Anzueto 2009

Methods	Randomised, double‐blind parallel study. Duration: 52 weeks.
Participants	Setting: 98 centre in USA and Canada. (study code SCO100250, clinicaltrials.gov# NCT00115492) Participants randomised: 797 (FPS: 394; salmeterol: 403) Baseline characteristics: Mean age: 65.4. Mean FEV1: 0.98L Inclusion criteria: aged ≥40 yrs. History ≥ 10 pack‐years, a pre‐albuterol FEV1/FVC ≤ 0.70, a FEV1 ≤ 50% of predicted normal and a documented history of at least 1 COPD exacerbation the year prior to the study that required treatment with antibiotics, oral corticosteroids, and/or hospitalisation. Exclusion criteria: current diagnosis of asthma, a respiratory disorder other than COPD, historical or current evidence of a clinically significant uncontrolled disease, or had a COPD exacerbation that was not resolved at screening
Interventions	Run‐in 4 weeks with open‐label fluticasone/salmeterol 250/50 Diskus BID. Following run‐in, subjects were randomised to FPS 250/50 or salmeterol twice‐daily via DISKUS for 52 weeks. Clinic visits were conducted at screening, day 1 (randomisation), and after 4, 8, 12, 20, 28, 36, 44, and 52 weeks. Treatments were assigned in blocks using a centre‐based randomisation schedule. Assignment to blinded study medication was stratified based on subjects' FEV1 response to albuterol at screen visit. Oral corticosteroids and antibiotics were allowed for the acute treatment of a COPD exacerbation.
Outcomes	The primary efficacy endpoint was the annual rate of moderate/severe exacerbations. Secondary endpoints were the time to first moderate/severe exacerbation, the annual rate of exacerbations requiring oral corticosteroids, and pre‐dose FEV1. Related endpoints included the annual rate of all exacerbations, time to onset of each moderate/severe exacerbation, and diary records of dyspnoea scores, nighttime awakenings due to COPD, and use of supplemental albuterol.
Notes	The run‐in with combined therapy precluded exacerbations due to ICS withdrawal.
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Assigned in block centre‐based randomisation schedule and stratified according to salbutamol response in FEV1 at baseline.
Allocation concealment (selection bias)	Unclear risk	Information not available.
Blinding (performance bias and detection bias) All outcomes	Low risk	Identical Diskus inhaler device.
Incomplete outcome data (attrition bias) Mortality	High risk	39% discontinued on salmeterol and 32% on FPS.
Incomplete outcome data (attrition bias) All other outcomes	High risk	39% discontinued on salmeterol and 32% on FPS.
Selective reporting (reporting bias)	Low risk	Contributes data to all primary outcomes.