Troosters 2016.

Methods	Study ID and dates performed: NCT02085161; PHYSACTO; dates not reported. Study design: Randomised, partially double‐blinded, placebo‐controlled, parallel‐group trial. Duration of study: 19 weeks (4‐week run‐in; 12‐week treatment period; 3‐week follow‐up). Study setting, location, number of centres: 34 sites in Australia, New Zealand, USA, Canada, Europe (17 academic centres, 15 secondary care and 5 primary care centres). Key inclusion criteria: COPD; aged ≥ 40 years and ≤ 75 years; smoking history of > 10 pack‐years; post‐bronchodilator FEV1 ≥ 30% and < 80% of predicted normal (GOLD 2–3) and no acute exacerbations in the month prior to the study; post‐bronchodilator FEV1/FVC < 70%. Key exclusion criteria: Significant disease other than COPD; history of asthma; clinically relevant abnormal baseline haematology, blood chemistry or urinalysis; conditions excluding participants from exercise. Concomitant medications: Not reported.
Participants	N randomised: TIO/OLO 5/5 µg: n = 76; placebo: n = 76. N analysed, n/N: TIO/OLO 5/5 µg: 72/76; placebo: 65/76. Mean age (SD), years: TIO/OLO 5/5 µg: 65.0 (6.9); placebo: 64.4 (6.6). Gender ‐ male, n/N (%): TIO/OLO 5/5 µg: 48/76 (63.2); placebo: 52/75 (69.3). Baseline lung function ‐ post‐bronchodilator % predicted FEV1: Not reported. Smoking status, current smoker, n/N (%): Not reported.
Interventions	Intervention: Once‐daily TIO/OLO 5/5 µg. Comparator: Once‐daily placebo.
Outcomes	Prespecified outcomes: Primary: Endurance time during endurance shuttle walk test (to symptom limitation) after 8 weeks. Secondary: average daily walking time measured by the activity monitor in the week prior to week 12; average daily walking intensity measured by the activity monitor in the week prior to 12 weeks of treatment; perceived difficulties as evaluated with functional performance inventory‐short form (FPI‐SF) total score at week 12; endurance time during endurance shuttle walk test (to symptom limitation) after 12 weeks; one‐hour, post‐dose FEV1 after 8 weeks of treatment; one‐hour, post‐dose FVC after 8 weeks of treatment; resting inspiratory capacity measured at 1.5 hours post‐dose after 8 weeks of treatment. Reported outcomes: Prespecified outcomes (clinicaltrials.gov) were well reported.
Notes	Funding for trial; notable author COIs: Study sponsored by BI. Authors had received funding or honoraria from BI, or were employees of BI.
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	High risk	“Randomisation is performed using a pseudo‐random number generator and block randomisation is used to achieve balanced allocation”.
Allocation concealment (selection bias)	Low risk	Web‐based and telephone‐based response system used.
Blinding of participants and personnel (performance bias) All outcomes	Low risk	'Partially double‐blind' as it was not possible to blind participants and personnel to the receipt of exercise training or behavioural modifications. However; the groups of interest (TIO/OLO and placebo) received treatments in double‐blind fashion (participants and personnel were blinded).
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	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 rate was < 20% and the difference in attrition rates between relevant treatment groups was < 10%
Selective reporting (reporting bias)	Low risk	Data presented on clinicaltrials.gov website appeared in line with protocol.
Other bias	Low risk	None identified.