ACCLAIM/COPD II.

Methods	Study design: double‐blind, randomised, placebo‐controlled, parallel‐group, phase III study Study duration: 52 weeks Run‐in: 14 days Setting: multicentre trial Number of study centres and location:119 sites in seven countries (72 sites in the United States, 13 sites in Argentina, 13 sites in Australia, seven sites in Canada, two sites in Mexico, three sites in New Zealand and nine sites in South Africa) Date of study: August 2006 to June 2008 Randomisation: yes Blinding: double‐blind (subject, investigator) Withdrawals: stated
Participants	Number screened: 1456 Number randomised: 804 Number in treatment group: 600 (inhaled aclidinium 200 μg once daily) Number in control group: 204 Number of withdrawals (treatment/control): 154/86 Number completing trial (treatment/control): 446/118 Mean age (years) (treatment/control): 65.1/65.2 Gender (male/female): 383/217 (treatment), 124/80 (control) Caucasian (%) (treatment/control): 92/92.7 Inclusion criteria: male and non‐pregnant, non‐lactating female patients aged ≥ 40 years with a diagnosis of COPD according to GOLD criteria, with a post‐bronchodilator FEV1/FVC ratio of ≤ 70% and FEV1 < 80% of the predicted value. The pre‐dose FEV1 at randomisation within 80‐120% of the pre‐bronchodilator FEV1 at screening. Current or previous cigarette smokers with a smoking history of ≥ 10 pack‐years Exclusion criteria: history or current diagnosis of asthma, allergic rhinitis or atopy; blood eosinophil count > 600 cell/mm3; respiratory tract infection or COPD exacerbation within six weeks prior to screening or during the run‐in period; hospitalisation for an acute COPD exacerbation within three months prior to screening; use of long‐term oxygen therapy; clinically significant respiratory diseases other than COPD; unstable cardiac conditions Baseline characteristics of treatment/control groups: comparable
Interventions	Intervention: aclidinium 200 μg once daily via the Genuair inhaler Comparison: matching placebo once daily via the Genuair inhaler As‐needed therapy: inhaled salbutamol was permitted on as‐needed basis, but had to be discontinued six hours prior to and during a study visit Concomitant medications: inhaled corticosteroids or oral sustained‐release theophyllines; oral or parenteral corticosteroids at maximal doses equivalent to 10 mg/day of prednisone or 20 mg every other day; oxygen therapy (less than 15 hours per day) were allowed if the dosage had been stable for at least four weeks prior to screening Definition of COPD exacerbations: an increase in COPD symptoms over at least two consecutive days, associated with increased use of bronchodilators (mild exacerbation), treatment with antibiotics and/or systemic corticosteroids (moderate exacerbation) or leading to hospitalisation (severe exacerbation)
Outcomes	Primary outcomes: trough FEV1 at weeks 12 and 28 Secondary outcomes: number of patients who achieved a clinically relevant improvement in health‐related quality of life at 52 weeks, as measured by a ≥ four units decrease from baseline on the SGRQ total score; and time to first moderate or severe COPD exacerbation Time points: spirometry was conducted according to American Thoracic Society (ATS)/European Respiratory Society (ERS) recommendations at one hour pre‐dose and immediately before dosing during study visits on day one (baseline); day two; week one; every month up to week 20; and thereafter every two months until week 52. Measurements were also performed at 0.25, 0.5, 1, 2 and 3 hours post‐dose on day one; and at 0.5, 1, 2 and 3 hours post‐dose at weeks 1, 4, 8, 12, 28, 44 and 52. Health status and dyspnoea were evaluated pre‐dose on day one (baseline) and at weeks 12, 28, 44 and 52 using the St George’s Respiratory Questionnaire (SGRQ; self administered) and Baseline/Transitional Dyspnoea Index (BDI/TDI; administered by an independent reviewer)
Notes	Full text publication Source of funding: Almirall, SA, Barcelona, Spain, and Forest Laboratories, Inc, NY, USA Study number: ClinicalTrials.gov NCT00358436
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	Quote (from report): "spirometry data were electronically transmitted to a data‐management centre where an independent, blinded, spirometric expert reviewed the acceptability and repeatability of the data. Dyspnoea was evaluated using baseline/transitional dyspnoea index (BDI/TDI) administered by an independent reviewer"
Incomplete outcome data (attrition bias) All outcomes	Low risk	Comment: dropout was higher in the placebo group (aclidinium 25.7% and placebo 42.2%) but efficacy analyses and safety summaries were performed on the intent‐to‐treat population, comprising all randomised patients who received at least one dose of study medication and who had a baseline and at least one post‐baseline trough FEV1 measurement Quote (from report): "missing data were imputed using a last observation carried forward approach"
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