Brusasco 2003.

Methods	Design: pooled results from two randomised, double‐blind, double‐dummy, parallel‐group studies Duration: 6 months (+ 2 weeks run‐in period) Location: The studies were performed in 18 countries The only difference in the two studies was the duration of serial spirometry in the clinic (12 hours in one study, 3 hours in the second)
Participants	Population: 805 participants were randomised to salmeterol (405) and placebo (400) Baseline characteristics Age (mean years): sal, 64.1; pbo, 64.6 % Male: sal, 75.1; pbo, 76.3 % FEV1 predicted: sal 37.7; pbo, 38.7 Pack‐years (mean): sal, 44.8; pbo, 42.4 Inclusion criteria: Participants were required to have relatively stable airway obstruction with FEV1 < 65% of predicted normal and < 70% of FVC, > 40 years of age, with a smoking history of > 10 pack‐years Exclusion criteria: Patients with a history of asthma, allergic rhinitis or atopy or with an increased total eosinophil count were excluded. Other exclusion criteria included use of supplemental oxygen or an upper respiratory tract infection in the six weeks before screening. Patients with a significant disease other than COPD were not enrolled. Significant disease was defined as a disease that, in the opinion of the investigator, would put the patient at risk because of participation in the study, or a disease that would influence the results of the study
Interventions	1. Salmeterol 50 bid (LABA) 2. Tiotropium 18 qd (LAMA) 3. Placebo (PBO) Inhaler device: metered dose Allowed co‐medications: Participants were allowed to continue previously prescribed regular inhaled steroids or regular oral steroids, not exceeding a dose equivalent to approximately 10 mg prednisone daily. The number of participants taking these medications during the study was not located
Outcomes	Mean change from baseline on the SGRQ and number whose score decreased by at least 4 units; exacerbations (number, time to first etc.), hospital admissions, FEV1, FVC, dyspnoea (evaluated using the Baseline Dyspnoea Index (BDI) and the TDI), diary card data
Notes	Funding: Boehringer Ingelheim Identifier(s): 205.130/205.137
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	The randomisation list was generated by Boehringer Ingelheim using a validated system, which involved a pseudo‐random number generator so that the resulting treatment sequence was both reproducible and non‐predictable
Allocation concealment (selection bias)	Low risk	All investigational medication for each patient was identified by a unique medication number. Each eligible patient was assigned the lowest medication number available to the investigator at the time of randomisation
Blinding of participants and personnel (performance bias) All outcomes	Low risk	Boehringer Ingelheim was responsible for preparing and coding study medication in a blinded fashion (Boehringer Ingelheim study drug and control were indistinguishable). Patients, investigators and study personnel remained blinded with regard to the treatment assignments up to database lock. Double dummy technique was used to blind different application devices
Blinding of outcome assessment (detection bias) All outcomes	Low risk	In all studies, a selection of standard respiratory endpoints like pulmonary function, SGRQ, TDI, treadmill, exacerbations, etc., were used. Outcome assessors remained blinded with regard to the treatment assignments up to database lock
Incomplete outcome data (attrition bias) All outcomes	Low risk	The withdrawal rates were relatively even between groups (salmeterol [18.8%], placebo [25.8%])
Selective reporting (reporting bias)	Low risk	Results for all expected and specified outcomes were reported (except FEV1 [secondary outcome] was not reported in a way that could be included in the qualitative synthesis.