olodaterol
Cross-References
| ID Source | ID |
|---|---|
| PubMed CID | 11504295 |
| CHEMBL ID | 605846 |
| CHEBI ID | 82700 |
| SCHEMBL ID | 560926 |
| MeSH ID | M0546842 |
Synonyms (53)
| Synonym |
|---|
| CHEMBL605846 |
| chebi:82700 , |
| olodaterol , |
| bi 1744 |
| olodaterol (usan/inn) |
| striverdi respimat (tn) |
| 868049-49-4 |
| D10145 |
| 6-hydroxy-8-((1r)-1-hydroxy-2-((2-(4-methoxyphenyl)-1,1-dimethylethyl)amino)ethyl)-2h-1,4-benzoxazin-3(4h)-one |
| 6-hydroxy-8-(1-hydroxy-2-((2-(4-methoxyphenyl)-1,1-dimethylethyl)amino)ethyl)-2h-1,4-benzoxazin-3(4h)-one |
| olodaterol [usan:inn] |
| unii-vd2ysn1afd |
| vd2ysn1afd , |
| 2h-1,4-benzoxazin-3(4h)-one, 6-hydroxy-8-((1r)-1-hydroxy-2-((2-(4-methoxyphenyl)- 1,1-dimethylethyl)amino)ethyl)- |
| S4485 |
| olodaterol [vandf] |
| olodaterol [mi] |
| olodaterol [usan] |
| olodaterol [who-dd] |
| 6-hydroxy-8-((1r)-1-hydroxy-2-((1-(4-methoxyphenyl)-2-methylpropan-2-yl)amino)ethyl)-2h-1,4-benzoxazin-3(4h)-one |
| olodaterol [inn] |
| bi-1744 |
| olodaterol hydrochloride [jan] |
| 2h-1,4-benzoxazin-3(4h)-one, 6-hydroxy-8-((1r)-1-hydroxy-2-((2-(4-methoxyphenyl)-1,1-dimethylethyl)amino)ethyl)- |
| SCHEMBL560926 |
| 6-hydroxy-8-[(1r)-1-hydroxy-2-[[2-(4-methoxyphenyl)-1,1-dimethylethyl]amino]ethyl]-2h-1,4-benzoxazin-3(4h)-one |
| 6-hydroxy-8-[(1r)-1-hydroxy-2-[[1-(4-methoxyphenyl)-2-methylpropan-2-yl]amino]ethyl]-4h-1,4-benzoxazin-3-one |
| striverdi |
| gtpl7543 |
| 6-hydroxy-8-[(1r)-1-hydroxy-2-{[1-(4-methoxyphenyl)-2-methylpropan-2-yl]amino}ethyl]-2h-1,4-benzoxazin-3(4h)-one |
| AC-29048 |
| DB09080 |
| AKOS026674098 |
| (r)-6-hydroxy-8-(1-hydroxy-2-((1-(4-methoxyphenyl)-2-methylpropan-2-yl)amino)ethyl)-2h-benzo[b][1,4]oxazin-3(4h)-one |
| 6-hydroxy-8-[(1r)-1-hydroxy-2-{[1-(4-methoxyphenyl)-2-methylpropan-2-yl]amino}ethyl]-3,4-dihydro-2h-1,4-benzoxazin-3-one |
| AS-74944 |
| EX-A1729 |
| HY-14301 |
| CS-6275 |
| olodaterol free base |
| 868049-49-4 (free base) |
| bi1744 |
| BCP11473 |
| Q7088466 |
| AMY16614 |
| NCGC00522533-01 |
| C76830 |
| olodaterol (bi 1744) |
| DTXSID601024792 |
| EN300-20331067 |
| olodaterolum |
| r03ac19 |
| bdbm50569861 |
Research Excerpts
Overview
Olodaterol is a novel long-acting β2-agonist with a 24-hour bronchodilator profile. It has proven to be effective in improving lung function, reducing rescue medication use, and improving dyspnea and health-related quality of life.
Effects
| Excerpt | Reference | Relevance |
|---|---|---|
| "Olodaterol has a rapid onset of action (comparable to formoterol) and provides bronchodilation over 24 hours." | ( Striving for optimal bronchodilation: focus on olodaterol. Incorvaia, C; Makri, E; Montagni, M; Riario-Sforza, GG; Ridolo, E, 2016) | 1.41 |
Treatment
Treatment with olodaterol or formoterol is not associated with arrhythmias or a persistent increase in heart rate as assessed by Holter ECG in patients with COPD. All olodeterol treatments demonstrated statistically significant improvements in FEV1 AUC0-24 response at 3 weeks versus placebo.
| Excerpt | Reference | Relevance |
|---|---|---|
| "All olodaterol treatments demonstrated statistically significant improvements in FEV1 AUC0-24 response at 3 weeks versus placebo (p < 0.0001); adjusted mean treatment difference versus placebo was 0.191 L for olodaterol 2.5 μg BID (95 % confidence interval [CI] 0.152, 0.229), 0.150 L for 5 μg QD (95 % CI 0.111, 0.189), 0.228 L for 5 μg BID (95 % CI 0.190, 0.266) and 0.209 L for 10 μg QD (95 % CI 0.170, 0.247)." | ( Randomised, double-blind, placebo-controlled crossover study to investigate different dosing regimens of olodaterol delivered via Respimat® in patients with moderate to severe persistent asthma. Beeh, KM; Fležar, M; Gahlemann, M; LaForce, C; Toorawa, R; Wenz, A, 2015) | 1.11 |
| "Treatment with olodaterol or formoterol is not associated with arrhythmias or a persistent increase in heart rate as assessed by Holter ECG in patients with COPD." | ( A Post Hoc Holter ECG Analysis of Olodaterol and Formoterol in Moderate-to-Very-Severe COPD. Alter, P; Andreas, S; Bothner, U; de la Hoz, A; Kloer, I; Trampisch, M, 2020) | 1.19 |
Toxicity
Randomized controlled trials comparing olodaterol with placebo for patients with COPD or asthma were included. We could not find any relationship between inhaled olodlerol use and nonfatal serious adverse events.
Pharmacokinetics
| Excerpt | Reference | Relevance |
|---|---|---|
| " The aim of the present study was to describe the plasma and urine pharmacokinetics of olodaterol after intravenous administration and oral inhalation in healthy volunteers by population pharmacokinetic modelling and thereby to infer its pulmonary fate." | ( Investigating pulmonary and systemic pharmacokinetics of inhaled olodaterol in healthy volunteers using a population pharmacokinetic approach. Borghardt, JM; Formella, S; Kloft, C; Kunz, C; Staab, A; Weber, B, 2016) | 0.89 |
| " A stepwise model building approach was applied, using population pharmacokinetic modelling." | ( Investigating pulmonary and systemic pharmacokinetics of inhaled olodaterol in healthy volunteers using a population pharmacokinetic approach. Borghardt, JM; Formella, S; Kloft, C; Kunz, C; Staab, A; Weber, B, 2016) | 0.67 |
| "A pharmacokinetic model, including three depot compartments with associated parallel first-order absorption processes (pulmonary model) on top of a four-compartment body model (systemic disposition model), was found to describe the data the best." | ( Investigating pulmonary and systemic pharmacokinetics of inhaled olodaterol in healthy volunteers using a population pharmacokinetic approach. Borghardt, JM; Formella, S; Kloft, C; Kunz, C; Staab, A; Weber, B, 2016) | 0.67 |
| " The aims of this population pharmacokinetic (PK) analysis were: (1) to investigate systemic PK and thereby make inferences about pulmonary PK in asthmatic patients, COPD patients and healthy volunteers, and (2) to assess whether differences in pulmonary efficacy might be expected based on pulmonary PK characteristics." | ( Model-based evaluation of pulmonary pharmacokinetics in asthmatic and COPD patients after oral olodaterol inhalation. Borghardt, JM; Kloft, C; Kunz, C; Staab, A; Weber, B, 2016) | 0.65 |
| "8%) of PBIO was slowly absorbed with an absorption half-life of 18." | ( Model-based evaluation of pulmonary pharmacokinetics in asthmatic and COPD patients after oral olodaterol inhalation. Borghardt, JM; Kloft, C; Kunz, C; Staab, A; Weber, B, 2016) | 0.65 |
| "This single site, open-label, phase Ib clinical study assessed the pharmacokinetic (PK) and safety profiles of once-daily Tio + Olo FDC (5 μg/5 μg) after single dose and at steady state in Chinese patients with moderate to severe COPD over 3 weeks." | ( Pharmacokinetics and safety of tiotropium+olodaterol 5 μg/5 μg fixed-dose combination in Chinese patients with COPD. Hu, C; Hu, N; Luo, Z; Shu, S; Tadayasu, Y; Wang, Z, 2020) | 0.82 |
Compound-Compound Interactions
| Excerpt | Reference | Relevance |
|---|---|---|
| " Subjects received single doses of 20 or 30 μg olodaterol administered with the Respimat Soft Mist inhaler." | ( Pharmacokinetics and safety of olodaterol administered with the Respimat Soft Mist inhaler in subjects with impaired hepatic or renal function. Formella, S; Halabi, A; Hamilton, A; Kunz, C; Luedtke, D; Unseld, A; Wein, M, 2016) | 0.98 |
Dosage Studied
Olodaterol appears to be a promising long-acting β(2)-adrenoceptor agonist. It offers an opportunity for once-daily dosing in patients who require maintenance bronchodilator therapy. A clear dose-response relationship was demonstrated regarding pulmo.
| Excerpt | Relevance | Reference |
|---|---|---|
| " In summary, the preclinical profile of compound (R)-4p (olodaterol, also known as BI 1744 CL) suggests a potential for once-daily dosing in man accompanied with an improved safety profile." | ( Discovery of olodaterol, a novel inhaled beta2-adrenoceptor agonist with a 24 h bronchodilatory efficacy. Bouyssou, T; Büttner, FH; Heine, C; Hoenke, C; Konetzki, I; Lotz, R; Lustenberger, P; Pestel, S; Rudolf, K; Schnapp, A; Sieger, P, 2010) | 0.98 |
| " Taken together, the preclinical behavior of olodaterol suggests that this novel beta(2)-AR agonist has the profile for once-daily dosing in humans concomitant with a fast onset of action and a favorable systemic pharmacodynamic profile." | ( Pharmacological characterization of olodaterol, a novel inhaled beta2-adrenoceptor agonist exerting a 24-hour-long duration of action in preclinical models. Bouyssou, T; Casarosa, P; Devillier, P; Konetzki, I; Naline, E; Pestel, S; Schnapp, A, 2010) | 0.9 |
| "A single-center, double-blind, placebo-controlled, 5-way crossover study including 24-h spirometry (FEV(1), FVC), safety, tolerability and pharmacokinetics (in a subset of patients) following dosing of olodaterol 2 μg, 5 μg, 10 μg and 20 μg; the washout period between test-days was at least 14 days." | ( 24-hour bronchodilation following a single dose of the novel β(2)-agonist olodaterol in COPD. Cornelissen, PJ; Drenth, BM; Hamilton, AL; Pivovarova, A; Rascher, J; Smeets, JJ; van Noord, JA, 2011) | 0.79 |
| "Olodaterol appears to be a promising long-acting β(2)-adrenoceptor agonist,with bronchodilation maintained over 24 h that offers an opportunity for once-daily dosing in patients who require maintenance bronchodilator therapy for the management of COPD symptoms." | ( 24-hour bronchodilation following a single dose of the novel β(2)-agonist olodaterol in COPD. Cornelissen, PJ; Drenth, BM; Hamilton, AL; Pivovarova, A; Rascher, J; Smeets, JJ; van Noord, JA, 2011) | 2.04 |
| " In these studies, once-daily olodaterol improved lung function relative to placebo over 48 weeks of treatment, with such improvements being achieved and maintained within the 24-h dosage interval, supporting its once-daily administration." | ( Olodaterol: a review of its use in chronic obstructive pulmonary disease. Deeks, ED, 2015) | 2.15 |
| "This randomised, double-blind, four-way, crossover, Phase II study compared the 24-h forced expiratory volume in 1 s (FEV1) profile of alternative dosing frequencies of two total daily doses of olodaterol (5 and 10 μg) in patients with chronic obstructive pulmonary disease (COPD)." | ( A randomised, double-blind, four-way, crossover trial comparing the 24-h FEV1 profile for once-daily versus twice-daily treatment with olodaterol, a novel long-acting β2-agonist, in patients with chronic obstructive pulmonary disease. Aalbers, R; Aumann, JL; Coeck, C; Hamilton, AL; Joos, GF; Korducki, L; Kunz, C, 2015) | 0.81 |
| " Furthermore, the in vivo data suggest that the anti-inflammatory properties of olodaterol are maintained after repeated dosing for 4 days." | ( The long-acting β2 -adrenoceptor agonist olodaterol attenuates pulmonary inflammation. Devillier, P; Duechs, MJ; Kollak, I; Naline, E; Wex, E; Wollin, L, 2015) | 0.91 |
| " A clear dose-response relationship was demonstrated regarding pulmonary function; the two highest olodaterol doses (10 and 20 μg) formed the plateau of the dose-response curve." | ( A randomised, placebo-controlled, Phase II, dose-ranging trial of once-daily treatment with olodaterol, a novel long-acting β2-agonist, for 4 weeks in patients with chronic obstructive pulmonary disease. Beck, E; Fogarty, C; Hamilton, AL; Koker, P; Korducki, L; Maleki-Yazdi, MR, 2015) | 0.85 |
| " These once-daily dosing inhalers are anticipated to impact favorably on patient preference and compliance." | ( Profile of a fixed-dose combination of tiotropium/olodaterol and its potential in the treatment of COPD. Jayaram, L; Muruganandan, S, 2015) | 0.67 |
| " Further studies are necessary to confirm the optimum dosing regimen in asthma." | ( Randomised, double-blind, placebo-controlled crossover study to investigate different dosing regimens of olodaterol delivered via Respimat® in patients with moderate to severe persistent asthma. Beeh, KM; Fležar, M; Gahlemann, M; LaForce, C; Toorawa, R; Wenz, A, 2015) | 0.63 |
| " PFTs were performed over a 24-hour dosing interval after 4 weeks; primary end point was FEV1 area under the curve from 0-24 hours (AUC0-24) response (change from study baseline [mean FEV1] after 4 weeks)." | ( Dose-finding evaluation of once-daily treatment with olodaterol, a novel long-acting β2-agonist, in patients with asthma: results of a parallel-group study and a crossover study. Beck, E; Beeh, KM; Blahova, Z; D'Urzo, T; Fležar, M; Gahlemann, M; Hart, L; O'Byrne, PM; Toorawa, R, 2015) | 0.67 |
| " A clear dose-response relationship was observed across all treatment groups." | ( Efficacy and safety of the long-acting β2-agonist olodaterol over 4 weeks in Japanese patients with chronic obstructive pulmonary disease. Fukuchi, Y; Hamilton, AL; Ichinose, M; Izumoto, T; Kunz, C; Tadayasu, Y; Takizawa, A, 2015) | 0.67 |
| " Tiotropium, a once-daily dosing LAMA, demonstrated sustained improvements in lung function as well as improved health-related quality of life, reduced exacerbations, and increased survival without altering the rate of decline in the mean forced expiratory volume in 1 second (FEV1) with fairly tolerable side effects." | ( Combined bronchodilators (tiotropium plus olodaterol) for patients with chronic obstructive pulmonary disease. Al Assir, SA; El Khoury, GM; Kabbara, WK; Ramadan, WH, 2015) | 0.68 |
| " Other clinical trials demonstrated that olodaterol produced beneficial effects on FEV1 measures throughout the 24-hour dosing interval." | ( Olodaterol for the treatment of chronic obstructive pulmonary disease. Abilmona, RM; Kabbara, WK; Ramadan, WH, 2016) | 2.14 |
| " Changes in heart rate and systolic/diastolic BP were measured before and after dosing with the study medication at each visit." | ( Effect of long-acting β Alter, P; Andreas, S; Bothner, U; Buhl, R; Haensel, M; Trampisch, M, 2018) | 0.48 |
| " Olodaterol and indacaterol are administered once-daily and may offer an adherence advantage over other LABAs with more frequent dosing schedules." | ( Olodaterol for the treatment of chronic obstructive pulmonary disease: a narrative review. Melani, AS, 2018) | 2.83 |
Roles (2)
| Role | Description |
|---|---|
| beta-adrenergic agonist | An agent that selectively binds to and activates beta-adrenergic receptors. |
| bronchodilator agent | An agent that causes an increase in the expansion of a bronchus or bronchial tubes. |
| [role information is derived from 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] | |
Drug Classes (5)
| Class | Description |
|---|---|
| benzoxazine | |
| phenols | Organic aromatic compounds having one or more hydroxy groups attached to a benzene or other arene ring. |
| aromatic ether | Any ether in which the oxygen is attached to at least one aryl substituent. |
| secondary alcohol | A secondary alcohol is a compound in which a hydroxy group, -OH, is attached to a saturated carbon atom which has two other carbon atoms attached to it. |
| secondary amino compound | A compound formally derived from ammonia by replacing two hydrogen atoms by organyl groups. |
| [compound class information is derived from 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] | |
Protein Targets (2)
Activation Measurements
| Protein | Taxonomy | Measurement | Average | Min (ref.) | Avg (ref.) | Max (ref.) | Bioassay(s) |
|---|---|---|---|---|---|---|---|
| Beta-2 adrenergic receptor | Homo sapiens (human) | EC50 (µMol) | 0.0001 | 0.0000 | 0.3111 | 10.0000 | AID1760531; AID1783430 |
| Beta-1 adrenergic receptor | Homo sapiens (human) | EC50 (µMol) | 0.1230 | 0.0001 | 0.4914 | 6.0000 | AID1783429 |
| [prepared from compound, protein, and bioassay information from National Library of Medicine (NLM), extracted Dec-2023] | |||||||
Biological Processes (37)
Molecular Functions (15)
Ceullar Components (13)
Bioassays (19)
| Assay ID | Title | Year | Journal | Article |
|---|---|---|---|---|
| AID1783428 | Selectivity ratio of EC50 for agonist activity at human beta2 adrenoreceptor overexpressed in HEK293 cells to EC50 for agonist activity at human beta1 adrenoreceptor overexpressed in HEK293 cells | 2021 | European journal of medicinal chemistry, Nov-15, Volume: 224 | 8-Hydroxyquinolin-2(1H)-one analogues as potential β |
| AID457589 | Apparent permeability from basolateral to apical side in human Caco-2 cells | 2010 | Bioorganic & medicinal chemistry letters, Feb-15, Volume: 20, Issue:4 | Discovery of olodaterol, a novel inhaled beta2-adrenoceptor agonist with a 24 h bronchodilatory efficacy. |
| AID457248 | Apparent permeability from apical to basolateral side in human Caco-2 cells | 2010 | Bioorganic & medicinal chemistry letters, Feb-15, Volume: 20, Issue:4 | Discovery of olodaterol, a novel inhaled beta2-adrenoceptor agonist with a 24 h bronchodilatory efficacy. |
| AID1783425 | Myorelaxant effect in guinea pig model of histamine-induced smooth muscle contraction assessed as time duration of action measured over 12 hrs | 2021 | European journal of medicinal chemistry, Nov-15, Volume: 224 | 8-Hydroxyquinolin-2(1H)-one analogues as potential β |
| AID1783429 | Agonist activity at human beta1 adrenoreceptor overexpressed in HEK293 cells assessed as cAMP accumulation | 2021 | European journal of medicinal chemistry, Nov-15, Volume: 224 | 8-Hydroxyquinolin-2(1H)-one analogues as potential β |
| AID1760530 | Agonist activity at beta1 adrenoceptor in electrically stimulated Dunkin Hartley guinea pig left atria assessed as induction of isoprenaline-induced contraction incubated for 10 to 15 mins by alphascreen technology | 2020 | Journal of medicinal chemistry, 12-24, Volume: 63, Issue:24 | Recent Advances in β |
| AID1783426 | Myorelaxant effect in guinea pig model of histamine-induced smooth muscle contraction assessed as time of onset of action measured over 12 hrs | 2021 | European journal of medicinal chemistry, Nov-15, Volume: 224 | 8-Hydroxyquinolin-2(1H)-one analogues as potential β |
| AID1783423 | In vivo agonist activity at beta2 adrenergic receptor isolated from guinea pig tracheal smooth muscle assessed as inhibition of histamine-induced tracheal smooth muscle contraction by measuring maximal relaxant effect relative to control | 2021 | European journal of medicinal chemistry, Nov-15, Volume: 224 | 8-Hydroxyquinolin-2(1H)-one analogues as potential β |
| AID457250 | Clearance in human hepatocytes | 2010 | Bioorganic & medicinal chemistry letters, Feb-15, Volume: 20, Issue:4 | Discovery of olodaterol, a novel inhaled beta2-adrenoceptor agonist with a 24 h bronchodilatory efficacy. |
| AID1783424 | In vivo agonist activity at beta2 adrenergic receptor isolated from guinea pig tracheal smooth muscle assessed as inhibition of histamine-induced tracheal smooth muscle contraction | 2021 | European journal of medicinal chemistry, Nov-15, Volume: 224 | 8-Hydroxyquinolin-2(1H)-one analogues as potential β |
| AID1760549 | Inhibition of acetylcholine-induced bronchoconstriction in guinea pig assessed as duration of action by measuring half life | 2020 | Journal of medicinal chemistry, 12-24, Volume: 63, Issue:24 | Recent Advances in β |
| AID1783427 | Agonist activity at human beta2 adrenoreceptor in HEK293 cells assessed as cAMP accumulation by measuring intrinsic activity relative to control | 2021 | European journal of medicinal chemistry, Nov-15, Volume: 224 | 8-Hydroxyquinolin-2(1H)-one analogues as potential β |
| AID1783430 | Agonist activity at human beta2 adrenoreceptor overexpressed in HEK293 cells assessed as cAMP accumulation | 2021 | European journal of medicinal chemistry, Nov-15, Volume: 224 | 8-Hydroxyquinolin-2(1H)-one analogues as potential β |
| AID457588 | Bronchoprotection in intratracheally dosed guinea pig Konzett-Roessler model assessed as inhibition of acetylcholine-induced increase in pulmonary resistance administered after 3 acetylcholine challenges every 10 mins for 5 hrs | 2010 | Bioorganic & medicinal chemistry letters, Feb-15, Volume: 20, Issue:4 | Discovery of olodaterol, a novel inhaled beta2-adrenoceptor agonist with a 24 h bronchodilatory efficacy. |
| AID457249 | Clearance in rat hepatocytes | 2010 | Bioorganic & medicinal chemistry letters, Feb-15, Volume: 20, Issue:4 | Discovery of olodaterol, a novel inhaled beta2-adrenoceptor agonist with a 24 h bronchodilatory efficacy. |
| AID457590 | Oral bioavailability in rat | 2010 | Bioorganic & medicinal chemistry letters, Feb-15, Volume: 20, Issue:4 | Discovery of olodaterol, a novel inhaled beta2-adrenoceptor agonist with a 24 h bronchodilatory efficacy. |
| AID1760531 | Agonist activity at beta2 adrenoceptor (unknown origin) | 2020 | Journal of medicinal chemistry, 12-24, Volume: 63, Issue:24 | Recent Advances in β |
| AID457587 | Lipophilicity, log D at pH 7.4 | 2010 | Bioorganic & medicinal chemistry letters, Feb-15, Volume: 20, Issue:4 | Discovery of olodaterol, a novel inhaled beta2-adrenoceptor agonist with a 24 h bronchodilatory efficacy. |
| AID1346250 | Human beta2-adrenoceptor (Adrenoceptors) | 2010 | The Journal of pharmacology and experimental therapeutics, Jul, Volume: 334, Issue:1 | Pharmacological characterization of olodaterol, a novel inhaled beta2-adrenoceptor agonist exerting a 24-hour-long duration of action in preclinical models. |
| [information is prepared from bioassay data collected from National Library of Medicine (NLM), extracted Dec-2023] | ||||
Research
Studies (93)
| Timeframe | Studies, This Drug (%) | All Drugs % |
|---|---|---|
| pre-1990 | 0 (0.00) | 18.7374 |
| 1990's | 0 (0.00) | 18.2507 |
| 2000's | 0 (0.00) | 29.6817 |
| 2010's | 71 (76.34) | 24.3611 |
| 2020's | 22 (23.66) | 2.80 |
| [information is prepared from research data collected from National Library of Medicine (NLM), extracted Dec-2023] | ||
Market Indicators
Research Demand Index: 79.78
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 (79.78) All Compounds (24.57) |
Study Types
| Publication Type | This drug (%) | All Drugs (%) |
|---|---|---|
| Trials | 37 (37.00%) | 5.53% |
| Reviews | 22 (22.00%) | 6.00% |
| Case Studies | 1 (1.00%) | 4.05% |
| Observational | 1 (1.00%) | 0.25% |
| Other | 39 (39.00%) | 84.16% |
| [information is prepared from research data collected from National Library of Medicine (NLM), extracted Dec-2023] | ||
Clinical Trials (80)
Trial Overview
| Trial | Phase | Enrollment | Study Type | Start Date | Status | ||
|---|---|---|---|---|---|---|---|
| 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 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 | ||
| Early Intervention Effectiveness of Tiotropium / Olodaterol Compared to Tiotropium in COPD [NCT04249310] | 6,788 participants (Actual) | Observational | 2020-03-27 | Completed | |||
| 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 | ||
| 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 | ||
| Comparison of 1-year Treatment With Inhaled Long Acting Bronchodilators (LABD) Plus Inhaled Glucocorticosteroids (ICS) Versus LABD Without ICS on Re-hospitalizations and/or Death in Elderly Patients With Chronic Obstructive Pulmonary Disease (COPD) Recent [NCT03662711] | Phase 4 | 843 participants (Actual) | Interventional | 2018-11-11 | Terminated(stopped due to Contract terminated between AIFA and the Sponsor (University of Ferrara)) | ||
| 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 | |||
| Taiwan Outcomes and Real-world Treatment Options for Chronic Obstructive Pulmonary Disease [NCT04011475] | 1,617 participants (Actual) | Observational | 2019-12-29 | Completed | |||
| A Randomised, Double-blind, Placebo-controlled (Within Dose Groups) Study to Assess Safety, Tolerability and Pharmacokinetics of Single Rising Inhaled Doses (0.5 μg to 70 μg Administered With the Respimat®) of BI 1744 CL in Healthy Male and Female Volunte [NCT02171780] | Phase 1 | 122 participants (Actual) | Interventional | 2005-02-28 | Completed | ||
| A Randomised, Single-blind, Placebo-controlled (Within Dose Groups) Study to Assess Safety, Tolerability and Pharmacokinetics of Single Rising Peroral Doses (15, 30, 40 μg Free Cation) BI 1744 CL in Healthy Male Volunteers [NCT02171793] | Phase 1 | 24 participants (Actual) | Interventional | 2007-06-30 | Completed | ||
| A Double-blind, Randomised, Placebo Controlled (Within a Dose Group) Study to Evaluate Safety, Tolerability and Pharmacokinetics of Multiple Rising Inhalative Doses (5 μg, 10 μg and 20 μg) of BI 1744 CL for 14 Days in Healthy Male Volunteers [NCT02172105] | Phase 1 | 36 participants (Actual) | Interventional | 2008-01-31 | 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, 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 | ||
| Pharmacokinetics, Safety and Tolerability of a Single Dose of BI 1744 CL (20 μg Administered With the Respimat® Inhaler) in Patients With Mild and Moderate Hepatic Impairment (Child Pugh Classifications A and B) in Comparison to a Single Dose of BI 1744 C [NCT02171832] | Phase 1 | 32 participants (Actual) | Interventional | 2009-07-31 | Completed | ||
| A Double-blind, Randomised, Placebo Controlled, Six-way Crossover Study Including an Open-label Positive Control (Moxifloxacin) to Assess the Influence of Via Respimat® Inhaled BI 1744 CL (Single Doses of 10 μg, 20 μg, 30 μg and 50 μg) on the QT/QTc Inter [NCT02172144] | Phase 1 | 24 participants (Actual) | Interventional | 2007-06-30 | Completed | ||
| A Single-blind, Randomised, Two-way Crossover Phase I Study to Assess Safety, Tolerability and Pharmacokinetics of the Fixed Dose Combination of BI 1744 CL Plus BI 54903 XX Via Respimat® B Versus the Free Combination of BI 1744 CL Via Respimat® A and BI 5 [NCT02220660] | Phase 1 | 32 participants (Actual) | Interventional | 2009-03-31 | Completed | ||
| Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of Multiple Rising Inhalative Doses (2.5 μg, 10 μg, and 30 μg) of BI 1744 CL for 14 Days in Healthy Male and Female Volunteers (Doubleblind, Randomised, Placebo Controlled [at Each Dose Level] St [NCT02171806] | Phase 1 | 47 participants (Actual) | Interventional | 2006-01-31 | Completed | ||
| An Open Label, Randomised, Three-way Crossover Phase I Study to Assess Safety, Tolerability and Pharmacokinetics of the Fixed Dose Combination of BI 1744 CL Plus BI 54903 XX Via Respimat® B Versus the Mono Products of BI 1744 CL Via Respimat® A and BI 549 [NCT02222428] | Phase 1 | 36 participants | Interventional | 2009-04-30 | 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 | |||
| 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 | |||
| 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 | ||
| Randomised, Double-Blind, Placebo-Controlled, 5-Way Cross-Over Study to Assess the Efficacy (Bronchoprotection) and Safety of a Single Dose of Orally Inhaled BI 1744 CL (2, 5, 10 and 20ug) in Patients With Intermittent Asthma [NCT00928668] | Phase 2 | 32 participants (Actual) | Interventional | 2006-01-31 | Completed | ||
| A Randomised, Double-Blind, Placebo- and Active-Controlled, Incomplete Crossover Efficacy and Safety Comparison of 4-week Treatment Periods of Once Daily Treatment of 4 Doses of BI 1744 CL Inhalation Solution Delivered by the Respimat® in Patients With As [NCT01013753] | Phase 2 | 198 participants (Actual) | Interventional | 2010-02-28 | Completed | ||
| Safety, Tolerability and Pharmacokinetics of Single Rising Doses of 0.5 μg, 2.5 μg, 5 μg, 10 μg, 15 μg, 20 μg, 25 μg and 30 μg BI 1744 CL (Calculated as Free Base) Given as Intravenous Infusion Over 30 Minutes to Healthy Male Subjects. A Single-centre, Si [NCT02172131] | Phase 1 | 64 participants (Actual) | Interventional | 2006-10-31 | Terminated | ||
| 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 | ||
| Investigation of the Metabolism and Pharmacokinetics of 20 μg (Calculated as Free Base) [14C]BI 1744 CL Administered as a 3-hour Infusion and 40 μg (Calculated as Free Base) [14C]BI 1744 CL Administered as an Oral Solution. [NCT02172157] | Phase 1 | 11 participants (Actual) | Interventional | 2008-02-29 | Completed | ||
| Randomised, Double-Blind, Placebo-Controlled, Parallel Group Study to Assess the Efficacy (Bronchodilation) and Safety of 4 Weeks of Treatment of Orally Inhaled BI 1744 CL (4 Doses) Delivered by the Respimat® Inhaler in Patients With Asthma [NCT00467740] | Phase 2 | 296 participants (Actual) | Interventional | 2007-05-31 | 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 | ||
| Randomised, Double-Blind, Placebo-Controlled, Parallel Group Study to Assess the Efficacy and Safety of 4 Weeks of Treatment of Orally Inhaled BI 1744 CL (3 - 4 Doses) Delivered by the Respimat® Inhaler in Patients With COPD [NCT00452400] | Phase 2 | 409 participants (Actual) | Interventional | 2007-03-31 | Completed | ||
| Randomised, Double-Blind, Cross-over Study to Determine the 24-hour FEV1-time Profile of Orally Inhaled BI 1744 CL, Delivered With the Respimat Inhaler, After 3 Weeks of Once Daily or Twice Daily Administration in Patients With Chronic Obstructive Pulmona [NCT00846768] | Phase 2 | 47 participants (Actual) | Interventional | 2009-02-28 | Completed | ||
| Randomised, Double-blind, Placebo-controlled, Parallel Group Study to Assess the Efficacy and Safety of 4 Weeks of Once Daily Treatment of Orally Inhaled BI 1744 CL Delivered by the Respimat Inhaler in Japanese Patients With COPD [NCT00824382] | Phase 2 | 328 participants (Actual) | Interventional | 2009-01-31 | Completed | ||
| Randomised, Double-blind, Placebo-controlled, Parallel Group Study to Assess the Efficacy and Safety of 48 Weeks of Once Daily Treatment of Orally Inhaled BI 1744 CL (5 mcg [2 Actuations of 2.5 mcg] and 10 mcg [2 Actuations of 5 mcg]) Delivered by the Res [NCT00782210] | Phase 3 | 625 participants (Actual) | Interventional | 2008-11-30 | Completed | ||
| A Randomised, Double-blind, Double-dummy, Placebo-controlled, Parallel Group Study to Assess the Efficacy and Safety of 48 Weeks of Once Daily Treatment of Orally Inhaled BI 1744 CL (5 µg [2 Actuations of 2.5 ug] and 10 ug [2 Actuations of 5 ug]) Delivere [NCT00796653] | Phase 3 | 937 participants (Actual) | Interventional | 2009-01-31 | Completed | ||
| Randomised, Double-blind, Placebo-controlled, 3-way Cross-over Study to Determine the Effect of Treatment of Orally Inhaled BI 1744 CL (5 µg [2 Actuations of 2.5 µg] and 10 µg [2 Actuations of 5 µg]) Delivered by the Respimat® Inhaler on Exercise Enduranc [NCT01040130] | Phase 3 | 151 participants (Actual) | Interventional | 2010-01-31 | Completed | ||
| 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 | ||
| Characterization of 24 Hour Spirometry Profiles of Inhaled BI 1744 CL and Inhaled Foradil in Patients With Chronic Obstructive Pulmonary Disease [NCT00932646] | Phase 3 | 100 participants (Actual) | Interventional | 2009-06-30 | Completed | ||
| Randomised, Double-blind, Placebo-controlled, Parallel Group Study to Assess the Efficacy and Safety of 48 Weeks of Once Daily Treatment of Orally Inhaled BI 1744 CL (5 mcg [2 Actuations of 2.5 mcg] and 10 mcg [2 Actuations of 5 mcg]) Delivered by the Res [NCT00782509] | Phase 3 | 644 participants (Actual) | Interventional | 2009-02-28 | 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 Randomised, Double-blind, Double-dummy, Placebo-controlled, Parallel Group Study to Assess the Efficacy and Safety of 48 Weeks of Once Daily Treatment of Orally Inhaled BI 1744 CL (5 µg [2 Actuations of 2.5 ug] and 10 ug [2 Actuations of 5 ug]) Delivere [NCT00793624] | Phase 3 | 906 participants (Actual) | Interventional | 2009-02-28 | 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 | ||
| 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 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 | ||
| Randomised, Double-blind, Placebo-controlled, 3-way Cross-over Study to Determine the Effect of Treatment of Orally Inhaled BI 1744 CL (5 µg [2 Actuations of 2.5 µg] and 10 µg [2 Actuations of 5 µg]) Delivered by the Respimat® Inhaler on Exercise Enduranc [NCT01040793] | Phase 3 | 157 participants (Actual) | Interventional | 2010-01-31 | 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 | ||
| Single Dose Comparison of 3 Doses of Olodaterol in Double Fixed Dose Combination With BI54903 vs. 3 Doses of Olodaterol Mono in Free Combination [NCT01428622] | Phase 2 | 0 participants (Actual) | Interventional | 2011-10-31 | Withdrawn | ||
| 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 | |||
| INvestigating COPD Outcomes, Genomics and Neutrophilic Inflammation With Tiotropium and Olodaterol [NCT03152149] | Phase 4 | 80 participants (Actual) | Interventional | 2017-06-01 | 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 [NCT02006732] | Phase 3 | 809 participants (Actual) | Interventional | 2013-11-30 | 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 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 | ||
| 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 | ||
| Phase II, Randomised, Double-Blind, Cross-over Study to Compare the 24-hour FEV1-time Profile of Orally Inhaled Olodaterol, Delivered With the Respimat® Inhaler, After 3 Weeks of Olodaterol Once Daily Medium Dose, Twice Daily Low Dose and Placebo or After [NCT01311661] | Phase 2 | 206 participants (Actual) | Interventional | 2011-03-31 | 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 | |||
| 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 | ||
| 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) | ||
| 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 | ||
| 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 | ||
| 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 | |||
| 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 | |||
| 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 | ||
| 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 | ||
| 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 | ||
| 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- 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 | ||
| 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 | ||
| 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 | ||
| 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 | |||
| 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 | ||
| Drug Utilization Study for Olodaterol [NCT03030638] | 27,606 participants (Actual) | Observational | 2017-02-08 | 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 | ||
| 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 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 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 | ||
| 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 | ||
| 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 | ||
| 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 | ||
| 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 | ||
| 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 | ||
| 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] | |||||||
Trial Outcomes
Time From Dosing to the Maximum Concentration (Tmax)
tmax represents the time from dosing to maximum concentration of olodaterol and olodaterol glucuronide in plasma. (NCT00452400)
Timeframe: Baseline and 4 weeks
| Intervention | hours (Median) | |
|---|---|---|
| Olodaterol (N=0;0;40;71;69) | Olodaterol glucuronide (N=0;0;54;71;66) | |
| Olo 10 mcg qd | 0.183 | 3.00 |
| Olo 20 mcg qd | 0.200 | 3.00 |
| Olo 5 mcg qd | 0.167 | 2.95 |
Trough FEV1 Response After 2 Weeks
Trough FEV1 is defined as the mean of the two FEV1 values (performed at -1 hour and -10 minutes prior to test-drug inhalation) at the end of the dosing interval, 24 hours post-drug administration. Trough FEV1 response is defined as the change from baseline in trough FEV1. Baseline FEV1 is the mean of the two pre-treatment FEV1 values measured at Visit 2 (- 1 hour and - 10 minutes) prior to administration of the first dose of study medication. (NCT00452400)
Timeframe: Baseline and 2 weeks
| Intervention | Liter (Least Squares Mean) |
|---|---|
| Placebo | -0.023 |
| Olo 2 mcg qd | 0.062 |
| Olo 5 mcg qd | 0.099 |
| Olo 10 mcg qd | 0.102 |
| Olo 20 mcg qd | 0.105 |
Trough FEV1 Response After 1 Week
Trough FEV1 is defined as the mean of the two FEV1 values (performed at -1 hour and -10 minutes prior to test-drug inhalation) at the end of the dosing interval, 24 hours post-drug administration. Trough FEV1 response is defined as the change from baseline in trough FEV1. Baseline FEV1 is the mean of the two pre-treatment FEV1 values measured at Visit 2 (- 1 hour and - 10 minutes) prior to administration of the first dose of study medication. (NCT00452400)
Timeframe: Baseline and 1 week
| Intervention | Liter (Least Squares Mean) |
|---|---|
| Placebo | -0.029 |
| Olo 2 mcg qd | 0.059 |
| Olo 5 mcg qd | 0.108 |
| Olo 10 mcg qd | 0.099 |
| Olo 20 mcg qd | 0.140 |
Peak FVC (0-3h) Response After 4 Weeks
Peak (0-3h) will be the maximum post-dose value during the first 3 hours. Response is defined as change from the baseline value. Study baseline FVC was defined as the mean of the available pre-dose FVC values prior to the first dose of randomized treatment. (NCT00452400)
Timeframe: 1 hour (h) and 10 minutes (min) prior to dose on the first day of randomized treatment (baseline) to 30 min, 1 h, 2 h, and 3 h relative to dose after 4 weeks
| Intervention | Liter (Least Squares Mean) |
|---|---|
| Placebo | 0.152 |
| Olo 2 mcg qd | 0.440 |
| Olo 5 mcg qd | 0.432 |
| Olo 10 mcg qd | 0.449 |
| Olo 20 mcg qd | 0.438 |
Clinical Relevant Abnormalities for Vital Signs, ECG and Physical Examination
Clinical relevant abnormalities for vital signs, ECG and physical examination. Any new or clinically relevant worsening of baseline conditions was reported as adverse events. (NCT00452400)
Timeframe: 4 weeks
| Intervention | participants (Number) | ||||||
|---|---|---|---|---|---|---|---|
| Electrocardiogram QT prolonged | Blood creatine phosphokinase increased | Gamma-glutamyltransferase increased | Atrioventricular block first degree | Sinus arrhythmia | Tachycardia | Palpitations | |
| Olo 10 mcg qd | 0 | 0 | 0 | 0 | 0 | 1 | 0 |
| Olo 2 mcg qd | 1 | 0 | 1 | 0 | 0 | 0 | 1 |
| Olo 20 mcg qd | 2 | 1 | 0 | 1 | 0 | 0 | 0 |
| Olo 5 mcg qd | 1 | 0 | 0 | 0 | 0 | 1 | 0 |
| Placebo | 0 | 0 | 0 | 0 | 1 | 0 | 0 |
Peak FEV1 (0-3h) Response After 4 Weeks
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 randomized treatment. Peak FEV1 (0-3h) values were obtained within 0 - 3 hours after treatment. Means are adjusted using a mixed effects model with baseline, treatment and centre (centre random, all other effects fixed). (NCT00452400)
Timeframe: 1 hour (h) and 10 minutes (min) prior to dose on the first day of randomized treatment (baseline) to 30 min, 1 h, 2 h, and 3 h relative to dose after 4 weeks
| Intervention | Liter (Least Squares Mean) |
|---|---|
| Placebo | 0.078 |
| Olo 2 mcg qd | 0.242 |
| Olo 5 mcg qd | 0.247 |
| Olo 10 mcg qd | 0.295 |
| Olo 20 mcg qd | 0.303 |
Peak FEV1 (0-3h) Response At Day 1
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 randomized treatment. Peak FEV1 (0-3h) values were obtained within 0 - 3 hours after treatment.Means are adjusted using a mixed effects model with baseline,treatment and centre (centre random, all other effects fixed). (NCT00452400)
Timeframe: 1 hour (h) and 10 minutes (min) prior to dose on the first day of randomized treatment (baseline) to 30 min, 1 h, 2 h, and 3 h relative to dose at day 1
| Intervention | Liter (Least Squares Mean) |
|---|---|
| Placebo | 0.104 |
| Olo 2 mcg qd | 0.259 |
| Olo 5 mcg qd | 0.288 |
| Olo 10 mcg qd | 0.335 |
| Olo 20 mcg qd | 0.335 |
Area Under Curve From 0 to 3 Hours at Steady State (AUC0-3,ss)
AUC0-3,ss represents the area under the concentration curve of olodaterol and olodaterol glucuronide in plasma from 0 to time t=3 at steady state. (NCT00452400)
Timeframe: Baseline and 4 weeks
| Intervention | Picogram*hours/milliliter (Geometric Mean) | |
|---|---|---|
| Olodaterol (N=0;0;0;63;70) | Olodaterol glucuronide (N=0;0;55;69;63) | |
| Olo 10 mcg qd | 15.6 | 11.4 |
| Olo 20 mcg qd | 27.7 | 23.9 |
| Olo 5 mcg qd | NA | 9.29 |
Trough FVC Response After 2 Weeks
Trough FVC was defined as the mean of the two values obtained at 1 hour and 10 minutes prior to the pulmonary function test maneuver. Response is defined as change from the baseline value. Study baseline FVC was defined as the mean of the available pre-dose FVC values prior to the first dose of randomized treatment. (NCT00452400)
Timeframe: Baseline and 2 weeks
| Intervention | Liter (Least Squares Mean) |
|---|---|
| Placebo | -0.000 |
| Olo 2 mcg qd | 0.090 |
| Olo 5 mcg qd | 0.171 |
| Olo 10 mcg qd | 0.149 |
| Olo 20 mcg qd | 0.148 |
Area Under Curve From 0 to 3 Hours (AUC0-3)
AUC0-3 represents the area under the concentration curve of olodaterol and olodaterol glucuronide in plasma from 0 to time t=3. (NCT00452400)
Timeframe: Baseline and 4 weeks
| Intervention | Picogram*hours/milliliter (Geometric Mean) | |
|---|---|---|
| Olodaterol (N=0;0;0;29;58) | Olodaterol glucuronide (N=0;0;0;44;44) | |
| Olo 10 mcg qd | 13.3 | 11.6 |
| Olo 20 mcg qd | 20.3 | 21.1 |
Area Under Curve From 0 to 24 Hours at Steady State (AUC0-24,ss)
AUC0-24,ss represents the area under the concentration curve of olodaterol and olodaterol glucuronide in plasma from 0 to time t=24 at steady state. (NCT00452400)
Timeframe: Baseline and 4 weeks
| Intervention | Picogram*hours/milliliter (Geometric Mean) | |
|---|---|---|
| Olodaterol | Olodaterol glucuronide | |
| Olo 10 mcg qd | 104 | NA |
| Olo 20 mcg qd | 145 | NA |
Weekly Mean Pre-dose Morning Peak Expiratory Flow Rate (PEFR) After 4 Weeks
Baseline PEFR was defined as the mean of the morning PEFR measurements obtained during the week just prior to first dose of randomized treatment. (NCT00452400)
Timeframe: 4 weeks
| Intervention | Liter/minute (Least Squares Mean) |
|---|---|
| Placebo | 212.69 |
| Olo 2 mcg qd | 226.39 |
| Olo 5 mcg qd | 233.97 |
| Olo 10 mcg qd | 250.77 |
| Olo 20 mcg qd | 235.75 |
Weekly Mean Number of Occasions of Rescue Therapy After 4 Weeks
Weekly mean number of occasions of rescue therapy used per day (PRN salbutamol (albuterol)) (NCT00452400)
Timeframe: 4 weeks
| Intervention | Number of puffs (Least Squares Mean) |
|---|---|
| Placebo | 2.914 |
| Olo 2 mcg qd | 2.393 |
| Olo 5 mcg qd | 3.052 |
| Olo 10 mcg qd | 1.949 |
| Olo 20 mcg qd | 2.500 |
Weekly Mean Evening PEFR After 4 Weeks
Baseline PEFR was defined as the mean of the evening PEFR measurements obtained during the week just prior to first dose of randomized treatment. (NCT00452400)
Timeframe: 4 weeks
| Intervention | Liter/minute (Least Squares Mean) |
|---|---|
| Placebo | 224.65 |
| Olo 2 mcg qd | 235.09 |
| Olo 5 mcg qd | 246.98 |
| Olo 10 mcg qd | 262.88 |
| Olo 20 mcg qd | 250.06 |
Trough FVC Response After 4 Weeks
Trough FVC was defined as the mean of the two values obtained at 1 hour and 10 minutes prior to the pulmonary function test maneuver. Response is defined as change from the baseline value. Study baseline FVC was defined as the mean of the available pre-dose FVC values prior to the first dose of randomized treatment. (NCT00452400)
Timeframe: Baseline and 4 weeks
| Intervention | Liter (Least Squares Mean) |
|---|---|
| Placebo | -0.026 |
| Olo 2 mcg qd | 0.068 |
| Olo 5 mcg qd | 0.136 |
| Olo 10 mcg qd | 0.146 |
| Olo 20 mcg qd | 0.153 |
Trough FVC Response After 1 Week
Trough FVC was defined as the mean of the two values obtained at 1 hour and 10 minutes prior to the pulmonary function test maneuver. Response is defined as change from the baseline value. Study baseline FVC was defined as the mean of the available pre-dose FVC values prior to the first dose of randomized treatment. (NCT00452400)
Timeframe: Baseline and 1 week
| Intervention | Liter (Least Squares Mean) |
|---|---|
| Placebo | -0.020 |
| Olo 2 mcg qd | 0.090 |
| Olo 5 mcg qd | 0.154 |
| Olo 10 mcg qd | 0.149 |
| Olo 20 mcg qd | 0.151 |
Trough FEV1 Response After 4 Weeks
Trough FEV1 is defined as the mean of the two FEV1 values (performed at -1 hour and -10 minutes prior to test-drug inhalation) at the end of the dosing interval, 24 hours post-drug administration. Trough FEV1 response is defined as the change from baseline in trough FEV1. Baseline FEV1 is the mean of the two pre-treatment FEV1 values measured at Visit 2 (- 1 hour and - 10 minutes) prior to administration of the first dose of study medication. (NCT00452400)
Timeframe: Baseline and 4 weeks
| Intervention | Liter (Least Squares Mean) |
|---|---|
| Placebo | -0.014 |
| Olo 2 mcg qd | 0.046 |
| Olo 5 mcg qd | 0.082 |
| Olo 10 mcg qd | 0.109 |
| Olo 20 mcg qd | 0.118 |
Forced Expiratory Volume in 1 Second (FEV1) Area Under Curve 0-3 h (AUC 0-3h) Response at Day 1
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 randomized treatment. Means are adjusted using a model with treatment (trt), baseline as fixed effects and centre as random effect. FEV1 AUC 0-3h was calculated from 0-3 hours postdose using the trapezoidal rule, divided by the observation time (3h) to report in litres. (NCT00452400)
Timeframe: 1 hour (h) and 10 minutes (min) prior to dose on first day of randomized treatment (baseline) and 30 min, 1h, 2h, 3h relative to dose at day 1
| Intervention | Liter (Least Squares Mean) |
|---|---|
| Placebo | 0.031 |
| Olo 2 mcg qd | 0.165 |
| Olo 5 mcg qd | 0.203 |
| Olo 10 mcg qd | 0.236 |
| Olo 20 mcg qd | 0.234 |
Forced Expiratory Volume in 1 Second (FEV1) (Unsupervised) Area Under Curve 6-12 h (AUC 6-12h) Response After 1 Week
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 randomized treatment. Means are adjusted using a model with treatment (trt), baseline as fixed effects and centre as random effect. FEV1 AUC 6-12h was calculated from 6-12 hours post-dose using the trapezoidal rule, divided by the observation time (6h) to report in litres. (NCT00452400)
Timeframe: Baseline and 1 week
| Intervention | Liter (Least Squares Mean) |
|---|---|
| Placebo | -0.018 |
| Olo 2 mcg qd | 0.067 |
| Olo 5 mcg qd | 0.156 |
| Olo 10 mcg qd | 0.132 |
| Olo 20 mcg qd | 0.118 |
Forced Expiratory Volume in 1 Second (FEV1) (Unsupervised) Area Under Curve 6-12 h (AUC 6-12h) Response After 2 Weeks
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 randomized treatment. Means are adjusted using a model with treatment (trt), baseline as fixed effects and centre as random effect. FEV1 AUC 6-12h was calculated from 6-12 hours post-dose using the trapezoidal rule, divided by the observation time (6h) to report in litres. (NCT00452400)
Timeframe: Baseline and 2 weeks
| Intervention | Liter (Least Squares Mean) |
|---|---|
| Placebo | 0.006 |
| Olo 2 mcg qd | 0.059 |
| Olo 5 mcg qd | 0.135 |
| Olo 10 mcg qd | 0.105 |
| Olo 20 mcg qd | 0.098 |
Forced Expiratory Volume in 1 Second (FEV1) (Unsupervised) Area Under Curve 6-12 h (AUC 6-12h) Response After 4 Weeks
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 randomized treatment. Means are adjusted using a model with treatment (trt), baseline as fixed effects and centre as random effect. FEV1 AUC 6-12h was calculated from 6-12 hours post-dose using the trapezoidal rule, divided by the observation time (6h) to report in litres. (NCT00452400)
Timeframe: Baseline and 4 weeks
| Intervention | Liter (Least Squares Mean) |
|---|---|
| Placebo | 0.005 |
| Olo 2 mcg qd | 0.058 |
| Olo 5 mcg qd | 0.134 |
| Olo 10 mcg qd | 0.145 |
| Olo 20 mcg qd | 0.094 |
Forced Expiratory Volume in 1 Second (FEV1) (Unsupervised) Area Under Curve 6-12 h (AUC 6-12h) Response at Day 1
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 randomized treatment. Means are adjusted using a model with treatment (trt), baseline as fixed effects and centre as random effect. FEV1 AUC 6-12h was calculated from 6-12 hours post-dose using the trapezoidal rule, divided by the observation time (6h) to report in litres. (NCT00452400)
Timeframe: baseline and day1
| Intervention | Liter (Least Squares Mean) |
|---|---|
| Placebo | 0.019 |
| Olo 2 mcg qd | 0.064 |
| Olo 5 mcg qd | 0.166 |
| Olo 10 mcg qd | 0.195 |
| Olo 20 mcg qd | 0.171 |
Forced Expiratory Volume in 1 Second (FEV1) Area Under Curve 0-3 h (AUC 0-3h) Response at Week 1
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 randomized treatment. Means are adjusted using a model with treatment (trt), baseline as fixed effects and centre as random effect. 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. (NCT00452400)
Timeframe: 1 hour (h) and 10 minutes (min) prior to dose on first day of randomized treatment (baseline) and 30 min, 1h, 2h, 3h relative to dose at Week 1
| Intervention | Liter (Least Squares Mean) |
|---|---|
| Placebo | -0.000 |
| Olo 2 mcg qd | 0.186 |
| Olo 5 mcg qd | 0.215 |
| Olo 10 mcg qd | 0.218 |
| Olo 20 mcg qd | 0.247 |
Forced Expiratory Volume in 1 Second (FEV1) Area Under Curve 0-3 h (AUC 0-3h) Response at Week 2
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 randomized treatment. Means are adjusted using a model with treatment (trt), baseline as fixed effects and centre as random effect. 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. (NCT00452400)
Timeframe: 1 hour (h) and 10 minutes (min) prior to dose on first day of randomized treatment (baseline) and 30 min, 1h, 2h, 3h relative to dose at Week 2
| Intervention | Liter (Least Squares Mean) |
|---|---|
| Placebo | 0.006 |
| Olo 2 mcg qd | 0.166 |
| Olo 5 mcg qd | 0.200 |
| Olo 10 mcg qd | 0.209 |
| Olo 20 mcg qd | 0.211 |
Forced Expiratory Volume in 1 Second (FEV1) Area Under Curve 0-6 h (AUC 0-6h) Response at Week 4
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 randomized treatment. Means are adjusted using a model with treatment (trt), baseline as fixed effects and centre as random effect. FEV1 AUC 0-6h was calculated from 0-6 hours post-dose using the trapezoidal rule, divided by the observation time (6h) to report in litres. (NCT00452400)
Timeframe: 1 hour (h) and 10 minutes (min) prior to dose on first day of randomized treatment (baseline) and 30 min, 1h, 2h, 3h, 4h, 5h, 6h relative to dose at Week 4
| Intervention | Liter (Least Squares Mean) |
|---|---|
| Placebo | 0.013 |
| Olo 2 mcg qd | 0.154 |
| Olo 5 mcg qd | 0.175 |
| Olo 10 mcg qd | 0.226 |
| Olo 20 mcg qd | 0.228 |
Forced Vital Capacity (FVC) Area Under Curve 0-6 h (AUC 0-6h) Response at Week 4
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 randomized treatment. Means are adjusted using a model with treatment (trt), baseline as fixed effects and centre as random effect. FVC AUC 0-6h was calculated from 0-6 hours post-dose using the trapezoidal rule, divided by the observation time (6h) to report in litres. (NCT00452400)
Timeframe: 1 hour (h) and 10 minutes (min) prior to dose on first day of randomized treatment (baseline) and 30 min, 1h, 2h, 3h, 4h, 5h, 6h relative to dose at Week 4
| Intervention | Liter (Least Squares Mean) |
|---|---|
| Placebo | 0.009 |
| Olo 2 mcg qd | 0.271 |
| Olo 5 mcg qd | 0.292 |
| Olo 10 mcg qd | 0.320 |
| Olo 20 mcg qd | 0.313 |
Area Under Curve From 0 to 6 Hours at Steady State (AUC0-6,ss)
AUC0-6,ss represents the area under the concentration curve of olodaterol and olodaterol glucuronide in plasma from 0 to time t=6 at steady state. (NCT00452400)
Timeframe: Baseline and 4 weeks
| Intervention | Picogram*hours/milliliter (Geometric Mean) | |
|---|---|---|
| Olodaterol (N=0;0;0;55;69) | Olodaterol glucuronide (N=0;0;32;50;48) | |
| Olo 10 mcg qd | 29.7 | 25.6 |
| Olo 20 mcg qd | 46.4 | 49.4 |
| Olo 5 mcg qd | NA | 21.4 |
Laboratory Testing: Average Change From Baseline of Potassium
Laboratory testing: Average change from baseline of potassium measured on test-days. Pre-dose value on test day 1 is the baseline value. (NCT00452400)
Timeframe: Baseline and day 29
| Intervention | mmol/L (Geometric Mean) |
|---|---|
| Placebo | 0.97 |
| Olo 2 mcg qd | 0.99 |
| Olo 5 mcg qd | 0.98 |
| Olo 10 mcg qd | 0.97 |
| Olo 20 mcg qd | 0.98 |
Peak FEV1 (0-3h) Response After 1 Weeks
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 randomized treatment. Peak FEV1 (0-3h) values were obtained within 0 - 3 hours after treatment. Means are adjusted using a mixed effects model with baseline, treatment and centre (centre random, all other effects fixed). (NCT00452400)
Timeframe: 1 hour (h) and 10 minutes (min) prior to dose on the first day of randomized treatment (baseline) to 30 min, 1 h, 2 h, and 3 h relative to dose after 1 week
| Intervention | Liter (Least Squares Mean) |
|---|---|
| Placebo | 0.062 |
| Olo 2 mcg qd | 0.264 |
| Olo 5 mcg qd | 0.293 |
| Olo 10 mcg qd | 0.295 |
| Olo 20 mcg qd | 0.321 |
Time From Dosing to the Maximum Concentration at Steady State (Tmax,ss)
tmax,ss represents the time from dosing to maximum concentration of olodaterol and olodaterol glucuronide in plasma at steady state. (NCT00452400)
Timeframe: Baseline and 4 weeks
| Intervention | hours (Median) | |
|---|---|---|
| Olodaterol (N=0;0;46;72;72) | Olodaterol glucuronide (N=0;0;60;72;66) | |
| Olo 10 mcg qd | 0.200 | 3.00 |
| Olo 20 mcg qd | 0.200 | 3.00 |
| Olo 5 mcg qd | 0.192 | 3.00 |
Peak FEV1 (0-3h) Response After 2 Weeks
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 randomized treatment. Peak FEV1 (0-3h) values were obtained within 0 - 3 hours after treatment. Means are adjusted using a mixed effects model with baseline, treatment and centre (centre random, all other effects fixed). (NCT00452400)
Timeframe: 1 hour (h) and 10 minutes (min) prior to dose on the first day of randomized treatment (baseline) to 30 min, 1 h, 2 h, and 3 h relative to dose after 2 weeks
| Intervention | Liter (Least Squares Mean) |
|---|---|
| Placebo | 0.079 |
| Olo 2 mcg qd | 0.243 |
| Olo 5 mcg qd | 0.267 |
| Olo 10 mcg qd | 0.282 |
| Olo 20 mcg qd | 0.280 |
Maximum Concentration at Steady State (Cmax,ss)
Cmax,ss represents the maximum concentration of olodaterol and olodaterol glucuronide in plasma at steady state. (NCT00452400)
Timeframe: Baseline and 4 weeks
| Intervention | Picogram/milliliter (Geometric Mean) | |
|---|---|---|
| Olodaterol (N=0;0;46;72;72) | Olodaterol glucuronide (N=0;0;60;72;66) | |
| Olo 10 mcg qd | 7.13 | 5.55 |
| Olo 20 mcg qd | 14.1 | 11.1 |
| Olo 5 mcg qd | 4.02 | 4.90 |
Maximum Concentration (Cmax)
Cmax represents the maximum concentration of olodaterol and olodaterol glucuronide in plasma. (NCT00452400)
Timeframe: Baseline and 4 weeks
| Intervention | Picogram/milliliter (Geometric Mean) | |
|---|---|---|
| Olodaterol (N=0;0;40;71;69) | Olodaterol glucuronide (N=0;0;54;71;66) | |
| Olo 10 mcg qd | 5.45 | 5.24 |
| Olo 20 mcg qd | 12.2 | 10.6 |
| Olo 5 mcg qd | 3.58 | 3.94 |
Forced Expiratory Volume in 1 Second (FEV1) Area Under Curve 0-3 h (AUC 0-3h) Response at Day 1
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 randomized treatment. 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. (NCT00467740)
Timeframe: 1 hour (h) and 10 minutes (min) prior to dose on first day of randomized treatment (baseline) and 30 min, 1h, 2h, 3h relative to dose at Day 1
| Intervention | Liter (Least Squares Mean) |
|---|---|
| Placebo | 0.092 |
| Olo 2 mcg qd | 0.271 |
| Olo 5 mcg qd | 0.275 |
| Olo 10 mcg qd | 0.265 |
| Olo 20 mcg qd | 0.383 |
Forced Expiratory Volume in 1 Second (FEV1) Area Under Curve 0-3 h (AUC 0-3h) Response at Week 1
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 randomized treatment. 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. (NCT00467740)
Timeframe: 1 hour (h) and 10 minutes (min) prior to dose on first day of randomized treatment (baseline) and 30 min, 1h, 2h, 3h relative to dose at Week 1
| Intervention | Liter (Least Squares Mean) |
|---|---|
| Placebo | 0.062 |
| Olo 2 mcg qd | 0.252 |
| Olo 5 mcg qd | 0.258 |
| Olo 10 mcg qd | 0.219 |
| Olo 20 mcg qd | 0.325 |
Forced Expiratory Volume in 1 Second (FEV1) Area Under Curve 0-3 h (AUC 0-3h) Response at Week 4
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 randomized treatment. 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. (NCT00467740)
Timeframe: 1 hour (h) and 10 minutes (min) prior to dose on first day of randomized treatment (baseline) and 30 min, 1h, 2h, 3h relative to dose at Week 4
| Intervention | Liter (Least Squares Mean) |
|---|---|
| Placebo | 0.092 |
| Olo 2 mcg qd | 0.271 |
| Olo 5 mcg qd | 0.224 |
| Olo 10 mcg qd | 0.192 |
| Olo 20 mcg qd | 0.332 |
Forced Expiratory Volume in 1 Second (FEV1) Area Under Curve 0-6 h (AUC 0-6h) Response at Week 4
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 randomized treatment. FEV1 AUC 0-6h was calculated from 0-6 hours post-dose using the trapezoidal rule, divided by the observation time (6h) to report in litres. (NCT00467740)
Timeframe: 1 hour (h) and 10 minutes (min) prior to dose on first day of randomized treatment (baseline) and 30 min, 1h, 2h, 3h, 4h, 5h, 6h relative to dose at Week 4
| Intervention | Liter (Least Squares Mean) |
|---|---|
| Placebo | 0.091 |
| Olo 2 mcg qd | 0.269 |
| Olo 5 mcg qd | 0.229 |
| Olo 10 mcg qd | 0.190 |
| Olo 20 mcg qd | 0.323 |
Forced Expiratory Volume in 1 Second (FEV1) Area Under Curve 6-12 h (AUC 6-12h) Response at Week 4
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 randomized treatment. FEV1 AUC 6-12h was calculated from 6-12 hours post-dose using the trapezoidal rule, divided by the observation time (12h) to report in litres. (NCT00467740)
Timeframe: 1 hour (h) prior to dose on first day of randomized treatment (baseline) and 1h, 3h, 6h, 9h, 12h relative to dose at Week 4
| Intervention | Liter (Least Squares Mean) |
|---|---|
| Placebo | 0.054 |
| Olo 2 mcg qd | 0.107 |
| Olo 5 mcg qd | 0.098 |
| Olo 10 mcg qd | 0.092 |
| Olo 20 mcg qd | 0.216 |
Forced Vital Capacity (FVC) Area Under Curve 0-6 h (AUC 0-6h) Response at Week 4
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 randomized treatment. FVC AUC 0-6h was calculated from 0-6 hours post-dose using the trapezoidal rule, divided by the observation time (6h) to report in litres. (NCT00467740)
Timeframe: 1 hour (h) and 10 minutes (min) prior to dose on first day of randomized treatment (baseline) and 30 min, 1h, 2h, 3h, 4h, 5h, 6h relative to dose at Week 4
| Intervention | Liter (Least Squares Mean) |
|---|---|
| Placebo | 0.076 |
| Olo 2 mcg qd | 0.159 |
| Olo 5 mcg qd | 0.154 |
| Olo 10 mcg qd | 0.113 |
| Olo 20 mcg qd | 0.267 |
Laboratory Testing: Average Change From Baseline of Potassium
Laboratory testing: Average change from baseline of potassium measured on test-days. Pre-dose value on test day 1 is the baseline value. (NCT00467740)
Timeframe: Baseline and 29 days
| Intervention | mmol/L (Geometric Mean) |
|---|---|
| Placebo | 0.98 |
| Olo 2 mcg qd | 0.97 |
| Olo 5 mcg qd | 1.00 |
| Olo 10 mcg qd | 0.99 |
| Olo 20 mcg qd | 0.97 |
Peak FEV1 (0-3h) Response After 1 Week
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 randomized treatment. Peak FEV1 (0-3h) values were obtained within 0 - 3 hours after treatment. (NCT00467740)
Timeframe: 1 hour (h) and 10 minutes (min) prior to dose on the first day of randomized treatment (baseline) to 30 min, 1 h, 2 h, and 3 h relative to dose after 1 week
| Intervention | Liter (Least Squares Mean) |
|---|---|
| Placebo | 0.170 |
| Olo 2 mcg qd | 0.343 |
| Olo 5 mcg qd | 0.355 |
| Olo 10 mcg qd | 0.308 |
| Olo 20 mcg qd | 0.407 |
Peak FEV1 (0-3h) Response After 2 Weeks
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 randomized treatment. Peak FEV1 (0-3h) values were obtained within 0 - 3 hours after treatment. (NCT00467740)
Timeframe: 1 hour (h) and 10 minutes (min) prior to dose on the first day of randomized treatment (baseline) to 30 min, 1 h, 2 h, and 3 h relative to dose after 2 weeks
| Intervention | Liter (Least Squares Mean) |
|---|---|
| Placebo | 0.182 |
| Olo 2 mcg qd | 0.386 |
| Olo 5 mcg qd | 0.335 |
| Olo 10 mcg qd | 0.261 |
| Olo 20 mcg qd | 0.403 |
Peak FVC (0-3h) Response After 1 Week
Response was defined as change from baseline. Study baseline FEV1 was defined as the mean of the available pre-dose FVC values prior to the first dose of randomized treatment. Peak FVC (0-3h) values were obtained within 0 - 3 hours after treatment. (NCT00467740)
Timeframe: 1 hour (h) and 10 minutes (min) prior to dose on the first day of randomized treatment (baseline) to 30 min, 1 h, 2 h, and 3 h relative to dose after 1 weeks
| Intervention | Liter (Least Squares Mean) |
|---|---|
| Placebo | 0.182 |
| Olo 2 mcg qd | 0.281 |
| Olo 5 mcg qd | 0.301 |
| Olo 10 mcg qd | 0.259 |
| Olo 20 mcg qd | 0.367 |
Peak FEV1 (0-3h) Response After 4 Weeks
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 randomized treatment. Peak FEV1 (0-3h) values were obtained within 0 - 3 hours after treatment. (NCT00467740)
Timeframe: 1 hour (h) and 10 minutes (min) prior to dose on the first day of randomized treatment (baseline) to 30 min, 1 h, 2 h, and 3 h relative to dose after 4 weeks
| Intervention | Liter (Least Squares Mean) |
|---|---|
| Placebo | 0.198 |
| Olo 2 mcg qd | 0.363 |
| Olo 5 mcg qd | 0.315 |
| Olo 10 mcg qd | 0.279 |
| Olo 20 mcg qd | 0.430 |
Weekly Mean Evening PEFR After 4 Weeks
Response was defined as change from baseline. Baseline PEFR was defined as the mean of the evening PEFR measurements obtained during the week just prior to first dose of randomized treatment. (NCT00467740)
Timeframe: Baseline and 4 weeks
| Intervention | Liter/minute (Least Squares Mean) |
|---|---|
| Placebo | 384.08 |
| Olo 2 mcg qd | 407.05 |
| Olo 5 mcg qd | 408.68 |
| Olo 10 mcg qd | 420.88 |
| Olo 20 mcg qd | 426.58 |
Trough FVC Response After 4 Weeks
Response was defined as change from baseline. Baseline trough FVC was defined as the mean of the -1 hour and -10 minute measurements performed just prior to first dose of randomized treatment. Trough FVC is defined as the FVC performed at -10 mins prior to study drug inhalation at the end of the dosing interval. (NCT00467740)
Timeframe: Baseline and 4 weeks
| Intervention | Liter (Least Squares Mean) |
|---|---|
| Placebo | 0.018 |
| Olo 2 mcg qd | 0.055 |
| Olo 5 mcg qd | 0.076 |
| Olo 10 mcg qd | 0.042 |
| Olo 20 mcg qd | 0.166 |
Trough FVC Response After 2 Weeks
Response was defined as change from baseline. Baseline trough FVC was defined as the mean of the -1 hour and -10 minute measurements performed just prior to first dose of randomized treatment. Trough FVC is defined as the FVC performed at -10 mins prior to study drug inhalation at the end of the dosing interval. (NCT00467740)
Timeframe: Baseline and 2 weeks
| Intervention | Liter (Least Squares Mean) |
|---|---|
| Placebo | -0.029 |
| Olo 2 mcg qd | 0.098 |
| Olo 5 mcg qd | 0.069 |
| Olo 10 mcg qd | -0.002 |
| Olo 20 mcg qd | 0.100 |
Trough FVC Response After 1 Week
Response was defined as change from baseline. Baseline trough FVC was defined as the mean of the -1 hour and -10 minute measurements performed just prior to first dose of randomized treatment. Trough FVC is defined as the FVC performed at -10 mins prior to study drug inhalation at the end of the dosing interval. (NCT00467740)
Timeframe: Baseline and 1 week
| Intervention | Liter (Least Squares Mean) |
|---|---|
| Placebo | 0.001 |
| Olo 2 mcg qd | 0.053 |
| Olo 5 mcg qd | 0.044 |
| Olo 10 mcg qd | 0.070 |
| Olo 20 mcg qd | 0.131 |
Trough FEV1 Response After 4 Weeks
Response was defined as change from baseline. Baseline trough FEV1 was defined as the mean of the -1 hour and -10 minute measurements performed just prior to first dose of randomized treatment. Trough FEV1 is defined as the FEV1 performed at -10 mins prior to study drug inhalation at the end of the dosing interval. (NCT00467740)
Timeframe: Baseline and 4 weeks
| Intervention | Liter (Least Squares Mean) |
|---|---|
| Placebo | 0.004 |
| Olo 2 mcg qd | 0.083 |
| Olo 5 mcg qd | 0.090 |
| Olo 10 mcg qd | 0.080 |
| Olo 20 mcg qd | 0.150 |
Trough FEV1 Response After 2 Weeks
Response was defined as change from baseline. Baseline trough FEV1 was defined as the mean of the -1 hour and -10 minute measurements performed just prior to first dose of randomized treatment. Trough FEV1 is defined as the FEV1 performed at -10 mins prior to study drug inhalation at the end of the dosing interval. (NCT00467740)
Timeframe: Baseline and 2 weeks
| Intervention | Liter (Least Squares Mean) |
|---|---|
| Placebo | -0.009 |
| Olo 2 mcg qd | 0.094 |
| Olo 5 mcg qd | 0.080 |
| Olo 10 mcg qd | 0.034 |
| Olo 20 mcg qd | 0.131 |
Trough FEV1 Response After 1 Week
Response was defined as change from baseline. Baseline trough FEV1 was defined as the mean of the -1 hour and -10 minute measurements performed just prior to first dose of randomized treatment. Trough FEV1 is defined as the FEV1 performed at -10 mins prior to study drug inhalation at the end of the dosing interval. (NCT00467740)
Timeframe: Baseline and 1 week
| Intervention | Liter (Least Squares Mean) |
|---|---|
| Placebo | -0.007 |
| Olo 2 mcg qd | 0.060 |
| Olo 5 mcg qd | 0.094 |
| Olo 10 mcg qd | 0.106 |
| Olo 20 mcg qd | 0.166 |
Total Score in Asthma Control Questionnaire After 4 Weeks
Adequacy of asthma control was assessed using a scale of: 0=totally controlled, to 6=Severely uncontrolled. (NCT00467740)
Timeframe: 4 weeks
| Intervention | units on a scale (Least Squares Mean) |
|---|---|
| Placebo | 1.456 |
| Olo 2 mcg qd | 1.314 |
| Olo 5 mcg qd | 1.260 |
| Olo 10 mcg qd | 1.129 |
| Olo 20 mcg qd | 1.181 |
PEFR Variability After 4 Weeks
PEFR variability represents the absolute difference between the highest morning PEFR value and the highest evening PEFR value of 1 day, divided by the arithmetic mean of these 2 PEFR values and expressed as a percent, weekly means. (NCT00467740)
Timeframe: 4 weeks
| Intervention | percentage of PEFR (Least Squares Mean) |
|---|---|
| Placebo | 11.694 |
| Olo 2 mcg qd | 10.575 |
| Olo 5 mcg qd | 9.343 |
| Olo 10 mcg qd | 8.649 |
| Olo 20 mcg qd | 8.756 |
Peak FEV1 (0-3h) Response At Day 1
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 randomized treatment. Peak FEV1 (0-3h) values were obtained within 0 - 3 hours after treatment. (NCT00467740)
Timeframe: 1 hour (h) and 10 minutes (min) prior to dose on the first day of randomized treatment (baseline) to 30 min, 1 h, 2 h, and 3 h relative to dose at day 1
| Intervention | Liter (Least Squares Mean) |
|---|---|
| Placebo | 0.203 |
| Olo 2 mcg qd | 0.372 |
| Olo 5 mcg qd | 0.378 |
| Olo 10 mcg qd | 0.376 |
| Olo 20 mcg qd | 0.499 |
Peak FVC (0-3h) Response After 4 Weeks
Response was defined as change from baseline. Study baseline FEV1 was defined as the mean of the available pre-dose FVC values prior to the first dose of randomized treatment. Peak FVC (0-3h) values were obtained within 0 - 3 hours after treatment. (NCT00467740)
Timeframe: 1 hour (h) and 10 minutes (min) prior to dose on the first day of randomized treatment (baseline) to 30 min, 1 h, 2 h, and 3 h relative to dose after 4 weeks
| Intervention | Liter (Least Squares Mean) |
|---|---|
| Placebo | 0.199 |
| Olo 2 mcg qd | 0.274 |
| Olo 5 mcg qd | 0.267 |
| Olo 10 mcg qd | 0.235 |
| Olo 20 mcg qd | 0.439 |
Peak FVC (0-3h) Response After 2 Weeks
Response was defined as change from baseline. Study baseline FEV1 was defined as the mean of the available pre-dose FVC values prior to the first dose of randomized treatment. Peak FVC (0-3h) values were obtained within 0 - 3 hours after treatment. (NCT00467740)
Timeframe: 1 hour (h) and 10 minutes (min) prior to dose on the first day of randomized treatment (baseline) to 30 min, 1 h, 2 h, and 3 h relative to dose after 2 weeks
| Intervention | Liter (Least Squares Mean) |
|---|---|
| Placebo | 0.184 |
| Olo 2 mcg qd | 0.327 |
| Olo 5 mcg qd | 0.290 |
| Olo 10 mcg qd | 0.234 |
| Olo 20 mcg qd | 0.361 |
Weekly Mean Number of Occasions of Rescue Therapy After 4 Weeks
Weekly mean number of occasions of rescue therapy used per day (prn salbutamol [albuterol]) as assessed by the e-Diary (e-Diary incorporated in AM2+). (NCT00467740)
Timeframe: 4 weeks
| Intervention | Number of Puffs (Least Squares Mean) |
|---|---|
| Placebo | 1.449 |
| Olo 2 mcg qd | 1.162 |
| Olo 5 mcg qd | 0.923 |
| Olo 10 mcg qd | 1.117 |
| Olo 20 mcg qd | 0.856 |
Weekly Mean Pre-dose Morning PEFR After 4 Weeks
Response was defined as change from baseline. Baseline peak expiratory flow response (PEFR) was defined as the mean of the morning PEFR measurements obtained during the week just prior to first dose of randomized treatment. (NCT00467740)
Timeframe: Baseline and 4 weeks
| Intervention | Liter/minute (Least Squares Mean) |
|---|---|
| Placebo | 368.18 |
| Olo 2 mcg qd | 384.42 |
| Olo 5 mcg qd | 396.06 |
| Olo 10 mcg qd | 404.26 |
| Olo 20 mcg qd | 411.13 |
Area Under Curve From 0 to 24 Hours at Steady State (AUC0-24,ss)
AUC0-24,ss represents the area under the concentration curve of olodaterol and olodaterol glucuronide (a metabolite of olodaterol) in plasma from 0 to time t=24 at steady state. (NCT00467740)
Timeframe: 30 minutes (mins) before drug administration and 5mins, 10mins, 20mins, 40mins, 1 hour (h), 3h and 6h after drug administration
| Intervention | Picogram*hours/milliliter (Geometric Mean) | |
|---|---|---|
| Olodaterol | Olodaterol glucuronide | |
| Olo 10 mcg qd | 83.7 | NA |
| Olo 20 mcg qd | 147 | NA |
Area Under Curve From 0 to 3 Hours (AUC0-3)
AUC0-3 represents the area under the concentration curve of olodaterol and olodaterol glucuronide (a metabolite of olodaterol) in plasma from 0 to time t=3 (NCT00467740)
Timeframe: 30 minutes (mins) before drug administration and 5mins, 10mins, 20mins, 40mins, 1 hour (h) and 3h after drug administration
| Intervention | Picogram*hours/milliliter (Geometric Mean) | |
|---|---|---|
| Olodaterol (N=0;0;0;20;44) | Olodaterol glucuronide (N=0;0;0;28;36) | |
| Olo 10 mcg qd | 11.8 | 9.14 |
| Olo 20 mcg qd | 17.8 | 20.3 |
Forced Expiratory Volume in 1 Second (FEV1) Area Under Curve 0-3 h (AUC 0-3h) Response at Week 2
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 randomized treatment. 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. (NCT00467740)
Timeframe: 1 hour (h) and 10 minutes (min) prior to dose on first day of randomized treatment (baseline) and 30 min, 1h, 2h, 3h relative to dose at Week 2
| Intervention | Liter (Least Squares Mean) |
|---|---|
| Placebo | 0.084 |
| Olo 2 mcg qd | 0.298 |
| Olo 5 mcg qd | 0.240 |
| Olo 10 mcg qd | 0.172 |
| Olo 20 mcg qd | 0.311 |
Area Under Curve From 0 to 3 Hours at Steady State (AUC0-3,ss)
AUC0-3,ss represents the area under the concentration curve of olodaterol and olodaterol glucuronide (a metabolite of olodaterol) in plasma from 0 to time t=3 at steady state. (NCT00467740)
Timeframe: 30 minutes (mins) before drug administration and 5mins, 10mins, 20mins, 40mins, 1 hour (h), 3h and 6h after drug administration
| Intervention | Picogram*hours/milliliter (Geometric Mean) | |
|---|---|---|
| Olodaterol (N=0;0;0;38;53) | Olodaterol glucuronide (N=0;0;38;44;54) | |
| Olo 10 mcg qd | 13.0 | 9.04 |
| Olo 20 mcg qd | 25.5 | 19.0 |
| Olo 5 mcg qd | NA | 7.71 |
Area Under Curve From 0 to 6 Hours at Steady State (AUC0-6,ss)
AUC0-6,ss represents the area under the concentration curve of olodaterol and olodaterol glucuronide (a metabolite of olodaterol) in plasma from 0 to time t=6 at steady state. (NCT00467740)
Timeframe: 30 minutes (mins) before drug administration and 5mins, 10mins, 20mins, 40mins, 1 hour (h), 3h and 6h after drug administration
| Intervention | Picogram*hours/milliliter (Geometric Mean) | |
|---|---|---|
| Olodaterol (N=0;0;0;32;50) | Olodaterol glucuronide (N=0;0;21;23;33) | |
| Olo 10 mcg qd | 25.3 | 21.3 |
| Olo 20 mcg qd | 46.3 | 37.6 |
| Olo 5 mcg qd | NA | 19.2 |
Clinical Relevant Abnormalities for Vital Signs, ECG and Physical Examination
Clinical relevant abnormalities for vital signs, ECG and physical examination. Any new or clinically relevant worsening of baseline conditions was reported as adverse events. (NCT00467740)
Timeframe: 4 weeks
| Intervention | participants (Number) | ||
|---|---|---|---|
| Palpitations | Ventricular extrasystoles | Blood creatine phosphokinase increased | |
| Olo 10 mcg qd | 0 | 0 | 0 |
| Olo 2 mcg qd | 0 | 0 | 0 |
| Olo 20 mcg qd | 2 | 0 | 1 |
| Olo 5 mcg qd | 1 | 1 | 0 |
| Placebo | 0 | 0 | 0 |
Peak FVC (0-3h) Response At Day 1
Response was defined as change from baseline. Study baseline FEV1 was defined as the mean of the available pre-dose FVC values prior to the first dose of randomized treatment. Peak FVC (0-3h) values were obtained within 0 - 3 hours after treatment. (NCT00467740)
Timeframe: 1 hour (h) and 10 minutes (min) prior to dose on the first day of randomized treatment (baseline) to 30 min, 1 h, 2 h, and 3 h relative to dose after 1 weeks
| Intervention | Liter (Least Squares Mean) |
|---|---|
| Placebo | 0.218 |
| Olo 2 mcg qd | 0.297 |
| Olo 5 mcg qd | 0.315 |
| Olo 10 mcg qd | 0.315 |
| Olo 20 mcg qd | 0.398 |
Maximum Concentration at Steady State (Cmax,ss)
Cmax,ss represents the maximum concentration of olodaterol and olodaterol glucuronide (a metabolite of olodaterol) in plasma at steady state. (NCT00467740)
Timeframe: 30 minutes (mins) before drug administration and 5mins, 10mins, 20mins, 40mins, 1 hour (h), 3h and 6h after drug administration
| Intervention | Picogram/milliliter (Geometric Mean) | |
|---|---|---|
| Olodaterol N=(0;0;39;45;56) | Olodaterol glucuronide N=(0;0;46;46;54) | |
| Olo 10 mcg qd | 5.09 | 5.04 |
| Olo 20 mcg qd | 12.1 | 9.19 |
| Olo 5 mcg qd | 3.19 | 4.16 |
Time From Dosing to the Maximum Concentration (Tmax)
tmax represents the time from dosing to maximum concentration of olodaterol and olodaterol glucuronide (a metabolite of olodaterol) in plasma. (NCT00467740)
Timeframe: 30 minutes (mins) before drug administration and 5mins, 10mins, 20mins, 40mins, 1 hour (h) and 3h after drug administration
| Intervention | hours (Median) | |
|---|---|---|
| Olodaterol (N=0;0;21;44;58) | Olodaterol glucuronide (N=0;0;38;54;57) | |
| Olo 10 mcg qd | 0.234 | 2.97 |
| Olo 20 mcg qd | 0.267 | 2.97 |
| Olo 5 mcg qd | 0.183 | 2.97 |
Time From Dosing to the Maximum Concentration at Steady State (Tmax,ss)
tmax,ss represents the time from dosing to maximum concentration of olodaterol and olodaterol glucuronide (a metabolite of olodaterol) in plasma at steady state. (NCT00467740)
Timeframe: 30 minutes (mins) before drug administration and 5mins, 10mins, 20mins, 40mins, 1 hour (h), 3h and 6h after drug administration
| Intervention | hours (Median) | |
|---|---|---|
| Olodaterol (N=0;0;39;45;56) | Olodaterol glucuronide (N=0;0;46;46;54) | |
| Olo 10 mcg qd | 0.333 | 3.00 |
| Olo 20 mcg qd | 0.333 | 2.97 |
| Olo 5 mcg qd | 0.333 | 3.00 |
Maximum Concentration (Cmax)
Cmax represents the maximum concentration of olodaterol and olodaterol glucuronide (a metabolite of olodaterol) in plasma. (NCT00467740)
Timeframe: 30 minutes (mins) before drug administration and 5mins, 10mins, 20mins, 40mins, 1 hour (h) and 3h after drug administration
| Intervention | Picogram/milliliter (Geometric Mean) | |
|---|---|---|
| Olodaterol (N=0;0;21;44;58) | Olodaterol glucuronide (N=0;0;38;54;57) | |
| Olo 10 mcg qd | 4.63 | 5.00 |
| Olo 20 mcg qd | 8.24 | 9.54 |
| Olo 5 mcg qd | 3.54 | 3.57 |
PEF (Unsupervised) AUC(6-12h) Response [L/Min] After First Administration and 1,2 and 4 Weeks of Treatment
"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 AUC(0-3h) Response [L/Min] After First Administration and After 1, 2 and 4 Weeks of Treatment.
"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 |
PEF Peak(0-3h) Response [L] After First Administration and After 1, 2 and 4 Weeks of Treatment
"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 |
Physician's Global Evaluation
"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 Response [L] After 1 and 2 Weeks of Treatment.
"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 Response [L] After 1, 2 and 4 Weeks of Treatment
"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 |
Weekly Mean Evening PEF [L/Min]
"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 |
Weekly Mean Pre-dose Morning PEF [L/Min]
"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 |
Tmax,ss Olodaterol [h]
"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 |
Weekly Mean Number of Occasions of Rescue Therapy Used Per Day
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 |
Tmax,ss Tiotropium [h]
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 Response [L] After 4 Weeks of Treatment
"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 (Unsupervised) AUC(6-12h) Response [L] After First Administration and 1,2 and 4 Weeks of Treatment
"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 |
FEV1 AUC(0-3h) Response [L] After First Administration and After 1, 2 and 4 Weeks of Treatment
"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 Peak(0-3h) Response [L] After First Administration and After 1, 2 and 4 Weeks of Treatment
"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 AUC(0-3h) Response [L] After First Administration and After 1, 2 and 4 Weeks of Treatment.
"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 Peak(0-3h) Response [L] After First Administration and After 1, 2 and 4 Weeks of Treatment
"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 AUC(0-6h) Response [L] After 4 Weeks of Treatment
"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 |
Patient's Global Rating
"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 |
FVC AUC(0-6h) Response [L] After 4 Weeks of Treatment
"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 |
FEV1 AUC(0-6h) Response [L] After 4 Weeks of Treatment
"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 |
Cmax,ss Tiotropium [pg/mL]
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 |
Cmax,ss Olodaterol [pg/mL]
"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 |
Clinically Significant Anormalities (Laboratory Data); Marked Changes From Baseline for Vital Signs, Notable Change in ECG and New Onset of ECG Abnormalities
"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 |
AUC(0-3h,ss) Tiotropium [pg*h/mL]
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 |
AUC(0-1h,ss) Olodaterol [pg*h/mL]
"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 |
Clinically Significant Abnormalities for Blood Chemistry, Haematology, Urinalysis and Physical Examination
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 QTcF Intervals
"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 QTcB Intervals
"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 |
12-lead ECG QT Intervals
"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
"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
"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 ECG Heart Rate
"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 |
PEFR Peak 0-3h Response
"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 |
PEFR AUC (0-3h) Response
"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 Vital Signs
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 |
Individual FVC Measurements
"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 |
Individual FEV1 Measurements
"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 |
Trough Forced Expiratory Volume in One Second (FEV1) Response [L] After Four Weeks of Treatment.
"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 |
Trough FEV1 Response [L] After 2 Weeks of Treatment
"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 |
FVC AUC (0-3h) Response
"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 0-3h Response
"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 AUC 0-3h, Response
"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 |
Weekly Mean Number of Occasions of Rescue Therapy Used Per Day (PRN Salbutamol [Albuterol])
"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
"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
"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 FVC Response
"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
"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 |
FEV1 (Unsupervised) AUC (6-12h) Response
"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 |
FEV1, AUC (0-6h) Response
"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 |
FVC AUC (0-6h) Response
"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 |
FVC Peak 0-3h Response
"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 |
Patient Global Rating
"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 |
PEFR AUC (6-12h) Response
"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 |
Peak FEV1 (0-3h) Response After 48 Weeks
Response was defined as change from baseline. Baseline peak FEV1 was defined as the mean of the available pre-dose peak FEV1 values prior to first dose of randomized treatment. Peak FEV1 (0-3h) values were obtained within 0 - 3 hours after treatment. Means are adjusted using a mixed effects model with treatment (trt), tio stratum, visit, trt-by-visit as fixed categorical effects, baseline and baseline-by-visit as fixed continuous covariates and patient as random effect. (NCT00782210)
Timeframe: 1 hour (h) and 10 minutes (min) prior to dose on the first day of randomized treatment (baseline) to -10 min, 5 min, 15 min, 30 min, 1 h, 2 h, and 3 h relative to dose after 48 weeks
| Intervention | Liter (Mean) |
|---|---|
| Placebo | 0.029 |
| Olo 5 mcg qd | 0.198 |
| Olo 10 mcg qd | 0.192 |
Peak FEV1 (0-3h) Response After 6 Weeks
Response was defined as change from baseline. Baseline peak FEV1 was defined as the mean of the available pre-dose peak FEV1 values prior to first dose of randomized treatment. Peak FEV1 (0-3h) values were obtained within 0 - 3 hours after treatment. Means are adjusted using a mixed effects model with treatment (trt), tio stratum, visit, trt-by-visit as fixed categorical effects, baseline and baseline-by-visit as fixed continuous covariates and patient as random effect. (NCT00782210)
Timeframe: 1 hour (h) and 10 minutes (min) prior to dose on the first day of randomized treatment (baseline) to -10 min, 5 min, 15 min, 30 min, 1 h, 2 h, and 3 h relative to dose after 6 weeks
| Intervention | Liter (Mean) |
|---|---|
| Placebo | 0.066 |
| Olo 5 mcg qd | 0.238 |
| Olo 10 mcg qd | 0.238 |
Peak FEV1 (0-3h) Response At Day 1
"Response was defined as change from baseline. Baseline peak FEV1 was defined as the mean of the available pre-dose peak FEV1 values prior to first dose of randomized treatment. Peak FEV1 (0-3h) values were obtained within 0 - 3 hours after treatment.~Means are adjusted using a mixed effects model with treatment (trt), tio stratum, visit, trt-by- visit as fixed categorical effects, baseline and baseline-by-visit as fixed continuous covariates and patient as random effect." (NCT00782210)
Timeframe: 1 hour (h) and 10 minutes (min) prior to dose on the first day of randomized treatment (baseline) to -10 min, 5 min, 15 min, 30 min, 1 h, 2 h, and 3 h relative to dose at Day 1
| Intervention | Liter (Mean) |
|---|---|
| Placebo | 0.104 |
| Olo 5 mcg qd | 0.259 |
| Olo 10 mcg qd | 0.275 |
Time to First Chronic Obstructive Pulmonary Disease (COPD) Exacerbation
Qualifying events of COPD were specifically pre-defined in the protocol. Other respiratory related events were evaluated by the investigator to see if they met the pre-defined criteria. Time to event was measured from the beginning of treatment. Cox regression analysis of treatment effect using tiotropium stratum as a stratification factor. Due to the limited number of events some statistics were not able to be calculated and are listed as N/A or are blank. The measure type is the First Quartile. (NCT00782210)
Timeframe: Baseline to end of study at 48 weeks.
| Intervention | days (Mean) |
|---|---|
| Placebo (Tiotropium) | 194.0 |
| Placebo (Non-tiotropium) | 160.0 |
| Olo 5 mcg qd (Tiotropium) | 203.0 |
| Olo 5 mcg qd (Non-tiotropium) | 236.0 |
| Olo 10 mcg qd (Tiotropium) | 167.0 |
| Olo 10 mcg qd(Non-tiotropium) | 239.0 |
Time to First Chronic Obstructive Pulmonary Disease (COPD) Exacerbation Leading to Hospitalization
Qualifying events of COPD were specifically pre-defined in the protocol. Other respiratory related events were evaluated by the investigator to see if they met the pre-defined criteria. These exacerbations required hospitalization. Time to event was measured from the beginning of treatment. Cox regression analysis of treatment effect using tiotropium stratum as a stratification factor. Due to the limited number of events some statistics were not able to be calculated and are listed as N/A or are blank. The measure type is the First Quartile. (NCT00782210)
Timeframe: Baseline to end of study at 48 weeks.
| Intervention | days (Mean) |
|---|---|
| Placebo (Tiotropium) | NA |
| Placebo (Non-tiotropium) | NA |
| Olo 5 mcg qd (Tiotropium) | NA |
| Olo 5 mcg qd (Non-tiotropium) | NA |
| Olo 10 mcg qd (Tiotropium) | NA |
| Olo 10 mcg qd(Non-tiotropium) | NA |
Time to First Moderate Chronic Obstructive Pulmonary Disease (COPD) Exacerbation
Qualifying events of COPD were specifically pre-defined in the protocol. Other respiratory related events were evaluated by the investigator to see if they met the pre-defined criteria. These exacerbations did not lead to hospitalization but included treatment with antibiotics and/or systemic steroids. Time to event was measured from the beginning of treatment. Cox regression analysis of treatment effect using tiotropium stratum as a stratification factor. Due to the limited number of events some statistics were not able to be calculated and are listed as N/A or are blank. The measure type is the First Quartile. (NCT00782210)
Timeframe: Baseline to end of study at 48 weeks.
| Intervention | days (Mean) |
|---|---|
| Placebo (Tiotropium) | 194.0 |
| Placebo (Non-tiotropium) | 216.0 |
| Olo 5 mcg qd (Tiotropium) | 218.0 |
| Olo 5 mcg qd (Non-tiotropium) | 344.0 |
| Olo 10 mcg qd (Tiotropium) | 170.0 |
| Olo 10 mcg qd(Non-tiotropium) | 309.0 |
Trough FEV1 Response After 18 Weeks
Response was defined as change from baseline. Baseline trough FEV1 was defined as the mean of the -1 hour and -10 minute measurements performed just prior to first dose of randomized treatment. Trough FEV1 is defined as the FEV1 performed at -10 mins prior to study drug inhalation as the end of the dosing interval or the mean of -1h and -10 min FEV1s if both available. Means are adjusted using a mixed effects model with treatment (trt), tio stratum, visit, trt-by-visit as fixed categorical effects, baseline and baseline-by-visit as fixed continuous covariates and patient as random effect. (NCT00782210)
Timeframe: 1 h and 10 min prior to dose on the first day of randomized treatment (baseline) and -1 h (if available) and - 10 mins prior to study drug after 18 weeks
| Intervention | Liter (Mean) |
|---|---|
| Placebo | -0.042 |
| Olo 5 mcg qd | 0.056 |
| Olo 10 mcg qd | 0.059 |
Trough FEV1 Response After 2 Weeks
Response was defined as change from baseline. Baseline trough FEV1 was defined as the mean of the -1 hour and -10 minute measurements performed just prior to first dose of randomized treatment. Trough FEV1 is defined as the FEV1 performed a -10 mins prior to study drug inhalation as the end of the dosing interval or the mean of -1h and -10 min FEV1s if both available. Means are adjusted using a mixed effects model with treatment (trt), tio stratum, visit, trt-by-visit as fixed categorical effects, baseline and baseline-by-visit as fixed continuous covariates and patient as random effect. (NCT00782210)
Timeframe: 1 h and 10 min prior to dose on the first day of randomized treatment (baseline) and -1 h (if available) and - 10 mins prior to study drug after 2 weeks
| Intervention | Liter (Mean) |
|---|---|
| Placebo | -0.019 |
| Olo 5 mcg qd | 0.076 |
| Olo 10 mcg qd | 0.091 |
Trough FEV1 Response After 24 Weeks
Response was defined as change from baseline. Baseline trough FEV1 was defined as the mean of the -1 hour and -10 minute measurements performed just prior to first dose of randomized treatment. Trough FEV1 is defined as the FEV1 performed at -10 mins prior to study drug inhalation as the end of the dosing interval or the mean of -1h and -10 min FEV1s if both available. Means are adjusted using a mixed effects model with treatment (trt), tio stratum, visit, trt-by-visit as fixed categorical effects, baseline and baseline-by-visit as fixed continuous covariates and patient as random effect. (NCT00782210)
Timeframe: 1 h and 10 min prior to dose on the first day of randomized treatment (baseline) and -1 h (if available) and - 10 mins prior to study drug after 24 weeks
| Intervention | Liter (Mean) |
|---|---|
| Placebo | -0.050 |
| Olo 5 mcg qd | 0.036 |
| Olo 10 mcg qd | 0.039 |
Trough FEV1 Response After 32 Weeks
Response was defined as change from baseline. Baseline trough FEV1 was defined as the mean of the -1 hour and -10 minute measurements performed just prior to first dose of randomized treatment. Trough FEV1 is defined as the FEV1 performed at -10 mins prior to study drug inhalation as the end of the dosing interval or the mean of -1h and -10 min FEV1s if both available. Means are adjusted using a mixed effects model with treatment (trt), tio stratum, visit, trt-by-visit as fixed categorical effects, baseline and baseline-by-visit as fixed continuous covariates and patient as random effect. (NCT00782210)
Timeframe: 1 h and 10 min prior to dose on the first day of randomized treatment (baseline) and -1 h (if available) and - 10 mins prior to study drug after 32 weeks
| Intervention | Liter (Mean) |
|---|---|
| Placebo | -0.051 |
| Olo 5 mcg qd | 0.041 |
| Olo 10 mcg qd | 0.034 |
Trough FEV1 Response After 40 Weeks
Response was defined as change from baseline. Baseline trough FEV1 was defined as the mean of the -1 hour and -10 minute measurements performed just prior to first dose of randomized treatment. Trough FEV1 is defined as the FEV1 performed at -10 mins prior to study drug inhalation as the end of the dosing interval or the mean of -1h and -10 min FEV1s if both available. Means are adjusted using a mixed effects model with treatment (trt), tio stratum, visit, trt-by-visit as fixed categorical effects, baseline and baseline-by-visit as fixed continuous covariates and patient as random effect. (NCT00782210)
Timeframe: 1 h and 10 min prior to dose on the first day of randomized treatment (baseline) and -1 h (if available) and - 10 mins prior to study drug after 40 weeks
| Intervention | Liter (Mean) |
|---|---|
| Placebo | -0.061 |
| Olo 5 mcg qd | 0.046 |
| Olo 10 mcg qd | 0.044 |
Trough FEV1 Response After 48 Weeks
Response was defined as change from baseline. Baseline trough FEV1 was defined as the mean of the -1 hour and -10 minute measurements performed just prior to first dose of randomized treatment. Trough FEV1 is defined as the FEV1 performed at -10 mins prior to study drug inhalation as the end of the dosing interval or the mean of -1h and -10 min FEV1s if both available. Means are adjusted using a mixed effects model with treatment (trt), tio stratum, visit, trt-by-visit as fixed categorical effects, baseline and baseline-by-visit as fixed continuous covariates and patient as random effect. (NCT00782210)
Timeframe: 1 h and 10 min prior to dose on the first day of randomized treatment (baseline) and -1 h (if available) and - 10 mins prior to study drug after 48 weeks
| Intervention | Liter (Mean) |
|---|---|
| Placebo | -0.74 |
| Olo 5 mcg qd | 0.019 |
| Olo 10 mcg qd | 0.017 |
Trough FEV1 Response After 6 Weeks
Response was defined as change from baseline. Baseline trough FEV1 was defined as the mean of the -1 hour and -10 minute measurements performed just prior to first dose of randomized treatment. Trough FEV1 is defined as the FEV1 performed at -10 mins prior to study drug inhalation as the end of the dosing interval or the mean of -1h and -10 min FEV1s if both available. Means are adjusted using a mixed effects model with treatment (trt), tio stratum, visit, trt-by-visit as fixed categorical effects, baseline and baseline-by-visit as fixed continuous covariates and patient as random effect. (NCT00782210)
Timeframe: 1 h and 10 min prior to dose on the first day of randomized treatment (baseline) and -1 h (if available) and - 10 mins prior to study drug after 6 weeks
| Intervention | Liter (Mean) |
|---|---|
| Placebo | -0.022 |
| Olo 5 mcg qd | 0.073 |
| Olo 10 mcg qd | 0.069 |
Trough FEV1 Response at Day 85 (12 Weeks)
Response was defined as change from baseline. Baseline trough FEV1 was defined as the mean of the -1 hour and -10 minute measurements performed just prior to first dose of randomized treatment. Trough FEV1 is defined as the FEV1 performed at -10 mins prior to study drug inhalation as the end of the dosing interval or the mean of -1h and -10 min FEV1s if both available. Means are adjusted using a mixed effects model with treatment (trt), tio stratum, visit, trt-by-visit as fixed categorical effects, baseline and baseline-by-visit as fixed continuous covariates and patient as random effect. (NCT00782210)
Timeframe: 1 h and 10 min prior to dose on the first day of randomized treatment (baseline) and -1 h and - 10 mins prior to study drug at Day 85.
| Intervention | Liter (Mean) |
|---|---|
| Placebo | -0.041 |
| Olo 5 mcg qd | 0.050 |
| Olo 10 mcg qd | 0.060 |
Trough FVC Response After 12 Weeks
Response was defined as change from baseline. Baseline trough FVC was defined as the mean of the -1 hour and -10 minute measurements performed just prior to first dose of randomized treatment. Trough FVC is defined as the FVCs obtained at -10 mins prior to study drug inhalation as the end of the dosing interval or the mean of -1h and -10 min FVCs if both available. Means are adjusted using a mixed effects model with treatment (trt), tio stratum, visit, trt-by-visit as fixed categorical effects, baseline and baseline-by-visit as fixed continuous covariates and patient as random effect. (NCT00782210)
Timeframe: 1 h and 10 min prior to dose on the first day of randomized treatment (baseline) and -1 h (if available) and - 10 mins prior to study drug after 12 weeks
| Intervention | Liter (Mean) |
|---|---|
| Placebo | -0.030 |
| Olo 5 mcg qd | 0.085 |
| Olo 10 mcg qd | 0.130 |
Trough FVC Response After 18 Weeks
Response was defined as change from baseline. Baseline trough FVC was defined as the mean of the -1 hour and -10 minute measurements performed just prior to first dose of randomized treatment. Trough FVC is defined as the FVCs obtained at -10 mins prior to study drug inhalation as the end of the dosing interval or the mean of -1h and -10 min FVCs if both available. Means are adjusted using a mixed effects model with treatment (trt), tio stratum, visit, trt-by-visit as fixed categorical effects, baseline and baseline-by-visit as fixed continuous covariates and patient as random effect. (NCT00782210)
Timeframe: 1 h and 10 min prior to dose on the first day of randomized treatment (baseline) and -1 h (if available) and - 10 mins prior to study drug after 18 weeks
| Intervention | Liter (Mean) |
|---|---|
| Placebo | -0.028 |
| Olo 5 mcg qd | 0.102 |
| Olo 10 mcg qd | 0.134 |
Trough FVC Response After 2 Weeks
Response was defined as change from baseline. Baseline trough FVC was defined as the mean of the -1 hour and -10 minute measurements performed just prior to first dose of randomized treatment. Trough FVC is defined as the FVCs obtained at -10 mins prior to study drug inhalation as the end of the dosing interval or the mean of -1h and -10 min FVCs if both available. Means are adjusted using a mixed effects model with treatment (trt), tio stratum, visit, trt-by-visit as fixed categorical effects, baseline and baseline-by-visit as fixed continuous covariates and patient as random effect. (NCT00782210)
Timeframe: 1 h and 10 min prior to dose on the first day of randomized treatment (baseline) and -1 h (if available) and - 10 mins prior to study drug after 2 weeks
| Intervention | Liter (Mean) |
|---|---|
| Placebo | -0.015 |
| Olo 5 mcg qd | 0.132 |
| Olo 10 mcg qd | 0.169 |
Trough FVC Response After 24 Weeks
Response was defined as change from baseline. Baseline trough FVC was defined as the mean of the -1 hour and -10 minute measurements performed just prior to first dose of randomized treatment. Trough FVC is defined as the FVCs obtained at -10 mins prior to study drug inhalation as the end of the dosing interval or the mean of -1h and -10 min FVCs if both available. Means are adjusted using a mixed effects model with treatment (trt), tio stratum, visit, trt-by-visit as fixed categorical effects, baseline and baseline-by-visit as fixed continuous covariates and patient as random effect. (NCT00782210)
Timeframe: 1 h and 10 min prior to dose on the first day of randomized treatment (baseline) and -1 h (if available) and - 10 mins prior to study drug after 24 weeks
| Intervention | Liter (Mean) |
|---|---|
| Placebo | -0.028 |
| Olo 5 mcg qd | 0.055 |
| Olo 10 mcg qd | 0.096 |
Trough FVC Response After 32 Weeks
Response was defined as change from baseline. Baseline trough FVC was defined as the mean of the -1 hour and -10 minute measurements performed just prior to first dose of randomized treatment. Trough FVC is defined as the FVCs obtained at -10 mins prior to study drug inhalation as the end of the dosing interval or the mean of -1h and -10 min FVCs if both available. Means are adjusted using a mixed effects model with treatment (trt), tio stratum, visit, trt-by-visit as fixed categorical effects, baseline and baseline-by-visit as fixed continuous covariates and patient as random effect. (NCT00782210)
Timeframe: 1 h and 10 min prior to dose on the first day of randomized treatment (baseline) and -1 h (if available) and - 10 mins prior to study drug after 32 weeks
| Intervention | Liter (Mean) |
|---|---|
| Placebo | -0.026 |
| Olo 5 mcg qd | 0.065 |
| Olo 10 mcg qd | 0.097 |
Trough FVC Response After 48 Weeks
Response was defined as change from baseline. Baseline trough FVC was defined as the mean of the -1 hour and -10 minute measurements performed just prior to first dose of randomized treatment. Trough FVC is defined as the FVCs obtained at -10 mins prior to study drug inhalation as the end of the dosing interval or the mean of -1h and -10 min FVCs if both available. Means are adjusted using a mixed effects model with treatment (trt), tio stratum, visit, trt-by-visit as fixed categorical effects, baseline and baseline-by-visit as fixed continuous covariates and patient as random effect. (NCT00782210)
Timeframe: 1 h and 10 min prior to dose on the first day of randomized treatment (baseline) and -1 h (if available) and - 10 mins prior to study drug after 48 weeks
| Intervention | Liter (Mean) |
|---|---|
| Placebo | -0.083 |
| Olo 5 mcg qd | 0.011 |
| Olo 10 mcg qd | 0.032 |
Trough FVC Response After 6 Weeks
Response was defined as change from baseline. Baseline trough FVC was defined as the mean of the -1 hour and -10 minute measurements performed just prior to first dose of randomized treatment. Trough FVC is defined as the FVCs obtained at -10 mins prior to study drug inhalation as the end of the dosing interval or the mean of -1h and -10 min FVCs if both available. Means are adjusted using a mixed effects model with treatment (trt), tio stratum, visit, trt-by-visit as fixed categorical effects, baseline and baseline-by-visit as fixed continuous covariates and patient as random effect. (NCT00782210)
Timeframe: 1 h and 10 min prior to dose on the first day of randomized treatment (baseline) and -1 h (if available) and - 10 mins prior to study drug after 6 weeks
| Intervention | Liter (Mean) |
|---|---|
| Placebo | -0.005 |
| Olo 5 mcg qd | 0.125 |
| Olo 10 mcg qd | 0.135 |
Weekly Mean Daily (24h) Rescue Use
The patient was to record in the e-Diary the number of puffs of salbutamol (albuterol) Metered-Dose Inhaler used each day and night. (NCT00782210)
Timeframe: From Screening to week 48
| Intervention | Number of puffs (Mean) |
|---|---|
| Placebo | 3.747 |
| Olodaterol (Olo) 5 mcg qd | 2.642 |
| Olodaterol (Olo) 10 mcg qd | 2.312 |
Weekly Mean Daytime Rescue Use
The patient was to record in the e-Diary the number of puffs of salbutamol (albuterol) Metered-Dose Inhaler used each day and night. (NCT00782210)
Timeframe: From Screening to week 48
| Intervention | Number of puffs (Mean) |
|---|---|
| Placebo | 1.487 |
| Olodaterol (Olo) 5 mcg qd | 0.967 |
| Olodaterol (Olo) 10 mcg qd | 0.839 |
Weekly Mean Evening Peak Expiratory Flow Rate (PEF)
Weekly mean evening peak expiratory flow rate (PEF) at 48 weeks. PEFR measurements recorded by means of an e-Diary on a daily basis. This e-Diary was used to record the twice daily PEFs, study drug use, and rescue salbutamol (albuterol) use. The best of three readings for each measurement was recorded. (NCT00782210)
Timeframe: at bedtime from Screening to week 48
| Intervention | L/min (Mean) |
|---|---|
| Placebo | 190.676 |
| Olodaterol (Olo) 5 mcg qd | 207.862 |
| Olodaterol (Olo) 10 mcg qd | 205.236 |
Weekly Mean Nighttime Rescue Use
The patient was to record in the e-Diary the number of puffs of salbutamol (albuterol) Metered-Dose Inhaler used each day and night. (NCT00782210)
Timeframe: From Screening to week 48
| Intervention | Number of puffs (Mean) |
|---|---|
| Placebo | 2.283 |
| Olodaterol (Olo) 5 mcg qd | 1.701 |
| Olodaterol (Olo) 10 mcg qd | 1.492 |
Weekly Mean Pre-dose Morning Peak Expiratory Flow Rate (PEF)
Weekly mean pre-dose morning peak expiratory flow rate (PEF) at 48 weeks. PEFR measurements recorded by means of an e-Diary on a daily basis. This e-Diary was used to record the twice daily PEFs, study drug use, and rescue salbutamol (albuterol) use. The best of three readings for each measurement was recorded. (NCT00782210)
Timeframe: immediately upon arising (before drug administration) from Screening to week 48
| Intervention | L/min (Mean) |
|---|---|
| Placebo | 180.019 |
| Olodaterol (Olo) 5 mcg qd | 193.376 |
| Olodaterol (Olo) 10 mcg qd | 195.475 |
Changes in Safety Parameters Related to Treatment
Occurrence of bronchoconstriction, cardiac disorders and investigations related to treatment. Bronchoconstriction is defined as any of the following events: Drop in trough FEV1 >= 15%, Rescue medication use within 30 min of inhaling randomized treatment on a clinic test day or Cough, wheeze, or dyspnoea AE within 30 min of inhaling randomized treatment on a clinic test day. (NCT00782210)
Timeframe: 48 weeks
| Intervention | percentage of participants (Number) | |||||
|---|---|---|---|---|---|---|
| Bronchoconstriction | Atrial fibrillation | Angina pectoris | Ventricular extrasystoles | Electrocardiogram QT prolonged | Forced expiratory volume decreased | |
| Olo 10 mcg qd | 3.9 | 1.0 | 0.0 | 0.0 | 0.0 | 0.5 |
| Olo 5 mcg qd | 2.4 | 0.0 | 0.5 | 0.5 | 0.5 | 0.0 |
| Placebo | 13.4 | 0.0 | 0.0 | 0.0 | 0.5 | 0.0 |
Trough FVC Response After 40 Weeks
Response was defined as change from baseline. Baseline trough FVC was defined as the mean of the -1 hour and -10 minute measurements performed just prior to first dose of randomized treatment. Trough FVC is defined as the FVCs obtained at -10 mins prior to study drug inhalation as the end of the dosing interval or the mean of -1h and -10 min FVCs if both available. Means are adjusted using a mixed effects model with treatment (trt), tio stratum, visit, trt-by-visit as fixed categorical effects, baseline and baseline-by-visit as fixed continuous covariates and patient as random effect. (NCT00782210)
Timeframe: 1 h and 10 min prior to dose on the first day of randomized treatment (baseline) and -1 h (if available) and - 10 mins prior to study drug after 40 weeks
| Intervention | Liter (Mean) |
|---|---|
| Placebo | -0.044 |
| Olo 5 mcg qd | 0.087 |
| Olo 10 mcg qd | 0.111 |
Change From Baseline in Potassium
Laboratory testing: Average change from baseline of potassium measured. The laboratory tests at Day 1 were considered the baseline measurements. (NCT00782210)
Timeframe: Day 1 and at 12, 24 and 48 weeks
| Intervention | mmol/L (Mean) |
|---|---|
| Placebo | 0.0 |
| Olodaterol (Olo) 5 mcg qd | 0.0 |
| Olodaterol (Olo) 10 mcg qd | 0.0 |
Forced Expiratory Volume in 1 Second (FEV1) Area Under Curve 0-12 h (AUC 0-12h) Response at Day 85 (12 Weeks)
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 randomized treatment. Means are adjusted using a non-mixed effects model with treatment (trt), tio stratum, baseline as fixed effects. 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. (NCT00782210)
Timeframe: 1 hour (h) and 10 minutes (min) prior to dose on first day of randomized treatment (baseline) and -1h and -10 min, 5 min, 15 min, 30 min, 1h, 2h, 3h, 4h, 5h, 6h, 8h, 10h, 12h relative to dose at Day 85 (12 weeks)
| Intervention | Liter (Mean) |
|---|---|
| Placebo | -0.029 |
| Olo 5 mcg qd | 0.144 |
| Olo 10 mcg qd | 0.139 |
Forced Expiratory Volume in One Second (FEV1) Area Under Curve 0-3 Hour (h) (AUC 0-3h) Response After 2 Weeks
Response was defined as change from baseline. Baseline FEV1 was defined as the mean of the -1 h and -10 min measurements performed just prior to administration of the first dose of randomized treatment. Means are adjusted using a mixed effects model with treatment (trt), tio stratum, visit, trt-by-visit interaction as fixed categorical effects, baseline and baseline-by-visit interaction as fixed continuous covariates and patient as random effect. 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. (NCT00782210)
Timeframe: 1 hour (h) and 10 minutes (min) prior to dose on the first day of randomized treatment (baseline) to -10 min, 5 min, 15 min, 30 min, 1 h, 2 h, and 3 h relative to dose after 2 weeks
| Intervention | Liter (Mean) |
|---|---|
| Placebo | -0.000 |
| Olo 5 mcg qd | 0.180 |
| Olo 10 mcg qd | 0.192 |
Forced Expiratory Volume in One Second (FEV1) Area Under Curve 0-3 Hour (h) (AUC 0-3h) Response After 24 Weeks
Response was defined as change from baseline. Baseline FEV1 was defined as the mean of the -1 h and -10 min measurements performed just prior to administration of the first dose of randomized treatment. Means are adjusted using a mixed effects model with treatment (trt), tio stratum, visit, trt-by-visit interaction as fixed categorical effects, baseline and baseline-by-visit interaction as fixed continuous covariates and patient as random effect. 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. (NCT00782210)
Timeframe: 1 hour (h) and 10 minutes (min) prior to dose on the first day of randomized treatment (baseline) to -10 min, 5 min, 15 min, 30 min, 1 h, 2 h, and 3 h relative to dose after 24 weeks
| Intervention | Liter (Mean) |
|---|---|
| Placebo | -0.18 |
| Olo 5 mcg qd | 0.156 |
| Olo 10 mcg qd | 0.143 |
Forced Expiratory Volume in One Second (FEV1) Area Under Curve 0-3 Hour (h) (AUC 0-3h) Response After 48 Weeks
Response was defined as change from baseline. Baseline FEV1 was defined as the mean of the -1 h and -10 min measurements performed just prior to administration of the first dose of randomized treatment. Means are adjusted using a mixed effects model with treatment (trt), tio stratum, visit, trt-by-visit interaction as fixed categorical effects, baseline and baseline-by-visit interaction as fixed continuous covariates and patient as random effect. 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. (NCT00782210)
Timeframe: 1 hour (h) and 10 minutes (min) prior to dose on the first day of randomized treatment (baseline) to -10 min, 5 min, 15 min, 30 min, 1 h, 2 h, and 3 h relative to dose after 48 weeks
| Intervention | Liter (Mean) |
|---|---|
| Placebo | -0.043 |
| Olo 5 mcg qd | 0.130 |
| Olo 10 mcg qd | 0.126 |
Forced Expiratory Volume in One Second (FEV1) Area Under Curve 0-3 Hour (h) (AUC 0-3h) Response After 6 Weeks
Response was defined as change from baseline. Baseline FEV1 was defined as the mean of the -1 h and -10 min measurements performed just prior to administration of the first dose of randomized treatment. Means are adjusted using a mixed effects model with treatment (trt), tio stratum, visit, trt-by-visit interaction as fixed categorical effects, baseline and baseline-by-visit interaction as fixed continuous covariates and patient as random effect. 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. (NCT00782210)
Timeframe: 1 hour (h) and 10 minutes (min) prior to dose on the first day of randomized treatment (baseline) to -1h, -10 min, 5 min, 15 min, 30 min, 1 h, 2 h, and 3 h relative to dose after 6 weeks
| Intervention | Liter (Mean) |
|---|---|
| Placebo | -0.001 |
| Olo 5 mcg qd | 0.169 |
| Olo 10 mcg qd | 0.165 |
Forced Expiratory Volume in One Second (FEV1) Area Under Curve 0-3 Hour (h) (AUC 0-3h) Response at Day 1
Response was defined as change from baseline. Baseline FEV1 was defined as the mean of the -1 h and -10 min measurements performed just prior to administration of the first dose of randomized treatment. Means are adjusted using a mixed effects model with treatment (trt), tio stratum, visit, trt-by-visit interaction as fixed categorical effects, baseline and baseline-by-visit interaction as fixed continuous covariates and patient as random effect. 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. (NCT00782210)
Timeframe: 1 hour (h) and 10 minutes (min) prior to dose on the first day of randomized treatment (baseline) to -10 min, 5 min, 15 min, 30 min, 1 h, 2 h, and 3 h relative to dose at day 1
| Intervention | Liter (Mean) |
|---|---|
| Placebo | 0.024 |
| Olo 5 mcg qd | 0.189 |
| Olo 10 mcg qd | 0.199 |
Forced Expiratory Volume in One Second (FEV1) Area Under Curve 0-3 Hour (h) (AUC 0-3h) Response at Day 85 (12 Weeks)
Response was defined as change from baseline. Baseline FEV1 was defined as the mean of the -1 h and -10 min measurements performed just prior to administration of the first am dose of randomized treatment. Means are adjusted using a mixed effects model with treatment (trt), tio stratum, visit, trt-by-visit interaction as fixed categorical effects, baseline and baseline-by-visit interaction as fixed continuous covariates and patient as random effect. 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. (NCT00782210)
Timeframe: 1 hour (h) and 10 minutes (min) prior to dose on the first day of randomized treatment (baseline) to -10 min, 5 min, 15 min, 30 min, 1 h, 2 h, and 3 h relative to dose on Day 85
| Intervention | Liter (Mean) |
|---|---|
| Placebo | -0.007 |
| Olo 5 mcg qd | 0.165 |
| Olo 10 mcg qd | 0.169 |
Forced Vital Capacity (FVC) Area Under Curve 0-12 h (AUC 0-12h) Response at Day 85 (12 Weeks)
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 randomized treatment. Means are adjusted using a non-mixed effects model with treatment (trt), tio stratum, baseline as fixed effects. FVC 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. (NCT00782210)
Timeframe: 1 hour (h) and 10 minutes (min) prior to dose on first day of randomized treatment (baseline) and -1h and -10 min, 5 min, 15 min, 30 min, 1h, 2h, 3h, 4h, 5h, 6h, 8h, 10h, 12h relative to dose at Day 85 (12 weeks)
| Intervention | Liter (Mean) |
|---|---|
| Placebo | -0.019 |
| Olo 5 mcg qd | 0.283 |
| Olo 10 mcg qd | 0.230 |
Forced Vital Capacity (FVC) Area Under Curve 0-3 Hours (AUC 0-3h) Response After 2 Weeks
Response was defined as change from baseline. Baseline FVC was defined as the mean of the available pre-dose FVC values prior to the first dose of randomized treatment. Means are adjusted using a mixed effects model with treatment (trt), tio stratum, visit, trt-by-visit as fixed categorical effects, baseline and baseline-by-visit as fixed continuous covariates and patient as random effect. FVC AUC 0-3h was calculated using the trapezoidal rule, divided by the observation time to report in litres. (NCT00782210)
Timeframe: 1 hour (h) and 10 minutes (min) prior to dose on the first day of randomized treatment (baseline) to -10 min, 5 min, 15 min, 30 min, 1 h, 2 h, and 3 h relative to dose after 2 weeks
| Intervention | Liter (Mean) |
|---|---|
| Placebo | 0.026 |
| Olo 5 mcg qd | 0.323 |
| Olo 10 mcg qd | 0.353 |
Forced Vital Capacity (FVC) Area Under Curve 0-3 Hours (AUC 0-3h) Response At Day 1
Response was defined as change from baseline. Baseline FVC was defined as the mean of the available pre-dose FVC values prior to the first dose of randomized treatment. Means are adjusted using a mixed effects model with treatment (trt), tio stratum, visit, trt-by-visit as fixed categorical effects, baseline and baseline-by-visit as fixed continuous covariates and patient as random effect. FVC AUC 0-3h was calculated using the trapezoidal rule, divided by the observation time to report in litres. (NCT00782210)
Timeframe: 1 hour (h) and 10 minutes (min) prior to dose on the first day of randomized treatment (baseline) to -10 min, 5 min, 15 min, 30 min, 1 h, 2 h, and 3 h relative to dose at Day 1
| Intervention | Liter (Mean) |
|---|---|
| Placebo | 0.063 |
| Olo 5 mcg qd | 0.350 |
| Olo 10 mcg qd | 0.392 |
FVC Area Under Curve 0-3 Hours (AUC 0-3h) Response After 12 Weeks
Response was defined as change from baseline. Baseline FVC was defined as the mean of the available pre-dose FVC values prior to the first dose of randomized treatment. Means are adjusted using a mixed effects model with treatment (trt), tio stratum, visit, trt-by-visit as fixed categorical effects, baseline and baseline-by-visit as fixed continuous covariates and patient as random effect. FVC AUC 0-3h was calculated using the trapezoidal rule, divided by the observation time to report in litres. (NCT00782210)
Timeframe: 1 hour (h) and 10 minutes (min) prior to dose on the first day of randomized treatment (baseline) to -10 min, 5 min, 15 min, 30 min, 1 h, 2 h, and 3 h relative to dose after 12 weeks
| Intervention | Liter (Mean) |
|---|---|
| Placebo | 0.003 |
| Olo 5 mcg qd | 0.277 |
| Olo 10 mcg qd | 0.295 |
FVC Area Under Curve 0-3 Hours (AUC 0-3h) Response After 24 Weeks
Response was defined as change from baseline. Baseline FVC was defined as the mean of the available pre-dose FVC values prior to the first dose of randomized treatment. Means are adjusted using a mixed effects model with treatment (trt), tio stratum, visit, trt-by-visit as fixed categorical effects, baseline and baseline-by-visit as fixed continuous covariates and patient as random effect. FVC AUC 0-3h was calculated using the trapezoidal rule, divided by the observation time to report in litres. (NCT00782210)
Timeframe: 1 hour (h) and 10 minutes (min) prior to dose on the first day of randomized treatment (baseline) to -10 min, 5 min, 15 min, 30 min, 1 h, 2 h, and 3 h relative to dose after 24 weeks
| Intervention | Liter (Mean) |
|---|---|
| Placebo | 0.026 |
| Olo 5 mcg qd | 0.261 |
| Olo 10 mcg qd | 0.281 |
FVC Area Under Curve 0-3 Hours (AUC 0-3h) Response After 48 Weeks
Response was defined as change from baseline. Baseline FVC was defined as the mean of the available pre-dose FVC values prior to the first dose of randomized treatment. Means are adjusted using a mixed effects model with treatment (trt), tio stratum, visit, trt-by-visit as fixed categorical effects, baseline and baseline-by-visit as fixed continuous covariates and patient as random effect. FVC AUC 0-3h was calculated using the trapezoidal rule, divided by the observation time to report in litres. (NCT00782210)
Timeframe: 1 hour (h) and 10 minutes (min) prior to dose on the first day of randomized treatment (baseline) to -10 min, 5 min, 15 min, 30 min, 1 h, 2 h, and 3 h relative to dose after 48 weeks
| Intervention | Liter (Mean) |
|---|---|
| Placebo | -0.040 |
| Olo 5 mcg qd | 0.204 |
| Olo 10 mcg qd | 0.231 |
FVC Area Under Curve 0-3 Hours (AUC 0-3h) Response After 6 Weeks
Response was defined as change from baseline. Baseline FVC was defined as the mean of the available pre-dose FVC values prior to the first dose of randomized treatment. Means are adjusted using a mixed effects model with treatment (trt), tio stratum, visit, trt-by-visit as fixed categorical effects, baseline and baseline-by-visit as fixed continuous covariates and patient as random effect. FVC AUC 0-3h was calculated using the trapezoidal rule, divided by the observation time to report in litres. (NCT00782210)
Timeframe: 1 hour (h) and 10 minutes (min) prior to dose on the first day of randomized treatment (baseline) to -10 min, 5 min, 15 min, 30 min, 1 h, 2 h, and 3 h relative to dose after 6 weeks
| Intervention | Liter (Mean) |
|---|---|
| Placebo | 0.022 |
| Olo 5 mcg qd | 0.276 |
| Olo 10 mcg qd | 0.316 |
FVC Peak (0-3h) Response After 12 Weeks
Response was defined as change from baseline. Baseline FVC peak (0-3h) was defined as the mean of the available pre-dose FVC peak (0-3h) values prior to first dose of randomized treatment. FVC Peak (0-3h) values were obtained within 0 - 3 hours after treatment. Means are adjusted using a mixed effects model with treatment (trt), tio stratum, visit, trt-by-visit as fixed categorical effects, baseline and baseline-by-visit as fixed continuous covariates and patient as random effect. (NCT00782210)
Timeframe: 1 hour (h) and 10 minutes (min) prior to dose on the first day of randomized treatment (baseline) to -10 min, 5 min, 15 min, 30 min, 1 h, 2 h, and 3 h relative to dose after 12 weeks
| Intervention | Liter (Mean) |
|---|---|
| Placebo | 0.169 |
| Olo 5 mcg qd | 0.421 |
| Olo 10 mcg qd | 0.430 |
FVC Peak (0-3h) Response After 2 Weeks
Response was defined as change from baseline. Baseline FVC peak (0-3h) was defined as the mean of the available pre-dose FVC peak (0-3h) values prior to first dose of randomized treatment. FVC Peak (0-3h) values were obtained within 0 - 3 hours after treatment. Means are adjusted using a mixed effects model with treatment (trt), tio stratum, visit, trt-by-visit as fixed categorical effects, baseline and baseline-by-visit as fixed continuous covariates and patient as random effect. (NCT00782210)
Timeframe: 1 hour (h) and 10 minutes (min) prior to dose on the first day of randomized treatment (baseline) to -10 min, 5 min, 15 min, 30 min, 1 h, 2 h, and 3 h relative to dose after 2 weeks
| Intervention | Liter (Mean) |
|---|---|
| Placebo | 0.207 |
| Olo 5 mcg qd | 0.471 |
| Olo 10 mcg qd | 0.499 |
FVC Peak (0-3h) Response After 24 Weeks
Response was defined as change from baseline. Baseline FVC peak (0-3h) was defined as the mean of the available pre-dose FVC peak (0-3h) values prior to first dose of randomized treatment. FVC Peak (0-3h) values were obtained within 0 - 3 hours after treatment. Means are adjusted using a mixed effects model with treatment (trt), tio stratum, visit, trt-by-visit as fixed categorical effects, baseline and baseline-by-visit as fixed continuous covariates and patient as random effect. (NCT00782210)
Timeframe: 1 hour (h) and 10 minutes (min) prior to dose on the first day of randomized treatment (baseline) to -10 min, 5 min, 15 min, 30 min, 1 h, 2 h, and 3 h relative to dose after 24 weeks
| Intervention | Liter (Mean) |
|---|---|
| Placebo | 0.188 |
| Olo 5 mcg qd | 0.419 |
| Olo 10 mcg qd | 0.420 |
FVC Peak (0-3h) Response After 48 Weeks
Response was defined as change from baseline. Baseline FVC peak (0-3h) was defined as the mean of the available pre-dose FVC peak (0-3h) values prior to first dose of randomized treatment. FVC Peak (0-3h) values were obtained within 0 - 3 hours after treatment. Means are adjusted using a mixed effects model with treatment (trt), tio stratum, visit, trt-by-visit as fixed categorical effects, baseline and baseline-by-visit as fixed continuous covariates and patient as random effect. (NCT00782210)
Timeframe: 1 hour (h) and 10 minutes (min) prior to dose on the first day of randomized treatment (baseline) to -10 min, 5 min, 15 min, 30 min, 1 h, 2 h, and 3 h relative to dose after 48 weeks
| Intervention | Liter (Mean) |
|---|---|
| Placebo | 0.109 |
| Olo 5 mcg qd | 0.356 |
| Olo 10 mcg qd | 0.369 |
FVC Peak (0-3h) Response After 6 Weeks
Response was defined as change from baseline. Baseline FVC peak (0-3h) was defined as the mean of the available pre-dose FVC peak (0-3h) values prior to first dose of randomized treatment. FVC Peak (0-3h) values were obtained within 0 - 3 hours after treatment. Means are adjusted using a mixed effects model with treatment (trt), tio stratum, visit, trt-by-visit as fixed categorical effects, baseline and baseline-by-visit as fixed continuous covariates and patient as random effect. (NCT00782210)
Timeframe: 1 hour (h) and 10 minutes (min) prior to dose on the first day of randomized treatment (baseline) to -10 min, 5 min, 15 min, 30 min, 1 h, 2 h, and 3 h relative to dose after 6 weeks
| Intervention | Liter (Mean) |
|---|---|
| Placebo | 0.180 |
| Olo 5 mcg qd | 0.430 |
| Olo 10 mcg qd | 0.460 |
FVC Peak (0-3h) Response At Day 1
Response was defined as change from baseline. Baseline FVC peak (0-3h) was defined as the mean of the available pre-dose FVC peak (0-3h) values prior to first dose of randomized treatment. FVC Peak (0-3h) values were obtained within 0 - 3 hours after treatment. Means are adjusted using a mixed effects model with treatment (trt), tio stratum, visit, trt-by-visit as fixed categorical effects, baseline and baseline-by-visit as fixed continuous covariates and patient as random effect. (NCT00782210)
Timeframe: 1 hour (h) and 10 minutes (min) prior to dose on the first day of randomized treatment (baseline) to -10 min, 5 min, 15 min, 30 min, 1 h, 2 h, and 3 h relative to dose at Day 1
| Intervention | Liter (Mean) |
|---|---|
| Placebo | 0.245 |
| Olo 5 mcg qd | 0.509 |
| Olo 10 mcg qd | 0.546 |
Number of COPD Exacerbations
Qualifying events of COPD were specifically pre-defined in the protocol. Other respiratory related events were evaluated by the investigator to see if they met the pre-defined criteria. (NCT00782210)
Timeframe: Baseline to end of study at week 48 visit
| Intervention | Number of COPD exacerbations (Mean) |
|---|---|
| Placebo | 0.7476 |
| Olo 5 mcg qd | 0.5842 |
| Olo 10 mcg qd | 0.6322 |
Number of COPD Exacerbations Requiring Hospitalization
Qualifying events of COPD were specifically pre-defined in the protocol. Other respiratory related events were evaluated by the investigator to see if they met the pre-defined criteria. These exacerbations required hospitalization. (NCT00782210)
Timeframe: Baseline to end of study at week 48 visit
| Intervention | Number of COPD exacerbations (Mean) |
|---|---|
| Placebo | 0.1010 |
| Olo 5 mcg qd | 0.0662 |
| Olo 10 mcg qd | 0.1133 |
Number of Moderate Chronic Obstructive Pulmonary Disease (COPD) Exacerbations
Qualifying events of COPD were specifically pre-defined in the protocol. Other respiratory related events were evaluated by the investigator to see if they met the pre-defined criteria. These exacerbations did not lead to hospitalization but included treatment with antibiotics and/or systemic steroids. (NCT00782210)
Timeframe: Baseline to end of study at 48 weeks.
| Intervention | Number of COPD exacerbations (Mean) |
|---|---|
| Placebo | 0.5745 |
| Olo 5 mcg qd | 0.4643 |
| Olo 10 mcg qd | 0.4875 |
Patient's Global Rating at Week 12
Patients were asked to rate their respiratory condition relative to their condition prior to the first dose of study medication. The scale is a seven 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 worst. (NCT00782210)
Timeframe: Week 12 visit
| Intervention | Point on scale (Mean) |
|---|---|
| Placebo | 3.4 |
| Olo 5 mcg qd | 3.0 |
| Olo 10 mcg qd | 3.0 |
Patient's Global Rating at Week 24
Patients were asked to rate their respiratory condition relative to their condition prior to the first dose of study medication. The scale is a seven 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 worst. (NCT00782210)
Timeframe: Week 24 visit
| Intervention | Point on scale (Mean) |
|---|---|
| Placebo | 3.5 |
| Olo 5 mcg qd | 3.0 |
| Olo 10 mcg qd | 3.0 |
Patient's Global Rating at Week 48
Patients were asked to rate their respiratory condition relative to their condition prior to the first dose of study medication. The scale is a seven 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 worst. (NCT00782210)
Timeframe: Week 48 visit
| Intervention | Point on scale (Mean) |
|---|---|
| Placebo | 3.4 |
| Olo 5 mcg qd | 3.1 |
| Olo 10 mcg qd | 3.1 |
Patient's Global Rating at Week 6
Patients were asked to rate their respiratory condition relative to their condition prior to the first dose of study medication. The scale is a seven 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 worst. (NCT00782210)
Timeframe: Week 6 visit
| Intervention | Point on scale (Mean) |
|---|---|
| Placebo | 3.5 |
| Olo 5 mcg qd | 3.0 |
| Olo 10 mcg qd | 3.0 |
Peak FEV1 (0-3h) Response After 12 Weeks
Response was defined as change from baseline. Baseline peak FEV1 was defined as the mean of the available pre-dose peak FEV1 values prior to first dose of randomized treatment. Peak FEV1 (0-3h) values were obtained within 0 - 3 hours after treatment. Means are adjusted using a mixed effects model with treatment (trt), tio stratum, visit, trt-by-visit as fixed categorical effects, baseline and baseline-by-visit as fixed continuous covariates and patient as random effect. (NCT00782210)
Timeframe: 1 hour (h) and 10 minutes (min) prior to dose on the first day of randomized treatment (baseline) to -10 min, 5 min, 15 min, 30 min, 1 h, 2 h, and 3 h relative to dose after 12 weeks
| Intervention | Liter (Mean) |
|---|---|
| Placebo | 0.071 |
| Olo 5 mcg qd | 0.235 |
| Olo 10 mcg qd | 0.236 |
Peak FEV1 (0-3h) Response After 2 Weeks
Response was defined as change from baseline. Baseline peak FEV1 was defined as the mean of the available pre-dose peak FEV1 values prior to first dose of randomized treatment. Peak FEV1 (0-3h) values were obtained within 0 - 3 hours after treatment. Means are adjusted using a mixed effects model with treatment (trt), tio stratum, visit, trt-by-visit as fixed categorical effects, baseline and baseline-by-visit as fixed continuous covariates and patient as random effect. (NCT00782210)
Timeframe: 1 hour (h) and 10 minutes (min) prior to dose on the first day of randomized treatment (baseline) to -10 min, 5 min, 15 min, 30 min, 1 h, 2 h, and 3 h relative to dose after 2 weeks
| Intervention | Liter (Mean) |
|---|---|
| Placebo | 0.077 |
| Olo 5 mcg qd | 0.254 |
| Olo 10 mcg qd | 0.267 |
Peak FEV1 (0-3h) Response After 24 Weeks
Response was defined as change from baseline. Baseline peak FEV1 was defined as the mean of the available pre-dose peak FEV1 values prior to first dose of randomized treatment. Peak FEV1 (0-3h) values were obtained within 0 - 3 hours after treatment. Means are adjusted using a mixed effects model with treatment (trt), tio stratum, visit, trt-by-visit as fixed categorical effects, baseline and baseline-by-visit as fixed continuous covariates and patient as random effect. (NCT00782210)
Timeframe: 1 hour (h) and 10 minutes (min) prior to dose on the first day of randomized treatment (baseline) to -10 min, 5 min, 15 min, 30 min, 1 h, 2 h, and 3 h relative to dose after 24 weeks
| Intervention | Liter (Mean) |
|---|---|
| Placebo | 0.055 |
| Olo 5 mcg qd | 0.230 |
| Olo 10 mcg qd | 0.206 |
FVC Peak (0-3h) Response After 2 Weeks
Response was defined as change from baseline. Baseline FVC peak (0-3h) was defined as the mean of the available pre-dose FVC peak (0-3h) values prior to first dose of randomized treatment. FVC Peak (0-3h) values were obtained within 0 - 3 hours after treatment. Means are adjusted using a mixed effects model with treatment (trt), tio stratum, visit, trt-by-visit as fixed categorical effects, baseline and baseline-by-visit as fixed continuous covariates and patient as random effect. (NCT00782509)
Timeframe: 1 hour (h) and 10 minutes (min) prior to dose on the first day of randomized treatment (baseline) to -10 min, 5 min, 15 min, 30 min, 1 h, 2 h, and 3 h relative to dose after 2 weeks
| Intervention | Liter (Mean) |
|---|---|
| Placebo | 0.254 |
| Olo 5 mcg qd | 0.479 |
| Olo 10 mcg qd | 0.464 |
Peak FEV1 (0-3h) Response After 48 Weeks
Response was defined as change from baseline. Baseline peak FEV1 was defined as the mean of the available pre-dose peak FEV1 values prior to first dose of randomized treatment. Peak FEV1 (0-3h) values were obtained within 0 - 3 hours after treatment. Means are adjusted using a mixed effects model with treatment (trt), tio stratum, visit, trt-by-visit as fixed categorical effects, baseline and baseline-by-visit as fixed continuous covariates and patient as random effect. (NCT00782509)
Timeframe: 1 hour (h) and 10 minutes (min) prior to dose on the first day of randomized treatment (baseline) to -10 min, 5 min, 15 min, 30 min, 1 h, 2 h, and 3 h relative to dose after 48 weeks
| Intervention | Liter (Mean) |
|---|---|
| Placebo | 0.041 |
| Olo 5 mcg qd | 0.197 |
| Olo 10 mcg qd | 0.198 |
Patient's Global Rating at Week 6
Patients were asked to rate their respiratory condition relative to their condition prior to the first dose of study medication. The scale is a seven 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 worst. (NCT00782509)
Timeframe: Week 6 visit
| Intervention | Point on scale (Mean) |
|---|---|
| Placebo | 3.3 |
| Olo 5 mcg qd | 3.0 |
| Olo 10 mcg qd | 2.9 |
Trough FVC Response After 12 Weeks
Response was defined as change from baseline. Baseline trough FVC was defined as the mean of the -1 hour and -10 minute measurements performed just prior to first dose of randomized treatment. Trough FVC is defined as the FVCs obtained at -10 mins prior to study drug inhalation as the end of the dosing interval or the mean of -1h and -10 min FVCs if both available. Means are adjusted using a mixed effects model with treatment (trt), tio stratum, visit, trt-by-visit as fixed categorical effects, baseline and baseline-by-visit as fixed continuous covariates and patient as random effect. (NCT00782509)
Timeframe: 1 h and 10 min prior to dose on the first day of randomized treatment (baseline) and -1 h (if available) and - 10 mins prior to study drug after 12 weeks
| Intervention | Liter (Mean) |
|---|---|
| Placebo | 0.043 |
| Olo 5 mcg qd | 0.075 |
| Olo 10 mcg qd | 0.091 |
Trough FEV1 Response at Day 85 (12 Weeks)
Response was defined as change from baseline. Baseline trough FEV1 was defined as the mean of the -1 hour and -10 minute measurements performed just prior to first dose of randomized treatment. Trough FEV1 is defined as the FEV1 performed at -10 mins prior to study drug inhalation as the end of the dosing interval or the mean of -1h and -10 min FEV1s if both available. Means are adjusted using a mixed effects model with treatment (trt), tio stratum, visit, trt-by-visit as fixed categorical effects, baseline and baseline-by-visit as fixed continuous covariates and patient as random effect. (NCT00782509)
Timeframe: 1 h and 10 min prior to dose on the first day of randomized treatment (baseline) and -1 h and - 10 mins prior to study drug at Day 85.
| Intervention | Liter (Mean) |
|---|---|
| Placebo | -0.003 |
| Olo 5 mcg qd | 0.044 |
| Olo 10 mcg qd | 0.045 |
Trough FEV1 Response After 6 Weeks
Response was defined as change from baseline. Baseline trough FEV1 was defined as the mean of the -1 hour and -10 minute measurements performed just prior to first dose of randomized treatment. Trough FEV1 is defined as the FEV1 performed at -10 mins prior to study drug inhalation as the end of the dosing interval or the mean of -1h and -10 min FEV1s if both available. Means are adjusted using a mixed effects model with treatment (trt), tio stratum, visit, trt-by-visit as fixed categorical effects, baseline and baseline-by-visit as fixed continuous covariates and patient as random effect. (NCT00782509)
Timeframe: 1 h and 10 min prior to dose on the first day of randomized treatment (baseline) and -1 h (if available) and - 10 mins prior to study drug after 6 weeks
| Intervention | Liter (Mean) |
|---|---|
| Placebo | -0.002 |
| Olo 5 mcg qd | 0.071 |
| Olo 10 mcg qd | 0.082 |
Trough FVC Response After 6 Weeks
Response was defined as change from baseline. Baseline trough FVC was defined as the mean of the -1 hour and -10 minute measurements performed just prior to first dose of randomized treatment. Trough FVC is defined as the FVCs obtained at -10 mins prior to study drug inhalation as the end of the dosing interval or the mean of -1h and -10 min FVCs if both available. Means are adjusted using a mixed effects model with treatment (trt), tio stratum, visit, trt-by-visit as fixed categorical effects, baseline and baseline-by-visit as fixed continuous covariates and patient as random effect. (NCT00782509)
Timeframe: 1 h and 10 min prior to dose on the first day of randomized treatment (baseline) and -1 h (if available) and - 10 mins prior to study drug after 6 weeks
| Intervention | Liter (Mean) |
|---|---|
| Placebo | 0.029 |
| Olo 5 mcg qd | 0.122 |
| Olo 10 mcg qd | 0.147 |
Weekly Mean Evening Peak Expiratory Flow Rate (PEF)
Weekly mean evening peak expiratory flow rate (PEF) at 48 weeks. PEFR measurements recorded by means of an e-Diary on a daily basis. This e-Diary was used to record the twice daily PEFs, study drug use, and rescue salbutamol (albuterol) use. The best of three readings for each measurement was recorded. (NCT00782509)
Timeframe: at bedtime from Screening to week 48
| Intervention | L/min (Mean) |
|---|---|
| Placebo | 195.502 |
| Olo 5 mcg qd | 207.958 |
| Olo 10 mcg qd | 216.155 |
Weekly Mean of Daily (24h) Rescue Use
The patient was to record in the e-Diary the number of puffs of salbutamol (albuterol) Metered-Dose Inhaler used each day and night. The weekly mean was calculated by taking the average of the number of puffs of rescue medication used each 24 hour period during week 48. (NCT00782509)
Timeframe: Week 48
| Intervention | Number of puffs (Mean) |
|---|---|
| Placebo | 3.436 |
| Olo 5 mcg qd | 2.599 |
| Olo 10 mcg qd | 2.158 |
Weekly Mean of Daily Daytime Rescue Use
The patient was to record in the e-Diary the number of puffs of salbutamol (albuterol) Metered-Dose Inhaler used each day and night. The weekly mean was calculated by taking the average of the number of puffs of rescue medication used each day during week 48. (NCT00782509)
Timeframe: Week 48
| Intervention | Number of puffs (Mean) |
|---|---|
| Placebo | 1.363 |
| Olo 5 mcg qd | 0.947 |
| Olo 10 mcg qd | 0.850 |
Weekly Mean of Daily Nighttime Rescue Use
The patient was to record in the e-Diary the number of puffs of salbutamol (albuterol) Metered-Dose Inhaler used each day and night. The weekly mean was calculated by taking the average of the number of puffs of rescue medication used each night during week 48. (NCT00782509)
Timeframe: Week 48
| Intervention | Number of puffs (Mean) |
|---|---|
| Placebo | 2.072 |
| Olo 5 mcg qd | 1.652 |
| Olo 10 mcg qd | 1.312 |
Weekly Mean Pre-dose Morning Peak Expiratory Flow Rate (PEF)
Weekly mean pre-dose morning peak expiratory flow rate (PEF) at 48 weeks. PEFR measurements recorded by means of an e-Diary on a daily basis. This e-Diary was used to record the twice daily PEFs, study drug use, and rescue salbutamol (albuterol) use. The best of three readings for each measurement was recorded. (NCT00782509)
Timeframe: immediately upon arising (before drug administration) from Screening to week 48
| Intervention | L/min (Mean) |
|---|---|
| Placebo | 182.939 |
| Olo 5 mcg qd | 196.300 |
| Olo 10 mcg qd | 203.873 |
Changes in Safety Parameters Related to Treatment
Occurence of bronchoconstriction, cardiac disorders and investigations related to treatment. Bronchoconstriction is defined as any of the following events: Drop in trough FEV1 >= 15%, Rescue medication use within 30 min of inhaling randomized treatment on a clinic test day or Cough, wheeze, or dyspnoea AE within 30 min of inhaling randomized treatment on a clinic test day. (NCT00782509)
Timeframe: 48 weeks
| Intervention | percentage of participants (Number) | |||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Bronchoconstriction | Blood glucose increased | Electrocardiogram QT prolonged | Ventricular tachycardia | Ventricular extrasystoles | Supraventricular extrasystoles | Atrial fibrillation | Atrioventricular block | Atrioventricular block first degree | Atrioventricular block second degree | Bundle branch block left | Palpitations | Sinus bradycardia | Sinus tachycardia | |
| Olo 10 mcg qd | 5.5 | 0.0 | 0.0 | 0.5 | 1.8 | 1.4 | 0.0 | 0.0 | 0.5 | 0.0 | 0.0 | 0.5 | 0.0 | 0.0 |
| Olo 5 mcg qd | 3.3 | 0.5 | 0.5 | 1.9 | 1.0 | 1.0 | 0.0 | 0.5 | 0.5 | 0.5 | 0.5 | 0.0 | 0.5 | 0.5 |
| Placebo | 13.9 | 0.0 | 0.0 | 0.0 | 0.0 | 0.0 | 0.5 | 0.0 | 0.0 | 0.0 | 0.0 | 0.0 | 0.0 | 0.0 |
Change From Baseline in Potassium
Laboratory testing: Average change from baseline of potassium measured. The laboratory tests at Day 1 were considered the baseline measurements. (NCT00782509)
Timeframe: Day 1 and at 12, 24 and 48 weeks
| Intervention | mmol/L (Mean) |
|---|---|
| Placebo | -0.0 |
| Olo 5 mcg qd | -0.0 |
| Olo 10 mcg qd | 0.0 |
Forced Expiratory Volume in 1 Second (FEV1) Area Under Curve 0-12 h (AUC 0-12h) Response at Day 85 (12 Weeks)
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 randomized treatment. Means are adjusted using a non-mixed effects model with treatment (trt), tio stratum, baseline as fixed effects. 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. (NCT00782509)
Timeframe: 1 hour (h) and 10 minutes (min) prior to dose on first day of randomized treatment (baseline) and -1h and -10 min, 5 min, 15 min, 30 min, 1h, 2h, 3h, 4h, 5h, 6h, 8h, 10h, 12h relative to dose at Day 85 (12 weeks)
| Intervention | Liter (Mean) |
|---|---|
| Placebo | 0.010 |
| Olo 5 mcg qd | 0.120 |
| Olo 10 mcg qd | 0.100 |
Forced Expiratory Volume in One Second (FEV1) Area Under Curve 0-3 Hour (h) (AUC 0-3h) Response After 2 Weeks
Response was defined as change from baseline. Baseline FEV1 was defined as the mean of the -1 h and -10 min measurements performed just prior to administration of the first dose of randomized treatment. Means are adjusted using a mixed effects model with treatment (trt), tio stratum, visit, trt-by-visit interaction as fixed categorical effects, baseline and baseline-by-visit interaction as fixed continuous covariates and patient as random effect. 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. (NCT00782509)
Timeframe: 1 hour (h) and 10 minutes (min) prior to dose on the first day of randomized treatment (baseline) to -10 min, 5 min, 15 min, 30 min, 1 h, 2 h, and 3 h relative to dose after 2 weeks
| Intervention | Liter (Mean) |
|---|---|
| Placebo | 0.025 |
| Olo 5 mcg qd | 0.188 |
| Olo 10 mcg qd | 0.177 |
Forced Expiratory Volume in One Second (FEV1) Area Under Curve 0-3 Hour (h) (AUC 0-3h) Response After 24 Weeks
Response was defined as change from baseline. Baseline FEV1 was defined as the mean of the -1 h and -10 min measurements performed just prior to administration of the first dose of randomized treatment. Means are adjusted using a mixed effects model with treatment (trt), tio stratum, visit, trt-by-visit interaction as fixed categorical effects, baseline and baseline-by-visit interaction as fixed continuous covariates and patient as random effect. 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. (NCT00782509)
Timeframe: 1 hour (h) and 10 minutes (min) prior to dose on the first day of randomized treatment (baseline) to -10 min, 5 min, 15 min, 30 min, 1 h, 2 h, and 3 h relative to dose after 24 weeks
| Intervention | Liter (Mean) |
|---|---|
| Placebo | -0.010 |
| Olo 5 mcg qd | 0.155 |
| Olo 10 mcg qd | 0.126 |
Forced Expiratory Volume in One Second (FEV1) Area Under Curve 0-3 Hour (h) (AUC 0-3h) Response After 48 Weeks
Response was defined as change from baseline. Baseline FEV1 was defined as the mean of the -1 h and -10 min measurements performed just prior to administration of the first dose of randomized treatment. Means are adjusted using a mixed effects model with treatment (trt), tio stratum, visit, trt-by-visit interaction as fixed categorical effects, baseline and baseline-by-visit interaction as fixed continuous covariates and patient as random effect. 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. (NCT00782509)
Timeframe: 1 hour (h) and 10 minutes (min) prior to dose on the first day of randomized treatment (baseline) to -10 min, 5 min, 15 min, 30 min, 1 h, 2 h, and 3 h relative to dose after 48 weeks
| Intervention | Liter (Mean) |
|---|---|
| Placebo | -0.030 |
| Olo 5 mcg qd | 0.132 |
| Olo 10 mcg qd | 0.128 |
Forced Expiratory Volume in One Second (FEV1) Area Under Curve 0-3 Hour (h) (AUC 0-3h) Response After 6 Weeks
Response was defined as change from baseline. Baseline FEV1 was defined as the mean of the -1 h and -10 min measurements performed just prior to administration of the first dose of randomized treatment. Means are adjusted using a mixed effects model with treatment (trt), tio stratum, visit, trt-by-visit interaction as fixed categorical effects, baseline and baseline-by-visit interaction as fixed continuous covariates and patient as random effect. 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. (NCT00782509)
Timeframe: 1 hour (h) and 10 minutes (min) prior to dose on the first day of randomized treatment (baseline) to -1h, -10 min, 5 min, 15 min, 30 min, 1 h, 2 h, and 3 h relative to dose after 6 weeks
| Intervention | Liter (Mean) |
|---|---|
| Placebo | 0.010 |
| Olo 5 mcg qd | 0.180 |
| Olo 10 mcg qd | 0.171 |
Forced Expiratory Volume in One Second (FEV1) Area Under Curve 0-3 Hour (h) (AUC 0-3h) Response At Day 1
Response was defined as change from baseline. Baseline FEV1 was defined as the mean of the -1 h and -10 min measurements performed just prior to administration of the first dose of randomized treatment. Means are adjusted using a mixed effects model with treatment (trt), tio stratum, visit, trt-by-visit interaction as fixed categorical effects, baseline and baseline-by-visit interaction as fixed continuous covariates and patient as random effect. 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. (NCT00782509)
Timeframe: 1 hour (h) and 10 minutes (min) prior to dose on the first day of randomized treatment (baseline) to -10 min, 5 min, 15 min, 30 min, 1 h, 2 h, and 3 h relative to dose at Day 1
| Intervention | Liter (Mean) |
|---|---|
| Placebo | 0.025 |
| Olo 5 mcg qd | 0.189 |
| Olo 10 mcg qd | 0.196 |
Forced Expiratory Volume in One Second (FEV1) Area Under Curve 0-3 Hour (h) (AUC 0-3h) Response at Day 85 (12 Weeks)
Response was defined as change from baseline. Baseline FEV1 was defined as the mean of the -1 h and -10 min measurements performed just prior to administration of the first am dose of randomized treatment. Means are adjusted using a mixed effects model with treatment (trt), tio stratum, visit, trt-by-visit interaction as fixed categorical effects, baseline and baseline-by-visit interaction as fixed continuous covariates and patient as random effect. 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. (NCT00782509)
Timeframe: 1 hour (h) and 10 minutes (min) prior to dose on the first day of randomized treatment (baseline) to -10 min, 5 min, 15 min, 30 min, 1 h, 2 h, and 3 h relative to dose on Day 85
| Intervention | Liter (Mean) |
|---|---|
| Placebo | 0.008 |
| Olo 5 mcg qd | 0.159 |
| Olo 10 mcg qd | 0.152 |
Forced Vital Capacity (FVC) Area Under Curve 0-12 h (AUC 0-12h) Response at Day 85 (12 Weeks)
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 randomized treatment. Means are adjusted using a non-mixed effects model with treatment (trt), tio stratum, baseline as fixed effects. FVC 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. (NCT00782509)
Timeframe: 1 hour (h) and 10 minutes (min) prior to dose on first day of randomized treatment (baseline) and -1h and -10 min, 5 min, 15 min, 30 min, 1h, 2h, 3h, 4h, 5h, 6h, 8h, 10h, 12h relative to dose at Day 85 (12 weeks)
| Intervention | Liter (Mean) |
|---|---|
| Placebo | 0.057 |
| Olo 5 mcg qd | 0.199 |
| Olo 10 mcg qd | 0.212 |
Forced Vital Capacity (FVC) Area Under Curve 0-3 Hours (AUC 0-3h) Response After 2 Weeks
Response was defined as change from baseline. Baseline FVC was defined as the mean of the available pre-dose FVC values prior to the first dose of randomized treatment. Means are adjusted using a mixed effects model with treatment (trt), tio stratum, visit, trt-by-visit as fixed categorical effects, baseline and baseline-by-visit as fixed continuous covariates and patient as random effect. FVC AUC 0-3h was calculated using the trapezoidal rule, divided by the observation time to report in litres. (NCT00782509)
Timeframe: 1 hour (h) and 10 minutes (min) prior to dose on the first day of randomized treatment (baseline) to -10 min, 5 min, 15 min, 30 min, 1 h, 2 h, and 3 h relative to dose after 2 weeks
| Intervention | Liter (Mean) |
|---|---|
| Placebo | 0.096 |
| Olo 5 mcg qd | 0.338 |
| Olo 10 mcg qd | 0.323 |
Forced Vital Capacity (FVC) Area Under Curve 0-3 Hours (AUC 0-3h) Response At Day 1
Response was defined as change from baseline. Baseline FVC was defined as the mean of the available pre-dose FVC values prior to the first dose of randomized treatment. Means are adjusted using a mixed effects model with treatment (trt), tio stratum, visit, trt-by-visit as fixed categorical effects, baseline and baseline-by-visit as fixed continuous covariates and patient as random effect. FVC AUC 0-3h was calculated using the trapezoidal rule, divided by the observation time to report in litres. (NCT00782509)
Timeframe: 1 hour (h) and 10 minutes (min) prior to dose on the first day of randomized treatment (baseline) to -10 min, 5 min, 15 min, 30 min, 1 h, 2 h, and 3 h relative to dose at Day 1
| Intervention | Liter (Mean) |
|---|---|
| Placebo | 0.052 |
| Olo 5 mcg qd | 0.383 |
| Olo 10 mcg qd | 0.384 |
FVC Area Under Curve 0-3 Hours (AUC 0-3h) Response After 12 Weeks
Response was defined as change from baseline. Baseline FVC was defined as the mean of the available pre-dose FVC values prior to the first dose of randomized treatment. Means are adjusted using a mixed effects model with treatment (trt), tio stratum, visit, trt-by-visit as fixed categorical effects, baseline and baseline-by-visit as fixed continuous covariates and patient as random effect. FVC AUC 0-3h was calculated using the trapezoidal rule, divided by the observation time to report in litres. (NCT00782509)
Timeframe: 1 hour (h) and 10 minutes (min) prior to dose on the first day of randomized treatment (baseline) to -10 min, 5 min, 15 min, 30 min, 1 h, 2 h, and 3 h relative to dose after 12 weeks
| Intervention | Liter (Mean) |
|---|---|
| Placebo | 0.046 |
| Olo 5 mcg qd | 0.284 |
| Olo 10 mcg qd | 0.291 |
FVC Area Under Curve 0-3 Hours (AUC 0-3h) Response After 24 Weeks
Response was defined as change from baseline. Baseline FVC was defined as the mean of the available pre-dose FVC values prior to the first dose of randomized treatment. Means are adjusted using a mixed effects model with treatment (trt), tio stratum, visit, trt-by-visit as fixed categorical effects, baseline and baseline-by-visit as fixed continuous covariates and patient as random effect. FVC AUC 0-3h was calculated using the trapezoidal rule, divided by the observation time to report in litres. (NCT00782509)
Timeframe: 1 hour (h) and 10 minutes (min) prior to dose on the first day of randomized treatment (baseline) to -10 min, 5 min, 15 min, 30 min, 1 h, 2 h, and 3 h relative to dose after 24 weeks
| Intervention | Liter (Mean) |
|---|---|
| Placebo | 0.062 |
| Olo 5 mcg qd | 0.303 |
| Olo 10 mcg qd | 0.281 |
FVC Area Under Curve 0-3 Hours (AUC 0-3h) Response After 48 Weeks
Response was defined as change from baseline. Baseline FVC was defined as the mean of the available pre-dose FVC values prior to the first dose of randomized treatment. Means are adjusted using a mixed effects model with treatment (trt), tio stratum, visit, trt-by-visit as fixed categorical effects, baseline and baseline-by-visit as fixed continuous covariates and patient as random effect. FVC AUC 0-3h was calculated using the trapezoidal rule, divided by the observation time to report in litres. (NCT00782509)
Timeframe: 1 hour (h) and 10 minutes (min) prior to dose on the first day of randomized treatment (baseline) to -10 min, 5 min, 15 min, 30 min, 1 h, 2 h, and 3 h relative to dose after 48 weeks
| Intervention | Liter (Mean) |
|---|---|
| Placebo | 0.053 |
| Olo 5 mcg qd | 0.271 |
| Olo 10 mcg qd | 0.271 |
FVC Area Under Curve 0-3 Hours (AUC 0-3h) Response After 6 Weeks
Response was defined as change from baseline. Baseline FVC was defined as the mean of the available pre-dose FVC values prior to the first dose of randomized treatment. Means are adjusted using a mixed effects model with treatment (trt), tio stratum, visit, trt-by-visit as fixed categorical effects, baseline and baseline-by-visit as fixed continuous covariates and patient as random effect. FVC AUC 0-3h was calculated using the trapezoidal rule, divided by the observation time to report in litres. (NCT00782509)
Timeframe: 1 hour (h) and 10 minutes (min) prior to dose on the first day of randomized treatment (baseline) to -10 min, 5 min, 15 min, 30 min, 1 h, 2 h, and 3 h relative to dose after 6 weeks
| Intervention | Liter (Mean) |
|---|---|
| Placebo | 0.048 |
| Olo 5 mcg qd | 0.312 |
| Olo 10 mcg qd | 0.294 |
FVC Peak (0-3h) Response After 12 Weeks
Response was defined as change from baseline. Baseline FVC peak (0-3h) was defined as the mean of the available pre-dose FVC peak (0-3h) values prior to first dose of randomized treatment. FVC Peak (0-3h) values were obtained within 0 - 3 hours after treatment. Means are adjusted using a mixed effects model with treatment (trt), tio stratum, visit, trt-by-visit as fixed categorical effects, baseline and baseline-by-visit as fixed continuous covariates and patient as random effect. (NCT00782509)
Timeframe: 1 hour (h) and 10 minutes (min) prior to dose on the first day of randomized treatment (baseline) to -10 min, 5 min, 15 min, 30 min, 1 h, 2 h, and 3 h relative to dose after 12 weeks
| Intervention | Liter (Mean) |
|---|---|
| Placebo | 0.213 |
| Olo 5 mcg qd | 0.439 |
| Olo 10 mcg qd | 0.422 |
Trough FEV1 Response After 48 Weeks
Response was defined as change from baseline. Baseline trough FEV1 was defined as the mean of the -1 hour and -10 minute measurements performed just prior to first dose of randomized treatment. Trough FEV1 is defined as the FEV1 performed at -10 mins prior to study drug inhalation as the end of the dosing interval or the mean of -1h and -10 min FEV1s if both available. Means are adjusted using a mixed effects model with treatment (trt), tio stratum, visit, trt-by-visit as fixed categorical effects, baseline and baseline-by-visit as fixed continuous covariates and patient as random effect. (NCT00782509)
Timeframe: 1 h and 10 min prior to dose on the first day of randomized treatment (baseline) and -1 h (if available) and - 10 mins prior to study drug after 48 weeks
| Intervention | Liter (Mean) |
|---|---|
| Placebo | -0.057 |
| Olo 5 mcg qd | 0.011 |
| Olo 10 mcg qd | 0.014 |
FVC Peak (0-3h) Response After 24 Weeks
Response was defined as change from baseline. Baseline FVC peak (0-3h) was defined as the mean of the available pre-dose FVC peak (0-3h) values prior to first dose of randomized treatment. FVC Peak (0-3h) values were obtained within 0 - 3 hours after treatment. Means are adjusted using a mixed effects model with treatment (trt), tio stratum, visit, trt-by-visit as fixed categorical effects, baseline and baseline-by-visit as fixed continuous covariates and patient as random effect. (NCT00782509)
Timeframe: 1 hour (h) and 10 minutes (min) prior to dose on the first day of randomized treatment (baseline) to -10 min, 5 min, 15 min, 30 min, 1 h, 2 h, and 3 h relative to dose after 24 weeks
| Intervention | Liter (Mean) |
|---|---|
| Placebo | 0.223 |
| Olo 5 mcg qd | 0.449 |
| Olo 10 mcg qd | 0.429 |
FVC Peak (0-3h) Response After 48 Weeks
Response was defined as change from baseline. Baseline FVC peak (0-3h) was defined as the mean of the available pre-dose FVC peak (0-3h) values prior to first dose of randomized treatment. FVC Peak (0-3h) values were obtained within 0 - 3 hours after treatment. Means are adjusted using a mixed effects model with treatment (trt), tio stratum, visit, trt-by-visit as fixed categorical effects, baseline and baseline-by-visit as fixed continuous covariates and patient as random effect. (NCT00782509)
Timeframe: 1 hour (h) and 10 minutes (min) prior to dose on the first day of randomized treatment (baseline) to -10 min, 5 min, 15 min, 30 min, 1 h, 2 h, and 3 h relative to dose after 48 weeks
| Intervention | Liter (Mean) |
|---|---|
| Placebo | 0.208 |
| Olo 5 mcg qd | 0.415 |
| Olo 10 mcg qd | 0.419 |
FVC Peak (0-3h) Response After 6 Weeks
Response was defined as change from baseline. Baseline FVC peak (0-3h) was defined as the mean of the available pre-dose FVC peak (0-3h) values prior to first dose of randomized treatment. FVC Peak (0-3h) values were obtained within 0 - 3 hours after treatment. Means are adjusted using a mixed effects model with treatment (trt), tio stratum, visit, trt-by-visit as fixed categorical effects, baseline and baseline-by-visit as fixed continuous covariates and patient as random effect. (NCT00782509)
Timeframe: 1 hour (h) and 10 minutes (min) prior to dose on the first day of randomized treatment (baseline) to -10 min, 5 min, 15 min, 30 min, 1 h, 2 h, and 3 h relative to dose after 6 weeks
| Intervention | Liter (Mean) |
|---|---|
| Placebo | 0.183 |
| Olo 5 mcg qd | 0.451 |
| Olo 10 mcg qd | 0.434 |
FVC Peak (0-3h) Response At Day 1
Response was defined as change from baseline. Baseline FVC peak (0-3h) was defined as the mean of the available pre-dose FVC peak (0-3h) values prior to first dose of randomized treatment. FVC Peak (0-3h) values were obtained within 0 - 3 hours aftertreatment. Means are adjusted using a mixed effects model with treatment (trt), tio stratum, visit, trt-by-visit as fixed categorical effects, baseline and baseline-by-visit as fixed continuous covariates and patient as random effect. (NCT00782509)
Timeframe: 1 hour (h) and 10 minutes (min) prior to dose on the first day of randomized treatment (baseline) to -10 min, 5 min, 15 min, 30 min, 1 h, 2 h, and 3 h relative to dose at Day 1
| Intervention | Liter (Mean) |
|---|---|
| Placebo | 0.202 |
| Olo 5 mcg qd | 0.534 |
| Olo 10 mcg qd | 0.535 |
Trough FEV1 Response After 40 Weeks
Response was defined as change from baseline. Baseline trough FEV1 was defined as the mean of the -1 hour and -10 minute measurements performed just prior to first dose of randomized treatment. Trough FEV1 is defined as the FEV1 performed at -10 mins prior to study drug inhalation as the end of the dosing interval or the mean of -1h and -10 min FEV1s if both available. Means are adjusted using a mixed effects model with treatment (trt), tio stratum, visit, trt-by-visit as fixed categorical effects, baseline and baseline-by-visit as fixed continuous covariates and patient as random effect. (NCT00782509)
Timeframe: 1 h and 10 min prior to dose on the first day of randomized treatment (baseline) and -1 h (if available) and - 10 mins prior to study drug after 40 weeks
| Intervention | Liter (Mean) |
|---|---|
| Placebo | -0.029 |
| Olo 5 mcg qd | 0.033 |
| Olo 10 mcg qd | 0.043 |
Trough FEV1 Response After 32 Weeks
Response was defined as change from baseline. Baseline trough FEV1 was defined as the mean of the -1 hour and -10 minute measurements performed just prior to first dose of randomized treatment. Trough FEV1 is defined as the FEV1 performed at -10 mins prior to study drug inhalation as the end of the dosing interval or the mean of -1h and -10 min FEV1s if both available. Means are adjusted using a mixed effects model with treatment (trt), tio stratum, visit, trt-by-visit as fixed categorical effects, baseline and baseline-by-visit as fixed continuous covariates and patient as random effect. (NCT00782509)
Timeframe: 1 h and 10 min prior to dose on the first day of randomized treatment (baseline) and -1 h (if available) and - 10 mins prior to study drug after 32 weeks
| Intervention | Liter (Mean) |
|---|---|
| Placebo | -0.029 |
| Olo 5 mcg qd | 0.029 |
| Olo 10 mcg qd | -0.002 |
Trough FEV1 Response After 24 Weeks
Response was defined as change from baseline. Baseline trough FEV1 was defined as the mean of the -1 hour and -10 minute measurements performed just prior to first dose of randomized treatment. Trough FEV1 is defined as the FEV1 performed at -10 mins prior to study drug inhalation as the end of the dosing interval or the mean of -1h and -10 min FEV1s if both available. Means are adjusted using a mixed effects model with treatment (trt), tio stratum, visit, trt-by-visit as fixed categorical effects, baseline and baseline-by-visit as fixed continuous covariates and patient as random effect. (NCT00782509)
Timeframe: 1 h and 10 min prior to dose on the first day of randomized treatment (baseline) and -1 h (if available) and - 10 mins prior to study drug after 24 weeks
| Intervention | Liter (Mean) |
|---|---|
| Placebo | -0.036 |
| Olo 5 mcg qd | 0.033 |
| Olo 10 mcg qd | 0.022 |
Trough FEV1 Response After 2 Weeks
Response was defined as change from baseline. Baseline trough FEV1 was defined as the mean of the -1 hour and -10 minute measurements performed just prior to first dose of randomized treatment. Trough FEV1 is defined as the FEV1 performed a -10 mins prior to study drug inhalation as the end of the dosing interval or the mean of -1h and -10 min FEV1s if both available. Means are adjusted using a mixed effects model with treatment (trt), tio stratum, visit, trt-by-visit as fixed categorical effects, baseline and baseline-by-visit as fixed continuous covariates and patient as random effect. (NCT00782509)
Timeframe: 1 h and 10 min prior to dose on the first day of randomized treatment (baseline) and -1 h (if available) and - 10 mins prior to study drug after 2 weeks
| Intervention | Liter (Mean) |
|---|---|
| Placebo | 0.013 |
| Olo 5 mcg qd | 0.066 |
| Olo 10 mcg qd | 0.078 |
Trough FEV1 Response After 18 Weeks
Response was defined as change from baseline. Baseline trough FEV1 was defined as the mean of the -1 hour and -10 minute measurements performed just prior to first dose of randomized treatment. Trough FEV1 is defined as the FEV1 performed at -10 mins prior to study drug inhalation as the end of the dosing interval or the mean of -1h and -10 min FEV1s if both available. Means are adjusted using a mixed effects model with treatment (trt), tio stratum, visit, trt-by-visit as fixed categorical effects, baseline and baseline-by-visit as fixed continuous covariates and patient as random effect. (NCT00782509)
Timeframe: 1 h and 10 min prior to dose on the first day of randomized treatment (baseline) and -1 h (if available) and - 10 mins prior to study drug after 18 weeks
| Intervention | Liter (Mean) |
|---|---|
| Placebo | -0.007 |
| Olo 5 mcg qd | 0.062 |
| Olo 10 mcg qd | 0.037 |
Time to First Moderate Chronic Obstructive Pulmonary Disease (COPD) Exacerbation
Qualifying events of COPD were specifically pre-defined in the protocol.Other respiratory related events were evaluated by the investigator to see if they met the pre-defined criteria. Moderate exacerbations were defined as exacerbations which did not lead to hospitalization but included treatment with antibiotics and/or systemic steroids. Time to event was measured from the beginning of treatment. Cox regression analysis of treatment effect using tiotropium stratum as a stratification factor.Due to the limited number of events some statistics were not able to be calculated and are listed as N/A or are blank. The measured values presented are actually the First Quartile and 95% confidence interval.. (NCT00782509)
Timeframe: Baseline to end of study at 48 weeks.
| Intervention | days (Mean) |
|---|---|
| Placebo (Tiotropium) | NA |
| Placebo (Non-tiotropium) | 362.0 |
| Olo 5 mcg qd (Tiotropium) | NA |
| Olo 5 mcg qd (Non-tiotropium) | NA |
| Olo 10 mcg qd (Tiotropium) | 225.0 |
| Olo 10 mcg qd(Non-tiotropium) | 308.0 |
Time to First Chronic Obstructive Pulmonary Disease (COPD) Exacerbation Leading to Hospitalization
Qualifying events of COPD were specifically pre-defined in the protocol. Other respiratory related events were evaluated by the investigator to see if they met the pre-defined criteria. These exacerbations required hospitalization. Time to event was measured from the beginning of treatment. Cox regression analysis of treatment effect using tiotropium stratum as a stratification factor. Due to the limited number of events some statistics were not able to be calculated and are listed as N/A or are blank. The measured values presented are actually the First Quartile and 95% confidence interval. (NCT00782509)
Timeframe: Baseline to end of study at 48 weeks.
| Intervention | days (Mean) |
|---|---|
| Placebo (Tiotropium) | NA |
| Placebo (Non-tiotropium) | NA |
| Olo 5 mcg qd (Tiotropium) | NA |
| Olo 5 mcg qd (Non-tiotropium) | NA |
| Olo 10 mcg qd (Tiotropium) | NA |
| Olo 10 mcg qd(Non-tiotropium) | NA |
Time to First Chronic Obstructive Pulmonary Disease (COPD) Exacerbation
"Qualifying events of COPD were specifically pre-defined in the protocol. Other respiratory related events were evaluated by the investigator to see if they met the pre-defined criteria. Time to event was measured from the beginning of treatment. Cox regression analysis of treatment effect using tiotropium stratum as a stratification factor. Due to the limited number of events some statistics were not able to be calculated and are listed as N/A or are blank.~The measured values presented are actually the First Quartile and 95% confidence interval." (NCT00782509)
Timeframe: Baseline to end of study at 48 weeks.
| Intervention | days (Mean) |
|---|---|
| Placebo (Tiotropium) | 306.0 |
| Placebo (Non-tiotropium) | 259.0 |
| Olo 5 mcg qd (Tiotropium) | 225.0 |
| Olo 5 mcg qd (Non-tiotropium) | 315.0 |
| Olo 10 mcg qd (Tiotropium) | 219.0 |
| Olo 10 mcg qd(Non-tiotropium) | 216.0 |
Peak FEV1 (0-3h) Response At Day 1
Response was defined as change from baseline. Baseline peak FEV1 was defined as the mean of the available pre-dose peak FEV1 values prior to first dose of randomized treatment. Peak FEV1 (0-3h) values were obtained within 0 - 3 hours after treatment. Means are adjusted using a mixed effects model with treatment (trt), tio stratum, visit, trt-by-visit as fixed categorical effects, baseline and baseline-by-visit as fixed continuous covariates and patient as random effect. (NCT00782509)
Timeframe: 1 hour (h) and 10 minutes (min) prior to dose on the first day of randomized treatment (baseline) to -10 min, 5 min, 15 min, 30 min, 1 h, 2 h, and 3 h relative to dose at Day 1
| Intervention | Liter (Mean) |
|---|---|
| Placebo | 0.099 |
| Olo 5 mcg qd | 0.267 |
| Olo 10 mcg qd | 0.276 |
Peak FEV1 (0-3h) Response After 6 Weeks
Response was defined as change from baseline. Baseline peak FEV1 was defined as the mean of the available pre-dose peak FEV1 values prior to first dose of randomized treatment. Peak FEV1 (0-3h) values were obtained within 0 - 3 hours after treatment. Means are adjusted using a mixed effects model with treatment (trt), tio stratum, visit, trt-by-visit as fixed categorical effects, baseline and baseline-by-visit as fixed continuous covariates and patient as random effect. (NCT00782509)
Timeframe: 1 hour (h) and 10 minutes (min) prior to dose on the first day of randomized treatment (baseline) to -10 min, 5 min, 15 min, 30 min, 1 h, 2 h, and 3 h relative to dose after 6 weeks
| Intervention | Liter (Mean) |
|---|---|
| Placebo | 0.080 |
| Olo 5 mcg qd | 0.252 |
| Olo 10 mcg qd | 0.246 |
Number of COPD Exacerbations
Mean number of COPD exacerbations per patient years. Qualifying events of COPD were specifically pre-defined in the protocol. Other respiratory related events were evaluated by the investigator to see if they met the pre-defined criteria. (NCT00782509)
Timeframe: Baseline to end of study at week 48 visit
| Intervention | COPD exacerbations (Mean) |
|---|---|
| Placebo | 0.4590 |
| Olo 5 mcg qd | 0.5453 |
| Olo 10 mcg qd | 0.5885 |
Number of COPD Exacerbations Requiring Hospitalization
Mean number of COPD exacerbations requiring hospitalization per patient years. Qualifying events of COPD were specifically pre-defined in the protocol. Other respiratory related events were evaluated by the investigator to see if they met the pre-defined criteria. These exacerbations required hospitalization. (NCT00782509)
Timeframe: Baseline to end of study at week 48 visit
| Intervention | COPD exacerbations (Mean) |
|---|---|
| Placebo | 0.0786 |
| Olo 5 mcg qd | 0.0811 |
| Olo 10 mcg qd | 0.0886 |
Number of Moderate Chronic Obstructive Pulmonary Disease (COPD) Exacerbations
Mean number of moderate COPD exacerbations per patient years. Qualifying events of COPD were specifically pre-defined in the protocol. Other respiratory related events were evaluated by the investigator to see if they met the pre-defined criteria. Moderate exacerbations were defined as exacerbations which did not lead to hospitalization but included treatment with antibiotics and/or systemic steroids. (NCT00782509)
Timeframe: Baseline to end of study at 48 weeks.
| Intervention | COPD exacerbations (Mean) |
|---|---|
| Placebo | 0.3375 |
| Olo 5 mcg qd | 0.4335 |
| Olo 10 mcg qd | 0.4513 |
Patient's Global Rating at Week 12
Patients were asked to rate their respiratory condition relative to their condition prior to the first dose of study medication. The scale is a seven 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 worst. (NCT00782509)
Timeframe: Week 12 visit
| Intervention | Point on scale (Mean) |
|---|---|
| Placebo | 3.2 |
| Olo 5 mcg qd | 2.9 |
| Olo 10 mcg qd | 3.0 |
Patient's Global Rating at Week 48
Patients were asked to rate their respiratory condition relative to their condition prior to the first dose of study medication. The scale is a seven 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 worst. (NCT00782509)
Timeframe: Week 48 visit
| Intervention | Point on scale (Mean) |
|---|---|
| Placebo | 3.3 |
| Olo 5 mcg qd | 3.1 |
| Olo 10 mcg qd | 3.0 |
Peak FEV1 (0-3h) Response After 12 Weeks
Response was defined as change from baseline. Baseline peak FEV1 was defined as the mean of the available pre-dose peak FEV1 values prior to first dose of randomized treatment. Peak FEV1 (0-3h) values were obtained within 0 - 3 hours after treatment. Means are adjusted using a mixed effects model with treatment (trt), tio stratum, visit, trt-by-visit as fixed categorical effects, baseline and baseline-by-visit as fixed continuous covariates and patient as random effect. (NCT00782509)
Timeframe: 1 hour (h) and 10 minutes (min) prior to dose on the first day of randomized treatment (baseline) to -10 min, 5 min, 15 min, 30 min, 1 h, 2 h, and 3 h relative to dose after 12 weeks
| Intervention | Liter (Mean) |
|---|---|
| Placebo | 0.088 |
| Olo 5 mcg qd | 0.232 |
| Olo 10 mcg qd | 0.217 |
Peak FEV1 (0-3h) Response After 2 Weeks
Response was defined as change from baseline. Baseline peak FEV1 was defined as the mean of the available pre-dose peak FEV1 values prior to first dose of randomized treatment. Peak FEV1 (0-3h) values were obtained within 0 - 3 hours after treatment. Means are adjusted using a mixed effects model with treatment (trt), tio stratum, visit, trt-by-visit as fixed categorical effects, baseline and baseline-by-visit as fixed continuous covariates and patient as random effect. (NCT00782509)
Timeframe: 1 hour (h) and 10 minutes (min) prior to dose on the first day of randomized treatment (baseline) to -10 min, 5 min, 15 min, 30 min, 1 h, 2 h, and 3 h relative to dose after 2 weeks
| Intervention | Liter (Mean) |
|---|---|
| Placebo | 0.104 |
| Olo 5 mcg qd | 0.259 |
| Olo 10 mcg qd | 0.251 |
Trough FVC Response After 48 Weeks
Response was defined as change from baseline. Baseline trough FVC was defined as the mean of the -1 hour and -10 minute measurements performed just prior to first dose of randomized treatment. Trough FVC is defined as the FVCs obtained at -10 mins prior to study drug inhalation as the end of the dosing interval or the mean of -1h and -10 min FVCs if both available. Means are adjusted using a mixed effects model with treatment (trt), tio stratum, visit, trt-by-visit as fixed categorical effects, baseline and baseline-by-visit as fixed continuous covariates and patient as random effect. (NCT00782509)
Timeframe: 1 h and 10 min prior to dose on the first day of randomized treatment (baseline) and -1 h (if available) and - 10 mins prior to study drug after 48 weeks
| Intervention | Liter (Mean) |
|---|---|
| Placebo | -0.008 |
| Olo 5 mcg qd | 0.038 |
| Olo 10 mcg qd | 0.054 |
Patient's Global Rating at Week 24
Patients were asked to rate their respiratory condition relative to their condition prior to the first dose of study medication. The scale is a seven 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 worst. (NCT00782509)
Timeframe: Week 24 visit
| Intervention | Point on scale (Mean) |
|---|---|
| Placebo | 3.3 |
| Olo 5 mcg qd | 3.0 |
| Olo 10 mcg qd | 2.9 |
Trough FVC Response After 18 Weeks
Response was defined as change from baseline. Baseline trough FVC was defined as the mean of the -1 hour and -10 minute measurements performed just prior to first dose of randomized treatment. Trough FVC is defined as the FVCs obtained at -10 mins prior to study drug inhalation as the end of the dosing interval or the mean of -1h and -10 min FVCs if both available. Means are adjusted using a mixed effects model with treatment (trt), tio stratum, visit, trt-by-visit as fixed categorical effects, baseline and baseline-by-visit as fixed continuous covariates and patient as random effect. (NCT00782509)
Timeframe: 1 h and 10 min prior to dose on the first day of randomized treatment (baseline) and -1 h (if available) and - 10 mins prior to study drug after 18 weeks
| Intervention | Liter (Mean) |
|---|---|
| Placebo | 0.064 |
| Olo 5 mcg qd | 0.114 |
| Olo 10 mcg qd | 0.098 |
Trough FVC Response After 2 Weeks
Response was defined as change from baseline. Baseline trough FVC was defined as the mean of the -1 hour and -10 minute measurements performed just prior to first dose of randomized treatment. Trough FVC is defined as the FVCs obtained at -10 mins prior to study drug inhalation as the end of the dosing interval or the mean of -1h and -10 min FVCs if both available. Means are adjusted using a mixed effects model with treatment (trt), tio stratum, visit, trt-by-visit as fixed categorical effects, baseline and baseline-by-visit as fixed continuous covariates and patient as random effect. (NCT00782509)
Timeframe: 1 h and 10 min prior to dose on the first day of randomized treatment (baseline) and -1 h (if available) and - 10 mins prior to study drug after 2 weeks
| Intervention | Liter (Mean) |
|---|---|
| Placebo | 0.054 |
| Olo 5 mcg qd | 0.113 |
| Olo 10 mcg qd | 0.141 |
Trough FVC Response After 24 Weeks
Response was defined as change from baseline. Baseline trough FVC was defined as the mean of the -1 hour and -10 minute measurements performed just prior to first dose of randomized treatment. Trough FVC is defined as the FVCs obtained at -10 mins prior to study drug inhalation as the end of the dosing interval or the mean of -1h and -10 min FVCs if both available. Means are adjusted using a mixed effects model with treatment (trt), tio stratum, visit, trt-by-visit as fixed categorical effects, baseline and baseline-by-visit as fixed continuous covariates and patient as random effect. (NCT00782509)
Timeframe: 1 h and 10 min prior to dose on the first day of randomized treatment (baseline) and -1 h (if available) and - 10 mins prior to study drug after 24 weeks
| Intervention | Liter (Mean) |
|---|---|
| Placebo | 0.021 |
| Olo 5 mcg qd | 0.066 |
| Olo 10 mcg qd | 0.091 |
Trough FVC Response After 32 Weeks
Response was defined as change from baseline. Baseline trough FVC was defined as the mean of the -1 hour and -10 minute measurements performed just prior to first dose of randomized treatment. Trough FVC is defined as the FVCs obtained at -10 mins prior to study drug inhalation as the end of the dosing interval or the mean of -1h and -10 min FVCs if both available. Means are adjusted using a mixed effects model with treatment (trt), tio stratum, visit, trt-by-visit as fixed categorical effects, baseline and baseline-by-visit as fixed continuous covariates and patient as random effect. (NCT00782509)
Timeframe: 1 h and 10 min prior to dose on the first day of randomized treatment (baseline) and -1 h (if available) and - 10 mins prior to study drug after 32 weeks
| Intervention | Liter (Mean) |
|---|---|
| Placebo | 0.061 |
| Olo 5 mcg qd | 0.099 |
| Olo 10 mcg qd | 0.058 |
Trough FVC Response After 40 Weeks
Response was defined as change from baseline. Baseline trough FVC was defined as the mean of the -1 hour and -10 minute measurements performed just prior to first dose of randomized treatment. Trough FVC is defined as the FVCs obtained at -10 mins prior to study drug inhalation as the end of the dosing interval or the mean of -1h and -10 min FVCs if both available. Means are adjusted using a mixed effects model with treatment (trt), tio stratum, visit, trt-by-visit as fixed categorical effects, baseline and baseline-by-visit as fixed continuous covariates and patient as random effect. (NCT00782509)
Timeframe: 1 h and 10 min prior to dose on the first day of randomized treatment (baseline) and -1 h (if available) and - 10 mins prior to study drug after 40 weeks
| Intervention | Liter (Mean) |
|---|---|
| Placebo | 0.062 |
| Olo 5 mcg qd | 0.104 |
| Olo 10 mcg qd | 0.131 |
Peak FEV1 (0-3h) Response After 24 Weeks
Response was defined as change from baseline. Baseline peak FEV1 was defined as the mean of the available pre-dose peak FEV1 values prior to first dose of randomized treatment. Peak FEV1 (0-3h) values were obtained within 0 - 3 hours after treatment. Means are adjusted using a mixed effects model with treatment (trt), tio stratum, visit, trt-by-visit as fixed categorical effects, baseline and baseline-by-visit as fixed continuous covariates and patient as random effect. (NCT00782509)
Timeframe: 1 hour (h) and 10 minutes (min) prior to dose on the first day of randomized treatment (baseline) to -10 min, 5 min, 15 min, 30 min, 1 h, 2 h, and 3 h relative to dose after 24 weeks
| Intervention | Liter (Mean) |
|---|---|
| Placebo | 0.062 |
| Olo 5 mcg qd | 0.226 |
| Olo 10 mcg qd | 0.197 |
Forced Expiratory Volume in One Second (FEV1) Area Under Curve 0-3 Hour (h) (AUC 0-3h) Response at 48 Weeks
Response was defined as change from baseline. Baseline FEV1 was defined as the mean of the -1 h and -10 min measurements performed just prior to administration of the first am dose of randomized treatment. Means are adjusted using a mixed effects model with treatment (trt), tio stratum, visit, trt-by-visit interaction as fixed categorical effects, baseline and baseline-by-visit interaction as fixed continuous covariates and patient as random effect. 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. (NCT00793624)
Timeframe: 1 hour (h) and 10 minutes (min) prior to dose on the first day of randomized treatment (baseline) to -10 min, 5 min, 15 min, 30 min, 1 h, 2 h, and 3 h relative to dose on Week 48
| Intervention | Liter (Least Squares Mean) |
|---|---|
| Placebo | -0.023 |
| Olo 5 mcg qd | 0.122 |
| Olo 10 mcg qd | 0.123 |
| Form 12 mcg | 0.149 |
Forced Expiratory Volume in One Second (FEV1) Area Under Curve 0-3 Hour (h) (AUC 0-3h) Response at 24 Weeks
Response was defined as change from baseline. Baseline FEV1 was defined as the mean of the -1 h and -10 min measurements performed just prior to administration of the first am dose of randomized treatment. Means are adjusted using a mixed effects model with treatment (trt), tio stratum, visit, trt-by-visit interaction as fixed categorical effects, baseline and baseline-by-visit interaction as fixed continuous covariates and patient as random effect. 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. (NCT00793624)
Timeframe: 1 hour (h) and 10 minutes (min) prior to dose on the first day of randomized treatment (baseline) to -10 min, 5 min, 15 min, 30 min, 1 h, 2 h, and 3 h relative to dose on Week 24
| Intervention | Liter (Least Squares Mean) |
|---|---|
| Placebo | -0.009 |
| Olo 5 mcg qd | 0.142 |
| Olo 10 mcg qd | 0.156 |
| Form 12 mcg | 0.168 |
Forced Expiratory Volume in One Second (FEV1) Area Under Curve 0-3 Hour (h) (AUC 0-3h) Response at 2 Weeks
Response was defined as change from baseline. Baseline FEV1 was defined as the mean of the -1 h and -10 min measurements performed just prior to administration of the first am dose of randomized treatment. Means are adjusted using a mixed effects model with treatment (trt), tio stratum, visit, trt-by-visit interaction as fixed categorical effects, baseline and baseline-by-visit interaction as fixed continuous covariates and patient as random effect. 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. (NCT00793624)
Timeframe: 1 hour (h) and 10 minutes (min) prior to dose on the first day of randomized treatment (baseline) to -10 min, 5 min, 15 min, 30 min, 1 h, 2 h, and 3 h relative to dose on Week 2
| Intervention | Liter (Least Squares Mean) |
|---|---|
| Placebo | 0.015 |
| Olo 5 mcg qd | 0.201 |
| Olo 10 mcg qd | 0.181 |
| Form 12 mcg | 0.221 |
Forced Expiratory Volume in One Second (FEV1) Area Under Curve 0-3 Hour (h) (AUC 0-3h) Response at 12 Weeks
Response was defined as change from baseline. Baseline FEV1 was defined as the mean of the -1 h and -10 min measurements performed just prior to administration of the first am dose of randomized treatment. Means are adjusted using a mixed effects model with treatment (trt), tio stratum, visit, trt-by-visit interaction as fixed categorical effects, baseline and baseline-by-visit interaction as fixed continuous covariates and patient as random effect. 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. (NCT00793624)
Timeframe: 1 hour (h) and 10 minutes (min) prior to dose on the first day of randomized treatment (baseline) to -10 min, 5 min, 15 min, 30 min, 1 h, 2 h, and 3 h relative to dose on Week 12
| Intervention | Liter (Least Squares Mean) |
|---|---|
| Placebo | -0.003 |
| Olo 5 mcg qd | 0.176 |
| Olo 10 mcg qd | 0.167 |
| Form 12 mcg | 0.182 |
Absolute Plasma Concentrations
Absolute plasma concentrations of Olodaterol. Values presented are across visits and summarised into geometric means. (NCT00793624)
Timeframe: within 2 hours before first drug administration and 10 minutes post-dose at week 6, 12 and 18
| Intervention | pg/mL (Geometric Mean) |
|---|---|
| Olo 5 mcg qd | 4.179 |
| Olo 10 mcg qd | 7.246 |
Changes in Safety Parameters Related to Treatment
Occurence of cardiac disorders and investigations related to treatment. (NCT00793624)
Timeframe: 48 weeks
| Intervention | percentage of participants (Number) | |||||||||
|---|---|---|---|---|---|---|---|---|---|---|
| Tachycardia | Arrhythmia | Atrial fibrillation | Atrioventricular block | Atrioventricular block first degree | Bundle branch block right | Palpitations | Ventricular extrasystoles | Electrocardiogram QT prolonged | Electrocardiogram T wave inversion | |
| Form 12 mcg | 0.9 | 0.0 | 0.4 | 0.0 | 0.4 | 0.0 | 0.4 | 0.0 | 0.4 | 0.4 |
| Olo 10 mcg qd | 0.0 | 0.0 | 0.0 | 0.0 | 0.0 | 0.0 | 0.0 | 0.0 | 0.0 | 0.0 |
| Olo 5 mcg qd | 0.0 | 0.4 | 0.0 | 0.0 | 0.0 | 0.4 | 0.0 | 0.0 | 0.4 | 0.0 |
| Placebo | 0.4 | 0.0 | 0.4 | 0.4 | 0.0 | 0.0 | 0.4 | 0.4 | 0.0 | 0.0 |
Use of Rescue Medication at Week 24
Mean number of puffs of rescue medication used per day (daytime/nighttime/total) (NCT00793624)
Timeframe: Week 24
| Intervention | Number of puffs (Mean) | ||
|---|---|---|---|
| Daytime | Nighttime | Total | |
| Form 12 mcg | 1.217 | 1.701 | 2.917 |
| Olo 10 mcg qd | 1.037 | 1.471 | 2.488 |
| Olo 5 mcg qd | 0.961 | 1.449 | 2.399 |
| Placebo | 1.364 | 2.051 | 3.390 |
Peak Expiratory Flow Rate (PEFR) at Week 24
Weekly mean pre-dose morning and evening PEFR. Results are from non-MMRM ANCOVA models by week, with Last observation carried forward (LOCF) up to each week. Fixed effects include treatment, tiotropium, strata and baseline. (NCT00793624)
Timeframe: Week 24
| Intervention | L/min (Mean) | |
|---|---|---|
| morning PEFR (N=214, 212, 216, 218) | evening PEFR (N=215, 211, 215, 221) | |
| Form 12 mcg | 214.070 | 220.129 |
| Olo 10 mcg qd | 211.428 | 220.727 |
| Olo 5 mcg qd | 211.496 | 219.977 |
| Placebo | 196.429 | 202.256 |
Trough FVC Response at Week 6
Response was defined as change from baseline. Baseline trough FVC was defined as the mean of the -1 hour and -10 minute measurements performed just prior to first dose of randomized treatment. Trough FVC is defined as the FVC performed at -10 mins prior to study drug inhalation as the end of the dosing interval or the mean of -1h and -10 min FVCs if both available. Means are adjusted using a mixed effects model with treatment (trt), tio stratum, visit, trt-by-visit as fixed categorical effects, baseline and baseline-by-visit as fixed continuous covariates and patient as random effect. (NCT00793624)
Timeframe: 1 h and 10 min prior to dose on the first day of randomized treatment (baseline) and -1 h (if available) and - 10 mins prior to study drug at week 6.
| Intervention | Liter (Least Squares Mean) |
|---|---|
| Placebo | -0.046 |
| Olo 5 mcg qd | 0.065 |
| Olo 10 mcg qd | 0.085 |
| Form 12 mcg | 0.090 |
Trough FVC Response at Week 48
Response was defined as change from baseline. Baseline trough FVC was defined as the mean of the -1 hour and -10 minute measurements performed just prior to first dose of randomized treatment. Trough FVC is defined as the FVC performed at -10 mins prior to study drug inhalation as the end of the dosing interval or the mean of -1h and -10 min FVCs if both available. Means are adjusted using a mixed effects model with treatment (trt), tio stratum, visit, trt-by-visit as fixed categorical effects, baseline and baseline-by-visit as fixed continuous covariates and patient as random effect. (NCT00793624)
Timeframe: 1 h and 10 min prior to dose on the first day of randomized treatment (baseline) and -1 h (if available) and - 10 mins prior to study drug at week 48.
| Intervention | Liter (Least Squares Mean) |
|---|---|
| Placebo | -0.061 |
| Olo 5 mcg qd | 0.022 |
| Olo 10 mcg qd | -0.002 |
| Form 12 mcg | 0.006 |
Trough FVC Response at Week 40
Response was defined as change from baseline. Baseline trough FVC was defined as the mean of the -1 hour and -10 minute measurements performed just prior to first dose of randomized treatment. Trough FVC is defined as the FVC performed at -10 mins prior to study drug inhalation as the end of the dosing interval or the mean of -1h and -10 min FVCs if both available. Means are adjusted using a mixed effects model with treatment (trt), tio stratum, visit, trt-by-visit as fixed categorical effects, baseline and baseline-by-visit as fixed continuous covariates and patient as random effect. (NCT00793624)
Timeframe: 1 h and 10 min prior to dose on the first day of randomized treatment (baseline) and -1 h (if available) and - 10 mins prior to study drug at week 40.
| Intervention | Liter (Least Squares Mean) |
|---|---|
| Placebo | 0.028 |
| Olo 5 mcg qd | 0.087 |
| Olo 10 mcg qd | 0.086 |
| Form 12 mcg | 0.052 |
Trough FVC Response at Week 32
Response was defined as change from baseline. Baseline trough FVC was defined as the mean of the -1 hour and -10 minute measurements performed just prior to first dose of randomized treatment. Trough FVC is defined as the FVC performed at -10 mins prior to study drug inhalation as the end of the dosing interval or the mean of -1h and -10 min FVCs if both available. Means are adjusted using a mixed effects model with treatment (trt), tio stratum, visit, trt-by-visit as fixed categorical effects, baseline and baseline-by-visit as fixed continuous covariates and patient as random effect. (NCT00793624)
Timeframe: 1 h and 10 min prior to dose on the first day of randomized treatment (baseline) and -1 h (if available) and - 10 mins prior to study drug at week 32.
| Intervention | Liter (Least Squares Mean) |
|---|---|
| Placebo | 0.019 |
| Olo 5 mcg qd | 0.080 |
| Olo 10 mcg qd | 0.084 |
| Form 12 mcg | 0.077 |
Trough FVC Response at Week 24
Response was defined as change from baseline. Baseline trough FVC was defined as the mean of the -1 hour and -10 minute measurements performed just prior to first dose of randomized treatment. Trough FVC is defined as the FVC performed at -10 mins prior to study drug inhalation as the end of the dosing interval or the mean of -1h and -10 min FVCs if both available. Means are adjusted using a mixed effects model with treatment (trt), tio stratum, visit, trt-by-visit as fixed categorical effects, baseline and baseline-by-visit as fixed continuous covariates and patient as random effect. (NCT00793624)
Timeframe: 1 h and 10 min prior to dose on the first day of randomized treatment (baseline) and -1 h (if available) and - 10 mins prior to study drug at week 24.
| Intervention | Liter (Least Squares Mean) |
|---|---|
| Placebo | -0.018 |
| Olo 5 mcg qd | 0.038 |
| Olo 10 mcg qd | 0.064 |
| Form 12 mcg | 0.001 |
Trough FVC Response at Week 2
Response was defined as change from baseline. Baseline trough FVC was defined as the mean of the -1 hour and -10 minute measurements performed just prior to first dose of randomized treatment. Trough FVC is defined as the FVC performed at -10 mins prior to study drug inhalation as the end of the dosing interval or the mean of -1h and -10 min FVCs if both available. Means are adjusted using a mixed effects model with treatment (trt), tio stratum, visit, trt-by-visit as fixed categorical effects, baseline and baseline-by-visit as fixed continuous covariates and patient as random effect. (NCT00793624)
Timeframe: 1 h and 10 min prior to dose on the first day of randomized treatment (baseline) and -1 h (if available) and - 10 mins prior to study drug at week 2.
| Intervention | Liter (Least Squares Mean) |
|---|---|
| Placebo | 0.042 |
| Olo 5 mcg qd | 0.110 |
| Olo 10 mcg qd | 0.119 |
| Form 12 mcg | 0.126 |
Trough FVC Response at Week 18
Response was defined as change from baseline. Baseline trough FVC was defined as the mean of the -1 hour and -10 minute measurements performed just prior to first dose of randomized treatment. Trough FVC is defined as the FVC performed at -10 mins prior to study drug inhalation as the end of the dosing interval or the mean of -1h and -10 min FVCs if both available. Means are adjusted using a mixed effects model with treatment (trt), tio stratum, visit, trt-by-visit as fixed categorical effects, baseline and baseline-by-visit as fixed continuous covariates and patient as random effect. (NCT00793624)
Timeframe: 1 h and 10 min prior to dose on the first day of randomized treatment (baseline) and -1 h (if available) and - 10 mins prior to study drug at week 18.
| Intervention | Liter (Least Squares Mean) |
|---|---|
| Placebo | 0.060 |
| Olo 5 mcg qd | 0.066 |
| Olo 10 mcg qd | 0.078 |
| Form 12 mcg | 0.063 |
Trough FVC Response at Week 12
Response was defined as change from baseline. Baseline trough FVC was defined as the mean of the -1 hour and -10 minute measurements performed just prior to first dose of randomized treatment. Trough FVC is defined as the FVC performed at -10 mins prior to study drug inhalation as the end of the dosing interval or the mean of -1h and -10 min FVCs if both available. Means are adjusted using a mixed effects model with treatment (trt), tio stratum, visit, trt-by-visit as fixed categorical effects, baseline and baseline-by-visit as fixed continuous covariates and patient as random effect. (NCT00793624)
Timeframe: 1 h and 10 min prior to dose on the first day of randomized treatment (baseline) and -1 h (if available) and - 10 mins prior to study drug at week 12.
| Intervention | Liter (Least Squares Mean) |
|---|---|
| Placebo | -0.018 |
| Olo 5 mcg qd | 0.079 |
| Olo 10 mcg qd | 0.087 |
| Form 12 mcg | 0.068 |
Trough FEV1 Response at Week 6
Response was defined as change from baseline. Baseline trough FEV1 was defined as the mean of the -1 hour and -10 minute measurements performed just prior to first dose of randomized treatment. Trough FEV1 is defined as the FEV1 performed at -10 mins prior to study drug inhalation as the end of the dosing interval or the mean of -1h and -10 min FEV1s if both available. Means are adjusted using a mixed effects model with treatment (trt), tio stratum, visit, trt-by-visit as fixed categorical effects, baseline and baseline-by-visit as fixed continuous covariates and patient as random effect. (NCT00793624)
Timeframe: 1 h and 10 min prior to dose on the first day of randomized treatment (baseline) and -1 h (if available) and - 10 mins prior to study drug at week 6.
| Intervention | Liter (Least Squares Mean) |
|---|---|
| Placebo | -0.037 |
| Olo 5 mcg qd | 0.049 |
| Olo 10 mcg qd | 0.041 |
| Form 12 mcg | 0.042 |
Trough FEV1 Response at Week 48
Response was defined as change from baseline. Baseline trough FEV1 was defined as the mean of the -1 hour and -10 minute measurements performed just prior to first dose of randomized treatment. Trough FEV1 is defined as the FEV1 performed at -10 mins prior to study drug inhalation as the end of the dosing interval or the mean of -1h and -10 min FEV1s if both available. Means are adjusted using a mixed effects model with treatment (trt), tio stratum, visit, trt-by-visit as fixed categorical effects, baseline and baseline-by-visit as fixed continuous covariates and patient as random effect. (NCT00793624)
Timeframe: 1 h and 10 min prior to dose on the first day of randomized treatment (baseline) and -1 h (if available) and - 10 mins prior to study drug at week 48.
| Intervention | Liter (Least Squares Mean) |
|---|---|
| Placebo | -0.065 |
| Olo 5 mcg qd | 0.003 |
| Olo 10 mcg qd | -0.009 |
| Form 12 mcg | -0.006 |
Trough FEV1 Response at Week 40
Response was defined as change from baseline. Baseline trough FEV1 was defined as the mean of the -1 hour and -10 minute measurements performed just prior to first dose of randomized treatment. Trough FEV1 is defined as the FEV1 performed at -10 mins prior to study drug inhalation as the end of the dosing interval or the mean of -1h and -10 min FEV1s if both available. Means are adjusted using a mixed effects model with treatment (trt), tio stratum, visit, trt-by-visit as fixed categorical effects, baseline and baseline-by-visit as fixed continuous covariates and patient as random effect. (NCT00793624)
Timeframe: 1 h and 10 min prior to dose on the first day of randomized treatment (baseline) and -1 h (if available) and - 10 mins prior to study drug at week 40.
| Intervention | Liter (Least Squares Mean) |
|---|---|
| Placebo | -0.020 |
| Olo 5 mcg qd | 0.020 |
| Olo 10 mcg qd | 0.017 |
| Form 12 mcg | 0.004 |
Trough FEV1 Response at Week 32
Response was defined as change from baseline. Baseline trough FEV1 was defined as the mean of the -1 hour and -10 minute measurements performed just prior to first dose of randomized treatment. Trough FEV1 is defined as the FEV1 performed at -10 mins prior to study drug inhalation as the end of the dosing interval or the mean of -1h and -10 min FEV1s if both available. Means are adjusted using a mixed effects model with treatment (trt), tio stratum, visit, trt-by-visit as fixed categorical effects, baseline and baseline-by-visit as fixed continuous covariates and patient as random effect. (NCT00793624)
Timeframe: 1 h and 10 min prior to dose on the first day of randomized treatment (baseline) and -1 h (if available) and - 10 mins prior to study drug at week 32.
| Intervention | Liter (Least Squares Mean) |
|---|---|
| Placebo | -0.023 |
| Olo 5 mcg qd | 0.023 |
| Olo 10 mcg qd | 0.026 |
| Form 12 mcg | 0.021 |
Trough FEV1 Response at Week 24
Response was defined as change from baseline. Baseline trough FEV1 was defined as the mean of the -1 hour and -10 minute measurements performed just prior to first dose of randomized treatment. Trough FEV1 is defined as the FEV1 performed at -10 mins prior to study drug inhalation as the end of the dosing interval or the mean of -1h and -10 min FEV1s if both available. Means are adjusted using a mixed effects model with treatment (trt), tio stratum, visit, trt-by-visit as fixed categorical effects, baseline and baseline-by-visit as fixed continuous covariates and patient as random effect. (NCT00793624)
Timeframe: 1 h and 10 min prior to dose on the first day of randomized treatment (baseline) and -1 h (if available) and - 10 mins prior to study drug at week 24.
| Intervention | Liter (Least Squares Mean) |
|---|---|
| Placebo | -0.056 |
| Olo 5 mcg qd | 0.021 |
| Olo 10 mcg qd | 0.028 |
| Form 12 mcg | -0.002 |
Trough FEV1 Response at Week 2
Response was defined as change from baseline. Baseline trough FEV1 was defined as the mean of the -1 hour and -10 minute measurements performed just prior to first dose of randomized treatment. Trough FEV1 is defined as the FEV1 performed at -10 mins prior to study drug inhalation as the end of the dosing interval or the mean of -1h and -10 min FEV1s if both available. Means are adjusted using a mixed effects model with treatment (trt), tio stratum, visit, trt-by-visit as fixed categorical effects, baseline and baseline-by-visit as fixed continuous covariates and patient as random effect. (NCT00793624)
Timeframe: 1 h and 10 min prior to dose on the first day of randomized treatment (baseline) and -1 h (if available) and - 10 mins prior to study drug at week 2.
| Intervention | Liter (Least Squares Mean) |
|---|---|
| Placebo | -0.019 |
| Olo 5 mcg qd | 0.068 |
| Olo 10 mcg qd | 0.060 |
| Form 12 mcg | 0.061 |
Trough FEV1 Response at Week 18
Response was defined as change from baseline. Baseline trough FEV1 was defined as the mean of the -1 hour and -10 minute measurements performed just prior to first dose of randomized treatment. Trough FEV1 is defined as the FEV1 performed at -10 mins prior to study drug inhalation as the end of the dosing interval or the mean of -1h and -10 min FEV1s if both available. Means are adjusted using a mixed effects model with treatment (trt), tio stratum, visit, trt-by-visit as fixed categorical effects, baseline and baseline-by-visit as fixed continuous covariates and patient as random effect. (NCT00793624)
Timeframe: 1 h and 10 min prior to dose on the first day of randomized treatment (baseline) and -1 h (if available) and - 10 mins prior to study drug at week 18.
| Intervention | Liter (Least Squares Mean) |
|---|---|
| Placebo | -0.019 |
| Olo 5 mcg qd | 0.046 |
| Olo 10 mcg qd | 0.026 |
| Form 12 mcg | 0.023 |
Trough FEV1 Response at Week 12
Response was defined as change from baseline. Baseline trough FEV1 was defined as the mean of the -1 hour and -10 minute measurements performed just prior to first dose of randomized treatment. Trough FEV1 is defined as the FEV1 performed at -10 mins prior to study drug inhalation as the end of the dosing interval or the mean of -1h and -10 min FEV1s if both available. Means are adjusted using a mixed effects model with treatment (trt), tio stratum, visit, trt-by-visit as fixed categorical effects, baseline and baseline-by-visit as fixed continuous covariates and patient as random effect. (NCT00793624)
Timeframe: 1 h and 10 min prior to dose on the first day of randomized treatment (baseline) and -1 h (if available) and - 10 mins prior to study drug at week 12.
| Intervention | Liter (Least Squares Mean) |
|---|---|
| Placebo | -0.027 |
| Olo 5 mcg qd | 0.056 |
| Olo 10 mcg qd | 0.048 |
| Form 12 mcg | 0.033 |
Time to First Moderate Chronic Obstructive Pulmonary Disease (CPOD) Exacerbation
Qualifying events of COPD were specifically pre-defined in the protocol. Other respiratory related events were evaluated by the investigator to see if they met the pre-defined criteria. These exacerbations did not lead to hospitalization but included treatment with antibiotics and/or systemic steroids. Time to event was measured from the beginning of treatment. Cox regression analysis of treatment effect using tiotropium stratum as a stratification factor. (NCT00793624)
Timeframe: Baseline to end of study at 48 weeks.
| Intervention | Days (Mean) |
|---|---|
| Placebo (Tiotropium) | 150 |
| Placebo (Non-tiotropium) | 296 |
| Olo 5 mcg qd (Tiotropium) | 239 |
| Olo 5 mcg qd (Non-tiotropium) | 244 |
| Olo 10 mcg qd (Tiotropium) | 175 |
| Olo 10 mcg qd(Non-tiotropium) | 302 |
| Form 12 mcg (Tiotropium) | 280 |
| Form 12 mcg (Non-tiotropium) | 270 |
Time to First Chronic Obstructive Pulmonary Disease (CPOD) Exacerbation Leading to Hospitalization
Qualifying events of COPD were specifically pre-defined in the protocol. Other respiratory related events were evaluated by the investigator to see if they met the pre-defined criteria. These exacerbations required hospitalization. Time to event was measured from the beginning of treatment. Cox regression analysis of treatment effect using tiotropium stratum as a stratification factor. (NCT00793624)
Timeframe: Baseline to end of study at 48 weeks.
| Intervention | Days (Mean) |
|---|---|
| Placebo (Tiotropium) | NA |
| Placebo (Non-tiotropium) | NA |
| Olo 5 mcg qd (Tiotropium) | NA |
| Olo 5 mcg qd (Non-tiotropium) | NA |
| Olo 10 mcg qd (Tiotropium) | NA |
| Olo 10 mcg qd(Non-tiotropium) | NA |
| Form 12 mcg (Tiotropium) | NA |
| Form 12 mcg (Non-tiotropium) | NA |
Time to First Chronic Obstructive Pulmonary Disease (COPD) Exacerbation
Qualifying events of COPD were specifically pre-defined in the protocol. Other respiratory related events were evaluated by the investigator to see if they met the pre-defined criteria. Time to event was measured from the beginning of treatment. Cox regression analysis of treatment effect using tiotropium stratum as a stratification factor. (NCT00793624)
Timeframe: Baseline to end of study at 48 weeks.
| Intervention | Days (Mean) |
|---|---|
| Placebo (Tiotropium) | 143 |
| Placebo (Non-tiotropium) | 268 |
| Olo 5 mcg qd (Tiotropium) | 136 |
| Olo 5 mcg qd (Non-tiotropium) | 189 |
| Olo 10 mcg qd (Tiotropium) | 134 |
| Olo 10 mcg qd(Non-tiotropium) | 209 |
| Form 12 mcg (Tiotropium) | 223 |
| Form 12 mcg (Non-tiotropium) | 310 |
Saint George's Respiratory Questionnaire (SGRQ) Total Score at 48 Weeks
Saint George's Respiratory Questionnaire (SGRQ) measures the impact of COPD on overall health, daily life, and perceived well-being ranging from 0 (no limitations) to 100 (most limitations). (NCT00793624)
Timeframe: Baseline, Week 48
| Intervention | score on a scale (Least Squares Mean) |
|---|---|
| Placebo | 40.415 |
| Olo 5 mcg qd | 38.545 |
| Olo 10 mcg qd | 36.850 |
| Form 12 mcg | 40.431 |
Saint George's Respiratory Questionnaire (SGRQ) Total Score at 24 Weeks for Combined Analysis
Saint George's Respiratory Questionnaire (SGRQ) measures the impact of COPD on overall health, daily life, and perceived well-being ranging from 0 (no limitations) to 100 (most limitations). This is a combined analysis of the data from NCT00793624 and NCT00796653 showing adjusted values using a MMRM model. (NCT00793624)
Timeframe: Baseline, Week 24
| Intervention | score on a scale (Mean) |
|---|---|
| Placebo | 41.639 |
| Olo 5 mcg qd | 38.794 |
| Olo 10 mcg qd | 38.205 |
| Form 12 mcg | 40.391 |
Saint George's Respiratory Questionnaire (SGRQ) Total Score at 24 Weeks
Saint George's Respiratory Questionnaire (SGRQ) measures the impact of COPD on overall health, daily life, and perceived well-being ranging from 0 (no limitations) to 100 (most limitations). (NCT00793624)
Timeframe: Baseline, Week 24
| Intervention | score on a scale (Least Squares Mean) |
|---|---|
| Placebo | 41.068 |
| Olo 5 mcg qd | 38.627 |
| Olo 10 mcg qd | 37.674 |
| Form 12 mcg | 40.116 |
Saint George's Respiratory Questionnaire (SGRQ) Total Score at 12 Weeks
Saint George's Respiratory Questionnaire (SGRQ) measures the impact of COPD on overall health, daily life, and perceived well-being ranging from 0 (no limitations) to 100 (most limitations). (NCT00793624)
Timeframe: Baseline, Week 12
| Intervention | score on a scale (Least Squares Mean) |
|---|---|
| Placebo | 42.105 |
| Olo 5 mcg qd | 39.320 |
| Olo 10 mcg qd | 36.961 |
| Form 12 mcg | 40.351 |
Peak FVC (0-3h) Response After 6 Weeks
Response was defined as change from baseline. Baseline peak FVC was defined as the mean of the available pre-dose peak FVC values prior to first dose of randomized treatment. Peak FVC (0-3h) values were obtained within 0 - 3 hours after treatment. Means are adjusted using a mixed effects model with treatment (trt), tio stratum, visit, trt-by-visit as fixed categorical effects, baseline and baseline-by-visit as fixed continuous covariates and patient as random effect. (NCT00793624)
Timeframe: 1 hour (h) and 10 minutes (min) prior to dose on the first day of randomized treatment (baseline) to -10 min, 5 min, 15 min, 30 min, 1 h, 2 h, and 3 h relative to dose after 6 weeks
| Intervention | Liter (Least Squares Mean) |
|---|---|
| Placebo | 0.202 |
| Olo 5 mcg qd | 0.411 |
| Olo 10 mcg qd | 0.433 |
| Form 12 mcg | 0.467 |
Peak FEV1 (0-3h) Response After 24 Weeks
Response was defined as change from baseline. Baseline peak FEV1 was defined as the mean of the available pre-dose peak FEV1 values prior to first dose of randomized treatment. Peak FEV1 (0-3h) values were obtained within 0 - 3 hours after treatment. Means are adjusted using a mixed effects model with treatment (trt), tio stratum, visit, trt-by-visit as fixed categorical effects, baseline and baseline-by-visit as fixed continuous covariates and patient as random effect. (NCT00793624)
Timeframe: 1 hour (h) and 10 minutes (min) prior to dose on the first day of randomized treatment (baseline) to -10 min, 5 min, 15 min, 30 min, 1 h, 2 h, and 3 h relative to dose after 24 weeks
| Intervention | Liter (Least Squares Mean) |
|---|---|
| Placebo | 0.068 |
| Olo 5 mcg qd | 0.216 |
| Olo 10 mcg qd | 0.225 |
| Form 12 mcg | 0.236 |
Peak FEV1 (0-3h) Response After 2 Weeks
Response was defined as change from baseline. Baseline peak FEV1 was defined as the mean of the available pre-dose peak FEV1 values prior to first dose of randomized treatment. Peak FEV1 (0-3h) values were obtained within 0 - 3 hours after treatment. Means are adjusted using a mixed effects model with treatment (trt), tio stratum, visit, trt-by-visit as fixed categorical effects, baseline and baseline-by-visit as fixed continuous covariates and patient as random effect. (NCT00793624)
Timeframe: 1 hour (h) and 10 minutes (min) prior to dose on the first day of randomized treatment (baseline) to -10 min, 5 min, 15 min, 30 min, 1 h, 2 h, and 3 h relative to dose after 2 weeks
| Intervention | Liter (Least Squares Mean) |
|---|---|
| Placebo | 0.100 |
| Olo 5 mcg qd | 0.277 |
| Olo 10 mcg qd | 0.250 |
| Form 12 mcg | 0.290 |
Peak FEV1 (0-3h) Response After 12 Weeks
Response was defined as change from baseline. Baseline peak FEV1 was defined as the mean of the available pre-dose peak FEV1 values prior to first dose of randomized treatment. Peak FEV1 (0-3h) values were obtained within 0 - 3 hours after treatment. Means are adjusted using a mixed effects model with treatment (trt), tio stratum, visit, trt-by-visit as fixed categorical effects, baseline and baseline-by-visit as fixed continuous covariates and patient as random effect. (NCT00793624)
Timeframe: 1 hour (h) and 10 minutes (min) prior to dose on the first day of randomized treatment (baseline) to -10 min, 5 min, 15 min, 30 min, 1 h, 2 h, and 3 h relative to dose after 12 weeks
| Intervention | Liter (Least Squares Mean) |
|---|---|
| Placebo | 0.082 |
| Olo 5 mcg qd | 0.247 |
| Olo 10 mcg qd | 0.241 |
| Form 12 mcg | 0.256 |
Patient's Global Rating (PGR) at 6 Weeks
Patient's Global Rating (PGR) was a patient assessment of their health (respiratory condition) at each visit (compared to the day before they started study drug) and ranged from 1 (very much better) to 7 (very much worse). (NCT00793624)
Timeframe: Week 6
| Intervention | score on a scale (Least Squares Mean) |
|---|---|
| Placebo | 3.4 |
| Olo 5 mcg qd | 3.0 |
| Olo 10 mcg qd | 3.1 |
| Form 12 mcg | 3.1 |
Patient's Global Rating (PGR) at 48 Weeks
Patient's Global Rating (PGR) was a patient assessment of their health (respiratory condition) at each visit (compared to the day before they started study drug) and ranged from 1 (very much better) to 7 (very much worse). (NCT00793624)
Timeframe: Week 48
| Intervention | score on a scale (Least Squares Mean) |
|---|---|
| Placebo | 3.1 |
| Olo 5 mcg qd | 3.0 |
| Olo 10 mcg qd | 2.9 |
| Form 12 mcg | 2.9 |
Patient's Global Rating (PGR) at 24 Weeks
Patient's Global Rating (PGR) was a patient assessment of their health (respiratory condition) at each visit (compared to the day before they started study drug) and ranged from 1 (very much better) to 7 (very much worse). (NCT00793624)
Timeframe: Week 24
| Intervention | score on a scale (Least Squares Mean) |
|---|---|
| Placebo | 3.1 |
| Olo 5 mcg qd | 2.9 |
| Olo 10 mcg qd | 2.9 |
| Form 12 mcg | 3.0 |
Patient's Global Rating (PGR) at 12 Weeks
Patient's Global Rating (PGR) was a patient assessment of their health (respiratory condition) at each visit (compared to the day before they started study drug) and ranged from 1 (very much better) to 7 (very much worse). (NCT00793624)
Timeframe: Week 12
| Intervention | score on a scale (Least Squares Mean) |
|---|---|
| Placebo | 3.3 |
| Olo 5 mcg qd | 3.0 |
| Olo 10 mcg qd | 2.9 |
| Form 12 mcg | 3.0 |
Number of Moderate Chronic Obstructive Pulmonary Disease (CPOD) Exacerbations
Qualifying events of COPD were specifically pre-defined in the protocol. Other respiratory related events were evaluated by the investigator to see if they met the pre-defined criteria. These exacerbations did not lead to hospitalization but included treatment with antibiotics and/or systemic steroids. (NCT00793624)
Timeframe: Baseline to end of study at 48 weeks.
| Intervention | Number of COPD ex. per patient year (Mean) |
|---|---|
| Placebo | 0.4765 |
| Olo 5 mcg qd | 0.5537 |
| Olo 10 mcg qd | 0.5114 |
| Form 12 mcg | 0.3721 |
Number of COPD Exacerbations Requiring Hospitalization
Qualifying events of COPD were specifically pre-defined in the protocol. Other respiratory related events were evaluated by the investigator to see if they met the pre-defined criteria. These exacerbations required hospitalization. (NCT00793624)
Timeframe: Baseline to end of study at week 48 visit
| Intervention | Number of COPD ex. per patient year (Mean) |
|---|---|
| Placebo | 0.0554 |
| Olo 5 mcg qd | 0.1043 |
| Olo 10 mcg qd | 0.1324 |
| Form 12 mcg | 0.0570 |
Number of COPD Exacerbations
Qualifying events of COPD were specifically pre-defined in the protocol. Other respiratory related events were evaluated by the investigator to see if they met the pre-defined criteria. (NCT00793624)
Timeframe: Baseline to end of study at week 48 visit
| Intervention | Number of COPD ex. per patient year (Mean) |
|---|---|
| Placebo | 0.5684 |
| Olo 5 mcg qd | 0.7117 |
| Olo 10 mcg qd | 0.6946 |
| Form 12 mcg | 0.5098 |
Mahler Transitional Dyspnea Index Focal Score at 6 Weeks
Mahler Transitional Dyspnea Index (TDI) focal score measures 3 components of dyspnea that evoke dyspnea in daily living: Functional Impairment, Magnitude of Task, and Magnitude of Effort. The TDI measures the change from the baseline assessment ranging from -9 (most deterioration) to +9 (most improvement). (NCT00793624)
Timeframe: Baseline, Week 6
| Intervention | score on a scale (Least Squares Mean) |
|---|---|
| Placebo | 0.995 |
| Olo 5 mcg qd | 1.566 |
| Olo 10 mcg qd | 1.660 |
| Form 12 mcg | 1.753 |
Mahler Transitional Dyspnea Index Focal Score at 48 Weeks
Mahler Transitional Dyspnea Index (TDI) focal score measures 3 components of dyspnea that evoke dyspnea in daily living: Functional Impairment, Magnitude of Task, and Magnitude of Effort. The TDI measures the change from the baseline assessment ranging from -9 (most deterioration) to +9 (most improvement). (NCT00793624)
Timeframe: Baseline, Week 48
| Intervention | score on a scale (Least Squares Mean) |
|---|---|
| Placebo | 1.940 |
| Olo 5 mcg qd | 2.035 |
| Olo 10 mcg qd | 2.324 |
| Form 12 mcg | 2.047 |
Mahler Transitional Dyspnea Index Focal Score at 40 Weeks
Mahler Transitional Dyspnea Index (TDI) focal score measures 3 components of dyspnea that evoke dyspnea in daily living: Functional Impairment, Magnitude of Task, and Magnitude of Effort. The TDI measures the change from the baseline assessment ranging from -9 (most deterioration) to +9 (most improvement). (NCT00793624)
Timeframe: Baseline, Week 40
| Intervention | score on a scale (Least Squares Mean) |
|---|---|
| Placebo | 1.952 |
| Olo 5 mcg qd | 1.839 |
| Olo 10 mcg qd | 1.887 |
| Form 12 mcg | 1.575 |
Mahler Transitional Dyspnea Index Focal Score at 32 Weeks
Mahler Transitional Dyspnea Index (TDI) focal score measures 3 components of dyspnea that evoke dyspnea in daily living: Functional Impairment, Magnitude of Task, and Magnitude of Effort. The TDI measures the change from the baseline assessment ranging from -9 (most deterioration) to +9 (most improvement). (NCT00793624)
Timeframe: Baseline, Week 32
| Intervention | score on a scale (Least Squares Mean) |
|---|---|
| Placebo | 1.732 |
| Olo 5 mcg qd | 1.898 |
| Olo 10 mcg qd | 1.698 |
| Form 12 mcg | 1.966 |
Peak FVC (0-3h) Response After 48 Weeks
Response was defined as change from baseline. Baseline peak FVC was defined as the mean of the available pre-dose peak FVC values prior to first dose of randomized treatment. Peak FVC (0-3h) values were obtained within 0 - 3 hours after treatment. Means are adjusted using a mixed effects model with treatment (trt), tio stratum, visit, trt-by-visit as fixed categorical effects, baseline and baseline-by-visit as fixed continuous covariates and patient as random effect. (NCT00793624)
Timeframe: 1 hour (h) and 10 minutes (min) prior to dose on the first day of randomized treatment (baseline) to -10 min, 5 min, 15 min, 30 min, 1 h, 2 h, and 3 h relative to dose after 48 weeks
| Intervention | Liter (Least Squares Mean) |
|---|---|
| Placebo | 0.193 |
| Olo 5 mcg qd | 0.344 |
| Olo 10 mcg qd | 0.371 |
| Form 12 mcg | 0.416 |
Mahler Transitional Dyspnea Index Focal Score at 24 Weeks for Combined Analysis
This outcome measure describes the combined analysis of the trials NCT00793624 and NCT00796653. Mahler Transitional Dyspnea Index (TDI) focal score measures 3 components of dyspnea that evoke dyspnea in daily living: Functional Impairment, Magnitude of Task, and Magnitude of Effort. The TDI measures the change from the baseline assessment ranging from -9 (most deterioration) to +9 (most improvement). (NCT00793624)
Timeframe: Baseline, Week 24
| Intervention | score on a scale (Mean) |
|---|---|
| Placebo | 1.471 |
| Olo 5 mcg qd | 1.980 |
| Olo 10 mcg qd | 1.996 |
| Form 12 mcg | 1.827 |
Mahler Transitional Dyspnea Index Focal Score at 24 Weeks
Mahler Transitional Dyspnea Index (TDI) focal score measures 3 components of dyspnea that evoke dyspnea in daily living: Functional Impairment, Magnitude of Task, and Magnitude of Effort. The TDI measures the change from the baseline assessment ranging from -9 (most deterioration) to +9 (most improvement). (NCT00793624)
Timeframe: Baseline, Week 24
| Intervention | score on a scale (Least Squares Mean) |
|---|---|
| Placebo | 2.046 |
| Olo 5 mcg qd | 2.234 |
| Olo 10 mcg qd | 2.068 |
| Form 12 mcg | 1.818 |
Mahler Transitional Dyspnea Index Focal Score at 18 Weeks
Mahler Transitional Dyspnea Index (TDI) focal score measures 3 components of dyspnea that evoke dyspnea in daily living: Functional Impairment, Magnitude of Task, and Magnitude of Effort. The TDI measures the change from the baseline assessment ranging from -9 (most deterioration) to +9 (most improvement). (NCT00793624)
Timeframe: Baseline, Week 18
| Intervention | score on a scale (Least Squares Mean) |
|---|---|
| Placebo | 1.665 |
| Olo 5 mcg qd | 1.897 |
| Olo 10 mcg qd | 2.099 |
| Form 12 mcg | 1.689 |
Forced Vital Capacity (FVC) Area Under Curve 0-3 Hour (h) (AUC 0-3h) Response at 2 Weeks
Response was defined as change from baseline. Baseline FVC was defined as the mean of the -1 h and -10 min measurements performed just prior to administration of the first am dose of randomized treatment. Means are adjusted using a mixed effects model with treatment (trt), tio stratum, visit, trt-by-visit interaction as fixed categorical effects, baseline and baseline-by-visit interaction as fixed continuous covariates and patient as random effect. 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. (NCT00793624)
Timeframe: 1 hour (h) and 10 minutes (min) prior to dose on the first day of randomized treatment (baseline) to -10 min, 5 min, 15 min, 30 min, 1 h, 2 h, and 3 h relative to dose on Week 2
| Intervention | Liter (Least Squares Mean) |
|---|---|
| Placebo | 0.076 |
| Olo 5 mcg qd | 0.299 |
| Olo 10 mcg qd | 0.311 |
| Form 12 mcg | 0.383 |
Mahler Transitional Dyspnea Index Focal Score at 12 Weeks
Mahler Transitional Dyspnea Index (TDI) focal score measures 3 components of dyspnea that evoke dyspnea in daily living: Functional Impairment, Magnitude of Task, and Magnitude of Effort. The TDI measures the change from the baseline assessment ranging from -9 (most deterioration) to +9 (most improvement). (NCT00793624)
Timeframe: Baseline, Week 12
| Intervention | score on a scale (Least Squares Mean) |
|---|---|
| Placebo | 1.412 |
| Olo 5 mcg qd | 1.792 |
| Olo 10 mcg qd | 1.955 |
| Form 12 mcg | 1.805 |
Forced Vital Capacity (FVC) Area Under Curve 0-3 Hour (h) (AUC 0-3h) Response at 6 Weeks
Response was defined as change from baseline. Baseline FVC was defined as the mean of the -1 h and -10 min measurements performed just prior to administration of the first am dose of randomized treatment. Means are adjusted using a mixed effects model with treatment (trt), tio stratum, visit, trt-by-visit interaction as fixed categorical effects, baseline and baseline-by-visit interaction as fixed continuous covariates and patient as random effect. 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. (NCT00793624)
Timeframe: 1 hour (h) and 10 minutes (min) prior to dose on the first day of randomized treatment (baseline) to -10 min, 5 min, 15 min, 30 min, 1 h, 2 h, and 3 h relative to dose on Week 6
| Intervention | Liter (Least Squares Mean) |
|---|---|
| Placebo | 0.016 |
| Olo 5 mcg qd | 0.252 |
| Olo 10 mcg qd | 0.265 |
| Form 12 mcg | 0.326 |
Forced Vital Capacity (FVC) Area Under Curve 0-3 Hour (h) (AUC 0-3h) Response at 48 Weeks
Response was defined as change from baseline. Baseline FVC was defined as the mean of the -1 h and -10 min measurements performed just prior to administration of the first am dose of randomized treatment. Means are adjusted using a mixed effects model with treatment (trt), tio stratum, visit, trt-by-visit interaction as fixed categorical effects, baseline and baseline-by-visit interaction as fixed continuous covariates and patient as random effect. 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. (NCT00793624)
Timeframe: 1 hour (h) and 10 minutes (min) prior to dose on the first day of randomized treatment (baseline) to -10 min, 5 min, 15 min, 30 min, 1 h, 2 h, and 3 h relative to dose on Week 48
| Intervention | Liter (Least Squares Mean) |
|---|---|
| Placebo | 0.016 |
| Olo 5 mcg qd | 0.196 |
| Olo 10 mcg qd | 0.219 |
| Form 12 mcg | 0.260 |
Peak FVC (0-3h) Response After 24 Weeks
Response was defined as change from baseline. Baseline peak FVC was defined as the mean of the available pre-dose peak FVC values prior to first dose of randomized treatment. Peak FVC (0-3h) values were obtained within 0 - 3 hours after treatment. Means are adjusted using a mixed effects model with treatment (trt), tio stratum, visit, trt-by-visit as fixed categorical effects, baseline and baseline-by-visit as fixed continuous covariates and patient as random effect. (NCT00793624)
Timeframe: 1 hour (h) and 10 minutes (min) prior to dose on the first day of randomized treatment (baseline) to -10 min, 5 min, 15 min, 30 min, 1 h, 2 h, and 3 h relative to dose after 24 weeks
| Intervention | Liter (Least Squares Mean) |
|---|---|
| Placebo | 0.207 |
| Olo 5 mcg qd | 0.379 |
| Olo 10 mcg qd | 0.414 |
| Form 12 mcg | 0.424 |
Peak FVC (0-3h) Response After 2 Weeks
Response was defined as change from baseline. Baseline peak FVC was defined as the mean of the available pre-dose peak FVC values prior to first dose of randomized treatment. Peak FVC (0-3h) values were obtained within 0 - 3 hours after treatment. Means are adjusted using a mixed effects model with treatment (trt), tio stratum, visit, trt-by-visit as fixed categorical effects, baseline and baseline-by-visit as fixed continuous covariates and patient as random effect. (NCT00793624)
Timeframe: 1 hour (h) and 10 minutes (min) prior to dose on the first day of randomized treatment (baseline) to -10 min, 5 min, 15 min, 30 min, 1 h, 2 h, and 3 h relative to dose after 2 weeks
| Intervention | Liter (Least Squares Mean) |
|---|---|
| Placebo | 0.268 |
| Olo 5 mcg qd | 0.454 |
| Olo 10 mcg qd | 0.474 |
| Form 12 mcg | 0.551 |
Peak FVC (0-3h) Response After 12 Weeks
Response was defined as change from baseline. Baseline peak FVC was defined as the mean of the available pre-dose peak FVC values prior to first dose of randomized treatment. Peak FVC (0-3h) values were obtained within 0 - 3 hours after treatment. Means are adjusted using a mixed effects model with treatment (trt), tio stratum, visit, trt-by-visit as fixed categorical effects, baseline and baseline-by-visit as fixed continuous covariates and patient as random effect. (NCT00793624)
Timeframe: 1 hour (h) and 10 minutes (min) prior to dose on the first day of randomized treatment (baseline) to -10 min, 5 min, 15 min, 30 min, 1 h, 2 h, and 3 h relative to dose after 12 weeks
| Intervention | Liter (Least Squares Mean) |
|---|---|
| Placebo | 0.194 |
| Olo 5 mcg qd | 0.382 |
| Olo 10 mcg qd | 0.432 |
| Form 12 mcg | 0.450 |
Peak FEV1 (0-3h) Response After 6 Weeks
Response was defined as change from baseline. Baseline peak FEV1 was defined as the mean of the available pre-dose peak FEV1 values prior to first dose of randomized treatment. Peak FEV1 (0-3h) values were obtained within 0 - 3 hours after treatment. Means are adjusted using a mixed effects model with treatment (trt), tio stratum, visit, trt-by-visit as fixed categorical effects, baseline and baseline-by-visit as fixed continuous covariates and patient as random effect. (NCT00793624)
Timeframe: 1 hour (h) and 10 minutes (min) prior to dose on the first day of randomized treatment (baseline) to -10 min, 5 min, 15 min, 30 min, 1 h, 2 h, and 3 h relative to dose after 6 weeks
| Intervention | Liter (Least Squares Mean) |
|---|---|
| Placebo | 0.081 |
| Olo 5 mcg qd | 0.248 |
| Olo 10 mcg qd | 0.234 |
| Form 12 mcg | 0.264 |
Peak FEV1 (0-3h) Response After 48 Weeks
Response was defined as change from baseline. Baseline peak FEV1 was defined as the mean of the available pre-dose peak FEV1 values prior to first dose of randomized treatment. Peak FEV1 (0-3h) values were obtained within 0 - 3 hours after treatment. Means are adjusted using a mixed effects model with treatment (trt), tio stratum, visit, trt-by-visit as fixed categorical effects, baseline and baseline-by-visit as fixed continuous covariates and patient as random effect. (NCT00793624)
Timeframe: 1 hour (h) and 10 minutes (min) prior to dose on the first day of randomized treatment (baseline) to -10 min, 5 min, 15 min, 30 min, 1 h, 2 h, and 3 h relative to dose after 48 weeks
| Intervention | Liter (Least Squares Mean) |
|---|---|
| Placebo | 0.053 |
| Olo 5 mcg qd | 0.192 |
| Olo 10 mcg qd | 0.193 |
| Form 12 mcg | 0.215 |
Forced Expiratory Volume in One Second (FEV1) Area Under Curve 0-3 Hour (h) (AUC 0-3h) Response at 6 Weeks
Response was defined as change from baseline. Baseline FEV1 was defined as the mean of the -1 h and -10 min measurements performed just prior to administration of the first am dose of randomized treatment. Means are adjusted using a mixed effects model with treatment (trt), tio stratum, visit, trt-by-visit interaction as fixed categorical effects, baseline and baseline-by-visit interaction as fixed continuous covariates and patient as random effect. 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. (NCT00793624)
Timeframe: 1 hour (h) and 10 minutes (min) prior to dose on the first day of randomized treatment (baseline) to -10 min, 5 min, 15 min, 30 min, 1 h, 2 h, and 3 h relative to dose on Week 6
| Intervention | Liter (Least Squares Mean) |
|---|---|
| Placebo | 0.001 |
| Olo 5 mcg qd | 0.178 |
| Olo 10 mcg qd | 0.161 |
| Form 12 mcg | 0.194 |
Forced Vital Capacity (FVC) Area Under Curve 0-3 Hour (h) (AUC 0-3h) Response at 12 Weeks
Response was defined as change from baseline. Baseline FVC was defined as the mean of the -1 h and -10 min measurements performed just prior to administration of the first am dose of randomized treatment. Means are adjusted using a mixed effects model with treatment (trt), tio stratum, visit, trt-by-visit interaction as fixed categorical effects, baseline and baseline-by-visit interaction as fixed continuous covariates and patient as random effect. 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. (NCT00793624)
Timeframe: 1 hour (h) and 10 minutes (min) prior to dose on the first day of randomized treatment (baseline) to -10 min, 5 min, 15 min, 30 min, 1 h, 2 h, and 3 h relative to dose on Week 12
| Intervention | Liter (Least Squares Mean) |
|---|---|
| Placebo | 0.023 |
| Olo 5 mcg qd | 0.233 |
| Olo 10 mcg qd | 0.278 |
| Form 12 mcg | 0.300 |
Forced Vital Capacity (FVC) Area Under Curve 0-3 Hour (h) (AUC 0-3h) Response at 24 Weeks
Response was defined as change from baseline. Baseline FVC was defined as the mean of the -1 h and -10 min measurements performed just prior to administration of the first am dose of randomized treatment. Means are adjusted using a mixed effects model with treatment (trt), tio stratum, visit, trt-by-visit interaction as fixed categorical effects, baseline and baseline-by-visit interaction as fixed continuous covariates and patient as random effect. 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. (NCT00793624)
Timeframe: 1 hour (h) and 10 minutes (min) prior to dose on the first day of randomized treatment (baseline) to -10 min, 5 min, 15 min, 30 min, 1 h, 2 h, and 3 h relative to dose on Week 24
| Intervention | Liter (Least Squares Mean) |
|---|---|
| Placebo | 0.037 |
| Olo 5 mcg qd | 0.220 |
| Olo 10 mcg qd | 0.252 |
| Form 12 mcg | 0.279 |
Forced Expiratory Volume in One Second (FEV1) Area Under Curve 0-3 Hour (h) (AUC 0-3h) Response at 2 Weeks
Response was defined as change from baseline. Baseline FEV1 was defined as the mean of the -1 h and -10 min measurements performed just prior to administration of the first am dose of randomized treatment. Means are adjusted using a mixed effects model with treatment (trt), tio stratum, visit, trt-by-visit interaction as fixed categorical effects, baseline and baseline-by-visit interaction as fixed continuous covariates and patient as random effect. 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. (NCT00796653)
Timeframe: 1 hour (h) and 10 minutes (min) prior to dose on the first day of randomized treatment (baseline) to -10 min, 5 min, 15 min, 30 min, 1 h, 2 h, and 3 h relative to dose on Week 2
| Intervention | Liter (Least Squares Mean) |
|---|---|
| Placebo | 0.021 |
| Olo 5 mcg qd | 0.181 |
| Olo 10 mcg qd | 0.214 |
| Form 12 mcg | 0.183 |
Forced Expiratory Volume in One Second (FEV1) Area Under Curve 0-3 Hour (h) (AUC 0-3h) Response at 24 Weeks
Response was defined as change from baseline. Baseline FEV1 was defined as the mean of the -1 h and -10 min measurements performed just prior to administration of the first am dose of randomized treatment. Means are adjusted using a mixed effects model with treatment (trt), tio stratum, visit, trt-by-visit interaction as fixed categorical effects, baseline and baseline-by-visit interaction as fixed continuous covariates and patient as random effect. 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. (NCT00796653)
Timeframe: 1 hour (h) and 10 minutes (min) prior to dose on the first day of randomized treatment (baseline) to -10 min, 5 min, 15 min, 30 min, 1 h, 2 h, and 3 h relative to dose on Week 24
| Intervention | Liter (Least Squares Mean) |
|---|---|
| Placebo | -0.013 |
| Olo 5 mcg qd | 0.116 |
| Olo 10 mcg qd | 0.140 |
| Form 12 mcg | 0.137 |
Forced Expiratory Volume in One Second (FEV1) Area Under Curve 0-3 Hour (h) (AUC 0-3h) Response at 48 Weeks
Response was defined as change from baseline. Baseline FEV1 was defined as the mean of the -1 h and -10 min measurements performed just prior to administration of the first am dose of randomized treatment. Means are adjusted using a mixed effects model with treatment (trt), tio stratum, visit, trt-by-visit interaction as fixed categorical effects, baseline and baseline-by-visit interaction as fixed continuous covariates and patient as random effect. 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. (NCT00796653)
Timeframe: 1 hour (h) and 10 minutes (min) prior to dose on the first day of randomized treatment (baseline) to -10 min, 5 min, 15 min, 30 min, 1 h, 2 h, and 3 h relative to dose on Week 48
| Intervention | Liter (Least Squares Mean) |
|---|---|
| Placebo | -0.025 |
| Olo 5 mcg qd | 0.093 |
| Olo 10 mcg qd | 0.116 |
| Form 12 mcg | 0.104 |
Forced Expiratory Volume in One Second (FEV1) Area Under Curve 0-3 Hour (h) (AUC 0-3h) Response at 6 Weeks
Response was defined as change from baseline. Baseline FEV1 was defined as the mean of the -1 h and -10 min measurements performed just prior to administration of the first am dose of randomized treatment. Means are adjusted using a mixed effects model with treatment (trt), tio stratum, visit, trt-by-visit interaction as fixed categorical effects, baseline and baseline-by-visit interaction as fixed continuous covariates and patient as random effect. 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. (NCT00796653)
Timeframe: 1 hour (h) and 10 minutes (min) prior to dose on the first day of randomized treatment (baseline) to -10 min, 5 min, 15 min, 30 min, 1 h, 2 h, and 3 h relative to dose on Week 6
| Intervention | Liter (Least Squares Mean) |
|---|---|
| Placebo | -0.010 |
| Olo 5 mcg qd | 0.162 |
| Olo 10 mcg qd | 0.181 |
| Form 12 mcg | 0.174 |
Forced Vital Capacity (FVC) Area Under Curve 0-3 Hour (h) (AUC 0-3h) Response at 12 Weeks
Response was defined as change from baseline. Baseline FVC was defined as the mean of the -1 h and -10 min measurements performed just prior to administration of the first am dose of randomized treatment. Means are adjusted using a mixed effects model with treatment (trt), tio stratum, visit, trt-by-visit interaction as fixed categorical effects, baseline and baseline-by-visit interaction as fixed continuous covariates and patient as random effect. 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. (NCT00796653)
Timeframe: 1 hour (h) and 10 minutes (min) prior to dose on the first day of randomized treatment (baseline) to -10 min, 5 min, 15 min, 30 min, 1 h, 2 h, and 3 h relative to dose on Week 12
| Intervention | Liter (Least Squares Mean) |
|---|---|
| Placebo | 0.006 |
| Olo 5 mcg qd | 0.235 |
| Olo 10 mcg qd | 0.253 |
| Form 12 mcg | 0.280 |
Forced Vital Capacity (FVC) Area Under Curve 0-3 Hour (h) (AUC 0-3h) Response at 24 Weeks
Response was defined as change from baseline. Baseline FVC was defined as the mean of the -1 h and -10 min measurements performed just prior to administration of the first am dose of randomized treatment. Means are adjusted using a mixed effects model with treatment (trt), tio stratum, visit, trt-by-visit interaction as fixed categorical effects, baseline and baseline-by-visit interaction as fixed continuous covariates and patient as random effect. 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. (NCT00796653)
Timeframe: 1 hour (h) and 10 minutes (min) prior to dose on the first day of randomized treatment (baseline) to -10 min, 5 min, 15 min, 30 min, 1 h, 2 h, and 3 h relative to dose on Week 24
| Intervention | Liter (Least Squares Mean) |
|---|---|
| Placebo | 0.012 |
| Olo 5 mcg qd | 0.212 |
| Olo 10 mcg qd | 0.225 |
| Form 12 mcg | 0.253 |
Forced Vital Capacity (FVC) Area Under Curve 0-3 Hour (h) (AUC 0-3h) Response at 48 Weeks
Response was defined as change from baseline. Baseline FVC was defined as the mean of the -1 h and -10 min measurements performed just prior to administration of the first am dose of randomized treatment. Means are adjusted using a mixed effects model with treatment (trt), tio stratum, visit, trt-by-visit interaction as fixed categorical effects, baseline and baseline-by-visit interaction as fixed continuous covariates and patient as random effect. 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. (NCT00796653)
Timeframe: 1 hour (h) and 10 minutes (min) prior to dose on the first day of randomized treatment (baseline) to -10 min, 5 min, 15 min, 30 min, 1 h, 2 h, and 3 h relative to dose on Week 48
| Intervention | Liter (Least Squares Mean) |
|---|---|
| Placebo | -0.036 |
| Olo 5 mcg qd | 0.182 |
| Olo 10 mcg qd | 0.201 |
| Form 12 mcg | 0.184 |
Forced Vital Capacity (FVC) Area Under Curve 0-3 Hour (h) (AUC 0-3h) Response at 6 Weeks
Response was defined as change from baseline. Baseline FVC was defined as the mean of the -1 h and -10 min measurements performed just prior to administration of the first am dose of randomized treatment. Means are adjusted using a mixed effects model with treatment (trt), tio stratum, visit, trt-by-visit interaction as fixed categorical effects, baseline and baseline-by-visit interaction as fixed continuous covariates and patient as random effect. 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. (NCT00796653)
Timeframe: 1 hour (h) and 10 minutes (min) prior to dose on the first day of randomized treatment (baseline) to -10 min, 5 min, 15 min, 30 min, 1 h, 2 h, and 3 h relative to dose on Week 6
| Intervention | Liter (Least Squares Mean) |
|---|---|
| Placebo | 0.027 |
| Olo 5 mcg qd | 0.277 |
| Olo 10 mcg qd | 0.276 |
| Form 12 mcg | 0.307 |
Mahler Transitional Dyspnea Index Focal Score at 12 Weeks
Mahler Transitional Dyspnea Index (TDI) focal score measures 3 components of dyspnea that evoke dyspnea in daily living: Functional Impairment, Magnitude of Task, and Magnitude of Effort. The TDI measures the change from the baseline assessment ranging from -9 (most deterioration) to +9 (most improvement). (NCT00796653)
Timeframe: Baseline, Week 12
| Intervention | score on a scale (Least Squares Mean) |
|---|---|
| Placebo | 1.080 |
| Olo 5 mcg qd | 1.742 |
| Olo 10 mcg qd | 1.747 |
| Form 12 mcg | 1.499 |
Mahler Transitional Dyspnea Index Focal Score at 18 Weeks
Mahler Transitional Dyspnea Index (TDI) focal score measures 3 components of dyspnea that evoke dyspnea in daily living: Functional Impairment, Magnitude of Task, and Magnitude of Effort. The TDI measures the change from the baseline assessment ranging from -9 (most deterioration) to +9 (most improvement). (NCT00796653)
Timeframe: Baseline, Week 18
| Intervention | score on a scale (Least Squares Mean) |
|---|---|
| Placebo | 1.0454 |
| Olo 5 mcg qd | 1.470 |
| Olo 10 mcg qd | 1.537 |
| Form 12 mcg | 1.579 |
Mahler Transitional Dyspnea Index Focal Score at 24 Weeks
Mahler Transitional Dyspnea Index (TDI) focal score measures 3 components of dyspnea that evoke dyspnea in daily living: Functional Impairment, Magnitude of Task, and Magnitude of Effort. The TDI measures the change from the baseline assessment ranging from -9 (most deterioration) to +9 (most improvement). (NCT00796653)
Timeframe: Baseline, Week 24
| Intervention | score on a scale (Least Squares Mean) |
|---|---|
| Placebo | 1.102 |
| Olo 5 mcg qd | 1.504 |
| Olo 10 mcg qd | 1.521 |
| Form 12 mcg | 1.703 |
Mahler Transitional Dyspnea Index Focal Score at 24 Weeks for Combined Analysis
This outcome measure describes the combined analysis of the trials NCT00793624 and NCT00796653. Mahler Transitional Dyspnea Index (TDI) focal score measures 3 components of dyspnea that evoke dyspnea in daily living: Functional Impairment, Magnitude of Task, and Magnitude of Effort. The TDI measures the change from the baseline assessment ranging from -9 (most deterioration) to +9 (most improvement). (NCT00796653)
Timeframe: Baseline, Week 24
| Intervention | score on a scale (Mean) |
|---|---|
| Placebo | 1.471 |
| Olo 5 mcg qd | 1.980 |
| Olo 10 mcg qd | 1.996 |
| Form 12 mcg | 1.827 |
Mahler Transitional Dyspnea Index Focal Score at 32 Weeks
Mahler Transitional Dyspnea Index (TDI) focal score measures 3 components of dyspnea that evoke dyspnea in daily living: Functional Impairment, Magnitude of Task, and Magnitude of Effort. The TDI measures the change from the baseline assessment ranging from -9 (most deterioration) to +9 (most improvement). (NCT00796653)
Timeframe: Baseline, Week 32
| Intervention | score on a scale (Least Squares Mean) |
|---|---|
| Placebo | 1.168 |
| Olo 5 mcg qd | 1.658 |
| Olo 10 mcg qd | 1.522 |
| Form 12 mcg | 1.477 |
Mahler Transitional Dyspnea Index Focal Score at 40 Weeks
Mahler Transitional Dyspnea Index (TDI) focal score measures 3 components of dyspnea that evoke dyspnea in daily living: Functional Impairment, Magnitude of Task, and Magnitude of Effort. The TDI measures the change from the baseline assessment ranging from -9 (most deterioration) to +9 (most improvement). (NCT00796653)
Timeframe: Baseline, Week 40
| Intervention | score on a scale (Least Squares Mean) |
|---|---|
| Placebo | 1.064 |
| Olo 5 mcg qd | 1.377 |
| Olo 10 mcg qd | 1.545 |
| Form 12 mcg | 1.178 |
Mahler Transitional Dyspnea Index Focal Score at 48 Weeks
Mahler Transitional Dyspnea Index (TDI) focal score measures 3 components of dyspnea that evoke dyspnea in daily living: Functional Impairment, Magnitude of Task, and Magnitude of Effort. The TDI measures the change from the baseline assessment ranging from -9 (most deterioration) to +9 (most improvement). (NCT00796653)
Timeframe: Baseline, Week 48
| Intervention | score on a scale (Least Squares Mean) |
|---|---|
| Placebo | 1.113 |
| Olo 5 mcg qd | 1.510 |
| Olo 10 mcg qd | 1.831 |
| Form 12 mcg | 1.280 |
Mahler Transitional Dyspnea Index Focal Score at 6 Weeks
Mahler Transitional Dyspnea Index (TDI) focal score measures 3 components of dyspnea that evoke dyspnea in daily living: Functional Impairment, Magnitude of Task, and Magnitude of Effort. The TDI measures the change from the baseline assessment ranging from -9 (most deterioration) to +9 (most improvement). (NCT00796653)
Timeframe: Baseline, Week 6
| Intervention | score on a scale (Least Squares Mean) |
|---|---|
| Placebo | 0.980 |
| Olo 5 mcg qd | 1.417 |
| Olo 10 mcg qd | 1.686 |
| Form 12 mcg | 1.444 |
Number of COPD Exacerbations
Qualifying events of COPD were specifically pre-defined in the protocol. Other respiratory related events were evaluated by the investigator to see if they met the pre-defined criteria. (NCT00796653)
Timeframe: Baseline to end of study at week 48 visit
| Intervention | Number of COPD ex. per patient year (Mean) |
|---|---|
| Placebo | 0.6890 |
| Olo 5 mcg qd | 0.5409 |
| Olo 10 mcg qd | 0.5947 |
| Form 12 mcg | 0.7325 |
Number of COPD Exacerbations Requiring Hospitalization
Qualifying events of COPD were specifically pre-defined in the protocol. Other respiratory related events were evaluated by the investigator to see if they met the pre-defined criteria. These exacerbations required hospitalization. (NCT00796653)
Timeframe: Baseline to end of study at week 48 visit
| Intervention | Number of COPD ex. per patient year (Mean) |
|---|---|
| Placebo | 0.0986 |
| Olo 5 mcg qd | 0.0781 |
| Olo 10 mcg qd | 0.0993 |
| Form 12 mcg | 0.1025 |
Number of Moderate Chronic Obstructive Pulmonary Disease (CPOD) Exacerbations
Qualifying events of COPD were specifically pre-defined in the protocol. Other respiratory related events were evaluated by the investigator to see if they met the pre-defined criteria. These exacerbations did not lead to hospitalization but included treatment with antibiotics and/or systemic steroids. (NCT00796653)
Timeframe: Baseline to end of study at 48 weeks.
| Intervention | Number of COPD ex. per patient year (Mean) |
|---|---|
| Placebo | 0.5548 |
| Olo 5 mcg qd | 0.4128 |
| Olo 10 mcg qd | 0.4351 |
| Form 12 mcg | 0.5415 |
Patient's Global Rating (PGR) at 12 Weeks
Patient's Global Rating (PGR) was a patient assessment of their health (respiratory condition) at each visit (compared to the day before they started study drug) and ranged from 1 (very much better) to 7 (very much worse). (NCT00796653)
Timeframe: Week 12
| Intervention | score on a scale (Least Squares Mean) |
|---|---|
| Placebo | 3.3 |
| Olo 5 mcg qd | 3.1 |
| Olo 10 mcg qd | 3.0 |
| Form 12 mcg | 3.0 |
Patient's Global Rating (PGR) at 24 Weeks
Patient's Global Rating (PGR) was a patient assessment of their health (respiratory condition) at each visit (compared to the day before they started study drug) and ranged from 1 (very much better) to 7 (very much worse). (NCT00796653)
Timeframe: Week 24
| Intervention | score on a scale (Least Squares Mean) |
|---|---|
| Placebo | 3.3 |
| Olo 5 mcg qd | 3.1 |
| Olo 10 mcg qd | 3.1 |
| Form 12 mcg | 3.1 |
Patient's Global Rating (PGR) at 48 Weeks
Patient's Global Rating (PGR) was a patient assessment of their health (respiratory condition) at each visit (compared to the day before they started study drug) and ranged from 1 (very much better) to 7 (very much worse). (NCT00796653)
Timeframe: Week 48
| Intervention | score on a scale (Least Squares Mean) |
|---|---|
| Placebo | 3.2 |
| Olo 5 mcg qd | 3.2 |
| Olo 10 mcg qd | 3.0 |
| Form 12 mcg | 3.2 |
Patient's Global Rating (PGR) at 6 Weeks
Patient's Global Rating (PGR) was a patient assessment of their health (respiratory condition) at each visit (compared to the day before they started study drug) and ranged from 1 (very much better) to 7 (very much worse). (NCT00796653)
Timeframe: Week 6
| Intervention | score on a scale (Least Squares Mean) |
|---|---|
| Placebo | 3.4 |
| Olo 5 mcg qd | 3.1 |
| Olo 10 mcg qd | 3.2 |
| Form 12 mcg | 3.1 |
Peak FEV1 (0-3h) Response After 12 Weeks
Response was defined as change from baseline. Baseline peak FEV1 was defined as the mean of the available pre-dose peak FEV1 values prior to first dose of randomized treatment. Peak FEV1 (0-3h) values were obtained within 0 - 3 hours after treatment. Means are adjusted using a mixed effects model with treatment (trt), tio stratum, visit, trt-by-visit as fixed categorical effects, baseline and baseline-by-visit as fixed continuous covariates and patient as random effect. (NCT00796653)
Timeframe: 1 hour (h) and 10 minutes (min) prior to dose on the first day of randomized treatment (baseline) to -10 min, 5 min, 15 min, 30 min, 1 h, 2 h, and 3 h relative to dose after 12 weeks
| Intervention | Liter (Least Squares Mean) |
|---|---|
| Placebo | 0.064 |
| Olo 5 mcg qd | 0.206 |
| Olo 10 mcg qd | 0.232 |
| Form 12 mcg | 0.228 |
Peak FEV1 (0-3h) Response After 2 Weeks
Response was defined as change from baseline. Baseline peak FEV1 was defined as the mean of the available pre-dose peak FEV1 values prior to first dose of randomized treatment. Peak FEV1 (0-3h) values were obtained within 0 - 3 hours after treatment. Means are adjusted using a mixed effects model with treatment (trt), tio stratum, visit, trt-by-visit as fixed categorical effects, baseline and baseline-by-visit as fixed continuous covariates and patient as random effect. (NCT00796653)
Timeframe: 1 hour (h) and 10 minutes (min) prior to dose on the first day of randomized treatment (baseline) to -10 min, 5 min, 15 min, 30 min, 1 h, 2 h, and 3 h relative to dose after 2 weeks
| Intervention | Liter (Least Squares Mean) |
|---|---|
| Placebo | 0.099 |
| Olo 5 mcg qd | 0.260 |
| Olo 10 mcg qd | 0.278 |
| Form 12 mcg | 0.253 |
Peak FEV1 (0-3h) Response After 24 Weeks
Response was defined as change from baseline. Baseline peak FEV1 was defined as the mean of the available pre-dose peak FEV1 values prior to first dose of randomized treatment. Peak FEV1 (0-3h) values were obtained within 0 - 3 hours after treatment. Means are adjusted using a mixed effects model with treatment (trt), tio stratum, visit, trt-by-visit as fixed categorical effects, baseline and baseline-by-visit as fixed continuous covariates and patient as random effect. (NCT00796653)
Timeframe: 1 hour (h) and 10 minutes (min) prior to dose on the first day of randomized treatment (baseline) to -10 min, 5 min, 15 min, 30 min, 1 h, 2 h, and 3 h relative to dose after 24 weeks
| Intervention | Liter (Least Squares Mean) |
|---|---|
| Placebo | 0.060 |
| Olo 5 mcg qd | 0.183 |
| Olo 10 mcg qd | 0.211 |
| Form 12 mcg | 0.203 |
Peak FEV1 (0-3h) Response After 48 Weeks
Response was defined as change from baseline. Baseline peak FEV1 was defined as the mean of the available pre-dose peak FEV1 values prior to first dose of randomized treatment. Peak FEV1 (0-3h) values were obtained within 0 - 3 hours after treatment. Means are adjusted using a mixed effects model with treatment (trt), tio stratum, visit, trt-by-visit as fixed categorical effects, baseline and baseline-by-visit as fixed continuous covariates and patient as random effect. (NCT00796653)
Timeframe: 1 hour (h) and 10 minutes (min) prior to dose on the first day of randomized treatment (baseline) to -10 min, 5 min, 15 min, 30 min, 1 h, 2 h, and 3 h relative to dose after 48 weeks
| Intervention | Liter (Least Squares Mean) |
|---|---|
| Placebo | 0.052 |
| Olo 5 mcg qd | 0.163 |
| Olo 10 mcg qd | 0.178 |
| Form 12 mcg | 0.170 |
Peak FEV1 (0-3h) Response After 6 Weeks
Response was defined as change from baseline. Baseline peak FEV1 was defined as the mean of the available pre-dose peak FEV1 values prior to first dose of randomized treatment. Peak FEV1 (0-3h) values were obtained within 0 - 3 hours after treatment. Means are adjusted using a mixed effects model with treatment (trt), tio stratum, visit, trt-by-visit as fixed categorical effects, baseline and baseline-by-visit as fixed continuous covariates and patient as random effect. (NCT00796653)
Timeframe: 1 hour (h) and 10 minutes (min) prior to dose on the first day of randomized treatment (baseline) to -10 min, 5 min, 15 min, 30 min, 1 h, 2 h, and 3 h relative to dose after 6 weeks
| Intervention | Liter (Least Squares Mean) |
|---|---|
| Placebo | 0.066 |
| Olo 5 mcg qd | 0.235 |
| Olo 10 mcg qd | 0.248 |
| Form 12 mcg | 0.242 |
Peak FVC (0-3h) Response After 12 Weeks
Response was defined as change from baseline. Baseline peak FVC was defined as the mean of the available pre-dose peak FVC values prior to first dose of randomized treatment. Peak FVC (0-3h) values were obtained within 0 - 3 hours after treatment. Means are adjusted using a mixed effects model with treatment (trt), tio stratum, visit, trt-by-visit as fixed categorical effects, baseline and baseline-by-visit as fixed continuous covariates and patient as random effect. (NCT00796653)
Timeframe: 1 hour (h) and 10 minutes (min) prior to dose on the first day of randomized treatment (baseline) to -10 min, 5 min, 15 min, 30 min, 1 h, 2 h, and 3 h relative to dose after 12 weeks
| Intervention | Liter (Least Squares Mean) |
|---|---|
| Placebo | 0.171 |
| Olo 5 mcg qd | 0.386 |
| Olo 10 mcg qd | 0.396 |
| Form 12 mcg | 0.436 |
Peak FVC (0-3h) Response After 2 Weeks
Response was defined as change from baseline. Baseline peak FVC was defined as the mean of the available pre-dose peak FVC values prior to first dose of randomized treatment. Peak FVC (0-3h) values were obtained within 0 - 3 hours after treatment. Means are adjusted using a mixed effects model with treatment (trt), tio stratum, visit, trt-by-visit as fixed categorical effects, baseline and baseline-by-visit as fixed continuous covariates and patient as random effect. (NCT00796653)
Timeframe: 1 hour (h) and 10 minutes (min) prior to dose on the first day of randomized treatment (baseline) to -10 min, 5 min, 15 min, 30 min, 1 h, 2 h, and 3 h relative to dose after 2 weeks
| Intervention | Liter (Least Squares Mean) |
|---|---|
| Placebo | 0.247 |
| Olo 5 mcg qd | 0.480 |
| Olo 10 mcg qd | 0.476 |
| Form 12 mcg | 0.495 |
Peak FVC (0-3h) Response After 24 Weeks
Response was defined as change from baseline. Baseline peak FVC was defined as the mean of the available pre-dose peak FVC values prior to first dose of randomized treatment. Peak FVC (0-3h) values were obtained within 0 - 3 hours after treatment. Means are adjusted using a mixed effects model with treatment (trt), tio stratum, visit, trt-by-visit as fixed categorical effects, baseline and baseline-by-visit as fixed continuous covariates and patient as random effect. (NCT00796653)
Timeframe: 1 hour (h) and 10 minutes (min) prior to dose on the first day of randomized treatment (baseline) to -10 min, 5 min, 15 min, 30 min, 1 h, 2 h, and 3 h relative to dose after 24 weeks
| Intervention | Liter (Least Squares Mean) |
|---|---|
| Placebo | 0.189 |
| Olo 5 mcg qd | 0.371 |
| Olo 10 mcg qd | 0.369 |
| Form 12 mcg | 0.397 |
Peak FVC (0-3h) Response After 48 Weeks
Response was defined as change from baseline. Baseline peak FVC was defined as the mean of the available pre-dose peak FVC values prior to first dose of randomized treatment. Peak FVC (0-3h) values were obtained within 0 - 3 hours after treatment. Means are adjusted using a mixed effects model with treatment (trt), tio stratum, visit, trt-by-visit as fixed categorical effects, baseline and baseline-by-visit as fixed continuous covariates and patient as random effect. (NCT00796653)
Timeframe: 1 hour (h) and 10 minutes (min) prior to dose on the first day of randomized treatment (baseline) to -10 min, 5 min, 15 min, 30 min, 1 h, 2 h, and 3 h relative to dose after 48 weeks
| Intervention | Liter (Least Squares Mean) |
|---|---|
| Placebo | 0.137 |
| Olo 5 mcg qd | 0.325 |
| Olo 10 mcg qd | 0.352 |
| Form 12 mcg | 0.329 |
Peak FVC (0-3h) Response After 6 Weeks
Response was defined as change from baseline. Baseline peak FVC was defined as the mean of the available pre-dose peak FVC values prior to first dose of randomized treatment. Peak FVC (0-3h) values were obtained within 0 - 3 hours after treatment. Means are adjusted using a mixed effects model with treatment (trt), tio stratum, visit, trt-by-visit as fixed categorical effects, baseline and baseline-by-visit as fixed continuous covariates and patient as random effect. (NCT00796653)
Timeframe: 1 hour (h) and 10 minutes (min) prior to dose on the first day of randomized treatment (baseline) to -10 min, 5 min, 15 min, 30 min, 1 h, 2 h, and 3 h relative to dose after 6 weeks
| Intervention | Liter (Least Squares Mean) |
|---|---|
| Placebo | 0.196 |
| Olo 5 mcg qd | 0.443 |
| Olo 10 mcg qd | 0.417 |
| Form 12 mcg | 0.450 |
Saint George's Respiratory Questionnaire (SGRQ) Total Score at 12 Weeks
Saint George's Respiratory Questionnaire (SGRQ) measures the impact of COPD on overall health, daily life, and perceived well-being ranging from 0 (no limitations) to 100 (most limitations). (NCT00796653)
Timeframe: Baseline, Week 12
| Intervention | score on a scale (Least Squares Mean) |
|---|---|
| Placebo | 42.679 |
| Olo 5 mcg qd | 40.054 |
| Olo 10 mcg qd | 40.190 |
| Form 12 mcg | 39.521 |
Saint George's Respiratory Questionnaire (SGRQ) Total Score at 24 Weeks for Combined Analysis
Saint George's Respiratory Questionnaire (SGRQ) measures the impact of COPD on overall health, daily life, and perceived well-being ranging from 0 (no limitations) to 100 (most limitations). This is a combined analysis of the data from NCT00793624 and NCT00796653 showing adjusted values using a MMRM model. (NCT00796653)
Timeframe: Baseline, Week 24
| Intervention | score on a scale (Least Squares Mean) |
|---|---|
| Placebo | 41.639 |
| Olo 5 mcg qd | 38.794 |
| Olo 10 mcg qd | 38.205 |
| Form 12 mcg | 40.391 |
Saint George's Respiratory Questionnaire (SGRQ) Total Score at 48 Weeks
Saint George's Respiratory Questionnaire (SGRQ) measures the impact of COPD on overall health, daily life, and perceived well-being ranging from 0 (no limitations) to 100 (most limitations). (NCT00796653)
Timeframe: Baseline, Week 48
| Intervention | score on a scale (Least Squares Mean) |
|---|---|
| Placebo | 39.914 |
| Olo 5 mcg qd | 39.562 |
| Olo 10 mcg qd | 38.824 |
| Form 12 mcg | 40.025 |
Time to First Chronic Obstructive Pulmonary Disease (COPD) Exacerbation
Qualifying events of COPD were specifically pre-defined in the protocol. Other respiratory related events were evaluated by the investigator to see if they met the pre-defined criteria. Time to event was measured from the beginning of treatment. Cox regression analysis of treatment effect using tiotropium stratum as a stratification factor. (NCT00796653)
Timeframe: Baseline to end of study at 48 weeks.
| Intervention | Days (Mean) |
|---|---|
| Placebo (Tiotropium) | 173 |
| Placebo (Non-tiotropium) | 177 |
| Olo 5 mcg qd (Tiotropium) | 252 |
| Olo 5 mcg qd (Non-tiotropium) | 270 |
| Olo 10 mcg qd (Tiotropium) | 252 |
| Olo 10 mcg qd(Non-tiotropium) | 234 |
| Form 12 mcg (Tiotropium) | 149 |
| Form 12 mcg (Non-tiotropium) | 232 |
Time to First Chronic Obstructive Pulmonary Disease (CPOD) Exacerbation Leading to Hospitalization
Qualifying events of COPD were specifically pre-defined in the protocol. Other respiratory related events were evaluated by the investigator to see if they met the pre-defined criteria. These exacerbations required hospitalization. Time to event was measured from the beginning of treatment. Cox regression analysis of treatment effect using tiotropium stratum as a stratification factor. (NCT00796653)
Timeframe: Baseline to end of study at 48 weeks.
| Intervention | Days (Mean) |
|---|---|
| Placebo (Tiotropium) | NA |
| Placebo (Non-tiotropium) | NA |
| Olo 5 mcg qd (Tiotropium) | NA |
| Olo 5 mcg qd (Non-tiotropium) | NA |
| Olo 10 mcg qd (Tiotropium) | NA |
| Olo 10 mcg qd(Non-tiotropium) | NA |
| Form 12 mcg (Tiotropium) | NA |
| Form 12 mcg (Non-tiotropium) | 368.0 |
Time to First Moderate Chronic Obstructive Pulmonary Disease (CPOD) Exacerbation
Qualifying events of COPD were specifically pre-defined in the protocol. Other respiratory related events were evaluated by the investigator to see if they met the pre-defined criteria. These exacerbations did not lead to hospitalization but included treatment with antibiotics and/or systemic steroids. Time to event was measured from the beginning of treatment. Cox regression analysis of treatment effect using tiotropium stratum as a stratification factor. (NCT00796653)
Timeframe: Baseline to end of study at 48 weeks.
| Intervention | Days (Mean) |
|---|---|
| Placebo (Tiotropium) | 176 |
| Placebo (Non-tiotropium) | 214 |
| Olo 5 mcg qd (Tiotropium) | 264 |
| Olo 5 mcg qd (Non-tiotropium) | 312 |
| Olo 10 mcg qd (Tiotropium) | 324 |
| Olo 10 mcg qd(Non-tiotropium) | 327 |
| Form 12 mcg (Tiotropium) | 190 |
| Form 12 mcg (Non-tiotropium) | 325 |
Trough FEV1 Response at Week 18
Response was defined as change from baseline. Baseline trough FEV1 was defined as the mean of the -1 hour and -10 minute measurements performed just prior to first dose of randomized treatment. Trough FEV1 is defined as the FEV1 performed at -10 mins prior to study drug inhalation as the end of the dosing interval or the mean of -1h and -10 min FEV1s if both available. Means are adjusted using a mixed effects model with treatment (trt), tio stratum, visit, trt-by-visit as fixed categorical effects, baseline and baseline-by-visit as fixed continuous covariates and patient as random effect. (NCT00796653)
Timeframe: 1 h and 10 min prior to dose on the first day of randomized treatment (baseline) and -1 h (if available) and - 10 mins prior to study drug at week 18.
| Intervention | Liter (Least Squares Mean) |
|---|---|
| Placebo | -0.036 |
| Olo 5 mcg qd | 0.013 |
| Olo 10 mcg qd | 0.049 |
| Form 12 mcg | 0.015 |
Trough FEV1 Response at Week 2
Response was defined as change from baseline. Baseline trough FEV1 was defined as the mean of the -1 hour and -10 minute measurements performed just prior to first dose of randomized treatment. Trough FEV1 is defined as the FEV1 performed at -10 mins prior to study drug inhalation as the end of the dosing interval or the mean of -1h and -10 min FEV1s if both available. Means are adjusted using a mixed effects model with treatment (trt), tio stratum, visit, trt-by-visit as fixed categorical effects, baseline and baseline-by-visit as fixed continuous covariates and patient as random effect. (NCT00796653)
Timeframe: 1 h and 10 min prior to dose on the first day of randomized treatment (baseline) and -1 h (if available) and - 10 mins prior to study drug at week 2.
| Intervention | Liter (Least Squares Mean) |
|---|---|
| Placebo | -0.016 |
| Olo 5 mcg qd | 0.053 |
| Olo 10 mcg qd | 0.103 |
| Form 12 mcg | 0.033 |
Trough FEV1 Response at Week 24
Response was defined as change from baseline. Baseline trough FEV1 was defined as the mean of the -1 hour and -10 minute measurements performed just prior to first dose of randomized treatment. Trough FEV1 is defined as the FEV1 performed at -10 mins prior to study drug inhalation as the end of the dosing interval or the mean of -1h and -10 min FEV1s if both available. Means are adjusted using a mixed effects model with treatment (trt), tio stratum, visit, trt-by-visit as fixed categorical effects, baseline and baseline-by-visit as fixed continuous covariates and patient as random effect. (NCT00796653)
Timeframe: 1 h and 10 min prior to dose on the first day of randomized treatment (baseline) and -1 h (if available) and - 10 mins prior to study drug at week 24.
| Intervention | Liter (Least Squares Mean) |
|---|---|
| Placebo | -0.055 |
| Olo 5 mcg qd | -0.003 |
| Olo 10 mcg qd | 0.014 |
| Form 12 mcg | -0.013 |
Trough FEV1 Response at Week 32
Response was defined as change from baseline. Baseline trough FEV1 was defined as the mean of the -1 hour and -10 minute measurements performed just prior to first dose of randomized treatment. Trough FEV1 is defined as the FEV1 performed at -10 mins prior to study drug inhalation as the end of the dosing interval or the mean of -1h and -10 min FEV1s if both available. Means are adjusted using a mixed effects model with treatment (trt), tio stratum, visit, trt-by-visit as fixed categorical effects, baseline and baseline-by-visit as fixed continuous covariates and patient as random effect. (NCT00796653)
Timeframe: 1 h and 10 min prior to dose on the first day of randomized treatment (baseline) and -1 h (if available) and - 10 mins prior to study drug at week 32.
| Intervention | Liter (Least Squares Mean) |
|---|---|
| Placebo | -0.039 |
| Olo 5 mcg qd | 0.023 |
| Olo 10 mcg qd | 0.034 |
| Form 12 mcg | 0.009 |
Trough FEV1 Response at Week 40
Response was defined as change from baseline. Baseline trough FEV1 was defined as the mean of the -1 hour and -10 minute measurements performed just prior to first dose of randomized treatment. Trough FEV1 is defined as the FEV1 performed at -10 mins prior to study drug inhalation as the end of the dosing interval or the mean of -1h and -10 min FEV1s if both available. Means are adjusted using a mixed effects model with treatment (trt), tio stratum, visit, trt-by-visit as fixed categorical effects, baseline and baseline-by-visit as fixed continuous covariates and patient as random effect. (NCT00796653)
Timeframe: 1 h and 10 min prior to dose on the first day of randomized treatment (baseline) and -1 h (if available) and - 10 mins prior to study drug at week 40.
| Intervention | Liter (Least Squares Mean) |
|---|---|
| Placebo | -0.043 |
| Olo 5 mcg qd | 0.019 |
| Olo 10 mcg qd | 0.041 |
| Form 12 mcg | 0.013 |
Trough FEV1 Response at Week 48
Response was defined as change from baseline. Baseline trough FEV1 was defined as the mean of the -1 hour and -10 minute measurements performed just prior to first dose of randomized treatment. Trough FEV1 is defined as the FEV1 performed at -10 mins prior to study drug inhalation as the end of the dosing interval or the mean of -1h and -10 min FEV1s if both available. Means are adjusted using a mixed effects model with treatment (trt), tio stratum, visit, trt-by-visit as fixed categorical effects, baseline and baseline-by-visit as fixed continuous covariates and patient as random effect. (NCT00796653)
Timeframe: 1 h and 10 min prior to dose on the first day of randomized treatment (baseline) and -1 h (if available) and - 10 mins prior to study drug at week 48.
| Intervention | Liter (Least Squares Mean) |
|---|---|
| Placebo | -0.060 |
| Olo 5 mcg qd | -0.016 |
| Olo 10 mcg qd | -0.001 |
| Form 12 mcg | -0.024 |
Trough FEV1 Response at Week 6
Response was defined as change from baseline. Baseline trough FEV1 was defined as the mean of the -1 hour and -10 minute measurements performed just prior to first dose of randomized treatment. Trough FEV1 is defined as the FEV1 performed at -10 mins prior to study drug inhalation as the end of the dosing interval or the mean of -1h and -10 min FEV1s if both available. Means are adjusted using a mixed effects model with treatment (trt), tio stratum, visit, trt-by-visit as fixed categorical effects, baseline and baseline-by-visit as fixed continuous covariates and patient as random effect. (NCT00796653)
Timeframe: 1 h and 10 min prior to dose on the first day of randomized treatment (baseline) and -1 h (if available) and - 10 mins prior to study drug at week 6.
| Intervention | Liter (Least Squares Mean) |
|---|---|
| Placebo | -0.036 |
| Olo 5 mcg qd | 0.047 |
| Olo 10 mcg qd | 0.068 |
| Form 12 mcg | 0.034 |
Trough FVC Response at Week 18
Response was defined as change from baseline. Baseline trough FVC was defined as the mean of the -1 hour and -10 minute measurements performed just prior to first dose of randomized treatment. Trough FVC is defined as the FVC performed at -10 mins prior to study drug inhalation as the end of the dosing interval or the mean of -1h and -10 min FVCs if both available. Means are adjusted using a mixed effects model with treatment (trt), tio stratum, visit, trt-by-visit as fixed categorical effects, baseline and baseline-by-visit as fixed continuous covariates and patient as random effect. (NCT00796653)
Timeframe: 1 h and 10 min prior to dose on the first day of randomized treatment (baseline) and -1 h (if available) and - 10 mins prior to study drug at week 18.
| Intervention | Liter (Least Squares Mean) |
|---|---|
| Placebo | -0.014 |
| Olo 5 mcg qd | 0.084 |
| Olo 10 mcg qd | 0.107 |
| Form 12 mcg | 0.064 |
Trough FVC Response at Week 2
Response was defined as change from baseline. Baseline trough FVC was defined as the mean of the -1 hour and -10 minute measurements performed just prior to first dose of randomized treatment. Trough FVC is defined as the FVC performed at -10 mins prior to study drug inhalation as the end of the dosing interval or the mean of -1h and -10 min FVCs if both available. Means are adjusted using a mixed effects model with treatment (trt), tio stratum, visit, trt-by-visit as fixed categorical effects, baseline and baseline-by-visit as fixed continuous covariates and patient as random effect. (NCT00796653)
Timeframe: 1 h and 10 min prior to dose on the first day of randomized treatment (baseline) and -1 h (if available) and - 10 mins prior to study drug at week 2.
| Intervention | Liter (Least Squares Mean) |
|---|---|
| Placebo | 0.030 |
| Olo 5 mcg qd | 0.118 |
| Olo 10 mcg qd | 0.173 |
| Form 12 mcg | 0.111 |
Trough FVC Response at Week 24
Response was defined as change from baseline. Baseline trough FVC was defined as the mean of the -1 hour and -10 minute measurements performed just prior to first dose of randomized treatment. Trough FVC is defined as the FVC performed at -10 mins prior to study drug inhalation as the end of the dosing interval or the mean of -1h and -10 min FVCs if both available. Means are adjusted using a mixed effects model with treatment (trt), tio stratum, visit, trt-by-visit as fixed categorical effects, baseline and baseline-by-visit as fixed continuous covariates and patient as random effect. (NCT00796653)
Timeframe: 1 h and 10 min prior to dose on the first day of randomized treatment (baseline) and -1 h (if available) and - 10 mins prior to study drug at week 24.
| Intervention | Liter (Least Squares Mean) |
|---|---|
| Placebo | -0.044 |
| Olo 5 mcg qd | 0.023 |
| Olo 10 mcg qd | 0.019 |
| Form 12 mcg | -0.005 |
Trough FVC Response at Week 32
Response was defined as change from baseline. Baseline trough FVC was defined as the mean of the -1 hour and -10 minute measurements performed just prior to first dose of randomized treatment. Trough FVC is defined as the FVC performed at -10 mins prior to study drug inhalation as the end of the dosing interval or the mean of -1h and -10 min FVCs if both available. Means are adjusted using a mixed effects model with treatment (trt), tio stratum, visit, trt-by-visit as fixed categorical effects, baseline and baseline-by-visit as fixed continuous covariates and patient as random effect. (NCT00796653)
Timeframe: 1 h and 10 min prior to dose on the first day of randomized treatment (baseline) and -1 h (if available) and - 10 mins prior to study drug at week 32.
| Intervention | Liter (Least Squares Mean) |
|---|---|
| Placebo | -0.007 |
| Olo 5 mcg qd | 0.081 |
| Olo 10 mcg qd | 0.063 |
| Form 12 mcg | 0.036 |
Trough FVC Response at Week 40
Response was defined as change from baseline. Baseline trough FVC was defined as the mean of the -1 hour and -10 minute measurements performed just prior to first dose of randomized treatment. Trough FVC is defined as the FVC performed at -10 mins prior to study drug inhalation as the end of the dosing interval or the mean of -1h and -10 min FVCs if both available. Means are adjusted using a mixed effects model with treatment (trt), tio stratum, visit, trt-by-visit as fixed categorical effects, baseline and baseline-by-visit as fixed continuous covariates and patient as random effect. (NCT00796653)
Timeframe: 1 h and 10 min prior to dose on the first day of randomized treatment (baseline) and -1 h (if available) and - 10 mins prior to study drug at week 40.
| Intervention | Liter (Least Squares Mean) |
|---|---|
| Placebo | -0.016 |
| Olo 5 mcg qd | 0.071 |
| Olo 10 mcg qd | 0.105 |
| Form 12 mcg | 0.037 |
Trough FVC Response at Week 48
Response was defined as change from baseline. Baseline trough FVC was defined as the mean of the -1 hour and -10 minute measurements performed just prior to first dose of randomized treatment. Trough FVC is defined as the FVC performed at -10 mins prior to study drug inhalation as the end of the dosing interval or the mean of -1h and -10 min FVCs if both available. Means are adjusted using a mixed effects model with treatment (trt), tio stratum, visit, trt-by-visit as fixed categorical effects, baseline and baseline-by-visit as fixed continuous covariates and patient as random effect. (NCT00796653)
Timeframe: 1 h and 10 min prior to dose on the first day of randomized treatment (baseline) and -1 h (if available) and - 10 mins prior to study drug at week 48.
| Intervention | Liter (Least Squares Mean) |
|---|---|
| Placebo | -0.069 |
| Olo 5 mcg qd | 0.012 |
| Olo 10 mcg qd | 0.032 |
| Form 12 mcg | -0.031 |
Trough FVC Response at Week 6
Response was defined as change from baseline. Baseline trough FVC was defined as the mean of the -1 hour and -10 minute measurements performed just prior to first dose of randomized treatment. Trough FVC is defined as the FVC performed at -10 mins prior to study drug inhalation as the end of the dosing interval or the mean of -1h and -10 min FVCs if both available. Means are adjusted using a mixed effects model with treatment (trt), tio stratum, visit, trt-by-visit as fixed categorical effects, baseline and baseline-by-visit as fixed continuous covariates and patient as random effect. (NCT00796653)
Timeframe: 1 h and 10 min prior to dose on the first day of randomized treatment (baseline) and -1 h (if available) and - 10 mins prior to study drug at week 6.
| Intervention | Liter (Least Squares Mean) |
|---|---|
| Placebo | -0.014 |
| Olo 5 mcg qd | 0.113 |
| Olo 10 mcg qd | 0.101 |
| Form 12 mcg | 0.085 |
Changes in Safety Parameters Related to Treatment
Occurence of cardiac disorders and investigations related to treatment. (NCT00796653)
Timeframe: 48 weeks
| Intervention | percentage of participants (Number) | ||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Atrial fibrillation | Sinus tachycardia | Acute coronary syndrome | Acute myocardial infarction | Angina unstable | Myocardial infarction | Ventricular extrasystoles | Alanine aminotransferase increased | Aspartate aminotransferase increased | Blood creatine phosphokinase increased | Electrocardiogram ST segment depression | Electrocardiogram T wave inversion | Gamma-glutamyltransferase increased | |
| Form 12 mcg | 0.0 | 0.9 | 0.0 | 0.0 | 0.0 | 0.0 | 0.4 | 0.0 | 0.4 | 0.4 | 0.0 | 0.0 | 0.0 |
| Olo 10 mcg qd | 0.9 | 0.0 | 0.0 | 0.4 | 0.0 | 0.0 | 0.0 | 0.0 | 0.0 | 0.0 | 0.0 | 0.0 | 0.0 |
| Olo 5 mcg qd | 0.0 | 0.0 | 0.0 | 0.0 | 0.0 | 0.0 | 0.4 | 0.0 | 0.0 | 0.0 | 0.4 | 0.0 | 0.0 |
| Placebo | 0.9 | 0.0 | 0.4 | 0.0 | 0.4 | 0.4 | 0.4 | 0.4 | 0.0 | 0.0 | 0.0 | 0.4 | 0.4 |
Peak Expiratory Flow Rate (PEFR) at Week 24
Weekly mean pre-dose morning and evening PEFR. Results are from non-MMRM ANCOVA models by week, with Last observation carried forward (LOCF) up to each week. Fixed effects include treatment, tiotropium, strata and baseline. (NCT00796653)
Timeframe: Week 24
| Intervention | L/min (Mean) | |
|---|---|---|
| morning PEFR (N=225, 227, 226, 224) | evening PEFR (N=224, 223, 227, 222) | |
| Form 12 mcg | 211.038 | 218.321 |
| Olo 10 mcg qd | 217.660 | 225.380 |
| Olo 5 mcg qd | 210.496 | 219.905 |
| Placebo | 196.789 | 202.505 |
Use of Rescue Medication at Week 24
Mean number of puffs of rescue medication used per day (daytime/nighttime/total) (NCT00796653)
Timeframe: Week 24
| Intervention | Number of puffs (Mean) | ||
|---|---|---|---|
| Daytime | Nighttime | Total | |
| Form 12 mcg | 0.967 | 1.393 | 2.353 |
| Olo 10 mcg qd | 0.923 | 1.348 | 2.277 |
| Olo 5 mcg qd | 1.036 | 1.435 | 2.470 |
| Placebo | 1.189 | 1.713 | 2.893 |
Saint George's Respiratory Questionnaire (SGRQ) Total Score at 24 Weeks
Saint George's Respiratory Questionnaire (SGRQ) measures the impact of COPD on overall health, daily life, and perceived well-being ranging from 0 (no limitations) to 100 (most limitations). (NCT00796653)
Timeframe: Baseline, Week 24
| Intervention | score on a scale (Least Squares Mean) |
|---|---|
| Placebo | 42.120 |
| Olo 5 mcg qd | 38.970 |
| Olo 10 mcg qd | 38.597 |
| Form 12 mcg | 40.704 |
Trough FVC Response at Week 12
Response was defined as change from baseline. Baseline trough FVC was defined as the mean of the -1 hour and -10 minute measurements performed just prior to first dose of randomized treatment. Trough FVC is defined as the FVC performed at -10 mins prior to study drug inhalation as the end of the dosing interval or the mean of -1h and -10 min FVCs if both available. Means are adjusted using a mixed effects model with treatment (trt), tio stratum, visit, trt-by-visit as fixed categorical effects, baseline and baseline-by-visit as fixed continuous covariates and patient as random effect. (NCT00796653)
Timeframe: 1 h and 10 min prior to dose on the first day of randomized treatment (baseline) and -1 h (if available) and - 10 mins prior to study drug at week 12.
| Intervention | Liter (Least Squares Mean) |
|---|---|
| Placebo | -0.041 |
| Olo 5 mcg qd | 0.062 |
| Olo 10 mcg qd | 0.062 |
| Form 12 mcg | 0.070 |
Forced Vital Capacity (FVC) Area Under Curve 0-3 Hour (h) (AUC 0-3h) Response at 2 Weeks
Response was defined as change from baseline. Baseline FVC was defined as the mean of the -1 h and -10 min measurements performed just prior to administration of the first am dose of randomized treatment. Means are adjusted using a mixed effects model with treatment (trt), tio stratum, visit, trt-by-visit interaction as fixed categorical effects, baseline and baseline-by-visit interaction as fixed continuous covariates and patient as random effect. 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. (NCT00796653)
Timeframe: 1 hour (h) and 10 minutes (min) prior to dose on the first day of randomized treatment (baseline) to -10 min, 5 min, 15 min, 30 min, 1 h, 2 h, and 3 h relative to dose on Week 2
| Intervention | Liter (Least Squares Mean) |
|---|---|
| Placebo | 0.082 |
| Olo 5 mcg qd | 0.312 |
| Olo 10 mcg qd | 0.332 |
| Form 12 mcg | 0.348 |
Absolute Plasma Concentrations
Absolute plasma concentrations of Olodaterol. Values presented are across visits and summarised into geometric means. (NCT00796653)
Timeframe: within 2 hours before first study drug administration and 10 minutes post-dose at week 6, 12 and 18
| Intervention | pg/mL (Geometric Mean) |
|---|---|
| Olo 5 mcg qd | 3.920 |
| Olo 10 mcg qd | 6.977 |
Forced Expiratory Volume in One Second (FEV1) Area Under Curve 0-3 Hour (h) (AUC 0-3h) Response at 12 Weeks
Response was defined as change from baseline. Baseline FEV1 was defined as the mean of the -1 h and -10 min measurements performed just prior to administration of the first am dose of randomized treatment. Means are adjusted using a mixed effects model with treatment (trt), tio stratum, visit, trt-by-visit interaction as fixed categorical effects, baseline and baseline-by-visit interaction as fixed continuous covariates and patient as random effect. 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. (NCT00796653)
Timeframe: 1 hour (h) and 10 minutes (min) prior to dose on the first day of randomized treatment (baseline) to -10 min, 5 min, 15 min, 30 min, 1 h, 2 h, and 3 h relative to dose on Week 12
| Intervention | Liter (Least Squares Mean) |
|---|---|
| Placebo | -0.008 |
| Olo 5 mcg qd | 0.138 |
| Olo 10 mcg qd | 0.167 |
| Form 12 mcg | 0.163 |
Trough FEV1 Response at Week 12
Response was defined as change from baseline. Baseline trough FEV1 was defined as the mean of the -1 hour and -10 minute measurements performed just prior to first dose of randomized treatment. Trough FEV1 is defined as the FEV1 performed at -10 mins prior to study drug inhalation as the end of the dosing interval or the mean of -1h and -10 min FEV1s if both available. Means are adjusted using a mixed effects model with treatment (trt), tio stratum, visit, trt-by-visit as fixed categorical effects, baseline and baseline-by-visit as fixed continuous covariates and patient as random effect. (NCT00796653)
Timeframe: 1 h and 10 min prior to dose on the first day of randomized treatment (baseline) and -1 h (if available) and - 10 mins prior to study drug at week 12.
| Intervention | Liter (Least Squares Mean) |
|---|---|
| Placebo | -0.041 |
| Olo 5 mcg qd | 0.018 |
| Olo 10 mcg qd | 0.052 |
| Form 12 mcg | 0.024 |
FEV1 Peak(0-3) Response at 4 Weeks
The change from baseline in FEV1 peak(0-3) after 4 weeks of treatment. (NCT00824382)
Timeframe: baseline and after 4 weeks treatment
| Intervention | Liter (Least Squares Mean) |
|---|---|
| Placebo | 0.025 |
| Olodaterol 2mcg | 0.170 |
| Olodaterol 5mcg | 0.227 |
| Olodaterol 10mcg | 0.220 |
Trough FVC Response at Week 4
The change from baseline in Trough FVC after 4 weeks of treatment (NCT00824382)
Timeframe: baseline and after 4 weeks treatment
| Intervention | Liter (Least Squares Mean) |
|---|---|
| Placebo | -0.037 |
| Olodaterol 2mcg | 0.154 |
| Olodaterol 5mcg | 0.154 |
| Olodaterol 10mcg | 0.150 |
Weekly Mean Evening PEFR After 4 Weeks
"PEFR measurements were recorded by means of a patient diary on a daily basis. This diary was used to record the twice daily PEFs,~Evening measurements were performed at bedtime.The highest of three readings for each measurement were recorded." (NCT00824382)
Timeframe: Week 4
| Intervention | Liter/minute (Least Squares Mean) |
|---|---|
| Placebo | 227.39 |
| Olodaterol 2mcg | 256.44 |
| Olodaterol 5mcg | 258.34 |
| Olodaterol 10mcg | 264.58 |
AUC0-1,ss
Area under the concentration curve from 0 to 1 hour at steady state using trapezoid rule, only calculated if >1/3 of the patients have available pharmacokinetic parameters, thus not applicable for Olodaterol 2mcg group (NCT00824382)
Timeframe: visit at week 4
| Intervention | pg*h/mL (Geometric Mean) |
|---|---|
| Olodaterol 5mcg | 4.85 |
| Olodaterol 10mcg | 10.8 |
Difference From Baseline in Potassium
Difference from baseline in Potassium (normalized values). Normalization means that the values from different laboratories are transformed in such a way that they are directly comparable. (NCT00824382)
Timeframe: Baseline, Week 4
| Intervention | mmol/L (Mean) |
|---|---|
| Placebo | 0.0 |
| Olodaterol 2mcg | 0.1 |
| Olodaterol 5mcg | -0.0 |
| Olodaterol 10mcg | 0.1 |
FEV1 AUC(0-3) Response at 4 Weeks
"The change from baseline in FEV1 AUC(0-3) after 4 weeks of treatment. 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 liters.~Due to normalization the unit is liters." (NCT00824382)
Timeframe: baseline and after 4 weeks treatment
| Intervention | Liter (Least Squares Mean) |
|---|---|
| Placebo | -0.020 |
| Olodaterol 2mcg | 0.118 |
| Olodaterol 5mcg | 0.177 |
| Olodaterol 10mcg | 0.173 |
FVC Peak(0-3) Response
The change from baseline in FVC peak(0-3) response after 4 weeks of treatment. (NCT00824382)
Timeframe: baseline and after 4 weeks treatment
| Intervention | Liter (Least Squares Mean) |
|---|---|
| Placebo | 0.109 |
| Olodaterol 2mcg | 0.362 |
| Olodaterol 5mcg | 0.351 |
| Olodaterol 10mcg | 0.335 |
Forced Expiratory Volume in 1 Second (FEV1) (Unsupervised) Area Under Curve 0-6h (AUC 0-6h) Response After 4 Weeks
"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 randomized treatment. Means are adjusted using a model with treatment (trt), baseline as fixed effects and centre as random effect.~FEV1 AUC 0-6h was calculated from 0-6 hours post-dose using the trapezoidal rule, divided by the observation time (6h) to report in liters." (NCT00824382)
Timeframe: baseline and after 4weeks treatment
| Intervention | Liter (Least Squares Mean) |
|---|---|
| Placebo | -0.022 |
| Olodaterol 2mcg | 0.090 |
| Olodaterol 5mcg | 0.195 |
| Olodaterol 10mcg | 0.195 |
AUC0-1
Area under the concentration curve from 0 to 1 hour using trapezoid rule, only calculated if >1/3 of the patients have available pharmacokinetic parameters,thus not applicable for Olodaterol 2mcg group (NCT00824382)
Timeframe: after first inhalated administration
| Intervention | pg*h/mL (Geometric Mean) |
|---|---|
| Olodaterol 5mcg | 3.67 |
| Olodaterol 10mcg | 6.08 |
Forced Expiratory Volume in 1 Second (FEV1) (Unsupervised) Area Under Curve 6-12 h (AUC 6-12h) Response After 4 Weeks
"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 randomized treatment. Means are adjusted using a model with treatment (trt), baseline as fixed effects and centre as random effect.~FEV1 AUC 6-12h was calculated from 6-12 hours post-dose using the trapezoidal rule, divided by the observation time (6h) to report in liters." (NCT00824382)
Timeframe: Baseline and after 4weeks treatment
| Intervention | Liter (Least Squares Mean) |
|---|---|
| Placebo | -0.005 |
| Olodaterol 2mcg | 0.078 |
| Olodaterol 5mcg | 0.171 |
| Olodaterol 10mcg | 0.186 |
FVC AUC(0-3) Response
"The change from baseline in FVC AUC(0-3) response after 4 weeks of treatment. 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 liters.~Due to normalization the unit is liters." (NCT00824382)
Timeframe: baseline and after 4 weeks treatment
| Intervention | Liter (Least Squares Mean) |
|---|---|
| Placebo | 0.004 |
| Olodaterol 2mcg | 0.257 |
| Olodaterol 5mcg | 0.254 |
| Olodaterol 10mcg | 0.237 |
Cmax (Maximum Measured Concentration of the Analyte in Plasma)
Cmax only calculated if >1/3 of the patients have available pharmacokinetic parameters,thus not applicable for the Olodaterol 2 mcg (NCT00824382)
Timeframe: after first inhalated administration
| Intervention | pg/mL (Geometric Mean) |
|---|---|
| Olodaterol 5mcg | 4.17 |
| Olodaterol 10mcg | 8.22 |
Weekly Mean Number of Occasions of Rescue Therapy After 4 Weeks
Weekly mean number of occasions of rescue therapy used per day (PRN salbutamol ) (NCT00824382)
Timeframe: Week 4
| Intervention | Number of puffs (Mean) |
|---|---|
| Placebo | 0.778 |
| Olodaterol 2mcg | 0.587 |
| Olodaterol 5mcg | 0.324 |
| Olodaterol 10mcg | 0.392 |
Trough FEV1 Response at Week 2
Trough FEV1 is defined as the mean of the two FEV1 values (performed at -1 hour and -10 minutes prior to next test-drug inhalation) at the end of the dosing interval, 24 hours post-drug administration. Trough FEV1 response is defined as the change from baseline in trough FEV1. Baseline trough FEV1 is the mean of the two pre-treatment FEV1 values measured at Visit 2 prior to administration of the first dose of study medication (NCT00824382)
Timeframe: baseline and after 2 weeks treatment
| Intervention | Liter (Least Squares Mean) |
|---|---|
| Placebo | -0.020 |
| Olodaterol 2mcg | 0.061 |
| Olodaterol 5mcg | 0.120 |
| Olodaterol 10mcg | 0.136 |
Trough FEV1 Response at Week 4
The change from baseline in trough FEV1 after 4 weeks of treatment. Trough FEV1 is defined as the mean of the two FEV1 values (performed at -1 hour and -10 minutes prior to next test-drug inhalation) at the end of the dosing interval, 24 hours post-drug administration. Trough FEV1 response is defined as the change from baseline . Baseline trough FEV1 is the mean of the two pre-treatment FEV1 values measured at Visit 2 prior to administration of the first dose of study medication. (NCT00824382)
Timeframe: baseline and after 4 weeks treatment
| Intervention | Liter (Least Squares Mean) |
|---|---|
| Placebo | -0.032 |
| Olodaterol 2mcg | 0.059 |
| Olodaterol 5mcg | 0.100 |
| Olodaterol 10mcg | 0.100 |
Weekly Mean Pre-dose Morning Peak Expiratory Flow Rate (PEFR) After 4 Weeks
"PEFR measurements were recorded by means of a patient diary on a daily basis. This diary was used to record the twice daily PEFs,~Morning measurements were performed immediately upon arising before administration of trial and/or rescue medication.The highest of three readings for each measurement were recorded." (NCT00824382)
Timeframe: Week 4
| Intervention | Liter/minute (Least Squares Mean) |
|---|---|
| Placebo | 217.54 |
| Olodaterol 2mcg | 244.80 |
| Olodaterol 5mcg | 246.93 |
| Olodaterol 10mcg | 254.22 |
Clinical Relevant Abnormalities for Vital Signs, Blood Chemistry, Haematology, Urinalysis, ECG and Physical Examination
Clinical relevant Abnormalities for Vital Signs, Blood Chemistry, Haematology, Urinalysis, ECG and Physical examination. New abnormal findings or worsenings of baseline conditions were reported as Adverse Events related to treatment (cardiac disorders and investigations). (NCT00824382)
Timeframe: 4 weeks
| Intervention | percentage of participants (Number) | |||
|---|---|---|---|---|
| Atrioventricular block second degree | Blood lactate dehydrogenase increased | Blood glucose increased | White blood cell count decreased | |
| Olodaterol 10mcg | 1.2 | 0.0 | 1.2 | 1.2 |
| Olodaterol 2mcg | 0.0 | 0.0 | 0.0 | 0.0 |
| Olodaterol 5mcg | 0.0 | 1.3 | 0.0 | 0.0 |
| Placebo | 0.0 | 0.0 | 0.0 | 0.0 |
Cmax,ss (Maximum Measured Concentration of the Analyte in Plasma at Steady State)
Cmax,ss only calculated if >1/3 of the patients have available pharmacokinetic parameters, thus not applicable for the Olodaterol 2 mcg (NCT00824382)
Timeframe: visit at week 4
| Intervention | pg/mL (Geometric Mean) |
|---|---|
| Olodaterol 5mcg | 5.92 |
| Olodaterol 10mcg | 13.1 |
Pharmacokinetics (PK): Amount of Analyte That is Eliminated in Urine at Steady State From the Time Point 0 Hours to Time Point 24 Hours
Amount of analyte that is eliminated in urine at steady state from the time point 0 hours to time point 24 hours after dosing in week 3. The start of inhalation was used as time point 0 for calculation of pharmacokinetic parameters. Descriptive statistics were calculated only if N>=16 had concentrations within the validated concentration range. (NCT00846768)
Timeframe: 3 weeks
| Intervention | ng (Geometric Mean) |
|---|---|
| Olo 5 mcg qd | 181 |
| Olo 10 mcg qd | 343 |
Peak FVC (0-3h) Response After 3 Weeks
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. Peak FVC (0-3h) values were obtained within 0 - 3 hours after the last dose after three weeks of treatment. (NCT00846768)
Timeframe: Baseline, 3 weeks
| Intervention | Liter (Least Squares Mean) |
|---|---|
| Olo 2 mcg Bid | 0.325 |
| Olo 5 mcg qd | 0.417 |
| Olo 5 mcg Bid | 0.349 |
| Olo 10 mcg qd | 0.433 |
Peak FEV1 (0-3h) Response After 3 Weeks
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. Peak FEV1 (0-3h) values were obtained within 0 - 3 hours after the last dose after three weeks of treatment. (NCT00846768)
Timeframe: Baseline, 3 weeks
| Intervention | Liter (Least Squares Mean) |
|---|---|
| Olo 2 mcg Bid | 0.187 |
| Olo 5 mcg qd | 0.249 |
| Olo 5 mcg Bid | 0.230 |
| Olo 10 mcg qd | 0.242 |
FVC Area Under Curve 12-24 h (AUC 12-24h) Response After 3 Weeks of Treatment
Response was defined as change from baseline. Baseline FVC AUC (12-24) was defined as the AUC performed on the baseline visit, prior to the first dose of randomized treatment. FVC 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. (NCT00846768)
Timeframe: Day 0: -0:10, 0:30, 1, 2, 10, 11, 11:50 h relative to planned evening dose on day 1; Day 21: -0:10, 0:30, 1, 2, 10, 11, 11:50 h relative to evening dose
| Intervention | Liter (Least Squares Mean) |
|---|---|
| Olo 2 mcg Bid | 0.239 |
| Olo 5 mcg qd | 0.215 |
| Olo 5 mcg Bid | 0.318 |
| Olo 10 mcg qd | 0.219 |
FVC Area Under Curve 0-24 h (AUC 0-24h) Response After 3 Weeks of Treatment
Response was defined as change from baseline. Baseline FVC AUC (0-24) was defined as the AUC performed on the baseline visit, prior to the first dose of randomized treatment. FVC 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. (NCT00846768)
Timeframe: Day0:-0:10,0:30,1,2,3,4,6,8,10,11:50h relative to planned morning dose on day1, 0:30,1,2,10,11,11:50h relative to planned evening dose on day1; Day21:-0:10,0:30,1,2,3,4,6,8,10,11:50h relative to morning dose,0:30,1,2,10,11,11:50h relative to evening dose
| Intervention | Liter (Least Squares Mean) |
|---|---|
| Olo 2 mcg Bid | 0.249 |
| Olo 5 mcg qd | 0.275 |
| Olo 5 mcg Bid | 0.306 |
| Olo 10 mcg qd | 0.279 |
Pharmacokinetics (PK): Concentration of the Analyte in Plasma Measured at 0.167 Hours Post Dosing at Steady State
Steady state concentration of the analyte in plasma measured at 0.167 hours post dosing in week 3. The start of inhalation was used as time point 0 for calculation of pharmacokinetic parameters. Descriptive statistics were calculated only if N>=16 had concentrations within the validated concentration range. (NCT00846768)
Timeframe: 3 weeks
| Intervention | pg/mL (Geometric Mean) |
|---|---|
| Olo 5 mcg qd | 3.52 |
| Olo 5 mcg Bid | 4.28 |
| Olo 10 mcg qd | 5.78 |
FVC Area Under Curve 0-12 h (AUC 0-12h) Response After 3 Weeks of Treatment
Response was defined as change from baseline. Baseline FVC AUC (0-12) was defined as the AUC performed on the baseline visit, prior to the first dose of randomized treatment. FVC 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. (NCT00846768)
Timeframe: Day 0: -0:10, 0:30, 1, 2, 3, 4, 6, 8, 10, 11:50 h relative to planned morning dose on day 1; Day 21: -0:10, 0:30, 1, 2, 3, 4, 6, 8, 10, 11:50 h relative to morning dose
| Intervention | Liter (Least Squares Mean) |
|---|---|
| Olo 2 mcg Bid | 0.262 |
| Olo 5 mcg qd | 0.335 |
| Olo 5 mcg Bid | 0.294 |
| Olo 10 mcg qd | 0.340 |
FEV1 Area Under Curve 12-24 h (AUC 12-24h) Response After 3 Weeks of Treatment
Response was defined as change from baseline. Baseline FEV1 AUC (12-24) was defined as the AUC performed on the baseline visit, prior to the first dose of randomized treatment. 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. (NCT00846768)
Timeframe: Day 0: -0:10, 0:30, 1, 2, 10, 11, 11:50 h relative to planned evening dose on day 1; Day 21: -0:10, 0:30, 1, 2, 10, 11, 11:50 h relative to evening dose
| Intervention | Liter (Least Squares Mean) |
|---|---|
| Olo 2 mcg Bid | 0.167 |
| Olo 5 mcg qd | 0.155 |
| Olo 5 mcg Bid | 0.201 |
| Olo 10 mcg qd | 0.149 |
FEV1 Area Under Curve 0-24 h (AUC 0-24h) Response After 3 Weeks of Treatment
Response was defined as change from baseline. Baseline FEV1 AUC (0-24) was defined as the AUC performed on the baseline visit, prior to the first dose of randomized treatment. 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. (NCT00846768)
Timeframe: Day0:-0:10,0:30,1,2,3,4,6,8,10,11:50h relative to planned morning dose on day1,0:30,1,2,10,11,11:50h relative to planned evening dose on day1; Day21:-0:10,0:30,1,2,3,4,6,8,10,11:50h relative to morning dose,0:30,1,2,10,11,11:50h relative to evening dose
| Intervention | Liter (Least Squares Mean) |
|---|---|
| Olo 2 mcg Bid | 0.160 |
| Olo 5 mcg qd | 0.182 |
| Olo 5 mcg Bid | 0.195 |
| Olo 10 mcg qd | 0.176 |
FEV1 Area Under Curve 0-12 h (AUC 0-12h) Response After 3 Weeks of Treatment
Response was defined as change from baseline. Baseline FEV1 AUC (0-12) was defined as the AUC performed on the baseline visit, prior to the first dose of randomized treatment. 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. (NCT00846768)
Timeframe: Day 0: -0:10, 0:30, 1, 2, 3, 4, 6, 8, 10, 11:50 h relative to planned morning dose on day 1; Day 21: -0:10, 0:30, 1, 2, 3, 4, 6, 8, 10, 11:50 h relative to morning dose
| Intervention | Liter (Least Squares Mean) |
|---|---|
| Olo 2 mcg Bid | 0.155 |
| Olo 5 mcg qd | 0.209 |
| Olo 5 mcg Bid | 0.189 |
| Olo 10 mcg qd | 0.204 |
Pharmacokinetics (PK): Fraction of Analyte Eliminated in Urine at Steady State From Time Point 0 Hours to Time Point 24 Hours
Fraction of analyte eliminated in urine at steady state from time point 0 hours to time point 24 hours after dosing in week 3. The start of inhalation was used as time point 0 for calculation of pharmacokinetic parameters. Descriptive statistics were calculated only if N>=16 had concentrations within the validated concentration range. (NCT00846768)
Timeframe: 3 weeks
| Intervention | percent (Geometric Mean) |
|---|---|
| Olo 5 mcg qd | 3.61 |
| Olo 10 mcg qd | 3.43 |
Trough FEV1 Response
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. Trough values were the mean of values obtained 23h and 23 h 50 min after the last dose of study drug after three weeks of treatment . (NCT00846768)
Timeframe: Baseline, 3 weeks
| Intervention | Liter (Least Squares Mean) |
|---|---|
| Olo 2 mcg Bid | 0.093 |
| Olo 5 mcg qd | 0.108 |
| Olo 5 mcg Bid | 0.129 |
| Olo 10 mcg qd | 0.087 |
Pharmacokinetics (PK): Fraction of Analyte Eliminated in Urine at Steady State From Time Point 0 Hours to Time Point 12 Hours
"Fraction of analyte eliminated in urine at steady state from time point 0 hours to time point 12 hours after dosing in week 3 (after the morning dose for the bid dose regimens). The start of inhalation was used as time point 0 for calculation of pharmacokinetic parameters.~Descriptive statistics were calculated only if N>=16 had concentrations within the validated concentration range." (NCT00846768)
Timeframe: 3 weeks
| Intervention | percent (Geometric Mean) |
|---|---|
| Olo 2 mcg Bid | 3.41 |
| Olo 5 mcg qd | 2.29 |
| Olo 5 mcg Bid | 3.55 |
| Olo 10 mcg qd | 2.13 |
Clinical Relevant Abnormalities for Vital Signs, Blood Chemistry, Haematology, Urinalysis, ECG and Physical Examination
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). (NCT00846768)
Timeframe: 3 weeks
| Intervention | percentage of participants (Number) | |
|---|---|---|
| Cardiac disorders | Investigations | |
| Olo 10 mcg qd | 0.0 | 0.0 |
| Olo 2 mcg Bid | 0.0 | 0.0 |
| Olo 5 mcg Bid | 0.0 | 0.0 |
| Olo 5 mcg qd | 0.0 | 0.0 |
Pharmacokinetics (PK): Amount of Analyte That is Eliminated in Urine at Steady State From the Time Point 0 Hours to Time Point 12 Hours
"Amount of analyte that is eliminated in urine at steady state from the time point 0 hours to time point 12 hours after dosing in week 3 (after the morning dose for the bid dose regimens). The start of inhalation was used as time point 0 for calculation of pharmacokinetic parameters.~Descriptive statistics were calculated only if N>=16 had concentrations within the validated concentration range." (NCT00846768)
Timeframe: 3 weeks
| Intervention | ng (Geometric Mean) |
|---|---|
| Olo 2 mcg Bid | 68.2 |
| Olo 5 mcg qd | 115 |
| Olo 5 mcg Bid | 177 |
| Olo 10 mcg qd | 213 |
Trough FVC Response
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. Trough values were the mean of values obtained 23h and 23 h 50 min after the last dose of study drug after three weeks of treatment . (NCT00846768)
Timeframe: Baseline, 3 weeks
| Intervention | Liter (Least Squares Mean) |
|---|---|
| Olo 2 mcg Bid | 0.111 |
| Olo 5 mcg qd | 0.177 |
| Olo 5 mcg Bid | 0.181 |
| Olo 10 mcg qd | 0.162 |
Adjusted Mean of Provocative Concentration of Methacholine Required to Produce a 20% Decrease in FEV1 (PC20FEV1) at 30 Minutes
Provocative concentration of methacholine required to produce a 20% decrease in FEV1 (PC20FEV1) at 30 minutes (NCT00928668)
Timeframe: 30 minutes post dose
| Intervention | Log base 2 (mg/ml) (Least Squares Mean) |
|---|---|
| Placebo | 0.393 |
| Olodaterol (Olo) 2 mcg qd | 2.532 |
| Olodaterol (Olo) 5 mcg qd | 3.029 |
| Olodaterol (Olo) 10 mcg qd | 3.953 |
| Olodaterol (Olo) 20 mcg qd | 4.617 |
Adjusted Mean of Provocative Concentration of Methacholine Required to Produce a 20% Decrease in FEV1 (PC20FEV1) at 24 Hours
Provocative concentration of methacholine required to produce a 20% decrease in FEV1 (PC20FEV1) at 24 hours (NCT00928668)
Timeframe: 24 hours post dose
| Intervention | Log base 2 (mg/ml) (Least Squares Mean) |
|---|---|
| Placebo | 0.793 |
| Olodaterol (Olo) 2 mcg qd | 1.950 |
| Olodaterol (Olo) 5 mcg qd | 2.504 |
| Olodaterol (Olo) 10 mcg qd | 3.236 |
| Olodaterol (Olo) 20 mcg qd | 3.777 |
Laboratory Testing: Average Change From Baseline of Potassium and Calcium
Laboratory testing: Average change from baseline of potassium and calcium measured on test-days (NCT00928668)
Timeframe: Baseline to Visit 6
| Intervention | mmol/L (Geometric Mean) | |
|---|---|---|
| Potassium | Calcium | |
| Olodaterol (Olo) 10 mcg qd | 1.00 | 1.00 |
| Olodaterol (Olo) 2 mcg qd | 1.04 | 1.01 |
| Olodaterol (Olo) 20 mcg qd | 0.98 | 1.01 |
| Olodaterol (Olo) 5 mcg qd | 1.02 | 1.00 |
| Placebo | 1.01 | 1.00 |
Clinical Relevant Abnormalities for Vital Signs, Blood Chemistry, Haematology, Urinalysis and ECG
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 (cardiac disorders and investigations). (NCT00928668)
Timeframe: 5 days
| Intervention | percentage of participants (Number) | |
|---|---|---|
| Cardiac disorders | Investigations | |
| Olo 10 mcg | 0 | 0 |
| Olo 2 mcg | 0 | 0 |
| Olo 20 mcg | 0 | 0 |
| Olo 5 mcg | 0 | 0 |
| Placebo | 0 | 0 |
Adjusted Mean of Provocative Concentration of Methacholine Required to Produce a 20% Decrease in FEV1 (PC20FEV1) at 8 Hours
Provocative concentration of methacholine required to produce a 20% decrease in FEV1 (PC20FEV1) at 8 hours (NCT00928668)
Timeframe: 8 hours post dose
| Intervention | Log base 2 (mg/ml) (Least Squares Mean) |
|---|---|
| Placebo | 0.576 |
| Olodaterol (Olo) 2 mcg qd | 2.484 |
| Olodaterol (Olo) 5 mcg qd | 3.050 |
| Olodaterol (Olo) 10 mcg qd | 3.903 |
| Olodaterol (Olo) 20 mcg qd | 4.796 |
Adjusted Mean of Provocative Concentration of Methacholine Required to Produce a 20% Decrease in FEV1 (PC20FEV1) at 4 Hours
Provocative concentration of methacholine required to produce a 20% decrease in FEV1 (PC20FEV1) at 4 hours (NCT00928668)
Timeframe: 4 hours post dose
| Intervention | Log base 2 (mg/ml) (Least Squares Mean) |
|---|---|
| Placebo | 0.577 |
| Olodaterol (Olo) 2 mcg qd | 2.602 |
| Olodaterol (Olo) 5 mcg qd | 2.957 |
| Olodaterol (Olo) 10 mcg qd | 4.126 |
| Olodaterol (Olo) 20 mcg qd | 4.786 |
Adjusted Mean of Provocative Concentration of Methacholine Required to Produce a 20% Decrease in FEV1 (PC20FEV1) at 32 Hours
Provocative concentration of methacholine required to produce a 20% decrease in FEV1 (PC20FEV1) at 32 hours (NCT00928668)
Timeframe: 32 hours post dose
| Intervention | Log base 2 (mg/ml) (Least Squares Mean) |
|---|---|
| Placebo | 0.960 |
| Olodaterol (Olo) 2 mcg qd | 2.189 |
| Olodaterol (Olo) 5 mcg qd | 2.785 |
| Olodaterol (Olo) 10 mcg qd | 3.074 |
| Olodaterol (Olo) 20 mcg qd | 3.605 |
Clinical Relevant Abnormalities for Vital Signs, Blood Chemistry, Haematology, Urinalysis and ECG
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). (NCT00932646)
Timeframe: 6 weeks
| Intervention | participants (Number) | ||
|---|---|---|---|
| Bundle branch block right | ECG QT prolonged | Tachycardia | |
| Form 12 mcg | 0 | 0 | 1 |
| Olo 10 mcg | 1 | 1 | 0 |
| Olo 5 mcg | 0 | 0 | 0 |
| Placebo | 0 | 0 | 0 |
Trough FVC Response
Response was defined as change from baseline. Study baseline FVC was defined as the mean of the available pre-dose FVC values at the randomisation visit. Trough values were obtained 30 minutes prior to the last am dose of study drug after six weeks of treatment . Means are adjusted using a mixed effects model with center, treatment and period as fixed effects and patient within center as random. (NCT00932646)
Timeframe: Baseline and 6 weeks
| Intervention | Liter (Least Squares Mean) |
|---|---|
| Placebo | -0.007 |
| Olo 5 mcg qd | 0.125 |
| Olo 10 mcg qd | 0.133 |
| Form 12 mcg Bid | 0.141 |
Trough FEV1 Response
Response was defined as change from baseline. Study baseline FEV1 was defined as the mean of the available pre-dose FEV1 values at the randomisation visit. Trough values were obtained 30 minutes prior to the last am dose of study drug after six weeks of treatment . Means are adjusted using a mixed effects model with center, treatment and period as fixed effects and patient within center as random. (NCT00932646)
Timeframe: Baseline and 6 weeks
| Intervention | Liter (Least Squares Mean) |
|---|---|
| Placebo | 0.012 |
| Olo 5 mcg qd | 0.109 |
| Olo 10 mcg qd | 0.115 |
| Form 12 mcg Bid | 0.093 |
Peak FVC (0-3h) Response
Response was defined as change from baseline. Study baseline FVC was defined as the mean of the available pre-dose FVC values at the randomisation visit. Peak FVC 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 center, treatment and period as fixed effects and patient within center as random. (NCT00932646)
Timeframe: Baseline and 6 weeks
| Intervention | Liter (Least Squares Mean) |
|---|---|
| Placebo | 0.138 |
| Olo 5 mcg qd | 0.436 |
| Olo 10 mcg qd | 0.440 |
| Form 12 mcg Bid | 0.475 |
FVC Area Under Curve 12-24 Hours (AUC 12-24h) Response
Response was defined as change from baseline. Study baseline FVC was defined as the mean of the available pre-dose FVC values at the randomisation visit. Means are adjusted using a mixed effects model with center, treatment and period as fixed effects and patient within center as random. FVC AUC 12-24h was calculated using the trapezoidal rule, divided by the observation time to report in litres. (NCT00932646)
Timeframe: 1 h and 10 min prior to am dose on the first day of treatment (baseline) and 12 h 30 min, 13 h, 14 h, 22 h, 23 h, and 23 h 50 min relative to am dose after six weeks of treatment
| Intervention | Liter (Least Squares Mean) |
|---|---|
| Placebo | -0.078 |
| Olo 5 mcg qd | 0.083 |
| Olo 10 mcg qd | 0.079 |
| Form 12 mcg Bid | 0.144 |
FVC Area Under Curve 0-24 Hours (AUC 0-24h) Response
Response was defined as change from baseline. Study baseline FVC was defined as the mean of the available pre-dose FVC values at the randomisation visit. Means are adjusted using a mixed effects model with center, treatment and period as fixed effects and patient within center as random. FVC AUC 0-24h was calculated using the trapezoidal rule, divided by the observation time to report in litres. (NCT00932646)
Timeframe: 1 h and 10 min prior to am dose on the first day of treatment (baseline) and -30 min, 30 min, 60 min, 2h, 3h, 4h, 6h, 8h, 10h, 11 hr 50 min,12 h 30 min, 13 h, 14 h, 22 h, 23 h, and 23 h 50 min relative to am dose after six weeks of treatment.
| Intervention | Liter (Least Squares Mean) |
|---|---|
| Placebo | -0.055 |
| Olo 5 mcg qd | 0.151 |
| Olo 10 mcg qd | 0.147 |
| Form 12 mcg Bid | 0.174 |
Forced Vital Capacity (FVC) Area Under Curve 0-12 Hours (AUC 0-12h) Response
Response was defined as change from baseline. Study baseline FVC was defined as the mean of the available pre-dose FVC values at the randomisation visit. Means are adjusted using a mixed effects model with center, treatment and period as fixed effects and patient within center as random. FVC AUC 0-12h was calculated using the trapezoidal rule, divided by the observation time to report in litres. (NCT00932646)
Timeframe: 1 hour (h) and 10 minutes (min) prior to am dose on the first day of treatment (baseline) and -30 min (zero time), 30 min, 60 min, 2 hour (h) , 3 h, 4 h, 6 h, 8 h, 10 h, 11 h 50 min relative to am dose after six weeks of treatment
| Intervention | Liter (Least Squares Mean) |
|---|---|
| Placebo | -0.032 |
| Olo 5 mcg qd | 0.219 |
| Olo 10 mcg qd | 0.214 |
| Form 12 mcg Bid | 0.203 |
Forced Expiratory Volume in 1 Second (FEV1) Area Under Curve 0-3 h (AUC 0-3h) Response After Six Weeks of Treatment
Response was defined as change from baseline. Study baseline FEV1 was defined as the mean of the available pre-dose FEV1 values at the randomisation visit. Means are adjusted using a mixed effects model with center, treatment and period as fixed effects and patient within center as random. 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. (NCT00932646)
Timeframe: 1 hour (h) prior and 10 minutes (min) prior to first dose (baseline) and -30 min, 30 min, 60 min, 2 h , 3 h, relative to am dose after six weeks of treatment
| Intervention | Liter (Least Squares Mean) |
|---|---|
| Placebo | 0.004 |
| Olo 5 mcg qd | 0.190 |
| Olo 10 mcg qd | 0.202 |
| Form 12 mcg Bid | 0.217 |
Forced Expiratory Volume in 1 Second (FEV1) Area Under Curve 0-24 h (AUC 0-24h) Response After Six Weeks of Treatment
Response was defined as change from baseline. Study baseline FEV1 was defined as the mean of the available pre-dose FEV1 values at the randomisation visit. Means are adjusted using a mixed effects model with center, treatment and period as fixed effects and patient within center as random.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. (NCT00932646)
Timeframe: 1 h and 10 min prior to am dose on the first day of the treatment (baseline) and -30 min, 30 min, 60 min, 2h, 3h, 4h, 6h, 8h, 10h, 11 hr 50 min,12 h 30 min, 13 h, 14 h, 22 h, 23 h, and 23 h 50 min relative to am dose after six weeks of treatment.
| Intervention | Liter (Least Squares Mean) |
|---|---|
| Placebo | -0.035 |
| Olo 5 mcg qd | 0.110 |
| Olo 10 mcg qd | 0.112 |
| Form 12 mcg Bid | 0.121 |
Peak FEV1 (0-3h) Response
Response was defined as change from baseline. Study baseline FEV1 was defined as the mean of the available pre-dose FEV1 values at the randomisation visit. Peak values were obtained within 0 - 3 hours after the last am dose after six weeks of treatment. Means are adjusted using a mixed effects model with center, treatment and period as fixed effects and patient within center as random. (NCT00932646)
Timeframe: Baseline and 6 weeks
| Intervention | Liter (Least Squares Mean) |
|---|---|
| Placebo | 0.076 |
| Olo 5 mcg qd | 0.268 |
| Olo 10 mcg qd | 0.273 |
| Form 12 mcg Bid | 0.293 |
FEV1 Area Under Curve 0-12 h (AUC 0-12h) Response After Six Weeks of Treatment
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, just prior to administration of the morning dose of randomized treatment. Means are adjusted using a mixed effects model with center, treatment and period as fixed effects and patient within center as random. 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. (NCT00932646)
Timeframe: 1 hour (h) and 10 minutes (min) prior to am dose on the first day of treatment (baseline) and -30 min (zero time), 30 min, 60 min, 2 hour (h) , 3 h, 4 h, 6 h, 8 h, 10 h, 11 h 50 min relative to am dose after six weeks of treatment
| Intervention | Liter (Least Squares Mean) |
|---|---|
| Placebo | -0.022 |
| Olo 5 mcg qd | 0.150 |
| Olo 10 mcg qd | 0.152 |
| Form 12 mcg Bid | 0.136 |
FEV1 Area Under Curve 12-24h (AUC 12-24h) Response After Six Weeks of Treatment
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, just prior to administration of the morning dose of randomized treatment. Means are adjusted using a mixed effects model with center, treatment and period as fixed effects and patient within center as random. 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. (NCT00932646)
Timeframe: 1 h and 10 min prior to am dose on the first day of treatment (baseline) and 12 h 30 min, 13 h, 14 h, 22 h, 23 h, and 23 h 50 min relative to am dose after six weeks of treatment
| Intervention | Liter (Least Squares Mean) |
|---|---|
| Placebo | -0.048 |
| Olo 5 mcg qd | 0.069 |
| Olo 10 mcg qd | 0.072 |
| Form 12 mcg Bid | 0.107 |
Peak FVC Within 24 Hours Post-dose Response
Response was defined as change from baseline. Study baseline FVC was defined as the mean of the available pre-dose FVC values at the randomisation visit. Peak FVC within 24 hours post dose measured following the trial drug inhalation at the end of each 4 week period of randomised treatment. Means are adjusted for treatment, period, patient and study baseline. (NCT01013753)
Timeframe: 1 hour (h) prior and 10 minutes (min) prior to first dose (baseline) and 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 after 4 weeks
| Intervention | Liter (Mean) |
|---|---|
| Placebo | 0.253 |
| Olo 2 mcg qd | 0.300 |
| Olo 5 mcg qd | 0.356 |
| Olo 10 mcg qd | 0.342 |
| Olo 20 mcg qd | 0.380 |
| Form 12 mcg Bid | 0.326 |
Peak PEF Within 24 Hours Post-dose Response
Response was defined as change from baseline. Study baseline PEF was defined as the mean of the available pre-dose PEF values at the randomisation visit. Peak PEF within 24 hours post-dose measured following the evening trial drug inhalation at the end of each 4 week period of randomised treatment. Means are adjusted for treatment, period, patient and study baseline. (NCT01013753)
Timeframe: 1 hour (h) prior and 10 minutes (min) prior to first dose (baseline) and 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 after 4 weeks
| Intervention | Liter/sec (Mean) |
|---|---|
| Placebo | 0.664 |
| Olo 2 mcg qd | 0.966 |
| Olo 5 mcg qd | 1.093 |
| Olo 10 mcg qd | 1.130 |
| Olo 20 mcg qd | 1.198 |
| Form 12 mcg Bid | 1.168 |
PEF Area Under Curve 12-24 Hours (AUC 12-24h) Response
Response was defined as change from baseline. Study baseline PEF was defined as the mean of the available pre-dose PEF values at the randomisation visit. Means are adjusted for treatment, period, patient and study baseline. PEF AUC 12-24h was calculated using the trapezoidal rule, divided by the observation time to report in litres/seconds. (NCT01013753)
Timeframe: 1 hour (h) prior and 10 minutes (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 after 4 weeks
| Intervention | Liter/sec (Mean) |
|---|---|
| Placebo | 0.043 |
| Olo 2 mcg qd | 0.380 |
| Olo 5 mcg qd | 0.528 |
| Olo 10 mcg qd | 0.575 |
| Olo 20 mcg qd | 0.692 |
| Form 12 mcg Bid | 0.594 |
PEF Daily Variability
PEF daily variability was assessed by patients at home using the AM2+ device (overall means obtained during each period of randomised treatment excluding the data of the first 2 weeks will be compared). PEF daily variability is the absolute difference between the morning and the evening PEF value divided by the mean of these two values, expressed as a percent. Means are adjusted for treatment, period, patient and study baseline. (NCT01013753)
Timeframe: 2-4 weeks
| Intervention | Percentage (Mean) |
|---|---|
| Placebo | 11.688 |
| Olo 2 mcg qd | 9.694 |
| Olo 5 mcg qd | 9.593 |
| Olo 10 mcg qd | 9.851 |
| Olo 20 mcg qd | 9.899 |
| Form 12 mcg Bid | 10.417 |
Percentage of Asthma Symptom Free Days
Percentage of asthma-symptom free days after the first 2 weeks of each treatment period was calculated as the number of symptom-free days divided by the number of days on treatment multiplied by 100. A symptom-free day was defined as a day in which no asthma symptoms were recorded, no rescue medication was recorded, activities during the day were not at all limited due to asthma, no shortness of breath during the day was recorded, no wheezing or coughing during the day and no night-time awakenings due to asthma were recorded. Assessed by patients at home using the AM2+ device. (NCT01013753)
Timeframe: 2-4 weeks
| Intervention | Percentage of asthma symptom free days (Mean) |
|---|---|
| Placebo | 18.502 |
| Olo 2 mcg qd | 26.430 |
| Olo 5 mcg qd | 22.348 |
| Olo 10 mcg qd | 23.624 |
| Olo 20 mcg qd | 21.326 |
| Form 12 mcg Bid | 23.664 |
Potassium 1 Hour Post-dose
Effect on potassium evaluated 1 hour post-dose. Analysis is based on the log of the potassium values. For the geometric means, the results were back-transformed to the original scale. (NCT01013753)
Timeframe: 4 weeks
| Intervention | mmol/L (Geometric Mean) |
|---|---|
| Placebo | 4.097 |
| Olo 2 mcg qd | 4.069 |
| Olo 5 mcg qd | 4.013 |
| Olo 10 mcg qd | 4.004 |
| Olo 20 mcg qd | 4.015 |
| Form 12 mcg Bid | 4.059 |
Potassium 1 Hour Pre-dose
Effect on potassium evaluated 1 hour pre-dose. Analysis is based on the log of the potassium values. For the geometric means, the results were back-transformed to the original scale. (NCT01013753)
Timeframe: 4 weeks
| Intervention | mmol/L (Geometric Mean) |
|---|---|
| Placebo | 4.067 |
| Olo 2 mcg qd | 4.051 |
| Olo 5 mcg qd | 4.051 |
| Olo 10 mcg qd | 4.061 |
| Olo 20 mcg qd | 4.057 |
| Form 12 mcg Bid | 4.080 |
Potassium 3 Hours Post-dose
Effect on potassium evaluated 3 hours post-dose. Analysis is based on the log of the potassium values. For the geometric means, the results were back-transformed to the original scale. (NCT01013753)
Timeframe: 4 weeks
| Intervention | mmol/L (Geometric Mean) |
|---|---|
| Placebo | 4.029 |
| Olo 2 mcg qd | 4.026 |
| Olo 5 mcg qd | 3.997 |
| Olo 10 mcg qd | 3.979 |
| Olo 20 mcg qd | 3.992 |
| Form 12 mcg Bid | 4.007 |
Total Asthma Control Questionnaire (ACQ) Score
Control of asthma as assessed by the ACQ at the end of each 4-week treatment period.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. (NCT01013753)
Timeframe: 4 weeks
| Intervention | units on a scale (Mean) |
|---|---|
| Placebo | 1.882 |
| Olo 2 mcg qd | 1.561 |
| Olo 5 mcg qd | 1.589 |
| Olo 10 mcg qd | 1.556 |
| Olo 20 mcg qd | 1.488 |
| Form 12 mcg Bid | 1.536 |
Total Asthma Quality of Life Questionnaire (AQLQ(s)) Score
Total score from the Standardised Asthma Quality of Life Questionnaire (AQLQ (s)) at the end of each 4 week treatment period. 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. (NCT01013753)
Timeframe: 4 weeks
| Intervention | units on a scale (Mean) |
|---|---|
| Placebo | 5.174 |
| Olo 2 mcg qd | 5.463 |
| Olo 5 mcg qd | 5.383 |
| Olo 10 mcg qd | 5.437 |
| Olo 20 mcg qd | 5.491 |
| Form 12 mcg Bid | 5.489 |
Trough FEV1 Response
Response was defined as change from baseline. Study baseline FEV1 was defined as the mean of the available pre-dose FEV1 values at the randomisation visit. Trough values were defined as the mean of 2 FEV1 values performed at the planned timepoints 23h and 23h 50min related to evening trial-drug inhalation at the end of each 4 week period of randomised treatment. Means are adjusted for treatment, period, patient and study baseline. (NCT01013753)
Timeframe: 1 hour (h) prior and 10 minutes (min) prior to first dose (baseline) and 23 h, and 23 h 50 min related to evening dose after 4 weeks
| Intervention | Liter (Mean) |
|---|---|
| Placebo | 0.013 |
| Olo 2 mcg qd | 0.116 |
| Olo 5 mcg qd | 0.146 |
| Olo 10 mcg qd | 0.182 |
| Olo 20 mcg qd | 0.211 |
| Form 12 mcg Bid | 0.115 |
Trough FVC Response
Response was defined as change from baseline. Study baseline FVC was defined as the mean of the available pre-dose FVC values at the randomisation visit. Trough values were defined as the mean of 2 FEV1 values performed at the planned timepoints 23h and 23h 50min related to evening trial-drug inhalation at the end of each 4 week period of randomised treatment. Means are adjusted for treatment, period, patient and study baseline. (NCT01013753)
Timeframe: 1 hour (h) prior and 10 minutes (min) prior to first dose (baseline) and 23 h, and 23 h 50 min related to evening dose after 4 weeks
| Intervention | Liter (Mean) |
|---|---|
| Placebo | -0.022 |
| Olo 2 mcg qd | 0.015 |
| Olo 5 mcg qd | 0.069 |
| Olo 10 mcg qd | 0.088 |
| Olo 20 mcg qd | 0.107 |
| Form 12 mcg Bid | 0.029 |
Trough PEF Response
Response was defined as change from baseline. Study baseline PEF was defined as the mean of the available pre-dose PEF values at the randomisation visit. Trough values were defined as the mean of 2 FEV1 values performed at the planned timepoints 23h and 23h 50min related to evening trial-drug inhalation at the end of each 4 week period of randomised treatment. Means are adjusted for treatment, period, patient and study baseline. (NCT01013753)
Timeframe: 1 hour (h) prior and 10 minutes (min) prior to first dose (baseline) and 23 h, and 23 h 50 min related to evening dose after 4 weeks
| Intervention | Liter/sec (Mean) |
|---|---|
| Placebo | 0.031 |
| Olo 2 mcg qd | 0.295 |
| Olo 5 mcg qd | 0.499 |
| Olo 10 mcg qd | 0.515 |
| Olo 20 mcg qd | 0.655 |
| Form 12 mcg Bid | 0.478 |
Clinical Relevant Abnormalities for Vital Signs, Blood Chemistry, Haematology, Urinalysis and ECG
Clinical relevant abnormalities for Vital Signs, Blood Chemistry, Haematology, Urinalysis and ECG. New abnormal findings or worsening of baseline conditions were reported as Adverse Events. (NCT01013753)
Timeframe: 4 weeks
| Intervention | Participants (Number) | |||||
|---|---|---|---|---|---|---|
| Atrioventricular block first degree | Blood creatine phosphokinase MB increased | Blood creatine phosphokinase increased | Blood pressure increased | Hypothyroidism | Hypertension | |
| Form 12 mcg Bid | 1 | 0 | 0 | 0 | 0 | 0 |
| Olo 10 mcg qd | 0 | 1 | 1 | 0 | 0 | 1 |
| Olo 2 mcg qd | 0 | 0 | 0 | 1 | 0 | 0 |
| Olo 20 mcg qd | 1 | 0 | 0 | 0 | 0 | 1 |
| Olo 5 mcg qd | 0 | 0 | 0 | 0 | 1 | 1 |
| Placebo | 0 | 0 | 0 | 0 | 0 | 0 |
Number of Patients Categorized by Highest Number of Night Time Awakenings (Overall)
Assessed by patients at home using the AM2+ device after the first 2 weeks of each period of randomised treatment. (NCT01013753)
Timeframe: 2-4 weeks
| Intervention | Number of patients (Number) | ||||
|---|---|---|---|---|---|
| Did not wake up | Woke up once | Woke up 2-5 times | Woke up > 5 times | Was awake all night | |
| Form 12 mcg Bid | 59 | 29 | 33 | 2 | 0 |
| Olo 10 mcg qd | 56 | 34 | 30 | 1 | 2 |
| Olo 2 mcg qd | 60 | 36 | 17 | 5 | 1 |
| Olo 20 mcg qd | 63 | 34 | 20 | 2 | 1 |
| Olo 5 mcg qd | 58 | 34 | 30 | 2 | 2 |
| Placebo | 55 | 37 | 26 | 3 | 1 |
Number of Patients Categorized by Worst Asthma Daytime Symptoms (Overall)
Assessed by patients at home using the AM2+ device after the first 2 weeks of each period of randomised treatment. (NCT01013753)
Timeframe: 2-4 weeks
| Intervention | Number of patients (Number) | ||||
|---|---|---|---|---|---|
| No asthma symptoms | Mild asthma symptoms | Moderate asthma symptoms | Severe asthma symptoms | Very severe asthma symptoms | |
| Form 12 mcg Bid | 24 | 37 | 49 | 12 | 1 |
| Olo 10 mcg qd | 23 | 37 | 52 | 10 | 1 |
| Olo 2 mcg qd | 26 | 46 | 37 | 10 | 0 |
| Olo 20 mcg qd | 21 | 38 | 54 | 6 | 1 |
| Olo 5 mcg qd | 29 | 29 | 51 | 12 | 5 |
| Placebo | 20 | 31 | 56 | 15 | 0 |
Number of Patients Categorized by Worst Asthma Nighttime Symptoms (Overall)
Assessed by patients at home using the AM2+ device after the first 2 weeks of each period of randomised treatment. (NCT01013753)
Timeframe: 2-4 weeks
| Intervention | Number of patients (Number) | ||||
|---|---|---|---|---|---|
| No asthma symptoms | Mild asthma symptoms | Moderate asthma symptoms | Severe asthma symptoms | Very severe asthma symptoms | |
| Form 12 mcg Bid | 26 | 39 | 46 | 10 | 2 |
| Olo 10 mcg qd | 25 | 40 | 46 | 10 | 2 |
| Olo 2 mcg qd | 31 | 47 | 29 | 10 | 2 |
| Olo 20 mcg qd | 27 | 45 | 43 | 5 | 0 |
| Olo 5 mcg qd | 22 | 48 | 45 | 11 | 0 |
| Placebo | 27 | 32 | 49 | 14 | 0 |
FEV1 Area Under Curve 0-12 h (AUC 0-12h) Response at the End of Each Treatment Period
Response was defined as change from baseline. Study baseline FEV1 was defined as the mean of the available pre-dose FEV1 values at the randomisation visit. Means are adjusted for treatment, period, patient and study baseline. 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. (NCT01013753)
Timeframe: 1 hour (h) prior and 10 minutes (min) prior to first dose (baseline) and -1 h, -10 mins, 30 min, 60 min, 2 h, 3 h, 4 h, 11 h 50 min related to evening dose after 4 weeks
| Intervention | Liter (Mean) |
|---|---|
| Placebo | -0.039 |
| Olo 2 mcg qd | 0.124 |
| Olo 5 mcg qd | 0.173 |
| Olo 10 mcg qd | 0.194 |
| Olo 20 mcg qd | 0.211 |
| Form 12 mcg Bid | 0.145 |
FEV1 Area Under Curve 12-24 h (AUC 12-24h) Response at the End of Each Treatment Period
Response was defined as change from baseline. Study baseline FEV1 was defined as the mean of the available pre-dose FEV1 values at the randomisation visit. Means are adjusted for treatment, period, patient and study baseline. 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. (NCT01013753)
Timeframe: 1 hour (h) prior and 10 minutes (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 after 4 weeks
| Intervention | Liter (Mean) |
|---|---|
| Placebo | 0.031 |
| Olo 2 mcg qd | 0.147 |
| Olo 5 mcg qd | 0.183 |
| Olo 10 mcg qd | 0.208 |
| Olo 20 mcg qd | 0.238 |
| Form 12 mcg Bid | 0.183 |
Forced Expiratory Volume in 1 Second (FEV1) Area Under Curve 0-24 Hours (AUC 0-24h) Response at the End of Each Treatment Period
Response was defined as change from baseline. Study baseline FEV1 was defined as the mean of the available pre-dose FEV1 values at the randomisation visit. Means are adjusted for treatment, period, patient and study baseline. 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. (NCT01013753)
Timeframe: 1 hour (h) prior and 10 minutes (min) prior to first dose (baseline) and -1 h, -10 mins, 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 after 4 weeks
| Intervention | Liter (Mean) |
|---|---|
| Placebo | -0.004 |
| Olo 2 mcg qd | 0.135 |
| Olo 5 mcg qd | 0.178 |
| Olo 10 mcg qd | 0.201 |
| Olo 20 mcg qd | 0.225 |
| Form 12 mcg Bid | 0.164 |
Forced Vital Capacity (FVC) Area Under Curve 0-12 Hours (AUC 0-12h) Response
Response was defined as change from baseline. Study baseline FVC was defined as the mean of the available pre-dose FVC values at the randomisation visit. Means are adjusted for treatment, period, patient and study baseline. FVC AUC 0-12h was calculated using the trapezoidal rule, divided by the observation time to report in litres. (NCT01013753)
Timeframe: 1 hour (h) prior and 10 minutes (min) prior to first dose (baseline) and -1 h, -10 mins, 30 min, 60 min, 2 h , 3 h, 4 h, 11 h 50 min related to evening dose after 4 weeks
| Intervention | Liter (Mean) |
|---|---|
| Placebo | -0.047 |
| Olo 2 mcg qd | 0.056 |
| Olo 5 mcg qd | 0.109 |
| Olo 10 mcg qd | 0.094 |
| Olo 20 mcg qd | 0.122 |
| Form 12 mcg Bid | 0.055 |
FVC Area Under Curve 0-24 Hours (AUC 0-24h) Response
Response was defined as change from baseline. Study baseline FVC was defined as the mean of the available pre-dose FVC values at the randomisation visit. Means are adjusted for treatment, period, patient and study baseline. FVC AUC 0-24h was calculated using the trapezoidal rule, divided by the observation time to report in litres. (NCT01013753)
Timeframe: 1 hour (h) prior and 10 minutes (min) prior to first dose (baseline) and -1 h, -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 after 4 weeks
| Intervention | Liter (Mean) |
|---|---|
| Placebo | -0.026 |
| Olo 2 mcg qd | 0.056 |
| Olo 5 mcg qd | 0.109 |
| Olo 10 mcg qd | 0.102 |
| Olo 20 mcg qd | 0.131 |
| Form 12 mcg Bid | 0.070 |
FVC Area Under Curve 12-24 Hours (AUC 12-24h) Response
Response was defined as change from baseline. Study baseline FVC was defined as the mean of the available pre-dose FVC values at the randomisation visit. Means are adjusted for treatment, period, patient and study baseline. FVC AUC 12-24h was calculated using the trapezoidal rule, divided by the observation time to report in litres. (NCT01013753)
Timeframe: 1 hour (h) prior and 10 minutes (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 after 4 weeks
| Intervention | Liter (Mean) |
|---|---|
| Placebo | -0.005 |
| Olo 2 mcg qd | 0.055 |
| Olo 5 mcg qd | 0.109 |
| Olo 10 mcg qd | 0.110 |
| Olo 20 mcg qd | 0.139 |
| Form 12 mcg Bid | 0.085 |
Mean Number of Puffs of Rescue Medication During the Whole Day
Mean of daily use of salbutamol (albuterol) rescue medication as needed during the entire study period. Assessed by patients at home using the AM2+ device (overall means obtained during each period of randomised treatment excluding the data of the first 2 weeks will be compared). Means are adjusted for treatment, period, patient and study baseline. (NCT01013753)
Timeframe: 2-4 weeks
| Intervention | Number of Puffs (Mean) |
|---|---|
| Placebo | 1.749 |
| Olo 2 mcg qd | 1.222 |
| Olo 5 mcg qd | 1.317 |
| Olo 10 mcg qd | 1.271 |
| Olo 20 mcg qd | 1.092 |
| Form 12 mcg Bid | 1.300 |
Mean Pre-dose Evening FEV1 (FEV1 p.m.)
FEV1 p.m. was measured by patients at home using the AM2+ device (overall means obtained during each period of randomised treatment excluding the data of the first 2 weeks will be compared). Means are adjusted for treatment, period, patient and study baseline. (NCT01013753)
Timeframe: 2-4 weeks
| Intervention | L (Mean) |
|---|---|
| Placebo | 2.378 |
| Olo 2 mcg qd | 2.428 |
| Olo 5 mcg qd | 2.460 |
| Olo 10 mcg qd | 2.467 |
| Olo 20 mcg qd | 2.495 |
| Form 12 mcg Bid | 2.457 |
Mean Pre-dose Evening PEF (PEF p.m.)
PEF p.m. was measured by patients at home using the AM2+ device (overall means obtained during each period of randomised treatment excluding the data of the first 2 weeks will be compared). Means are adjusted for treatment, period, patient and study baseline. (NCT01013753)
Timeframe: 2-4 weeks
| Intervention | Liter/min (Mean) |
|---|---|
| Placebo | 379.44 |
| Olo 2 mcg qd | 394.36 |
| Olo 5 mcg qd | 404.28 |
| Olo 10 mcg qd | 403.06 |
| Olo 20 mcg qd | 407.89 |
| Form 12 mcg Bid | 399.88 |
Mean Pre-dose Morning FEV1 (FEV1 a.m.)
FEV1 a.m. was measured by patients at home using the AM2+ device (overall means obtained during each period of randomised treatment excluding the data of the first 2 weeks will be compared). Means are adjusted for treatment, period, patient and study baseline. (NCT01013753)
Timeframe: 2-4 weeks
| Intervention | L (Mean) |
|---|---|
| Placebo | 2.309 |
| Olo 2 mcg qd | 2.402 |
| Olo 5 mcg qd | 2.438 |
| Olo 10 mcg qd | 2.445 |
| Olo 20 mcg qd | 2.479 |
| Form 12 mcg Bid | 2.403 |
Mean Pre-dose Morning PEF (PEF a.m.)
PEF a.m. was measured by patients at home using the AM2+ device (overall means obtained during each period of randomised treatment excluding the data of the first 2 weeks will be compared). Means are adjusted for treatment, period, patient and study baseline. (NCT01013753)
Timeframe: 2-4 weeks
| Intervention | Liter/min (Mean) |
|---|---|
| Placebo | 361.89 |
| Olo 2 mcg qd | 383.90 |
| Olo 5 mcg qd | 390.91 |
| Olo 10 mcg qd | 389.78 |
| Olo 20 mcg qd | 394.82 |
| Form 12 mcg Bid | 385.42 |
Peak Expiratory Flow (PEF) Area Under Curve 0-12 Hours (AUC 0-12h) Response
Response was defined as change from baseline. Study baseline PEF was defined as the mean of the available pre-dose PEF values at the randomisation visit. Means are adjusted for treatment, period, patient and study baseline. PEF AUC 0-12h was calculated using the trapezoidal rule, divided by the observation time to report in litres/seconds. (NCT01013753)
Timeframe: 1 hour (h) prior and 10 minutes (min) prior to first dose (baseline) and -1 h, -10 mins, 30 min, 60 min, 2 h, 3 h, 4 h, 11 h 50 min related to evening dose after 4 weeks
| Intervention | Liter/sec (Mean) |
|---|---|
| Placebo | -0.117 |
| Olo 2 mcg qd | 0.291 |
| Olo 5 mcg qd | 0.449 |
| Olo 10 mcg qd | 0.495 |
| Olo 20 mcg qd | 0.553 |
| Form 12 mcg Bid | 0.471 |
Peak Expiratory Flow (PEF) Area Under Curve 0-24 Hours (AUC 0-24h) Response
Response was defined as change from baseline. Study baseline PEF was defined as the mean of the available pre-dose PEF values at the randomisation visit. Means are adjusted for treatment, period, patient and study baseline. PEF AUC 0-24h was calculated using the trapezoidal rule, divided by the observation time to report in litres/seconds. (NCT01013753)
Timeframe: 1 hour (h) prior and 10 minutes (min) prior to first dose (baseline) and -1h, -10 mins, 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 after 4 weeks
| Intervention | Liter/sec (Mean) |
|---|---|
| Placebo | -0.038 |
| Olo 2 mcg qd | 0.336 |
| Olo 5 mcg qd | 0.489 |
| Olo 10 mcg qd | 0.534 |
| Olo 20 mcg qd | 0.623 |
| Form 12 mcg Bid | 0.532 |
Peak FEV1 Within 24 Hours Post-dose Response
Response was defined as change from baseline. Study baseline FEV1 was defined as the mean of the available pre-dose FEV1 values at the randomisation visit. Peak FEV1 within 24 hours post dose measured following the evening trial drug inhalation at the end of each 4 week period of randomised treatment. Means are adjusted for treatment, period, patient and study baseline. (NCT01013753)
Timeframe: 1 hour (h) prior and 10 minutes (min) prior to first dose (baseline) and 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 after 4 weeks
| Intervention | Liter (Mean) |
|---|---|
| Placebo | 0.224 |
| Olo 2 mcg qd | 0.326 |
| Olo 5 mcg qd | 0.359 |
| Olo 10 mcg qd | 0.385 |
| Olo 20 mcg qd | 0.404 |
| Form 12 mcg Bid | 0.390 |
Adjusted Mean Forced Expiratory Volume in 1 Second, 1 Hour Post-dose After 6 Weeks
(NCT01040130)
Timeframe: 6 weeks
| Intervention | liters (Least Squares Mean) |
|---|---|
| Placebo | 1.473 |
| Olo 5 mcg qd | 1.698 |
| Olo 10 mcg qd | 1.699 |
Adjusted Mean Peak Expiratory Flow Rate, 30 Minutes Pre-dose After 6 Weeks
(NCT01040130)
Timeframe: 6 weeks
| Intervention | liters/second (Least Squares Mean) |
|---|---|
| Placebo | 4.374 |
| Olo 5 mcg qd | 4.692 |
| Olo 10 mcg qd | 4.677 |
Adjusted Mean Forced Vital Capacity, 30 Minutes Pre-dose After 6 Weeks
(NCT01040130)
Timeframe: 6 weeks
| Intervention | liters (Least Squares Mean) |
|---|---|
| Placebo | 3.212 |
| Olo 5 mcg qd | 3.319 |
| Olo 10 mcg qd | 3.310 |
Adjusted Mean Functional Residual Capacity 1 Hour Post-dose After 6 Weeks
(NCT01040130)
Timeframe: 6 weeks
| Intervention | liters (Least Squares Mean) |
|---|---|
| Placebo | 4.950 |
| Olo 5 mcg qd | 4.740 |
| Olo 10 mcg qd | 4.577 |
Number of Patients With Notable Increase in QRS Intervals
Number of Patients with notable increase in QRS intervals. Notable QRS interval increase defined as >=10% increase and on-treatment QRS interval > 110 ms. (NCT01040130)
Timeframe: Baseline and Week 6
| Intervention | percentage of participants (Number) | |||
|---|---|---|---|---|
| 30 min pre-dose: increase (N=138, 139, 140) | 30 min pre-dose: no increase (N=138, 139, 140) | 40 min post-dose: increase (N=138, 141, 138) | 40 min post-dose: no increase (N=138, 141, 138) | |
| Olo 10 mcg | 0.0 | 100.0 | 0.7 | 99.3 |
| Olo 5 mcg | 0.7 | 99.3 | 0.7 | 99.3 |
| Placebo | 0.7 | 99.3 | 0.7 | 99.3 |
Number of Patients With Notable Increase in PR Intervals
Number of Patients with notable increase in PR intervals. Notable PR interval increase defined as >=25% increase and on-treatment PR interval > 200 ms. (NCT01040130)
Timeframe: Baseline and Week 6
| Intervention | percentage of participants (Number) | |||
|---|---|---|---|---|
| 30 min pre-dose: increase (N=137, 137, 139) | 30 min pre-dose: no increase (N=137, 137, 139) | 40 min post-dose: increase (N=137, 140, 137) | 40 min post-dose: no increase (N=137, 140, 137) | |
| Olo 10 mcg | 0.0 | 100.0 | 0.7 | 99.3 |
| Olo 5 mcg | 0.7 | 99.3 | 0.0 | 100.0 |
| Placebo | 0.0 | 100.0 | 0.0 | 100.0 |
Adjusted Mean Peak Expiratory Flow Rate, 1 Hour Post-dose After 6 Weeks
(NCT01040130)
Timeframe: 6 weeks
| Intervention | liters/second (Least Squares Mean) |
|---|---|
| Placebo | 4.363 |
| Olo 5 mcg qd | 4.949 |
| Olo 10 mcg qd | 4.981 |
Adjusted Mean Inspiratory Capacity at Pre-exercise After 6 Weeks
(NCT01040130)
Timeframe: 6 weeks
| Intervention | liters (Least Squares Mean) |
|---|---|
| Placebo | 2.220 |
| Olo 5 mcg qd | 2.478 |
| Olo 10 mcg qd | 2.513 |
Adjusted Mean Inspiratory Capacity at Isotime After 6 Weeks
Isotime is defined as the endurance time of the constant work rate exercise test of shortest duration from Baseline visit, and Week 6 of each of the three treatment periods. (NCT01040130)
Timeframe: 6 weeks
| Intervention | liters (Least Squares Mean) |
|---|---|
| Placebo | 1.917 |
| Olo 5 mcg qd | 2.099 |
| Olo 10 mcg qd | 2.091 |
Adjusted Mean Inspiratory Capacity at End of Exercise After 6 Weeks
(NCT01040130)
Timeframe: 6 weeks
| Intervention | liters (Least Squares Mean) |
|---|---|
| Placebo | 1.887 |
| Olo 5 mcg qd | 2.067 |
| Olo 10 mcg qd | 2.024 |
Adjusted Mean Inspiratory Capacity 30 Minutes Pre-dose After 6 Weeks
Measured using body plethysmography (NCT01040130)
Timeframe: 6 weeks
| Intervention | liters (Least Squares Mean) |
|---|---|
| Placebo | 2.170 |
| Olo 5 mcg qd | 2.289 |
| Olo 10 mcg qd | 2.262 |
Adjusted Mean Inspiratory Capacity 1 Hour Post-dose After 6 Weeks
Measured using body plethysmography (NCT01040130)
Timeframe: 6 weeks
| Intervention | liters (Least Squares Mean) |
|---|---|
| Placebo | 2.221 |
| Olo 5 mcg qd | 2.427 |
| Olo 10 mcg qd | 2.437 |
Adjusted Mean Forced Vital Capacity, 1 Hour Post-dose After 6 Weeks
(NCT01040130)
Timeframe: 6 weeks
| Intervention | liters (Least Squares Mean) |
|---|---|
| Placebo | 3.187 |
| Olo 5 mcg qd | 3.471 |
| Olo 10 mcg qd | 3.477 |
Adjusted Mean Functional Residual Capacity 30 Minutes Pre-dose After 6 Weeks
(NCT01040130)
Timeframe: 6 weeks
| Intervention | liters (Least Squares Mean) |
|---|---|
| Placebo | 4.977 |
| Olo 5 mcg qd | 4.855 |
| Olo 10 mcg qd | 4.862 |
Number of Patients With Notable Changes in Heart Rate
Number of Patients with notable changes in heart rate (HR). Notable HR increase defined as >=25% increase and on-treatment HR > 100 bpm; Notable HR decrease defined as >=25% decrease and on-treatment HR < 50 bpm. (NCT01040130)
Timeframe: Baseline and Week 6
| Intervention | percentage of participants (Number) | |||||
|---|---|---|---|---|---|---|
| 30 min pre-dose: increase (N=138, 139, 140) | 30 min pre-dose: decrease (N=138, 139, 140) | 30 min pre-dose: no change (N=138, 139, 140) | 40 min post-dose: increase (N=138, 141, 138) | 40 min post-dose: decrease (N=138, 141, 138) | 40 min post-dose: no change (N=138, 141, 138) | |
| Olo 10 mcg | 0.7 | 2.1 | 97.1 | 2.9 | 6.5 | 90.6 |
| Olo 5 mcg | 0.7 | 2.9 | 96.4 | 1.4 | 5.0 | 93.6 |
| Placebo | 0.7 | 1.4 | 97.8 | 2.2 | 4.3 | 93.5 |
Change From Baseline to Day 43 in Blood Pressure
Change from Baseline to Day 43 in Blood Pressure with spirometry. Baseline is defined as mean of pre-treatment values at a given time point. (NCT01040130)
Timeframe: Baseline and Week 6
| Intervention | mmHg (Mean) | |
|---|---|---|
| Systolic blood pressure | Diastolic blood pressure | |
| Olo 10 mcg | -3.3 | -1.1 |
| Olo 5 mcg | -2.7 | -1.8 |
| Placebo | -3.5 | -1.7 |
Change From Baseline to Day 43 in Pulse Rate
Change from Baseline to Day 43 in Pulse rate with spirometry. Baseline is defined as mean of pre-treatment values at a given time point. (NCT01040130)
Timeframe: Baseline and Week 6
| Intervention | beats/min (Mean) |
|---|---|
| Placebo | -5.1 |
| Olo 5 mcg | -5.1 |
| Olo 10 mcg | -3 |
Adjusted Mean Borg Scale of Breathing Discomfort at End of Exercise After 6 Weeks
Borg scale rates discomfort with breathing at rest, during exercise and at end-exercise on a scale from 0=Nothing at all to 10=Maximal discomfort. (NCT01040130)
Timeframe: 6 weeks
| Intervention | Scores on a scale (Least Squares Mean) |
|---|---|
| Placebo | 6.978 |
| Olo 5 mcg qd | 6.890 |
| Olo 10 mcg qd | 7.234 |
Adjusted Mean Borg Scale of Breathing Discomfort at Isotime After 6 Weeks
"Isotime is defined as the endurance time of the constant work rate exercise test of shortest duration from Baseline visit, and Week 6 of each of the three treatment periods.~Borg scale rates discomfort with breathing at rest, during exercise and at end-exercise on a scale from 0=Nothing at all to 10=Maximal discomfort." (NCT01040130)
Timeframe: 6 weeks
| Intervention | Scores on a scale (Least Squares Mean) |
|---|---|
| Placebo | 5.870 |
| Olo 5 mcg qd | 5.104 |
| Olo 10 mcg qd | 5.235 |
Adjusted Mean Borg Scale of Breathing Discomfort at Pre-exercise After 6 Weeks
Borg scale rates discomfort with breathing at rest, during exercise and at end-exercise on a scale from 0=Nothing at all to 10=Maximal discomfort. (NCT01040130)
Timeframe: 6 weeks
| Intervention | Scores on a scale (Least Squares Mean) |
|---|---|
| Placebo | 0.288 |
| Olo 5 mcg qd | 0.185 |
| Olo 10 mcg qd | 0.224 |
Adjusted Mean Endurance Time After 6 Weeks
Primary endpoint was endurance time during constant work rate ergometry to symptom limitation at 75% of maximal work capacity after 6 weeks of treatment. Mixed effects model on log10 transformation data. Adjusted means are back transformed to report as geometric means. Standard errors (SEs) are calculated using the delta method. (NCT01040130)
Timeframe: 6 weeks
| Intervention | seconds (Geometric Mean) |
|---|---|
| Placebo | 369.81 |
| Olo 5 mcg qd | 421.58 |
| Olo 10 mcg qd | 420.72 |
Adjusted Mean Forced Expiratory Volume in 1 Second, 30 Minutes Pre-dose After 6 Weeks
(NCT01040130)
Timeframe: 6 weeks
| Intervention | liters (Least Squares Mean) |
|---|---|
| Placebo | 1.475 |
| Olo 5 mcg qd | 1.564 |
| Olo 10 mcg qd | 1.576 |
Adjusted Mean Total Lung Capacity 30 Minutes Pre-dose After 6 Weeks
Measured using body plethysmography (NCT01040130)
Timeframe: 6 weeks
| Intervention | liters (Least Squares Mean) |
|---|---|
| Placebo | 7.142 |
| Olo 5 mcg qd | 7.148 |
| Olo 10 mcg qd | 7.121 |
Adjusted Mean Total Lung Capacity 1 Hour Post-dose After 6 Weeks
(NCT01040130)
Timeframe: 6 weeks
| Intervention | liters (Least Squares Mean) |
|---|---|
| Placebo | 7.156 |
| Olo 5 mcg qd | 7.142 |
| Olo 10 mcg qd | 6.997 |
PEF Peak 0-3h Response After the First Dose
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 |
PEF AUC 0-3h Response After the First Dose
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 |
Patients Global Rating
"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 |
FVC Peak 0-3h Response After the First Dose
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 |
FVC Peak 0-3h Response
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 |
FVC AUC 0-3h Response After First Dose
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 |
FEV1 Peak 0-3h Response After the First Dose
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 |
FEV1 Peak 0-3h Response
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 |
FEV1 AUC 0-3h Response After the First Dose
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 |
PEF Peak 0-3h Response
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 |
Weekly Mean Number of Puffs of Rescue Medication Used Per Day
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
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 |
Physicians Global Evaluation
"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 |
PEF AUC 0-3h and AUC 0-6h Responses
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 |
Individual PEF Measurements at Each Time Point on Day 29
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 |
Individual FVC Measurements at Each Time Point on Day 29
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 |
Individual FEV1 Measurements at Each Time Point on Day 29
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 |
FVC AUC 0-3h and FEV1 AUC 0-6h Responses
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 |
FEV1 AUC 0-3h and FEV1 AUC 0-6h Response
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 |
Trough Forced Vital Capacity (FVC) Response
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 |
Trough FEV1 Response
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
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 |
Peak FVC (0-3h) Response
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 |
FVC Area Under Curve 12-24 Hours (AUC 12-24h) Response
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 |
Peak FEV1 (0-3h) Response
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 |
FEV1 Area Under Curve 0-12 h (AUC 0-12h) Response After Six Weeks of Treatment
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 |
FEV1 Area Under Curve 12-24h (AUC 12-24h) Response After Six Weeks of Treatment
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 |
Forced Expiratory Volume in 1 Second (FEV1) Area Under Curve 0-3 h (AUC 0-3h) Response After First Dose of Treatment
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 |
Forced Expiratory Volume in 1 Second (FEV1) Area Under Curve 0-24 h (AUC 0-24h) Response After Six Weeks of Treatment
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 |
Peak FEV1 (0-3h) Response
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 |
Forced Expiratory Volume in 1 Second (FEV1) Area Under Curve 0-3 h (AUC 0-3h) Response After Six Weeks of Treatment
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 |
Forced Vital Capacity (FVC) Area Under Curve 0-12 Hours (AUC 0-12h) Response
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 |
FVC Area Under Curve 0-24 Hours (AUC 0-24h) Response
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 |
FVC Area Under Curve 0-3 Hours (AUC 0-3h) Response
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 |
FVC Area Under Curve 0-3 Hours (AUC 0-3h) Response
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 |
Clinical Relevant Abnormalities for Vital Signs, Blood Chemistry, Haematology, Urinalysis and ECG
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 |
Trough FVC Response
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 |
Trough FEV1 Response
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 |
Trough FEV1 Response
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 |
FVC Area Under Curve 0-24 Hours (AUC 0-24h) Response
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 |
FEV1 Area Under Curve 0-12 h (AUC 0-12h) Response After Six Weeks of Treatment
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 |
Peak FVC (0-3h) Response
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 |
Peak FEV1 (0-3h) Response
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 |
Peak FEV1 (0-3h) Response
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 |
FVC Area Under Curve 12-24 Hours (AUC 12-24h) Response
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 |
FVC Area Under Curve 0-3 Hours (AUC 0-3h) Response
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 |
FVC Area Under Curve 0-3 Hours (AUC 0-3h) Response
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 |
Forced Vital Capacity (FVC) Area Under Curve 0-12 Hours (AUC 0-12h) Response
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 |
Forced Expiratory Volume in 1 Second (FEV1) Area Under Curve 0-3 h (AUC 0-3h) Response After Six Weeks of Treatment
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 |
Forced Expiratory Volume in 1 Second (FEV1) Area Under Curve 0-3 h (AUC 0-3h) Response After First Dose of Treatment
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 |
Forced Expiratory Volume in 1 Second (FEV1) Area Under Curve 0-24 h (AUC 0-24h) Response After Six Weeks of Treatment
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 |
FEV1 Area Under Curve 12-24h (AUC 12-24h) Response After Six Weeks of Treatment
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 |
Clinical Relevant Abnormalities for Vital Signs, Blood Chemistry, Haematology, Urinalysis and ECG
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 |
Trough FVC Response
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 |
Adjusted Mean Endurance Time After 6 Weeks
Primary endpoint was endurance time during constant work rate ergometry to symptom limitation at 75% of maximal work capacity after 6 weeks of treatment. Mixed effects model on log10 transformation data. Adjusted means are back transformed to report as geometric means. Standard errors (SEs) are calculated using the delta method. (NCT01040793)
Timeframe: 6 weeks
| Intervention | seconds (Geometric Mean) |
|---|---|
| Placebo | 354.33 |
| Olo 5 mcg qd | 396.31 |
| Olo 10 mcg qd | 391.45 |
Adjusted Mean Forced Expiratory Volume in 1 Second, 1 Hour Post-dose After 6 Weeks
(NCT01040793)
Timeframe: 6 weeks
| Intervention | liters (Least Squares Mean) |
|---|---|
| Placebo | 1.577 |
| Olo 5 mcg qd | 1.768 |
| Olo 10 mcg qd | 1.771 |
Adjusted Mean Forced Expiratory Volume in 1 Second, 30 Minutes Pre-dose After 6 Weeks
(NCT01040793)
Timeframe: 6 weeks
| Intervention | liters (Least Squares Mean) |
|---|---|
| Placebo | 1.520 |
| Olo 5 mcg qd | 1.630 |
| Olo 10 mcg qd | 1.630 |
Adjusted Mean Forced Vital Capacity, 1 Hour Post-dose After 6 Weeks
(NCT01040793)
Timeframe: 6 weeks
| Intervention | liters (Least Squares Mean) |
|---|---|
| Placebo | 3.144 |
| Olo 5 mcg qd | 3.409 |
| Olo 10 mcg qd | 3.425 |
Adjusted Mean Borg Scale of Breathing Discomfort at End of Exercise After 6 Weeks
Borg scale rates discomfort with breathing at rest, during exercise and at end-exercise on a scale from 0=Nothing at all to 10=Maximal discomfort. (NCT01040793)
Timeframe: 6 weeks
| Intervention | Scores on a scale (Least Squares Mean) |
|---|---|
| Placebo | 7.010 |
| Olo 5 mcg qd | 7.101 |
| Olo 10 mcg qd | 7.351 |
Adjusted Mean Forced Vital Capacity, 30 Minutes Pre-dose After 6 Weeks
(NCT01040793)
Timeframe: 6 weeks
| Intervention | liters (Least Squares Mean) |
|---|---|
| Placebo | 3.103 |
| Olo 5 mcg qd | 3.222 |
| Olo 10 mcg qd | 3.222 |
Adjusted Mean Inspiratory Capacity at End of Exercise After 6 Weeks
(NCT01040793)
Timeframe: 6 weeks
| Intervention | liters (Least Squares Mean) |
|---|---|
| Placebo | 2.158 |
| Olo 5 mcg qd | 2.236 |
| Olo 10 mcg qd | 2.330 |
Adjusted Mean Functional Residual Capacity 1 Hour Post-dose After 6 Weeks
Measured using body plethysmography (NCT01040793)
Timeframe: 6 weeks
| Intervention | liters (Least Squares Mean) |
|---|---|
| Placebo | 4.770 |
| Olo 5 mcg qd | 4.557 |
| Olo 10 mcg qd | 4.583 |
Adjusted Mean Functional Residual Capacity 30 Minutes Pre-dose After 6 Weeks
Measured using body plethysmography (NCT01040793)
Timeframe: 6 weeks
| Intervention | liters (Least Squares Mean) |
|---|---|
| Placebo | 4.842 |
| Olo 5 mcg qd | 4.757 |
| Olo 10 mcg qd | 4.723 |
Adjusted Mean Inspiratory Capacity 1 Hour Post-dose After 6 Weeks
(NCT01040793)
Timeframe: 6 weeks
| Intervention | liters (Least Squares Mean) |
|---|---|
| Placebo | 2.493 |
| Olo 5 mcg qd | 2.725 |
| Olo 10 mcg qd | 2.696 |
Adjusted Mean Borg Scale of Breathing Discomfort at Isotime After 6 Weeks
"Isotime is defined as the endurance time of the constant work rate exercise test of shortest duration from Baseline visit, and Week 6 of each of the three treatment periods.~Borg scale rates discomfort with breathing at rest, during exercise and at end-exercise on a scale from 0=Nothing at all to 10=Maximal discomfort." (NCT01040793)
Timeframe: 6 weeks
| Intervention | Scores on a scale (Least Squares Mean) |
|---|---|
| Placebo | 5.585 |
| Olo 5 mcg qd | 5.250 |
| Olo 10 mcg qd | 5.520 |
Adjusted Mean Borg Scale of Breathing Discomfort at Pre-exercise After 6 Weeks
Borg scale rates discomfort with breathing at rest, during exercise and at end-exercise on a scale from 0=Nothing at all to 10=Maximal discomfort. (NCT01040793)
Timeframe: 6 weeks
| Intervention | Scores on a scale (Least Squares Mean) |
|---|---|
| Placebo | 0.389 |
| Olo 5 mcg qd | 0.315 |
| Olo 10 mcg qd | 0.364 |
Adjusted Mean Inspiratory Capacity 30 Minutes Pre-dose After 6 Weeks
Measured using body plethysmography (NCT01040793)
Timeframe: 6 weeks
| Intervention | liters (Least Squares Mean) |
|---|---|
| Placebo | 2.463 |
| Olo 5 mcg qd | 2.613 |
| Olo 10 mcg qd | 2.618 |
Adjusted Mean Total Lung Capacity 30 Minutes Pre-dose After 6 Weeks
Measured using body plethysmography (NCT01040793)
Timeframe: 6 weeks
| Intervention | liters (Least Squares Mean) |
|---|---|
| Placebo | 7.311 |
| Olo 5 mcg qd | 7.368 |
| Olo 10 mcg qd | 7.340 |
Change From Baseline to Day 43 in Pulse Rate
Change from Baseline to Day 43 in Pulse rate with spirometry. Baseline is defined as mean of pre-treatment values at a given time point. (NCT01040793)
Timeframe: Baseline and Week 6
| Intervention | beats/min (Mean) |
|---|---|
| Placebo | -2.3 |
| Olo 5 mcg | -1.8 |
| Olo 10 mcg | -1.6 |
Change From Baseline to Day 43 in Blood Pressure
Change from Baseline to Day 43 in Blood Pressure with spirometry. Baseline is defined as mean of pre-treatment values at a given time point. (NCT01040793)
Timeframe: Baseline and Week 6
| Intervention | mmHg (Mean) | |
|---|---|---|
| Systolic blood pressure | Diastolic blood pressure | |
| Olo 10 mcg | -1.4 | -2.2 |
| Olo 5 mcg | -1.5 | -1.8 |
| Placebo | -0.5 | -0.8 |
Number of Patients With Notable Changes in Heart Rate
Number of Patients with notable changes in heart rate (HR). Notable HR increase defined as >=25% increase and on-treatment HR > 100 bpm; Notable HR decrease defined as >=25% decrease and on-treatment HR < 50 bpm. (NCT01040793)
Timeframe: Baseline and Week 6
| Intervention | percentage of participants (Number) | |||||
|---|---|---|---|---|---|---|
| 30 min pre-dose: increase | 30 min pre-dose: decrease | 30 min pre-dose: no notable change | 40 min post-dose: increase (N=147,142,140) | 40 min post-dose: decrease (N=147,142,140) | 40 min post-dose: no notable change(N=147,142,140) | |
| Olo 10 mcg | 0.0 | 2.9 | 97.1 | 0.0 | 3.6 | 96.4 |
| Olo 5 mcg | 0.7 | 1.4 | 97.9 | 0.0 | 4.2 | 95.8 |
| Placebo | 0.7 | 0.7 | 98.6 | 0.0 | 0.7 | 99.3 |
Number of Patients With Notable Increase in PR Intervals
Number of Patients with notable increase in PR intervals. Notable PR interval increase defined as >=25% increase and on-treatment PR interval > 200 ms. (NCT01040793)
Timeframe: Baseline and Week 6
| Intervention | percentage of participants (Number) | |||
|---|---|---|---|---|
| 30 min pre-dose: increase | 30 min pre-dose: no increase | 40 min post-dose: increase (N=147, 142, 140) | 40 min post-dose: no increase (N=147, 142, 140) | |
| Olo 10 mcg | 0.0 | 100.0 | 0.0 | 100.0 |
| Olo 5 mcg | 0.0 | 100.0 | 0.0 | 100.0 |
| Placebo | 0.0 | 100.0 | 0.7 | 99.3 |
Number of Patients With Notable Increase in QRS Intervals
Number of Patients with notable increase in QRS intervals. Notable QRS interval increase defined as >=10% increase and on-treatment QRS interval > 110 ms. (NCT01040793)
Timeframe: Baseline and Week 6
| Intervention | percentage of participants (Number) | |||
|---|---|---|---|---|
| 30 min pre-dose: increase | 30 min pre-dose: no increase | 40 min post-dose: increase (N=147, 142, 140) | 40 min post-dose: no increase (N=147, 142, 140) | |
| Olo 10 mcg | 0.7 | 99.3 | 0.7 | 99.3 |
| Olo 5 mcg | 0.7 | 99.3 | 0.7 | 99.3 |
| Placebo | 0.7 | 99.3 | 1.4 | 98.6 |
Adjusted Mean Inspiratory Capacity at Isotime After 6 Weeks
Isotime is defined as the endurance time of the constant work rate exercise test of shortest duration from Baseline visit, and Week 6 of each of the three treatment periods. (NCT01040793)
Timeframe: 6 weeks
| Intervention | liters (Least Squares Mean) |
|---|---|
| Placebo | 2.162 |
| Olo 5 mcg qd | 2.246 |
| Olo 10 mcg qd | 2.328 |
Adjusted Mean Inspiratory Capacity at Pre-exercise After 6 Weeks
(NCT01040793)
Timeframe: 6 weeks
| Intervention | liters (Least Squares Mean) |
|---|---|
| Placebo | 2.273 |
| Olo 5 mcg qd | 2.437 |
| Olo 10 mcg qd | 2.468 |
Adjusted Mean Peak Expiratory Flow Rate, 1 Hour Post-dose After 6 Weeks
(NCT01040793)
Timeframe: 6 weeks
| Intervention | liters/second (Least Squares Mean) |
|---|---|
| Placebo | 4.324 |
| Olo 5 mcg qd | 4.904 |
| Olo 10 mcg qd | 4.876 |
Adjusted Mean Peak Expiratory Flow Rate, 30 Minutes Pre-dose After 6 Weeks
(NCT01040793)
Timeframe: 6 weeks
| Intervention | liters/second (Least Squares Mean) |
|---|---|
| Placebo | 4.258 |
| Olo 5 mcg qd | 4.539 |
| Olo 10 mcg qd | 4.549 |
Adjusted Mean Total Lung Capacity 1 Hour Post-dose After 6 Weeks
Measured using body plethysmography (NCT01040793)
Timeframe: 6 weeks
| Intervention | liters (Least Squares Mean) |
|---|---|
| Placebo | 7.262 |
| Olo 5 mcg qd | 7.285 |
| Olo 10 mcg qd | 7.272 |
Forced Vital Capacity (FVC) Area Under Curve 0-12 Hours (AUC 0-12h) Response
Response was defined as change from baseline. Study baseline FVC was defined as the mean of the available pre-dose FVC values at the randomisation visit. Means are adjusted for treatment, period, patient and study baseline. FVC AUC 0-12h was calculated using the trapezoidal rule, divided by the observation time to report in litres. (NCT01311661)
Timeframe: 1 hour (h) prior and 10 minutes (min) prior to first dose (baseline) and -1 h, -10 mins, 30 min, 60 min, 2 h, 3 h, 4 h, 6 h, 8 h, 10 h, 11 h 50 min related to morning dose after 3 weeks
| Intervention | Liter (Mean) |
|---|---|
| Placebo | -0.004 |
| Olo 2.5 mcg Bid | 0.132 |
| Olo 5 mcg qd | 0.119 |
| Olo 5 mcg Bid | 0.138 |
| Olo 10 mcg qd | 0.143 |
FVC Area Under Curve 0-24 Hours (AUC 0-24h) Response
Response was defined as change from baseline. Study baseline FVC was defined as the mean of the available pre-dose FVC values at the randomisation visit. Means are adjusted for treatment, period, patient and study baseline. FVC AUC 0-24h was calculated using the trapezoidal rule, divided by the observation time to report in litres. (NCT01311661)
Timeframe: 1 hour (h) prior and 10 minutes (min) prior to first dose (baseline) and -1 h, -10 mins, 30 min, 60 min, 2 h, 3 h, 4 h, 6 h, 8h, 10 h, 11 h 50 min, 12 h 30 min, 13 h, 14 h, 22 h, 23 h, and 23 h 50 min related to morning dose after 3 weeks
| Intervention | Liter (Mean) |
|---|---|
| Placebo | -0.029 |
| Olo 2.5 mcg Bid | 0.116 |
| Olo 5 mcg qd | 0.099 |
| Olo 5 mcg Bid | 0.127 |
| Olo 10 mcg qd | 0.111 |
FVC Area Under Curve 12-24 Hours (AUC 12-24h) Response
Response was defined as change from baseline. Study baseline FVC was defined as the mean of the available pre-dose FVC values at the randomisation visit. Means are adjusted for treatment, period, patient and study baseline. FVC AUC 12-24h was calculated using the trapezoidal rule, divided by the observation time to report in litres. (NCT01311661)
Timeframe: 1 hour (h) prior and 10 minutes (min) prior to first dose (baseline) and 11 h 50 min, 12 h 30 min, 13 h, 14 h, 22 h, 23 h, and 23 h 50 min related to morning dose after 3 weeks
| Intervention | Liter (Mean) |
|---|---|
| Placebo | -0.056 |
| Olo 2.5 mcg Bid | 0.102 |
| Olo 5 mcg qd | 0.081 |
| Olo 5 mcg Bid | 0.114 |
| Olo 10 mcg qd | 0.079 |
Forced Expiratory Volume in 1 Second (FEV1) Area Under Curve 0-24 Hours (AUC 0-24h) Response at the End of Each Treatment Period
Response was defined as change from baseline. Study baseline FEV1 was defined as the mean of the available pre-dose FEV1 values at the randomisation visit. Means are adjusted for treatment, period, patient and study baseline. 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. (NCT01311661)
Timeframe: 1 hour (h) prior and 10 minutes (min) prior to first dose (baseline) and -1 h, -10 mins, 30 min, 60 min, 2 h, 3 h, 4 h, 6 h, 8 h, 10 h, 11 h 50 min, 12 h 30 min, 13 h, 14 h, 22 h, 23 h, and 23 h 50 min related to morning dose after 3 weeks
| Intervention | Liter (Mean) |
|---|---|
| Placebo | 0.022 |
| Olo 2.5 mcg Bid | 0.213 |
| Olo 5 mcg qd | 0.173 |
| Olo 5 mcg Bid | 0.250 |
| Olo 10 mcg qd | 0.231 |
Peak FVC Within 24 Hours Post-dose Response
Response was defined as change from baseline. Study baseline FVC was defined as the mean of the available pre-dose FVC values at the randomisation visit. Peak FVC within 24 hours post-dose measured following the morning trial drug inhalation at the end of each 3 week period of randomised treatment. Means are adjusted for treatment, period, patient and study baseline. (NCT01311661)
Timeframe: 1 hour (h) prior and 10 minutes (min) prior to first dose (baseline) and 30 min, 60 min, 2 h, 3 h, 4 h, 6 h, 8h, 10 h, 11 h 50 min, 12 h 30 min, 13 h, 14 h, 22 h, 23 h, and 23 h 50 min related to morning dose after 3 weeks
| Intervention | Liter (Mean) |
|---|---|
| Placebo | 0.246 |
| Olo 2.5 mcg Bid | 0.382 |
| Olo 5 mcg qd | 0.371 |
| Olo 5 mcg Bid | 0.390 |
| Olo 10 mcg qd | 0.373 |
Peak PEF Within 24 Hours Post-dose Response
Response was defined as change from baseline. Study baseline PEF was defined as the mean of the available pre-dose PEF values at the randomisation visit. Peak PEF within 24 hours post dose measured following the morning trial drug inhalation at the end of each 3 week period of randomised treatment. Means are adjusted for treatment, period, patient and study baseline. (NCT01311661)
Timeframe: 1 hour (h) prior and 10 minutes (min) prior to first dose (baseline) and 30 min, 60 min, 2 h, 3 h, 4 h, 6 h, 8h, 10 h, 11 h 50 min, 12 h 30 min, 13 h, 14 h, 22 h, 23 h, and 23 h 50 min related to morning dose after 3 weeks
| Intervention | Liter/sec (Mean) |
|---|---|
| Placebo | 0.663 |
| Olo 2.5 mcg Bid | 1.254 |
| Olo 5 mcg qd | 1.185 |
| Olo 5 mcg Bid | 1.257 |
| Olo 10 mcg qd | 1.286 |
Number of Patients Categorized by Worst Asthma Nighttime Symptoms (Overall)
Assessed by patients at home using the AM3 device during each period of randomised treatment. (NCT01311661)
Timeframe: 0-3 weeks
| Intervention | Number of patients (Number) | ||||
|---|---|---|---|---|---|
| No asthma symptoms | Mild asthma symptoms | Moderate asthma symptoms | Severe asthma symptoms | Very severe asthma symptoms | |
| Olo 10 mcg qd | 21 | 40 | 35 | 3 | 2 |
| Olo 2.5 mcg Bid | 32 | 35 | 26 | 4 | 2 |
| Olo 5 mcg Bid | 21 | 48 | 29 | 2 | 1 |
| Olo 5 mcg qd | 29 | 38 | 32 | 1 | 0 |
| Placebo | 39 | 76 | 74 | 9 | 3 |
PEF Area Under Curve 12-24 Hours (AUC 12-24h) Response
Response was defined as change from baseline. Study baseline PEF was defined as the mean of the available pre-dose PEF values at the randomisation visit. Means are adjusted for treatment, period, patient and study baseline. PEF AUC 12-24h was calculated using the trapezoidal rule, divided by the observation time to report in litres/seconds. (NCT01311661)
Timeframe: 1 hour (h) prior and 10 minutes (min) prior to first dose (baseline) and 11 h 50 min, 12 h 30 min, 13 h, 14 h, 22 h, 23 h, and 23 h 50 min related to morning dose after 3 weeks
| Intervention | Liter/sec (Mean) |
|---|---|
| Placebo | -0.135 |
| Olo 2.5 mcg Bid | 0.530 |
| Olo 5 mcg qd | 0.430 |
| Olo 5 mcg Bid | 0.567 |
| Olo 10 mcg qd | 0.464 |
PEF Daily Variability
PEF daily variability was assessed by patients at home using the AM3 device (overall means obtained during each period of randomised treatment will be compared). PEF daily variability is the absolute difference between the morning and the evening PEF value divided by the mean of these two values, expressed as a percent. Means are adjusted for treatment, period, patient and study baseline. (NCT01311661)
Timeframe: 0-3 weeks
| Intervention | Percentage (Mean) |
|---|---|
| Placebo | 10.157 |
| Olo 2.5 mcg Bid | 8.576 |
| Olo 5 mcg qd | 8.732 |
| Olo 5 mcg Bid | 8.419 |
| Olo 10 mcg qd | 9.468 |
Percentage of Asthma Symptom Free Days
Percentage of asthma-symptom free days of each treatment period was calculated as the number of symptom-free days divided by the number of days on treatment multiplied by 100. A symptom-free day was defined as a day in which no asthma symptoms were recorded, no rescue medication was recorded, activities during the day were not at all limited due to asthma, no shortness of breath during the day was recorded, no wheezing or coughing during the day and no night-time awakenings due to asthma were recorded. Assessed by patients at home using the AM3 device. (NCT01311661)
Timeframe: 0-3 weeks
| Intervention | Percentage of asthma symptom free days (Mean) |
|---|---|
| Placebo | 23.630 |
| Olo 2.5 mcg Bid | 33.929 |
| Olo 5 mcg qd | 36.306 |
| Olo 5 mcg Bid | 28.844 |
| Olo 10 mcg qd | 28.049 |
FEV1 Area Under Curve 0-12 Hours (AUC 0-12h) Response at the End of Each Treatment Period
Response was defined as change from baseline. Study baseline FEV1 was defined as the mean of the available pre-dose FEV1 values at the randomisation visit. Means are adjusted for treatment, period, patient and study baseline. 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. (NCT01311661)
Timeframe: 1 hour (h) prior and 10 minutes (min) prior to first dose (baseline) and -1 h, -10 mins, 30 min, 60 min, 2 h, 3 h, 4 h, 6 h, 8 h, 10 h, 11 h 50 min related to morning dose after 3 weeks
| Intervention | Liter (Mean) |
|---|---|
| Placebo | 0.052 |
| Olo 2.5 mcg Bid | 0.242 |
| Olo 5 mcg qd | 0.212 |
| Olo 5 mcg Bid | 0.266 |
| Olo 10 mcg qd | 0.272 |
FEV1 Area Under Curve 12-24 Hours (AUC 12-24h) Response at the End of Each Treatment Period
Response was defined as change from baseline. Study baseline FEV1 was defined as the mean of the available pre-dose FEV1 values at the randomisation visit. Means are adjusted for treatment, period, patient and study baseline. 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. (NCT01311661)
Timeframe: 1 hour (h) prior and 10 minutes (min) prior to first dose (baseline) and 11 h 50 min, 12 h 30 min, 13 h, 14 h, 22 h, 23 h, and 23 h 50 min related to morning dose after 3 weeks
| Intervention | Liter (Mean) |
|---|---|
| Placebo | -0.010 |
| Olo 2.5 mcg Bid | 0.186 |
| Olo 5 mcg qd | 0.135 |
| Olo 5 mcg Bid | 0.233 |
| Olo 10 mcg qd | 0.189 |
Peak FEV1 Within 24 Hours Post-dose Response
Response was defined as change from baseline. Study baseline FEV1 was defined as the mean of the available pre-dose FEV1 values at the randomisation visit. Peak FEV1 within 24 hours post dose measured following the morning trial drug inhalation at the end of each 3 week period of randomised treatment. Means are adjusted for treatment, period, patient and study baseline. (NCT01311661)
Timeframe: 1 hour (h) prior and 10 minutes (min) prior to first dose (baseline) and 30 min, 60 min, 2 h, 3 h, 4 h, 6 h, 8h, 10 h, 11 h 50 min, 12 h 30 min, 13 h, 14 h, 22 h, 23 h, and 23 h 50 min related to morning dose after 3 weeks
| Intervention | Liter (Mean) |
|---|---|
| Placebo | 0.227 |
| Olo 2.5 mcg Bid | 0.410 |
| Olo 5 mcg qd | 0.380 |
| Olo 5 mcg Bid | 0.449 |
| Olo 10 mcg qd | 0.437 |
Peak Expiratory Flow (PEF) Area Under Curve 0-24 Hours (AUC 0-24h) Response
Response was defined as change from baseline. Study baseline PEF was defined as the mean of the available pre-dose PEF values at the randomisation visit. Means are adjusted for treatment, period, patient and study baseline. PEF AUC 0-24h was calculated using the trapezoidal rule, divided by the observation time to report in litres/seconds. (NCT01311661)
Timeframe: 1 hour (h) prior and 10 minutes (min) prior to first dose (baseline) and -1 h, -10 mins, 30 min, 60 min, 2 h, 3 h, 4 h, 6 h, 8h, 10 h, 11 h 50 min, 12 h 30 min, 13 h, 14 h, 22 h, 23 h, and 23 h 50 min related to morning dose after 3 weeks
| Intervention | Liter/sec (Mean) |
|---|---|
| Placebo | -0.014 |
| Olo 2.5 mcg Bid | 0.627 |
| Olo 5 mcg qd | 0.563 |
| Olo 5 mcg Bid | 0.653 |
| Olo 10 mcg qd | 0.629 |
Peak Expiratory Flow (PEF) Area Under Curve 0-12 Hours (AUC 0-12h) Response
Response was defined as change from baseline. Study baseline PEF was defined as the mean of the available pre-dose PEF values at the randomisation visit. Means are adjusted for treatment, period, patient and study baseline. PEF AUC 0-12h was calculated using the trapezoidal rule, divided by the observation time to report in litres/seconds. (NCT01311661)
Timeframe: 1 hour (h) prior and 10 minutes (min) prior to first dose (baseline) and -1 h, -10 mins, 30 min, 60 min, 2 h, 3 h, 4 h, 6 h, 8h, 10 h, 11 h 50 min related to morning dose after 3 weeks
| Intervention | Liter/sec (Mean) |
|---|---|
| Placebo | 0.101 |
| Olo 2.5 mcg Bid | 0.730 |
| Olo 5 mcg qd | 0.703 |
| Olo 5 mcg Bid | 0.732 |
| Olo 10 mcg qd | 0.787 |
Number of Patients Categorized by Worst Asthma Daytime Symptoms (Overall)
Assessed by patients at home using the AM3 device during each period of randomised treatment . (NCT01311661)
Timeframe: 0-3 weeks
| Intervention | Number of patients (Number) | ||||
|---|---|---|---|---|---|
| No asthma symptoms | Mild asthma symptoms | Moderate asthma symptoms | Severe asthma symptoms | Very severe asthma symptoms | |
| Olo 10 mcg qd | 20 | 41 | 37 | 2 | 1 |
| Olo 2.5 mcg Bid | 24 | 45 | 25 | 4 | 1 |
| Olo 5 mcg Bid | 18 | 42 | 36 | 4 | 1 |
| Olo 5 mcg qd | 27 | 42 | 27 | 3 | 1 |
| Placebo | 31 | 66 | 85 | 18 | 1 |
Number of Patients Categorized by Highest Number of Night Time Awakenings (Overall)
Assessed by patients at home using the AM3 device during each period of randomised treatment. (NCT01311661)
Timeframe: 0-3 weeks
| Intervention | Number of patients (Number) | ||||
|---|---|---|---|---|---|
| Did not wake up | Woke up once | Woke up 2-5 times | Woke up > 5 times | Was awake all night | |
| Olo 10 mcg qd | 47 | 32 | 19 | 2 | 1 |
| Olo 2.5 mcg Bid | 50 | 31 | 18 | 0 | 0 |
| Olo 5 mcg Bid | 44 | 41 | 14 | 0 | 2 |
| Olo 5 mcg qd | 53 | 36 | 10 | 1 | 0 |
| Placebo | 93 | 67 | 36 | 5 | 0 |
Clinical Relevant Abnormalities for Vital Signs, Blood Chemistry, Haematology, Urinalysis and ECG
Clinical relevant abnormalities for Vital Signs, Blood Chemistry, Haematology, Urinalysis and ECG. New abnormal findings or worsening of baseline conditions were reported as Adverse Events. Time frame for adverse event reporting includes 12 days into the subsequent washout or post-treatment period. (NCT01311661)
Timeframe: 3 weeks + 12 days
| Intervention | Participants (Number) | ||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|
| Atrioventricular block first degree | Sinus tachycardia | Aspartate aminotransferase increased | Blood creatinine increased | Blood glucose increased | Blood urea abnormal | Gamma-glutamyltransferase increased | Blood creatine phosphokinase increased | Blood urine present | Anaemia | Hypertension | |
| Olo 10 mcg qd | 0 | 0 | 1 | 0 | 1 | 0 | 1 | 0 | 0 | 0 | 0 |
| Olo 2.5 mcg Bid | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 |
| Olo 5 mcg Bid | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 1 | 2 |
| Olo 5 mcg qd | 1 | 0 | 0 | 1 | 0 | 1 | 0 | 0 | 0 | 0 | 0 |
| Placebo | 0 | 1 | 0 | 0 | 0 | 0 | 0 | 1 | 1 | 0 | 0 |
Trough PEF Response
Response was defined as change from baseline. Study baseline PEF was defined as the mean of the available pre-dose PEF values at the randomisation visit. Trough values were defined as the mean of 2 PEF values performed at 23 h and 23 h 50 min after the last morning trial drug inhalation at the end of each 3 week period of randomised treatment. Means are adjusted for treatment, period, patient and study baseline. (NCT01311661)
Timeframe: 1 hour (h) prior and 10 minutes (min) prior to first dose (baseline) and 23 h, and 23 h 50 min related to morning dose after 3 weeks
| Intervention | Liter/sec (Mean) |
|---|---|
| Placebo | -0.009 |
| Olo 2.5 mcg Bid | 0.520 |
| Olo 5 mcg qd | 0.401 |
| Olo 5 mcg Bid | 0.594 |
| Olo 10 mcg qd | 0.472 |
Trough FVC Response
Response was defined as change from baseline. Study baseline FVC was defined as the mean of the available pre-dose FVC values at the randomisation visit. Trough values were defined as the mean of 2 FVC values performed at 23 h and 23 h 50 min after the last morning trial drug inhalation at the end of each 3 week period of randomised treatment. Means are adjusted for treatment, period, patient and study baseline. (NCT01311661)
Timeframe: 1 hour (h) prior and 10 minutes (min) prior to first dose (baseline) and 23 h, and 23 h 50 min related to morning dose after 3 weeks
| Intervention | Liter (Mean) |
|---|---|
| Placebo | -0.013 |
| Olo 2.5 mcg Bid | 0.096 |
| Olo 5 mcg qd | 0.079 |
| Olo 5 mcg Bid | 0.105 |
| Olo 10 mcg qd | 0.098 |
Trough FEV1 Response
Response was defined as change from baseline. Study baseline FEV1 was defined as the mean of the available pre-dose FEV1 values at the randomisation visit. Trough values were defined as the mean of 2 FEV1 values performed at 23 h and 23 h 50 min after the last morning trial drug inhalation at the end of each 3 week period of randomised treatment. Means are adjusted for treatment, period, patient and study baseline. (NCT01311661)
Timeframe: 1 hour (h) prior and 10 minutes (min) prior to first dose (baseline) and 23 h, and 23 h 50 min related to morning dose after 3 weeks
| Intervention | Liter (Mean) |
|---|---|
| Placebo | 0.033 |
| Olo 2.5 mcg Bid | 0.189 |
| Olo 5 mcg qd | 0.134 |
| Olo 5 mcg Bid | 0.229 |
| Olo 10 mcg qd | 0.205 |
Total Asthma Control Questionnaire (ACQ) Score
Control of asthma as assessed by the ACQ at the end of each 3-week treatment period.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. (NCT01311661)
Timeframe: 3 weeks
| Intervention | Units on a scale (Mean) |
|---|---|
| Placebo | 1.613 |
| Olo 2.5 mcg Bid | 1.256 |
| Olo 5 mcg qd | 1.317 |
| Olo 5 mcg Bid | 1.312 |
| Olo 10 mcg qd | 1.311 |
Mean Pre-dose Morning PEF (PEF a.m.)
PEF a.m. was measured by patients at home using the AM3 device (overall means obtained during each period of randomised treatment will be compared). Means are adjusted for treatment, period, patient and study baseline. (NCT01311661)
Timeframe: 0-3 weeks
| Intervention | Liter/min (Mean) |
|---|---|
| Placebo | 395.36 |
| Olo 2.5 mcg Bid | 428.32 |
| Olo 5 mcg qd | 427.99 |
| Olo 5 mcg Bid | 427.02 |
| Olo 10 mcg qd | 424.26 |
Mean Pre-dose Morning FEV1 (FEV1 a.m.)
FEV1 a.m. was measured by patients at home using the AM3 device (overall means obtained during each period of randomised treatment will be compared). Means are adjusted for treatment, period, patient and study baseline. (NCT01311661)
Timeframe: 0-3 weeks
| Intervention | mL (Mean) |
|---|---|
| Placebo | 2425.1 |
| Olo 2.5 mcg Bid | 2598.5 |
| Olo 5 mcg qd | 2580.2 |
| Olo 5 mcg Bid | 2574.3 |
| Olo 10 mcg qd | 2575.5 |
Mean Pre-dose Evening PEF (PEF p.m.)
PEF p.m. was measured by patients at home using the AM3 device (overall means obtained during each period of randomised treatment will be compared). Means are adjusted for treatment, period, patient and study baseline. (NCT01311661)
Timeframe: 0-3 weeks
| Intervention | Liter/min (Mean) |
|---|---|
| Placebo | 409.93 |
| Olo 2.5 mcg Bid | 438.80 |
| Olo 5 mcg qd | 441.98 |
| Olo 5 mcg Bid | 441.74 |
| Olo 10 mcg qd | 443.25 |
Mean Pre-dose Evening FEV1 (FEV1 p.m.)
FEV1 p.m. was measured by patients at home using the AM3 device (overall means obtained during each period of randomised treatment will be compared). Means are adjusted for treatment, period, patient and study baseline. (NCT01311661)
Timeframe: 0-3 weeks
| Intervention | mL (Mean) |
|---|---|
| Placebo | 2474.3 |
| Olo 2.5 mcg Bid | 2616.6 |
| Olo 5 mcg qd | 2606.5 |
| Olo 5 mcg Bid | 2616.5 |
| Olo 10 mcg qd | 2631.7 |
Mean Number of Puffs of Rescue Medication During the Whole Day
Mean of daily use of salbutamol (albuterol) rescue medication as needed during the entire study period. Assessed by patients at home using the AM3 device (overall mean number obtained during each period of randomised treatment will be compared). Means are adjusted for treatment, period, patient and study baseline. (NCT01311661)
Timeframe: 0-3 weeks
| Intervention | Puffs (Mean) |
|---|---|
| Placebo | 1.665 |
| Olo 2.5 mcg Bid | 1.110 |
| Olo 5 mcg qd | 1.028 |
| Olo 5 mcg Bid | 1.077 |
| Olo 10 mcg qd | 1.119 |
FEV1 AUC(0-3h) Response on Day 1
"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) Response in the Sub-set of Patients With 12-h PFTs on Day 169 From the Two Twin Trials, Present 1237.5 (NCT01431274) and 1237.6 (NCT01431287)
"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) Response in the Sub-set of Patients With 12-hour Pulmonary Function Test (PFT) on Day 169 From the Two Twin Trials, Present 1237.5 (NCT01431274) and 1237.6 (NCT01431287)
"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 |
Trough FEV1 Response on Day 15.
"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 |
Trough FVC Response on Day 85.
"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 Response on Day 43.
"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 |
Trough FVC Response on Day 365.
"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 Response on Day 170.
"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 |
Trough FVC Response on Day 15.
"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 Response on Day 85
"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 |
Trough FEV1 Response on Day 43
"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 Response on Day 365
"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 Response on Day 170.
"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 Response on Day 169
"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 |
Saint George's Respiratory Questionnaire (SGRQ) Total Score on Day 85 From the Two Twin Trials, Present 1237.5 (NCT01431274) and 1237.6 (NCT01431287)
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 |
Saint George's Respiratory Questionnaire (SGRQ) Total Score on Day 365 From the Two Twin Trials, Present 1237.5 (NCT01431274) and 1237.6 (NCT01431287)
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 |
Saint George's Respiratory Questionnaire (SGRQ) Total Score on Day 169 From the Two Twin Trials, Present 1237.5 (NCT01431274) and 1237.6 (NCT01431287)
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 |
Mahler Transitional Dyspnoea Index (TDI) Focal Score on Day 85 From the Two Twin Trials, Present 1237.5 (NCT01431274) and 1237.6 (NCT01431287)
"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 |
Mahler Transitional Dyspnoea Index (TDI) Focal Score on Day 43 From the Two Twin Trials, Present 1237.5 (NCT01431274) and 1237.6 (NCT01431287)
"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 365 From the Two Twin Trials, Present 1237.5 (NCT01431274) and 1237.6 (NCT01431287)
"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 |
Mahler Transitional Dyspnoea Index (TDI) Focal Score on Day 169 From the Two Twin Trials, Present 1237.5 (NCT01431274) and 1237.6 (NCT01431287)
"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 |
FVC AUC(0-24h) Response in Sub-set of Patients With 24-h PFTs on Day 169 From the Two Twin Trials, Present 1237.5 (NCT01431274) and 1237.6 (NCT01431287)
"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 |
FVC AUC(0-12h) Response in the Sub-set of Patients With 12-h PFTs on Day 169 From the Two Twin Trials, Present 1237.5 (NCT01431274) and 1237.6 (NCT01431287)
"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 |
FVC (Forced Vital Capacity) AUC(0-3h) Response on Day 85
"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 |
FVC (Forced Vital Capacity) AUC(0-3h) Response on Day 365
"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 (Forced Vital Capacity) AUC(0-3h) Response on Day 169
"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 (Forced Vital Capacity) AUC(0-3h) Response on Day 1
"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 |
Forced Expiratory Volume in One Second (FEV1) Area Under the Curve (AUC) (0-3h) Response on Day 169.
"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) Response on Day 85
"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) Response on Day 365
"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 |
Trough FEV1 Response on Day 43
"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 FVC Response on Day 365
"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 Response on Day 43
"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 |
FVC AUC(0-12h) Response in Sub-set of Patients With 12-hour PFTs on Day 169 From Two Twin Trials, Present 1237.6 (NCT01431287) and 1237.5 (NCT01431274)
"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) Response in Sub-set of Patients With 12-hour PFTs on Day 169 From the Two Twin Trials, Present 1237.6 (NCT01431287) and 1237.5 (NCT01431274)
"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)
"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 Transitional Dyspnoea Index (TDI) Focal Score on Day 365 From the Two Twin Trials, Present 1237.6 (NCT01431287) and 1237.5 (NCT01431274)
"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 Transitional Dyspnoea Index (TDI) Focal Score on Day 43 From the Two Twin Trials, Present 1237.6 (NCT01431287) and 1237.5 (NCT01431274)
"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 |
Forced Expiratory Volume in One Second (FEV1) Area Under the Curve (AUC) (0-3h) Response on Day 169
"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 |
Mahler Transitional Dyspnoea Index (TDI) Focal Score on Day 85 From the Two Twin Trials, Present 1237.6 (NCT01431287) and 1237.5 (NCT01431274)
"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 |
Saint George's Respiratory Questionnaire (SGRQ) Total Score on Day 169 From the Two Twin Trials, Present 1237.6 (NCT01431287) and 1237.5 (NCT01431274).
"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 |
Saint George's Respiratory Questionnaire (SGRQ) Total Score on Day 365 From the Two Twin Trials, Present 1237.6 (NCT01431287) and 1237.5 (NCT01431274)
"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 |
FEV1 AUC(0-12h) Response in Sub-set of Patients With 12-hour Pulmonary Function Test (PFT) on Day 169 From the Two Twin Trials, Present 1237.6 (NCT01431287) and 1237.5 (NCT01431274)
"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 |
Forced Vital Capacity (FVC) AUC(0-3h) Response on Day 169
"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 |
FEV1 AUC(0-24h) Response in Sub-set of Patients With 12-hour PFTs on Day 169 From the Two Twin Trials, Present 1237.6 (NCT01431287) and 1237.5 (NCT01431274)
"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) Response on Day 1
"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) Response on Day 365
"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) Response on Day 85
"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 |
Forced Vital Capacity (FVC) AUC(0-3h) Response on Day 1
"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 |
Forced Vital Capacity (FVC) AUC(0-3h) Response on Day 365
"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 |
Saint George's Respiratory Questionnaire (SGRQ) Total Score on Day 85 From the Two Twin Trials, Present 1237.6 (NCT01431287) and 1237.5 (NCT01431274)
"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 |
Trough FEV1 Response on Day 15
"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 Response on Day 169
"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 Response on Day 170
"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 Response on Day 365
"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 Response on Day 85
"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 Response on Day 15
"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 Response on Day 85
"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 |
Forced Vital Capacity (FVC) AUC(0-3h) Response on Day 85
"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 |
Trough FVC Response on Day 170
"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 |
Adjusted Mean Slope of the Intensity of Breathing Discomfort After Week 12
"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 |
Adjusted Mean Inspiratory Capacity at Pre-exercise After 6 Weeks
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 |
Adjusted Mean Inspiratory Capacity at Pre-exercise After 12 Weeks
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 |
Adjusted Mean Inspiratory Capacity at Pre-exercise After 1 Day
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 |
Adjusted Mean Endurance Time During Endurance Shuttle Walk Test (ESWT) After 12 Weeks
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 |
Adjusted Mean Endurance Time During Constant Work Rate Cycle Ergometry (CWRCE) on Day 1
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 |
Adjusted Mean Endurance Time During Constant Work Rate Cycle Ergometry (CWRCE) After 12 Weeks
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 |
Adjusted Mean 1-hour, Post-dose Forced Expiratory Volume in One Second (FEV1) on Day 1
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 |
Adjusted Mean 1-hour, Post-dose Forced Expiratory Volume in One Second (FEV1) After 6 Weeks
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 |
Adjusted Mean 1-hour, Post-dose Forced Expiratory Volume in One Second (FEV1) After 12 Weeks
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 |
Adjusted Mean Endurance Time During Constant Work Rate Cycle Ergometry (CWRCE) After 6 Weeks Treatment
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 |
Adjusted Mean Slope of the Intensity of Breathing Discomfort on Day 1
"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 |
Adjusted Mean Slope of the Intensity of Breathing Discomfort After Week 6
"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 |
Slope of the Intensity of Breathing Discomfort During Constant Work Rate Cycle Ergometry to Symptom Limitation at 75% Work Capacity
"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 |
Endurance Time During Constant Work Rate Cycle Ergometry to Symptom Limitation at 75% Wcap
"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 (One Hour Post-dose)
"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 at Rest Before Constant Work Rate Cycle Ergometry to Symptom Limitation at 75% Wcap
"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 (Borg Scale) During Constant Work Rate Cycle Ergometry to Symptom Limitation at 75% Wcap
"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 |
Endurance Time During Constant Work Rate Cycle Ergometry to Symptom Limitation at 75% Wcap
"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 |
FEV1 (1 Hour Post-dose)
"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 |
Inspiratory Capacity at Rest Before Constant Work Rate Cycle Ergometry to Symptom Limitation at 75% Work Capacity
"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 |
Trough FEV1 Response
"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 AEs
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 |
FEV1 AUC0-3h Response
"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 |
FVC AUC0-24h Response [L] After 6 Weeks Treatment.
"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 |
Peak(0-3h) FEV1 Response [L] After 6 Weeks Treatment.
"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 |
Peak (0-3h) FVC Response [L] After 6 Weeks Treatment.
"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 |
Trough FEV1 Response [L] After 6 Weeks Treatment.
"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 |
FVC AUC12-24h Response [L] After 6 Weeks Treatment.
"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 |
FVC AUC0-12h Response [L] After 6 Weeks Treatment.
"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 |
Forced Expiratory Volume in 1 Second (FEV1) AUC0-24h Response [L] After 6 Weeks Treatment.
"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 |
Trough FVC Response [L] After 6 Weeks Treatment.
"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 |
FEV1 AUC12-24h Response [L] After 6 Weeks Treatment.
"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 |
FEV1 AUC0-12h Response [L] After 6 Weeks Treatment.
"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 |
Peak FEV1 Response at 12 Weeks - Defined as Change From Baseline
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 |
Rescue Medication Usage - Percentage of Rescue Free Days
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)
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 (Nighttime)
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 (Daytime)
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 |
Trough FVC Response at 12 Weeks- Defined as Change From Baseline
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 |
Trough FEV1 Response at 12 Weeks; Defined as Change From Baseline to Week 12
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 |
Peak FVC Response at 12 Weeks - Defined as Change From Baseline
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 |
FVC AUC0-3h Response at 12 Weeks - Defined as Change From Baseline
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 AUC0-3h Response at 12 Weeks; Defined as Change From Baseline to Week 12
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 |
FEV1 AUC0-3h Response at 12 Weeks; Defined as Change From Baseline to Week 12
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 |
Rescue Medication Usage - Mean Weekly Rescue Usage (Total Daily)
"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 |
Peak FEV1 Response at 12 Weeks - Defined as Change From Baseline
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
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 |
Saint George Respiratory Questionnaire - (Total Score) Based on Combined 1222.51 and 1222.52 Data
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 Response at 12 Weeks; Defined as Change From Baseline to Week 12
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 |
Trough FVC Response at 12 Weeks; Defined as Change From Baseline
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 (Daytime)
"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 (Nighttime)
"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 - Percentage of Rescue Free Days
"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 |
FVC AUC0-3h Response at 12 Weeks; Defined as Change From Baseline
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 |
CLR,t1-t2,ss (Tiotropium)
"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 |
Aet1-t2,ss (Olodaterol)
"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 |
AUC0-tz,ss (Olodaterol)
"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 |
AUC0-tz,ss (Tiotropium)
"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 |
AUCt1-t2,ss (Olodaterol)
"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 |
AUCt1-t2,ss (Tiotropium)
"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 |
CLR,t1-t2,ss (Olodaterol)
"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 |
Number of Participants With Clinically Relevant Abnormalities in Vital Signs, Clinical Laboratory Tests and ECG
"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 |
Cmax,ss (Olodaterol)
"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 |
fe t1-t2,ss (Olodaterol)
"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 |
fe t1-t2,ss (Tiotropium)
"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 |
Cmax,ss (Tiotropium)
"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 |
Number of Participants With Adverse Events (Including Assessment Based on Physical Examination)
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 |
Tmax,ss (Olodaterol)
"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 |
Tmax,ss (Tiotropium)
"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 |
Aet1-t2,ss (Tiotropium)
"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 |
FVC AUC0-3h Response (Change From Baseline)
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 |
FEV1 AUC0-3h Response
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 |
TDI Focal Score
"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 |
Trough FEV1 Response (Change From Baseline)
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 |
Trough Forced Vital Capacity (FVC) Response (Change From Baseline)
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 |
St. George's Respiratory Questionnaire (SGRQ) Total Score
"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 FEV1 Change From Patient Baseline After 6 Weeks of Treatment
"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 |
FEV1 AUC (0-12h) Change From Patient Baseline After 6 Weeks of Treatment
"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 |
FEV1 AUC (0-24h) Change From Patient Baseline After 6 Weeks of Treatment
"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 |
FEV1 AUC (12-24h) Change From Patient Baseline After 6 Weeks of Treatment
"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 |
FEV1 Peak (0-3h) Change From Patient Baseline After 6 Weeks of Treatment
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 |
St. George's Respiratory Questionnaire (SGRQ) Total Score Based on Combined Dataset From This Study and the Replicate Study NCT01964352
"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 |
TDI Focal Score Based on Combined Dataset From This Study and the Replicate Study NCT01964352
"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 |
St. George's Respiratory Questionnaire (SGRQ) Total Score Based on Data From This Individual Study
"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 |
FVC AUC0-3h Response (Change From Baseline)
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 |
FEV1 AUC0-3h Response
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 |
TDI Focal Score Based on Data From This Individual Study
"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 |
Trough FEV1 Response (Change From Baseline)
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 |
Trough Forced Vital Capacity (FVC) Response (Change From Baseline)
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 |
QRS Change From Patient Baseline at Individual Post-dose Time Points
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
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 |
QTcB Change From Patient Baseline at Individual Post-dose Time Points
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 |
RR Change From Patient Baseline at Individual Post-dose Time Points
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 PR (Time Interval of ECG) Change From Patient Baseline Over All Post-dose Time Points
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 Heart Rate Change From Patient Baseline Over All Post-dose Time Points
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 |
Mean RR (Time Interval of ECG) Change From Patient Baseline Over All Post-dose Time Points
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 |
Peak QTcB (Heart Rate Corrected QT Interval (Using Bazett Adjustment)) Change From Patient Baseline Over All Post-dose Time Points
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 QT (Time Interval of ECG) Change From Patient Baseline Over All Post-dose Time Points
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 QRS (Time Interval of ECG) Change From Patient Baseline Over All Post-dose Time Points
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 PR (Time Interval of ECG) Change From Patient Baseline Over All Post-dose Time Points
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 Heart Rate Change From Patient Baseline Over All Post-dose Time Points
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 |
Peak QTcF Interval Change From Patient Baseline Over All Post-dose Time Points
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 |
Peak RR Change From Patient Baseline Over All Post-dose Time Points
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 |
Mean (Heart Rate Corrected QT Interval (Using Fredericia Adjustment)) QTcF Interval Change From Patient Baseline Over All Post-dose Time Points
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 |
Forced Expiratory Volume in One Second (FEV1) Area Under the Curve (AUC) (0-3hours) Response After Single-dose Administration
"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 |
Peak QRS (Time Interval of ECG) Change From Patient Baseline Over All Post-dose Time Points
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 |
Mean QTcB (Heart Rate Corrected QT Interval (Using Bazett Adjustment)) Change From Patient Baseline Over All Post-dose Time Points
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 |
Heart Rate Change From Patient Baseline at Individual Post-dose Time Points
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 |
PR Change From Patient Baseline at Individual Post-dose Time Points
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 |
Peak QT (Time Interval of ECG) Change From Patient Baseline Over All Post-dose Time Points
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 |
Endurance Time During Endurance Shuttle Walk Test (ESWT) to Symptom Limitation After 8 Weeks
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 |
One Hour, Post-dose Forced Expiratory Volume in One Second (FEV1) After 8 Weeks of Treatment
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 |
One Hour, Post-dose Forced Vital Capacity (FVC) After 8 Weeks of Treatment
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 |
Perceived Difficulties as Evaluated With Functional Performance Inventory-Short Form (FPI-SF) Total Score at Week 12
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 |
Average Daily Walking Time Measured by the Activity Monitor in the Week Prior to Week 12
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 |
Resting Inspiratory Capacity (IC) Measured at 1.5 Hours Post Dose After 8 Weeks of Treatment
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 |
Average Daily Walking Intensity Measured by the Activity Monitor in the Week Prior to 12 Weeks of Treatment
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 |
Endurance Time During Endurance Shuttle Walk Test (ESWT) to Symptom Limitation After 12 Weeks
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 |
General Health of the Patient After 4-6 Weeks
"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 |
General Health of the Patient at Baseline
"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: Overall Satisfaction
"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 |
Patient Satisfaction: Satisfaction With Handling of Inhaler
"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 |
Patient Satisfaction: Satisfaction With Inhaler
"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"
"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 |
Absolute Changes in the PF-10 Score
"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 |
Ae(0-24h,ss) of Olodaterol
"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 |
AUC(0-1h,ss) of Olodaterol
"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 |
AUC(0-2h,ss) of Olodaterol
"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 |
AUC(0-4h,ss) of Tiotropium
"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 |
AUC(0-tz,ss) of Olodaterol
"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 |
Tmax,ss of Tiotropium
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 |
Cmax,ss of Olodaterol
"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 |
AUC(0-6h,ss) of Tiotropium
"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 |
Cmax,ss of Tiotropium
"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 |
Cmin,ss of Olodaterol
"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 |
Cmin,ss of Tiotropium
"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 |
fe(0-24,ss) of Olodaterol
"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 |
Clinical Relevant Abnormalities in Vital Signs, Physical Examination, Blood Chemistry, Haematology, Urinanalysis and ECG
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 |
fe(0-24,ss) of Tiotropium
"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 |
Tmax,ss of Olodaterol
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 |
AUC(0-tz,ss) of Tiotropium
"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 |
FVC Change From Baseline
"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 |
FEV1 Change From Baseline
"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 |
Ae(0-24h,ss) of Tiotropium
"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 |
Tmin,ss of Tiotropium
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 |
Tmin,ss of Olodaterol
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 |
Concentration of Olodaterol in Plasma
"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 Tiotropium in Plasma
"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 |
Annualised Rate of Exacerbations Leading to Hospitalisation During the Actual Treatment Period.
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.
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.
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.
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 |
Number of Patients With at Least One Moderate to Severe COPD Exacerbation During the Actual Treatment Period.
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 |
Average Daily Duration (Minutes) of ≥ 4 Metabolic Equivalents (METs)
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 |
Average Daily Duration (Minutes) of ≥ 3 Metabolic Equivalents (METs)
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 |
Average Daily Active Strength (Metabolic Equivalents*Minutes) of ≥ 3 METs
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 |
60 Minutes Post-dose Slow Vital Capacity (SVC) (in Litre)
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 |
6-minute Walk Distance [Meter]
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 |
30 Minutes Post-dose Forced Vital Capacity (FVC) (in Litre)
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 |
Inspiratory Capacity at Rest Measured at 60 Minutes Post-dose
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 |
30 Minutes Post-dose Forced Expiratory Volume in One Second (FEV1) (in Litre)
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 |
Average Number of Step Per Day (Step/Day)
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 |
Average Daily Duration (Minutes) of ≥ 2 Metabolic Equivalents (METs)
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 |
Inspiratory Capacity [Litre] Treatment Comparisons of Subgroup of Global Initiative for Chronic Obstructive Lung Disease (GOLD) Stage III/IV
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 |
Inspiratory Capacity [Litre] Treatment Comparisons of Subgroup of Global Initiative for Chronic Obstructive Lung Disease (GOLD) Stage I/II
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 |
Inspiratory Capacity [Litre] Treatment Comparisons of 6-Minute Walk Test (6MWT) in-Completer at Baseline Period
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 |
Inspiratory Capacity [Litre] Treatment Comparisons of 6-Minute Walk Test (6MWT) Completer at Treatment Period
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 |
Inspiratory Capacity [Litre] Treatment Comparisons of 6-Minute Walk Test (6MWT) Completer at Baseline Period
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 |
Inspiratory Capacity [Litre] Test Comparisons of 6-Minute Walk Treatment (6MWT) in-Completer at Treatment Period
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 |
Trough Forced Vital Capacity (FVC) (in Liter) After 28 Days of Treatment
"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 |
Trough Forced Expiratory Volume in 1 Second (FEV1) (in Liter) After 28 Days of Treatment
"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 |
Chronic Obstructive Pulmonary Disease (COPD) Assessment Test™ (CAT) Score on Day 28
"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 |
Change From Period Baseline in the Exercise-isotime Borg CR-10 Rating of Perceived Dyspnea During CWR
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 |
Change From Period Baseline in the Exercise-isotime Borg CR-10 Rating of Perceived Leg Fatigue During CWR
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 |
Change From Period Baseline in the Exercise-isotime Frontal Lobe Oxygen Saturation During CWR
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 |
Change From Period Baseline in the Exercise-isotime in Pulse Oximeter Oxygen Saturation During CWR
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 |
Change From Period Baseline in the Exercise-isotime Inspiratory Capacity During CWR
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 |
Change From Period Baseline in the Exercise-isotime Muscle Oxygen Saturation During CWR
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 |
Change From Period Baseline in the Exercise-isotime Oxygen Uptake (VO2) During CWR
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 |
Change From Period Baseline in the Exercise-isotime Ventilation During CWR
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 |
Change From Period Baseline in the Forced Expiratory Volume in 1 Second (FEV1)
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 |
Change From Period Baseline in the Pre/Post Exercise-induced Decline in Peak Isokinetic Power Normalized to the Measured Muscle Activity (Muscle Fatigue, MF) During CWR
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 |
Exercise Endurance Time During CWR Cycling Exercise
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 |
The Magnitude of Change Electromyographic (EMG) Muscle Activity (Activation Fatigue, AF) Associated With Stiolto Respimat Compared With Placebo Respimat at Isotime During Constant Work Rate Exercise (CWR)
"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 |
The Magnitude of Change in Isokinetic Power (Performance Fatigue, PF) Associated With Stiolto Respimat Compared With Placebo Respimat at Isotime During Constant Work Rate Exercise (CWR)
"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 |
Change From Period Baseline in the Exercise-isotime Inspiratory Reserve Volume During CWR
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 |
Change From Baseline in Intensity of Breathlessness Measured Using the Modified Borg Scale at the End of the 3 Minute (Min) Constant Speed Shuttle Test After 6 Weeks of Treatment.
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 |
Change From Baseline After 6 Weeks of Treatment for Intensity of Breathlessness (MBS-S) at 1, 2 and 2.5 Minute (Min) During the 3 Min Constant Speed Shuttle Test
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 |
Change From Baseline After 6 Weeks of Treatment for Inspiratory Capacity Measured Prior to Exercise
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 |
Change From Baseline After 6 Weeks of Treatment for Chronic Respiratory Questionnaire - Self Administered Standardized (CRQ-SAS) Dyspnoea Domain Score
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 |
Change From Baseline After 6 Weeks of Treatment for 1 Hour Post-dose Forced Expiratory Volume
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 |
Change From Baseline After 6 Weeks of Treatment for 1 Hour Post-dose Forced Vital Capacity
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 |
Change From Baseline After 6 Weeks of Treatment for Inspiratory Capacity Measured at the End of Exercise
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 |
Change From Baseline After 6 Weeks of Treatment for Chronic Respiratory Questionnaire - Self Administered Individualized (CRQ-SAI) Dyspnoea Domain Score
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 |
Percentage of Subjects With Any Adverse Event (AE) in the Long-term Safety Analysis Set
"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) Focal Score at Week 24 in the Effectiveness Analysis Set
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 |
Transition Dyspnea Index (TDI) Focal Score at Week 24 in the Long-term Effectiveness Analysis Set
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 |
Transition Dyspnea Index (TDI) Focal Score at Week 52 in the Effectiveness Analysis Set
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) Focal Score at Week 52 in the Long-term Effectiveness Analysis Set
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 |
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
"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 |
Percentage of Subjects With Any Adverse Event, Unexpected Adverse Event, Unexpected Serious Adverse Event, Adverse Event Leading to Discontinuation
"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 |
Change From Baseline in Post Bronchodilator Percent Predicted Forced Expiratory Volume in One Second (FEV1) to Week 24 in the Effectiveness Analysis Set
"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 |
Change From Baseline in Post Bronchodilator Percent Predicted Forced Expiratory Volume in One Second (FEV1) to Week 24 in the Long-term Effectiveness Analysis Set
"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 |
Change From Baseline in Post Bronchodilator Percent Predicted Forced Expiratory Volume in One Second (FEV1) to Week 52 in the Effectiveness Analysis Set
"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 |
Change From Baseline in Post Bronchodilator Percent Predicted Forced Expiratory Volume in One Second (FEV1) to Week 52 in the Long-term Effectiveness Analysis Set
"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 |
Change From Baseline in Pre-dose Percent Predicted Forced Expiratory Volume in One Second (FEV1) to Week 24 in the Effectiveness Analysis Set
"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 |
Change From Baseline in Pre-dose Percent Predicted Forced Expiratory Volume in One Second (FEV1) to Week 24 in the Long-term Effectiveness Analysis Set
"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 |
Change From Baseline in Pre-dose Percent Predicted Forced Expiratory Volume in One Second (FEV1) to Week 52 in the Effectiveness Analysis Set
"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 |
Change From Baseline in Pre-dose Percent Predicted Forced Expiratory Volume in One Second (FEV1) to Week 52 in the Long-term Effectiveness Analysis Set
"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 |
Effectiveness Rate in the Effectiveness Analysis Set
"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 |
Effectiveness Rate in the Long-term Effectiveness Analysis Set
"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 |
Maximum Measured Concentration of Olodaterol in Plasma (Cmax)
"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 |
Maximum Measured Concentration of Tiotropium in Plasma (Cmax)
"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 |
Maximum Measured Concentration of Tiotropium in Plasma at Steady State (Cmax,ss)
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 |
Pre-dose Concentration of Olodaterol in Plasma at Steady State (Cpre,ss)
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 |
Pre-dose Concentration of Tiotropium in Plasma at Steady State (Cpre,ss)
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 |
Time From Dosing to the Maximum Concentration of Olodaterol in Plasma (Tmax)
"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 |
Time From Dosing to the Maximum Concentration of Olodaterol in Plasma at Steady State (Tmax,ss)
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 |
Time From Dosing to the Maximum Concentration of Tiotropium in Plasma at Steady State (Tmax,ss)
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 |
Accumulation Ratios in Plasma of Olodaterol (RA,Cmax =Cmax,ss/Cmax)
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 |
Accumulation Ratios in Plasma of Tiotropium (RA,Cmax =Cmax,ss/Cmax)
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 |
Area Under the Concentration Time Curve of Olodaterol in Plasma Over the Time Interval From 0 to 6 Hours at Steady State (AUC0-6,ss)
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 |
Area Under the Concentration Time Curve of Tiotropium in Plasma Over the Time Interval From 0 to 6 Hours at Steady State (AUC0-6,ss)
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 |
Area Under the Concentration-time Curve of Olodaterol in Plasma at Steady State Over a Uniform Dosing Interval τ at Steady State (AUCτ,ss)
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 |
Area Under the Concentration-time Curve of Tiotropium in Plasma at Steady State Over a Uniform Dosing Interval τ at Steady State (AUCτ,ss)
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 |
Time From Dosing to the Maximum Concentration of Tiotropium in Plasma (Tmax)
"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 |
Maximum Measured Concentration of Olodaterol in Plasma at Steady State (Cmax,ss)
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 |
Baseline Characteristics of New Users of Indacaterol: Age
Baseline characteristics of patients in treatment group by data source: Age (NCT03030638)
Timeframe: Baseline
| Intervention | Years (Median) |
|---|---|
| Indacaterol - PHARMO Overall | 67 |
| Indacaterol - National Health Databases, Denmark | 69 |
| Indacaterol - IMS RWE LPD GP Panel | 63 |
| Indacaterol - IMS RWE LPD Pulmonologist Panel | 68 |
Baseline Characteristics of New Users of Olodaterol: Age
Baseline characteristics of patients in treatment group by data source: Age (NCT03030638)
Timeframe: Baseline
| Intervention | Years (Median) |
|---|---|
| Olodaterol - PHARMO Overall | 68 |
| Olodaterol - National Health Databases, Denmark | 71 |
| Olodaterol - IMS RWE LPD General Practitioner (GP) Panel | 63 |
| Olodaterol - IMS RWE LPD Pulmonologist Panel | 67 |
Percentage of Off-label Use of Indacaterol Among New Users
Percentage of off-label use of Indacaterol among new users of this medication. Potential off-label are the patients, aged 18 years or older with no recorded COPD diagnosis and no asthma diagnosis. Off-label are the patients, aged 17 years or younger or patients aged 18 years or older with no recorded COPD diagnosis but with a diagnosis of asthma. (NCT03030638)
Timeframe: 01March2014 to 30November2017 up to 30 days after index date, up to 1370 days.
| Intervention | Percentage of participants (Number) | |
|---|---|---|
| Potential off-label | Off-label | |
| Indacaterol - IMS RWE LPD GP Panel | 34.9 | 11.9 |
| Indacaterol - IMS RWE LPD Pulmonologist Panel | 20.5 | 9.4 |
| Indacaterol - National Health Databases, Denmark | 66.6 | 4.6 |
| Indacaterol - PHARMO Overall | 61.1 | 3.5 |
| Indacaterol - PHARMO-GP | 29.2 | 6.8 |
Percentage of Off-label Use of Olodaterol Among New Users
Percentage of off-label use of olodaterol among new users of this medication. Potential off-label are the patients, aged 18 years or older with no recorded Chronic Obstructive Pulmonary Disease (COPD) diagnosis and no asthma diagnosis. Off-label are the patients, aged 17 years or younger or patients aged 18 years or older with no recorded COPD diagnosis but with a diagnosis of asthma. Index date is defined as the date an eligible patient receives the first dispensing of olodaterol or indacaterol during the study period. (NCT03030638)
Timeframe: 01March2014 to 30November2017 up to 30 days after index date, up to 1370 days.
| Intervention | Percentage of participants (Number) | |
|---|---|---|
| Potential off-label | Off-label | |
| Olodaterol - IMS RWE LPD General Practitioner (GP) Panel | 33.9 | 12.4 |
| Olodaterol - IMS RWE LPD Pulmonologist Panel | 17.3 | 4.9 |
| Olodaterol - National Health Databases, Denmark | 30.3 | 4.4 |
| Olodaterol - PHARMO Overall | 48.6 | 3.5 |
| Olodaterol - PHARMO-GP | 19.6 | 6.2 |
Change From Baseline in 1.5 Hour Post Dose Forced Expiratory Volume in 1st Second (FEV1) After 6 Weeks of Treatment
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 Aortic Augmentation Index After 6 Weeks of Treatment
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 Pulse Pressure After 6 Weeks of Treatment
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 Pulmonary Artery Pulsatility After 6 Weeks of Treatment
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 Left Ventricular End Diastolic Volume Index (LVEDVI) in the 6th Week of Treatment
"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 Functional Residual Capacity Body Plethysmography (FRCpleth) % Predicted After 6 Weeks of Treatment
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 |
Change From Baseline in Central Systolic Pressure After 6 Weeks of Treatment
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 1.5 Hour Post Dose Forced Vital Capacity (FVC) After 6 Weeks of Treatment
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 Aortic Distensibility After 6 Weeks of Treatment
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 |
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
"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 |
Peak 0-3 Hours Forced Expiratory Volume in One Second (FEV1) Response (Change From Baseline) [L] After 12 Weeks Treatment
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 |
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
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 |
Trough Forced Expiratory Volume in One Second (FEV1) Response (Change From Baseline) [L] After 12 Weeks Treatment
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 |
Residual Volume on Day 3
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 |
Functional Residual Capacity on Day 3
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 From Baseline in Peak FEV1 After Evening Dose on Day 3
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 From Baseline in Peak FEV1 on Day 3
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 From Baseline in Peak FEV1 on Day 1
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 |
Specific Airway Conductance on Day 1
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 |
Specific Airway Conductance on Day 3
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 |
Residual Volume on Day 1
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 |
Functional Residual Capacity on Day 1
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 |
Determination of Onset of Action on Day 1
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 Trough FEV1 on Day 4
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 in AUC0-12h FEV1 on Day 1
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 |
Change From Baseline in AUC0-12h FEV1 on Day 3
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 in AUC0-4h FEV1 on Day 3
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 |
Rate of Discontinuation of Index Treatment (Olodaterol/Tiotropium Bromide or Umeclidinium/Vilanterol)
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 |
Annualized Rate of Moderate-to-severe Exacerbation
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 |
Annualized Rate of Moderate Exacerbation
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 |
Percentage of Patients Using Rescue Medications
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 LABA+LAMA or LAMA Initiation Evaluating by COPD Assessment Test (CAT) Score at 12 Months After Index Date
"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 |
Annualized Rate of Mild Exacerbation
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 |
Annualized Rate of Severe Exacerbation
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 LABA+LAMA or LAMA Initiation Evaluating by Modified Medical Research Council Dyspnea Scale (mMRC) at 12 Months After Index Date
"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 |
Change From Baseline in Pulmonary Function After LABA+LAMA or LAMA Initiation Evaluating by Post-bronchodilator Forced Expiratory Volume in One Second (Post-FEV1) at 12 Months After Index Date
"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 |
Change From Baseline in Pulmonary Function After LABA+LAMA or LAMA Initiation Evaluating by Post-bronchodilator Forced Volume Vital Capacity (Post-FVC) at 12 Months After Index Date
"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)
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
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 Escalated to Triple Therapy or LAMA Escalated to Dual Therapy
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 |
Incidence Rate of Any Element of a Composite Outcome Including Exacerbation, Hospitalization for Pneumonia, or Escalation (Alternative Case Definition) to Triple Therapy
"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 Chronic Obstructive Pulmonary Disease (COPD) Exacerbation
"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 First Hospitalization for Community-acquired Pneumonia
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 (Alternative Case Definition) to Triple Therapy
"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 Any Element of a Composite Outcome Including Exacerbation, Hospitalization for Pneumonia, or Escalation (Original Case Definition) to Triple Therapy
"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 the First Date of a Pharmacy Dispensing Indicating Escalation (Original Case Definition) to Triple Therapy
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 |
Incidence Rate of Chronic Obstructive Pulmonary Disease (COPD) Exacerbation
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 |
Overall Incidence Rate of Hospitalization for Community-acquired Pneumonia (Serious Pneumonia)
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 |
Incidence Rate of Chronic Obstructive Pulmonary Disease (COPD) Exacerbation - Without Exacerbation Within 30 Days Prior to Cohort Entry
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 |
Change From Baseline in Trough Forced Expiratory Volume in One Second (FEV1) After 4 Weeks of Treatment
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 |
Change From Baseline in Forced Expiratory Volume in One Second (FEV1) Area Under the Curve From 0 to 3 Hours (AUC0-3h) After 4 Weeks of Treatment.
"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
"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 |
Time to First Moderate or Severe Chronic Obstructive Pulmonary Disease (COPD) Exacerbation
"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 |
Number of Moderate or Severe Chronic Obstructive Pulmonary Disease (COPD) Exacerbations
"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 |
Percentage of Patients With Improved / Worsen Condition in Self-care According to the European Quality of Life-5 Dimensions-5 Level (EQ-5D-5L) Questionnaire After 3 Months
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 |
Percentage of Patients With Adherence to the Medication
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 |
Percentage of Patients by Preference for Inhaler
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 |
Change From Baseline in Patients' Quality of Life (QoL) According to the Total Score of COPD Assessment Test (CAT) at Month 3
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 With Improved / Worsen Condition Pain/Discomfort According to the European Quality of Life-5 Dimensions-5 Level (EQ-5D-5L) Questionnaire After 3 Months
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 |
Total Score in Abbreviated Patient Satisfaction and Preference Questionnaire (PASAPQ)
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 |
Percentage of Patients With Improved / Worsened Condition Mobility According to the European Quality of Life-5 Dimensions-5 Level (EQ-5D-5L) Questionnaire After 3 Months
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
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 | |||||||||||
Overall Satisfaction of Inhaler
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 |
Days of Missed Medication for COPD
Days of missed medication for COPD is reported. (NCT04672941)
Timeframe: up to 3 months
| Intervention | days (Mean) |
|---|---|
| COPD Patients | 1.55 |
Willingness to Continue With Inhaler
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 |
Change From Baseline in the Percentage of Patients With CAT≥10 at Month 3
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 |
Change From Baseline in the Total European Quality of Life-Visual Analogue Scale (EQ-VAS) at Month 3
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 |
Percentage of Patients With Improved / Worsen Condition Anxiety/Depression According to the European Quality of Life-5 Dimensions-5 Level (EQ-5D-5L) Questionnaire After 3 Months
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 |
Change From Baseline of Patients' Dyspnea Status According to the Modified Medical Research Council (mMRC) Scale at Month 3
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 |
Percentage of Patients With Improved / Worsen Condition Usual Activities According to the European Quality of Life-5 Dimensions-5 Level (EQ-5D-5L) Questionnaire After 3 Months
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 |
Characteristics of Patients Receiving Second Maintenance Treatment - UK
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 |
Characteristics of Patients Receiving Second Maintenance Treatment - US
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 |
Number of Participants With Zero Exacerbations in the Year Prior to the Start of Second Maintenance Therapy - UK
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 |
Age of the Chronic Obstructive Pulmonary Disease (COPD) Patients at the Time of COPD Diagnosis - US
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 - UK
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 |
Age of Patients Receiving First Maintenance Treatment - US
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 |
Age of Patients Receiving Second Maintenance Treatment - UK
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 - US
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 |
Age of the Chronic Obstructive Pulmonary Disease (COPD) Patients at the Time of COPD Diagnosis - UK
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 |
Charlson Comorbidity Index (CCI) at the Time of COPD Diagnosis
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 |
Charlson Comorbidity Index (CCI) of Patients Receiving First Maintenance Treatment - US
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 |
Charlson Comorbidity Index (CCI) of Patients Receiving Second Maintenance Treatment - US
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 |
Days Between First and Second Maintenance Therapy - UK
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 |
Days Between First and Second Maintenance Therapy - US
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 |
Days Between Index and Initiation of First Maintenance Therapy - UK
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 - US
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 |
Number of Participants With Zero Exacerbations in the Year Prior to the Start of First Maintenance Therapy - UK
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 |
Number of Participants With Zero Exacerbations in the Year Prior to the Start of First Maintenance Therapy - US
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 |
Number of Participants With Zero Exacerbations in the Year Prior to the Start of Second Maintenance Therapy - US
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 - US
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 First Maintenance Treatment - UK
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 |
COPD or Pneumonia-attributable Health Care Costs (Insurer + Patient Paid Amounts)
"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 |
COPD and/or Pneumonia-related Health Care Resource Utilization
"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 |
COPD and/or Pneumonia-related Health Care Costs (Insurer + Patient Paid Amounts)
"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) Exacerbations
"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
"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 (Insurer + Patient Paid Amounts)
"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 |
Pneumonia-related Health Care Resource Utilization: Inpatient Days
"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 |
Percentage of Patients With 30-day All-cause Readmission After COPD Hospitalization
"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 |
COPD-related Health Care Resource Utilization: Pharmacy Fills
"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 |
COPD-related Health Care Resource Utilization: Inpatient Days
"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 |
COPD or Pneumonia-attributable Health Care Resource Utilization: Pharmacy Fills
"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 |
COPD or Pneumonia-attributable Health Care Resource Utilization: Inpatient Days
"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-related Health Care Resource Utilization
"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 and/or Pneumonia-related Health Care Resource Utilization: Pharmacy Fills
"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 and/or Pneumonia-related Health Care Resource Utilization: Inpatient Days
"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 |
All-cause Health Care Resource Utilization: Inpatient Days
"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
"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 |
COPD or Pneumonia-attributable Health Care Resource Utilization
"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 |
Pneumonia-related Health Care Resource Utilization
"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 |
COPD-related Health Care Costs (Insurer + Patient Paid Amounts)
"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 |
Pneumonia-related Health Care Costs (Insurer + Patient Paid Amounts)
"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 |
Total Costs of All-cause HCRU
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 Pneumonia Hospitalization (Diagnosis in Any Position) - Among Patients With no Baseline Exacerbation
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 |
Incidence Rate of Pneumonia Hospitalization (Diagnosis in Any Position) - Among Patients With 2 or More Baseline Exacerbations
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 Pneumonia Hospitalization (Diagnosis in Any Position) - Among Patients With 0 or 1 Baseline Exacerbation
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
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 |
Incidence Rate of Pneumonia Hospitalization (Diagnosis in Any Position)
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 |
Incidence Rate of Chronic Obstructive Pulmonary Disease (COPD) Exacerbation After Cohort Entry - Among Patients With no Baseline Exacerbation
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 |
Incidence Rate of Chronic Obstructive Pulmonary Disease (COPD) Exacerbation After Cohort Entry - Among Patients With 2 or More Baseline Exacerbations
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 0 or 1 Baseline Exacerbation
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 |
Total Costs of COPD-related HCRU
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 |
Total Costs of COPD or Pneumonia-related Health Care Cost and Resource Utilization (HCRU)
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 |
Total Costs of COPD or Pneumonia Attributable HCRU
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 |
Total Costs of Pneumonia-related HCRU
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 |
Related Drugs (35)
| Substance | Relationship Strength | Studies | Trials | Classes | Roles |
|---|---|---|---|---|---|
| citric acid, anhydrous Citric Acid: A key intermediate in metabolism. It is an acid compound found in citrus fruits. The salts of citric acid (citrates) can be used as anticoagulants due to their calcium chelating ability.. citric acid : A tricarboxylic acid that is propane-1,2,3-tricarboxylic acid bearing a hydroxy substituent at position 2. It is an important metabolite in the pathway of all aerobic organisms. | 2.11 | 1 | 0 | tricarboxylic acid | antimicrobial agent; chelator; food acidity regulator; fundamental metabolite |
| histamine [no description available] | 2.52 | 2 | 0 | aralkylamino compound; imidazoles | human metabolite; mouse metabolite; neurotransmitter |
| 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). | 3.91 | 3 | 0 | phenols; phenylethanolamines; secondary amino compound | beta-adrenergic agonist; bronchodilator agent; environmental contaminant; xenobiotic |
| isoproterenol Isoproterenol: Isopropyl analog of EPINEPHRINE; beta-sympathomimetic that acts on the heart, bronchi, skeletal muscle, alimentary tract, etc. It is used mainly as bronchodilator and heart stimulant.. isoprenaline : A secondary amino compound that is noradrenaline in which one of the hydrogens attached to the nitrogen is replaced by an isopropyl group. A sympathomimetic acting almost exclusively on beta-adrenergic receptors, it is used (mainly as the hydrochloride salt) as a bronghodilator and heart stimulant for the management of a variety of cardiac disorders. | 2.31 | 1 | 0 | catechols; secondary alcohol; secondary amino compound | beta-adrenergic agonist; bronchodilator agent; cardiotonic drug; sympathomimetic agent |
| 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. | 3.78 | 2 | 0 | ether; phenols; primary alcohol; secondary alcohol; secondary amino compound | |
| carbachol Carbachol: A slowly hydrolyzed CHOLINERGIC AGONIST that acts at both MUSCARINIC RECEPTORS and NICOTINIC RECEPTORS. | 2.1 | 1 | 0 | ammonium salt; carbamate ester | cardiotonic drug; miotic; muscarinic agonist; nicotinic acetylcholine receptor agonist; non-narcotic analgesic |
| 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. | 6.42 | 7 | 0 | monohydroxyquinoline; quinolone | bacterial xenobiotic metabolite |
| cycloheximide Cycloheximide: Antibiotic substance isolated from streptomycin-producing strains of Streptomyces griseus. It acts by inhibiting elongation during protein synthesis.. cycloheximide : A dicarboximide that is 4-(2-hydroxyethyl)piperidine-2,6-dione in which one of the hydrogens attached to the carbon bearing the hydroxy group is replaced by a 3,5-dimethyl-2-oxocyclohexyl group. It is an antibiotic produced by the bacterium Streptomyces griseus. | 2.07 | 1 | 0 | antibiotic fungicide; cyclic ketone; dicarboximide; piperidine antibiotic; piperidones; secondary alcohol | anticoronaviral agent; bacterial metabolite; ferroptosis inhibitor; neuroprotective agent; protein synthesis inhibitor |
| penicillanic acid Penicillanic Acid: A building block of penicillin, devoid of significant antibacterial activity. (From Merck Index, 11th ed). penicillanic acid : A penam that consists of 3,3-dimethyl-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane bearing a carboxy group at position 2 and having (2S,5R)-configuration. | 3.21 | 1 | 0 | penicillanic acids | |
| quinuclidines Quinuclidines: A class of organic compounds which contain two rings that share a pair of bridgehead carbon atoms and contains an amine group. | 4.95 | 5 | 0 | quinuclidines; saturated organic heterobicyclic parent | |
| 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. | 2.11 | 1 | 0 | hydrochloride; organoammonium salt | anti-allergic agent; antiemetic; antiparkinson drug; antipruritic drug; H1-receptor antagonist; local anaesthetic; muscarinic antagonist; sedative |
| cyclopentane Cyclopentanes: A group of alicyclic hydrocarbons with the general formula R-C5H9.. cyclopentanes : Cyclopentane and its derivatives formed by substitution. | 3.21 | 1 | 0 | cycloalkane; cyclopentanes; volatile organic compound | non-polar solvent |
| 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. | 3.99 | 3 | 0 | organic bromide salt; quaternary ammonium salt | |
| 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. | 3.88 | 2 | 1 | naphthoic acid | |
| cephalosporin c cephalosporin C: RN given refers to parent cpd; structure in Merck, 9th ed, #1937. cephalosporin C : A cephalosporin antibiotic carrying a 3-acetoxymethyl substituent and a 6-oxo-N(6)-L-lysino group at position 7. | 3.21 | 1 | 0 | cephalosporin | fungal metabolite |
| 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. | 3.21 | 1 | 0 | 1,2,3-triazole | |
| bosentan anhydrous Bosentan: A sulfonamide and pyrimidine derivative that acts as a dual endothelin receptor antagonist used to manage PULMONARY HYPERTENSION and SYSTEMIC SCLEROSIS. | 2.07 | 1 | 0 | primary alcohol; pyrimidines; sulfonamide | antihypertensive agent; endothelin receptor antagonist |
| tazobactam Tazobactam: A penicillanic acid and sulfone derivative and potent BETA-LACTAMASE inhibitor that enhances the activity of other anti-bacterial agents against beta-lactamase producing bacteria.. tazobactam : A member of the class of penicillanic acids that is sulbactam in which one of the exocyclic methyl hydrogens is replaced by a 1,2,3-triazol-1-yl group; used (in the form of its sodium salt) in combination with ceftolozane sulfate for treatment of complicated intra-abdominal infections and complicated urinary tract infections. | 3.21 | 1 | 0 | penicillanic acids; triazoles | antiinfective agent; antimicrobial agent; EC 3.5.2.6 (beta-lactamase) inhibitor |
| dactinomycin Dactinomycin: A compound composed of a two CYCLIC PEPTIDES attached to a phenoxazine that is derived from STREPTOMYCES parvullus. It binds to DNA and inhibits RNA synthesis (transcription), with chain elongation more sensitive than initiation, termination, or release. As a result of impaired mRNA production, protein synthesis also declines after dactinomycin therapy. (From AMA Drug Evaluations Annual, 1993, p2015) | 2.07 | 1 | 0 | actinomycin | mutagen |
| efinaconazole efinaconazole: an antifungal agent; structure in first source. efinaconazole : A member of the class of triazoles that is butan-2-ol which is substituted at positions 1, 2, and 3 by 1,2,4-triazol-1-yl, 2,4-difluorophenyl, and 4-methylenepiperidin-1-yl groups, respectively (the 2R,3R stereoisomer). It is an antifungal drug used for the topical treatment of onychomycosis (a nail infection caused mainly by dermatophytes). | 3.21 | 1 | 0 | conazole antifungal drug; olefinic compound; organofluorine compound; piperidines; tertiary alcohol; tertiary amino compound; triazole antifungal drug | EC 1.14.13.70 (sterol 14alpha-demethylase) inhibitor |
| nnd 502 luliconazole: structure in first source | 3.21 | 1 | 0 | dichlorobenzene | |
| arformoterol arformoterol : An N-[2-hydroxy-5-(1-hydroxy-2-{[1-(4-methoxyphenyl)propan-2-yl]amino}ethyl)phenyl]formamide in which both of the stereocentres have R configuration. The active enantiomer of formoterol, it is administered by inhalation (generally as the tartrate salt) as a direct-acting sympathomimetic and bronchodilator for the treatment of chronic obstructive pulmonary disease (any progressive respiratory disease that makes it harder to breathe over time, such as chronic bronchitis and emphysema). | 3.35 | 1 | 0 | N-[2-hydroxy-5-(1-hydroxy-2-{[1-(4-methoxyphenyl)propan-2-yl]amino}ethyl)phenyl]formamide | anti-asthmatic drug; beta-adrenergic agonist; bronchodilator agent |
| 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. | 4.26 | 3 | 1 | 11beta-hydroxy steroid; 17alpha-hydroxy steroid; 3-oxo-Delta(4) steroid; corticosteroid; fluorinated steroid; thioester | anti-allergic agent; anti-asthmatic drug |
| tiotropium bromide 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.. 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. | 16.5 | 60 | 27 | ||
| 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. | 6.8 | 8 | 0 | 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. | 7.6 | 1 | 0 | 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 |
| vilanterol [no description available] | 5.58 | 7 | 0 | benzyl alcohols; dichlorobenzene; ether; phenols; secondary amino compound | beta-adrenergic agonist; bronchodilator agent |
| tavaborole tavaborole: has antifungal activity; structure in first source. tavaborole : A member of the class of benzoxaboroles that is 1,3-dihydro-1-hydroxy-2,1-benzoxaborole substituted at position 5 by a fluoro group. A topical antifungal agent used for the treatment of onychomycosis (fungal infection of the toenails and fingernails). | 3.21 | 1 | 0 | benzoxaborole; organofluorine compound | antifungal agent; EC 6.1.1.4 (leucine--tRNA ligase) inhibitor; protein synthesis inhibitor |
| 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. | 4.33 | 4 | 0 | ||
| peramivir peramivir hydrate : A hydrate that is the trihydrate form of peramivir. Used for the treatment of acute uncomplicated influenza in patients 18 years and older who have been symptomatic for no more than two days.. peramivir : A member of the class of guanidines that is used (as its trihydrate) for the treatment of acute uncomplicated influenza in patients 18 years and older who have been symptomatic for no more than two days. | 3.21 | 1 | 0 | ||
| endothelin-1 Endothelin-1: A 21-amino acid peptide produced in a variety of tissues including endothelial and vascular smooth-muscle cells, neurons and astrocytes in the central nervous system, and endometrial cells. It acts as a modulator of vasomotor tone, cell proliferation, and hormone production. (N Eng J Med 1995;333(6):356-63) | 2.07 | 1 | 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. | 4.83 | 2 | 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. | 2.1 | 1 | 0 | ||
| 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. | 2.15 | 1 | 0 | ||
| oxyntomodulin Glucagon-Like Peptides: Peptides derived from proglucagon which is also the precursor of pancreatic GLUCAGON. Despite expression of proglucagon in multiple tissues, the major production site of glucagon-like peptides (GLPs) is the INTESTINAL L CELLS. GLPs include glucagon-like peptide 1, glucagon-like peptide 2, and the various truncated forms. | 3.21 | 1 | 0 |
Related Conditions (39)
| Condition | Indicated | Relationship Strength | Studies | Trials |
|---|---|---|---|---|
| Airflow Obstruction, Chronic [description not available] | 0 | 20.19 | 142 | 83 |
| Asthma, Bronchial [description not available] | 0 | 11.86 | 17 | 7 |
| Cardiac Failure [description not available] | 0 | 3.17 | 1 | 0 |
| 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). | 1 | 13.86 | 17 | 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 | 3.17 | 1 | 0 |
| 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 | 3.51 | 2 | 0 |
| Pulmonary Disease, Chronic Obstructive A disease of chronic diffuse irreversible airflow obstruction. Subcategories of COPD include CHRONIC BRONCHITIS and PULMONARY EMPHYSEMA. | 1 | 22.19 | 142 | 83 |
| Heart Disease, Ischemic [description not available] | 0 | 2.41 | 1 | 0 |
| Cardiovascular Diseases Pathological conditions involving the CARDIOVASCULAR SYSTEM including the HEART; the BLOOD VESSELS; or the PERICARDIUM. | 0 | 7.78 | 5 | 4 |
| 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 | 2.41 | 1 | 0 |
| Experimental Lung Inflammation Inflammation of any part, segment or lobe, of the lung parenchyma. | 0 | 2.6 | 1 | 0 |
| Pneumonia Infection of the lung often accompanied by inflammation. | 0 | 2.6 | 1 | 0 |
| Arrhythmia [description not available] | 0 | 5.11 | 4 | 0 |
| 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 | 5.11 | 4 | 0 |
| Breathlessness [description not available] | 0 | 9.92 | 2 | 1 |
| Dyspnea Difficult or labored breathing. | 0 | 4.92 | 2 | 1 |
| Innate Inflammatory Response [description not available] | 0 | 2.86 | 3 | 0 |
| 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 | 7.86 | 3 | 0 |
| Disease Models, Animal Naturally-occurring or experimentally-induced animal diseases with pathological processes analogous to human diseases. | 0 | 2.82 | 3 | 0 |
| Cryptogenic Fibrosing Alveolitis [description not available] | 0 | 2.15 | 1 | 0 |
| Idiopathic Pulmonary Fibrosis A common interstitial lung disease of unknown etiology, usually occurring between 50-70 years of age. Clinically, it is characterized by an insidious onset of breathlessness with exertion and a nonproductive cough, leading to progressive DYSPNEA. Pathological features show scant interstitial inflammation, patchy collagen fibrosis, prominent fibroblast proliferation foci, and microscopic honeycomb change. | 0 | 2.15 | 1 | 0 |
| Kidney Diseases Pathological processes of the KIDNEY or its component tissues. | 0 | 3.94 | 2 | 1 |
| Disease Exacerbation [description not available] | 0 | 9.93 | 10 | 10 |
| Airway Hyper-Responsiveness [description not available] | 0 | 2.1 | 1 | 0 |
| Apoplexy [description not available] | 0 | 9.73 | 9 | 9 |
| Cardiac Diseases [description not available] | 0 | 9.73 | 9 | 9 |
| Blood Pressure, High [description not available] | 0 | 9.73 | 9 | 9 |
| Cardiovascular Stroke [description not available] | 0 | 9.73 | 9 | 9 |
| Cardiac Arrest, Sudden [description not available] | 0 | 9.73 | 9 | 9 |
| Heart Diseases Pathological conditions involving the HEART including its structural and functional abnormalities. | 0 | 9.73 | 9 | 9 |
| 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 | 9.73 | 9 | 9 |
| Myocardial Infarction NECROSIS of the MYOCARDIUM caused by an obstruction of the blood supply to the heart (CORONARY CIRCULATION). | 0 | 9.73 | 9 | 9 |
| 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 | 9.73 | 9 | 9 |
| 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 | 9.73 | 9 | 9 |
| 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 | 7.11 | 1 | 0 |
| Disease, Pulmonary [description not available] | 0 | 2.11 | 1 | 0 |
| Lung Diseases Pathological processes involving any part of the LUNG. | 0 | 2.11 | 1 | 0 |
| Liver Dysfunction [description not available] | 0 | 2.13 | 1 | 0 |
| Liver Diseases Pathological processes of the LIVER. | 1 | 4.13 | 1 | 0 |