Anzueto 2009.

Methods	Design: Randomised, double‐blind, parallel‐group, multicenter study Duration: 52 weeks (+ 4 week run‐in) Location: 98 centres in the USA and Canada
Participants	Population: 797 participants were randomised to salmeterol alone (403) and salmeterol/fluticasone combination therapy (394) Baseline characteristics Age (mean years): sal 65.3, sal/flut 65.4 % Male: sal 57, sal/flut 51 % FEV1 predicted (pre BD): sal 33.9, sal/flut 34.1 Pack‐years (mean): sal 56.5, sal/flut 57.8 Inclusion criteria: >40 years of age with a diagnosis of COPD, a cigarette smoking 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	1. Salmeterol 50 bid (LABA) 2. Salmeterol/fluticasone 50/250 bid (LABA/ICS) Inhaler device: Diskus Allowed co‐medications: As‐needed albuterol was provided for use throughout the study. As needed ipratropium was not provided; however, it could be used during the study. The use of concurrent inhaled long‐acting bronchodilators (beta2‐agonist and anticholinergic), ipratropium/albuterol combination products, oral beta‐agonists, inhaled corticosteroids (ICS), leukotriene modifiers, inhaled nedocromil and cromolyn, theophylline preparations, ritonavir and other investigational medications were not allowed during the treatment period. Oral corticosteroids and antibiotics were allowed for the acute treatment of a COPD exacerbation.
Outcomes	Annual rate of moderate/severe exacerbations, time to first moderate/severe exacerbation, the annual rate of exacerbations requiring oral corticosteroids, and pre‐dose FEV1. Diary records and health status measured on the St George's Respiratory Questionnaire (SGRQ).
Notes	Funding: GlaxoSmithKline Identifier(s): NCT00115492, GSK NCT00115492
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Treatments were assigned in blocks using a centre‐based randomisation schedule. Since bronchodilator response to FSC 250/50 is generally larger in subjects with COPD who demonstrate FEV1 reversibility to albuterol, assignment to blinded study medication was stratified based on subjects’ FEV1 response to albuterol at screening to provide a similar distribution of albuterol‐responsive and non‐responsive subjects in each treatment group.
Allocation concealment (selection bias)	Unclear risk	Not described
Blinding of participants and personnel (performance bias) All outcomes	Low risk	Described as double‐blind [assumed participants and personnel/investigators]
Blinding of outcome assessment (detection bias) All outcomes	Unclear risk	Not described
Incomplete outcome data (attrition bias) All outcomes	Unclear risk	The withdrawal rates were very high compared to the number of events for the different outcomes
Selective reporting (reporting bias)	Low risk	All outcomes stated in the protocol were reported and could be included