Beeh 2006.

Methods	Design: a randomised, double blind, parallel group, placebo controlled study. The study took place in 294 respiratory trial centres in Germany. They were outpatient clinics predominantly run by chest specialists with a few run by general internal physicians (N < 10). The duration of treatment was 12 weeks
Participants	Population: 1639 patients with COPD were randomised to tiotropium (1236) and placebo (403) Baseline Characteristics: mean age 62 years, 76% male, mean FEV1 1.3 L, mean FEV1 predicted 45%, 36 pack‐years smoking history Inclusion Criteria: stable COPD, FEV1 ≤ 70% predicted, FEV1/FVC ratio of < 0.7, smoking history of at least 10 pack‐years, at least 40 years of age Exclusion Criteria: history of asthma, atopic disease which was suggestive of asthma, requirement for long‐term oxygen therapy, respiratory infection in the six weeks prior to screening, significant co‐morbidities
Interventions	1. 18 mcg tiotropium bromide once daily 2. Placebo once daily Inhaler device: dry powder inhaler Co‐medication: LABAs were not permitted during the course of the study. Short‐acting relief medications were substituted for fenoterol as needed
Outcomes	Lung function and exacerbations were evaluated by respective pulmonary function tests (spirometry), before (trough value), and 2 hours after inhalation of study medication, FVC, Inspiratory Vital Capacity, and tolerability
Notes	Funding: Boehringer Ingelheim Study number: Boehringer Ingelheim 205.257, ClinicalTrials.gov NCT00274573 Definitions: exacerbations were defined as a respiratory event which lasted for more than 3 days which required treatment or significant increase in the dose of COPD medication (bronchodilator and/or systemic corticosteroids or treatment with antibiotics)
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	The withdrawal rates were relatively even (tiotropium 17.6%, placebo 22.3%)
Selective reporting (reporting bias)	Low risk	Results for all specified outcomes were reported