O'Donnell 2015b.

Methods	Study ID and dates performed: NCT01533935 (MORACTO‐2); study dates not stated. Study design: Double‐blind, 6‐week incomplete cross‐over study. Duration of study: 38–40 weeks, including a 2–4 week run‐in period. Study setting, location, number of centres: 82 investigational sites in 13 countries. Key inclusion criteria: Aged 40–75 years; post‐bronchodilator (400 μg salbutamol) FEV1/FVC < 70%; post‐bronchodilator FEV1 ≥ 30% and < 80% of predicted normal (GOLD 2–3); current or ex‐smokers with a smoking history of > 10 pack‐years. Key exclusion criteria: Significant disease other than COPD; unstable or life‐threatening cardiac arrhythmia; hospitalisation for heart failure or myocardial infarction within the past year; regular use of daytime oxygen therapy for > 1 h per day; history of asthma and contraindications to exercise as per the ERS guidelines. Concomitant medications: Permitted: Participants continued with inhaled corticosteroids if taken at baseline; open‐label salbutamol (albuterol) was provided as rescue medication throughout the study. Restricted/not permitted: LABA or LAMA (other than study medication) during the baseline, treatment, and washout periods; short‐acting muscarinic antagonists during the treatment periods (permitted only during baseline and washout periods, with an 8‐h washout prior to assessments).
Participants	Note: cross‐over study therefore participant data reported for whole cohort; baseline characteristics and participant flow reported for combined studies (MORACTO‐1 and MORACTO‐2). N randomised: N = 586. N analysed, n/N: TIO/OLO 2.5/5 µg: 424/442; TIO/OLO 5/5µg: 28/450; placebo: 413/438. Mean age (SD), years: 61.7 (7.7). Gender ‐ male, n/N (%): 417/586 (71.2). Baseline lung function ‐ mean (SD) post‐bronchodilator % predicted FEV1: 58 (13). Smoking status, current smoker, n/N (%): 229/586 (39.1).
Interventions	Intervention: Once‐daily TIO/OLO 2.5/5 µg; once‐daily TIO/OLO 5/5µg. Comparator: Once‐daily placebo.
Outcomes	Prespecified outcomes: Primary: Inspiratory capacity at rest immediately before constant work rate cycle ergometry (assessed at 6 weeks); endurance time during constant work rate cycle ergometry. Secondary: Slope of the intensity of breathing discomfort during constant work rate cycle ergometry (assessed at 6 weeks); 1‐hour post‐dose FEV1 (assessed at 6 weeks). Reported outcomes: All prespecified outcomes (see above) plus FVC and safety and tolerability.
Notes	Funding for trial; notable author COIs: This work was funded by BI Pharma GmbH & Co. All authors were either employees of BI or had received research funding or 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	Similar attrition with similar reasons for combined treatment arm and placebo arm; discontinuation rates < 5%.
Selective reporting (reporting bias)	Low risk	Prespecified outcomes (clinicaltrials.gov) were well reported.
Other bias	Low risk	None identified.