Covelli 2005.

Methods	Design: a randomised, double‐blind, placebo‐controlled, parallel‐group trial with 12 weeks treatment duration, conducted at 12 sites in the USA between July 2003 and March 2004
Participants	Population: 196 patients with COPD were randomised to tiotropium (100) and placebo (96) Baseline Characteristics: mean age 65 years, 47% to 66% male, mean FEV1 1.0 L, mean FEV1 predicted 39%, 66 pack‐years smoking history Inclusion Criteria: patients included in the study had a clinical diagnosis of COPD, were at least 40 years of age, and had a smoking history of at least 10 pack‐years. Patients were required to have a FEV1 of 60% or less of predicted normal and a FVC of 70% or less Exclusion Criteria: patients with significant disease other than COPD were excluded. Significant disease was defined as a disease or a condition that, in the opinion of the investigator, may put the patient at risk because of participation in the study, or may influence either the results of the study or the patient’s ability to participate in the study. Patients also were excluded if they had a history of asthma or atopy, had abnormal liver enzyme levels or evidence of chronic renal dysfunction, or had experienced a respiratory tract infection or COPD exacerbation within six weeks of randomisation. In addition, patients were excluded if they were taking systematic corticosteroids at unstable dosages or prednisone 10 mg/day or greater (or its equivalent), or were using oxygen for more than 12 hours/day. Patients with pre‐existing cardiovascular disease were permitted to participate in the trial unless they had experienced myocardial infarction within the preceding six months, hospitalisation for heart failure within the preceding year, or life threatening arrhythmias requiring intervention or change in drug therapy within the last year
Interventions	1. 18 mcg tiotropium 2. Matching placebo Inhaler device: dry powder inhaler Co‐medication: during the study, treatment with respiratory drugs such as ICS, both SABAs and LABAs, and theophyllines was permitted; however, treatment with cromones, leukotriene antagonists, and inhaled anticholinergics was not permitted
Outcomes	ECG, Holter Monitoring Primary: morning trough FEV1 after 12 weeks of treatment (day 84) Secondary: predose FEV1 on day 56 and FVC on days 56 and 84, postdose FEV1 (90 min) and FVC on all test days, patient and physician global COPD ratings, scores on the EuroQol Health Questionnaire (EQ‐5D), and treatment with rescue medication
Notes	Funding: Boehringer Ingelheim Study number: Boehringer Ingelheim 205.284, ClinicalTrials.gov NCT00239460
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	A third‐party Interactive Voice Response System was used to randomise patients via a unique randomisation number to study drug medication
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	Withdrawal rates were relatively low, but uneven (tiotropium 10%, placebo 17%)
Selective reporting (reporting bias)	Unclear risk	For quality of life the results were only described but no data presented