albuterol and Disease Exacerbation studies

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).

Research Excerpts

Excerpt	Relevance	Reference
"Plasma albuterol was significantly correlated with serum lactate concentration after adjusting for asthma severity."	9.19	Albuterol administration is commonly associated with increases in serum lactate in patients with asthma treated for acute exacerbation of asthma. ( Aubuchon, K; Ferguson, I; House, SL; Johnson, K; Lewis, LM; Matsuda, K; Schneider, J, 2014)
"Caregivers reported that they would use albuterol to treat their child's worsening asthma symptoms, but many described inappropriate use."	9.14	Home use of albuterol for asthma exacerbations. ( Freiner, D; Garbutt, JM; Highstein, GR; Nelson, KA; Smith, SR; Strunk, RC, 2009)
"The benefits of metered-dose inhalers with a spacer (MDI+S) have increasingly been recognized as an alternative method of albuterol administration for treating pediatric asthma exacerbations."	9.05	Metered-dose inhalers versus nebulization for the delivery of albuterol for acute exacerbations of wheezing or asthma in children: A systematic review with meta-analysis. ( Barrios-Sanjuanelo, A; Contreras-Arrieta, S; Florez-García, V; Payares-Salamanca, L; Rodriguez-Martinez, CE; Stand-Niño, I, 2020)
"To determine if nitrites (nitric oxide metabolites) measured in induced sputum decrease and correlate with improvement of clinical asthma symptoms after treatment, we performed a prospective longitudinal study in a tertiary care hospital in Arequipa, Peru."	7.80	Correlation between nitrites in induced sputum and asthma symptoms in asthmatic schoolchildren. ( Cáceres, M; Castro-Rodriguez, JA; Molina, RO; Recabarren, A, 2014)
"The Arg16 genotype of ADRB2 is associated with exacerbations in asthmatic children and young adults exposed daily to beta(2)-agonists, regardless of whether the exposure is to albuterol or long-acting agonists, such as salmeterol."	7.75	Adrenergic beta(2)-receptor genotype predisposes to exacerbations in steroid-treated asthmatic patients taking frequent albuterol or salmeterol. ( Basu, K; Lipworth, BJ; Mukhopadhyay, S; Palmer, CN; Tavendale, R, 2009)
"To identify the relationship between resource utilization and treatment of asthma in subjects who were first time users of controller therapies, either fluticasone propionate (FP) and salmeterol delivered in a single Diskus device (FSC) or FP monotherapy."	7.74	An observational study of fixed dose combination fluticasone propionate/salmeterol or fluticasone propionate alone on asthma-related outcomes . ( Fuhlbrigge, A; Rey, GG; Riedel, A; Stanford, RH; Stempel, DA, 2008)
"Plasma albuterol was significantly correlated with serum lactate concentration after adjusting for asthma severity."	5.19	Albuterol administration is commonly associated with increases in serum lactate in patients with asthma treated for acute exacerbation of asthma. ( Aubuchon, K; Ferguson, I; House, SL; Johnson, K; Lewis, LM; Matsuda, K; Schneider, J, 2014)
"Children with mild persistent asthma should not be treated with rescue albuterol alone and the most effective treatment to prevent exacerbations is daily inhaled corticosteroids."	5.15	Use of beclomethasone dipropionate as rescue treatment for children with mild persistent asthma (TREXA): a randomised, double-blind, placebo-controlled trial. ( Bacharier, LB; Bade, E; Boehmer, SJ; Chinchilli, VM; Covar, RA; Friedman, NJ; Guilbert, TW; Heidarian-Raissy, H; Kelly, HW; Lemanske, RF; Malka-Rais, J; Martinez, FD; Mauger, DT; Mellon, MH; Morgan, WJ; Sorkness, CA; Strunk, RC; Szefler, SJ; Taussig, L; Zeiger, RS, 2011)
" Here, we investigated the long-term effects of therapy with fluticasone propionate (FP) alone, salmeterol (SAL) alone, and a SAL/FP combination (SFC) on bone mineral density (BMD) and bone fractures in patients with moderate-to-severe COPD in the TOwards a Revolution in COPD Health (TORCH) study."	5.14	Prevalence and progression of osteoporosis in patients with COPD: results from the TOwards a Revolution in COPD Health study. ( Anderson, JA; Calverley, PMA; Celli, B; Ferguson, GT; Jenkins, CR; Jones, PW; Vestbo, J; Willits, LR; Yates, JC, 2009)
" Overall, there was a higher incidence of pneumonia in the fluticasone propionate and SFC arms, compared with other treatments in all GOLD stages."	5.14	Efficacy of salmeterol/fluticasone propionate by GOLD stage of chronic obstructive pulmonary disease: analysis from the randomised, placebo-controlled TORCH study. ( Anderson, JA; Calverley, PM; Celli, B; Ferguson, GT; Jenkins, CR; Jones, PW; Vestbo, J; Willits, LR; Yates, JC, 2009)
"Caregivers reported that they would use albuterol to treat their child's worsening asthma symptoms, but many described inappropriate use."	5.14	Home use of albuterol for asthma exacerbations. ( Freiner, D; Garbutt, JM; Highstein, GR; Nelson, KA; Smith, SR; Strunk, RC, 2009)
"The benefits of metered-dose inhalers with a spacer (MDI+S) have increasingly been recognized as an alternative method of albuterol administration for treating pediatric asthma exacerbations."	5.05	Metered-dose inhalers versus nebulization for the delivery of albuterol for acute exacerbations of wheezing or asthma in children: A systematic review with meta-analysis. ( Barrios-Sanjuanelo, A; Contreras-Arrieta, S; Florez-García, V; Payares-Salamanca, L; Rodriguez-Martinez, CE; Stand-Niño, I, 2020)
"Levalbuterol is an alternative to racemic albuterol with the potential to improve patient outcomes and reduce costs in the treatment of acute asthma exacerbations."	4.83	Asthma pathophysiology and evidence-based treatment of severe exacerbations. ( Schreck, DM, 2006)
" Effectiveness of switch was assessed as the proportion without severe asthma exacerbation and the proportion achieving risk domain asthma control (RDAC; no asthma-related hospitalization, antibiotics without upper respiratory diagnosis or acute course of oral corticosteroids) and overall asthma control (OAC; RDAC and ≤ 200 μg salbutamol/≤500 μg terbutaline average daily dose) comparing 1 year after and before the switch."	3.91	Real-life effectiveness of inhaler device switch from dry powder inhalers to pressurized metred-dose inhalers in patients with asthma treated with ICS/LABA. ( Ban, GY; Carter, V; Hardjojo, A; Jie, JLZ; Lee, HY; Park, HS; Price, DB; Van Boven, JFM; Wan Yau Ming, S; Yoon, D, 2019)
"To determine if nitrites (nitric oxide metabolites) measured in induced sputum decrease and correlate with improvement of clinical asthma symptoms after treatment, we performed a prospective longitudinal study in a tertiary care hospital in Arequipa, Peru."	3.80	Correlation between nitrites in induced sputum and asthma symptoms in asthmatic schoolchildren. ( Cáceres, M; Castro-Rodriguez, JA; Molina, RO; Recabarren, A, 2014)
"To examine the use of intravenous magnesium in Canadian pediatric emergency departments (EDs) in children requiring hospitalization for acute asthma and association of administration of frequent albuterol/ipratropium and timely corticosteroids with hospitalization."	3.78	Magnesium use in asthma pharmacotherapy: a Pediatric Emergency Research Canada study. ( Black, KJ; Freedman, S; Gouin, S; Hernandez, A; Johnson, DW; Plint, A; Porter, R; Schuh, S; Zemek, R, 2012)
" Despite similar clinical asthma scores on hospital admission, the children with the Gly/Gly genotype had significantly shorter hospital ICU length of stay and duration of continuously nebulized albuterol therapy and were significantly less likely to require IV beta(2)-AR therapy than those with Arg/Arg or Arg/Gly genotypes."	3.75	Beta2-adrenergic receptor polymorphisms affect response to treatment in children with severe asthma exacerbations. ( Carroll, CL; Schramm, CM; Stoltz, P; Zucker, AR, 2009)
"The Arg16 genotype of ADRB2 is associated with exacerbations in asthmatic children and young adults exposed daily to beta(2)-agonists, regardless of whether the exposure is to albuterol or long-acting agonists, such as salmeterol."	3.75	Adrenergic beta(2)-receptor genotype predisposes to exacerbations in steroid-treated asthmatic patients taking frequent albuterol or salmeterol. ( Basu, K; Lipworth, BJ; Mukhopadhyay, S; Palmer, CN; Tavendale, R, 2009)
"To identify the relationship between resource utilization and treatment of asthma in subjects who were first time users of controller therapies, either fluticasone propionate (FP) and salmeterol delivered in a single Diskus device (FSC) or FP monotherapy."	3.74	An observational study of fixed dose combination fluticasone propionate/salmeterol or fluticasone propionate alone on asthma-related outcomes . ( Fuhlbrigge, A; Rey, GG; Riedel, A; Stanford, RH; Stempel, DA, 2008)
"Coronary vasodilator function and atherosclerotic plaque progression have both been shown to be associated with adverse cardiovascular events."	2.87	Evaluation of human coronary vasodilator function predicts future coronary atheroma progression. ( Baillie, TJ; Beltrame, JF; Delacroix, S; Honda, S; Howell, S; Kim, S; Montarello, N; Nicholls, SJ; Psaltis, PJ; Shishikura, D; Sidharta, SL; Worthley, MI; Worthley, SG, 2018)
"In exacerbations of chronic obstructive pulmonary disease, administration of high concentrations of oxygen may cause hypercapnia and increase mortality compared with oxygen titrated, if required, to achieve an oxygen saturation of 88-92%."	2.87	Oxygen versus air-driven nebulisers for exacerbations of chronic obstructive pulmonary disease: a randomised controlled trial. ( Bardsley, G; Beasley, R; Berry, J; Fingleton, J; McKinstry, S; Pilcher, J; Shirtcliffe, P; Weatherall, M, 2018)
"30 patients presenting to ED with AECOPD were included."	2.80	Intravenous magnesium sulphate as an adjuvant therapy in acute exacerbations of chronic obstructive pulmonary disease: a single centre, randomised, double-blinded, parallel group, placebo-controlled trial: a pilot study. ( Armstrong, P; Clayton-Smith, B; Hardy, M; Marchant, G; Marsh, E; Mukerji, S; Shahpuri, B; Smith, N, 2015)
"A core feature of chronic obstructive pulmonary disease (COPD) is the accelerated decline in forced expiratory volume in one second (FEV1)."	2.79	Airway gene expression in COPD is dynamic with inhaled corticosteroid treatment and reflects biological pathways associated with disease activity. ( Alekseyev, YO; Heijink, IH; Hiemstra, PS; Lenburg, ME; Liu, G; Postma, DS; Spira, A; Steiling, K; Sterk, PJ; Timens, W; van den Berge, M, 2014)
"Patients with the most severe COPD may be more refractory to treatment."	2.79	Fluticasone propionate/salmeterol 250/50 μg versus salmeterol 50 μg after chronic obstructive pulmonary disease exacerbation. ( Crater, GD; Dransfield, MT; Emmett, A; Ferro, TJ; Morris, AN; Ohar, JA; Raphiou, I; Sriram, PS, 2014)
"Chronic obstructive pulmonary disease (COPD) affects millions worldwide."	2.79	Comparison of conventional medicine, TCM treatment, and combination of both conventional medicine and TCM treatment for patients with chronic obstructive pulmonary disease: study protocol of a randomized comparative effectiveness research trial. ( Li, JS; Li, SY; Xie, Y; Yu, XQ, 2014)
"The Global initiative for chronic Obstructive Lung Disease (GOLD) Committee has proposed a chronic obstructive pulmonary disease (COPD) assessment framework focused on symptoms and on exacerbation risk."	2.78	A study to assess COPD Symptom-based Management and to Optimise treatment Strategy in Japan (COSMOS-J) based on GOLD 2011. ( Betsuyaku, T; Fujimoto, K; Hagan, G; Hitosugi, H; James, M; Jones, PW; Kato, M; Kobayashi, A, 2013)
"Exacerbations of COPD are associated with increased symptoms that persist for weeks and the course is very similar between a first and second exacerbation."	2.77	Prediction and course of symptoms and lung function around an exacerbation in chronic obstructive pulmonary disease. ( Creemers, JP; Hop, WC; Postma, DS; Schreurs, AJ; van den Berge, M; van der Molen, T; van Noord, JA; Wouters, EF, 2012)
"Our data suggest that COPD patients benefit from the addition of Ismigen on top of the routine maintenance treatment with SFC."	2.74	Value of adding a polyvalent mechanical bacterial lysate to therapy of COPD patients under regular treatment with salmeterol/fluticasone. ( Cazzola, M; Di Perna, F; Noschese, P, 2009)
"Chronic obstructive pulmonary disease (COPD) is characterized by an accelerated decline in lung function."	2.73	Effect of pharmacotherapy on rate of decline of lung function in chronic obstructive pulmonary disease: results from the TORCH study. ( Anderson, JA; Calverley, PM; Celli, BR; Ferguson, GT; Jenkins, CR; Jones, PW; Knobil, K; Thomas, NE; Vestbo, J; Yates, JC, 2008)
"Acute exacerbations of chronic obstructive pulmonary disease (COPD)--characterized by shortness of breath, increased sputum production, increased purulence, or a combination of these signs--are costly and can have major impacts on the patient's health."	2.53	Treating and preventing acute exacerbations of COPD. ( Aboussouan, LS; Hatipoglu, US, 2016)
"Chronic obstructive pulmonary disease (COPD) is the third leading cause of death worldwide."	2.52	Early chronic obstructive pulmonary disease: definition, assessment, and prevention. ( Drummond, MB; Rennard, SI, 2015)
"The addition of FSC to subjects with COPD treated with tiotropium significantly improves lung function, quality of life and COPD exacerbations without increasing the risk of adverse events."	2.50	Benefits of adding fluticasone propionate/salmeterol to tiotropium in COPD: a meta-analysis. ( Li, M; Liu, Y; Mi, L; Shi, H; Sun, X; Yang, K; Zhang, D; Zhang, Y, 2014)
"Pregnancy is also associated with a physiological suppression of the immune system."	2.49	Management of asthma during pregnancy. ( Adams, SG; Levine, SM; Maselli, DJ; Peters, JI, 2013)
"A previously published, validated COPD progression model was updated with new exacerbation data and adapted to the Dutch setting by including Dutch estimates of healthcare use for COPD maintenance treatment and Dutch unit costs."	2.48	Which long-acting bronchodilator is most cost-effective for the treatment of COPD? ( Hoogendoorn, M; Kappelhoff, BS; Overbeek, JA; Rutten-van Mölken, MP; Wouters, EF, 2012)
"In people with COPD, the evidence is equivocal as to whether or not tiotropium offers greater benefit than LABAs in improving quality of life; however, this is complicated by differences in effect among the LABA types."	2.48	Tiotropium versus long-acting beta-agonists for stable chronic obstructive pulmonary disease. ( Chong, J; Karner, C; Poole, P, 2012)
"Exacerbations of chronic obstructive pulmonary disease contribute to the high mortality rate associated with the disease."	2.46	Management of COPD exacerbations. ( Evensen, AE, 2010)
"Influencing the progression of COPD has long been an elusive goal of drug therapy."	2.45	Insights into interventions in managing COPD patients: lessons from the TORCH and UPLIFT studies. ( Anzueto, A; Miravitlles, M, 2009)
"For the acute COPD studies, one was double-blind and randomised, one was single-blind and randomised, and one was open-label."	2.45	Use of dry powder inhalers in acute exacerbations of asthma and COPD. ( Borgström, L; Ingelf, J; Selroos, O, 2009)
"Airway inflammation is a key factor in the mechanisms of asthma."	2.42	Mechanisms of asthma. ( Busse, WW; Rosenwasser, LJ, 2003)
"Exacerbations of COPD are now the second largest cause of emergency hospitalisation in the UK."	1.56	Management of COPD exacerbations: pharmacotherapeutics of medications. ( Moore, D, 2020)
" Safety in terms of adverse events (AEs) was also examined."	1.48	Real-life effectiveness and safety of salbutamol Steri-Neb™ vs. Ventolin Nebules® for exacerbations in patients with COPD: Historical cohort study. ( Davis, E; Gefen, E; Gopalan, G; McDonald, R; Ming, SWY; Price, DB; Thomas, V, 2018)
"Asthma and chronic obstructive pulmonary disease (COPD) are common lung diseases characterized by chronic airway inflammation and airway obstruction."	1.42	[Asthma-COPD overlap syndrome]. ( Bavbek, S; Çelik, G; Demir, T; Gemicioğlu, B; Günen, H; Kıyan, E; Mungan, D; Oğuzülgen, K; Polatlı, M; Saryal, S; Sayıner, A; Şen, E; Türktaş, H; Yıldırım, N; Yıldız, F; Yorgancıoğlu, A, 2015)
"A total of 77,480 newly-diagnosed COPD patients with a mean age of 68."	1.40	The association between inhaled long-acting bronchodilators and less in-hospital care in newly-diagnosed COPD patients. ( Kim, J; Kim, K; Kim, Y; Kim, YS; Lee, CK; Lee, JH; Lee, SD; Lee, SW; Oh, YM; Park, YB; Yoo, KH; Yoon, HK, 2014)
"The risks of COPD exacerbations and healthcare costs were compared between cohorts during 1 year of follow-up."	1.38	Observational study on the impact of initiating tiotropium alone versus tiotropium with fluticasone propionate/salmeterol combination therapy on outcomes and costs in chronic obstructive pulmonary disease. ( Bechtel, B; Chatterjee, A; Crater, G; D'Souza, AO; Dalal, AA; Shah, M, 2012)
"Among those with confirmed COPD, dyspnoea was worse in those with more severe airflow limitation though exacerbation frequency was comparable across COPD stages."	1.37	Disease severity and symptoms among patients receiving monotherapy for COPD. ( Bailey, W; Crater, G; Dransfield, MT; Emmett, A; O'Dell, DM; Yawn, B, 2011)
"Prevalence of wheezing is increasing, bronchodilators are sub-optimally utilized and antibiotics are over-prescribed."	1.35	Are we adequately managing children with wheeze using the standard case management guidelines? ( Bunnag, T; Jatanachai, P; Lochindarat, S; Nisar, YB; Qazi, SA, 2008)
"Chronic obstructive pulmonary disease (COPD) exacerbations are associated with increased airway and systemic inflammation, though relationships between exacerbation recovery, recurrent exacerbation and inflammation have not been previously reported."	1.34	Inflammatory changes, recovery and recurrence at COPD exacerbation. ( Donaldson, GC; Hurst, JR; Müllerova, H; Perera, WR; Sapsford, RJ; Wedzicha, JA; Wilkinson, TM, 2007)

Research

Studies (97)

Authors

Clinical Trials (25)

Trial Overview

Trial Outcomes

Change of FEV1 (Forced Expiratory Volume in 1 Second) Expressed as Percent of Predicted After Two Doses of Albuterol (5 mg Each) and Ipratropium (0.5 mg Each) When Compared to FEV1 at Hour 2 After the Start of the Infusion of MN-221 or Placebo.

Timeframe	Studies, this research(%)	All Research%
pre-1990	0 (0.00)	18.7374
1990's	1 (1.03)	18.2507
2000's	25 (25.77)	29.6817
2010's	67 (69.07)	24.3611
2020's	4 (4.12)	2.80

Authors	Studies
Pertzborn, MC	1
Prabhakaran, S	1
Abu-Hasan, M	1
Baker, D	1
Wu, S	1
Wu, Y	1
Hendeles, L	1
Moore, D	1
Payares-Salamanca, L	1
Contreras-Arrieta, S	1
Florez-García, V	1
Barrios-Sanjuanelo, A	1
Stand-Niño, I	1
Rodriguez-Martinez, CE	1
Xu, H	1
Tong, L	1
Gao, P	1
Hu, Y	1
Wang, H	1
Chen, Z	1
Fang, L	1
Konno, S	1
Makita, H	1
Suzuki, M	1
Shimizu, K	1
Kimura, H	2
Nishimura, M	1
Forouzan, A	1
Masoumi, K	1
Delirrooyfard, A	1
Asgari Darian, A	1
Mokhtar Gandomani, L	1
Morjaria, JB	1
Rigby, AS	1
Morice, AH	1
Price, DB	2
Gefen, E	1
Gopalan, G	1
McDonald, R	1
Thomas, V	1
Ming, SWY	1
Davis, E	1
Sidharta, SL	1
Baillie, TJ	1
Howell, S	1
Nicholls, SJ	1
Montarello, N	1
Honda, S	1
Shishikura, D	1
Delacroix, S	1
Kim, S	1
Beltrame, JF	1
Psaltis, PJ	1
Worthley, SG	1
Worthley, MI	1
Rex, CE	1
Eckerström, F	1
Heiberg, J	1
Maagaard, M	1
Rubak, S	1
Redington, A	1
Hjortdal, VE	1
Chachi, L	1
Alzahrani, A	1
Koziol-White, C	1
Biddle, M	1
Bagadood, R	1
Panettieri, RA	1
Bradding, P	1
Amrani, Y	1
Bardsley, G	1
Pilcher, J	1
McKinstry, S	1
Shirtcliffe, P	2
Berry, J	1
Fingleton, J	1
Weatherall, M	2
Beasley, R	3
Langton, D	1
Ing, A	1
Sha, J	1
Bennetts, K	1
Hersch, N	1
Kwok, M	1
Plummer, V	1
Thien, F	1
Farah, C	1
Shafuddin, E	1
Chang, CL	1
Cooray, M	1
Tuffery, CM	1
Hopping, SJ	1
Sullivan, GD	1
Jacobson, GA	1
Hancox, RJ	1
Ibrahim, WH	1
Rasul, F	1
Ahmad, M	1
Bajwa, AS	1
Alamlih, LI	1
El Arabi, AM	1
Al-Mohannadi, D	1
Siddiqui, MY	1
Al-Sheikh, IS	1
Ibrahim, AA	1
Park, HS	1
Yoon, D	1
Lee, HY	1
Ban, GY	1
Wan Yau Ming, S	1
Jie, JLZ	1
Carter, V	1
Hardjojo, A	1
Van Boven, JFM	1
Char, DS	1
Ibsen, LM	1
Ramamoorthy, C	1
Bratton, SL	1
Giubergia, V	1
Gravina, L	1
Castaños, C	1
Chertkoff, L	1
Castro-Rodriguez, JA	2
Molina, RO	1
Cáceres, M	1
Recabarren, A	1
van den Berge, M	2
Steiling, K	1
Timens, W	1
Hiemstra, PS	1
Sterk, PJ	1
Heijink, IH	1
Liu, G	1
Alekseyev, YO	1
Lenburg, ME	1
Spira, A	1
Postma, DS	3
Lewis, LM	1
Ferguson, I	1
House, SL	1
Aubuchon, K	1
Schneider, J	1
Johnson, K	1
Matsuda, K	1
Kim, J	1
Kim, K	1
Kim, Y	1
Yoo, KH	1
Lee, CK	1
Yoon, HK	1
Kim, YS	1
Park, YB	1
Lee, JH	1
Oh, YM	1
Lee, SD	1
Lee, SW	1
Betsuyaku, T	1
Kato, M	1
Fujimoto, K	1
Hagan, G	2
Kobayashi, A	1
Hitosugi, H	1
James, M	1
Jones, PW	5
Beeh, KM	1
Glaab, T	1
Stowasser, S	1
Schmidt, H	1
Fabbri, LM	1
Rabe, KF	1
Vogelmeier, CF	2
Kaplan, A	1
Gruffydd-Jones, K	1
van Gemert, F	1
Kirenga, BJ	1
Medford, AR	1
Ismaila, A	2
Corriveau, D	2
Vaillancourt, J	2
Parsons, D	2
Stanford, R	1
Su, Z	2
Sampalis, JS	2
Dalal, A	1
Tsuchida, T	1
Matsuse, H	1
Bateman, ED	1
Mahler, DA	1
Wedzicha, JA	3
Patalano, F	1
Banerji, D	1
Liu, Y	1
Shi, H	1
Sun, X	1
Zhang, D	1
Zhang, Y	1
Yang, K	1
Mi, L	1
Li, M	1
Li, JS	1
Xie, Y	1
Li, SY	1
Yu, XQ	1
Bhatt, SP	1
Wells, JM	1
Kim, V	1
Criner, GJ	1
Hersh, CP	1
Hardin, M	1
Bailey, WC	1
Nath, H	1
Kim, YI	1
Foreman, MG	1
Stinson, DS	1
Wilson, CG	1
Rennard, SI	2
Silverman, EK	1
Make, BJ	2
Dransfield, MT	3
Ohar, JA	1
Crater, GD	1
Emmett, A	2
Ferro, TJ	1
Morris, AN	1
Raphiou, I	1
Sriram, PS	1
Rodrigo, GJ	1
Rossi, A	1
van der Molen, T	2
del Olmo, R	1
Papi, A	1
Wehbe, L	1
Quinn, M	1
Lu, C	1
Young, D	1
Cameron, R	1
Bucchioni, E	1
Altman, P	1
Eriksson, G	1
Calverley, PM	5
Jenkins, CR	4
Peterson, S	1
Östlund, O	1
Anzueto, A	2
Drummond, MB	1
Miller, AG	1
Breslin, ME	1
Pineda, LC	1
Fox, JW	1
Perez, T	1
Chanez, P	1
Dusser, D	1
Devillier, P	1
Wechsler, ME	2
Yawn, BP	1
Fuhlbrigge, AL	1
Pace, WD	1
Pencina, MJ	1
Doros, G	1
Kazani, S	1
Raby, BA	1
Lanzillotti, J	1
Madison, S	1
Israel, E	3
Chauhan, BF	1
Chartrand, C	1
Ni Chroinin, M	1
Milan, SJ	1
Ducharme, FM	1
Mukerji, S	1
Shahpuri, B	1
Clayton-Smith, B	1
Smith, N	1
Armstrong, P	1
Hardy, M	1
Marchant, G	1
Marsh, E	1
Şen, E	1
Oğuzülgen, K	1
Bavbek, S	1
Günen, H	1
Kıyan, E	1
Türktaş, H	1
Yorgancıoğlu, A	1
Polatlı, M	1
Yıldız, F	1
Çelik, G	1
Demir, T	1
Gemicioğlu, B	1
Mungan, D	1
Saryal, S	1
Sayıner, A	1
Yıldırım, N	1
Hatipoglu, US	1
Aboussouan, LS	1
Virchow, JC	1
Backer, V	1
Kuna, P	1
Prieto, L	1
Nolte, H	1
Villesen, HH	1
Ljørring, C	1
Riis, B	1
de Blay, F	1
Denlinger, LC	2
Phillips, BR	1
Ramratnam, S	1
Ross, K	1
Bhakta, NR	1
Cardet, JC	1
Castro, M	2
Peters, SP	2
Phipatanakul, W	1
Aujla, S	1
Bacharier, LB	3
Bleecker, ER	1
Comhair, SA	1
Coverstone, A	1
DeBoer, M	1
Erzurum, SC	1
Fain, SB	1
Fajt, M	1
Fitzpatrick, AM	1
Gaffin, J	1
Gaston, B	1
Hastie, AT	1
Hawkins, GA	2
Holguin, F	1
Irani, AM	1
Levy, BD	1
Ly, N	1
Meyers, DA	2
Moore, WC	1
Myers, R	1
Opina, MT	1
Peters, MC	1
Schiebler, ML	1
Sorkness, RL	1
Teague, WG	1
Wenzel, SE	1
Woodruff, PG	1
Mauger, DT	2
Fahy, JV	2
Jarjour, NN	2
Quan-Jun, Y	1
Jian-Ping, Z	1
Jian-Hua, Z	1
Yong-Long, H	1
Bo, X	1
Jing-Xian, Z	1
Bona, D	1
Yuan, Z	1
Cheng, G	1
Celli, BR	2
Thomas, NE	1
Anderson, JA	4
Ferguson, GT	4
Vestbo, J	4
Knobil, K	1
Yates, JC	4
Stanford, RH	1
Fuhlbrigge, A	1
Riedel, A	1
Rey, GG	1
Stempel, DA	1
Carroll, CL	1
Stoltz, P	1
Schramm, CM	1
Zucker, AR	1
Dhuper, S	1
Chandra, A	1
Ahmed, A	1
Bista, S	1
Moghekar, A	1
Verma, R	1
Chong, C	1
Shim, C	1
Cohen, H	1
Choksi, S	1
Lindmark, B	1
Ramnarayan, P	1
Chhabra, R	1
Maheshwari, P	1
Marchand, E	1
Lochindarat, S	1
Qazi, SA	1
Bunnag, T	1
Nisar, YB	1
Jatanachai, P	1
Vangveeravong, M	1
Cazzola, M	1
Noschese, P	1
Di Perna, F	1
Selroos, O	1
Borgström, L	1
Ingelf, J	1
Miravitlles, M	1
Garbutt, JM	1
Freiner, D	1
Highstein, GR	1
Nelson, KA	1
Smith, SR	1
Strunk, RC	3
Celli, B	2
Willits, LR	2
Calverley, PMA	1
Basu, K	1
Palmer, CN	1
Tavendale, R	1
Lipworth, BJ	1
Mukhopadhyay, S	1
Dalal, AA	2
Petersen, H	1
Simoni-Wastila, L	1
Blanchette, CM	1
Evensen, AE	1
Dilaghi, B	1
Modesti, PA	1
Conti, AA	1
Nozzoli, C	1
McDonough, C	1
Blanchard, AR	1
Van den Bruel, A	1
Gailly, J	1
Neyt, M	1
Bailey, W	1
Crater, G	2
O'Dell, DM	1
Yawn, B	1
Martinez, FD	1
Chinchilli, VM	1
Morgan, WJ	2
Boehmer, SJ	1
Lemanske, RF	2
Szefler, SJ	4
Zeiger, RS	1
Bade, E	1
Covar, RA	1
Friedman, NJ	1
Guilbert, TW	1
Heidarian-Raissy, H	1
Kelly, HW	1
Malka-Rais, J	1
Mellon, MH	1
Sorkness, CA	3
Taussig, L	1
Price, D	1
Roche, N	1
Christian Virchow, J	1
Burden, A	1
Ali, M	1
Chisholm, A	1
Lee, AJ	1
Hillyer, EV	1
von Ziegenweidt, J	1
Jenkins, C	1
Spencer, MD	1
Kemp, J	1
Armstrong, L	1
Wan, Y	1
Alagappan, VK	1
Ohlssen, D	1
Pascoe, S	1
Patel, M	1
Perrin, K	1
Wildfire, JJ	1
Gergen, PJ	1
Mitchell, HE	1
Calatroni, A	1
Kattan, M	1
Teach, SJ	1
Bloomberg, GR	1
Wood, RA	1
Liu, AH	1
Pongracic, JA	1
Chmiel, JF	1
Conroy, K	1
Rivera-Sanchez, Y	1
Busse, WW	2
Yasmin, S	1
Mollah, AH	1
Basak, R	1
Islam, KT	1
Chowdhury, YS	1
Chatterjee, A	1
Shah, M	1
D'Souza, AO	1
Bechtel, B	1
Schuh, S	1
Zemek, R	1
Plint, A	1
Black, KJ	1
Freedman, S	1
Porter, R	1
Gouin, S	1
Hernandez, A	1
Johnson, DW	1
Dodda, VR	1
Spiro, P	1
Hop, WC	1

Trial	Phase	Enrollment	Study Type	Start Date	Status
Cardiopulmonary Function in Adults Born With a Ventricular Septal Defect[NCT03684161]		95 participants (Actual)	Observational	2018-09-24	Completed
A Phase II, Randomized, Modified Single-Blind, Placebo-Controlled Dose Escalation Study to Evaluate the Safety and Efficacy of MN-221 When Administered Intravenously as an Adjunct to Standard Therapy to Adults With an Acute Exacerbation of Asthma[NCT00683449]	Phase 2	29 participants (Actual)	Interventional	2008-06-30	Terminated (stopped due to Data from Dose Groups 1,2 and other MN-221 studies resulted in the determination of a more appropriate dosing scheme for MN-221 in subjects with asthma.)
Evaluating the Control of COPD Symptoms in Patients Treated With Tiotropium Bromide 18mcg Once Daily Alone, ADOAIR 50/250mcg Twice Daily Alone or ADOAIR 50/250mcg Plus Tiotropium Bromide 18mcg[NCT01762800]	Phase 4	407 participants (Actual)	Interventional	2013-02-28	Completed
Effect of Inhalation of Tiotropium Once Daily 18 Mcg Versus Salmeterol Twice Daily 50 Mcg on Time to First Exacerbation in COPD Patients (a Randomised, Double-blind, Double-dummy, Parallel Group, One-year Study).[NCT00563381]	Phase 4	7,376 participants (Actual)	Interventional	2008-01-31	Completed
Comparison of Conventional Medicine, TCM Treatment and Combination of Both Conventional Medicine and TCM Treatment for Patients With Chronic Obstructive Pulmonary Disease: A Randomized Comparative Effectiveness Research Trial[NCT01836016]	Phase 3	360 participants (Anticipated)	Interventional	2013-05-31	Not yet recruiting
A Randomized, Double-Blind, Parallel Group, Multicenter Study of the Effects of Fluticasone Propionate/Salmeterol Combination Product 250/50mcg BID (ADVAIR DISKUS™) in Comparison to Salmeterol 50mcg BID (SEREVENT DISKUS™) on the Rate of Exacerbations of C[NCT01110200]	Phase 4	639 participants (Actual)	Interventional	2010-04-30	Completed
A 12-Month Double-Blind, Double-Dummy, Randomized, Parallel Group, Multicenter Efficacy and Safety Study of Symbicort® pMDI 2 x 160/4.5 μg Bid and 2 x 80/4.5 μg Bid Compared to Formoterol Turbuhaler® 2 x 4.5 μg Bid and Placebo in Patients With COPD[NCT00206167]	Phase 3	1,600 participants	Interventional	2005-04-30	Completed
A 6-Month Double-Blind, Double-Dummy, Randomized, Parallel Group, Multicenter Efficacy & Safety Study of SYMBICORT® pMDI 2 x 160/4.5 µg & 80/4.5 µg Bid Compared to Formoterol TBH, Budesonide pMDI (& the Combination) & Placebo in COPD Patients[NCT00206154]	Phase 3	1,500 participants (Anticipated)	Interventional	2005-04-30	Completed
A Phase IIIB, 12-Month, Double-blind, Double-dummy,Randomised, Parallel-group, Multicentre Exacerbation Study of SYMBICORT® pMDI 160/4.5 μg x 2 Actuations Twice-daily and 80/4.5 μg x 2 Actuations Twice-daily Compared to Formoterol Turbuhaler® 4.5 μg x 2 I[NCT00419744]	Phase 3	1,200 participants (Actual)	Interventional	2007-01-31	Completed
Site and Mechanism(s) of Expiratory Airflow Limitation in COPD, Emphysema and Asthma-COPD Overlap[NCT03263130]		60 participants (Anticipated)	Observational [Patient Registry]	2017-01-01	Recruiting
Evaluation of the Prevalence and the Reversibility of the Lung Hyperinflation in Uncontrolled Persistent Asthmatic Patients With Dyspnea[NCT01573364]		450 participants (Actual)	Observational	2011-02-28	Completed
Blacks and Exacerbations on LABA vs. Tiotropium (BELT)[NCT01290874]	Phase 3	1,070 participants (Actual)	Interventional	2011-03-30	Completed
Severe Asthma Research Program (SARP) - University of Wisconsin[NCT01760915]		107 participants (Actual)	Observational	2012-11-28	Completed
A Multicentre, Randomised, Double-blind, Parallel Group, Placebo-controlled Study to Investigate the Long-term Effects of Salmeterol/Fluticasone Propionate (Seretide tm) 50/500mcg BD, Salmeterol 50mcg BD and Fluticasone Propionate 500mcg BD, All Delivered[NCT00268216]	Phase 3	6,228 participants (Actual)	Interventional	2000-09-30	Completed
A 6-week, Multicenter, Randomized, Double-blind, Placebo and Active-controlled, Parallel Group, Dose-ranging Study to Evaluate the Efficacy and Safety of 4 Doses of CHF 5259 pMDI (HFA Glycopyrronium Bromide Via Pressurized Metered Dose Inhaler) in Subject[NCT03084796]	Phase 2	733 participants (Actual)	Interventional	2017-07-28	Completed
An 8-week, Multicenter, Randomized, Double-blind, Placebo and Active-controlled, Parallel Group, Dose-ranging Study to Evaluate the Efficacy and Safety of 3 Doses of CHF 718 pMDI (HFA Beclomethasone Dipropionate Via Pressured Metered Dose Inhaler) in Asth[NCT03084718]	Phase 2	610 participants (Actual)	Interventional	2017-07-28	Completed
A Randomized, Double-blind, Placebo and Active-controlled, Incomplete Block Cross-over, Dose Ranging Study to Evaluate the Efficacy and Safety of 4 Doses of CHF 1531 pMDI (Formoterol Fumarate) in Asthmatic Subjects[NCT03086460]	Phase 2	67 participants (Actual)	Interventional	2017-09-08	Completed
A Prospective Baseline Assessment of the Risk of Osteoporosis in Patients With Chronic Obstructive Lung Disease and Outcomes After 2 Years; a Pilot Study[NCT01161680]		30 participants (Actual)	Observational	2010-07-31	Completed
Prescribing Asthma Controller Medication According to Gene Status to Improve Quality of Life in Young People With Asthma[NCT02758873]		241 participants (Actual)	Interventional	2016-02-29	Completed
Reducing Diagnostic Error to Improve Patient Safety in COPD and Asthma (REDEFINE Study)[NCT03137303]	Phase 3	402 participants (Actual)	Interventional	2017-07-01	Completed
An Evaluation of Lung Function and Symptoms in Patients With Chronic Obstructive Pulmonary Disease (COPD) on Long-Acting Bronchodilator Monotherapy[NCT00791518]		1,084 participants (Actual)	Observational	2008-12-31	Completed
Childhood Asthma Research and Education (CARE) Network Trial - Treating Children to Prevent Exacerbations of Asthma (TREXA)[NCT00394329]	Phase 3	288 participants (Actual)	Interventional	2006-11-30	Completed
Randomized, Placebo-controlled, Multicenter Study to Assess the Efficacy, Safety and Tolerability of ORal Bacterial EXtract for the Prevention of Wheezing Lower Respiratory Tract Illness (ORBEX)[NCT02148796]	Phase 2	822 participants (Actual)	Interventional	2017-01-03	Active, not recruiting
Childhood Asthma Management Program[NCT00000575]	Phase 3	1,041 participants (Actual)	Interventional	1991-09-30	Completed
Multicentre, Randomised, Double-Blind, Double Dummy, Parallel Group, 104-week Study to Compare the Effect of the Salmeterol/Fluticasone Propionate Combination Product (SERETIDE) 50/500mcg Delivered Twice Daily Via the DISKUS/ACCUHALER* Inhaler With Tiot[NCT00361959]	Phase 4	1,270 participants (Actual)	Interventional	2003-06-30	Completed
[information is prepared from clinicaltrials.gov, extracted Sep-2024]

The primary efficacy summary was change from Baseline in FEV1 (percent predicted), at Hour 2. Baseline was defined as FEV1 (percent predicted) after two doses of albuterol (5 mg each) and ipratropium (0.5 mg each) and FEV1 (percent predicted) FEV1 at Hour 2 was defined as the FEV1 (percent predicted) at 2 hours after the start of the infusion of MN-221 or placebo. Change from Baseline in FEV1 (percent predicted), was summarized by treatment group at Hour 2. (NCT00683449)
Timeframe: Baseline and Hour 2

FEV1 (L) The Forced Expiratory Volume in One Second as Measured in Liters Per Second.

Intervention	FEV1 (percent of predicted) (Mean)
240 μg MN-221 i.v. (Intravenous) Infusion for 15 Minutes	16.57
MN-221 Placebo i.v. Infusion	3.88
1,000-1,080 μg MN-221 i.v.	3.03
450 μg MN-221 i.v. for 15 Minutes	4.27
1,995 μg MN-221 i.v. Over 15 Minutes and 25 Minutes	-0.82

FEV1 (L) was determined over time using a spirometer. Measure the mean change in FEV1 (L) from Baseline. (NCT00683449)
Timeframe: Baseline to Hour 2

Hospital Admission Rate During Visit 1

Intervention	liters per second (Mean)
MN-221 at 16.0 μg/Min for 15 Min (Total 240 μg)	0.60
Placebo Administered Intravenously	0.10
450 μg MN-221 Given i.v.	0.12
1,000-1,080 μg MN-221 Given i.v. for 15 Minutes	0.10
1,995 MN-221 Administered i.v. for 15 Minutes and 25 Minutes	-0.02

After a patient in the emergency department (ED) presents with an acute exacerbation of asthma, the hospital proceeds with SOC procedures for this condition. Despite treatment in the ED, it is sometimes necessary to admit the patient into the hospital. In the study described here, the rate of hospital admissions was recorded. (NCT00683449)
Timeframe: Hour -1.5 through Hour 5

Percentage of Participants Managed by TRIPLE Therapy

Intervention	participants (Number)
240 μg MN-221 i.v. (Intravenous) Infusion for 15 Minutes	0
MN-221 Placebo i.v. Infusion	7
1,000-1,080 μg MN-221 i.v.	0
450 μg MN-221 i.v. for 15 Minutes	3
1,995 μg MN-221 i.v. Over 15 Minutes and 25 Minutes	1

Percentage of participants managed by TRIPLE therapy was calculated as [(number of participants who switched to TRIPLE therapy) - (number of participants who stepped down)/ number of evaluable population]*100 (NCT01762800)
Timeframe: 24 weeks

Percentage of Participants Who Dropped Out

Intervention	Percentage of participants (Number)
TIO 18 µg QD	36.82
SAL/FLU 50/250 µg BID	32.35

The percentage of participants who were withdrawn from the study. (NCT01762800)
Timeframe: 24 weeks

Percentage of Participants Who Required Additional Treatment to TRIPLE Therapy

Intervention	Percentage of participants (Number)
TIO 18 µg QD	9
SAL/FLU 50/250 µg BID	10

The percentage of participants who required additional treatment to TRIPLE therapy is defined as number of participants who took additional medicine or therapy in TRIPLE therapy divided by number of participants who switch to TRIPLE therapy multiplied by 100. (NCT01762800)
Timeframe: 24 weeks

Percentage of Participants Who Stepped Down From TRIPLE Therapy to Initial Randomized Treatment

Intervention	Percentage of participants (Number)
TIO 18 µg QD	77.33
SAL/FLU 50/250 µg BID	72.06

The percentage of participants who stepped down from TRIPLE therapy to initial randomized treatment was calculated as number of participants who step-down from TRIPLE therapy divided by number of participants who switch to TRIPLE therapy and then multiplied by 100. (NCT01762800)
Timeframe: 24 weeks

Percentage of Participants Who Switched to TRIPLE Therapy

Intervention	Percentage of participants (Number)
TIO 18 µg QD	1.33
SAL/FLU 50/250 µg BID	2.94

Switched to TRIPLE therapy is defined as: 1. Date of switch: when SAL/FLU or TIO was administered additionally to randomised treatment. 2. Date of randomisation was a start point and timing of switching (first switch if there are more than once) to TRIPLE was event. For participants without switching, last day of study or follow up period was regarded as censored. Percentage of participants who switched to TRIPLE therapy was calculated as: number of participants who switched to TRIPLE therapy divided by number of evaluable population and then multiplied by 100. (NCT01762800)
Timeframe: 24 weeks

Percentage of Participants Who Used Relief Medication (Salbutamol)

Intervention	Percentage of participants (Number)
TIO 18 µg QD	37.31
SAL/FLU 50/250 µg BID	33.33

Each evening participants recorded the number of occasions in the last 24 hours when they used their salbutamol for symptomatic relief of COPD symptoms. The percentage of participants who used relief medication in the study are presented. (NCT01762800)
Timeframe: 24 weeks

Percentage of Participants Who Were Able to Remain on the Randomized Treatment

Intervention	Percentage of participants (Number)
SAL/FLU 50/250 µg BID-Single	40.4
SAL/FLU 50/250 µg BID-TRIPLE	61.8
TIO 18 µg QD-Single	43.7
TIO 18 µg QD-TRIPLE	70.7

The randomized treatment could be switched to TRIPLE therapy in the case that chronic obstructive pulmonary disease (COPD) is not controlled by the randomized treatment. Participants on TRIPLE therapy received SAL/FLU 50/250 µg BID plus TIO 18 µg QD together. The percentage of participants who were able to remain on the randomized treatment was calculated by the following formula: 100 minus percentage of participants who switched over to TRIPLE therapy. (NCT01762800)
Timeframe: 24 weeks

Time to First Exacerbation by EXAcerbations of Chronic Pulmonary Disease Tool (EXACT)

Intervention	Percentage of participants (Number)
TIO 18 µg QD	62.69
SAL/FLU 50/250 µg BID	66.67

The EXAcerbations of Chronic pulmonary disease Tool (EXACT) is a 14-item patient-reported outcome (PRO) daily diary used to quantify and measure exacerbations of chronic obstructive pulmonary disease (COPD). Reported as units on a 0 [best health status] to 100 [worst possible status] scale). The day of detection of first exacerbation in any participant in each arm by EXACT. (NCT01762800)
Timeframe: 24 weeks

Time to First Exacerbation by Physician's Diagnosis

Intervention	Days (Number)
SAL/FLU 50/250 µg BID-Single	0
SAL/FLU 50/250 µg BID-TRIPLE	0
TIO 18 µg QD-Single	0
TIO 18 µg QD-TRIPLE	1

The day of detection of first exacerbation in any participant in each arm as diagnosed by physician. Exacerbation is defined primarily by physician's judgment. Date of randomisation will be start point and timing of exacerbation (first exacerbation if there are more than one) will be event. For subjects without exacerbation, last day of study or follow up period is regarded as censor. (NCT01762800)
Timeframe: 24 weeks

Time to First Switching to TRIPLE Therapy

Intervention	Days (Number)
SAL/FLU 50/250 µg BID-Single	3
SAL/FLU 50/250 µg BID-TRIPLE	5
TIO 18 µg QD-Single	10
TIO 18 µg QD-TRIPLE	2

The day of first switch to TRIPLE therapy (SAL/FLU 50/250 µg BID+TIO 18 µg QD) for the first switching participant in each arm. (NCT01762800)
Timeframe: 24 weeks

Change From Baseline in CAT Total Score

Intervention	Days (Number)
TIO 18 µg QD	5
SAL/FLU 50/250 µg BID	5

Participants were assessed for COPD symptoms by means of CAT at each Visit. This assessment was performed prior to the spirometry testing. A CAT total score of less than 10 represents best health status and greater than 15 represents worst health status. Baseline was the value at Visit 2 (randomization). Change from Baseline was calculated as specific timepoint value minus Visit 2 value. Scores were assessed at Visit 2 (Baseline), Visit 3 (Week 4), Visit 4 (Week 8), Visit 5 (Week 8), Visit 6 (Week 12), Visit 7 (Week 16), and Visit 8 (Week 24). Scores range from 0 to 40, high value in score indicate worse outcome. (NCT01762800)
Timeframe: Baseline and up to 24 weeks

Change From Baseline in FEV1

Intervention	Scores on a scale (Mean)
	Visit 3, n=132, 68, 121, 75	Visit 4, n=127, 68, 116, 74	Visit 5, n=123, 68, 116, 73	Visit 6, n=120, 66, 115, 74	Visit 7, n=120, 66, 113, 71	Visit 8, n=117, 66, 113, 70
SAL/FLU 50/250 µg BID-Single	-1.6	-1.7	-1.6	-2.3	-2.0	-2.4
SAL/FLU 50/250 µg BID-TRIPLE	0.1	-0.2	-0.8	0.0	-0.8	-1.0
TIO 18 µg QD-Single	0.1	-0.3	-0.7	-0.7	-0.8	-1.4
TIO 18 µg QD-TRIPLE	2.1	1.6	0.8	0.0	-0.6	-0.5

FEV1 is defined as the volume of air forcefully expelled from the lungs in one second. Baseline was a value at Visit 2 (randomization). Change from Baseline was calculated as specific timepoint value minus Visit 2 value. FEV1 was assessed at Visit 2 (Baseline), Visit 3 (Week 4), Visit 4 (Week 8), Visit 5 (Week 8), Visit 6 (Week 12), Visit 7 (Week 16), and Visit 8 (Week 24). (NCT01762800)
Timeframe: Baseline (Visit 2) and up to 24 weeks

Chronic Obstructive Pulmonary Disease (COPD) Assessment Test (CAT) Total Score

Intervention	Liters (Mean)
	Visit 3; n=131, 68, 119, 75	Visit 4; n=127, 68, 116, 74	Visit 5; n=122, 68, 116, 72	Visit 6; n=120, 66, 114, 74	Visit 7; n=119, 66, 113, 71	Visit 8; n=117, 66, 113, 70
SAL/FLU 50/250 µg BID-Single	0.024	0.008	-0.010	-0.007	-0.012	-0.019
SAL/FLU 50/250 µg BID-TRIPLE	-0.043	-0.030	-0.001	0.027	0.018	0.049
TIO 18 µg QD-Single	0.007	-0.011	-0.006	0.002	-0.010	-0.017
TIO 18 µg QD-TRIPLE	-0.077	-0.032	0.005	0.037	0.050	0.027

Participants were assessed for COPD symptoms by means of CAT at each Visit. This assessment was performed prior to the spirometry testing. A CAT total score of less than 10 represents best health status and greater than 15 represents worst health status. Scores were assessed at Visit 1 (Screening), Visit 2 (Baseline), Visit 3 (Week 4), Visit 4 (Week 8), Visit 5 (Week 8), Visit 6 (Week 12), Visit 7 (Week 16), and Visit 8 (Week 24). Scores range from 0 to 40, high value in score indicate worse outcome. (NCT01762800)
Timeframe: 24 weeks

Comparison of Number of Exacerbations Between Two Detection Methods: EXACT and Physician Diagnosis

Intervention	Scores on a scale (Mean)
	Visit 1, n=136, 68, 126, 75	Visit 2, n=136, 68, 126, 75	Visit 3, n=132, 68, 121, 75	Visit 4, n=127, 68, 116, 74	Visit 5, n=123, 68, 116, 73	Visit 6, n=120, 66, 115, 74	Visit 7, n=120, 66, 113, 71	Visit 8, n=117, 66, 113, 70
SAL/FLU 50/250 µg BID-Single	11.3	9.9	8.4	8.3	8.3	7.4	7.7	7.2
SAL/FLU 50/250 µg BID-TRIPLE	13.3	13.4	13.5	13.2	12.6	13.3	12.4	12.3
TIO 18 µg QD-Single	11.2	9.6	9.2	8.8	8.4	8.5	8.3	7.8
TIO 18 µg QD-TRIPLE	13.4	12.1	14.3	13.6	12.8	12.0	11.4	11.6

The comparison of number of exacerbation between two detection methods EXACT and physician diagnosis: number of exacerbations detected by EXACT and number of exacerbations judged by physician. (NCT01762800)
Timeframe: 24 weeks

Continuation Percentage of Participants Managed by Randomized Treatment Plus TRIPLE Therapy

Intervention	Number of exacerbations (Mean)
	EXACT	Physician's diagnosis
SAL/FLU 50/250 µg BID	0.7	0.1
TIO 18 µg QD	0.9	0.2

The randomized treatment could be switched to TRIPLE therapy in the case that chronic obstructive pulmonary disease (COPD) was not controlled by the randomized treatment. Participants on TRIPLE therapy received SAL/FLU 50/250 µg BID plus TIO 18 µg QD together. Continuation TRIPLE proportion is defined as [(number of subjects who switched to TRIPLE) - (number of subjects who stepped down)/ number of evaluable population]*100. Randomised treatment continuation proportion is calculated by a formula: (100 - switch proportion). (NCT01762800)
Timeframe: 24 weeks

E-RS Subscale Score

Intervention	Percentage of participants (Number)
	Randomised treatment	TRIPLE therapy
SAL/FLU 50/250 µg BID	66.67	32.35
TIO 18 µg QD	62.69	36.82

The E-RS total score is an 11-item patient questionnaire, which provides information specific to respiratory symptoms-severity of respiratory symptoms overall and severity of breathlessness, cough and sputum, and chest symptoms. The E-RS subscale scores for respiratory symptoms (RS)-breathlessness (RS-BRL), RS-cough and sputum (RS-CSP), and RS-chest symptoms (RS-CSY) are presented. Scores were assessed at Baseline, Week 1-4, Week 5-8, Week 9-12, Week 13-16, Week 17-20 and at Week 21-24. Daily EXACT total score is obtained as total score of 14 items from diary. Daily E-RS total score as 11 items and Daily E-RS subscale scores are subset of E-RS total score. Mean EXACT total score is mean value of daily EXACT total score within subject by every 4 weeks(Week1-4, Week5-8, Week9-12, Week13-16, Week17-20, Week21-24). Same calculation of mean values are applied to E-RS total and E-RS subscale scores. RS total scores range from 0 to 40, high value in score indicate worse outcome. (NCT01762800)
Timeframe: 24 weeks

EXACT Respiratory Symptoms (E-RS) Total Score

Intervention	Scores on a scale (Mean)
	RS-BRL; Baseline; n=135, 68, 125, 73	RS-BRL; Week 1-4; n=131, 68, 121, 75	RS-BRL; Week 5-8; n=126, 68, 115, 73	RS-BRL; Week 9-12; n=122, 68, 116, 74	RS-BRL; Week 13-16; n=121, 66, 116, 74	RS-BRL; Week 17-20; n=118, 66, 114, 72	RS-BRL; Week 21-24; n=93, 51, 94, 51	RS-CSP; Baseline; n=135, 68, 124, 73	RS-CSP; Week 1-4; n=131, 68, 121, 75	RS-CSP; Week 5-8; n=126, 68, 116, 73	RS-CSP; Week 9-12; n=122, 68, 116, 74	RS-CSP; Week 13-16; n=121, 66, 116, 74	RS-CSP; Week 17-20; n=119, 66, 114, 72	RS-CSP; Week 21-24; n=93, 51, 94, 51	RS-CSY; Baseline; n=135, 67, 125, 73	RS-CSY; Week 1-4; n=131, 68, 121, 75	RS-CSY; Week 5-8; n=126, 68, 116, 73	RS-CSY; Week 9-12; n=122, 68, 116, 74	RS-CSY; Week 13-16; n=121, 66, 116, 74	RS-CSY; Week 17-20; n=119, 66, 114, 72	RS-CSY; Week 21-24; n=93, 51, 94, 51
SAL/FLU 50/250 µg BID-Single	3.36	3.06	3.08	3.08	2.80	2.82	2.79	2.29	2.12	2.03	2.06	1.98	2.06	1.82	1.77	1.58	1.65	1.54	1.46	1.48	1.38
SAL/FLU 50/250 µg BID-TRIPLE	5.81	6.28	5.96	5.87	5.81	5.56	4.94	2.73	2.90	2.83	2.81	2.74	2.43	2.27	2.93	3.21	3.05	3.12	3.11	2.81	2.61
TIO 18 µg QD-Single	3.41	3.36	3.18	2.98	3.04	3.04	2.95	2.23	2.13	2.13	2.11	2.09	2.09	1.99	1.84	1.69	1.70	1.60	1.70	1.72	1.64
TIO 18 µg QD-TRIPLE	5.62	6.59	5.38	5.52	5.11	4.94	4.71	2.81	3.05	2.74	2.77	2.49	2.40	2.34	2.92	3.59	2.99	3.01	2.66	2.55	2.53

"The E-RS total score is an 11-item patient questionnaire, which provides information specific to respiratory symptoms-severity of respiratory symptoms overall and severity of breathlessness, cough and sputum, and chest symptoms. Scores were assessed at Baseline, Week 1-4, Week 5-8, Week 9-12, Week 13-16, Week 17-20 and at Week 21-24. Daily EXACT total score is obtained as total score of 14 items from diary. Daily E-RS total score as 11 items and Daily E-RS subscale scores are subset of E-RS total score.~Mean EXACT total score is mean value of daily EXACT total score within subject by every 4 weeks(Week1-4, Week5-8, Week9-12, Week13-16, Week17-20, Week21-24). Same calculation of mean values are applied to E-RS total and E-RS subscale scores. Scores range from 0-100, high value in score indicate worse outcome." (NCT01762800)
Timeframe: Baseline and up to 24 weeks

EXACT Total Score.

Intervention	Scores on a scale (Mean)
	Baseline; n=135, 67, 124, 73	Week 1-4; n=131, 68, 121, 75	Week 5-8; n=126, 68, 115, 73	Week 9-12; n=122, 68, 116, 74	Week 13-16; n=121, 66, 116, 74	Week 17-20; n=118, 66, 114, 72	Week 21-24; n=93, 51, 94, 51
SAL/FLU 50/250 µg BID-Single	7.42	6.76	6.75	6.69	6.23	6.33	5.99
SAL/FLU 50/250 µg BID-TRIPLE	11.43	12.39	11.86	11.79	11.66	10.80	9.82
TIO 18 µg QD-Single	7.51	7.18	6.99	6.70	6.82	6.85	6.58
TIO 18 µg QD-TRIPLE	11.36	13.23	11.11	11.30	10.26	9.89	9.59

"EXACT is a 14-item patient questionnaire used as a measure of respiratory symptoms (reported as units on a 0 [best health status] to 100 [worst possible status] scale). Scores were assessed at Baseline, Week 1-4, Week 5-8, Week 9-12, Week 13-16, Week 17-20 and Week 21-24. Daily EXACT total score is obtained as total score of 14 items from diary. Daily E-RS total score as 11 items and Daily E-RS subscale scores are subset of E-RS total score.~Mean EXACT total score is mean value of daily EXACT total score within subject by every 4 weeks(Week1-4, Week5-8, Week9-12, Week13-16, Week17-20, Week21-24). Same calculation of mean values are applied to E-RS total and E-RS subscale scores." (NCT01762800)
Timeframe: Baseline and up to 24 weeks

Forced Expiratory Volume in One Second (FEV1)

Intervention	Scores on a scale (Mean)
	Baseline; n=125, 66, 111, 71	Week 1-4; n=120, 67, 109, 73	Week 5-8; n=117, 63, 102, 69	Week 9-12; n=109, 67, 101, 72	Week 13-16; n=105, 65, 100, 71	Week 17-20; n=107, 65, 97, 66	Week 21-24; n=79, 51, 77, 46
SAL/FLU 50/250 µg BID-Single	28.99	27.83	27.35	27.63	27.33	26.98	26.50
SAL/FLU 50/250 µg BID-TRIPLE	36.00	36.92	37.58	36.16	35.92	34.92	32.72
TIO 18 µg QD-Single	29.77	28.88	28.80	28.40	28.93	28.66	28.80
TIO 18 µg QD-TRIPLE	35.78	38.26	35.87	35.57	33.79	34.03	33.67

FEV1 is defined as the volume of air forcefully expelled from the lungs in one second. At Screening (Visit 1) spirometric assessments were conducted before (Visit 1A) and 30 to 60 minutes after a bronchodilator challenge (400 µg of salbutamol) (Visit 1B). FEV1 during each visit are presented. FEV1 was assessed at Visit 1A (Screening), Visit 1B (Screening), Visit 2 (Baseline), Visit 3 (Week 4), Visit 4 (Week 8), Visit 5 (Week 8), Visit 6 (Week 12), Visit 7 (Week 16), and Visit 8 (Week 24). (NCT01762800)
Timeframe: Up to 24 weeks

Number of Participants in Each Treatment Efficacy Grade Evaluated by Participants

Intervention	Liters (Mean)
	Visit 1A; n=136, 68, 126, 75	Visit 1B; n=136, 68, 126, 75	Visit 2; n=136, 68, 126, 75	Visit 3; n=131, 68, 119, 75	Visit 4; n=127, 68, 116, 74	Visit 5; n=122, 68, 116, 72	Visit 6; n=120, 66, 114, 74	Visit 7; n=119, 66, 113, 71	Visit 8; n=117, 66, 113, 70
SAL/FLU 50/250 µg BID-Single	1.687	1.764	1.695	1.731	1.713	1.718	1.716	1.710	1.694
SAL/FLU 50/250 µg BID-TRIPLE	1.401	1.471	1.385	1.342	1.355	1.384	1.413	1.404	1.435
TIO 18 µg QD-Single	1.675	1.754	1.681	1.710	1.703	1.708	1.712	1.694	1.688
TIO 18 µg QD-TRIPLE	1.349	1.429	1.362	1.285	1.336	1.376	1.405	1.423	1.390

Participants evaluated treatment efficacy by using the following grades: significantly improved (SII), moderately improved (MOI), mildly improved (MII), no change (NC), mildly worse (MIW), moderately worse (MOW), and significantly worse (SIW). Treatment efficacy was assessed at Visit 3 (Week 4), Visit 4 (Week 8), Visit 5 (Week 8), Visit 6 (Week 12), Visit 7 (Week 16), and Visit 8 (Week 24). (NCT01762800)
Timeframe: Up to 24 weeks

Number of Participants in Each Treatment Efficacy Grade Evaluated by Physician

Intervention	Participants (Number)
	Visit 3; SII	Visit 3; MOI	Visit 3; MII	Visit 3; NC	Visit 3; MIW	Visit 3; MOW	Visit 3; SIW	Visit 4; SII	Visit 4; MOI	Visit 4; MII	Visit 4; NC	Visit 4; MIW	Visit 4; MOW	Visit 5; SII	Visit 5; MOI	Visit 5; MII	Visit 5; NC	Visit 5; MIW	Visit 5; MOW	Visit 5; SIW	Visit 6; SII	Visit 6; MOI	Visit 6; MII	Visit 6; NC	Visit 6; MIW	Visit 6; MOW	Visit 6; SIW	Visit 7; SII	Visit 7; MOI	Visit 7; MII	Visit 7; NC	Visit 7; MIW	Visit 7; MOW	Visit 8; SII	Visit 8; MOI	Visit 8; MII	Visit 8; NC	Visit 8; MIW	Visit 8; MOW
SAL/FLU 50/250 µg BID-Single	5	9	35	74	7	1	1	3	15	31	67	10	1	2	13	31	66	10	0	1	2	13	35	66	4	0	0	1	13	27	75	4	0	5	9	39	58	5	1
SAL/FLU 50/250 µg BID-TRIPLE	0	2	10	32	19	5	0	1	6	12	39	8	2	1	7	17	34	7	2	0	1	4	16	33	11	0	1	2	4	17	37	5	1	1	4	19	37	5	0
TIO 18 µg QD-Single	1	3	20	85	9	3	0	2	5	25	79	5	0	2	3	31	78	2	0	0	2	4	30	72	7	0	0	2	5	28	71	7	0	2	8	30	69	3	1
TIO 18 µg QD-TRIPLE	1	3	7	32	22	9	1	1	6	21	28	13	5	4	6	20	31	9	3	0	4	13	14	34	7	2	0	4	11	20	26	9	1	4	9	19	34	4	0

Physician evaluated treatment efficacy by using the following grades: significantly improved (SII), moderately improved (MOI), mildly improved (MII), no change (NC), mildly worse (MIW), moderately worse (MOW), and significantly worse (SIW). Treatment efficacy was assessed at Visit 3 (Week 4), Visit 4 (Week 8), Visit 5 (Week 8), Visit 6 (Week 12), Visit 7 (Week 16), and Visit 8 (Week 24). (NCT01762800)
Timeframe: 24 weeks

COPD Exacerbations Per Patient-year

COPD Exacerbations Per Patient-year Leading to Hospitalisation

Intervention	Participants (Number)
	Visit 3; SII	Visit 3; MOI	Visit 3; MII	Visit 3; NC	Visit 3; MIW	Visit 3; MOW	Visit 3; SIW	Visit 4; SII	Visit 4; MOI	Visit 4; MII	Visit 4; NC	Visit 4; MIW	Visit 4; MOW	Visit 4; SIW	Visit 5; SII	Visit 5; MOI	Visit 5; MII	Visit 5; NC	Visit 5; MIW	Visit 5; MOW	Visit 5; SIW	Visit 6; SII	Visit 6; MOI	Visit 6; MII	Visit 6; NC	Visit 6; MIW	Visit 6; MOW	Visit 6; SIW	Visit 7; SII	Visit 7; MOI	Visit 7; MII	Visit 7; NC	Visit 7; MIW	Visit 7; MOW	Visit 8; SII	Visit 8; MOI	Visit 8; MII	Visit 8; NC	Visit 8; MIW	Visit 8; MOW
SAL/FLU 50/250 µg BID-Single	6	11	40	67	7	0	1	3	14	28	74	6	1	1	1	12	29	73	7	0	1	2	10	31	74	3	0	0	0	13	25	79	3	0	2	7	36	70	1	1
SAL/FLU 50/250 µg BID-TRIPLE	0	1	12	31	16	8	0	1	3	13	33	12	6	0	2	6	14	35	10	1	0	1	1	18	33	11	1	1	1	2	18	38	5	2	1	4	19	39	2	1
TIO 18 µg QD-Single	1	5	21	83	7	3	1	2	8	23	79	4	0	0	2	4	22	83	5	0	0	2	3	28	72	10	0	0	2	5	23	77	5	1	3	7	27	71	4	1
TIO 18 µg QD-TRIPLE	1	4	3	32	23	12	0	0	9	18	27	12	8	0	4	8	19	29	10	3	0	2	11	17	32	9	3	0	3	12	12	35	8	1	3	9	13	40	5	0

Intervention	exacerbations per patient-year (Mean)
Tiotropium	0.64
Salmeterol	0.72

An exacerbation was defined as an increase or new onset of more than 1 symptom (cough, sputum, wheezing, dyspnoea, chest tightness), with at least 1 symptom lasting at least 3 days and requiring treatment with systemic steroids and/or antibiotics (moderate exacerbation) or hospitalisation (severe exacerbation). (NCT00563381)
Timeframe: 52 weeks

COPD Exacerbations Treated With Antibiotics Per Patient-year

Intervention	Hospitalizations per patient-year (Mean)
Tiotropium	0.09
Salmeterol	0.13

COPD Exacerbations Treated With Systemic Steroids and Antibiotics Per Patient-year

Intervention	exacerbations per patient-year (Mean)
Tiotropium	0.53
Salmeterol	0.59

COPD Exacerbations Treated With Systemic Steroids Per Patient-year

Intervention	exacerbations per patient-year (Mean)
Tiotropium	0.23
Salmeterol	0.28

First Occurrence of (Moderate or Severe) COPD Exacerbation

Intervention	exacerbations per patient-year (Mean)
Tiotropium	0.33
Salmeterol	0.41

First occurrence analysed by Cox regression as time to first exacerbation and reported as hazard ratio. An exacerbation was defined as an increase or new onset of more than 1 symptom (cough, sputum, wheezing, dyspnoea, chest tightness), with at least 1 symptom lasting at least 3 days and requiring treatment with systemic steroids and/or antibiotics (moderate exacerbation) or hospitalisation (severe exacerbation). (NCT00563381)
Timeframe: 52 weeks

First Occurrence of COPD Exacerbation Leading to Hospitalization

Intervention	number of first occurrences (Number)
Tiotropium	1277
Salmeterol	1414

First occurrence analysed by Cox regression as time to first exacerbation leading to hospitalisation and reported as hazard ratio. An exacerbation was defined as an increase or new onset of more than 1 symptom (cough, sputum, wheezing, dyspnoea, chest tightness), with at least 1 symptom lasting at least 3 days and requiring treatment with systemic steroids and/or antibiotics (moderate exacerbation) or hospitalisation (severe exacerbation). (NCT00563381)
Timeframe: 52 weeks

First Occurrence of COPD Exacerbation or Discontinuation of Trial Medication Because of Worsening of Underlying Disease, Whichever Comes First

Intervention	number of first occurrences (Number)
Tiotropium	262
Salmeterol	336

First occurrence analysed by Cox regression as time to first exacerbation or discontinuation of trial medication because of worsening of underlying disease, whichever comes first and reported as hazard ratio. An exacerbation was defined as an increase or new onset of more than 1 symptom (cough, sputum, wheezing, dyspnoea, chest tightness), with at least 1 symptom lasting at least 3 days and requiring treatment with systemic steroids and/or antibiotics (moderate exacerbation) or hospitalisation (severe exacerbation). (NCT00563381)
Timeframe: 52 weeks

First Occurrence of COPD Exacerbations Treated With Antibiotics

Intervention	number of first occurrences (Number)
Tiotropium	1316
Salmeterol	1448

First occurrence analysed by Cox regression as time to first exacerbation treated with antibiotics and reported as hazard ratio. An exacerbation was defined as an increase or new onset of more than 1 symptom (cough, sputum, wheezing, dyspnoea, chest tightness), with at least 1 symptom lasting at least 3 days and requiring treatment with systemic steroids and/or antibiotics (moderate exacerbation) or hospitalisation (severe exacerbation). (NCT00563381)
Timeframe: 52 weeks

First Occurrence of COPD Exacerbations Treated With Systemic Steroids

Intervention	number of first occurrences (Number)
Tiotropium	1154
Salmeterol	1259

First occurrence analysed by Cox regression as time to first exacerbation treated with systemic steroids and reported as hazard ratio. An exacerbation was defined as an increase or new onset of more than 1 symptom (cough, sputum, wheezing, dyspnoea, chest tightness), with at least 1 symptom lasting at least 3 days and requiring treatment with systemic steroids and/or antibiotics (moderate exacerbation) or hospitalisation (severe exacerbation). (NCT00563381)
Timeframe: 52 weeks

First Occurrence of COPD Exacerbations Treated With Systemic Steroids and Antibiotics

Intervention	number of first occurrences (Number)
Tiotropium	715
Salmeterol	852

First occurrence analysed by Cox regression as time to first exacerbation treated with systemic steroids and antibiotics and reported as hazard ratio. An exacerbation was defined as an increase or new onset of more than 1 symptom (cough, sputum, wheezing, dyspnoea, chest tightness), with at least 1 symptom lasting at least 3 days and requiring treatment with systemic steroids and/or antibiotics (moderate exacerbation) or hospitalisation (severe exacerbation). (NCT00563381)
Timeframe: 52 weeks

Occurrence of Premature Discontinuation of Trial Medication

Intervention	number of first occurrences (Number)
Tiotropium	562
Salmeterol	671

Occurrence analysed by Cox regression as time to premature discontinuation of trial medication and reported as hazard ratio (NCT00563381)
Timeframe: 52 weeks

Pre-dose Morning PEFR Measured by Patients at Home During the First Four Months of Randomised Treatment (Weekly Means Will be Calculated), Week 1

Intervention	number of first occurrences (Number)
Tiotropium	585
Salmeterol	648