Wedzicha 2016.

Methods	Design: randomised, double‐blind, parallel‐group, double‐dummy, placebo‐controlled trial. Countries: 43 countries. Site: 496 centres. Study duration: 52 weeks. Study start: July 2013. Run‐in period: 4 weeks.
Participants	Key inclusion criteria: %pred FEV1 25% to 60%, mMRC ≥ 2, with recent exacerbation. Numbers of randomised and completed cases: 3362 and 2760. Age: 64.6 years (SD 7.8). Male/female: 2557/805. %pred FEV1: 44.1% (SD 9.5%).
Interventions	LAMA/LABA: indacaterol/glycopyrronium (110/50 μg). LABA/ICS: salmeterol/fluticasone (50/500 μg) twice daily.
Outcomes	Primary outcome: rate of COPD exacerbations per year. LAMA/LABA: 3.59 (95% CI 3.28 to 3.94). LABA/ICS: 4.03 (95% CI 3.68 to 4.41).
Notes	Registration: NCT01782326. COI: sponsored by Novartis. Study name: FLAME.
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Participants were randomised via Interactive Response Technology to 1 of the treatment arms.
Allocation concealment (selection bias)	Low risk	Participants were randomised via Interactive Response Technology to 1 of the treatment arms.
Blinding of participants and personnel (performance bias) All outcomes	Low risk	Study was double‐blinded. Performance bias was not suspected.
Blinding of outcome assessment (detection bias) All outcomes	Low risk	Study was double‐blinded. Detection bias was not suspected.
Incomplete outcome data (attrition bias) All outcomes	Low risk	2760/3362 participants completed the study. Considerable attrition bias was not suspected because attrition was < 20%. Attrition was 16.6% in indacaterol/glycopyrronium arm and 19.0% in salmeterol/fluticasone arm.
Selective reporting (reporting bias)	Low risk	Study was registered and the prespecified outcomes were appropriately described.
Other bias	High risk	COI: sponsored by Novartis.