Bateman 2010a.

Methods	Design: a randomised, double‐blind, placebo‐controlled, parallel group trial with recruitment from October 2006 to December 2007. The trial included 336 outpatient centres spanning five continents and involving 31 countries. Duration of treatment was 48 weeks
Participants	Population: 3991 patients with COPD, as defined by GOLD guidelines, were randomised to tiotropium (1989) and placebo (2002) Baseline Characteristics: mean age 65 years, 78% male, mean FEV1 1.1 L, mean FEV1 predicted 40%, 45 pack‐years smoking history Inclusion Criteria: COPD patients of either sex were eligible for study entry if they were aged > 40 years, had pre‐bronchodilator FEV1 of ≤ 60% of predicted normal and a FEV1 / FVC ≤ 70%, and were current or ex‐smokers (smoking history of ≥ 10 pack‐years) Exclusion Criteria: patients were excluded if they had a significant disease other than COPD that, in the investigator’s judgment, could affect the patient’s ability to complete the trial, or if they had clinically significant abnormal results of haematology, urinalysis, or blood chemistry tests, a history of asthma or allergic rhinitis, or a blood eosinophil count of ≥ 600/mm3. Other exclusion criteria included previous lung resection surgery, participation in a pulmonary rehabilitation programme in the previous six weeks, and regular daytime oxygen use (>1 h/day). Less stringent exclusion criteria relating to cardiovascular disorders were employed, with the aim of making the patient sample more representative of the range of COPD patients typically encountered in clinical practice, but patients with a history of unstable arrhythmias, myocardial infarction in the previous 6 months or heart failure requiring in‐hospital treatment in the previous 12 months were excluded. Patients who had previously used tiotropium delivered via Respimat were also excluded, but those who had previously used tiotropium delivered via HandiHaler could enter the trial if they stopped taking it at least 28 days before the randomisation visit
Interventions	1. tiotropium 5 mcg (two puffs of 2.5 mcg each) once daily in the morning 2. placebo (two puffs) once daily in the morning Inhaler device: Respimat inhaler Co‐medication: Salbutamol pMDI was provided to all patients for use as rescue medication at any time during the study. All respiratory medications were permitted during the trial other than inhaled anticholinergics.
Outcomes	Primary: trough FEV1 response, i.e. the difference between predose FEV1 on Day 1 of the treatment period and the corresponding value after 48 weeks of treatment, and time to first COPD exacerbation Secondary: mean number of COPD exacerbations per patient‐year; the total number of exacerbations that resulted in urgent visits to a health care provider or emergency department; the number of hospitalisations for COPD; the total number of hospitalisations for all‐causes; changes in health‐related quality of life, dyspnoea, lung function
Notes	Funding: Boehringer Ingelheim Study number: Boehringer Ingelheim 205.372, European Clinical Trials Database 2006‐001009‐27, ClinicalTrials.gov NCT00387088 Definitions: exacerbations were defined as a complex of respiratory events or symptoms that lasted ≥ 3 days and required treatment with antibiotics and/or systemic corticosteroids, or prompted the investigator to change the patient’s regular respiratory medication
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Treatment allocation was determined by a computer‐generated randomisation code provided by Boehringer Ingelheim. Randomisation was stratified by study centre and within centres, and performed in blocks to ensure balanced distribution of the treatment groups at any time
Allocation concealment (selection bias)	Low risk	Individuals directly involved in the conduct and analysis of the trial had no access to the allocation sequence until after the trial was completed
Blinding of participants and personnel (performance bias) All outcomes	Low risk	Identity of treatments was blinded to investigators, assessors and patients. Tiotropium and placebo were both inhaled via the Respimat inhaler once daily in the morning
Blinding of outcome assessment (detection bias) All outcomes	Low risk	Identity of treatments was blinded to investigators, assessors and patients
Incomplete outcome data (attrition bias) All outcomes	Low risk	Withdrawal rates were 16.0% in the tiotropium group and 18.6% in the placebo group. Mortality was assessed for the planned duration of the trial for all patients, including those who prematurely discontinued study medication
Selective reporting (reporting bias)	Low risk	Results for all specified outcomes were reported