Bateman 2010b.

Methods	Design: two identical multicenter, randomized, double‐blind, parallel‐group studies Duration: 48 weeks (+ 2 week run‐in) Location: 73 centres in 14 countries (NCT00168844) , and 78 in 15 countries (NCT00168831)
Participants	Population: 1990 participants were randomised to two doses of tiotropium (670 and 665), and placebo (653) Baseline characteristics Age (mean years): tio5 64.7, tio10 65.1, pbo 65.2 % Male: tio5 73.3, tio10 74.7, pbo 74.6 % FEV1 predicted: tio5 38.0, tio10 37.7, pbo 37.5 Pack‐years (mean): not reported Inclusion criteria: Males and females aged > 40 years with a diagnosis of COPD and stable, moderate‐to‐severe airway obstruction as defined by the American Thoracic Society (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 β‐adrenergics, or long‐acting β‐adrenergics; or significant alcohol or drug abuse.
Interventions	1. Tiotropium 5 qd (LAMA) 2. Tiotropium 10 qd (LAMA) 3. Placebo (PBO) Inhaler device: Respimat® Soft Mist Inhaler Allowed co‐medications: Oral (up to 10 mg daily of prednisone) and inhaled corticosteroids, theophylline preparations, mucolytic agents and antileukotrienes were allowed if stabilized for at least 6 weeks prior to and during the study. Patients on long‐acting β‐adrenergics and inhaled corticosteroids were switched to a monoproduct inhaled corticosteroid prior to run‐in. Salbutamol MDI was used as rescue medication
Outcomes	Trough FEV1, St George's Respiratory Questionnaire (SGRQ)< Mahler Transition Dyspnoea Index (TDI) focal score, exacerbations per patient year, FVC, PEF, diary card data and safety.
Notes	Funding: Boehringer Ingelheim Identifier(s): BI 205.254 and 205.255, corresponding to NCT00168844 and NCT00168831 respectively
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Allocation described as randomised in the reports and on clinicaltrials.gov. Methods not described, but industry funded.
Allocation concealment (selection bias)	Unclear risk	Not described
Blinding of participants and personnel (performance bias) All outcomes	Low risk	Double‐blind. Not defined, assumed at least participants and personnel
Blinding of outcome assessment (detection bias) All outcomes	Unclear risk	Not described
Incomplete outcome data (attrition bias) All outcomes	High risk	Only those patients with baseline and on‐treatment data for at least one primary endpoint were included in the efficacy analyses. Randomized patients who received at least 1 dose of study medication were included in the safety analysis. The primary article stated that the data reported were the per protocol analysis. Dropout was much higher in the placebo group (31.4%) than the two tiotropium groups (17.2% and 20.4%).
Selective reporting (reporting bias)	Low risk	Studies were prospectively registered and results were well reported.