Up to 1 year after index date (Baseline).
| Intervention | Percentage of participants (Number) |
|---|---|
| Tiotropium+Olodaterol (Group A) | 8.8 |
| Other Long-Acting Beta-Agonist (LABA)+Long-Acting Muscarinic Antagonist (LAMA) (Group B) | 14.9 |
| Long-Acting Muscarinic Antagonist (LAMA) (Group C) | 16.7 |
Percentage of patients using rescue medications within 1 year after index date was reported. (NCT04011475)
Timeframe: Up to 1 year after index date (Baseline).
| Intervention | Percentage of participants (Number) |
|---|---|
| Tiotropium+Olodaterol (Group A) | 58.8 |
| Other Long-Acting Beta-Agonist (LABA)+Long-Acting Muscarinic Antagonist (LAMA) (Group B) | 43.9 |
| Long-Acting Muscarinic Antagonist (LAMA) (Group C) | 45.6 |
"Change from baseline in pulmonary function after Long-Acting Beta-Agonist (LABA)+Long-Acting Muscarinic Antagonist (LAMA) (Tiotropium+Olodaterol or other LABA+LAMA therapy) or LAMA initiation evaluating by modified Medical Research Council dyspnea scale (mMRC) at 12 months after index date is reported.~Modified Medical Research Council dyspnea scale (mMRC) is a 5 points scale measuring the severity of dyspnea of patients. The scale ranges from 0 (better outcome) to 4 (worse outcome). The higher the scale value, the more severe the dyspnea is. If mMRC scale of the patient was > 2, it means the patient may suffer from dyspnea." (NCT04011475)
Timeframe: At index date (baseline) and at 12 months after index date
| Intervention | Score on a scale (Mean) |
|---|---|
| Tiotropium+Olodaterol (Group A) | 0.1 |
| Other Long-Acting Beta-Agonist (LABA)+Long-Acting Muscarinic Antagonist (LAMA) (Group B) | 0.1 |
| Long-Acting Muscarinic Antagonist (LAMA) (Group C) | 0.2 |
The annualized rate of mild exacerbation was calculated as: total number of episodes of mild exacerbation of all participants divided by the sum of follow-up period [years] of all participants. The corresponding 95% confidence interval was from Poisson regression. (NCT04011475)
Timeframe: Up to 1 year after the index date (Baseline).
| Intervention | episodes/patient-year (Number) |
|---|---|
| Tiotropium+Olodaterol (Group A) | 0.00 |
| Other Long-Acting Beta-Agonist (LABA)+Long-Acting Muscarinic Antagonist (LAMA) (Group B) | 0.04 |
| Long-Acting Muscarinic Antagonist (LAMA) (Group C) | 0.04 |
The annualized rate of moderate exacerbation was calculated as: total number of episodes of moderate exacerbation of all participants divided by the sum of follow-up period [years] of all participants. The corresponding 95% confidence interval was from Poisson regression. (NCT04011475)
Timeframe: Up to 1 year after the index date (Baseline).
| Intervention | episodes/patient-year (Number) |
|---|---|
| Tiotropium+Olodaterol (Group A) | 0.19 |
| Other Long-Acting Beta-Agonist (LABA)+Long-Acting Muscarinic Antagonist (LAMA) (Group B) | 0.30 |
| Long-Acting Muscarinic Antagonist (LAMA) (Group C) | 0.08 |
The annualized rate of moderate-to-severe exacerbation was calculated as: total number of episodes of moderate-to-severe exacerbation of all participants divided by the sum of follow-up period [years] of all participants. The corresponding 95% confidence interval was from Poisson regression. (NCT04011475)
Timeframe: Up to 1 year after the index date (Baseline).
| Intervention | episodes/patient-year (Number) |
|---|---|
| Tiotropium+Olodaterol (Group A) | 0.28 |
| Other Long-Acting Beta-Agonist (LABA)+Long-Acting Muscarinic Antagonist (LAMA) (Group B) | 0.42 |
| Long-Acting Muscarinic Antagonist (LAMA) (Group C) | 0.10 |
The annualized rate of severe exacerbation was calculated as: total number of episodes of severe exacerbation of all participants divided by the sum of follow-up period [years] of all participants. The corresponding 95% confidence interval was from Poisson regression. (NCT04011475)
Timeframe: Up to 1 year after the index date (Baseline).
| Intervention | episodes/patient-year (Number) |
|---|---|
| Tiotropium+Olodaterol (Group A) | 0.09 |
| Other Long-Acting Beta-Agonist (LABA)+Long-Acting Muscarinic Antagonist (LAMA) (Group B) | 0.12 |
| Long-Acting Muscarinic Antagonist (LAMA) (Group C) | 0.02 |
"Change from baseline in pulmonary function after Long-Acting Beta-Agonist (LABA)+Long-Acting Muscarinic Antagonist (LAMA) (Tiotropium+Olodaterol or other LABA+LAMA therapy) or LAMA initiation evaluating by Chronic Obstructive Pulmonary Disease (COPD) Assessment Test (CAT) score at 12 months after index date was reported.~The COPD assessment test (CAT) was a simple, 8-item, health status instrument which provided a simple method for assessing the impact of COPD on the patient's health and the quality of life. Each item was on a 6-point scale: 0 (no impact) to 5 (maximum impact). The CAT score ranging from 0 (better health status) to 40 (worse health status) was calculated by summing the points for each item. A decrease in CAT score represents an improvement in health status, whereas an increase in CAT score represents a worsening in health status." (NCT04011475)
Timeframe: At index date (Baseline) and at 12 months after index date.
| Intervention | Score on a scale (Mean) |
|---|---|
| Tiotropium+Olodaterol (Group A) | 0.0 |
| Other Long-Acting Beta-Agonist (LABA)+Long-Acting Muscarinic Antagonist (LAMA) (Group B) | 1.0 |
| Long-Acting Muscarinic Antagonist (LAMA) (Group C) | 2.4 |
"Change from baseline in pulmonary function after Long-Acting Beta-Agonist (LABA)+Long-Acting Muscarinic Antagonist (LAMA) (Tiotropium+Olodaterol or other LABA+LAMA therapy) or LAMA initiation evaluating by post-bronchodilatorForced Expiratory Volume in one second (Post-FEV1) at 12 months after index date was reported.~Spirometry was the most common tool to evaluate the lung function of patients with respiratory disease. Among the results of spirometry, post-bronchodilator Forced Expiratory Volume in one second was used for assisting in the diagnosis, determining disease severity, and following up the prognosis." (NCT04011475)
Timeframe: At index date (Baseline) and at 12 months after index date.
| Intervention | milliliter (Mean) |
|---|---|
| Tiotropium+Olodaterol (Group A) | -142.0 |
| Other Long-Acting Beta-Agonist (LABA)+Long-Acting Muscarinic Antagonist (LAMA) (Group B) | 20.0 |
| Long-Acting Muscarinic Antagonist (LAMA) (Group C) | -2.1 |
10 Questions regarding the Ease of Handling were asked, using a 7 point scale ranging from 1 (very dissatisfied) to 7 (very satisfied). Reported is the number of patients by answer category. (NCT04011735)
Timeframe: At follow-up assessment, 4 to 6 weeks after baseline.
| Intervention | Participants (Count of Participants) | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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| Q1: How satisfied are you with the ease of removing the clear base?72503453 | Q1: How satisfied are you with the ease of removing the clear base?72503454 | Q1: How satisfied are you with the ease of removing the clear base?72503455 | Q2: How satisfied are you with the grip of the cartridge?72503453 | Q2: How satisfied are you with the grip of the cartridge?72503454 | Q2: How satisfied are you with the grip of the cartridge?72503455 | Q3: How satisfied are you with inserting a new cartridge?72503454 | Q3: How satisfied are you with inserting a new cartridge?72503455 | Q3: How satisfied are you with inserting a new cartridge?72503453 | Q4: How satisfied are you with the readability of the dose indicator?72503454 | Q4: How satisfied are you with the readability of the dose indicator?72503455 | Q4: How satisfied are you with the readability of the dose indicator?72503453 | Q5: How satisfied are you with recognising when you need to replace the cartridge?72503453 | Q5: How satisfied are you with recognising when you need to replace the cartridge?72503454 | Q5: How satisfied are you with recognising when you need to replace the cartridge?72503455 | Q6: How satisfied are you with automatic detachment of the clear base when the cartridge is empty?72503454 | Q6: How satisfied are you with automatic detachment of the clear base when the cartridge is empty?72503453 | Q6: How satisfied are you with automatic detachment of the clear base when the cartridge is empty?72503455 | Q7: How satisfied are you with automatic return to start-use position when replacing the clear base?72503454 | Q7: How satisfied are you with automatic return to start-use position when replacing the clear base?72503455 | Q7: How satisfied are you with automatic return to start-use position when replacing the clear base?72503453 | Q8: How satisfied are you with the overall ease of handling the inhaler?72503453 | Q8: How satisfied are you with the overall ease of handling the inhaler?72503454 | Q8: How satisfied are you with the overall ease of handling the inhaler?72503455 | Q9: How satisfied are you with the sustainability concept of the inhaler, due to re-use ability?72503454 | Q9: How satisfied are you with the sustainability concept of the inhaler, due to re-use ability?72503453 | Q9: How satisfied are you with the sustainability concept of the inhaler, due to re-use ability?72503455 | Q10: How satisfied are you with recognising when to replace the inhaler?72503453 | Q10: How satisfied are you with recognising when to replace the inhaler?72503454 | Q10: How satisfied are you with recognising when to replace the inhaler?72503455 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Very satisfied | Not applicable | Very dissatisfied | Dissatisfied | Somewhat dissatisfied | Neither satisfied nor dissatisfied | Somewhat satisfied | Satisfied | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Respimat® SMI-experienced: Maintenance With Re-usable SMI | 0 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Respimat® SMI-experienced: Switching to Re-usable SMI | 3 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Respimat® SMI-experienced: Maintenance With Re-usable SMI | 4 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Respimat® SMI-experienced: Switching to Re-usable SMI | 2 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Respimat® SMI-experienced: Maintenance With Re-usable SMI | 3 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Respimat® SMI-experienced: Switching to Re-usable SMI | 5 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Respimat® SMI-experienced: Maintenance With Re-usable SMI | 5 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Respimat® SMI-experienced: Switching to Re-usable SMI | 4 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Respimat® SMI-experienced: Maintenance With Re-usable SMI | 64 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Respimat® SMI-experienced: Switching to Re-usable SMI | 29 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Respimat® SMI-experienced: Maintenance With Re-usable SMI | 49 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Respimat® SMI-experienced: Switching to Re-usable SMI | 21 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Respimat® SMI-naïve | 21 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Respimat® SMI-experienced: Switching to Re-usable SMI | 0 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Respimat® SMI-experienced: Maintenance With Re-usable SMI | 2 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Respimat® SMI-experienced: Maintenance With Re-usable SMI | 6 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Respimat® SMI-naïve | 4 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Respimat® SMI-experienced: Maintenance With Re-usable SMI | 66 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Respimat® SMI-experienced: Switching to Re-usable SMI | 38 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Respimat® SMI-naïve | 31 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Respimat® SMI-experienced: Maintenance With Re-usable SMI | 51 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Respimat® SMI-experienced: Switching to Re-usable SMI | 23 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Respimat® SMI-experienced: Switching to Re-usable SMI | 6 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Respimat® SMI-experienced: Maintenance With Re-usable SMI | 10 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Respimat® SMI-experienced: Maintenance With Re-usable SMI | 57 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Respimat® SMI-experienced: Switching to Re-usable SMI | 31 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Respimat® SMI-experienced: Maintenance With Re-usable SMI | 47 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Respimat® SMI-experienced: Switching to Re-usable SMI | 17 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Respimat® SMI-naïve | 14 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Respimat® SMI-experienced: Maintenance With Re-usable SMI | 62 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Respimat® SMI-experienced: Switching to Re-usable SMI | 27 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Respimat® SMI-naïve | 34 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Respimat® SMI-experienced: Maintenance With Re-usable SMI | 53 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Respimat® SMI-experienced: Switching to Re-usable SMI | 35 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Respimat® SMI-naïve | 15 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Respimat® SMI-experienced: Maintenance With Re-usable SMI | 65 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Respimat® SMI-experienced: Maintenance With Re-usable SMI | 52 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Respimat® SMI-experienced: Switching to Re-usable SMI | 28 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Respimat® SMI-naïve | 2 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Respimat® SMI-naïve | 33 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Respimat® SMI-experienced: Maintenance With Re-usable SMI | 43 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Respimat® SMI-experienced: Switching to Re-usable SMI | 19 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Respimat® SMI-naïve | 13 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Respimat® SMI-experienced: Switching to Re-usable SMI | 7 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Respimat® SMI-naïve | 6 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Respimat® SMI-experienced: Maintenance With Re-usable SMI | 69 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Respimat® SMI-naïve | 30 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Respimat® SMI-experienced: Maintenance With Re-usable SMI | 41 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Respimat® SMI-experienced: Switching to Re-usable SMI | 15 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Respimat® SMI-naïve | 17 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Respimat® SMI-naïve | 3 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Respimat® SMI-naïve | 27 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Respimat® SMI-experienced: Switching to Re-usable SMI | 25 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Respimat® SMI-naïve | 22 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Respimat® SMI-naïve | 0 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Respimat® SMI-naïve | 1 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Respimat® SMI-naïve | 5 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Respimat® SMI-experienced: Switching to Re-usable SMI | 26 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Respimat® SMI-naïve | 26 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Respimat® SMI-experienced: Maintenance With Re-usable SMI | 67 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Respimat® SMI-experienced: Switching to Re-usable SMI | 33 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Respimat® SMI-experienced: Maintenance With Re-usable SMI | 1 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Respimat® SMI-experienced: Switching to Re-usable SMI | 1 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Respimat® SMI-experienced: Maintenance With Re-usable SMI | 7 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Respimat® SMI-experienced: Maintenance With Re-usable SMI | 54 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Respimat® SMI-experienced: Switching to Re-usable SMI | 39 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Respimat® SMI-experienced: Maintenance With Re-usable SMI | 56 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Respimat® SMI-experienced: Switching to Re-usable SMI | 20 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
"The convenience domain score of PASAPQ contained 6 items (Question 6-9 and 12-13), each item had response options ranging from 1 (very dissatisfied) to 7 (very satisfied). To calculate the domain score, the items were first summed and then transformed to a 0 (least) to 100 (most) point scale, with higher scores indicating greater satisfaction:~Convenience score = 100 * [(Q6+Q7+Q8+Q9+Q12+Q13)-6] / (42-6)" (NCT04011735)
Timeframe: At follow-up assessment, 4 to 6 weeks after baseline.
| Intervention | Score on a scale (Mean) |
|---|---|
| Respimat® SMI-experienced: Maintenance With Re-usable SMI | 83.74 |
| Respimat® SMI-experienced: Switching to Re-usable SMI | 80.08 |
| Respimat® SMI-naïve | 84.24 |
"The performance domain score of PASAPQ contained 7 items (Q 1-5 and 10-11), each item had response options ranging from 1 (very dissatisfied) to 7 (very satisfied). To calculate the domain score, the items were first summed and then transformed to a 0 (least) to 100 (most) point scale, with higher scores indicating greater satisfaction:~Performance score = 100 * [(Q1+ Q2+Q3+Q4+Q5+Q10+Q11)-7] / (49-7)" (NCT04011735)
Timeframe: At follow-up assessment, 4 to 6 weeks after baseline.
| Intervention | Score on a scale (Mean) |
|---|---|
| Respimat® SMI-experienced: Maintenance With Re-usable SMI | 84.70 |
| Respimat® SMI-experienced: Switching to Re-usable SMI | 82.88 |
| Respimat® SMI-naïve | 82.38 |
"To assess the willingness to continue with inhaler, the following questions was asked: How would you feel about continuing to use the inhaler?, using a value from 0-100, with zero indicating that the patient is not willing to continue using the inhaler and 100 indicating that the patient is definitely willing to continue using the inhaler." (NCT04011735)
Timeframe: At follow-up assessment, 4 to 6 weeks after baseline.
| Intervention | Score on a scale (Mean) |
|---|---|
| Respimat® SMI-experienced: Maintenance With Re-usable SMI | 89.1 |
| Respimat® SMI-experienced: Switching to Re-usable SMI | 88.0 |
| Respimat® SMI-naïve | 84.1 |
"Total PASAPQ score is a measure of patient's satisfaction regarding the handling of the re-usable Respimat® SMI. The total score was the sum of the 13 items related to Performance and Convenience PASAPG domains (7 items for Performance domain: Q 1-5, 10-11, and 6 items for convenience domain: Q6-9, 12-13).~Each PASAPQ item had response options ranging from 1 (very dissatisfied) to 7 (very satisfied). To calculate the total and domain score, the items within each domain were first summed and then transformed to a 0 (least) or 100 (most) point scale, with higher scores indicating greater satisfaction:~Performance score = 100 *[(Q1+Q2 +Q3+ Q4+Q5+Q10+Q11)-7] /(49-7)~Convenience score = 100 *[(Q6+ Q7+Q8+Q9+Q12+Q13)-6] / (42-6)~Total score = 100 *[(Q1+Q2 +Q3+Q4+ Q5+Q6 + Q7+Q8+ Q9+Q10+Q11+Q12+Q13)-13] / (91-13)" (NCT04011735)
Timeframe: At follow-up assessment, 4 to 6 weeks after baseline.
| Intervention | Score on a scale (Mean) |
|---|---|
| Respimat® SMI-experienced: Maintenance With Re-usable SMI | 84.26 |
| Respimat® SMI-experienced: Switching to Re-usable SMI | 81.59 |
| Respimat® SMI-naïve | 83.24 |
"Difference in the mean Total PASAPQ score between study entry (baseline visit) and at study end (follow-up assessment) in Respimat SMI-experienced patients who switched from a disposable to a re-usable Respimat SMI product at study entry.~The total score was the sum of the 13 items related to Performance and Convenience PASAPG domains (7 items for Performance domain: Q 1-5, 10-11, and 6 items for convenience domain: Q6-9, 12-13).~Each PASAPQ item had response options ranging from 1 (very dissatisfied) to 7 (very satisfied). To calculate the total and domain score, the items within each domain were first summed and then transformed to a 0 (least) or 100 (most) point scale, with higher scores indicating greater satisfaction." (NCT04011735)
Timeframe: At study entry (baseline) and at study end (4 to 6 weeks after baseline).
| Intervention | Score on a scale (Mean) |
|---|---|
| Respimat® SMI-experienced: Switching to Re-usable SMI | 1.10 |
"Incidence rate of Chronic Obstructive Pulmonary Disease (COPD) exacerbation after cohort entry. The event was defined as follows:~Severe exacerbation: Hospitalization with a principal discharge diagnosis of COPD.~or Moderate exacerbation: An emergency department (ED) visit with a discharge diagnosis of COPD, or, an antibiotic for a respiratory condition dispensed the same day as an oral corticosteroid." (NCT04138758)
Timeframe: From cohort entry (index date) until the occurrence of a hospitalization for COPD (severe exacerbation), ED visit for COPD or prescription of an antibiotic and oral corticosteroid on the same day (moderate exacerbation). Up to one year after cohort entry.
| Intervention | Events per 1,000 Person-days (Number) |
|---|---|
| Tiotropium + Olodaterol | 1.63 |
| Long-acting Beta Agonist / Inhaled Corticosteroid Therapy | 2.43 |
"Incidence rate of any element of a composite outcome including exacerbation, hospitalization for pneumonia, or escalation (alternative case definition) to triple therapy.~Exacerbation was defined as follows: Severe exacerbation: Hospitalization with a principal discharge diagnosis of COPD. Moderate exacerbation: An emergency department (ED) visit with a discharge diagnosis of COPD, or, an antibiotic for a respiratory condition dispensed the same day as an oral corticosteroid.~Pneumonia was defined using ICD-9-CM diagnoses and ICD-10 diagnosis codes. Escalation was defined as the initiation of any treatment including simultaneous LABA (long-acting beta agonist) /LAMA (Long-acting Muscarinic Antagonists) /ICS (inhaled corticosteroid therapy) use in free or fixed combination." (NCT04138758)
Timeframe: From cohort entry (index date) until exacerbation, hospitalization (for community-acquired pneumonia) or escalation, up to one year after cohort entry.
| Intervention | events per 1,000 Person-days (Number) |
|---|---|
| Tiotropium + Olodaterol | 2.16 |
| Long-acting Beta Agonist / Inhaled Corticosteroid Therapy | 5.67 |
"Incidence rate of any element of a composite outcome including exacerbation, hospitalization for pneumonia, or escalation (original case definition) to triple therapy.~Exacerbation was defined as follows: Severe exacerbation: Hospitalization with a principal discharge diagnosis of COPD. Moderate exacerbation: An emergency department (ED) visit with a discharge diagnosis of COPD, or, an antibiotic for a respiratory condition dispensed the same day as an oral corticosteroid.~Pneumonia was defined using ICD-9-CM diagnoses and ICD-10 diagnosis codes. Escalation was defined as the addition of Inhaled Corticosteroids to Tiotropium and Olodaterol or a Long-acting Muscarinic Antagonists to long-acting beta agonist / inhaled corticosteroid therapy." (NCT04138758)
Timeframe: From cohort entry (index date) until exacerbation, hospitalization (for community-acquired pneumonia) or escalation, up to one year after cohort entry.
| Intervention | events per 1,000 Person-days (Number) |
|---|---|
| Tiotropium + Olodaterol | 2.14 |
| Long-acting Beta Agonist / Inhaled Corticosteroid Therapy | 5.45 |
Incidence rate of first hospitalization for community-acquired pneumonia (serious pneumonia). Pneumonia was defined using ICD-9-CM diagnoses and ICD-10 diagnosis codes. (NCT04138758)
Timeframe: From cohort entry (index date) until the occurrence of first hospitalization for community-acquired pneumonia (serious pneumonia). Up to one year after cohort entry.
| Intervention | events per 1,000 Person-days (Number) |
|---|---|
| Tiotropium + Olodaterol | 0.23 |
| Long-acting Beta Agonist / Inhaled Corticosteroid Therapy | 0.34 |
"Incidence rate of the first date of a pharmacy dispensing indicating escalation to triple therapy.~Based on feedback from clinical experts during review of study results, an alternative post-hoc definition was also assessed in which initiation of any treatment including simultaneous LABA (long-acting beta agonist) /LAMA (Long-acting Muscarinic Antagonists) /ICS (inhaled corticosteroid therapy) use in free or fixed combination was counted as an outcome." (NCT04138758)
Timeframe: From cohort entry (index date) until the escalation, up to one year after cohort entry.
| Intervention | events per 1,000 Person-days (Number) |
|---|---|
| Tiotropium + Olodaterol | 0.57 |
| Long-acting Beta Agonist / Inhaled Corticosteroid Therapy | 3.14 |
Incidence rate of the first date of a pharmacy dispensing indicating escalation to triple therapy, (i.e., addition of Inhaled Corticosteroids to Tiotropium and Olodaterol or a Long-acting Muscarinic Antagonists to long-acting beta agonist / inhaled corticosteroid therapy). (NCT04138758)
Timeframe: From cohort entry (index date) until the escalation, up to one year after cohort entry.
| Intervention | events per 1,000 Person-days (Number) |
|---|---|
| Tiotropium + Olodaterol | 0.54 |
| Long-acting Beta Agonist / Inhaled Corticosteroid Therapy | 2.90 |
"CASI was measured by questionnaire and is a severity score of symptom burden, exacerbations, healthcare utilization, lung function and dose of inhaled corticosteroids. The change in CASI score was calculated between V1 (Baseline), V2 (Guideline Care - before intervention), and V3 (12 Months).~[The CASI score has a minimum value = 0, maximum value = 20, a higher score indicates greater asthma severity]" (NCT04179461)
Timeframe: Baseline to 12 months
| Intervention | score on a scale (Median) | ||
|---|---|---|---|
| V1 | V2 | V3 | |
| Personalized Treatment | 5 | 5 | 5 |
"FEV1 is air volume exhaled in 1 second during spirometry. Forced vital capacity is the amount of air that can be forcibly exhaled from the lungs after taking the deepest breath possible. The change in FEV1/FVC was calculated between V1 (Baseline), V2 (Guideline Care - before intervention), and V3 (12 Months). This will be used as a measurement in asthma severity.~[A lower FEV1/FVC ratio indicates more severe asthma]" (NCT04179461)
Timeframe: Baseline to 12 months
| Intervention | Ratio (Median) | ||
|---|---|---|---|
| V1 | V2 | V3 | |
| Personalized Treatment | 0.81 | 0.8 | 0.8 |
"ACT was measured by questionnaire, assessing frequency of reported asthma symptoms, rescue medication use, the effect of asthma on daily functioning, and overall asthma control. The change in ACT score was calculated between V1 (Baseline), V2 (Guideline Care - before intervention), and V3 (12 Months).~[The ACT score has a minimum value = 5, maximum value = 25, a score 19 indicates well-controlled asthma]" (NCT04179461)
Timeframe: Baseline to 12 months
| Intervention | score on a scale (Median) | ||
|---|---|---|---|
| V1 | V2 | V3 | |
| Personalized Treatment | 23.0 | 21.7 | 22.5 |
Adherence was measured using the Propeller Health Inhaler monitor and web-based software management platform that tracks adherence of asthma medications. The change in adherence was calculated between V1 (baseline) to V3 (12 Months). (NCT04179461)
Timeframe: Baseline to 12 months
| Intervention | percentage of medication taken (Median) | |
|---|---|---|
| V1 | V3 | |
| Personalized Treatment | 42 | 36 |
Incidence rate of Chronic Obstructive Pulmonary Disease (COPD) exacerbation was reported. Time to the first Chronic obstructive pulmonary disease (COPD) exacerbation will be measured from cohort entry until the occurrence of a hospitalization for COPD (severe exacerbation) or Emergency Department (ED) visit for COPD with the prescription of an antibiotic and/or an oral corticosteroid on the same day (moderate exacerbation). (NCT04184297)
Timeframe: From cohort entry (index date) until the occurrence of a hospitalization for COPD (severe exacerbation), ED visit for COPD or prescription of an antibiotic and oral corticosteroid on the same day (moderate exacerbation). Up to 1 year after cohort entry.
| Intervention | Events per 1000 person-days (Number) |
|---|---|
| Tiotropium+Olodaterol | 1.32 |
| LABA/LAMA/ICS | 1.14 |
Incidence rate of Chronic Obstructive Pulmonary Disease (COPD) exacerbation excluding participants who had exacerbation within 30 days prior to cohort entry, was reported. Time to the first Chronic obstructive pulmonary disease (COPD) exacerbation will be measured from cohort entry until the occurrenceof a hospitalization for COPD (severe exacerbation) or Emergency Department (ED) visit for COPD with the prescription of an antibiotic and/or an oral corticosteroid on the same day (moderate exacerbation). (NCT04184297)
Timeframe: From cohort entry (index date) until the occurrence of a hospitalization for COPD (severe exacerbation), ED visit for COPD or prescription of an antibiotic and oral corticosteroid on the same day (moderate exacerbation). Up to 1 year after cohort entry.
| Intervention | Events per 1000 person-days (Number) |
|---|---|
| Tiotropium+Olodaterol | 1.18 |
| LABA/LAMA/ICS | 0.99 |
Overall incidence rate of first hospitalization for community-acquired pneumonia (serious pneumonia). (NCT04184297)
Timeframe: From cohort entry (index date) until the occurrence of hospitalization for community-acquired pneumonia (serious pneumonia). Up to 1 year after cohort entry.
| Intervention | Events per 1000 person-days (Number) |
|---|---|
| Tiotropium+Olodaterol | 0.25 |
| LABA/LAMA/ICS | 0.24 |
Change from baseline in trough Forced Expiratory Volume in one second (FEV1) after 4 weeks of treatment. (NCT04223843)
Timeframe: At baseline and at week 4.
| Intervention | Liter (Mean) |
|---|---|
| Tio+Olo (5μg/5μg) - Sub-optimal PIFR | 0.095 |
| Matching Placebo - Sub-optimal PIFR | -0.106 |
| Tio+Olo (5μg/5μg ) - Optimal PIFR | 0.177 |
| Matching Placebo - Optimal PIFR | -0.040 |
"FEV1 AUC0-3h was calculated as the area under the FEV1-time curve from 0 to 3h post-dose using the trapezoidal rule, divided by the duration (3h) to report in liters. Mean is adjusted mean.~A hierarchical testing procedure was used to test the primary endpoint. Each of the tests were considered confirmatory only if all previous tests were successful." (NCT04223843)
Timeframe: At baseline and at week 4: 10 minutes (min) prior and 5 min, 15 min, 30 min and 1 hour (h), 2h and 3h after drug administration, respectively.
| Intervention | Liter (L) (Mean) |
|---|---|
| Tio+Olo (5μg/5μg) - Sub-optimal PIFR | 0.250 |
| Matching Placebo - Sub-optimal PIFR | -0.086 |
| Tio+Olo (5μg/5μg ) - Optimal PIFR | 0.333 |
| Matching Placebo - Optimal PIFR | 0.012 |
"Time to triple therapy initiation (first event per patient) defined as any fixed dose combination of Long-acting muscarinic antagonists (LAMA) / Long-acting beta agonist (LABA) / Inhaled Corticosteroid (ICS) or any concurrent use for 30 consecutive days of the following:~any LAMA/LABA fixed dose combination + any ICS single formulation~any LAMA single formulation + any LABA/ICS fixed dose combination~any LAMA single formulation + any LABA single formulation + any ICS single formulation.~Patients will be censored if they had an occurrence of any of the following: outcome (initiation of triple therapy), death, or end of data. The analysis will use an intention-to-treat censoring approach, which does not account for treatment change." (NCT04249310)
Timeframe: From index date (cohort entry date) until first occurence of event, up to 42 months.
| Intervention | Days (Mean) |
|---|---|
| Tiotropium/Olodaterol (Spiolto®) | 195.0 |
| Tiotropium (Spiriva®) | 89.5 |
"Number of Moderate or Severe Chronic Obstructive Pulmonary Disease (COPD) Exacerbations.~Moderate exacerbation is defined as an outpatient visit with a diagnosed code for COPD in any field + a prescription for an oral corticosteroid or an antibiotic for respiratory infections. Severe exacerbations will be defined as a hospitalization with a primary diagnosis for COPD.~Patients will be censored if they had an occurrence of any of the following: outcome (initiation of triple therapy), death, or end of data. The analysis will use an intention-to-treat censoring approach, which does not account for treatment change." (NCT04249310)
Timeframe: From index date until first occurence of event, up to 42 months.
| Intervention | Number of Exacerbations (Mean) | ||
|---|---|---|---|
| Moderate or Severe Exacerbations | Moderate Exacerbations | Severe Exacerbations | |
| Tiotropium (Spiriva®) | 0.08 | 0.04 | 0.05 |
| Tiotropium/Olodaterol (Spiolto®) | 0.08 | 0.04 | 0.05 |
"Time to First Moderate or Severe COPD Exacerbation. Moderate exacerbation is defined as an outpatient visit with a diagnosed code for COPD in any field + a prescription for an oral corticosteroid or an antibiotic for respiratory infections. Severe exacerbations will be defined as a hospitalization with a primary diagnosis for COPD.~Patients will be censored if they had an occurrence of any of the following: outcome (initiation of triple therapy), death, or end of data. The analysis will use an intention-to-treat censoring approach, which does not account for treatment change." (NCT04249310)
Timeframe: From index date until first occurence of event, up to 42 months.
| Intervention | Days (Mean) | ||
|---|---|---|---|
| Moderate or Severe | Moderate Exacerbation | Severe Exacerbation | |
| Tiotropium (Spiriva®) | 118.8 | 139.0 | 134.5 |
| Tiotropium/Olodaterol (Spiolto®) | 116.3 | 125.6 | 134.0 |
Days of missed medication for COPD is reported. (NCT04672941)
Timeframe: up to 3 months
| Intervention | days (Mean) |
|---|---|
| COPD Patients | 1.55 |
Overall satisfaction according to Question 14 of PASAPQ (Part 1). Question 14 of PASAPQ has a score range from 1= very dissatisfied to 7 = very satisfied. (NCT04672941)
Timeframe: At 3 months after baseline.
| Intervention | Score on a scale (Mean) |
|---|---|
| COPD Patients | 6.15 |
Calculated from questions 1 to 13 in Part 1 of the PASAPQ. All questions in PASAPQ were answered on a 7-point scale ranging from 1= very dissatisfied to 7 = very satisfied. To calculate the total score, the sum of the 13 items of the two domains (performance and convenience) was transformed to a 0- (least) to 100- (most) point scale which is scaled positively: higher scores represent higher levels of satisfaction. (NCT04672941)
Timeframe: At 3 months after baseline.
| Intervention | Score on a scale (Mean) |
|---|---|
| COPD Patients | 78.74 |
According to Part 2 of the PASAPQ; willingness to continue is self-reported by the patient by providing a single value between 1 and 100. 0 indicates that the patient is not willing to continue using the inhaler and 100 indicates that the patient is definitely willing to continue. (NCT04672941)
Timeframe: At 3 months after baseline.
| Intervention | Score on a scale (Mean) |
|---|---|
| COPD Patients | 88.39 |
The CAT is a patient-completed questionnaire assessing globally the impact of COPD on health status. It contains 8 items, where each item has a score range from 0 to 5. The CAT score is calculated by summing up the scores from the 8 items. CAT score ranges from 0 to 40. Higher score denotes a more severe impact of COPD on a patient's life. CAT score <10 corresponding to mild impact on patients life is usually considered representing patients without impaired health status. (NCT04672941)
Timeframe: At baseline and at 3 months after baseline.
| Intervention | Score on a scale (Mean) | |
|---|---|---|
| Baseline | Change from baseline | |
| COPD Patients | 18.41 | -5.25 |
Percentage of patients by preference for inhaler according to Part 2 of the PASAPQ is reported. (NCT04672941)
Timeframe: At 3 months after baseline.
| Intervention | Percentage of participants (Number) | ||
|---|---|---|---|
| Spiriva® Handihaler® | Spiolto® Respimat® | No preference | |
| COPD Patients | 4.06 | 87.09 | 8.85 |
Adherence is measured with the Simplified Medication Adherence Questionnaire (SMAQ), which is a short questionnaire including 6 questions, that assess patient adherence to the medication. (NCT04672941)
Timeframe: At 3 months after baseline.
| Intervention | Percentage of participants (Number) | |
|---|---|---|
| Yes | No | |
| COPD Patients | 67.20 | 32.80 |
EQ-5D-5L descriptive system comprises of 5 dimensions-mobility, self-care, usual activities, pain/discomfort & anxiety/depression. Each dimension has 5 levels: not at all (level 1), mild (level 2), moderate (level 3), severe (level 4), extreme/leading to incapacity (level 5), with highest level corresponding to worst outcome. Subjects had to indicate their health state by choosing the appropriate level from each dimension. The dimension for anxiety/depression is reported in this endpoint. (NCT04672941)
Timeframe: At baseline and at 3 months after baseline.
| Intervention | Percentage of participants (Number) | |
|---|---|---|
| Improvement compared to baseline | Deterioration compared to baseline | |
| COPD Patients | 43.27 | 4.01 |
EQ-5D-5L descriptive system comprises of 5 dimensions-mobility, self-care, usual activities, pain/discomfort & anxiety/depression. Each dimension has 5 levels: not at all (level 1), mild (level 2), moderate (level 3), severe (level 4), extreme/leading to incapacity (level 5), with highest level corresponding to worst outcome. Subjects had to indicate their health state by choosing the appropriate level from each dimension. The dimension for self-care is reported in this endpoint. (NCT04672941)
Timeframe: At baseline and at 3 months after baseline.
| Intervention | Percentage of participants (Number) | |
|---|---|---|
| Improvement compared to baseline | Deterioration compared to baseline | |
| COPD Patients | 30.59 | 3.80 |
EQ-5D-5L descriptive system comprises of 5 dimensions-mobility, self-care, usual activities, pain/discomfort & anxiety/depression. Each dimension has 5 levels: not at all (level 1), mild (level 2), moderate (level 3), severe (level 4), extreme/leading to incapacity (level 5), with highest level corresponding to worst outcome. Subjects had to indicate their health state by choosing the appropriate level from each dimension. The dimension for pain/discomfort is reported in this endpoint. (NCT04672941)
Timeframe: At baseline and at 3 months after baseline.
| Intervention | Percentage of participants (Number) | |
|---|---|---|
| Improvement compared to baseline | Deterioration compared to baseline | |
| COPD Patients | 43.55 | 4.87 |
EQ-5D-5L descriptive system comprises of 5 dimensions-mobility, self-care, usual activities, pain/discomfort & anxiety/depression. Each dimension has 5 levels: not at all (level 1), mild (level 2), moderate (level 3), severe (level 4), extreme/leading to incapacity (level 5), with highest level corresponding to worst outcome. Subjects had to indicate their health state by choosing the appropriate level from each dimension. The dimension for usual activities is reported in this endpoint. (NCT04672941)
Timeframe: At baseline and at 3 months after baseline.
| Intervention | Percentage of participants (Number) | |
|---|---|---|
| Improvement compared to baseline | Deterioration compared to baseline | |
| COPD Patients | 43.62 | 4.08 |
EQ-5D-5L descriptive system comprises of 5 dimensions-mobility, self-care, usual activities, pain/discomfort & anxiety/depression. Each dimension has 5 levels: not at all (level 1), mild (level 2), moderate (level 3), severe (level 4), extreme/leading to incapacity (level 5), with highest level corresponding to worst outcome. Subjects had to indicate their health state by choosing the appropriate level from each dimension. The dimension for mobility is reported in this endpoint. (NCT04672941)
Timeframe: At baseline and at 3 months after baseline.
| Intervention | Percentage of participants (Number) | |
|---|---|---|
| Improvement compared to baseline | Deterioration compared to baseline | |
| COPD Patients | 44.27 | 2.87 |
Number of patients adherence to medication of COPD patients according to the Simplified Medication Adherence Questionnaire (SMAQ) three-months after the switch is reported. (NCT04672941)
Timeframe: At 3 months after baseline.
| Intervention | Participants (Count of Participants) | |||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Forget to take the medication for COPD72504161 | Always take your medication for COPD at the indicated time72504161 | If feel worse, do you stop taking the medication for COPD?72504161 | At the last weekend, did you miss your medication?72504161 | |||||||||
| Missing | Yes | No | ||||||||||
| COPD Patients | 154 | |||||||||||
| COPD Patients | 1162 | |||||||||||
| COPD Patients | 1030 | |||||||||||
| COPD Patients | 286 | |||||||||||
| COPD Patients | 40 | |||||||||||
| COPD Patients | 41 | |||||||||||
| COPD Patients | 1275 | |||||||||||
| COPD Patients | 53 | |||||||||||
| COPD Patients | 1263 | |||||||||||
The CAT is a patient-completed questionnaire assessing globally the impact of COPD on health status. It contains 8 items, where each item has a score range from 0 to 5. The CAT score is calculated by summing up the scores from the 8 items. CAT score ranges from 0 to 40. Higher score denotes a more severe impact of COPD on a patient's life. CAT score <10 corresponding to mild impact on patient's life is usually considered representing patients without impaired health status. CAT≥10 refers to impaired health status. The percentages of patients with CAT CAT≥10 at baseline and at Month 3 were reported below. (NCT04672941)
Timeframe: At baseline and at 3 months after baseline.
| Intervention | Percentage of participants (Number) |
|---|---|
| COPD Patients - Baseline | 91.76 |
| COPD Patients - Month 3 | 66.12 |
The EQ VAS records the patient's self-rated health on a vertical visual analogue scale. EQ-VAS score ranges from 0 to 100 where 0 represents the worst state the patient can imagine and 100 the best. Higher scores indicated better health state. (NCT04672941)
Timeframe: At baseline and at 3 months after baseline.
| Intervention | Score on a scale (Mean) |
|---|---|
| COPD Patients | 11.44 |
mMRC is a five-level rating scale ranging from 0 to 4 based on the patient's perception of dyspnea in daily activities. A higher score indicates a higher grade of breathlessness. (NCT04672941)
Timeframe: At baseline and at 3 months after baseline.
| Intervention | Score on a scale (Mean) |
|---|---|
| COPD Patients | -0.55 |
The Charlson Comorbidity Index (CCI) was a method of categorizing comorbidities of patients based on the International Classification of Diseases diagnosis. The CCI score ranged from 0 (better outcome) to 21 (worse outcome). The higher the score, the more fragile/ill the patient was. (NCT04926233)
Timeframe: At index date of the first maintenance treatment
| Intervention | Score on a scale (Mean) |
|---|---|
| US IBM Marketscan - 1MT - Overall | 2.0 |
| US IBM Marketscan - 1MT - ICS | 2.0 |
| US IBM Marketscan - 1MT - LABA | 2.0 |
| US IBM Marketscan - 1MT - LABA+ICS | 2.0 |
| US IBM Marketscan - 1MT - LAMA+LABA | 2.0 |
| US IBM Marketscan - 1MT - LAMA+LABA+ICS | 2.0 |
| US IBM Marketscan - 1MT - LAMA | 2.0 |
| US IBM Marketscan - 1MT - LAMA+ICS | 2.0 |
The Charlson Comorbidity Index (CCI) was a method of categorizing comorbidities of patients based on the International Classification of Diseases diagnosis. The CCI score ranged from 0 (better outcome) to 21 (worse outcome). The higher the score, the more fragile/ill the patient was. (NCT04926233)
Timeframe: At index date of cohort entry (baseline; time of COPD diagnosis).
| Intervention | Score on a scale (Mean) |
|---|---|
| US IBM Marketscan - Overall | 1.6 |
| US IBM Marketscan - COPD Diagnosis Before Tio+Olo Approval | 1.5 |
| US IBM Marketscan - COPD Diagnosis After Tio+Olo Approval | 1.9 |
| UK CPRD GOLD - Overall | 1.89 |
| UK CPRD GOLD - COPD Diagnosis Before Tio+Olo Approval | 1.83 |
| UK CPRD GOLD - COPD Diagnosis After Tio+Olo Approval | 2.31 |
Age of the chronic obstructive pulmonary disease (COPD) patients at the time of COPD diagnosis from the United States (US) IBM MarketScan was reported by groups stratified according to their COPD diagnosis times (Before versus after the approval of Tiotropium + Olodaterol in 2015). (NCT04926233)
Timeframe: At index date of cohort entry (baseline; time of COPD diagnosis).
| Intervention | Years (Mean) |
|---|---|
| US IBM Marketscan - COPD Diagnosis Before Tio+Olo Approval | 65.6 |
| US IBM Marketscan - COPD Diagnosis After Tio+Olo Approval | 64.4 |
Age of patients receiving first maintenance treatment from chronic obstructive pulmonary disease (COPD) patients initiated their first maintenance therapy in the United Kingdom (UK) CPRD GOLD database was reported. (NCT04926233)
Timeframe: At index date of the first maintenance treatment
| Intervention | Years (Median) |
|---|---|
| UK CPRD GOLD - 1MT - Overall | 68.0 |
| UK CPRD GOLD - 1MT - ICS | 67.0 |
| UK CPRD GOLD - 1MT - LABA | 67.0 |
| UK CPRD GOLD - 1MT - LABA+ICS | 67.0 |
| UK CPRD GOLD - 1MT - LAMA+LABA | 68.0 |
| UK CPRD GOLD - 1MT - LAMA+LABA+ICS | 70.0 |
| UK CPRD GOLD - 1MT - LAMA | 68.0 |
| UK CPRD GOLD - 1MT - LAMA+ICS | 69.0 |
The Charlson Comorbidity Index (CCI) was a method of categorizing comorbidities of patients based on the International Classification of Diseases diagnosis. The CCI score ranged from 0 (better outcome) to 21 (worse outcome). The higher the score, the more fragile/ill the patient was. (NCT04926233)
Timeframe: At index date of the second maintenance treatment
| Intervention | Score on a scale (Median) |
|---|---|
| US IBM Marketscan - 2MT - Overall | 2.0 |
| US IBM Marketscan - 2MT - ICS | 2.0 |
| US IBM Marketscan - 2MT - LABA | 3.0 |
| US IBM Marketscan - 2MT - LABA+ICS | 2.0 |
| US IBM Marketscan - 2MT - LAMA+LABA | 2.0 |
| US IBM Marketscan - 2MT - LAMA+LABA+ICS | 2.0 |
| US IBM Marketscan - 2MT - LAMA | 3.0 |
| US IBM Marketscan - 2MT - LAMA+ICS | 2.0 |
Age of chronic obstructive pulmonary disease (COPD) patients initiated their first maintenance therapy in the United States (US) IBM MarketScan database was reported. (NCT04926233)
Timeframe: At index date of the first maintenance treatment
| Intervention | Years (Mean) |
|---|---|
| US IBM Marketscan - 1MT - Overall | 63.0 |
| US IBM Marketscan - 1MT - ICS | 62.0 |
| US IBM Marketscan - 1MT - LABA | 67.0 |
| US IBM Marketscan - 1MT - LABA+ICS | 62.0 |
| US IBM Marketscan - 1MT - LAMA+LABA | 62.0 |
| US IBM Marketscan - 1MT - LAMA+LABA+ICS | 63.0 |
| US IBM Marketscan - 1MT - LAMA | 64.0 |
| US IBM Marketscan - 1MT - LAMA+ICS | 65.0 |
Days between index and initiation of first maintenance therapy among the chronic obstructive pulmonary disease (COPD) patients initiated their first maintenance therapy in the United Kingdom (UK) CPRD GOLD database were reported. (NCT04926233)
Timeframe: From index date until initiation of first maintenance therapy, up to 9795 days before this study started.
| Intervention | Days (Median) |
|---|---|
| UK CPRD GOLD - 1MT - Overall | 28.5 |
| UK CPRD GOLD - 1MT - ICS | 708.0 |
| UK CPRD GOLD - 1MT - LABA | 43.5 |
| UK CPRD GOLD - 1MT - LABA+ICS | 32.0 |
| UK CPRD GOLD - 1MT - LAMA+LABA | 19.0 |
| UK CPRD GOLD - 1MT - LAMA+LABA+ICS | 19.0 |
| UK CPRD GOLD - 1MT - LAMA | 22.0 |
| UK CPRD GOLD - 1MT - LAMA+ICS | 19.0 |
Days between index and initiation of first maintenance therapy among the chronic obstructive pulmonary disease (COPD) patients initiated their first maintenance therapy the United States (US) IBM MarketScan database was reported. (NCT04926233)
Timeframe: From index date until initiation of first maintenance, up to 3368 days before this study started.
| Intervention | Days (Median) |
|---|---|
| US IBM Marketscan - 1MT - Overall | 158.0 |
| US IBM Marketscan - 1MT - ICS | 242.0 |
| US IBM Marketscan - 1MT - LABA | 233.0 |
| US IBM Marketscan - 1MT - LABA+ICS | 165.0 |
| US IBM Marketscan - 1MT - LAMA+LABA | 116.0 |
| US IBM Marketscan - 1MT - LAMA+LABA+ICS | 78.0 |
| US IBM Marketscan - 1MT - LAMA | 136.0 |
| US IBM Marketscan - 1MT - LAMA+ICS | 85.0 |
Days between first and second maintenance therapy among chronic obstructive pulmonary disease (COPD) patients initiated their second maintenance therapy in the United Kingdom (UK) CPRD GOLD database were reported. (NCT04926233)
Timeframe: From the index date of first maintenance initiation until the initiation of the second maintenance therapy, up to 10133 days before this study started.
| Intervention | Days (Median) |
|---|---|
| UK CPRD GOLD - 2MT - Overall | 218.0 |
| UK CPRD GOLD - 2MT - ICS | 239.5 |
| UK CPRD GOLD - 2MT - LABA | 141.0 |
| UK CPRD GOLD - 2MT - LABA+ICS | 155.5 |
| UK CPRD GOLD - 2MT - LAMA+LABA | 284.0 |
| UK CPRD GOLD - 2MT - LAMA+LABA+ICS | 197.0 |
| UK CPRD GOLD - 2MT - LAMA | 225.5 |
| UK CPRD GOLD - 2MT - LAMA+ICS | 158.0 |
Number of participants with zero exacerbations in the year prior to the start of second maintenance therapy among chronic obstructive pulmonary disease (COPD) patients initiated their second maintenance therapy in the United Kingdom (UK) CPRD GOLD database was reported. (NCT04926233)
Timeframe: At index date of the second maintenance treatment
| Intervention | Participants (Count of Participants) |
|---|---|
| UK CPRD GOLD - 2MT - Overall | 1351 |
| UK CPRD GOLD - 2MT - ICS | 34 |
| UK CPRD GOLD - 2MT - LABA | 63 |
| UK CPRD GOLD - 2MT - LABA+ICS | 172 |
| UK CPRD GOLD - 2MT - LAMA+LABA | 590 |
| UK CPRD GOLD - 2MT - LAMA+LABA+ICS | 299 |
| UK CPRD GOLD - 2MT - LAMA | 144 |
| UK CPRD GOLD - 2MT - LAMA+ICS | 49 |
Number of participants with zero exacerbations in the year prior to the start of second maintenance therapy among the chronic obstructive pulmonary disease (COPD) patients initiated their second maintenance therapy the United States (US) IBM MarketScan database was reported. (NCT04926233)
Timeframe: At index date of the second maintenance treatment
| Intervention | Participants (Count of Participants) |
|---|---|
| US IBM Marketscan - 2MT - Overall | 2361 |
| US IBM Marketscan - 2MT - ICS | 226 |
| US IBM Marketscan - 2MT - LABA | 29 |
| US IBM Marketscan - 2MT - LABA+ICS | 684 |
| US IBM Marketscan - 2MT - LAMA+LABA | 426 |
| US IBM Marketscan - 2MT - LAMA+LABA+ICS | 505 |
| US IBM Marketscan - 2MT - LAMA | 451 |
| US IBM Marketscan - 2MT - LAMA+ICS | 40 |
Characteristics of patients receiving first maintenance treatment from chronic obstructive pulmonary disease (COPD) patients initiated their first maintenance therapy in the United Kingdom (UK) CPRD GOLD database were reported. (NCT04926233)
Timeframe: At index date of the first maintenance treatment
| Intervention | Participants (Count of Participants) | |||
|---|---|---|---|---|
| Upper respiratory tract infection | Lower respiratory tract infection (not pneumonia) | Concomitant medications - Oral corticosteroids | Concomitant medications - Oral antibiotics | |
| UK CPRD GOLD - 1MT - ICS | 454 | 501 | 207 | 480 |
| UK CPRD GOLD - 1MT - LABA | 166 | 220 | 87 | 204 |
| UK CPRD GOLD - 1MT - LABA+ICS | 545 | 721 | 453 | 796 |
| UK CPRD GOLD - 1MT - LAMA | 1946 | 2486 | 1140 | 2624 |
| UK CPRD GOLD - 1MT - LAMA+ICS | 7 | 11 | 6 | 8 |
| UK CPRD GOLD - 1MT - LAMA+LABA | 541 | 732 | 353 | 797 |
| UK CPRD GOLD - 1MT - LAMA+LABA+ICS | 143 | 164 | 121 | 224 |
| UK CPRD GOLD - 1MT - Overall | 3802 | 4835 | 2367 | 5133 |
Characteristics of patients receiving first maintenance treatment among chronic obstructive pulmonary disease (COPD) patients initiated their first maintenance therapy in the United States (US) IBM MarketScan database were reported. (NCT04926233)
Timeframe: At index date of the first maintenance treatment
| Intervention | Participants (Count of Participants) | |||||||
|---|---|---|---|---|---|---|---|---|
| Upper respiratory tract infection | Lower respiratory tract infection | Pneumonia | Chronic bronchitis | Lung fibrosis | Concomitant medications - Oral corticosteroids | Concomitant medications - Oral antibiotics | Concomitant medications - Oxygen therapy | |
| US IBM Marketscan - 1MT - ICS | 2114 | 1160 | 1253 | 603 | 239 | 3172 | 5047 | 425 |
| US IBM Marketscan - 1MT - LABA | 87 | 46 | 77 | 42 | 22 | 152 | 249 | 57 |
| US IBM Marketscan - 1MT - LABA+ICS | 7151 | 4577 | 4762 | 2642 | 882 | 12240 | 19168 | 2094 |
| US IBM Marketscan - 1MT - LAMA | 2299 | 1474 | 2160 | 1066 | 405 | 3959 | 7116 | 1058 |
| US IBM Marketscan - 1MT - LAMA+ICS | 34 | 16 | 29 | 12 | 5 | 50 | 96 | 16 |
| US IBM Marketscan - 1MT - LAMA+LABA | 1632 | 885 | 1014 | 502 | 207 | 2770 | 4645 | 625 |
| US IBM Marketscan - 1MT - LAMA+LABA+ICS | 486 | 367 | 651 | 294 | 108 | 929 | 1508 | 305 |
| US IBM Marketscan - 1MT - Overall | 13803 | 8525 | 9946 | 5161 | 1868 | 23272 | 37829 | 4580 |
Characteristics of patients receiving second maintenance treatment from chronic obstructive pulmonary disease (COPD) patients initiated their second maintenance therapy in the United Kingdom (UK) CPRD GOLD database were reported. (NCT04926233)
Timeframe: At index date of the second maintenance treatment
| Intervention | Participants (Count of Participants) | |
|---|---|---|
| Male | Concomitant medications - Oral corticosteroids | |
| UK CPRD GOLD - 2MT - ICS | 31 | 25 |
| UK CPRD GOLD - 2MT - LABA | 51 | 36 |
| UK CPRD GOLD - 2MT - LABA+ICS | 191 | 152 |
| UK CPRD GOLD - 2MT - LAMA | 127 | 71 |
| UK CPRD GOLD - 2MT - LAMA+ICS | 37 | 41 |
| UK CPRD GOLD - 2MT - LAMA+LABA | 555 | 356 |
| UK CPRD GOLD - 2MT - LAMA+LABA+ICS | 383 | 385 |
| UK CPRD GOLD - 2MT - Overall | 1375 | 1066 |
Number of participants with zero exacerbations in the year prior to the start of first maintenance therapy among the chronic obstructive pulmonary disease (COPD) patients initiated their first maintenance therapy the United States (US) IBM MarketScan database was reported. (NCT04926233)
Timeframe: At index date of the first maintenance treatment
| Intervention | Participants (Count of Participants) |
|---|---|
| US IBM Marketscan - 1MT - Overall | 26242 |
| US IBM Marketscan - 1MT - ICS | 3518 |
| US IBM Marketscan - 1MT - LABA | 183 |
| US IBM Marketscan - 1MT - LABA+ICS | 12483 |
| US IBM Marketscan - 1MT - LAMA+LABA | 3818 |
| US IBM Marketscan - 1MT - LAMA+LABA+ICS | 676 |
| US IBM Marketscan - 1MT - LAMA | 5515 |
| US IBM Marketscan - 1MT - LAMA+ICS | 49 |
Days between first and second maintenance therapy among the chronic obstructive pulmonary disease (COPD) patients initiated their second maintenance therapy the United States (US) IBM MarketScan database were reported. (NCT04926233)
Timeframe: From the index date of first maintenance initiation until the initiation of the second maintenance therapy, up to 1020 days before this study started.
| Intervention | Days (Median) |
|---|---|
| US IBM Marketscan - 2MT - Overall | 160.0 |
| US IBM Marketscan - 2MT - ICS | 181.5 |
| US IBM Marketscan - 2MT - LABA | 176.0 |
| US IBM Marketscan - 2MT - LABA+ICS | 158.0 |
| US IBM Marketscan - 2MT - LAMA+LABA | 223.0 |
| US IBM Marketscan - 2MT - LAMA+LABA+ICS | 143.5 |
| US IBM Marketscan - 2MT - LAMA | 137.0 |
| US IBM Marketscan - 2MT - LAMA+ICS | 125.0 |
Age of the chronic obstructive pulmonary disease (COPD) patients at the time of COPD diagnosis from the the United Kingdom (UK) CPRD GOLD database was reported by groups stratified according to their COPD diagnosis times (Before versus after the approval of Tiotropium + Olodaterol in 2015). (NCT04926233)
Timeframe: At index date of cohort entry (baseline; time of COPD diagnosis).
| Intervention | Years (Mean) |
|---|---|
| UK CPRD GOLD - COPD Diagnosis Before Tio+Olo Approval | 65.82 |
| UK CPRD GOLD - COPD Diagnosis After Tio+Olo Approval | 66.17 |
Age of patients receiving second maintenance treatment from chronic obstructive pulmonary disease (COPD) patients initiated their second maintenance therapy in the United Kingdom (UK) CPRD GOLD database was reported. (NCT04926233)
Timeframe: At index date of the second maintenance treatment
| Intervention | Years (Median) |
|---|---|
| UK CPRD GOLD - 2MT - Overall | 68.0 |
| UK CPRD GOLD - 2MT - ICS | 68.0 |
| UK CPRD GOLD - 2MT - LABA | 71.0 |
| UK CPRD GOLD - 2MT - LABA+ICS | 69.0 |
| UK CPRD GOLD - 2MT - LAMA+LABA | 68.0 |
| UK CPRD GOLD - 2MT - LAMA+LABA+ICS | 68.0 |
| UK CPRD GOLD - 2MT - LAMA | 70.0 |
| UK CPRD GOLD - 2MT - LAMA+ICS | 68.0 |
Age of patients receiving second maintenance treatment from the United States (US) IBM MarketScan database was reported. (NCT04926233)
Timeframe: At index date of the second maintenance treatment
| Intervention | Years (Median) |
|---|---|
| US IBM Marketscan - 2MT - Overall | 64.0 |
| US IBM Marketscan - 2MT - ICS | 63.0 |
| US IBM Marketscan - 2MT - LABA | 70.0 |
| US IBM Marketscan - 2MT - LABA+ICS | 63.0 |
| US IBM Marketscan - 2MT - LAMA+LABA | 63.0 |
| US IBM Marketscan - 2MT - LAMA+LABA+ICS | 64.0 |
| US IBM Marketscan - 2MT - LAMA | 64.0 |
| US IBM Marketscan - 2MT - LAMA+ICS | 65.0 |
Number of participants with zero exacerbations in the year prior to the start of first maintenance therapy among the chronic obstructive pulmonary disease (COPD) patients initiated their first maintenance therapy in the United Kingdom (UK) CPRD GOLD database was reported. (NCT04926233)
Timeframe: At index date of the first maintenance treatment
| Intervention | Participants (Count of Participants) |
|---|---|
| UK CPRD GOLD - 1MT - Overall | 5942 |
| UK CPRD GOLD - 1MT - ICS | 498 |
| UK CPRD GOLD - 1MT - LABA | 275 |
| UK CPRD GOLD - 1MT - LABA+ICS | 712 |
| UK CPRD GOLD - 1MT - LAMA+LABA | 960 |
| UK CPRD GOLD - 1MT - LAMA+LABA+ICS | 207 |
| UK CPRD GOLD - 1MT - LAMA | 3281 |
| UK CPRD GOLD - 1MT - LAMA+ICS | 9 |
Characteristics of patients receiving second maintenance treatment from chronic obstructive pulmonary disease (COPD) patients initiated their second maintenance therapy in the United States (US) IBM MarketScan database were reported. (NCT04926233)
Timeframe: At index date of the second maintenance treatment
| Intervention | Participants (Count of Participants) | ||||||
|---|---|---|---|---|---|---|---|
| Male | Upper respiratory tract infection | Lower respiratory infections | Chronic bronchitis | Lung fibrosis | Concomitant medications - Oral corticosteroids | Concomitant medications - Oral antibiotics | |
| US IBM Marketscan - 2MT - ICS | 265 | 196 | 130 | 89 | 37 | 355 | 481 |
| US IBM Marketscan - 2MT - LABA | 41 | 25 | 13 | 11 | 11 | 44 | 64 |
| US IBM Marketscan - 2MT - LABA+ICS | 920 | 497 | 368 | 264 | 101 | 1019 | 1399 |
| US IBM Marketscan - 2MT - LAMA | 749 | 343 | 260 | 243 | 79 | 851 | 1126 |
| US IBM Marketscan - 2MT - LAMA+ICS | 73 | 32 | 29 | 26 | 12 | 75 | 108 |
| US IBM Marketscan - 2MT - LAMA+LABA | 628 | 307 | 213 | 165 | 43 | 595 | 833 |
| US IBM Marketscan - 2MT - LAMA+LABA+ICS | 998 | 442 | 372 | 297 | 105 | 1125 | 1388 |
| US IBM Marketscan - 2MT - Overall | 3674 | 1842 | 1385 | 1095 | 388 | 4065 | 5399 |
"Pneumonia-related health care resource utilization: This utilization was calculated for medical claims with a diagnosis for pneumonia in any position.~Population annualized averages of inpatient days is reported.~Population annualized averages of inpatient days were calculated as: ([sum of all inpatient days for all individuals during the follow-up period] / [sum of follow-up on-treatment time in years (365 days) for all individuals])." (NCT05127304)
Timeframe: Follow-up period (started on the day after the index date, with a minimum of 30-days duration (index date + 1 through index date+30) up to a maximum of 12 months duration (index date + 1 through index date +365).
| Intervention | inpatient days/year (Mean) |
|---|---|
| Tiotropium Bromide/Olodaterol (TIO/OLO) | 1.72 |
| Fluticasone Furoate/Umeclidinium/Vilanterol (FF/UMEC/VI) | 1.98 |
"These costs were calculated for medical claims with a diagnosis for pneumonia in any position.~Annualized population averages of pneumonia-related health care costs for the categories below is reported:~Medical costs (includes physician office costs, hospital outpatient costs, emergency services costs, inpatient costs, and other costs)~Ambulatory~Office visits~Outpatient visits~Emergency room visits~Inpatient stay~Other medical costs~Pharmacy costs~Total (medical + pharmacy) costs. Annualized population averages=([sum of all costs for all individuals during the follow-up period] / [sum of follow-up on-treatment time in years (365 days) for all individuals]).~Costs were adjusted to 2020 dollars using the most recent year of the medical care component of the Consumer Price Index (CPI) to reflect inflation between the claim date and 2020." (NCT05127304)
Timeframe: Follow-up period (started on the day after the index date, with a minimum of 30-days duration (index date + 1 through index date+30) up to a maximum of 12 months duration (index date + 1 through index date +365).
| Intervention | dollars/year (Mean) | |||||||
|---|---|---|---|---|---|---|---|---|
| Medical costs | Ambulatory costs | Office visits costs | Outpatient visits costs | Emergency room visits costs | Inpatient stay costs | Other medical costs | Total (medical + pharmacy) costs | |
| Fluticasone Furoate/Umeclidinium/Vilanterol (FF/UMEC/VI) | 3466.72 | 98.19 | 18.03 | 80.16 | 51.33 | 3297.65 | 19.56 | 3466.72 |
| Tiotropium Bromide/Olodaterol (TIO/OLO) | 2857.23 | 80.62 | 15.03 | 65.59 | 48.91 | 2714.94 | 12.77 | 2857.23 |
"Percentage of patients with 30-day all-cause readmission after Chronic Obstructive Pulmonary Disease (COPD) hospitalization is reported.~Hospitalizations were classified as COPD-related if they met either of the following 2 criteria:~≥1 diagnosis of COPD in the primary position any time during the acute inpatient stay; or~≥1 diagnosis of acute respiratory failure in the primary position and a diagnosis of acute exacerbation of COPD in a later position on the same claim during an acute inpatient stay." (NCT05127304)
Timeframe: Follow-up period (started on the day after the index date, with a minimum of 30-days duration (index date + 1 through index date+30) up to a maximum of 12 months duration (index date + 1 through index date +365).
| Intervention | percentage of patients (Number) |
|---|---|
| Tiotropium Bromide/Olodaterol (TIO/OLO) | 12.04 |
| Fluticasone Furoate/Umeclidinium/Vilanterol (FF/UMEC/VI) | 18.25 |
"These costs were calculated for medical claims with a diagnosis for COPD, pneumonia, or acute bronchitis/bronchiolitis in any position and pharmacy claims for a COPD-related treatment, including COPD-guideline recommended antibiotics.~Annualized population averages of costs for categories below is reported:~Medical costs (includes physician office costs, hospital outpatient costs, emergency services costs, inpatient costs, and other costs)~Ambulatory~Office visits~Outpatient visits~Emergency room visits~Inpatient stay~Other medical costs~Pharmacy costs~Total (medical + pharmacy) costs. Annualized population averages=([sum of all costs for all individuals during the follow-up period] / [sum of follow-up on-treatment time in years (365 days) for all individuals]).~Costs were adjusted to 2020 dollars using the most recent year of the medical care component of the Consumer Price Index (CPI) to reflect inflation between the claim date and 2020." (NCT05127304)
Timeframe: Follow-up period (started on the day after the index date, with a minimum of 30-days duration (index date + 1 through index date+30) up to a maximum of 12 months duration (index date + 1 through index date +365).
| Intervention | dollars/year (Mean) | ||||||||
|---|---|---|---|---|---|---|---|---|---|
| Medical costs | Ambulatory costs | Office visits costs | Outpatient visits costs | Emergency room visits costs | Inpatient stay costs | Other medical costs | Pharmacy costs | Total (medical + pharmacy) costs | |
| Fluticasone Furoate/Umeclidinium/Vilanterol (FF/UMEC/VI) | 11065.38 | 2316.77 | 508.60 | 1808.18 | 482.53 | 7769.37 | 496.70 | 6567.16 | 17632.54 |
| Tiotropium Bromide/Olodaterol (TIO/OLO) | 9828.60 | 2121.76 | 481.16 | 1640.60 | 448.83 | 6811.63 | 446.38 | 4729.11 | 14557.70 |
"Chronic Obstructive Pulmonary Disease (COPD) and/or pneumonia-related health care resource utilization (medical claims with a diagnosis for COPD, pneumonia, or acute bronchitis/bronchiolitis in any position and pharmacy claims for a COPD-related treatment, including COPD-guideline recommended antibiotics).~Population annualized averages of visits in each of the following categories is reported:~Ambulatory visits~Office visits~Outpatient visits~Emergency room visits~Inpatient visits~Other medical visits (independent laboratory, home health, durable medical equipment, etc.)~Population annualized averages of visits were calculated as: ([sum of all visits for all individuals during the follow-up period] / [sum of follow-up on-treatment time in years (365 days) for all individuals])." (NCT05127304)
Timeframe: Follow-up period (started on the day after the index date, with a minimum of 30-days duration (index date + 1 through index date+30) up to a maximum of 12 months duration (index date + 1 through index date +365).
| Intervention | visits/year (Mean) | |||||
|---|---|---|---|---|---|---|
| Ambulatory visits | Office visits | Outpatient visits | Emergency room visits | Inpatient visits | Other medical visits | |
| Fluticasone Furoate/Umeclidinium/Vilanterol (FF/UMEC/VI) | 9.85 | 4.19 | 5.67 | 0.70 | 0.45 | 4.94 |
| Tiotropium Bromide/Olodaterol (TIO/OLO) | 9.01 | 4.04 | 4.98 | 0.70 | 0.40 | 4.36 |
"Pneumonia-related health care resource utilization: This utilization was calculated for medical claims with a diagnosis for pneumonia in any position.~Population annualized averages of visits in each of the following categories is reported:~Ambulatory visits~Office visits~Outpatient visits~Emergency room visits~Inpatient visits~Other medical visits (independent laboratory, home health, durable medical equipment, etc.)~Population annualized averages of visits were calculated as: ([sum of all visits for all individuals during the follow-up period] / [sum of follow-up on-treatment time in years (365 days) for all individuals])." (NCT05127304)
Timeframe: Follow-up period (started on the day after the index date, with a minimum of 30-days duration (index date + 1 through index date+30) up to a maximum of 12 months duration (index date + 1 through index date +365).
| Intervention | visits/year (Mean) | |||||
|---|---|---|---|---|---|---|
| Ambulatory visits | Office visits | Outpatient visits | Emergency room visits | Inpatient visits | Other medical visits | |
| Fluticasone Furoate/Umeclidinium/Vilanterol (FF/UMEC/VI) | 0.66 | 0.15 | 0.50 | 0.11 | 0.15 | 0.12 |
| Tiotropium Bromide/Olodaterol (TIO/OLO) | 0.49 | 0.13 | 0.36 | 0.10 | 0.12 | 0.12 |
"Chronic Obstructive Pulmonary Disease (COPD)-related (medical claims with a diagnosis for COPD in any position and pharmacy claims for a COPD-related treatment, including COPD-guideline recommended antibiotics) health care resource utilization. Population annualized averages of visits for each of the following categories is reported:~Ambulatory visits~Office visits~Outpatient visits~Emergency room visits~Inpatient visits~Other medical visits (included services like independent laboratory, home health, durable medical equipment, etc.).~Annualized population averages of visits were calculated as: ([sum of all visits for all individuals during the follow-up period] / [sum of follow-up on-treatment time in years (365 days) for all individuals])." (NCT05127304)
Timeframe: Follow-up period (started on the day after the index date, with a minimum of 30-days duration (index date + 1 through index date+30) up to a maximum of 12 months duration (index date + 1 through index date +365).
| Intervention | visits/year (Mean) | |||||
|---|---|---|---|---|---|---|
| Ambulatory visits | Office visits | Outpatient visits | Emergency room visits | Inpatient visits | Other medical visits | |
| Fluticasone Furoate/Umeclidinium/Vilanterol (FF/UMEC/VI) | 9.56 | 4.07 | 5.51 | 0.65 | 0.44 | 4.87 |
| Tiotropium Bromide/Olodaterol (TIO/OLO) | 8.77 | 3.92 | 4.85 | 0.65 | 0.39 | 4.28 |
"COPD-related health care costs (HCC) cover the costs for medical claims with a diagnosis for COPD in any position and pharmacy claims for a COPD-related treatment, including COPD-guideline recommended antibiotics. Annualized population averages of COPD-related HCC for the categories below are reported:~Medical costs (includes physician office costs, hospital outpatient costs, emergency services costs, inpatient costs, and other costs)~Ambulatory~Office visits~Outpatient visits~Emergency room visits~Inpatient stay~Other medical costs~Pharmacy costs~Total (medical + pharmacy) costs. Annualized population averages of costs = ([sum of all costs for all individuals during the follow-up period] / [sum of follow-up on-treatment time in years (365 days) for all individuals]).~Costs are adjusted to 2020 dollars using the most recent year of the medical care component of the Consumer Price Index (CPI) to reflect inflation between the claim date and 2020." (NCT05127304)
Timeframe: Follow-up period (started on the day after the index date, with a minimum of 30-days duration (index date + 1 through index date+30) up to a maximum of 12 months duration (index date + 1 through index date +365).
| Intervention | dollars/year (Mean) | ||||||||
|---|---|---|---|---|---|---|---|---|---|
| Medical costs | Ambulatory costs | Office visits costs | Outpatient visits costs | Emergency room visits costs | Inpatient stay costs | Other medical costs | Pharmacy costs | Total (medical + pharmacy) costs | |
| Fluticasone Furoate/Umeclidinium/Vilanterol (FF/UMEC/VI) | 10820.05 | 2278.21 | 493.42 | 1784.78 | 455.87 | 7596.04 | 489.92 | 6567.16 | 17387.20 |
| Tiotropium Bromide/Olodaterol (TIO/OLO) | 9635.45 | 2088.43 | 468.94 | 1619.49 | 426.02 | 6681.35 | 439.65 | 4729.11 | 14364.56 |
"COPD or pneumonia-attributable health care resource utilization: This utilization was calculated for medical claims with a diagnosis for COPD, pneumonia, or acute bronchitis/bronchiolitis in the primary position or a diagnosis for acute respiratory failure in the primary position and a diagnosis for COPD, pneumonia, or acute bronchitis/bronchiolitis in a non-primary position and pharmacy claims for a COPD-related treatment, including COPD-guideline recommended antibiotics.~Population annualized averages of visits in each of the following categories is reported:~Ambulatory visits~Office visits~Outpatient visits~Emergency room visits~Inpatient visits~Other medical visits (independent laboratory, home health, durable medical equipment, etc.)~Population annualized averages of visits were calculated as: ([sum of all visits for all individuals during the follow-up period] / [sum of follow-up on-treatment time in years (365 days) for all individuals])." (NCT05127304)
Timeframe: Follow-up period (started on the day after the index date, with a minimum of 30-days duration (index date + 1 through index date+30) up to a maximum of 12 months duration (index date + 1 through index date +365).
| Intervention | visits/year (Mean) | |||||
|---|---|---|---|---|---|---|
| Ambulatory visits | Office visits | Outpatient visits | Emergency room visits | Inpatient visits | Other medical visits | |
| Fluticasone Furoate/Umeclidinium/Vilanterol (FF/UMEC/VI) | 4.90 | 2.14 | 2.77 | 0.26 | 0.25 | 4.27 |
| Tiotropium Bromide/Olodaterol (TIO/OLO) | 4.20 | 2.09 | 2.12 | 0.29 | 0.24 | 3.82 |
"These costs were calculated for medical claims with a diagnosis for COPD, pneumonia, or acute bronchitis/bronchiolitis in the primary position or a diagnosis for acute respiratory failure in the primary position and a diagnosis for COPD, pneumonia, or acute bronchitis/bronchiolitis in a non-primary position, or pharmacy claims for a COPD-related treatment, including COPD-guideline recommended antibiotics.~Annualized population averages are reported and were calculated as=([sum of all costs for all individuals during the follow-up period] / [sum of follow-up on-treatment time in years (365 days) for all individuals]).~Costs were adjusted to 2020 dollars using the most recent year of the medical care component of the Consumer Price Index (CPI) to reflect inflation between the claim date and 2020." (NCT05127304)
Timeframe: Follow-up period (started on the day after the index date, with a minimum of 30-days duration (index date + 1 through index date+30) up to a maximum of 12 months duration (index date + 1 through index date +365).
| Intervention | dollars/year (Mean) | ||||||||
|---|---|---|---|---|---|---|---|---|---|
| Medical costs | Ambulatory costs | Office visits costs | Outpatient visits costs | Emergency room visits costs | Inpatient stay costs | Other medical costs | Pharmacy costs | Total (medical + pharmacy) costs | |
| Fluticasone Furoate/Umeclidinium/Vilanterol (FF/UMEC/VI) | 6006.47 | 623.53 | 242.99 | 380.53 | 130.00 | 4885.72 | 367.22 | 6567.16 | 12573.62 |
| Tiotropium Bromide/Olodaterol (TIO/OLO) | 5630.81 | 517.27 | 231.09 | 286.18 | 153.87 | 4595.72 | 363.95 | 4729.11 | 10359.92 |
"Annualized population averages of COPD exacerbations for the categories below are reported:~Any COPD exacerbation~Severe COPD exacerbation (defined as an inpatient admission or an emergency room (ER) visit with a COPD diagnosis code in the primary position; or an inpatient admission or an ER visit with a diagnosis code for acute respiratory failure in the primary position and a COPD diagnosis code in any position; or an inpatient admission or an ER visit with a diagnosis code for acute respiratory failure in the primary position + an inpatient admission or an ER visit within ±7 days with a COPD diagnosis code in any position).~Annualized population averages= ([sum of all exacerbations for all individuals during the follow-up period] / [sum of follow-up on-treatment time in years (365 days) for all individuals])." (NCT05127304)
Timeframe: Follow-up period (started on the day after the index date, with a minimum of 30-days duration (index date + 1 through index date+30) up to a maximum of 12 months duration (index date + 1 through index date +365).
| Intervention | exacerbations/year (Mean) | |
|---|---|---|
| Any COPD exacerbation | Severe COPD exacerbation | |
| Fluticasone Furoate/Umeclidinium/Vilanterol (FF/UMEC/VI) | 0.98 | 0.26 |
| Tiotropium Bromide/Olodaterol (TIO/OLO) | 1.02 | 0.28 |
"All-cause health care resource utilization. Annualized population averages of visits for each of the following categories is reported:~Ambulatory visits~Office visits~Outpatient visits~Emergency room visits~Inpatient visits~Other medical visits (included services like independent laboratory, home health, durable medical equipment, etc.) Annualized population averages of visits were calculated as: ([sum of all visits for all individuals during the follow-up period] / [sum of follow-up on-treatment time in years (365 days) for all individuals])." (NCT05127304)
Timeframe: Follow-up period (started on the day after the index date, with a minimum of 30-days duration (index date + 1 through index date+30) up to a maximum of 12 months duration (index date + 1 through index date +365).
| Intervention | visits/year (Mean) | |||||
|---|---|---|---|---|---|---|
| Ambulatory visits | Office visits | Outpatient visits | Emergency room visits | Inpatient visits | Other medical visits | |
| Fluticasone Furoate/Umeclidinium/Vilanterol (FF/UMEC/VI) | 32.91 | 17.57 | 15.42 | 1.39 | 0.48 | 10.48 |
| Tiotropium Bromide/Olodaterol (TIO/OLO) | 32.54 | 17.80 | 14.82 | 1.26 | 0.45 | 10.09 |
"All-cause health care costs were computed from the payer and patient perspective together.~Annualized population averages of all-cause health care costs in each of the following categories is reported:~Medical costs (includes physician office costs, hospital outpatient costs, emergency services costs, inpatient costs, and other costs)~Ambulatory~Office visits~Outpatient visits~Emergency room visits~Inpatient stay~Other medical costs~Pharmacy costs~Total (medical + pharmacy) costs. Annualized population averages of costs were calculated as: ([sum of all costs for all individuals during the follow-up period] / [sum of follow-up on-treatment time in years (365 days) for all individuals]).~Costs were adjusted to 2020 dollars using the most recent year of the medical care component of the Consumer Price Index (CPI) to reflect inflation between the date of the claim and 2020." (NCT05127304)
Timeframe: Follow-up period (started on the day after the index date, with a minimum of 30-days duration (index date + 1 through index date+30) up to a maximum of 12 months duration (index date + 1 through index date +365).
| Intervention | dollars/year (Mean) | ||||||||
|---|---|---|---|---|---|---|---|---|---|
| Medical costs | Ambulatory costs | Office visits costs | Outpatient visits costs | Emergency room visits costs | Inpatient stay costs | Other medical costs | Pharmacy costs | Total (medical + pharmacy) costs | |
| Fluticasone Furoate/Umeclidinium/Vilanterol (FF/UMEC/VI) | 18471.61 | 7858.06 | 3030.56 | 4827.50 | 1086.48 | 8139.51 | 1387.55 | 11963.02 | 30434.63 |
| Tiotropium Bromide/Olodaterol (TIO/OLO) | 16911.48 | 7321.14 | 2986.46 | 4334.68 | 991.35 | 7480.17 | 1118.83 | 10192.10 | 27103.58 |
"All-cause health care resource utilization: Inpatient days. Annualized population averages of inpatient days is reported.~Annualized population averages of inpatient days were calculated as: ([sum of all inpatient days for all individuals during the follow-up period] / [sum of follow-up on-treatment time in years (365 days) for all individuals])." (NCT05127304)
Timeframe: Follow-up period (started on the day after the index date, with a minimum of 30-days duration (index date + 1 through index date+30) up to a maximum of 12 months duration (index date + 1 through index date +365).
| Intervention | inpatient days/year (Mean) |
|---|---|
| Tiotropium Bromide/Olodaterol (TIO/OLO) | 4.30 |
| Fluticasone Furoate/Umeclidinium/Vilanterol (FF/UMEC/VI) | 4.68 |
"All-cause health care resource utilization: Pharmacy fills. Annualized population averages for pharmacy fills is reported.~Annualized population averages of pharmacy fills were calculated as:([sum of all pharmacy fills for all individuals during the follow-up period] / [sum of follow-up on-treatment time in years (365 days) for all individuals])." (NCT05127304)
Timeframe: Follow-up period (started on the day after the index date, with a minimum of 30-days duration (index date + 1 through index date+30) up to a maximum of 12 months duration (index date + 1 through index date +365).
| Intervention | pharmacy fills/year (Mean) |
|---|---|
| Tiotropium Bromide/Olodaterol (TIO/OLO) | 59.39 |
| Fluticasone Furoate/Umeclidinium/Vilanterol (FF/UMEC/VI) | 57.13 |
"Chronic Obstructive Pulmonary Disease (COPD) and/or pneumonia-related health care resource utilization (medical claims with a diagnosis for COPD, pneumonia, or acute bronchitis/bronchiolitis in any position and pharmacy claims for a COPD-related treatment, including COPD-guideline recommended antibiotics).~Population annualized averages of inpatient days is reported.~Population annualized averages of inpatient days were calculated as: ([sum of all inpatient days for all individuals during the follow-up period] / [sum of follow-up on-treatment time in years (365 days) for all individuals])." (NCT05127304)
Timeframe: Follow-up period (started on the day after the index date, with a minimum of 30-days duration (index date + 1 through index date+30) up to a maximum of 12 months duration (index date + 1 through index date +365).
| Intervention | inpatient days/year (Mean) |
|---|---|
| Tiotropium Bromide/Olodaterol (TIO/OLO) | 3.97 |
| Fluticasone Furoate/Umeclidinium/Vilanterol (FF/UMEC/VI) | 4.49 |
"Chronic Obstructive Pulmonary Disease (COPD) and/or pneumonia-related health care resource utilization (medical claims with a diagnosis for COPD, pneumonia, or acute bronchitis/bronchiolitis in any position and pharmacy claims for a COPD-related treatment, including COPD-guideline recommended antibiotics).~Population annualized averages of pharmacy fills is reported.~Population annualized averages of pharmacy fills were calculated as: ([sum of all pharmacy fills for all individuals during the follow-up period] / [sum of follow-up on-treatment time in years (365 days) for all individuals])." (NCT05127304)
Timeframe: Follow-up period (started on the day after the index date, with a minimum of 30-days duration (index date + 1 through index date+30) up to a maximum of 12 months duration (index date + 1 through index date +365).
| Intervention | pharmacy fills/year (Mean) |
|---|---|
| Tiotropium Bromide/Olodaterol (TIO/OLO) | 15.48 |
| Fluticasone Furoate/Umeclidinium/Vilanterol (FF/UMEC/VI) | 15.08 |
"COPD or pneumonia-attributable health care resource utilization: This utilization was calculated for medical claims with a diagnosis for COPD, pneumonia, or acute bronchitis/bronchiolitis in the primary position or a diagnosis for acute respiratory failure in the primary position and a diagnosis for COPD, pneumonia, or acute bronchitis/bronchiolitis in a non-primary position and pharmacy claims for a COPD-related treatment, including COPD-guideline recommended antibiotics.~Population annualized averages of inpatient days is reported.~Population annualized averages of inpatient days were calculated as: ([sum of all inpatient days for all individuals during the follow-up period] / [sum of follow-up on-treatment time in years (365 days) for all individuals])." (NCT05127304)
Timeframe: Follow-up period (started on the day after the index date, with a minimum of 30-days duration (index date + 1 through index date+30) up to a maximum of 12 months duration (index date + 1 through index date +365).
| Intervention | inpatient days/year (Mean) |
|---|---|
| Tiotropium Bromide/Olodaterol (TIO/OLO) | 2.87 |
| Fluticasone Furoate/Umeclidinium/Vilanterol (FF/UMEC/VI) | 3.08 |
"COPD or pneumonia-attributable health care resource utilization: This utilization was calculated for medical claims with a diagnosis for COPD, pneumonia, or acute bronchitis/bronchiolitis in the primary position or a diagnosis for acute respiratory failure in the primary position and a diagnosis for COPD, pneumonia, or acute bronchitis/bronchiolitis in a non-primary position and pharmacy claims for a COPD-related treatment, including COPD-guideline recommended antibiotics.~Annualized population averages for pharmacy claims are calculated as the ([sum of all pharmacy fills for all individuals during the follow-up period] / [sum of follow-up on-treatment time in years (365 days) for all individuals]). Wald 95% confidence limits for this ratio used the Taylor expansion to estimate the standard error." (NCT05127304)
Timeframe: Follow-up period (started on the day after the index date, with a minimum of 30-days duration (index date + 1 through index date+30) up to a maximum of 12 months duration (index date + 1 through index date +365).
| Intervention | pharmacy fills/year (Mean) |
|---|---|
| Tiotropium Bromide/Olodaterol (TIO/OLO) | 15.48 |
| Fluticasone Furoate/Umeclidinium/Vilanterol (FF/UMEC/VI) | 15.08 |
"Chronic Obstructive Pulmonary Disease (COPD)-related (medical claims with a diagnosis for COPD in any position and pharmacy claims for a COPD-related treatment, including COPD-guideline recommended antibiotics) health care resource utilization: Inpatient days. Population annualized averages of inpatient days is reported.~Annualized population averages of inpatient days were calculated as: ([sum of all inpatient days for all individuals during the follow-up period] / [sum of follow-up on-treatment time in years (365 days) for all individuals])." (NCT05127304)
Timeframe: Follow-up period (started on the day after the index date, with a minimum of 30-days duration (index date + 1 through index date+30) up to a maximum of 12 months duration (index date + 1 through index date +365).
| Intervention | inpatient days/year (Mean) |
|---|---|
| Tiotropium Bromide/Olodaterol (TIO/OLO) | 3.91 |
| Fluticasone Furoate/Umeclidinium/Vilanterol (FF/UMEC/VI) | 4.42 |
"Chronic Obstructive Pulmonary Disease (COPD)-related (medical claims with a diagnosis for COPD in any position and pharmacy claims for a COPD-related treatment, including COPD-guideline recommended antibiotics) health care resource utilization. Population annualized averages for pharmacy fills is reported.~Annualized population averages of pharmacy fills were calculated as: ([sum of all pharmacy fills for all individuals during the follow-up period] / [sum of follow-up on-treatment time in years (365 days) for all individuals])." (NCT05127304)
Timeframe: Follow-up period (started on the day after the index date, with a minimum of 30-days duration (index date + 1 through index date+30) up to a maximum of 12 months duration (index date + 1 through index date +365).
| Intervention | pharmacy fills/year (Mean) |
|---|---|
| Tiotropium Bromide/Olodaterol (TIO/OLO) | 15.48 |
| Fluticasone Furoate/Umeclidinium/Vilanterol (FF/UMEC/VI) | 15.08 |
The incidence rates of pneumonia (pneu.) hospitalization (diagnosis in any position) among patients with no baseline exacerbation were reported. The incidence rate was calculated as totaling the number of pneumonia hospitalization for all patients / total follow-up in days * 365. (NCT05169424)
Timeframe: From index date (i.e. baseline, cohort entry, 15 September 2017) until 31st March 2020, up to 30 months and 16 days.
| Intervention | pneu. hospitalization per patient-year (Number) |
|---|---|
| Stiolto Initiators | 0.024 |
| Trelegy Initiators | 0.023 |
The incidence rates of pneumonia (pneu.) hospitalization (diagnosis in any position) among patients with 2 or more baseline exacerbations were reported. The incidence rate was calculated as totaling the number of pneumonia hospitalization for all patients / total follow-up in days * 365. (NCT05169424)
Timeframe: From index date (i.e. baseline, cohort entry, 15 September 2017) until 31st March 2020, up to 30 months and 16 days.
| Intervention | pneu. hospitalization per patient-year (Number) |
|---|---|
| Stiolto Initiators | 0.075 |
| Trelegy Initiators | 0.072 |
Incidence rate of chronic obstructive pulmonary disease (COPD) exacerbation after cohort entry among patients with 2 or more baseline exacerbations were reported. The incidence rate was calculated as totaling the number of exacerbation for all patients / total follow-up in days * 365. (NCT05169424)
Timeframe: From index date (i.e. baseline, cohort entry, 15 September 2017) until 31st March 2020, up to 30 months and 16 days.
| Intervention | exacerbation per patient-year (Number) |
|---|---|
| Stiolto Initiators | 0.49 |
| Trelegy Initiators | 0.58 |
Incidence rate of chronic obstructive pulmonary disease (COPD) exacerbation after cohort entry among patients with no baseline exacerbation were reported. The incidence rate was calculated as totaling the number of exacerbation for all patients / total follow-up in days * 365. (NCT05169424)
Timeframe: From index date (i.e. baseline, cohort entry, 15 September 2017) until 31st March 2020, up to 30 months and 16 days.
| Intervention | exacerbation per patient-year (Number) |
|---|---|
| Stiolto Initiators | 0.25 |
| Trelegy Initiators | 0.3 |
The incidence rates of pneumonia (pneu.) hospitalization (diagnosis in any position) were reported. The incidence rate was calculated as totaling the number of pneumonia hospitalization for all patients / total follow-up in days * 365. (NCT05169424)
Timeframe: From index date (i.e. baseline, cohort entry, 15 September 2017) until 31st March 2020, up to 30 months and 16 days.
| Intervention | pneu. hospitalization per patient-year (Number) |
|---|---|
| Stiolto Initiators | 0.025 |
| Trelegy Initiators | 0.030 |
The incidence rates of pneumonia (pneu.) hospitalization (diagnosis in any position) among patients with 0 or 1 baseline exacerbation were reported. The incidence rate was calculated as totaling the number of pneumonia hospitalization for all patients / total follow-up in days * 365. (NCT05169424)
Timeframe: From index date (i.e. baseline, cohort entry, 15 September 2017) until 31st March 2020, up to 30 months and 16 days.
| Intervention | pneu. hospitalization per patient-year (Number) |
|---|---|
| Stiolto Initiators | 0.024 |
| Trelegy Initiators | 0.028 |
Incidence rate of chronic obstructive pulmonary disease (COPD) exacerbation after cohort entry among patients with 0 or 1 baseline exacerbation were reported. The incidence rate was calculated as totaling the number of exacerbation for all patients / total follow-up in days * 365. (NCT05169424)
Timeframe: From index date (i.e. baseline, cohort entry, 15 September 2017) until 31st March 2020, up to 30 months and 16 days.
| Intervention | exacerbation per patient-year (Number) |
|---|---|
| Stiolto Initiators | 0.27 |
| Trelegy Initiators | 0.31 |
The total annualized costs of COPD-related HCRU were calculated for each cohort by totaling the costs for all patients divided by the total follow-up in days, multiplied by 365. (NCT05169424)
Timeframe: From index date (i.e. baseline, cohort entry, 15 September 2017) until 31st March 2020, up to 30 months and 16 days.
| Intervention | dollars per year (Number) |
|---|---|
| Stiolto Initiators | 9688 |
| Trelegy Initiators | 9834 |
The total annualized costs of COPD or pneumonia-related health care cost and resource utilization (HCRU) were calculated for each cohort by totaling the costs for all patients divided by the total follow-up in days, multiplied by 365. (NCT05169424)
Timeframe: From index date (i.e. baseline, cohort entry, 15 September 2017) until 31st March 2020, up to 30 months and 16 days.
| Intervention | dollars per year (Number) |
|---|---|
| Stiolto Initiators | 9834 |
| Trelegy Initiators | 10020 |
The total annualized costs of pneumonia-related HCRU were calculated for each cohort by totaling the costs for all patients divided by the total follow-up in days, multiplied by 365. (NCT05169424)
Timeframe: From index date (i.e. baseline, cohort entry, 15 September 2017) until 31st March 2020, up to 30 months and 16 days.
| Intervention | dollars per year (Number) |
|---|---|
| Stiolto Initiators | 2244 |
| Trelegy Initiators | 2274 |
The total annualized costs of COPD or pneumonia attributable HCRU were calculated for each cohort by totaling the costs for all patients divided by the total follow-up in days, multiplied by 365. (NCT05169424)
Timeframe: From index date (i.e. baseline, cohort entry, 15 September 2017) until 31st March 2020, up to 30 months and 16 days.
| Intervention | dollars per year (Number) |
|---|---|
| Stiolto Initiators | 5729 |
| Trelegy Initiators | 5409 |
The total annualized costs of all-cause HCRU were calculated for each cohort by totaling the costs for all patients divided by the total follow-up in days, multiplied by 365. (NCT05169424)
Timeframe: From index date (i.e. baseline, cohort entry, 15 September 2017) until 31st March 2020, up to 30 months and 16 days.
| Intervention | dollars per year (Number) |
|---|---|
| Stiolto Initiators | 20849 |
| Trelegy Initiators | 19384 |
Incidence rate of chronic obstructive pulmonary disease (COPD) exacerbation after cohort entry were reported. The incidence rate was calculated as totaling the number of exacerbation for all patients / total follow-up in days * 365. (NCT05169424)
Timeframe: From index date (i.e. baseline, cohort entry, 15 September 2017) until 31st March 2020, up to 30 months and 16 days.
| Intervention | exacerbation per patient-year (Number) |
|---|---|
| Stiolto Initiators | 0.28 |
| Trelegy Initiators | 0.32 |
| Substance | Relationship Strength | Studies | Trials | Classes | Roles |
|---|---|---|---|---|---|
| formoterol fumarate N-[2-hydroxy-5-(1-hydroxy-2-{[1-(4-methoxyphenyl)propan-2-yl]amino}ethyl)phenyl]formamide : A phenylethanoloamine having 4-hydroxy and 3-formamido substituents on the phenyl ring and an N-(4-methoxyphenyl)propan-2-yl substituent. | 2.06 | 1 | 0 | formamides; phenols; phenylethanolamines; secondary alcohol; secondary amino compound | |
| 2-cyclopentyl-2-hydroxy-2-phenylacetic acid (1,1-dimethyl-3-pyrrolidin-1-iumyl) ester [no description available] | 2.76 | 3 | 0 | benzenes | |
| salmeterol xinafoate salmeterol : A racemate consisting of equal parts of (R)- and (S)-salmeterol. It is a potent and selective beta2-adrenoceptor agonist (EC50 = 5.3 nM). Unlike other beta2 agonists, it binds to the exo-site domain of beta2 receptors, producing a slow onset of action and prolonged activation.. 2-(hydroxymethyl)-4-(1-hydroxy-2-{[6-(4-phenylbutoxy)hexyl]amino}ethyl)phenol : A phenol having a hydroxymethyl group at C-2 and a 1-hydroxy-2-{[6-(4-phenylbutoxy)hexyl]amino}ethyl group at C-4; derivative of phenylethanolamine. | 2.06 | 1 | 0 | ether; phenols; primary alcohol; secondary alcohol; secondary amino compound | |
| glycopyrrolate Glycopyrrolate: A muscarinic antagonist used as an antispasmodic, in some disorders of the gastrointestinal tract, and to reduce salivation with some anesthetics.. glycopyrronium bromide : A quaternary ammonium salt composed of 3-{[cyclopentyl(hydroxy)phenylacetyl]oxy}-1,1-dimethylpyrrolidin-1-ium and bromide ions in a 1:1 ratio. | 2.48 | 2 | 0 | organic bromide salt; quaternary ammonium salt | |
| solifenacin [no description available] | 2.06 | 1 | 0 | isoquinolines | |
| solifenacin succinate Solifenacin Succinate: A quinuclidine and tetrahydroisoquinoline derivative and selective M3 MUSCARINIC ANTAGONIST. It is used as a UROLOGIC AGENT in the treatment of URINARY INCONTINENCE. | 2.06 | 1 | 0 | isoquinolines | |
| darifenacin darifenacin : 2-[(3S)-1-Ethylpyrrolidin-3-yl]-2,2-diphenylacetamide in which one of the hydrogens at the 2-position of the ethyl group is substituted by a 2,3-dihydro-1-benzofuran-5-yl group. It is a selective antagonist for the M3 muscarinic acetylcholine receptor, which is primarily responsible for bladder muscle contractions, and is used as the hydrobromide salt in the management of urinary incontinence. | 2.06 | 1 | 0 | 1-benzofurans; monocarboxylic acid amide; pyrrolidines | antispasmodic drug; muscarinic antagonist |
| ipratropium bromide anhydrous [no description available] | 4.7 | 6 | 1 | ||
| quinuclidinyl benzilate [no description available] | 2.05 | 1 | 0 | ||
| n-methylscopolamine bromide scopolamine methobromide : A quaternary ammonium salt resulting from the reaction of the amino group of scopolamine with methyl bromide. | 2.08 | 1 | 0 | ||
| aclidinium bromide aclidinium bromide: a long-acting, inhaled antimuscarinic; in phase I trial 8/2008. aclidinium bromide : A quaternary ammonium salt that is the bromide salt of aclidinium. A muscarinic acetylcholine M3 receptor antagonist, for the long-term maintenance treatment of bronchospasm associated with chronic obstructive pulmonary disease (COPD). | 3.16 | 5 | 0 | organic bromide salt; quaternary ammonium salt | bronchodilator agent; muscarinic antagonist |
| azd9164 AZD9164: structure in first source | 2.06 | 1 | 0 | ||
| bromide Bromides: Salts of hydrobromic acid, HBr, with the bromine atom in the 1- oxidation state. (From McGraw-Hill Dictionary of Scientific and Technical Terms, 4th ed) | 2.05 | 1 | 0 | halide anion; monoatomic bromine | |
| carbamates [no description available] | 8.01 | 7 | 4 | amino-acid anion | |
| carbon monoxide Carbon Monoxide: Carbon monoxide (CO). A poisonous colorless, odorless, tasteless gas. It combines with hemoglobin to form carboxyhemoglobin, which has no oxygen carrying capacity. The resultant oxygen deprivation causes headache, dizziness, decreased pulse and respiratory rates, unconsciousness, and death. (From Merck Index, 11th ed). carbon monoxide : A one-carbon compound in which the carbon is joined only to a single oxygen. It is a colourless, odourless, tasteless, toxic gas. | 3.42 | 1 | 1 | carbon oxide; gas molecular entity; one-carbon compound | biomarker; EC 1.9.3.1 (cytochrome c oxidase) inhibitor; human metabolite; ligand; metabolite; mitochondrial respiratory-chain inhibitor; mouse metabolite; neurotoxin; neurotransmitter; P450 inhibitor; probe; signalling molecule; vasodilator agent |
| carnitine [no description available] | 2.25 | 1 | 0 | amino-acid betaine | human metabolite; mouse metabolite |
| choline [no description available] | 2.07 | 1 | 0 | cholines | allergen; Daphnia magna metabolite; Escherichia coli metabolite; human metabolite; mouse metabolite; neurotransmitter; nutrient; plant metabolite; Saccharomyces cerevisiae metabolite |
| hydrochloric acid Hydrochloric Acid: A strong corrosive acid that is commonly used as a laboratory reagent. It is formed by dissolving hydrogen chloride in water. GASTRIC ACID is the hydrochloric acid component of GASTRIC JUICE.. hydrogen chloride : A mononuclear parent hydride consisting of covalently bonded hydrogen and chlorine atoms. | 2.05 | 1 | 0 | chlorine molecular entity; gas molecular entity; hydrogen halide; mononuclear parent hydride | mouse metabolite |
| hydrogen carbonate Bicarbonates: Inorganic salts that contain the -HCO3 radical. They are an important factor in determining the pH of the blood and the concentration of bicarbonate ions is regulated by the kidney. Levels in the blood are an index of the alkali reserve or buffering capacity.. hydrogencarbonate : The carbon oxoanion resulting from the removal of a proton from carbonic acid. | 2.05 | 1 | 0 | carbon oxoanion | cofactor; Escherichia coli metabolite; human metabolite; mouse metabolite; Saccharomyces cerevisiae metabolite |
| histamine [no description available] | 4.36 | 4 | 0 | aralkylamino compound; imidazoles | human metabolite; mouse metabolite; neurotransmitter |
| taurine [no description available] | 3.13 | 1 | 0 | amino sulfonic acid; zwitterion | antioxidant; Escherichia coli metabolite; glycine receptor agonist; human metabolite; mouse metabolite; nutrient; radical scavenger; Saccharomyces cerevisiae metabolite |
| xanthine 7H-xanthine : An oxopurine in which the purine ring is substituted by oxo groups at positions 2 and 6 and N-7 is protonated.. 9H-xanthine : An oxopurine in which the purine ring is substituted by oxo groups at positions 2 and 6 and N-9 is protonated. | 4.45 | 1 | 1 | xanthine | Saccharomyces cerevisiae metabolite |
| 4-diphenylacetoxy-1,1-dimethylpiperidinium 4-diphenylacetoxy-1,1-dimethylpiperidinium: muscarinic receptor antagonist; RN given refers to parent cpd; do not confuse abbreviation 4-DAMP with a similar cpd which does not contain dimethyl groups. 4-DAMP(1+) : A quaternary ammonium salt obtained by formal methylation of the tertiary amino function of 4-diphenylacetoxy-N-methylpiperidine. | 2.46 | 2 | 0 | quaternary ammonium ion | cholinergic antagonist; muscarinic antagonist |
| albuterol Albuterol: A short-acting beta-2 adrenergic agonist that is primarily used as a bronchodilator agent to treat ASTHMA. Albuterol is prepared as a racemic mixture of R(-) and S(+) stereoisomers. The stereospecific preparation of R(-) isomer of albuterol is referred to as levalbuterol.. albuterol : A member of the class of phenylethanolamines that is 4-(2-amino-1-hydroxyethyl)-2-(hydroxymethyl)phenol having a tert-butyl group attached to the nirogen atom. It acts as a beta-adrenergic agonist used in the treatment of asthma and chronic obstructive pulmonary disease (COPD). | 21.55 | 206 | 95 | phenols; phenylethanolamines; secondary amino compound | beta-adrenergic agonist; bronchodilator agent; environmental contaminant; xenobiotic |
| ambroxol Ambroxol: A metabolite of BROMHEXINE that stimulates mucociliary action and clears the air passages in the respiratory tract. It is usually administered as the hydrochloride. | 3.7 | 1 | 1 | aromatic amine | |
| theophylline [no description available] | 11.29 | 17 | 10 | dimethylxanthine | adenosine receptor antagonist; anti-asthmatic drug; anti-inflammatory agent; bronchodilator agent; drug metabolite; EC 3.1.4.* (phosphoric diester hydrolase) inhibitor; fungal metabolite; human blood serum metabolite; immunomodulator; muscle relaxant; vasodilator agent |
| amlodipine Amlodipine: A long-acting dihydropyridine calcium channel blocker. It is effective in the treatment of ANGINA PECTORIS and HYPERTENSION.. amlodipine : A fully substituted dialkyl 1,4-dihydropyridine-3,5-dicarboxylate derivative, which is used for the treatment of hypertension, chronic stable angina and confirmed or suspected vasospastic angina. | 3.12 | 1 | 0 | dihydropyridine; ethyl ester; methyl ester; monochlorobenzenes; primary amino compound | antihypertensive agent; calcium channel blocker; vasodilator agent |
| arecoline Arecoline: An alkaloid obtained from the betel nut (Areca catechu), fruit of a palm tree. It is an agonist at both muscarinic and nicotinic acetylcholine receptors. It is used in the form of various salts as a ganglionic stimulant, a parasympathomimetic, and a vermifuge, especially in veterinary practice. It has been used as a euphoriant in the Pacific Islands.. arecoline : A tetrahydropyridine that is 1,2,5,6-tetrahydropyridine with a methyl group at position 1, and a methoxycarbonyl group at position 3. An alkaloid found in the areca nut, it acts as an agonist of muscarinic acetylcholine. | 3.21 | 1 | 0 | enoate ester; methyl ester; pyridine alkaloid; tetrahydropyridine | metabolite; muscarinic agonist |
| bisindolylmaleimide i bisindolylmaleimide I: a bis(indolyl)maleimide | 2.04 | 1 | 0 | ||
| clenbuterol Clenbuterol: A substituted phenylaminoethanol that has beta-2 adrenomimetic properties at very low doses. It is used as a bronchodilator in asthma.. clenbuterol : A substituted aniline that is 2,6-dichloroaniline in which the hydrogen at position 4 has been replaced by a 2-(tert-butylamino)-1-hydroxyethyl group. | 2.03 | 1 | 0 | amino alcohol; dichlorobenzene; ethanolamines; primary arylamine; secondary amino compound; substituted aniline | beta-adrenergic agonist; bronchodilator agent; sympathomimetic agent |
| berotek Fenoterol: A synthetic adrenergic beta-2 agonist that is used as a bronchodilator and tocolytic.. fenoterol : A member of the class resorcinols that is 5-(1-hydroxyethyl)benzene-1,3-diol in which one of the methyl hydrogens is replaced by a 1-(4-hydroxyphenyl)propan-2-amino group. A beta2-adrenergic agonist, it is used (as the hydrobromide salt) as a bronchodilator in the management of reversible airway obstruction. | 4.34 | 1 | 1 | resorcinols; secondary alcohol; secondary amino compound | beta-adrenergic agonist; bronchodilator agent; sympathomimetic agent; tocolytic agent |
| flurbiprofen Flurbiprofen: An anti-inflammatory analgesic and antipyretic of the phenylalkynoic acid series. It has been shown to reduce bone resorption in periodontal disease by inhibiting CARBONIC ANHYDRASE.. flurbiprofen : A monocarboxylic acid that is a 2-fluoro-[1,1'-biphenyl-4-yl] moiety linked to C-2 of propionic acid. A non-steroidal anti-inflammatory, analgesic and antipyretic, it is used as a pre-operative anti-miotic as well as orally for arthritis or dental pain. | 2.03 | 1 | 0 | fluorobiphenyl; monocarboxylic acid | antipyretic; EC 1.14.99.1 (prostaglandin-endoperoxide synthase) inhibitor; non-narcotic analgesic; non-steroidal anti-inflammatory drug |
| guaifenesin Guaifenesin: An expectorant that also has some muscle relaxing action. It is used in many cough preparations. | 8.73 | 8 | 3 | methoxybenzenes | |
| imipramine Imipramine: The prototypical tricyclic antidepressant. It has been used in major depression, dysthymia, bipolar depression, attention-deficit disorders, agoraphobia, and panic disorders. It has less sedative effect than some other members of this therapeutic group.. imipramine : A dibenzoazepine that is 5H-dibenzo[b,f]azepine substituted by a 3-(dimethylamino)propyl group at the nitrogen atom. | 2.25 | 1 | 0 | dibenzoazepine | adrenergic uptake inhibitor; antidepressant; EC 3.4.21.26 (prolyl oligopeptidase) inhibitor |
| ketoprofen Ketoprofen: An IBUPROFEN-type anti-inflammatory analgesic and antipyretic. It is used in the treatment of rheumatoid arthritis and osteoarthritis.. ketoprofen : An oxo monocarboxylic acid that consists of propionic acid substituted by a 3-benzoylphenyl group at position 2. | 2.03 | 1 | 0 | benzophenones; oxo monocarboxylic acid | antipyretic; drug allergen; EC 1.14.99.1 (prostaglandin-endoperoxide synthase) inhibitor; environmental contaminant; non-steroidal anti-inflammatory drug; xenobiotic |
| memantine [no description available] | 4.04 | 2 | 0 | adamantanes; primary aliphatic amine | antidepressant; antiparkinson drug; dopaminergic agent; neuroprotective agent; NMDA receptor antagonist |
| oxybutynin oxybutynin: RN given refers to parent cpd. oxybutynin : A racemate comprising equimolar amounts of (R)-oxybutynin and esoxybutynin. An antispasmodic used for the treatment of overactive bladder. | 3.45 | 1 | 1 | acetylenic compound; carboxylic ester; racemate; tertiary alcohol; tertiary amino compound | antispasmodic drug; calcium channel blocker; local anaesthetic; muscarinic antagonist; muscle relaxant; parasympatholytic |
| pd 98059 2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one: inhibits MAP kinase kinase (MEK) activity, p42 MAPK and p44 MAPK; structure in first source. 2-(2-amino-3-methoxyphenyl)chromen-4-one : A member of the class of monomethoxyflavones that is 3'-methoxyflavone bearing an additional amino substituent at position 2'. | 2.04 | 1 | 0 | aromatic amine; monomethoxyflavone | EC 2.7.11.24 (mitogen-activated protein kinase) inhibitor; geroprotector |
| pioglitazone Pioglitazone: A thiazolidinedione and PPAR GAMMA agonist that is used in the treatment of TYPE 2 DIABETES MELLITUS.. pioglitazone : A member of the class of thiazolidenediones that is 1,3-thiazolidine-2,4-dione substituted by a benzyl group at position 5 which in turn is substituted by a 2-(5-ethylpyridin-2-yl)ethoxy group at position 4 of the phenyl ring. It exhibits hypoglycemic activity. | 2.05 | 1 | 0 | aromatic ether; pyridines; thiazolidinediones | antidepressant; cardioprotective agent; EC 2.7.1.33 (pantothenate kinase) inhibitor; EC 6.2.1.3 (long-chain-fatty-acid--CoA ligase) inhibitor; ferroptosis inhibitor; geroprotector; hypoglycemic agent; insulin-sensitizing drug; PPARgamma agonist; xenobiotic |
| pirenzepine Pirenzepine: An antimuscarinic agent that inhibits gastric secretion at lower doses than are required to affect gastrointestinal motility, salivary, central nervous system, cardiovascular, ocular, and urinary function. It promotes the healing of duodenal ulcers and due to its cytoprotective action is beneficial in the prevention of duodenal ulcer recurrence. It also potentiates the effect of other antiulcer agents such as CIMETIDINE and RANITIDINE. It is generally well tolerated by patients. | 2.46 | 2 | 0 | pyridobenzodiazepine | anti-ulcer drug; antispasmodic drug; muscarinic antagonist |
| propranolol Propranolol: A widely used non-cardioselective beta-adrenergic antagonist. Propranolol has been used for MYOCARDIAL INFARCTION; ARRHYTHMIA; ANGINA PECTORIS; HYPERTENSION; HYPERTHYROIDISM; MIGRAINE; PHEOCHROMOCYTOMA; and ANXIETY but adverse effects instigate replacement by newer drugs.. propranolol : A propanolamine that is propan-2-ol substituted by a propan-2-ylamino group at position 1 and a naphthalen-1-yloxy group at position 3. | 3.48 | 1 | 1 | naphthalenes; propanolamine; secondary amine | anti-arrhythmia drug; antihypertensive agent; anxiolytic drug; beta-adrenergic antagonist; environmental contaminant; human blood serum metabolite; vasodilator agent; xenobiotic |
| risperidone Risperidone: A selective blocker of DOPAMINE D2 RECEPTORS and SEROTONIN 5-HT2 RECEPTORS that acts as an atypical antipsychotic agent. It has been shown to improve both positive and negative symptoms in the treatment of SCHIZOPHRENIA.. risperidone : A member of the class of pyridopyrimidines that is 2-methyl-6,7,8,9-tetrahydropyrido[1,2-a]pyrimidin-4-one carrying an additional 2-[4-(6-fluoro-1,2-benzoxazol-3-yl)piperidin-1-yl]ethyl group at position 2. | 2.08 | 1 | 0 | 1,2-benzoxazoles; heteroarylpiperidine; organofluorine compound; pyridopyrimidine | alpha-adrenergic antagonist; dopaminergic antagonist; EC 3.4.21.26 (prolyl oligopeptidase) inhibitor; H1-receptor antagonist; psychotropic drug; second generation antipsychotic; serotonergic antagonist |
| telenzepine telenzepine: structure given in first source | 2.04 | 1 | 0 | benzodiazepine | |
| terbutaline Terbutaline: A selective beta-2 adrenergic agonist used as a bronchodilator and tocolytic.. terbutaline : A member of the class of phenylethanolamines that is catechol substituted at position 5 by a 2-(tert-butylamino)-1-hydroxyethyl group. | 5.55 | 4 | 4 | phenylethanolamines; resorcinols | anti-asthmatic drug; beta-adrenergic agonist; bronchodilator agent; EC 3.1.1.7 (acetylcholinesterase) inhibitor; hypoglycemic agent; sympathomimetic agent; tocolytic agent |
| tulobuterol [no description available] | 5.55 | 4 | 4 | organochlorine compound | |
| zopiclone zopiclone: S(+)-enantiomer of racemic zopiclone; azabicyclo(4.3.0)nonane; a nonbenzodiazepine; one of the so-called of Z drugs (zopiclone, eszopiclone, zolpidem, and zaleplon) for which there is some correlation with tumors; was term of zopiclone 2004-2007. zopiclone : A pyrrolo[3,4-b]pyrazine compound having a 4-methylpiperazine-1-carboxyl group at the 5-position, a 5-chloropyridin-2-yl group at the 6-position and an oxo-substituent at the 7-position. | 3.13 | 1 | 0 | monochloropyridine; pyrrolopyrazine | central nervous system depressant; sedative |
| corticosterone [no description available] | 2.06 | 1 | 0 | 11beta-hydroxy steroid; 20-oxo steroid; 21-hydroxy steroid; 3-oxo-Delta(4) steroid; C21-steroid; glucocorticoid; primary alpha-hydroxy ketone | human metabolite; mouse metabolite |
| prednisolone Prednisolone: A glucocorticoid with the general properties of the corticosteroids. It is the drug of choice for all conditions in which routine systemic corticosteroid therapy is indicated, except adrenal deficiency states.. prednisolone : A glucocorticoid that is prednisone in which the oxo group at position 11 has been reduced to the corresponding beta-hydroxy group. It is a drug metabolite of prednisone. | 3.48 | 1 | 1 | 11beta-hydroxy steroid; 17alpha-hydroxy steroid; 20-oxo steroid; 21-hydroxy steroid; 3-oxo-Delta(1),Delta(4)-steroid; C21-steroid; glucocorticoid; primary alpha-hydroxy ketone; tertiary alpha-hydroxy ketone | adrenergic agent; anti-inflammatory drug; antineoplastic agent; drug metabolite; environmental contaminant; immunosuppressive agent; xenobiotic |
| carbachol Carbachol: A slowly hydrolyzed CHOLINERGIC AGONIST that acts at both MUSCARINIC RECEPTORS and NICOTINIC RECEPTORS. | 3.34 | 6 | 0 | ammonium salt; carbamate ester | cardiotonic drug; miotic; muscarinic agonist; nicotinic acetylcholine receptor agonist; non-narcotic analgesic |
| spironolactone Spironolactone: A potassium sparing diuretic that acts by antagonism of aldosterone in the distal renal tubules. It is used mainly in the treatment of refractory edema in patients with congestive heart failure, nephrotic syndrome, or hepatic cirrhosis. Its effects on the endocrine system are utilized in the treatments of hirsutism and acne but they can lead to adverse effects. (From Martindale, The Extra Pharmacopoeia, 30th ed, p827). spironolactone : A steroid lactone that is 17alpha-pregn-4-ene-21,17-carbolactone substituted by an oxo group at position 3 and an alpha-acetylsulfanyl group at position 7. | 3.12 | 1 | 0 | 3-oxo-Delta(4) steroid; oxaspiro compound; steroid lactone; thioester | aldosterone antagonist; antihypertensive agent; diuretic; environmental contaminant; xenobiotic |
| prednisone Prednisone: A synthetic anti-inflammatory glucocorticoid derived from CORTISONE. It is biologically inert and converted to PREDNISOLONE in the liver.. prednisone : A synthetic glucocorticoid drug that is particularly effective as an immunosuppressant, and affects virtually all of the immune system. Prednisone is a prodrug that is converted by the liver into prednisolone (a beta-hydroxy group instead of the oxo group at position 11), which is the active drug and also a steroid. | 3.87 | 3 | 0 | 11-oxo steroid; 17alpha-hydroxy steroid; 20-oxo steroid; 21-hydroxy steroid; 3-oxo-Delta(1),Delta(4)-steroid; C21-steroid; glucocorticoid; primary alpha-hydroxy ketone; tertiary alpha-hydroxy ketone | adrenergic agent; anti-inflammatory drug; antineoplastic agent; immunosuppressive agent; prodrug |
| pilocarpine Pilocarpine: A slowly hydrolyzed muscarinic agonist with no nicotinic effects. Pilocarpine is used as a miotic and in the treatment of glaucoma.. (+)-pilocarpine : The (+)-enantiomer of pilocarpine. | 2.08 | 1 | 0 | pilocarpine | antiglaucoma drug |
| carbostyril Quinolones: A group of derivatives of naphthyridine carboxylic acid, quinoline carboxylic acid, or NALIDIXIC ACID.. quinolin-2(1H)-one : A quinolone that is 1,2-dihydroquinoline substituted by an oxo group at position 2. | 17.57 | 75 | 32 | monohydroxyquinoline; quinolone | bacterial xenobiotic metabolite |
| methacholine chloride Methacholine Chloride: A quaternary ammonium parasympathomimetic agent with the muscarinic actions of ACETYLCHOLINE. It is hydrolyzed by ACETYLCHOLINESTERASE at a considerably slower rate than ACETYLCHOLINE and is more resistant to hydrolysis by nonspecific CHOLINESTERASES so that its actions are more prolonged. It is used as a parasympathomimetic bronchoconstrictor agent and as a diagnostic aid for bronchial asthma. (From Martindale, The Extra Pharmacopoeia, 30th ed, p1116) | 7.18 | 9 | 4 | quaternary ammonium salt | |
| lactose Lactose: A disaccharide of GLUCOSE and GALACTOSE in human and cow milk. It is used in pharmacy for tablets, in medicine as a nutrient, and in industry.. lactose : A glycosylglucose disaccharide, found most notably in milk, that consists of D-galactose and D-glucose fragments bonded through a beta-1->4 glycosidic linkage. The glucose fragment can be in either the alpha- or beta-pyranose form, whereas the galactose fragment can only have the beta-pyranose form.. beta-lactose : The beta-anomer of lactose. | 2.15 | 1 | 0 | lactose | |
| gallamine triethiodide Gallamine Triethiodide: A synthetic nondepolarizing blocking drug. The actions of gallamine triethiodide are similar to those of TUBOCURARINE, but this agent blocks the cardiac vagus and may cause sinus tachycardia and, occasionally, hypertension and increased cardiac output. It should be used cautiously in patients at risk from increased heart rate but may be preferred for patients with bradycardia. (From AMA Drug Evaluations Annual, 1992, p198) | 2.04 | 1 | 0 | ||
| arginine Arginine: An essential amino acid that is physiologically active in the L-form.. arginine : An alpha-amino acid that is glycine in which the alpha-is substituted by a 3-guanidinopropyl group. | 4.76 | 2 | 1 | arginine; glutamine family amino acid; L-alpha-amino acid; proteinogenic amino acid | biomarker; Escherichia coli metabolite; micronutrient; mouse metabolite; nutraceutical |
| mepenzolate bromide [no description available] | 2.21 | 1 | 0 | diarylmethane | |
| quinuclidines Quinuclidines: A class of organic compounds which contain two rings that share a pair of bridgehead carbon atoms and contains an amine group. | 14.43 | 35 | 12 | quinuclidines; saturated organic heterobicyclic parent | |
| pyrroles 1H-pyrrole : A tautomer of pyrrole that has the double bonds at positions 2 and 4.. pyrrole : A five-membered monocyclic heteroarene comprising one NH and four CH units which forms the parent compound of the pyrrole group of compounds. Its five-membered ring structure has three tautomers. A 'closed class'.. azole : Any monocyclic heteroarene consisting of a five-membered ring containing nitrogen. Azoles can also contain one or more other non-carbon atoms, such as nitrogen, sulfur or oxygen. | 3.12 | 1 | 0 | pyrrole; secondary amine | |
| thiophenes Thiophenes: A monocyclic heteroarene furan in which the oxygen atom is replaced by a sulfur.. thiophenes : Compounds containing at least one thiophene ring. | 3.56 | 2 | 0 | mancude organic heteromonocyclic parent; monocyclic heteroarene; thiophenes; volatile organic compound | non-polar solvent |
| diphenhydramine hydrochloride Antitussive Agents: Agents that suppress cough. They act centrally on the medullary cough center. EXPECTORANTS, also used in the treatment of cough, act locally.. diphenhydramine hydrochloride : The hydrochloride salt of diphenhydramine. | 2.13 | 1 | 0 | hydrochloride; organoammonium salt | anti-allergic agent; antiemetic; antiparkinson drug; antipruritic drug; H1-receptor antagonist; local anaesthetic; muscarinic antagonist; sedative |
| quinazolines Quinazolines: A group of aromatic heterocyclic compounds that contain a bicyclic structure with two fused six-membered aromatic rings, a benzene ring and a pyrimidine ring.. quinazoline : A mancude organic heterobicyclic parent that is naphthalene in which the carbon atoms at positions 1 and 3 have been replaced by nitrogen atoms.. quinazolines : Any organic heterobicyclic compound based on a quinazoline skeleton and its substituted derivatives. | 2.08 | 1 | 0 | azaarene; mancude organic heterobicyclic parent; ortho-fused heteroarene; quinazolines | |
| hemicholinium 3 Hemicholinium 3: A potent inhibitor of the high affinity uptake system for CHOLINE. It has less effect on the low affinity uptake system. Since choline is one of the components of ACETYLCHOLINE, treatment with hemicholinium can deplete acetylcholine from cholinergic terminals. Hemicholinium 3 is commonly used as a research tool in animal and in vitro experiments. | 2.1 | 1 | 0 | ||
| alpha-aminopyridine alpha-aminopyridine: RN given refers to parent cpd; structure in Merck Index, 9th ed, #485. aminopyridine : Compounds containing a pyridine skeleton substituted by one or more amine groups. | 10.35 | 12 | 3 | ||
| glycopyrrolate Glycopyrrolate: A muscarinic antagonist used as an antispasmodic, in some disorders of the gastrointestinal tract, and to reduce salivation with some anesthetics.. glycopyrronium bromide : A quaternary ammonium salt composed of 3-{[cyclopentyl(hydroxy)phenylacetyl]oxy}-1,1-dimethylpyrrolidin-1-ium and bromide ions in a 1:1 ratio. | 17.4 | 70 | 32 | organic bromide salt; quaternary ammonium salt | |
| isodesmosine Isodesmosine: 2-(4-Amino-4-carboxybutyl)-1-(5-amino-5-carboxypentyl)-3,5-bis(3-amino-3-carboxypropyl)pyridinium. A rare amino acid found in elastin, formed by condensation of four molecules of lysine into a pyridinium ring.. isodesmosine : A pyridinium ion obtained by formal condensation of four molecules of lysine. | 2.05 | 1 | 0 | lysine derivative; pyridinium ion | biomarker |
| fluorescein-5-isothiocyanate Fluorescein-5-isothiocyanate: Fluorescent probe capable of being conjugated to tissue and proteins. It is used as a label in fluorescent antibody staining procedures as well as protein- and amino acid-binding techniques.. fluorescein 5-isothiocyanate : The 5-isomer of fluorescein isothiocyanate. Acts as a fluorescent probe capable of being conjugated to tissue and proteins; used as a label in fluorescent antibody staining procedures as well as protein- and amino acid-binding techniques. | 2.15 | 1 | 0 | fluorescein isothiocyanate | |
| lanthanum [no description available] | 3.13 | 1 | 0 | f-block element atom; lanthanoid atom; scandium group element atom | |
| cadmium Cadmium: An element with atomic symbol Cd, atomic number 48, and atomic weight 112.41. It is a metal and ingestion will lead to CADMIUM POISONING.. elemental cadmium : An element in the zinc group of the periodic table with atomic number 48, atomic mass 112, M.P. 321degreeC, and B.P. 765degreeC). An odourless, tasteless, and highly poisonous soft, ductile, lustrous metal with electropositive properties. It has eight stable isotopes: (106)Cd, (108)Cd,(110)Cd, (111)Cd, (112)Cd, (113)Cd, (114)Cd and (116)Cd, with (112)Cd and (114)Cd being the most common. | 2.17 | 1 | 0 | cadmium molecular entity; zinc group element atom | |
| helium Helium: A noble gas with the atomic symbol He, atomic number 2, and atomic weight 4.003. It is a colorless, odorless, tasteless gas that is not combustible and does not support combustion. It was first detected in the sun and is now obtained from natural gas. Medically it is used as a diluent for other gases, being especially useful with oxygen in the treatment of certain cases of respiratory obstruction, and as a vehicle for general anesthetics. | 2.05 | 1 | 0 | monoatomic helium; noble gas atom; s-block element atom | food packaging gas |
| ferrous sulfate ferrous sulfate: Ferro-Gradumet is ferrous sulfate in controlled release form; RN given refers to Fe(+2)[1:1] salt. iron(2+) sulfate (anhydrous) : A compound of iron and sulfate in which the ratio of iron(2+) to sulfate ions is 1:1. Various hydrates occur naturally - most commonly the heptahydrate, which loses water to form the tetrahydrate at 57degreeC and the monohydrate at 65degreeC. | 2.06 | 1 | 0 | iron molecular entity; metal sulfate | reducing agent |
| phenyl acetate phenyl acetate: The ester formed between phenol and acetic acid. Don't confuse with phenylacetic acid derivatives listed under PHENYLACETATES.. phenyl acetate : An acetate ester obtained by the formal condensation of phenol with acetic acid. | 5.64 | 3 | 2 | benzenes; phenyl acetates | |
| triamcinolone Triamcinolone: A glucocorticoid given, as the free alcohol or in esterified form, orally, intramuscularly, by local injection, by inhalation, or applied topically in the management of various disorders in which corticosteroids are indicated. (From Martindale, The Extra Pharmacopoeia, 30th ed, p739). triamcinolone : A C21-steroid hormone that is 1,4-pregnadiene-3,20-dione carrying four hydroxy substituents at positions 11beta, 16alpha, 17alpha and 21 as well as a fluoro substituent at position 9. Used in the form of its 16,17-acetonide to treat various skin infections. | 4.09 | 2 | 0 | 11beta-hydroxy steroid; 16alpha-hydroxy steroid; 17alpha-hydroxy steroid; 20-oxo steroid; 21-hydroxy steroid; 3-oxo-Delta(4) steroid; C21-steroid hormone; fluorinated steroid; glucocorticoid; primary alpha-hydroxy ketone; tertiary alpha-hydroxy ketone | anti-allergic agent; anti-inflammatory drug |
| almitrine Almitrine: A respiratory stimulant that enhances respiration by acting as an agonist of peripheral chemoreceptors located on the carotid bodies. The drug increases arterial oxygen tension while decreasing arterial carbon dioxide tension in patients with chronic obstructive pulmonary disease. It may also prove useful in the treatment of nocturnal oxygen desaturation without impairing the quality of sleep.. almitrine : A triamino-1,3,5-triazine compound having allylamino substituents at the 2- and 4-positions and a 4-(bis(p-fluorophenyl)methyl)-1-piperazinyl group at the 6-position. | 3.43 | 1 | 1 | piperazines; triamino-1,3,5-triazine | central nervous system stimulant |
| diltiazem Diltiazem: A benzothiazepine derivative with vasodilating action due to its antagonism of the actions of CALCIUM ion on membrane functions.. diltiazem : A 5-[2-(dimethylamino)ethyl]-2-(4-methoxyphenyl)-4-oxo-2,3,4,5-tetrahydro-1,5-benzothiazepin-3-yl acetate in which both stereocentres have S configuration. A calcium-channel blocker and vasodilator, it is used as the hydrochloride in the management of angina pectoris and hypertension. | 2.1 | 1 | 0 | 5-[2-(dimethylamino)ethyl]-2-(4-methoxyphenyl)-4-oxo-2,3,4,5-tetrahydro-1,5-benzothiazepin-3-yl acetate | antihypertensive agent; calcium channel blocker; vasodilator agent |
| nedocromil Nedocromil: A pyranoquinolone derivative that inhibits activation of inflammatory cells which are associated with ASTHMA, including EOSINOPHILS; NEUTROPHILS; MACROPHAGES; MAST CELLS; MONOCYTES; AND PLATELETS. | 4.45 | 1 | 1 | dicarboxylic acid; organic heterotricyclic compound | anti-allergic agent; anti-asthmatic drug; non-steroidal anti-inflammatory drug |
| doxofylline doxofylline : An oxopurine that is a derivative of xanthine, methylated at N-1 and N-3 and carrying a 1,3-dioxolan-2-ylmethyl group at N-7, used in the treatment of asthma. | 11 | 3 | 3 | oxopurine | anti-asthmatic drug; antitussive; bronchodilator agent |
| fomesafen fomesafen: a protoporphyrinogen oxidase-inhibiting herbicide. fomesafen : An N-sulfonylcarboxamide that is N-(methylsulfonyl)benzamide in which the phenyl ring is substituted by a nitro group at position 2 and a 2-chloro-4-(trifluoromethyl)phenoxy group at position 5. A protoporphyrinogen oxidase inhibitor, it was specially developed for use (generally as the corresponding sodium salt, fomesafen-sodium) for post-emergence control of broad-leaf weeds in soya. | 3.99 | 1 | 1 | aromatic ether; C-nitro compound; monochlorobenzenes; N-sulfonylcarboxamide; organofluorine compound; phenols | agrochemical; EC 1.3.3.4 (protoporphyrinogen oxidase) inhibitor; herbicide |
| itraconazole Itraconazole: A triazole antifungal agent that inhibits cytochrome P-450-dependent enzymes required for ERGOSTEROL synthesis.. itraconazole : An N-arylpiperazine that is cis-ketoconazole in which the imidazol-1-yl group is replaced by a 1,2,4-triazol-1-yl group and in which the actyl group attached to the piperazine moiety is replaced by a p-[(+-)1-sec-butyl-5-oxo-1,5-dihydro-4H-1,2,4-triazol-4-yl]phenyl group. A potent P-glycoprotein and CYP3A4 inhibitor, it is used as an antifungal drug for the treatment of various fungal infections, including aspergillosis, blastomycosis, candidiasis, chromoblastomycosis, coccidioidomycosis, cryptococcosis, histoplasmosis, and sporotrichosis. | 2.21 | 1 | 0 | aromatic ether; conazole antifungal drug; cyclic ketal; dichlorobenzene; dioxolane; N-arylpiperazine; triazole antifungal drug; triazoles | EC 3.6.3.44 (xenobiotic-transporting ATPase) inhibitor; Hedgehog signaling pathway inhibitor; P450 inhibitor |
| salmeterol xinafoate Salmeterol Xinafoate: A selective ADRENERGIC BETA-2 RECEPTOR agonist that functions as a BRONCHODILATOR when administered by inhalation. It is used to manage the symptoms of ASTHMA and CHRONIC OBSTRUCTIVE PULMONARY DISEASE. | 20.67 | 169 | 73 | naphthoic acid | |
| esmolol methyl 3-{4-[2-hydroxy-3-(propan-2-ylamino)propoxy]phenyl}propanoate : A methyl ester that is methyl 3-(4-hydroxyphenyl)propanoate in which the hydrogen attached to the phenolic hydroxy group is substituted by a 2-hydroxy-3-(isopropylamino)propyl group.. esmolol : A racemate comprising equimolar amounts of (R)- and (S)-esmolol. A cardioselective and short-acting beta1 receptor blocker with rapid onset but lacking intrinsic sympathomimetic and membrane-stabilising properties, it is used as the hydrochloride salt in the management of supraventricular arrhythmias, and for the control of hypertension and tachycardia during surgery. While the S enantiomer possesses all of the heart rate control, both enantiomers contribute to lowering blood pressure. | 3.48 | 1 | 1 | aromatic ether; ethanolamines; methyl ester; secondary alcohol; secondary amino compound | |
| duloxetine hydrochloride Duloxetine Hydrochloride: A thiophene derivative and selective NEUROTRANSMITTER UPTAKE INHIBITOR for SEROTONIN and NORADRENALINE (SNRI). It is an ANTIDEPRESSIVE AGENT and ANXIOLYTIC, and is also used for the treatment of pain in patients with DIABETES MELLITUS and FIBROMYALGIA.. (S)-duloxetine hydrochloride : A duloxetine hydrochloride in which the duloxetine moiety has S configuration. | 3.12 | 1 | 0 | duloxetine hydrochloride | antidepressant |
| ibandronic acid Ibandronic Acid: Aminobisphosphonate that is a potent inhibitor of BONE RESORPTION. It is used in the treatment of HYPERCALCEMIA associated with malignancy, for the prevention of fracture and bone complications in patients with breast cancer and bone metastases, and for the treatment and prevention of POSTMENOPAUSAL OSTEOPOROSIS. | 3.13 | 1 | 0 | ||
| zanamivir Zanamivir: A guanido-neuraminic acid that is used to inhibit NEURAMINIDASE. | 2.15 | 1 | 0 | guanidines | antiviral agent; EC 3.2.1.18 (exo-alpha-sialidase) inhibitor |
| carmoterol carmoterol: CHF4226.01 and CHF4232.01 are diastereoisomers; structure in first source | 3.82 | 2 | 0 | ||
| anisodamine anisodamine: alkaloid isolated from Chinese solanacea plant | 2.11 | 1 | 0 | ||
| triazoles Triazoles: Heterocyclic compounds containing a five-membered ring with two carbon atoms and three nitrogen atoms with the molecular formula C2H3N3.. triazoles : An azole in which the five-membered heterocyclic aromatic skeleton contains three N atoms and two C atoms. | 3.64 | 2 | 0 | 1,2,3-triazole | |
| acamprosate Acamprosate: Structural analog of taurine that is used for the prevention of relapse in individuals with ALCOHOLISM.. acamprosate : An organosulfonic acid that is propane-1-sulfonic acid substituted by an acetylamino group at position 3. | 3.13 | 1 | 0 | acetamides; organosulfonic acid | environmental contaminant; neurotransmitter agent; xenobiotic |
| n-methylscopolamine N-Methylscopolamine: A muscarinic antagonist used to study binding characteristics of muscarinic cholinergic receptors. | 2.03 | 1 | 0 | ||
| rosiglitazone [no description available] | 2.05 | 1 | 0 | aminopyridine; thiazolidinediones | EC 6.2.1.3 (long-chain-fatty-acid--CoA ligase) inhibitor; ferroptosis inhibitor; insulin-sensitizing drug |
| fibrinogen Fibrinogen: Plasma glycoprotein clotted by thrombin, composed of a dimer of three non-identical pairs of polypeptide chains (alpha, beta, gamma) held together by disulfide bonds. Fibrinogen clotting is a sol-gel change involving complex molecular arrangements: whereas fibrinogen is cleaved by thrombin to form polypeptides A and B, the proteolytic action of other enzymes yields different fibrinogen degradation products.. D-iditol : The D-enantiomer of iditol. | 3.15 | 1 | 0 | iditol | fungal metabolite |
| methoctramine methoctramine: structure given in first source. methoctramine : A tetramine that is N,N'-bis(6-aminohexyl)octane-1,8-diamine where the primary amino groups both carry 2-methoxybenzyl substituents.. methoctramine tetrahydrochloride : A hydrochloride obtained by combining methoctramine with four molar equivalents of hydrochloric acid. | 2.05 | 1 | 0 | hydrochloride | muscarinic antagonist |
| afdx 116 otenzepad: cardioselective muscarinic receptor antagonist; structure given in first source | 2.08 | 1 | 0 | benzodiazepine | |
| gefitinib [no description available] | 2.08 | 1 | 0 | aromatic ether; monochlorobenzenes; monofluorobenzenes; morpholines; quinazolines; secondary amino compound; tertiary amino compound | antineoplastic agent; epidermal growth factor receptor antagonist |
| anisodine anisodine: structure in first source | 2.11 | 1 | 0 | ||
| lanthanum carbonate lanthanum carbonate: a phosphate binder used for hyperphosphatemia treatment in end-stage renal disease | 3.13 | 1 | 0 | ||
| atropine tropan-3alpha-yl 3-hydroxy-2-phenylpropanoate : A tropane alkaloid that is (1R,5)-8-methyl-8-azabicyclo[3.2.1]octane substituted by a (3-hydroxy-2-phenylpropanoyl)oxy group at position 3. | 3.33 | 6 | 0 | ||
| zm 241385 ZM 241385: a high affinity radioligand selective for the A2a adenosine receptor | 3.27 | 1 | 0 | diamino-1,3,5-triazine | |
| erlotinib hydrochloride [no description available] | 2.08 | 1 | 0 | hydrochloride; terminal acetylenic compound | antineoplastic agent; protein kinase inhibitor |
| elastin [no description available] | 2.05 | 1 | 0 | oligopeptide | |
| mometasone furoate Mometasone Furoate: A pregnadienediol derivative ANTI-ALLERGIC AGENT and ANTI-INFLAMMATORY AGENT that is used in the management of ASTHMA and ALLERGIC RHINITIS. It is also used as a topical treatment for skin disorders. | 7.81 | 7 | 1 | 11beta-hydroxy steroid; 2-furoate ester; 20-oxo steroid; 3-oxo-Delta(1),Delta(4)-steroid; organochlorine compound; steroid ester | anti-allergic agent; anti-inflammatory drug |
| eplerenone Eplerenone: A spironolactone derivative and selective ALDOSTERONE RECEPTOR antagonist that is used in the management of HYPERTENSION and CONGESTIVE HEART FAILURE, post-MYOCARDIAL INFARCTION. | 3.12 | 1 | 0 | 3-oxo-Delta(4) steroid; epoxy steroid; gamma-lactone; methyl ester; organic heteropentacyclic compound; oxaspiro compound; steroid acid ester | aldosterone antagonist; antihypertensive agent |
| darifenacin darifenacin : 2-[(3S)-1-Ethylpyrrolidin-3-yl]-2,2-diphenylacetamide in which one of the hydrogens at the 2-position of the ethyl group is substituted by a 2,3-dihydro-1-benzofuran-5-yl group. It is a selective antagonist for the M3 muscarinic acetylcholine receptor, which is primarily responsible for bladder muscle contractions, and is used as the hydrobromide salt in the management of urinary incontinence. | 2.25 | 1 | 0 | 1-benzofurans; monocarboxylic acid amide; pyrrolidines | antispasmodic drug; muscarinic antagonist |
| zithromax Azithromycin: A semi-synthetic macrolide antibiotic structurally related to ERYTHROMYCIN. It has been used in the treatment of Mycobacterium avium intracellulare infections, toxoplasmosis, and cryptosporidiosis.. azithromycin : A macrolide antibiotic useful for the treatment of bacterial infections. | 3.35 | 1 | 0 | macrolide antibiotic | antibacterial drug; environmental contaminant; xenobiotic |
| roflumilast [no description available] | 10.35 | 12 | 3 | aromatic ether; benzamides; chloropyridine; cyclopropanes; organofluorine compound | anti-asthmatic drug; phosphodiesterase IV inhibitor |
| capsaicin ALGRX-4975: an injectable capsaicin (TRPV1 receptor agonist) formulation for longlasting pain relief. capsaicinoid : A family of aromatic fatty amides produced as secondary metabolites by chilli peppers. | 3.98 | 2 | 1 | capsaicinoid | non-narcotic analgesic; TRPV1 agonist; voltage-gated sodium channel blocker |
| digoxin Digoxin: A cardiotonic glycoside obtained mainly from Digitalis lanata; it consists of three sugars and the aglycone DIGOXIGENIN. Digoxin has positive inotropic and negative chronotropic activity. It is used to control ventricular rate in ATRIAL FIBRILLATION and in the management of congestive heart failure with atrial fibrillation. Its use in congestive heart failure and sinus rhythm is less certain. The margin between toxic and therapeutic doses is small. (From Martindale, The Extra Pharmacopoeia, 30th ed, p666). digoxin : A cardenolide glycoside that is digitoxin beta-hydroxylated at C-12. A cardiac glycoside extracted from the foxglove plant, Digitalis lanata, it is used to control ventricular rate in atrial fibrillation and in the management of congestive heart failure with atrial fibrillation, but the margin between toxic and therapeutic doses is small. | 2.55 | 2 | 0 | cardenolide glycoside; steroid saponin | anti-arrhythmia drug; cardiotonic drug; EC 3.6.3.9 (Na(+)/K(+)-transporting ATPase) inhibitor; epitope |
| ovalbumin Ovalbumin: An albumin obtained from the white of eggs. It is a member of the serpin superfamily. | 5.38 | 7 | 0 | ||
| leukotriene b4 Leukotriene B4: The major metabolite in neutrophil polymorphonuclear leukocytes. It stimulates polymorphonuclear cell function (degranulation, formation of oxygen-centered free radicals, arachidonic acid release, and metabolism). (From Dictionary of Prostaglandins and Related Compounds, 1990). leukotriene B4 : A leukotriene composed of (6Z,8E,10E,14Z)-icosatetraenoic acid having (5S)- and (12R)-hydroxy substituents. It is a lipid mediator of inflammation that is generated from arachidonic acid via the 5-lipoxygenase pathway. | 3.84 | 2 | 1 | dihydroxy monocarboxylic acid; hydroxy polyunsaturated fatty acid; leukotriene; long-chain fatty acid | human metabolite; mouse metabolite; plant metabolite; vasoconstrictor agent |
| pulmicort Budesonide: A glucocorticoid used in the management of ASTHMA, the treatment of various skin disorders, and allergic RHINITIS.. budesonide : A glucocorticoid steroid having a highly oxygenated pregna-1,4-diene structure. It is used mainly in the treatment of asthma and non-infectious rhinitis and for treatment and prevention of nasal polyposis. | 13.57 | 31 | 10 | 11beta-hydroxy steroid; 20-oxo steroid; 21-hydroxy steroid; 3-oxo-Delta(1),Delta(4)-steroid; cyclic acetal; glucocorticoid; primary alpha-hydroxy ketone | anti-inflammatory drug; bronchodilator agent; drug allergen |
| montelukast montelukast: a leukotriene D4 receptor antagonist | 5.64 | 3 | 2 | aliphatic sulfide; monocarboxylic acid; quinolines | anti-arrhythmia drug; anti-asthmatic drug; leukotriene antagonist |
| fondaparinux Fondaparinux: Synthetic pentasaccharide that mediates the interaction of HEPARIN with ANTITHROMBINS and inhibits FACTOR Xa; it is used for prevention of VENOUS THROMBOEMBOLISM after surgery.. fondaparinux : A synthetic pentasaccharide which, apart from the O-methyl group at the reducing end of the molecule, consists of monomeric sugar units which are identical to a sequence of five monomeric sugar units that can be isolated after either chemical or enzymatic cleavage of the polymeric glycosaminoglycans heparin and heparan sulfate. | 3.11 | 1 | 0 | amino sugar; oligosaccharide sulfate; pentasaccharide derivative | anticoagulant |
| thromboxane b2 Thromboxane B2: A stable, physiologically active compound formed in vivo from the prostaglandin endoperoxides. It is important in the platelet-release reaction (release of ADP and serotonin).. thromboxane B2 : A member of the class of thromboxanes B that is (5Z,13E)-thromboxa-5,13-dien-1-oic acid substituted by hydroxy groups at positions 9, 11 and 15. | 3.82 | 2 | 0 | thromboxanes B | human metabolite; mouse metabolite |
| fluticasone Fluticasone: A STEROID with GLUCOCORTICOID RECEPTOR activity that is used to manage the symptoms of ASTHMA; ALLERGIC RHINITIS, and ATOPIC DERMATITIS.. fluticasone : A trifluorinated corticosteroid used in the form of its propionate ester for treatment of allergic rhinitis. | 17.62 | 73 | 39 | 11beta-hydroxy steroid; 17alpha-hydroxy steroid; 3-oxo-Delta(4) steroid; corticosteroid; fluorinated steroid; thioester | anti-allergic agent; anti-asthmatic drug |
| bay 11-7082 (E)-3-tosylacrylonitrile : A nitrile that is acrylonitrile in which the hydrogen located beta,trans to the cyano group is replaced by a tosyl group. It is an inhibitor of cytokine-induced IkappaB-alpha phosphorylation in cells. | 2.04 | 1 | 0 | nitrile; sulfone | apoptosis inducer; EC 2.7.11.10 (IkappaB kinase) inhibitor; EC 3.1.3.48 (protein-tyrosine-phosphatase) inhibitor; non-steroidal anti-inflammatory drug; platelet aggregation inhibitor |
| fumarates Fumarates: Compounds based on fumaric acid.. fumarate(2-) : A C4-dicarboxylate that is the E-isomer of but-2-enedioate(2-) | 4.21 | 2 | 0 | butenedioate; C4-dicarboxylate | human metabolite; metabolite; Saccharomyces cerevisiae metabolite |
| oxitropium oxitropium: RN given refers to bromide; structure | 12.67 | 7 | 3 | ||
| ciclesonide ciclesonide: nasal spray approved for seasonal and perennial allergic rhinitis | 3.91 | 4 | 0 | organic molecular entity | |
| indacaterol indacaterol: a beta2 adrenoceptor agonist; indacaterol is the (R)-isomer; structure in first source. indacaterol : A monohydroxyquinoline that consists of 5-[(1R)-2-amino-1-hydroxyethyl]-8-hydroxyquinolin-2-one having a 5,6-diethylindan-2-yl group attached to the amino function. Used as the maleate salt for treatment of chronic obstructive pulmonary disease. | 16.69 | 62 | 26 | indanes; monohydroxyquinoline; quinolone; secondary alcohol; secondary amino compound | beta-adrenergic agonist; bronchodilator agent |
| fluticasone furoate fluticasone furoate: a glucocorticoid; structure in first source. fluticasone furoate : A trifluorinated corticosteroid that consists of 6alpha,9-difluoro-11beta,17alpha-dihydroxy-17beta-{[(fluoromethyl)sulfanyl]carbonyl}-16-methyl-3-oxoandrosta-1,4-diene bearing a 2-furoyl substituent at position 17. Used in combination with vilanterol trifenate for treatment of bronchospasm associated with chronic obstructive pulmonary disease. | 12.04 | 4 | 2 | 11beta-hydroxy steroid; 2-furoate ester; 3-oxo-Delta(1),Delta(4)-steroid; corticosteroid; fluorinated steroid; steroid ester; thioester | anti-allergic agent; anti-asthmatic drug; prodrug |
| mocetinostat mocetinostat: undergoing phase II clinical trials for treatment of cancer. mocetinostat : A benzamide obtained by formal condensation of the carboxy group of 4-({[4-(pyridin-3-yl)pyrimidin-2-yl]amino}methyl)benzoic acid with one of the amino groups of benzene-1,2-diamine. It is an orally active and isotype-selective HDAC inhibitor which exhibits antitumour activity (IC50 = 0.15, 0.29, 1.66 and 0.59 muM for HDAC1, HDAC2, HDAC3 and HDAC11). | 6.06 | 3 | 2 | aminopyrimidine; benzamides; pyridines; secondary amino compound; secondary carboxamide; substituted aniline | antineoplastic agent; apoptosis inducer; autophagy inducer; cardioprotective agent; EC 3.5.1.98 (histone deacetylase) inhibitor; hepatotoxic agent |
| rpl 554 ensifentrine: a phosphodiesterase 3/4 inhibitor; structure in first source | 5.91 | 2 | 2 | ||
| vilanterol [no description available] | 13.57 | 29 | 10 | benzyl alcohols; dichlorobenzene; ether; phenols; secondary amino compound | beta-adrenergic agonist; bronchodilator agent |
| batefenterol batefenterol: a bronchodilator | 4.8 | 2 | 1 | ||
| olodaterol [no description available] | 16.5 | 60 | 27 | aromatic ether; benzoxazine; phenols; secondary alcohol; secondary amino compound | beta-adrenergic agonist; bronchodilator agent |
| gsk573719 GSK573719: Muscarinic Antagonist. umeclidinium : A quaternary ammonium ion that is quinuclidine substituted at positions 1 and 4 by 2-(benzyloxy)ethyl and hydroxy(diphenyl)methyl groups respectively. | 13.16 | 29 | 8 | ||
| aclidinium bromide aclidinium bromide: a long-acting, inhaled antimuscarinic; in phase I trial 8/2008. aclidinium bromide : A quaternary ammonium salt that is the bromide salt of aclidinium. A muscarinic acetylcholine M3 receptor antagonist, for the long-term maintenance treatment of bronchospasm associated with chronic obstructive pulmonary disease (COPD). | 17.4 | 28 | 7 | organic bromide salt; quaternary ammonium salt | bronchodilator agent; muscarinic antagonist |
| ru 66647 telithromycin: a ketolide; semisynthetic derivative of erythromycin with cycling of the C11-12 positions to form a carbamate ring to avoid acquired resistance to macrolides; binds 70S bacterial rRNA, specifically to the 23S part (23S RIBOSOMAL RNA), preventing protein synthesis; | 4.04 | 2 | 0 | ||
| td-4208 revefenacin: structure in first source | 7.08 | 4 | 3 | ||
| scopolamine hydrobromide [no description available] | 2.11 | 1 | 0 | ||
| amlodipine, atorvastatin drug combination [no description available] | 3.12 | 1 | 0 | ||
| rifamycins [no description available] | 4.04 | 2 | 0 | ||
| desmosine Desmosine: A rare amino acid found in elastin, formed by condensation of four molecules of lysine into a pyridinium ring. | 2.05 | 1 | 0 | aromatic amino acid | |
| (9R)-9-chloro-11,17-dihydroxy-17-(2-hydroxy-1-oxoethyl)-10,13,16-trimethyl-6,7,8,11,12,14,15,16-octahydrocyclopenta[a]phenanthren-3-one Beclomethasone: An anti-inflammatory, synthetic glucocorticoid. It is used topically as an anti-inflammatory agent and in aerosol form for the treatment of ASTHMA.. beclomethasone : A 17alpha-hydroxy steroid that is prednisolone in which the hydrogens at the 9alpha and 16beta positions are substituted by a chlorine and a methyl group, respectively. | 11.56 | 14 | 6 | 21-hydroxy steroid | |
| sodium pertechnetate tc 99m Sodium Pertechnetate Tc 99m: A gamma-emitting radionuclide imaging agent used for the diagnosis of diseases in many tissues, particularly in the gastrointestinal system, cardiovascular and cerebral circulation, brain, thyroid, and joints. | 3.42 | 1 | 1 | ||
| chiniofon Hydroxyquinolines: The 8-hydroxy derivatives inhibit various enzymes and their halogenated derivatives, though neurotoxic, are used as topical anti-infective agents, among other uses. | 3.82 | 2 | 0 | ||
| combivent respimat Albuterol, Ipratropium Drug Combination: A combined pharmaceutical preparation of Ipratropium Bromide and Albuterol Sulfate that is used to treat the symptoms of ASTHMA and CHRONIC OBSTRUCTIVE PULMONARY DISEASE. | 5.27 | 6 | 2 | ||
| cardiovascular agents Cardiovascular Agents: Agents that affect the rate or intensity of cardiac contraction, blood vessel diameter, or blood volume. | 3.12 | 1 | 0 | ||
| piperidines Piperidines: A family of hexahydropyridines. | 5.06 | 3 | 1 | ||
| interleukin-8 Interleukin-8: A member of the CXC chemokine family that plays a role in the regulation of the acute inflammatory response. It is secreted by variety of cell types and induces CHEMOTAXIS of NEUTROPHILS and other inflammatory cells. | 8.36 | 11 | 4 | ||
| azd9164 AZD9164: structure in first source | 4.39 | 1 | 1 | ||
| n-((5-(methanesulfonyl)pyridin-2-yl)methyl)-6-methyl-5-(1-methyl-1h-pyrazol-5-yl)-2-oxo-1-(3-(trifluoromethyl)phenyl)-1,2-dihydropyridine-3-carboxamide N-((5-(methanesulfonyl)pyridin-2-yl)methyl)-6-methyl-5-(1-methyl-1H-pyrazol-5-yl)-2-oxo-1-(3-(trifluoromethyl)phenyl)-1,2-dihydropyridine-3-carboxamide: structure in first source | 4.37 | 1 | 1 | ||
| budesonide, formoterol fumarate drug combination Budesonide, Formoterol Fumarate Drug Combination: A pharmaceutical preparation of budesonide and formoterol fumarate that is used as an ANTI-ASTHMATIC AGENT and for the treatment of CHRONIC OBSTRUCTIVE PULMONARY DISEASE. | 9.48 | 10 | 3 | ||
| fluticasone propionate, salmeterol xinafoate drug combination Fluticasone-Salmeterol Drug Combination: A drug combination of fluticasone and salmeterol that is used as an inhaler formulation to manage the symptoms of ASTHMA and CHRONIC OBSTRUCTIVE PULMONARY DISEASE. | 14.63 | 38 | 18 | ||
| transforming growth factor beta Transforming Growth Factor beta: A factor synthesized in a wide variety of tissues. It acts synergistically with TGF-alpha in inducing phenotypic transformation and can also act as a negative autocrine growth factor. TGF-beta has a potential role in embryonal development, cellular differentiation, hormone secretion, and immune function. TGF-beta is found mostly as homodimer forms of separate gene products TGF-beta1, TGF-beta2 or TGF-beta3. Heterodimers composed of TGF-beta1 and 2 (TGF-beta1.2) or of TGF-beta2 and 3 (TGF-beta2.3) have been isolated. The TGF-beta proteins are synthesized as precursor proteins. | 2.05 | 1 | 0 | ||
| daptomycin [no description available] | 3.13 | 1 | 0 | ||
| sildenafil citrate Sildenafil Citrate: A PHOSPHODIESTERASE TYPE-5 INHIBITOR; VASODILATOR AGENT and UROLOGICAL AGENT that is used in the treatment of ERECTILE DYSFUNCTION and PRIMARY PULMONARY HYPERTENSION.. sildenafil citrate : The citrate salt of sildenafil. | 2.01 | 1 | 0 | citrate salt | EC 3.1.4.35 (3',5'-cyclic-GMP phosphodiesterase) inhibitor; vasodilator agent |
| eye [no description available] | 3.43 | 1 | 1 | ||
| pyrimidinones Pyrimidinones: Heterocyclic compounds known as 2-pyrimidones (or 2-hydroxypyrimidines) and 4-pyrimidones (or 4-hydroxypyrimidines) with the general formula C4H4N2O. | 5.91 | 2 | 2 |
| Condition | Indicated | Relationship Strength | Studies | Trials |
|---|---|---|---|---|
| Airflow Obstruction, Chronic [description not available] | 0 | 28.44 | 1,234 | 593 |
| Pulmonary Disease, Chronic Obstructive A disease of chronic diffuse irreversible airflow obstruction. Subcategories of COPD include CHRONIC BRONCHITIS and PULMONARY EMPHYSEMA. | 0 | 28.44 | 1,234 | 593 |
| Bronchospasm [description not available] | 0 | 5.37 | 7 | 0 |
| Bronchial Spasm Spasmodic contraction of the smooth muscle of the bronchi. | 0 | 5.37 | 7 | 0 |
| Muscle Relaxation That phase of a muscle twitch during which a muscle returns to a resting position. | 0 | 3.87 | 2 | 1 |
| Disease Models, Animal Naturally-occurring or experimentally-induced animal diseases with pathological processes analogous to human diseases. | 0 | 6.9 | 24 | 0 |
| Centriacinar Emphysema [description not available] | 0 | 5.61 | 6 | 1 |
| Asthma, Bronchial [description not available] | 0 | 21.34 | 233 | 67 |
| Asthma A form of bronchial disorder with three distinct components: airway hyper-responsiveness (RESPIRATORY HYPERSENSITIVITY), airway INFLAMMATION, and intermittent AIRWAY OBSTRUCTION. It is characterized by spasmodic contraction of airway smooth muscle, WHEEZING, and dyspnea (DYSPNEA, PAROXYSMAL). | 0 | 21.34 | 233 | 67 |
| Bronchiectasis Persistent abnormal dilatation of the bronchi. | 0 | 12 | 7 | 2 |
| Innate Inflammatory Response [description not available] | 0 | 11.25 | 19 | 5 |
| Inflammation A pathological process characterized by injury or destruction of tissues caused by a variety of cytologic and chemical reactions. It is usually manifested by typical signs of pain, heat, redness, swelling, and loss of function. | 0 | 11.25 | 19 | 5 |
| Apoplexy [description not available] | 0 | 8.41 | 15 | 0 |
| Stroke A group of pathological conditions characterized by sudden, non-convulsive loss of neurological function due to BRAIN ISCHEMIA or INTRACRANIAL HEMORRHAGES. Stroke is classified by the type of tissue NECROSIS, such as the anatomic location, vasculature involved, etiology, age of the affected individual, and hemorrhagic vs. non-hemorrhagic nature. (From Adams et al., Principles of Neurology, 6th ed, pp777-810) | 0 | 13.41 | 15 | 0 |
| Carcinoma, Non-Small Cell Lung [description not available] | 0 | 5.08 | 3 | 1 |
| Cancer of Lung [description not available] | 0 | 7.11 | 10 | 2 |
| Carcinoma, Non-Small-Cell Lung A heterogeneous aggregate of at least three distinct histological types of lung cancer, including SQUAMOUS CELL CARCINOMA; ADENOCARCINOMA; and LARGE CELL CARCINOMA. They are dealt with collectively because of their shared treatment strategy. | 0 | 5.08 | 3 | 1 |
| Lung Neoplasms Tumors or cancer of the LUNG. | 0 | 7.11 | 10 | 2 |
| Breathlessness [description not available] | 0 | 18.9 | 104 | 70 |
| Dyspnea Difficult or labored breathing. | 0 | 18.9 | 104 | 70 |
| Cardiovascular Stroke [description not available] | 0 | 8.41 | 13 | 0 |
| Myocardial Infarction NECROSIS of the MYOCARDIUM caused by an obstruction of the blood supply to the heart (CORONARY CIRCULATION). | 0 | 8.41 | 13 | 0 |
| Breathing Sounds [description not available] | 0 | 7.76 | 6 | 4 |
| Infections, Respiratory [description not available] | 0 | 7.03 | 4 | 4 |
| Respiratory Sounds Noises, normal and abnormal, heard on auscultation over any part of the RESPIRATORY TRACT. | 0 | 7.76 | 6 | 4 |
| Respiratory Tract Infections Invasion of the host RESPIRATORY SYSTEM by microorganisms, usually leading to pathological processes or diseases. | 0 | 7.03 | 4 | 4 |
| Coronary Heart Disease [description not available] | 0 | 2.41 | 1 | 0 |
| Coronary Disease An imbalance between myocardial functional requirements and the capacity of the CORONARY VESSELS to supply sufficient blood flow. It is a form of MYOCARDIAL ISCHEMIA (insufficient blood supply to the heart muscle) caused by a decreased capacity of the coronary vessels. | 0 | 2.41 | 1 | 0 |
| Allergic Rhinitis [description not available] | 0 | 2.6 | 1 | 0 |
| Rhinitis, Allergic An inflammation of the NASAL MUCOSA triggered by ALLERGENS. | 0 | 2.6 | 1 | 0 |
| Infections, Coronavirus [description not available] | 0 | 2.6 | 1 | 0 |
| Coronavirus Infections Virus diseases caused by the CORONAVIRUS genus. Some specifics include transmissible enteritis of turkeys (ENTERITIS, TRANSMISSIBLE, OF TURKEYS); FELINE INFECTIOUS PERITONITIS; and transmissible gastroenteritis of swine (GASTROENTERITIS, TRANSMISSIBLE, OF SWINE). | 0 | 2.6 | 1 | 0 |
| Cough A sudden, audible expulsion of air from the lungs through a partially closed glottis, preceded by inhalation. It is a protective response that serves to clear the trachea, bronchi, and/or lungs of irritants and secretions, or to prevent aspiration of foreign materials into the lungs. | 0 | 8.78 | 11 | 4 |
| Experimental Lung Inflammation Inflammation of any part, segment or lobe, of the lung parenchyma. | 0 | 12.7 | 28 | 13 |
| Pneumonia Infection of the lung often accompanied by inflammation. | 0 | 12.7 | 28 | 13 |
| Asthma-Chronic Obstructive Pulmonary Disease Overlap Syndrome Syndrome with clinical features of both ASTHMA and COPD. | 0 | 2.6 | 1 | 0 |
| Bronchiolitis, Exudative [description not available] | 0 | 6.79 | 7 | 1 |
| Bronchiolitis Obliterans Inflammation of the BRONCHIOLES leading to an obstructive lung disease. Bronchioles are characterized by fibrous granulation tissue with bronchial exudates in the lumens. Clinical features include a nonproductive cough and DYSPNEA. | 0 | 11.79 | 7 | 1 |
| Atelectasis [description not available] | 0 | 3.59 | 1 | 1 |
| Disease Exacerbation [description not available] | 0 | 20.64 | 139 | 85 |
| Eosinophilia, Tropical [description not available] | 0 | 4.42 | 4 | 0 |
| Eosinophilia Abnormal increase of EOSINOPHILS in the blood, tissues or organs. | 0 | 4.42 | 4 | 0 |
| Cancer of Esophagus [description not available] | 0 | 3.64 | 1 | 1 |
| Complication, Postoperative [description not available] | 0 | 5.12 | 5 | 2 |
| Esophageal Neoplasms Tumors or cancer of the ESOPHAGUS. | 0 | 3.64 | 1 | 1 |
| Postoperative Complications Pathologic processes that affect patients after a surgical procedure. They may or may not be related to the disease for which the surgery was done, and they may or may not be direct results of the surgery. | 0 | 5.12 | 5 | 2 |
| Arrhythmia [description not available] | 0 | 7.08 | 9 | 0 |
| Cardiac Failure [description not available] | 0 | 5.88 | 8 | 1 |
| Arrhythmias, Cardiac Any disturbances of the normal rhythmic beating of the heart or MYOCARDIAL CONTRACTION. Cardiac arrhythmias can be classified by the abnormalities in HEART RATE, disorders of electrical impulse generation, or impulse conduction. | 0 | 7.08 | 9 | 0 |
| Cardiovascular Diseases Pathological conditions involving the CARDIOVASCULAR SYSTEM including the HEART; the BLOOD VESSELS; or the PERICARDIUM. | 0 | 15.25 | 62 | 7 |
| Heart Failure A heterogeneous condition in which the heart is unable to pump out sufficient blood to meet the metabolic need of the body. Heart failure can be caused by structural defects, functional abnormalities (VENTRICULAR DYSFUNCTION), or a sudden overload beyond its capacity. Chronic heart failure is more common than acute heart failure which results from sudden insult to cardiac function, such as MYOCARDIAL INFARCTION. | 0 | 5.88 | 8 | 1 |
| Bronchospasm, Exercise-Induced [description not available] | 0 | 3.17 | 1 | 0 |
| Asthma, Exercise-Induced Asthma attacks following a period of exercise. Usually the induced attack is short-lived and regresses spontaneously. The magnitude of postexertional airway obstruction is strongly influenced by the environment in which exercise is performed (i.e. inhalation of cold air during physical exertion markedly augments the severity of the airway obstruction; conversely, warm humid air blunts or abolishes it). | 0 | 3.17 | 1 | 0 |
| Obesity A status with BODY WEIGHT that is grossly above the recommended standards, usually due to accumulation of excess FATS in the body. The standards may vary with age, sex, genetic or cultural background. In the BODY MASS INDEX, a BMI greater than 30.0 kg/m2 is considered obese, and a BMI greater than 40.0 kg/m2 is considered morbidly obese (MORBID OBESITY). | 0 | 3.44 | 2 | 0 |
| Chronic Illness [description not available] | 0 | 6.53 | 9 | 0 |
| Esophageal Reflux [description not available] | 0 | 4.64 | 3 | 0 |
| Chronic Disease Diseases which have one or more of the following characteristics: they are permanent, leave residual disability, are caused by nonreversible pathological alteration, require special training of the patient for rehabilitation, or may be expected to require a long period of supervision, observation, or care (Dictionary of Health Services Management, 2d ed). For epidemiological studies chronic disease often includes HEART DISEASES; STROKE; CANCER; and diabetes (DIABETES MELLITUS, TYPE 2). | 0 | 6.53 | 9 | 0 |
| Gastroesophageal Reflux Retrograde flow of gastric juice (GASTRIC ACID) and/or duodenal contents (BILE ACIDS; PANCREATIC JUICE) into the distal ESOPHAGUS, commonly due to incompetence of the LOWER ESOPHAGEAL SPHINCTER. | 0 | 4.64 | 3 | 0 |
| Diffuse Parenchymal Lung Disease [description not available] | 0 | 2.15 | 1 | 0 |
| Hyperplasia An increase in the number of cells in a tissue or organ without tumor formation. It differs from HYPERTROPHY, which is an increase in bulk without an increase in the number of cells. | 0 | 2.15 | 1 | 0 |
| Lung Diseases, Interstitial A diverse group of lung diseases that affect the lung parenchyma. They are characterized by an initial inflammation of PULMONARY ALVEOLI that extends to the interstitium and beyond leading to diffuse PULMONARY FIBROSIS. Interstitial lung diseases are classified by their etiology (known or unknown causes), and radiological-pathological features. | 0 | 2.15 | 1 | 0 |
| Bronchial Hyperreactivity Tendency of the smooth muscle of the tracheobronchial tree to contract more intensely in response to a given stimulus than it does in the response seen in normal individuals. This condition is present in virtually all symptomatic patients with asthma. The most prominent manifestation of this smooth muscle contraction is a decrease in airway caliber that can be readily measured in the pulmonary function laboratory. | 0 | 5.07 | 3 | 1 |
| Eosinophilia, Pulmonary [description not available] | 0 | 4.45 | 1 | 1 |
| Pulmonary Eosinophilia A condition characterized by infiltration of the lung with EOSINOPHILS due to inflammation or other disease processes. Major eosinophilic lung diseases are the eosinophilic pneumonias caused by infections, allergens, or toxic agents. | 0 | 4.45 | 1 | 1 |
| Muscle Contraction A process leading to shortening and/or development of tension in muscle tissue. Muscle contraction occurs by a sliding filament mechanism whereby actin filaments slide inward among the myosin filaments. | 0 | 2.97 | 4 | 0 |
| Cholera Infantum [description not available] | 0 | 4.8 | 2 | 1 |
| Bilateral Headache [description not available] | 0 | 5.38 | 2 | 2 |
| Headache The symptom of PAIN in the cranial region. It may be an isolated benign occurrence or manifestation of a wide variety of HEADACHE DISORDERS. | 0 | 5.38 | 2 | 2 |
| Genetic Predisposition [description not available] | 0 | 4.14 | 3 | 1 |
| Allergy, Food [description not available] | 0 | 2.15 | 1 | 0 |
| Hives [description not available] | 0 | 2.15 | 1 | 0 |
| Enterocolitis Inflammation of the MUCOSA of both the SMALL INTESTINE and the LARGE INTESTINE. Etiology includes ISCHEMIA, infections, allergic, and immune responses. | 0 | 2.15 | 1 | 0 |
| Food Hypersensitivity Gastrointestinal disturbances, skin eruptions, or shock due to allergic reactions to allergens in food. | 0 | 2.15 | 1 | 0 |
| Urticaria A vascular reaction of the skin characterized by erythema and wheal formation due to localized increase of vascular permeability. The causative mechanism may be allergy, infection, or stress. | 0 | 2.15 | 1 | 0 |
| Chronic Bronchitis [description not available] | 0 | 3.09 | 1 | 0 |
| Bronchitis, Chronic A subcategory of CHRONIC OBSTRUCTIVE PULMONARY DISEASE. The disease is characterized by hypersecretion of mucus accompanied by a chronic (more than 3 months in 2 consecutive years) productive cough. Infectious agents are a major cause of chronic bronchitis. | 0 | 3.09 | 1 | 0 |
| Cystic Fibrosis of Pancreas [description not available] | 0 | 10.44 | 10 | 7 |
| Cystic Fibrosis An autosomal recessive genetic disease of the EXOCRINE GLANDS. It is caused by mutations in the gene encoding the CYSTIC FIBROSIS TRANSMEMBRANE CONDUCTANCE REGULATOR expressed in several organs including the LUNG, the PANCREAS, the BILIARY SYSTEM, and the SWEAT GLANDS. Cystic fibrosis is characterized by epithelial secretory dysfunction associated with ductal obstruction resulting in AIRWAY OBSTRUCTION; chronic RESPIRATORY INFECTIONS; PANCREATIC INSUFFICIENCY; maldigestion; salt depletion; and HEAT PROSTRATION. | 0 | 15.44 | 10 | 7 |
| Acute Disease Disease having a short and relatively severe course. | 0 | 12.22 | 22 | 4 |
| Catarrh Inflammation of a mucous membrane with increased flow of mucous in humans or animals. Catarrh is used mostly in a historical context. | 0 | 3.09 | 1 | 0 |
| Haemophilus Infections Infections with bacteria of the genus HAEMOPHILUS. | 0 | 3.09 | 1 | 0 |
| Moraxella Infections [description not available] | 0 | 3.09 | 1 | 0 |
| Common Cold A catarrhal disorder of the upper respiratory tract, which may be viral or a mixed infection. It generally involves a runny nose, nasal congestion, and sneezing. | 0 | 3.09 | 1 | 0 |
| Airway Remodeling The structural changes in the number, mass, size and/or composition of the airway tissues. | 0 | 10.53 | 9 | 0 |
| Community Acquired Infection [description not available] | 0 | 2.17 | 1 | 0 |
| Kidney Diseases Pathological processes of the KIDNEY or its component tissues. | 0 | 3.56 | 1 | 1 |
| Central Nervous System Disease [description not available] | 0 | 6.46 | 9 | 0 |
| Central Nervous System Diseases Diseases of any component of the brain (including the cerebral hemispheres, diencephalon, brain stem, and cerebellum) or the spinal cord. | 0 | 6.46 | 9 | 0 |
| Recrudescence [description not available] | 0 | 5.79 | 4 | 1 |
| Undifferentiated Connective Tissue Disease [description not available] | 0 | 3.59 | 1 | 1 |
| Koch's Disease [description not available] | 0 | 2.21 | 1 | 0 |
| Tuberculosis Any of the infectious diseases of man and other animals caused by species of MYCOBACTERIUM TUBERCULOSIS. | 0 | 2.21 | 1 | 0 |
| Adverse Drug Event [description not available] | 0 | 7.71 | 7 | 2 |
| Drug-Related Side Effects and Adverse Reactions Disorders that result from the intended use of PHARMACEUTICAL PREPARATIONS. Included in this heading are a broad variety of chemically-induced adverse conditions due to toxicity, DRUG INTERACTIONS, and metabolic effects of pharmaceuticals. | 0 | 7.71 | 7 | 2 |
| Bronchial Pneumonia [description not available] | 0 | 2.21 | 1 | 0 |
| Candida Infection [description not available] | 0 | 2.21 | 1 | 0 |
| Candidiasis Infection with a fungus of the genus CANDIDA. It is usually a superficial infection of the moist areas of the body and is generally caused by CANDIDA ALBICANS. (Dorland, 27th ed) | 0 | 2.21 | 1 | 0 |
| Disease, Pulmonary [description not available] | 0 | 3.84 | 2 | 1 |
| Lung Diseases Pathological processes involving any part of the LUNG. | 0 | 3.84 | 2 | 1 |
| Sore Throat [description not available] | 0 | 3.47 | 1 | 1 |
| Asialia [description not available] | 0 | 8.8 | 8 | 7 |
| Pharyngitis Inflammation of the throat (PHARYNX). | 0 | 3.47 | 1 | 1 |
| Xerostomia Decreased salivary flow. | 0 | 8.8 | 8 | 7 |
| Cardiac Diseases [description not available] | 0 | 3.39 | 2 | 0 |
| Heart Diseases Pathological conditions involving the HEART including its structural and functional abnormalities. | 0 | 3.39 | 2 | 0 |
| Adenocarcinoma, Basal Cell [description not available] | 0 | 2.08 | 1 | 0 |
| Experimental Neoplasms [description not available] | 0 | 2.08 | 1 | 0 |
| Adenocarcinoma A malignant epithelial tumor with a glandular organization. | 0 | 2.08 | 1 | 0 |
| Airway Hyper-Responsiveness [description not available] | 0 | 2.1 | 1 | 0 |
| Inhalation Injury, Smoke [description not available] | 0 | 2.48 | 2 | 0 |
| Burns Injuries to tissues caused by contact with heat, steam, chemicals (BURNS, CHEMICAL), electricity (BURNS, ELECTRIC), or the like. | 0 | 2.1 | 1 | 0 |
| Heart Disease, Ischemic [description not available] | 0 | 3.41 | 2 | 0 |
| Myocardial Ischemia A disorder of cardiac function caused by insufficient blood flow to the muscle tissue of the heart. The decreased blood flow may be due to narrowing of the coronary arteries (CORONARY ARTERY DISEASE), to obstruction by a thrombus (CORONARY THROMBOSIS), or less commonly, to diffuse narrowing of arterioles and other small vessels within the heart. Severe interruption of the blood supply to the myocardial tissue may result in necrosis of cardiac muscle (MYOCARDIAL INFARCTION). | 0 | 3.41 | 2 | 0 |
| Absence Status [description not available] | 0 | 2.1 | 1 | 0 |
| Status Epilepticus A prolonged seizure or seizures repeated frequently enough to prevent recovery between episodes occurring over a period of 20-30 minutes. The most common subtype is generalized tonic-clonic status epilepticus, a potentially fatal condition associated with neuronal injury and respiratory and metabolic dysfunction. Nonconvulsive forms include petit mal status and complex partial status, which may manifest as behavioral disturbances. Simple partial status epilepticus consists of persistent motor, sensory, or autonomic seizures that do not impair cognition (see also EPILEPSIA PARTIALIS CONTINUA). Subclinical status epilepticus generally refers to seizures occurring in an unresponsive or comatose individual in the absence of overt signs of seizure activity. (From N Engl J Med 1998 Apr 2;338(14):970-6; Neurologia 1997 Dec;12 Suppl 6:25-30) | 0 | 2.1 | 1 | 0 |
| Rhinitis, Allergic, Nonseasonal [description not available] | 0 | 2.1 | 1 | 0 |
| Rhinitis, Allergic, Perennial Inflammation of the mucous membrane of the nose similar to that found in hay fever except that symptoms persist throughout the year. The causes are usually air-borne allergens, particularly dusts, feathers, molds, animal fur, etc. | 0 | 2.1 | 1 | 0 |
| Airway Obstruction Any hindrance to the passage of air into and out of the lungs. | 0 | 7.56 | 9 | 2 |
| Bagassosis A diffuse parenchymal lung disease caused by inhaled dust from processing SUGARCANE (bagasse), usually in the manufacturing of wallboard. | 0 | 2.11 | 1 | 0 |
| Pneumoconiosis A diffuse parenchymal lung disease caused by inhalation of dust and by tissue reaction to their presence. These inorganic, organic, particulate, or vaporized matters usually are inhaled by workers in their occupational environment, leading to the various forms (ASBESTOSIS; BYSSINOSIS; and others). Similar air pollution can also have deleterious effects on the general population. | 0 | 2.11 | 1 | 0 |
| Metaplasia A condition in which there is a change of one adult cell type to another similar adult cell type. | 0 | 2.48 | 2 | 0 |
| Bradyarrhythmia [description not available] | 0 | 2.11 | 1 | 0 |
| Blood Pressure, Low [description not available] | 0 | 2.11 | 1 | 0 |
| Bradycardia Cardiac arrhythmias that are characterized by excessively slow HEART RATE, usually below 50 beats per minute in human adults. They can be classified broadly into SINOATRIAL NODE dysfunction and ATRIOVENTRICULAR BLOCK. | 0 | 2.11 | 1 | 0 |
| Hypotension Abnormally low BLOOD PRESSURE that can result in inadequate blood flow to the brain and other vital organs. Common symptom is DIZZINESS but greater negative impacts on the body occur when there is prolonged depravation of oxygen and nutrients. | 0 | 2.11 | 1 | 0 |
| Mydriasis Dilation of pupils to greater than 6 mm combined with failure of the pupils to constrict when stimulated with light. This condition may occur due to injury of the pupillary fibers in the oculomotor nerve, in acute angle-closure glaucoma, and in ADIE SYNDROME. | 0 | 2.11 | 1 | 0 |
| Acute Symptom Flare [description not available] | 0 | 4.43 | 1 | 1 |
| Cancer of Stomach [description not available] | 0 | 3.5 | 1 | 1 |
| Stomach Neoplasms Tumors or cancer of the STOMACH. | 0 | 3.5 | 1 | 1 |
| Acute Confusional Senile Dementia [description not available] | 0 | 2.13 | 1 | 0 |
| Dementia Praecox [description not available] | 0 | 2.13 | 1 | 0 |
| Alzheimer Disease A degenerative disease of the BRAIN characterized by the insidious onset of DEMENTIA. Impairment of MEMORY, judgment, attention span, and problem solving skills are followed by severe APRAXIAS and a global loss of cognitive abilities. The condition primarily occurs after age 60, and is marked pathologically by severe cortical atrophy and the triad of SENILE PLAQUES; NEUROFIBRILLARY TANGLES; and NEUROPIL THREADS. (From Adams et al., Principles of Neurology, 6th ed, pp1049-57) | 0 | 2.13 | 1 | 0 |
| Schizophrenia A severe emotional disorder of psychotic depth characteristically marked by a retreat from reality with delusion formation, HALLUCINATIONS, emotional disharmony, and regressive behavior. | 0 | 2.13 | 1 | 0 |
| Long Sleeper Syndrome [description not available] | 0 | 3.51 | 1 | 1 |
| Sleep Wake Disorders Abnormal sleep-wake schedule or pattern associated with the CIRCADIAN RHYTHM which affect the length, timing, and/or rigidity of the sleep-wake cycle relative to the day-night cycle. | 0 | 3.51 | 1 | 1 |
| Body Weight The mass or quantity of heaviness of an individual. It is expressed by units of pounds or kilograms. | 0 | 2.13 | 1 | 0 |
| Asymptomatic Conditions [description not available] | 0 | 3.04 | 1 | 0 |
| Sensitivity and Specificity Binary classification measures to assess test results. Sensitivity or recall rate is the proportion of true positives. Specificity is the probability of correctly determining the absence of a condition. (From Last, Dictionary of Epidemiology, 2d ed) | 0 | 5.82 | 4 | 2 |
| Smoking Cessation Discontinuing the habit of SMOKING. | 0 | 8.56 | 15 | 1 |
| Anesthesia A state characterized by loss of feeling or sensation. This depression of nerve function is usually the result of pharmacologic action and is induced to allow performance of surgery or other painful procedures. | 0 | 2.76 | 3 | 0 |
| Allergic Reaction [description not available] | 0 | 4.36 | 4 | 1 |
| Hypersensitivity Altered reactivity to an antigen, which can result in pathologic reactions upon subsequent exposure to that particular antigen. | 0 | 4.36 | 4 | 1 |
| Anxiety Feelings or emotions of dread, apprehension, and impending disaster but not disabling as with ANXIETY DISORDERS. | 0 | 2.48 | 2 | 0 |
| Obstructive Lung Diseases [description not available] | 0 | 9.09 | 14 | 5 |
| Lung Diseases, Obstructive Any disorder marked by obstruction of conducting airways of the lung. AIRWAY OBSTRUCTION may be acute, chronic, intermittent, or persistent. | 0 | 9.09 | 14 | 5 |
| Blood Pressure, High [description not available] | 0 | 2.04 | 1 | 0 |
| Hypertension Persistently high systemic arterial BLOOD PRESSURE. Based on multiple readings (BLOOD PRESSURE DETERMINATION), hypertension is currently defined as when SYSTOLIC PRESSURE is consistently greater than 140 mm Hg or when DIASTOLIC PRESSURE is consistently 90 mm Hg or more. | 0 | 2.04 | 1 | 0 |
| Adenoma, Prostatic [description not available] | 0 | 2.04 | 1 | 0 |
| Prostatic Hyperplasia Increase in constituent cells in the PROSTATE, leading to enlargement of the organ (hypertrophy) and adverse impact on the lower urinary tract function. This can be caused by increased rate of cell proliferation, reduced rate of cell death, or both. | 0 | 2.04 | 1 | 0 |
| Urinary Retention Inability to empty the URINARY BLADDER with voiding (URINATION). | 0 | 3.15 | 5 | 0 |
| Kidney Failure A severe irreversible decline in the ability of kidneys to remove wastes, concentrate URINE, and maintain ELECTROLYTE BALANCE; BLOOD PRESSURE; and CALCIUM metabolism. | 0 | 4.11 | 3 | 1 |
| Renal Insufficiency Conditions in which the KIDNEYS perform below the normal level in the ability to remove wastes, concentrate URINE, and maintain ELECTROLYTE BALANCE; BLOOD PRESSURE; and CALCIUM metabolism. Renal insufficiency can be classified by the degree of kidney damage (as measured by the level of PROTEINURIA) and reduction in GLOMERULAR FILTRATION RATE. | 0 | 4.11 | 3 | 1 |
| Hyperventilation A pulmonary ventilation rate faster than is metabolically necessary for the exchange of gases. It is the result of an increased frequency of breathing, an increased tidal volume, or a combination of both. It causes an excess intake of oxygen and the blowing off of carbon dioxide. | 0 | 7.51 | 7 | 2 |
| Viral Diseases [description not available] | 0 | 2.96 | 1 | 0 |
| Virus Diseases A general term for diseases caused by viruses. | 0 | 2.96 | 1 | 0 |
| Depression Depressive states usually of moderate intensity in contrast with MAJOR DEPRESSIVE DISORDER present in neurotic and psychotic disorders. | 0 | 2.05 | 1 | 0 |
| Esophagitis INFLAMMATION, acute or chronic, of the ESOPHAGUS caused by BACTERIA, chemicals, or TRAUMA. | 0 | 2.05 | 1 | 0 |
| Auricular Fibrillation [description not available] | 0 | 3.83 | 2 | 1 |
| Tachyarrhythmia [description not available] | 0 | 2.05 | 1 | 0 |
| Atrial Fibrillation Abnormal cardiac rhythm that is characterized by rapid, uncoordinated firing of electrical impulses in the upper chambers of the heart (HEART ATRIA). In such case, blood cannot be effectively pumped into the lower chambers of the heart (HEART VENTRICLES). It is caused by abnormal impulse generation. | 0 | 3.83 | 2 | 1 |
| Tachycardia Abnormally rapid heartbeat, usually with a HEART RATE above 100 beats per minute for adults. Tachycardia accompanied by disturbance in the cardiac depolarization (cardiac arrhythmia) is called tachyarrhythmia. | 0 | 2.05 | 1 | 0 |
| Drug Overdose Accidental or deliberate use of a medication or street drug in excess of normal dosage. | 0 | 2.05 | 1 | 0 |
| Breast Cancer [description not available] | 0 | 2.05 | 1 | 0 |
| Cancer of Cervix [description not available] | 0 | 2.05 | 1 | 0 |
| Breast Neoplasms Tumors or cancer of the human BREAST. | 0 | 2.05 | 1 | 0 |
| Uterine Cervical Neoplasms Tumors or cancer of the UTERINE CERVIX. | 0 | 2.05 | 1 | 0 |
| Diathesis [description not available] | 0 | 2.97 | 1 | 0 |
| Brain Vascular Disorders [description not available] | 0 | 6.53 | 11 | 0 |
| Cerebrovascular Disorders A spectrum of pathological conditions of impaired blood flow in the brain. They can involve vessels (ARTERIES or VEINS) in the CEREBRUM, the CEREBELLUM, and the BRAIN STEM. Major categories include INTRACRANIAL ARTERIOVENOUS MALFORMATIONS; BRAIN ISCHEMIA; CEREBRAL HEMORRHAGE; and others. | 0 | 6.53 | 11 | 0 |
| Hematologic Malignancies [description not available] | 0 | 4.92 | 4 | 0 |
| Hematologic Neoplasms Neoplasms located in the blood and blood-forming tissue (the bone marrow and lymphatic tissue). The commonest forms are the various types of LEUKEMIA, of LYMPHOMA, and of the progressive, life-threatening forms of the MYELODYSPLASTIC SYNDROMES. | 0 | 4.92 | 4 | 0 |
| Aging The gradual irreversible changes in structure and function of an organism that occur as a result of the passage of time. | 0 | 2.97 | 1 | 0 |
| Acute Respiratory Distress Syndrome [description not available] | 0 | 2.05 | 1 | 0 |
| Respiratory Distress Syndrome A syndrome characterized by progressive life-threatening RESPIRATORY INSUFFICIENCY in the absence of known LUNG DISEASES, usually following a systemic insult such as surgery or major TRAUMA. | 0 | 2.05 | 1 | 0 |
| Weight Reduction [description not available] | 0 | 3.35 | 2 | 0 |
| Bronchitis Inflammation of the large airways in the lung including any part of the BRONCHI, from the PRIMARY BRONCHI to the TERTIARY BRONCHI. | 0 | 3.37 | 2 | 0 |
| Weight Loss Decrease in existing BODY WEIGHT. | 0 | 3.35 | 2 | 0 |
| Alveolitis, Fibrosing [description not available] | 0 | 2.45 | 2 | 0 |
| Emphysema A pathological accumulation of air in tissues or organs. | 0 | 4.14 | 3 | 1 |
| Pulmonary Fibrosis A process in which normal lung tissues are progressively replaced by FIBROBLASTS and COLLAGEN causing an irreversible loss of the ability to transfer oxygen into the bloodstream via PULMONARY ALVEOLI. Patients show progressive DYSPNEA finally resulting in death. | 0 | 2.45 | 2 | 0 |
| Respiratory Tract Diseases Diseases involving the RESPIRATORY SYSTEM. | 0 | 2.76 | 3 | 0 |
| Anterior Circulation Transient Ischemic Attack [description not available] | 0 | 2.07 | 1 | 0 |
| Ischemic Attack, Transient Brief reversible episodes of focal, nonconvulsive ischemic dysfunction of the brain having a duration of less than 24 hours, and usually less than one hour, caused by transient thrombotic or embolic blood vessel occlusion or stenosis. Events may be classified by arterial distribution, temporal pattern, or etiology (e.g., embolic vs. thrombotic). (From Adams et al., Principles of Neurology, 6th ed, pp814-6) | 0 | 2.07 | 1 | 0 |
| Death, Sudden The abrupt cessation of all vital bodily functions, manifested by the permanent loss of total cerebral, respiratory, and cardiovascular functions. | 0 | 3.46 | 1 | 1 |
| Cardiac Arrest, Sudden [description not available] | 0 | 3.46 | 1 | 1 |
| Death, Sudden, Cardiac Unexpected rapid natural death due to cardiovascular collapse within one hour of initial symptoms. It is usually caused by the worsening of existing heart diseases. The sudden onset of symptoms, such as CHEST PAIN and CARDIAC ARRHYTHMIAS, particularly VENTRICULAR TACHYCARDIA, can lead to the loss of consciousness and cardiac arrest followed by biological death. (from Braunwald's Heart Disease: A Textbook of Cardiovascular Medicine, 7th ed., 2005) | 0 | 3.46 | 1 | 1 |
| Atherogenesis [description not available] | 0 | 2.06 | 1 | 0 |
| Atherosclerosis A thickening and loss of elasticity of the walls of ARTERIES that occurs with formation of ATHEROSCLEROTIC PLAQUES within the ARTERIAL INTIMA. | 0 | 2.06 | 1 | 0 |
| Infections, Picornaviridae [description not available] | 0 | 2.07 | 1 | 0 |
| Silicosis A form of pneumoconiosis resulting from inhalation of dust containing crystalline form of SILICON DIOXIDE, usually in the form of quartz. Amorphous silica is relatively nontoxic. | 0 | 8.45 | 1 | 1 |
| Depression, Endogenous [description not available] | 0 | 2.08 | 1 | 0 |
| Central Retinal Edema, Cystoid [description not available] | 0 | 2.08 | 1 | 0 |
| Depressive Disorder An affective disorder manifested by either a dysphoric mood or loss of interest or pleasure in usual activities. The mood disturbance is prominent and relatively persistent. | 0 | 2.08 | 1 | 0 |
| Macular Edema Fluid accumulation in the outer layer of the MACULA LUTEA that results from intraocular or systemic insults. It may develop in a diffuse pattern where the macula appears thickened or it may acquire the characteristic petaloid appearance referred to as cystoid macular edema. Although macular edema may be associated with various underlying conditions, it is most commonly seen following intraocular surgery, venous occlusive disease, DIABETIC RETINOPATHY, and posterior segment inflammatory disease. (From Survey of Ophthalmology 2004; 49(5) 470-90) | 0 | 2.08 | 1 | 0 |
| Grippe [description not available] | 0 | 4.39 | 1 | 1 |
| Influenza, Human An acute viral infection in humans involving the respiratory tract. It is marked by inflammation of the NASAL MUCOSA; the PHARYNX; and conjunctiva, and by headache and severe, often generalized, myalgia. | 0 | 4.39 | 1 | 1 |
| Respiration Disorders Diseases of the respiratory system in general or unspecified or for a specific respiratory disease not available. | 0 | 2.49 | 2 | 0 |
| Impotence [description not available] | 0 | 2.01 | 1 | 0 |
| Erectile Dysfunction The inability in the male to have a PENILE ERECTION due to psychological or organ dysfunction. | 0 | 2.01 | 1 | 0 |
| Diabetes Mellitus A heterogeneous group of disorders characterized by HYPERGLYCEMIA and GLUCOSE INTOLERANCE. | 0 | 2.01 | 1 | 0 |
| Chronic Idiopathic Intestinal Pseudo-Obstruction [description not available] | 0 | 2.02 | 1 | 0 |
| Intestinal Pseudo-Obstruction A type of ILEUS, a functional not mechanical obstruction of the INTESTINES. This syndrome is caused by a large number of disorders involving the smooth muscles (MUSCLE, SMOOTH) or the NERVOUS SYSTEM. | 0 | 2.02 | 1 | 0 |
| Bone Loss, Perimenopausal [description not available] | 0 | 2.94 | 1 | 0 |
| Osteoporosis, Postmenopausal Metabolic disorder associated with fractures of the femoral neck, vertebrae, and distal forearm. It occurs commonly in women within 15-20 years after menopause, and is caused by factors associated with menopause including estrogen deficiency. | 0 | 2.94 | 1 | 0 |
| Remission, Spontaneous A spontaneous diminution or abatement of a disease over time, without formal treatment. | 0 | 2.02 | 1 | 0 |
| Lupus Erythematosus, Cutaneous, Subacute [description not available] | 0 | 2.02 | 1 | 0 |
| Lupus Erythematosus, Cutaneous A form of lupus erythematosus in which the skin may be the only organ involved or in which skin involvement precedes the spread into other body systems. It has been classified into three forms - acute (= LUPUS ERYTHEMATOSUS, SYSTEMIC with skin lesions), subacute, and chronic (= LUPUS ERYTHEMATOSUS, DISCOID). | 0 | 2.02 | 1 | 0 |
| ATLL [description not available] | 0 | 2.03 | 1 | 0 |
| Leukemia-Lymphoma, Adult T-Cell Aggressive T-Cell malignancy with adult onset, caused by HUMAN T-LYMPHOTROPIC VIRUS 1. It is endemic in Japan, the Caribbean basin, Southeastern United States, Hawaii, and parts of Central and South America and sub-Saharan Africa. | 0 | 2.03 | 1 | 0 |
| Glaucoma, Angle Closure [description not available] | 0 | 2.03 | 1 | 0 |
| Glaucoma, Angle-Closure A form of glaucoma in which the intraocular pressure increases because the angle of the anterior chamber is blocked and the aqueous humor cannot drain from the anterior chamber. | 0 | 2.03 | 1 | 0 |
| Dermatitis, Contact, Photoallergic [description not available] | 0 | 2.03 | 1 | 0 |
| Licheniform Eruptions [description not available] | 0 | 2.03 | 1 | 0 |
| Dermatitis Medicamentosa [description not available] | 0 | 2.03 | 1 | 0 |
| Mouth Ulcer [description not available] | 0 | 2.03 | 1 | 0 |
| Oral Ulcer A loss of mucous substance of the mouth showing local excavation of the surface, resulting from the sloughing of inflammatory necrotic tissue. It is the result of a variety of causes, e.g., denture irritation, aphthous stomatitis (STOMATITIS, APHTHOUS); NOMA; necrotizing gingivitis (GINGIVITIS, NECROTIZING ULCERATIVE); TOOTHBRUSHING; and various irritants. (From Jablonski, Dictionary of Dentistry, 1992, p842) | 0 | 2.03 | 1 | 0 |
| Acute Edematous Pancreatitis [description not available] | 0 | 2.03 | 1 | 0 |
| Pancreatitis INFLAMMATION of the PANCREAS. Pancreatitis is classified as acute unless there are computed tomographic or endoscopic retrograde cholangiopancreatographic findings of CHRONIC PANCREATITIS (International Symposium on Acute Pancreatitis, Atlanta, 1992). The two most common forms of acute pancreatitis are ALCOHOLIC PANCREATITIS and gallstone pancreatitis. | 0 | 2.03 | 1 | 0 |
| Bleb [description not available] | 0 | 2.03 | 1 | 0 |
| Nasal Catarrh [description not available] | 0 | 2.91 | 1 | 0 |
| Rhinitis Inflammation of the NASAL MUCOSA, the mucous membrane lining the NASAL CAVITIES. | 0 | 2.91 | 1 | 0 |