Maltais 2014b.

Methods	Study ID and dates performed: NCT01323660 (Study 417). Study design: Two multicentre, double‐blind, randomised cross‐over studies (incomplete treatment block). Duration of study: 12–21‐day run‐in period; two 12‐week treatment periods separated by a 14‐day washout period. Study setting, location, number of centres: 31 centres in 6 countries. Key inclusion criteria: Current or former smokers; ≤ 40 years of age; smoking history of ≥ 10 pack‐years; clinical diagnosis of moderate‐to‐severe stable COPD (post‐bronchodilator FEV1/FVC < 70% and FEV1 ≥ 35% and ≤ 70% predicted); score of ≥ 2 on the mMRC Dyspnoea Scale at visit 1; resting FRC ≥ 120% of predicted (to ensure participants were hyperinflated, as hyperinflation is associated with exercise intolerance). Key exclusion criteria: Comorbid conditions or current diagnosis of asthma. Concomitant medications: All participants were provided with salbutamol for use on an ‘as‐needed’ basis throughout the run‐in, washout, and treatment periods. Stable/regular doses of ICS were permitted.
Participants	Note: cross‐over study therefore participant data reported for whole cohort. N randomised: N = 349. N analysed, n/N: 341/349. Mean age (SD), years: 61.6 (8.3). Gender ‐ male, n/N (%): 195/348 (56.0). Baseline lung function ‐ mean (SD) post‐bronchodilator % predicted FEV1: 51.3 (9.8). Smoking status, current smoker, n/N (%): 220/348 (63.2).
Interventions	Intervention: Once‐daily UMEC/VI 62.5/25 µg; once‐daily UMEC/VI 125/25 µg. Comparator: Once‐daily placebo.
Outcomes	Prespecified outcomes: Primary: Change from baseline in exercise endurance time post‐dose at week 12 of each treatment period; change from baseline in trough FEV1 at week 12 of each treatment period. Secondary: Change from baseline in inspiratory capacity (trough and 3 hours post‐dose) at week 12 of each treatment period; change from baseline in functional residual capacity (trough and 3 hours post‐dose) at week 12 of each treatment period; change from baseline in residual volume (trough and 3 hours post‐dose) at week 12 of each treatment period; change from baseline in 3 hours post‐dose FEV1 at week 12 of each treatment period. Reported outcomes: All prespecified outcomes (see above) plus safety were reported.
Notes	Funding for trial; notable author COIs: The studies were sponsored by GSK; all authors were employees of, or had received honoraria/research funding from, GSK.
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Simple randomisation was performed through a validated computerised system, then communicated to the study team via an IVRS.
Allocation concealment (selection bias)	Low risk	Allocation of treatments was controlled by RAMOS, a telephone‐based IRVS.
Blinding of participants and personnel (performance bias) All outcomes	Low risk	Trial registry states that participants and investigators were blinded to treatment allocation. All six treatments options were administered in a ‘double‐blind fashion’ via the same model of inhaler.
Blinding of participants and personnel (objective outcomes ‐ performance bias) Objective outcomes	Low risk	Trial registry states that participants and investigators were blinded to treatment allocation. All six treatments options were administered in a ‘double‐blind fashion’ via the same model of inhaler.
Blinding of outcome assessment (detection bias) All outcomes	Low risk	Participants for subjective outcomes were the outcome assessors; therefore, low risk of bias.
Blinding of outcome assessment (objective outcomes ‐ detection bias) All outcomes	Low risk	Assessment of objective outcomes (including a co‐primary endpoint of exercise tolerance time) would be unlikely to be influenced by knowledge of treatment allocation.
Incomplete outcome data (attrition bias) All outcomes	Low risk	Low and comparable attrition in UME/VI and placebo arms.
Selective reporting (reporting bias)	Low risk	Prespecified outcomes (clinicaltrials.gov) were well reported.
Other bias	Low risk	None identified.