ACCORD COPD II.

Methods	Study design: randomised, double‐blind, placebo‐controlled, parallel group, phase III study Study duration: 12 weeks Run‐in: two weeks Follow‐up: phone call or visit two weeks after the last study treatment dose Setting: multicentre trial Number of study centres and location: 103 study centres (101 in the United States and two in Canada) Date of study: December 2009 to September 2010 Randomisation: yes Blinding: double blind (subject, caregiver, investigator, outcomes assessor) Withdrawals: stated
Participants	Number screened: 1236 Number randomised: 544 Number in treatment group: 184 (Inhaled aclidinium 200 μg twice daily), 178 (Inhaled aclidinium 400 μg twice daily) Number in control group:182 Number of withdrawals (treatment/control): 29 (200 μg), 30 (400 μg)/31 Number completing trial (treatment/control): 155 (200 μg), 148 (400 μg)/151 Mean age (years): 63.4 (200 μg), 63.2 (400 μg), 61.7 (control) Gender (male/female): 100/82 (200 μg), 99/84 (400 μg), 89/88 (control) Caucasian (%): 89.1 (200 μg), 90.4 (400 μg), 92.3 (control) Inclusion criteria: male and female patients ≥ 40 years old, current or former cigarette smokers with a smoking history of ≥ 10 pack‐years and diagnosed with stable moderate‐to‐severe COPD according to GOLD guidelines (post‐bronchodilator FEV1/FVC < 70% and FEV1 ≥ 30% and < 80% of predicted) Exclusion criteria: COPD exacerbation requiring hospitalisation ≤ three months before screening, respiratory tract infection or COPD exacerbation ≤ six weeks before screening, other clinically significant respiratory condition including asthma, clinically significant cardiovascular conditions including myocardial infarction ≤ six months or newly diagnosed arrhythmia ≤ three months before screening, history of hypersensitivity reaction or contraindications to inhaled anticholinergics Baseline characteristics of treatment/control groups: percentage of severe (GOLD stage III) patients: 46.4% (aclidinium 200 μg), 54.2% (aclidinium 400 μg), 36.8% (placebo) baseline mean FEV1 (L): 1.40 (aclidinium 200 μg), 1.25 (aclidinium 400 μg), 1.46 (placebo)
Interventions	Intervention: inhaled aclidinium 200 μg twice daily, inhaled aclidinium 400 μg twice daily via a multiple‐dose dry powder inhaler (Genuair/Pressair) Comparison: inhaled placebo twice daily As‐needed therapy: albuterol (salbutamol) was permitted as rescue medication but was discontinued ≥ six hours before study visits Concomitant medications: theophylline, inhaled corticosteroids (ICS), oral or parenteral corticosteroids equivalent to ≤ 10mg/day of prednisone or 20 mg every other day were allowed if treatment was stable for ≥ four weeks before screening. These medications were discontinued ≥ six hours before each study visit Other short/long acting anticholinergics and LABAs were prohibited throughout the study
Outcomes	Primary outcomes: change in morning pre‐dose (trough) FEV1 from baseline to week 12 Secondary outcomes: change in peak FEV1 (maximum FEV1 reading observed ≤ three hours post‐morning dose) from baseline to week 12 Other outcomes: changes from baseline in morning trough and peak FEV1 at day one (peak FEV1 only) and weeks 1, 4, and 8. Changes from baseline in FEV1 at 0.5‐3 hour post‐dose and area under the concentration‐time curve from 0 to 3 hour normalized over 3 hour (AUC0‐3/3h), FVC (trough, peak), and IC (trough, three hours post‐dose) at day one (except for trough) and weeks 1, 4, 8 and 12. Changes from baseline in SGRQ score at weeks 4, 8 and 12 and TDI at week 12, percentage of patients with a minimal clinically important differences from baseline in SGRQ (decrease of ≥ four points) or TDI (increase of ≥ one unit) at study end
Notes	Full text publication Source of funding: Almirall, SA, Barcelona, Spain, and Forest Laboratories, Inc, NY, USA Study number: ClinicalTrials.gov NCT01045161
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, caregiver 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	Low risk	Comment: number of withdrawals were low and even across the groups with similar reasons (aclidinium 200 μg 15.8%, aclidinium 400 μg 16.9% and placebo 17%). Efficacy analyses and safety summaries were based on the intent‐to‐treat population, defined as all randomised patients who received at least one dose of double blind study medication and who had a baseline and at least one post‐baseline trough FEV1 assessment. Quote (from report): "missing data were imputed by the last‐observation‐carried‐forward approach"
Selective reporting (reporting bias)	Low risk	Comment: study protocol was not available, but the published report included all pre‐specified outcomes
Other bias	Low risk	Comment: no apparent source of bias was observed Relatively higher percentage of severe COPD patients were recruited in aclidinium 400 μg arm than placebo, however sensitivity analysis by exclusion of this study data had no significant change on the overall effect estimates