Maltais 2011.

Methods	Study design: randomised, double‐blind, parallel group, phase III study Study duration: six weeks Run‐in: two weeks Setting: multicentre trial Number of study centres and location: 52 study sites (42 sites in the United States and 10 additional sites in Canada) Date of study: July 2007 to October 2007 Randomisation: yes Blinding: double‐blind (subject, investigator, outcomes assessor) Withdrawals: stated
Participants	Number screened: 587 Number randomised: 181 Number in treatment group: 86 Number in control group: 95 Number of withdrawals (treatment/control): 5/17 Number completing trial (treatment/control): 81/78 Mean age (years) (treatment/control): 64.0/65.6 Gender (male/female): 52/34 (treatment), 53/42 (control) Caucasian (%) (treatment/control): 96.5/96.8 Inclusion criteria: males and females ≥ 40 years, current and ex‐smokers with a smoking history ≥ 10 pack‐years, clinical diagnosis of moderate to severe stable COPD (post‐bronchodilator FEV1/FVC < 70% and FEV1 ≥ 30% and < 80% predicted), functional residual capacity (FRC) ≥ 120% predicted at screening, and Baseline Dyspnoea Index (BDI) focal score ≤ seven Exclusion criteria: previous hospitalisation for an acute COPD exacerbation ≤ three months pre‐screening, or respiratory tract infection or COPD exacerbation six weeks pre‐screening, history of asthma, allergic rhinitis or atopy, contraindications to clinical exercise testing according to the American Thoracic Society (2003), cycled ≥ 20 min during constant work‐rate exercise tests during run‐in or participated in current or previous COPD rehabilitation programs ≤ six weeks pre‐randomisation Baseline characteristics of treatment/control groups: comparable
Interventions	Intervention: inhaled aclidinium 200 μg once‐daily via a multidose dry powder inhaler (Genuair) Comparison: placebo once‐daily As‐needed therapy: levalbuterol (US) or salbutamol (Canada) was allowed ≥ six hours before each visit Concomitant medications: inhaled, oral or parenteral corticosteroids at doses ≤ 10 mg/day or 20 mg every other day were allowed if use was stable ≥ four weeks before screening. No other COPD medications were allowed. Oxygen therapy was allowed ≤ 15 hours/day but not within two hours of study visits
Outcomes	Primary outcomes: change in exercise tolerance from baseline to week six Secondary outcomes: changes in exercise tolerance from baseline to day one (randomisation) and week three, and changes in trough FEV1, IC, FRC, IC/TLC from baseline to day one, week three and week six Other outcomes: changes from baseline in exercise measures of Inspiratory capacity (IC) and breathing pattern, dyspnoea and leg discomfort Time points: pulmonary function tests and cycle ergometry performed at study visits (screening, run‐in, randomisation, weeks three and six)
Notes	Full text publication Source of funding: Forest Laboratories, Inc. and Almirall, SA Study number: ClinicalTrials.gov NCT00500318
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Quote (from correspondence): "a computer generated randomisation schedule was prepared to assign a treatment sequence to a randomisation number. The block size was determined in agreement with the clinical trial manager and the statistician and was not to be communicated to the investigators"
Allocation concealment (selection bias)	Low risk	Quote (from correspondence): "IVRS (or IWRS in some cases) was used to sequentially randomise patients to the intervention arms according to the randomisation ratio and the block size determined as mentioned above"
Blinding of participants and personnel (performance bias) Aclidinium versus placebo	Low risk	Double‐blind (subject and investigator) Quote (from correspondence): "matching placebo of aclidinium bromide had the same external appearance with the same composition, except for the active ingredient. Blinding was applicable for all study outcomes"
Blinding of outcome assessment (detection bias) All outcomes	Low risk	Double‐blind including blinding of outcomes assessor
Incomplete outcome data (attrition bias) All outcomes	Unclear risk	Comment: dropout was three times higher for placebo arm (aclidinium 5.8%, placebo 17.9%). Analyses of efficacy endpoints and safety outcomes were performed on the intent‐to‐treat (ITT) population, defined as patients who received one dose of study drug and with a baseline value and one post‐baseline assessment of exercise tolerance. However, no clear information on the method of imputation for the missing data
Selective reporting (reporting bias)	Low risk	Comment: study protocol was not available, but the published reports included all pre‐specified outcomes
Other bias	Low risk	Comment: no apparent source of bias was observed