Chan 2007.

Methods	Design: a multicentre, randomised, double‐blind, placebo‐controlled, parallel‐group study with 48 weeks treatment duration, conducted in 101 centres in Canada involving 72 specialists and 29 general practitioners from 24 January 2002 to 07 May 2004
Participants	Population: 913 patients with COPD were randomised to tiotropium (608) and placebo (305) Baseline Characteristics: mean age 67 years, 60% male, mean FEV1 0.97 L, mean FEV1 predicted 39%, 51 pack‐years smoking history Inclusion Criteria: male and female outpatients aged 40 years or older, with a clinical diagnosis of COPD (FEV1 65% predicted or less and FEV1/FVC 70% or less) were considered for inclusion in the present study. Participants were required to have a smoking history of 10 pack‐years or greater. The inclusion criteria relating to ‘exacerbation history’ initially required that patients had experienced one or more exacerbation(s) within the past year (requiring treatment with antibiotics and/or oral steroids), but not within the six weeks before entering the study. However, due to slower than expected enrolment, this criterion was amended to include patients with fewer exacerbations (one exacerbation in the past two years) Exclusion Criteria: history of asthma, allergic rhinitis or atopy; a recent lower respiratory tract infection or any exacerbation (within the previous six weeks); a recent history of myocardial infarction (within the previous six months) or cardiac arrhythmia requiring drug therapy; and oral corticosteroid use at unstable doses during the six weeks before entering the study or at a stable dose exceeding the equivalent of 10 mg prednisone daily. In addition, those patients with a significant disease other than COPD that would put the patient at risk because of participation in the study, or patients with a disease that may have influenced the results of the study, were not enrolled
Interventions	1. Tiotropium 18 mcg once daily 2. Placebo once daily Inhaler device: dry powder inhaler Co‐medication: during the treatment period, patients were permitted oral corticosteroids (at a stable dose of 10 mcg or less of prednisone daily or equivalent), stable doses of ICS, theophylline preparations, mucolytic preparations (not containing bronchodilators), LABAs and, for acute symptom relief, as‐needed salbutamol MDI. Patients were not allowed to use inhaled anticholinergics (other than the study drug) or oral beta2‐agonists during the treatment period. To treat COPD exacerbations during the trial, the investigators were permitted to administer any additional medication deemed necessary
Outcomes	Primary: morning predose (trough) FEV1 at study end Secondary: predose FVC and forced expiratory volume in six seconds (FEV6), HRQoL (SGRQ), exacerbations and associated hospitalisations, and the number of courses of both oral steroids and antibiotics administered for the treatment of exacerbations
Notes	Funding: Boehringer Ingelheim Study number: Boehringer Ingelheim 205.259, ClinicalTrials.gov NCT00277264 Definitions: an exacerbation was defined as a complex of respiratory symptoms (new onset or an increase in at least one of cough, sputum, sputum purulence, dyspnoea, wheeze, chest discomfort) lasting at least three days and requiring treatment with antibiotics and/or systemic steroids
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	Unclear risk	Withdrawal rates were 22.2% in the tiotropium group and 27.5% in the placebo group
Selective reporting (reporting bias)	Low risk	Results for all specified outcomes were reported