Tashkin 2008.

Methods	Design: a randomised, double‐blind, parallel‐group, placebo‐controlled study with four‐year treatment duration, conducted at 490 investigational centres in 37 countries. Patients were recruited from January 2003 through March 2004; the study ended in February 2008
Participants	Population: 5993 patients with COPD were randomised to tiotropium (2987) and placebo (3006) Baseline Characteristics: mean age 65 years, 75% male, mean FEV1 1.1 L, mean FEV1 predicted 39%, 49 pack‐years smoking history Inclusion Criteria: a diagnosis of COPD, an age of 40 years or more, a smoking history of at least 10 pack‐years, a post‐bronchodilator FEV1 of 70% or less of the predicted value, and an FEV1 of 70% or less of the FVC (after supervised administration of 80 mcg of ipratropium (four actuations), followed by 400 mcg of albuterol (four actuations) 60 minutes later) Exclusion Criteria: a history of asthma, a COPD exacerbation or respiratory infection within four weeks before screening, a history of pulmonary resection, use of supplemental oxygen for more than 12 hours per day, and the presence of a coexisting illness that could preclude participation in the study or interfere with the study results
Interventions	1. 18 mcg of tiotropium once daily 2. A matching placebo once daily Inhaler device: dry powder inhaler Co‐medication: all respiratory medications, except other inhaled anticholinergic drugs, were permitted during the trial
Outcomes	Primary: yearly rate of decline in the mean FEV1 before the use of a study drug and short‐acting bronchodilators in the morning (pre‐bronchodilator) and after the use of a study drug (post‐bronchodilator) from day 30 (steady state) until completion of double‐blind treatment Secondary: rate of decline in the mean FVC and SVC, health‐related quality of life, as measured by the total score on SGRQ, exacerbations of COPD and related hospitalisations; and the rate of death from any cause and from lower respiratory conditions
Notes	Funding: Boehringer Ingelheim Study number: Boehringer Ingelheim 205.235, ClinicalTrials.gov NCT00144339 Definitions: exacerbations were defined as an increase in or the new onset of more than one respiratory symptom (cough, sputum, sputum purulence, wheezing, or dyspnoea) lasting three days or more and requiring treatment with an antibiotic or a systemic corticosteroid
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Randomly assigned in a 1:1 ratio to receive either tiotropium or placebo with the use of centralised randomisation in blocks of four, stratified according to site. The randomisation list will be generated using a validated system, which involves a pseudo‐random number generator so that the resulting treatment sequence will be both reproducible and non‐predictable
Allocation concealment (selection bias)	Low risk	An Interactive Voice Response System will be used for patient randomisation and drug supply management. Each site will be provided with a telephone number (with 24‐hour access) and password that will connect them to a series of instructions on how to assign a medication kit to a patient
Blinding of participants and personnel (performance bias) All outcomes	Low risk	Blinding of the study drugs will be such that the treatments will be indistinguishable
Blinding of outcome assessment (detection bias) All outcomes	Low risk	An independent data and safety monitoring committee reviewed data throughout the trial. A mortality adjudication committee evaluated the primary cause of death from blinded data
Incomplete outcome data (attrition bias) All outcomes	High risk	The withdrawal rates were high (tiotropium 36.8%, placebo 45.2%). However, data regarding vital status were systematically requested for patients who prematurely discontinued study participation on a recorded date determined as four years from the first day of administration of a study drug
Selective reporting (reporting bias)	Low risk	Results for all specified outcomes were reported