NCT00626522.

Methods	Study ID and dates performed: NCT00626522; not published (source clinicaltrials.gov); study completed 2008. Study design: Randomised, 4‐week, placebo‐controlled, double‐blind, 6‐arm parallel‐group, dose‐finding trial. Duration of study: 4‐week treatment period. Study setting, location, number of centres: 11 sites in 4 countries. Key inclusion criteria: Aged 40–85 years; clinical diagnosis of stable moderate‐to‐severe COPD (GOLD 2006 stages II–III); current or ex‐cigarette smoker with a smoking history of ≥ 10 pack‐years; FEV1 at screening measured between 30‐45 minutes post‐inhalation of 400 μg of salbutamol was 30% ≤ FEV1 < 80% of the predicted normal value; FEV1/FVC at screening measured between 30‐ 45 minutes post inhalation of 400 μg of salbutamol was < 70%. Key exclusion criteria: History or current diagnosis of asthma, allergic rhinitis or atopy, or exercise‐induced bronchospasm; clinically significant respiratory conditions at the time of screening visit; hospitalisation due to COPD exacerbation within 3 months prior to screening; signs of COPD exacerbation or respiratory infection up to 6 weeks prior to screening visit; clinically significant cardiovascular conditions. Concomitant medications: Not reported.
Participants	N randomised: ACL/FOR 200/6 µg: n = 121; ACL/FOR 200/12 µg: n = 120; ACL/FOR 200/18 µg: n = 125; placebo: n = 59. N analysed: ACL/FOR 200/6 µg: 121/121 (100); ACL/FOR 200/12 µg: 120/120 (100); ACL/FOR 200/18 µg: 125/125 (100); placebo: 59/59 (100). Mean age (SD), years: ACL/FOR 200/6 µg: 62.9 (9.0); ACL/FOR 200/12 µg: 63.6 (8.9); ACL/FOR 200/18 µg: 63.9 (8.1); placebo: 60.7 (7.8). Gender ‐ male, n/N: ACL/FOR 200/6 µg: 91/121; ACL/FOR 200/12 µg: 98/120; ACL/FOR 200/18 µg: 96/125; placebo: 44/59. Baseline lung function ‐ post‐bronchodilator % predicted FEV1: Not reported. Smoking status, current smoker, n/N (%): Not reported.
Interventions	Intervention: Once‐daily ACL/FOR 200/6 µg; once‐daily ACL/FOR 200/12 µg; once‐daily ACL/FOR 200/18 µg. Comparator: Once‐daily placebo.
Outcomes	Prespecified outcomes: Primary: Change from baseline in normalised FEV1 AUC for 0‐12 hr at week 4. Secondary: Change from baseline in trough FEV1 at week 4; change from baseline in peak FEV1 at week 4; change from baseline in normalised FEV1 AUC 0–3 hours at week 4; change from baseline in normalised FEV1 AUC 0–6 hours at week 4. Reported outcomes: All of the prespecified outcomes (see above) plus safety were reported on the clinicaltrials.gov site.
Notes	Funding for trial; notable author COIs: The study was sponsored by AstraZeneca.
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Insufficient information provided (trial registry only).
Allocation concealment (selection bias)	Unclear risk	Insufficient information provided (trial registry only).
Blinding of participants and personnel (performance bias) All outcomes	Low risk	Participants and investigators blinded.
Blinding of participants and personnel (objective outcomes ‐ performance bias) Objective outcomes	Low risk	Participants and investigators blinded.
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 would be unlikely to be influenced by knowledge of treatment allocation.
Incomplete outcome data (attrition bias) All outcomes	Low risk	Attrition rates were low and balanced between treatment groups.
Selective reporting (reporting bias)	Low risk	Prespecified outcomes (clinicaltrials.gov) were well reported.
Other bias	Low risk	None identified.