Freeman 2007.

Methods	Design: randomised, double‐blind, placebo‐controlled, parallel‐group study with 12 weeks treatment duration, conducted at 44 primary care centres throughout England, Scotland and Wales from October 2002 to October 2003
Participants	Population: 395 patients with COPD were randomised to tiotropium (200) and placebo (195) Baseline Characteristics: mean age 65 years, 50% to 59% male, mean FEV1 1.3 L, mean FEV1 predicted 49%, 37 pack‐years smoking history Inclusion Criteria: patients were required to have a COPD diagnosis according to BTS criteria and recent stable disease (no exacerbation or respiratory infection within four weeks), with airway obstruction FEV1 between 30% and 65% of predicted normal value and FEV1/FVC ≤ 70% pre‐bronchodilators. Patients had to be at least 40 years old, have at least a 10 pack‐year smoking history and had to be receiving SABAs as rescue medication (salbutamol or terbutaline MDI or dry powder inhaler) with no anticholinergic drug prescribed in the preceding year. Patients had to be able to undergo spirometry and be able to use the HandiHaler device Exclusion Criteria: patients with a history of allergy or asthma were excluded. Patients were excluded if they had any other significant medical condition that might interfere with the study or preclude their use of study medication, such as known hypersensitivity to anticholinergic drugs, known symptomatic prostatic hypertrophy, narrow angle glaucoma, severe cardiovascular disease, or recent myocardial infarction (≤ 1 year). Patients who were on long‐term oxygen therapy were also excluded
Interventions	1. Tiotropium 18 mcg 2. Placebo Inhaler device: dry powder inhaler Co‐medication: usual treatment
Outcomes	Primary: trough FEV1 response end of study Secondary: trough FEV1 response after 2 and 6 weeks, trough FVC response after 2, 6 and 12 weeks, mean daily SABA use, COPD exacerbations, dyspnoea measured by the Oxygen Cost Diagram
Notes	Funding: Boehringer Ingelheim Study number: Boehringer Ingelheim 205.276, ClinicalTrials.gov NCT00274079 Definitions: an exacerbation of COPD was defined as a complex of respiratory events/symptoms with duration of three or more days (from patient's diary card) requiring a change in treatment (including patient‐initiated increases). A complex of respiratory events/symptoms meant ≥ two of the following (increase of symptom or new onset): shortness of breath, sputum production (volume), cough, wheezing and chest tightness. The change in (or requirement of) treatment included prescription of antibiotics and/or systemic steroids and/or a significant change (including increase) of the prescribed respiratory medication (bronchodilators including theophylline)
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	Medication and placebo were delivered by identical‐appearing lactose‐based inhalers
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	The withdrawal rates were relatively low, but uneven (tiotropium 9.5%, placebo 17.9%)
Selective reporting (reporting bias)	Low risk	Results for all specified outcomes were reported