Maltais 2014.

Methods	Study ID and dates performed: NCT01525615 (TORRACTO); study dates not reported. Study design: Multicentre, multinational, randomised, double‐blind, placebo‐controlled, parallel‐group trial. Duration of study: 1‐week run‐in, 12‐week treatment period, 3‐week follow‐up. Study setting, location, number of centres: 58 centres in 10 countries. Key inclusion criteria: Aged 40–75 years; clinical diagnosis of COPD and stable airway obstruction; post‐bronchodilator FEV1/FVC < 70% and post‐bronchodilator FEV1 < 80% and ≥ 30% predicted normal; current or ex‐smokers with a smoking history of > 10 pack‐years. Key exclusion criteria: Significant disease other than COPD; a history of asthma, myocardial infarction in the previous year; unstable or life‐threatening cardiac arrhythmia, or hospitalisation for heart failure within the previous year; a recognised contraindication to exercise; participated in a pulmonary rehabilitation program within the 6 weeks prior to the screening visit; an exercise limitation other than leg fatigue or exertional dyspnoea (e.g. arthritis in the leg or morbid obesity). Concomitant medications: Participants continued with inhaled corticosteroids if taken at baseline. Open‐label salbutamol (albuterol) was provided as rescue medication throughout the study.
Participants	N randomised: TIO/OLO 2.5/5 µg: N = 133; TIO/OLO 5/5 µg: N = 139; placebo: N = 132. N analysed, n/N: TIO/OLO 2.5/5 µg: 129/133 ; TIO/OLO 5/5 µg: n = 135/139; placebo: n = 121/132. Mean age (SD), years: TIO/OLO 2.5/5 µg: 61.9 (7.3); TIO/OLO 5/5 µg: 63.1 (7.5); placebo: 60.8 (7.6). Gender ‐ male, n/N (%): TIO/OLO 2.5/5 µg: 87 (65.4); TIO/OLO 5/5 µg: 95 (68.3); placebo: 87 (65.9). Baseline lung function ‐ mean (SD) post‐bronchodilator % predicted FEV1: Not reported. Smoking status, current smoker, n/N (%): Not reported.
Interventions	Intervention: Once‐daily TIO/OLO 2.5/5 µg; once‐daily TIO/OLO 5/5 µg. Comparator: Once‐daily placebo.
Outcomes	Prespecified outcomes: Primary: Adjusted mean endurance time during constant work rate cycle ergometry after 12 weeks. Secondary: Adjusted mean endurance time during endurance shuttle walk test after 12 weeks; adjusted mean inspiratory capacity at pre‐exercise after 12 weeks; adjusted mean endurance time during constant work rate cycle ergometry on day 1, after 6 weeks treatment; adjusted mean inspiratory capacity at pre‐exercise after 1 day and 6 weeks; adjusted mean slope of the intensity of breathing discomfort on day 1 and after weeks 6 and 12; adjusted mean 1‐hour, post‐dose FEV1 on day 1, and after 6 and 12 weeks. Reported outcomes: The majority of prespecified outcomes (see above) were reported although no data provided for FEV1‐related outcomes.
Notes	Funding for trial; notable author COIs: The study was sponsored by Boehringer Ingelheim Pharma GmbH & Co. KG. All authors except JBGI were either employees of BI or had received research funding/honoraria from BI.
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Insufficient information provided.
Allocation concealment (selection bias)	Unclear risk	Insufficient information provided.
Blinding of participants and personnel (performance bias) All outcomes	Unclear risk	Insufficient information provided.
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	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	According to clinicaltrials.gov results tab, noncompletion < 20% in each arm (in fact < 11%) and reasonably balanced across arms.
Selective reporting (reporting bias)	Low risk	Prespecified outcomes (clinicaltrials.gov) were well reported.
Other bias	Low risk	None identified.