Briggs 2005.

Methods	Design: 12‐week, randomised, double‐blind, double‐dummy, parallel‐group study Setting: the study was conducted in 50 centres located in 8 countries, including Finland, Greece, Italy, Portugal, Sweden, Turkey, the United Kingdom and the United States Date of study: May 2002 to March 2003
Participants	Participants: n = 653 (tiotropium: 328, salmeterol: 325) Baseline characteristics: mean age (tiotropium: 64.2 years, salmeterol 64.6 years); gender (tiotropium 65% male, salmeterol 68% male); mean % predicted FEV1 (tiotropium 37.7, salmeterol 37.7%); mean smoking pack year history (tiotropium 55.6 years, salmeterol 56.1 years) Diagnostic criteria: not specified COPD severity: severe Inclusion criteria: patients who were ≥ 40 years of age, with a cigarette smoking history of ≥ 10 pack years, and a clinical diagnosis of COPD, were eligible for inclusion in the study if they had a FEV1 % predicted  ≤ 60% and FVC ≤ 70% Exclusion criteria: patients with a history of asthma, allergic rhinitis, atopy or a total (absolute) blood eosinophil count ≥ 600 mm were excluded from the study, as were those with any significant medical condition that could preclude participation for the full duration of the trial or interfere with the interpretation of the study results. Patients were also excluded from the study if they took systemic corticosteroids at unstable doses or in daily doses of ≥ 10 mg (or its equivalent), if they were using beta‐blockers, cromones, or anti‐leukotrienes prior to enrolment in the trial, or if they had experienced a respiratory tract infection or a COPD exacerbation within 30 days of randomisation. Patients using oxygen for more than 1 h per day and who were unable to refrain from its use during pulmonary function testing were also excluded. Additionally, patients were excluded who were actively participating in a rehabilitation programme or had completed such a programme during the previous 30 days.
Interventions	Run‐in period: a 2‐week screening period during which baseline use of rescue salbutamol (albuterol) use was recorded on a diary card. During the screening period, patients who were taking fixed combination respiratory medications (i.e. combinations of ICS plus LABA, or anticholinergics plus short‐acting beta‐agonists) prior to study enrolment were switched to the component monoproducts. Patients taking LABAs were required to stop this medication 24 h prior to randomisation. Interventions: 1. Tiotropium, 18 µg once daily via the HandiHaler device; or 2. Salmeterol, 2 actuations of 25 µg each, twice daily via a metered dose inhaler Concomitant medication Short‐acting anticholingeric: no Short‐acting beta2‐agonist: yes Inhaled corticosteroid: yes Long‐acting beta2‐agonist: no Other: theophylline compounds "Patients were not permitted to take anticholinergic agents or LABAs other than study medication during the treatment period. Patients otherwise received usual medical care, and were permitted to use rescue salbutamol, which was provided during the study, as well as previously prescribed theophylline compounds, inhaled steroids, and modest doses of oral steroids".
Outcomes	Primary outcome(s): the co‐primary efficacy outcomes were average post‐dose FEV1 over 12 h and peak FEV1 after 12 weeks of treatment. Average FEV1 was estimated from the area under the curve from 0 to 12 h (AUC 0–12). Secondary outcome(s): secondary outcomes including morning pre‐dose FEV1, FEV1 at each time point over 12 h, corresponding FVC parameters, incidence and frequency of COPD exacerbations (the number or percentage of patients with at least one COPD exacerbation, time to first exacerbation, number of exacerbations, and exacerbation days), rescue medication use, and incidence of serious adverse events
Notes	Funding: this study was funded by Boehringer Ingelheim and Pfizer Boehringer Ingelheim trial number 205.264
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.
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 the groups and relatively small (tiotropium 8.8%, salmeterol 12.6%)
Selective reporting (reporting bias)	Low risk	All collected data reported