Tonnel 2008.

Methods	Design: a randomised, double‐blind, parallel‐group, placebo‐controlled study with nine months treatment duration, conducted at 123 centres in France. Patients were recruited between May 2002 and June 2003, and follow‐up was from August 2002 through April 2004
Participants	Population: 554 patients with COPD, as defined by ATS guidelines, were randomised to tiotropium (266) and placebo (288) Baseline Characteristics: mean age 64 years, 86% male, mean FEV1 1.4 L, mean FEV1 predicted 44%, 44 pack‐years smoking history Inclusion Criteria: male and female outpatients aged ≥ 40 years with a clinical diagnosis of COPD (pre‐ and post‐bronchodilator FEV1 20% to– 70% predicted and FEV1/SVC ≤ 70%,) corresponding to mild, moderate, or severe COPD according to 1995 ATS and a smoking history of > 10 pack‐years were eligible for inclusion in the study. Exclusion Criteria: a history of asthma, allergic rhinitis, or atopy; regular use of daytime oxygen therapy; a recent respiratory tract infection (within the previous six weeks); a recent history of myocardial infarction (within the previous six months); cardiac arrhythmia requiring drug therapy (within the previous year); or hospitalisation for either heart failure or pulmonary edema (within the previous 3 years).
Interventions	1. Tiotropium 18 mcg once daily 2. Placebo ones daily Inhaler device: dry powder inhaler Co‐medication: patients were permitted to use salbutamol (Ventolin®; GlaxoSmithKline, UK) delivered via a MDI, as needed, for acute symptom relief. Concomitant use of theophylline preparations (excluding 24‐hour preparations), mucolytics, (ICS), and oral steroids (at a dose of < 10 mg prednisone daily or equivalent) was allowed if the dosage was stabilised for ≥ 6 weeks before study entry. During the treatment period, patients were not allowed to use beta‐blockers, antileukotrienes, oral or inhaled LABAs, short‐acting anticholinergics, or any other investigational drug. One 10‐day course of oral steroids was permitted for the treatment of a COPD exacerbation during the study period. Investigators were also permitted to administer antibiotics as deemed necessary for the treatment of exacerbations.
Outcomes	Primary: the proportion of patients achieving a reduction of at least 4 units in the SGRQ total score at study end Secondary: Visual Simplified Respiratory Questionnaire (VSRQ) total score (improvement in health status), FEV1, FVC, IC, SVC, and FIV1; measured at selected sites only), exacerbations of COPD
Notes	Funding: Boehringer Ingelheim Study number: Boehringer Ingelheim 205.256, ClinicalTrials.gov NCT00274053 Definitions: an acute exacerbation was defined as a sustained worsening of the patient’s COPD (from the stable state and beyond normal day‐to‐day variation) that was acute in onset and necessitated a change in regular medication.
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Patients were assigned using a computer‐generated randomisation schedule, with no stratification (block size of 4)
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 uneven (tiotropium 14.7%, placebo 25.7%)
Selective reporting (reporting bias)	Low risk	Results for all specified outcomes were reported