Singh 2016b.

Methods	Study ID and dates performed: NCT02006732 (OTEMTO 2). Study design: One of two multinational, double‐blind, parallel‐group, placebo‐controlled studies. Duration of study: 2‐week run‐in period; 12‐week treatment period; 3‐week follow‐up. Study setting, location, number of centres: Not stated. Key inclusion criteria: Participants aged ≥ 40 years with moderate to severe COPD (GOLD 2–3); post‐bronchodilator FEV1 ≥ 30% and < 80% of predicted normal), FEV1/FVC < 70% predicted and a smoking history of > 10 pack‐years. Key exclusion criteria: A history of asthma, another significant disease, COPD exacerbation or symptoms of lower respiratory tract infection within the previous 3 months; unstable or life‐threatening cardiac arrhythmia, hospitalisation for heart failure within the past year; a history of myocardial infarction within 1 year of screening; a history of life‐threatening pulmonary obstruction. Concomitant medications: Participants were allowed to continue their ICS therapy (if they were on a stable dose for 6 weeks prior to screening). LAMAs or LABAs other than study medication were prohibited; short‐acting muscarinic antagonists were permitted only during the screening period. Open‐label salbutamol was provided as rescue medication for use throughout the study.
Participants	N randomised: TIO/OLO 2.5/5 µg: n = 202; TIO/OLO 5/5 µg: n = 202; placebo: n = 202. N analysed, n/N: TIO/OLO 2.5/5 µg: 193/202; TIO/OLO 5/5 µg: 198/202; placebo: 182/202. Mean age (SD), years: TIO/OLO 2.5/5 µg: 64.4 (8.6); TIO/OLO 5/5 µg: 65.2 (8.5); placebo: 64.0 (8.3). Gender ‐ male, n/N (%): TIO/OLO 2.5/5 µg: 126 (62.4); TIO/OLO 5/5 µg: 133 (65.8); placebo: 117 (57.9). Baseline lung function ‐ mean (SD) post‐bronchodilator % predicted FEV1: TIO/OLO 2.5/5 µg: 54.5 (12.7); TIO/OLO 5/5 µg: 54.8 (12.8); placebo: 54.3 (13.4). Smoking status, current smoker, n/N (%): TIO/OLO 2.5/5 µg: 90/202 (44.6) ; TIO/OLO 5/5 µg: 92/202 (45.5); placebo: 95/202 (47.0).
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: FEV1 AUC 0‐3 h response at 12 weeks; trough FEV1 response at 12 weeks; SGRQ total score at 12 weeks. Secondary: trough FVC response (change from baseline) at 12 weeks; TDI focal score at 12 weeks; FVC AUC 0‐3 h response (change from baseline) at 12 weeks. Reported outcomes: All prespecified outcomes (see above) were reported.
Notes	Funding for trial; notable author COIs: This study was funded by Boehringer Ingelheim Pharma GmbH & Co. KG. Seven of nine authors were employees of, or had received funding/honoraria from, BI. Two authors disclosed no conflicts of interest.
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	Attrition rate was < 15% in placebo and combined LABA/LAMA arms.
Selective reporting (reporting bias)	Low risk	Prespecified outcomes (clinicaltrials.gov) were well reported.
Other bias	Low risk	None identified. Note slightly higher rates of discontinuation in placebo arm ‐ likely accounted for due to the most severely ill participants dropping out. Potential positive placebo treatment effect not observed.