Siler 2016.

Methods	Study ID and dates performed: NCT02152605; September 2014 to March 2015. Study design: Multicentre, randomised, double‐blind, parallel‐group, placebo‐controlled study. Duration of study: 7–14 day run‐in period; 12‐week treatment period. Study setting, location, number of centres: 55 centres in Bulgaria, Germany, Hungary, Romania, Russian Federation, Ukraine, and US. Key inclusion criteria: ≥ 40 years of age; diagnosis of COPD; current or prior history of ≥ 10 pack‐years of cigarette smoking at screening; a pre‐ and post‐albuterol (salbutamol) FEV1/FVC < 0.70 and a post‐albuterol FEV1 ≤ 70% of predicted normal values at screening (based on NHANES III reference equations; a score ≥ 2 on the mMRC Dyspnoea Scale at screening. Key exclusion criteria: Current diagnosis of asthma or other known respiratory conditions (α1‐antitrypsin deficiency, active tuberculosis, lung cancer, bronchiectasis, sarcoidosis, lung fibrosis, pulmonary hypertension, interstitial lung diseases, or other active pulmonary diseases); hospitalisation for COPD or pneumonia within 12 weeks prior to visit 1; lung volume reduction surgery within the 12 months prior to visit 1; use of long‐term oxygen therapy (prescribed for > 12 h/day); severe hepatic impairment; any rapidly progressing disease or immediate life‐threatening illness (e.g. cancer); any condition that was likely to affect respiratory function (e.g. neurological condition); abnormal, clinically significant electrocardiogram finding at screening (atrial fibrillation with rapid ventricular rate > 120 bpm; sustained or nonsustained ventricular tachycardia; second‐degree heart block Mobitz type II, and third‐degree heart block (unless pacemaker or defibrillator had been inserted)). Concomitant medications: Use of study‐provided albuterol was permitted, except in the 4‐hour period prior to spirometry testing. Excluded medications prior to visit 1: depot corticosteroids; systemic, oral or parenteral corticosteroids; ICS/LABA combination products; ICS at a dose > 1000 µg/day of FP or equivalent; initiation or discontinuation of ICS use; PDE4 inhibitors; LAMAs, inhaled LABAs, LABA/LAMA combination products; theophyllines; oral beta2‐agonists; inhaled SABA or inhaled short‐acting anticholinergics, or any combination of the two.
Participants	N randomised: UMEC/VI 62.5/25 µg: n = 249; placebo: n = 249. N analysed, n/N: UMEC/VI 62.5/25 µg: 248/249; placebo: 248/249. Mean age (SD), years: UMEC/VI 62.5/25 µg: 64.1 (8.70); placebo: 62.6 (8.23). Gender ‐ male, n/N (%): UMEC/VI 62.5/25 µg: 144/248 (58); placebo: 149/248 (60). Baseline lung function ‐ mean (SD) post‐bronchodilator % predicted FEV1: UMEC/VI 62.5/25 µg: 46.5 (12.81); placebo: 48.4 (14.06). Smoking status, current smoker, n/N (%): UMEC/VI 62.5/25 µg: 137/248 (55); placebo: 129/248 (52).
Interventions	Intervention: Once‐daily UMEC/VI 62.5/25 µg. Comparator: Once‐daily placebo.
Outcomes	Prespecified outcomes: Primary: Change from baseline in mean SGRQ total score at day 84. Secondary: Change from baseline in trough FEV1 at day 84; change from baseline in mean number of puffs of rescue medication per day used over weeks 1‐12. Reported outcomes: plus the proportion of SGRQ responders at days 28, 56, and 84; SGRQ total score at days 28 and 56 (SGRQ responders were defined as having a total score ≥ 4 units below baseline); percentage of rescue‐free days; trough FEV1 at days 28 and 56; trough FVC at days 28, 56, and 84; safety.
Notes	Funding for trial; notable author COIs: The study was funded by GSK. Lead author had received research funding from GSK. All other authors were employees of GSK.
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Centralised IRVS system used for randomisation.
Allocation concealment (selection bias)	Low risk	Centralised IRVS system used for randomisation.
Blinding of participants and personnel (performance bias) All outcomes	Low risk	Participants and investigators were blinded to treatment (see clinicaltrial.gov).
Blinding of participants and personnel (objective outcomes ‐ performance bias) Objective outcomes	Low risk	Participants and investigators were blinded to treatment (see clinicaltrial.gov).
Blinding of outcome assessment (detection bias) All outcomes	Unclear risk	Insufficient information provided.
Blinding of outcome assessment (objective outcomes ‐ detection bias) All outcomes	Low risk	Assessment of objective outcomes would be unlikely to be influenced by knowledge of treatment allocation.
Incomplete outcome data (attrition bias) All outcomes	Low risk	Similar loss in both arms (treatment and placebo) for similar reasons and loss < 10%.
Selective reporting (reporting bias)	Low risk	Prespecified outcomes (clinicaltrials.gov) were well reported.
Other bias	High risk	Greater proportion of participants with GOLD category D in the active treatment group; favoured placebo and underestimation of treatment effect.