Trooster 2011.

Methods	Design: a randomised, double‐blind, parallel‐group, placebo‐controlled study with 24 weeks (6 months) treatment duration, conducted at 70 centres (of which, 11 did not randomise subjects); Belgium 4 centres; Canada 4 centres (of which, 2 did not randomise subjects), Czech Republic 12 centres; Germany 5 centres; Greece 4 centres; Netherlands 4 centres; Portugal 3 centres; Ukraine 7 centres; United Kingdom 4 centres; (of which, 2 did not randomise subjects); and United States 23 centres (7 did not randomise subjects). The study took place from April 2007 to July 2010
Participants	Population: 457 patients with COPD were randomised to tiotropium (238) and placebo (219) Baseline Characteristics: mean age 62 years, 69% male, mean FEV1 2.0 L, mean FEV1 predicted 66% Inclusion Criteria: subjects were men and women current or ex‐smokers (smoking history of ≥ 10 pack‐years) with GOLD Stage 2 COPD, post‐bronchodilator FEV1 ≥ 50% and < 80% of predicted normal, and were from 40 to 80 years of age. Subjects were required to have post‐bronchodilator FEV1/FVC ratio < 70% (Week ‐4 [screening]) and a Medical Research Council dyspnoea score of ≥ 2 Exclusion Criteria: subjects could not be treated previously with maintenance medications for chronic respiratory disease (e.g. LABAs, inhaled anticholinergics, inhaled or systemic corticosteroids, theophylline, leukotriene receptor antagonists) within six months prior to screening and who had symptomatic shortness of breath).
Interventions	1. Tiotropium 18 mcg once daily in the morning 2. Placebo once daily in the morning Inhaler device: dry powder inhaler Co‐medication: albuterol (salbutamol) was provided for use by all subjects (for use as rescue therapy) during the screening and treatment period
Outcomes	Spirometry: predose FEV1 and FVC measurements, postdose measurements were performed at 30, 60, 120, and 180 minutes (±5 minutes) postdose, Activity Monitor, Physician’s and Patient’s Global Assessment, Work Productivity and Activity Impairment (WPAI) Questionnaire, Subject Diary: the number of rescue albuterol (salbutamol) inhalations
Notes	Funding: Boehringer Ingelheim Study number: Boehringer Ingelheim 205.365, ClinicalTrials.gov NCT00523991 Definitions: an exacerbation of COPD was defined as a complex of respiratory symptoms (increase or new onset) of more than one of the following: cough, sputum, sputum purulence, wheezing, and dyspnoea with duration of at least three days 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	Low risk	The withdrawal rates were relatively low and even (tiotropium 11.3%, placebo 9.6%)
Selective reporting (reporting bias)	Low risk	Results for all specified outcomes were reported