Bateman 2010b.

Methods	Design: two identical, multicentre, multinational, randomised, double‐blind, parallel‐group studies. The run‐in phase was two weeks and the duration of treatment was 48 weeks, recruitment for the studies took place from January 2003 to December 2005
Participants	Population: 1990 patients with COPD, as defined by ATS guidelines, were randomised to tiotropium 5 mcg (670), tiotropium 10 mcg (667), and placebo (653) Baseline Characteristics: mean age 65 years, 74% male, mean FEV1 1.06 L, mean FEV1 predicted 38%, 48 pack‐years smoking history Inclusion Criteria: males and females aged ≥ 40 years with a diagnosis of COPD and stable, moderate‐to‐severe airway obstruction (pre‐bronchodilator FEV1 ≤ 60% predicted and FEV1 ≤ 70% of FVC), and with a smoking history of ≥ 10 pack‐years were included Exclusion Criteria: patients with a confounding disease, including other significant respiratory conditions, were excluded, as were those who had a disease that might put them at risk because of study participation. Other exclusion criteria included known hypersensitivity to anticholinergics or any component of the Respimat inhalation solution; drugs contraindicated with anticholinergics; prior use of Spiriva HandiHaler; regular use of daytime oxygen therapy, oral beta‐adrenergics, or LABAs; or significant alcohol or drug abuse
Interventions	1. Orally inhaled tiotropium 5 mcg, 2 actuations of 2.5 mcg tiotropium once daily in the morning 2. Orally inhaled tiotropium 10 mcg, 2 actuations of 5 mcg tiotropium once daily in the morning 3. 2 actuations of placebo inhalation solution once daily in the morning Inhaler device: soft mist inhaler Co‐medication: oral (up to 10 mg daily of prednisone) and ICS, theophylline preparations, mucolytic agents and antileukotrienes were allowed if stabilised for at least six weeks prior to and during the study. Patients on LABAs and ICS were switched to a monoproduct ICS prior to run‐in. Salbutamol metered‐dose inhaler (MDI) was used as rescue medication
Outcomes	Primary: there were 4 co‐primary endpoints for both studies: the trough FEV1 response at week 48 (24‐hour postdose FEV1 expressed as change from study baseline predose FEV1) SGRQ total score at the end of the 48‐week treatment period the Mahler TDI focal score after 48 weeks of treatment COPD exacerbations per patient‐year the exacerbation endpoints in the study included: the patients (%) with at least 1 COPD exacerbation the number of exacerbations per patient‐year of treatment the time to first COPD exacerbation Secondary: secondary endpoints included FVC, peak expiratory flow rate (PEFR) and weekly mean number of occasions (per day as needed) that rescue medication was used. COPD symptom scores (wheezing, shortness of breath, coughing, and tightness of chest) were based on the investigator’s assessment of the patient’s condition during the week just prior to the clinic visit. The Physician's Global Evaluation, was based on the physician’s opinion of the patient’s overall clinical condition, and the Patient's Global Rating, was performed by the patients. Detailed information on exacerbations and COPD exacerbation‐related hospitalisations were recorded. Clinical efficacy measures, including spirometry and health‐related quality of life (HRQoL), patient diary cards information (predose and evening PEFR, occasions of rescue medication use, and drug compliance, i.e. whether treatment was taken or not) were measured throughout the 48‐week treatment period
Notes	Funding: Boehringer Ingelheim Study number: Boehringer Ingelheim 205.254 / 205.255, ClinicalTrials.gov NCT00168844 / NCT00168831 Definitions: exacerbation defined as respiratory adverse events lasting ≥3 days and requiring treatment with antibiotics and/or oral corticosteroids and/or a significant change in prescribed respiratory medication including inhaled bronchodilators. Note: all‐cause mortality included patients who had discontinued the study. Cardiovascular safety was monitored in a subset of patients using 12‐lead electrocardiogram (ECG) and Holter monitoring
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	High risk	The withdrawal rates were relatively large and uneven (tiotropium 5 mcg 17.2%, tiotropium 10 mcg 20.4%, placebo 31.4%). However, information on vital status was collected for all patients, including patients who discontinued prematurely
Selective reporting (reporting bias)	Low risk	Data for cardiovascular safety not reported. All other specified outcomes were reported