Johansson 2008.

Methods	Design: randomised, double‐blind, parallel‐group study with 12 weeks treatment duration, conducted at 27 centres in Sweden from March 2004 to July 2005
Participants	Population: 224 patients with COPD, as defined by GOLD guidelines, were randomised to tiotropium (107) and placebo (117) Baseline Characteristics: mean age 62 years, 43% to 53% male, mean FEV1 2.1 L, mean FEV1 predicted 73%, 31 pack‐years smoking history Inclusion Criteria: outpatients aged > 40 years old with a diagnosis of mild COPD by 2003 Swedish guidelines (post‐bronchodilator FEV1/FVC < 70% and FEV1 > 60% predicted); smoking history of > 10 pack‐years; and a Medical Research Council dyspnoea score of > 2 Exclusion Criteria: history of asthma, allergic rhinitis or atopy; blood eosinophil count > 600/mm3; recent lower respiratory tract infection or any exacerbation (within the previous six weeks); recent history of myocardial infarction (within the previous six months); unstable cardiac arrhythmia; regular use of oxygen therapy; use of oral or inhaled steroids (within the previous three months); and significant diseases other than COPD
Interventions	1. Tiotropium 18 mcg once daily in the morning 2. Placebo once daily in the morning Inhaler device: dry powder inhaler Co‐medication: patients were permitted salbutamol MDI as rescue medication, as‐needed, for acute symptom relief, with an 8‐hour washout period before spirometry. Use of short‐acting anticholinergics, beta2‐agonists (other than rescue medication), oral or ICS, or theophylline, was not permitted. However, to treat COPD exacerbations, investigators could prescribe antibiotics and oral corticosteroids (for < 2 weeks) or theophylline (for ≤ 7 days)
Outcomes	Primary: change in FEV1 area under the curve from predose (zero time) to 2 hours postdose (AUC0‐2 h), from baseline to 12 weeks Secondary: FEV1 and FVC trough responses, use of rescue medication, adverse events, dyspnoea BDI, Medical Research Council dyspnoea scale, HRQL (generic European Quality of Life Questionnaire, EuroQol (EQ‐5D and VAS), use of rescue medication, adverse events, COPD exacerbations
Notes	Funding: Boehringer Ingelheim Study number: Boehringer Ingelheim 205.281, ClinicalTrials.gov NCT00144196 Definitions: an exacerbation of COPD is a complex of COPD‐related respiratory symptoms (increase or new onset) of a duration of at least three days, usually requiring treatment with systemic corticosteroids or antibiotics. COPD‐related respiratory symptoms consist of more than one of the following: cough, wheeze, dyspnoea, chest congestion, shortness of breath, chest tightness, or sputum production
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 (tiotropium 1.9%, placebo 3.4%)
Selective reporting (reporting bias)	Low risk	Results for all specified outcomes were reported