Donohue 2013.

Methods	Study ID and dates performed: NCT01313650. 30 March 2011 to 5 April 2012. Study design: Randomised, double‐blind, placebo‐controlled, multicentre, parallel‐group study. Duration of study: 24 weeks. Study setting, location, number of centres: 163 centres in 13 countries. Key inclusion criteria: Current or former cigarette smokers; aged > 40 years; clinically established history of COPD characterised by airflow limitation that is not fully reversible (ATS/ERS criteria) and documented based on a smoking history of ≥ 10 pack years; post‐salbutamol FEV1/FVC ratio < 0.70; post‐salbutamol FEV1 of ≤ 70% of predicted normal values; dyspnoea score ≥ 2 on modified MRC dyspnoea scale. Key exclusion criteria: Current diagnosis of asthma or other known respiratory disorder; abnormal or clinically significant electrocardiogram or 24‐hour Holter ECG; clinically significant clinical laboratory finding. Concomitant medications: Permitted: Inhaled salbutamol as rescue medication; ICS at a stable dose of ≤ 1000 µg/day fluticasone propionate or equivalent from 30 days prior to screening onward.
Participants	N randomised: UMEC/VI 62.5/25 µg: N = 413; placebo: N = 280. N analysed, n/N (%): UMEC/VI 62.5/25 µg: 413/413 (100); placebo: 280/280 (100). Mean age (SD), years: UMEC/VI 62.5/25 µg: 63.1 (8.71); placebo: 62.2 (9.04). Gender ‐ male, n/N (%): UMEC/VI 62.5/25 µg: 305/413 (74); placebo: 195/280 (70). Baseline lung function ‐ mean (SD) post‐bronchodilator % predicted FEV1: UMEC/VI 62.5/25 µg: 47.8 (13.19); placebo:46.7 (12.71). Smoking status, current smoker, n/N (%): UMEC/VI 62.5/25 µg: 203/413 (49); placebo: 150/280 (54).
Interventions	Intervention: Once‐daily UMEC/VI 62.5/25 µg. Comparator: Once‐daily placebo.
Outcomes	Prespecified outcomes: Primary endpoint: Pre‐dose trough FEV1 on day 169. Secondary lung function endpoints: Mean TDI focal score at day 168 (week 24); change from baseline in weighted mean 0‐6 hour FEV1 obtained post‐dose at day 168 baseline and day 168. Other outcomes: Change from baseline in the mean Shortness of Breath With Daily Activities (SOBDA) score for (baseline and week 24). Reported outcomes: Pre‐dose trough FEV1 on treatment day 169, defined as the mean of FEV1 values obtained 23 h and 24 h after dosing on day 168 (week 24 visit). Secondary and additional lung function endpoints: weighted mean FEV1 over 0–6 h post‐dose on day 168; trough and 0–6 h weighted mean FEV1 at other visits, serial FEV1 assessments, time to onset during 0–6 h post‐dose on day 1, proportion of participants achieving an increase in FEV1 of ≥ 12% and ≥ 0.2 L above baseline at any time during 0–6 h post‐dose on day 1, proportion of participants achieving an increase of ≥ 0.1 L above baseline in trough FEV1, peak FEV1 and serial and trough FVC. Serial FEV1 over 0–24 h post‐dose was obtained in a subset of participants to characterise changes in lung function over the dosing interval.
Notes	Funding for trial; notable author COIs: The design, concept and conduct of the study and development of the manuscript was funded by GSK. Both external authors had acted as consultants and received research grants from GSK. All other co‐authors were GSK employees.
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Simple randomisation was performed centrally through a validated computerised system and an interactive voice response system was then used to communicate the randomisation to the study team.
Allocation concealment (selection bias)	Low risk	Participants were randomised using an automated, interactive voice response system.
Blinding of participants and personnel (performance bias) All outcomes	Low risk	Masking quadruple (participants, care provider, investigator, outcome assessor).
Blinding of participants and personnel (objective outcomes ‐ performance bias) Objective outcomes	Low risk	Knowledge of treatment allocation by participant or personnel would be unlikely to influence objective outcomes.
Blinding of outcome assessment (detection bias) All outcomes	Low risk	Masking quadruple (participants, care provider, investigator, outcome assessor).
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	Attrition balanced across treatment groups; ITT analysis performed.
Selective reporting (reporting bias)	Low risk	Prespecified outcomes (clinicaltrials.gov) were well reported.
Other bias	Low risk	None identified.