Moita 2008.

Methods	Design: a randomised, double‐blind, parallel‐group, placebo‐controlled study with 12 weeks treatment duration, conducted at 31 centres in Portugal
Participants	Population: 311 patients with COPD, as defined by ATS guidelines were randomised to tiotropium (147) and placebo (164) Baseline Characteristics: mean age 64 years, 95% male, mean FEV1 1.2 L, mean FEV1 predicted 38% to 44%, 54 to 60 pack‐years smoking history Inclusion Criteria: males or females aged ≥ 40 years with a diagnosis of COPD (FEV1 ≤ 70% of predicted and FEV1/FVC ≤ 70%) and a smoking history of ≥ 10 pack‐years were eligible for inclusion Exclusion Criteria: patients were not included if they had a history of asthma, allergic rhinitis, atopy, myocardial infarction, unstable arrhythmia, or if they had any clinically significant disease that might put the patient at risk because of study participation. Patients with > 3 exacerbations of COPD in the preceding year or an exacerbation or lower respiratory tract infection within the six weeks prior to randomisation were also excluded
Interventions	1. Tiotropium 18 mcg once daily 2. Placebo once daily Inhaler device: dry powder inhaler Co‐medication: concomitant use of prn salbutamol MDI (100 mg/puff; withheld for at least 6 hours prior to each clinic visit), LABAs and continued use of theophylline preparations (excluding 24 hour preparations) (both withheld for at least 24 hours prior to each clinic visit) were allowed during the study period. Concomitant use of mucolytics, orally ICS, minimal doses of oral corticosteroids (equivalent to prednisone ≤ 10 mg/day or ≤ 20 mg/alternate days) were allowed if the dosage was stabilised for at least six weeks before the study. Temporary increases in the dose of theophylline preparation of ≤ 7 days or addition/increased dose of oral steroids for ≤ 2 weeks were allowed for the treatment of an exacerbation during the study period. If appropriate, scheduled visits were postponed for at least one week, but not more than two weeks. Use of antibiotics was not restricted. Short‐acting anticholinergics, oral beta2‐agonists, antileukotrienes, and other investigational drugs were not allowed during the study
Outcomes	Primary: change in trough FEV1 after 12 weeks of treatment Secondary: trough FEV1 after six weeks of treatment, trough FVC after 6 and 12 weeks of treatment, assessment of COPD symptoms, Physician's Global Evaluation, Quality of Life Questionnaire (EQ‐5D) and use of daytime and night‐time rescue medication (salbutamol MDI 100 mcg/puff). Rescue medication use, cigarette consumption and drug compliance were recorded in patient diary cards. Adverse events were collected throughout the study
Notes	Funding: Boehringer Ingelheim Study number: Boehringer Ingelheim 205.282, ClinicalTrials.gov NCT00239408 Definitions: an exacerbation was defined as an increase or new onset of more than one of the following respiratory symptoms (cough, sputum, sputum purulence, wheezing, dyspnoea) with a duration of three or more days requiring treatment with antibiotics and/or systemic (oral, intramuscular or intravenous) steroids
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	Low risk	The withdrawal rates were low and even (tiotropium 7.5%, placebo 6.7%)
Selective reporting (reporting bias)	Low risk	Results for all specified outcomes were reported