Beier 2013.

Methods	Study design: randomised, double‐blind, double‐dummy, placebo‐ and active comparator‐controlled, parallel‐group, phase IIIb study Study duration: six weeks Run‐in: two to three weeks Setting: multicentre trial Number of study centres and location: 49 study sites in four countries (three sites in the Czech Republic, 23 in Germany, eight in Hungary and 15 in Poland) Date of study: October 2011 to March 2012 Randomisation: yes Blinding: double‐blind (subject, investigator) Withdrawals: stated
Participants	Number screened: 485 Number randomised: 414 Number in treatment group: 171 (aclidinium 400 μg twice daily), 158 (tiotropium 18 μg once daily) Number in control group: 85 Number of withdrawals (treatment/control): 5 (aclidinium 400 μg twice daily), 4 (tiotropium 18 μg once daily)/5 Number completing trial (treatment/control): 166 (aclidinium 400 μg twice daily), 154 (tiotropium 18 μg once daily)/80 Mean age (years): 61.8 (aclidinium 400 μg twice daily), 62.8 (tiotropium 18 μg once daily), 62.2 (placebo) Gender (male/female): 114/57(aclidinium 400 μg twice daily), 116/42 (tiotropium 18 μg once daily), 48/37 (placebo) Caucasian (%): 100 (aclidinium 400 μg twice daily), 100 (tiotropium 18 μg once daily), 98.8 (placebo) Inclusion criteria: patients aged ≥ 40 years with a clinical diagnosis of stable moderate‐to‐severe COPD (post‐bronchodilator FEV1/FVC < 70%, and FEV1 ≥ 30% and < 80%), either current or former cigarette smokers (smoking history of ≥ 10 pack‐years) Exclusion criteria: history or current diagnosis of asthma or other clinically significant respiratory or cardiovascular conditions, any respiratory tract infection or COPD exacerbation ≤ six weeks before screening (≤ three months if hospitalisation), contraindications and hypersensitivity to muscarinic antagonists and inability to use the study inhalers properly Baseline characteristics of treatment/control groups: comparable
Interventions	Intervention: aclidinium bromide 400 μg twice daily in the morning (9:00 ± 1 hour) and evening (21:00 ± 1 hour) via the Genuair/Pressair multidose dry powder inhaler, tiotropium 18 μg once daily in the morning (9:00 ± 1 hour) via the HandiHaler Comparison: matched placebo As‐needed therapy: inhaled salbutamol 100 μg/puff was permitted except ≤ six hours before each visit Concomitant medications: stable use of oral sustained‐release theophylline (not other methylxanthines), inhaled corticosteroids and oral or parenteral corticosteroids (prednisone ≤ 10 mg/day or 20 mg/every other day, or equivalent) were permitted except ≤ six hours before each visit. Oxygen therapy (except ≤ two hours before each visit) was also allowed
Outcomes	Primary outcomes: change from baseline in normalized FEV1 area under the curve over the 24‐hour period post‐morning dose (AUC0–24) at week six Secondary outcomes: change from baseline in normalized FEV1 AUC over the nighttime period (AUC12–24) at week six Other outcomes: changes from baseline in normalized FEV1 AUC for the 12‐hour period post‐morning treatment (AUC0–12), morning predose (trough) and peak FEV1 and FVC Time points: spirometry was conducted according to American Thoracic Society (ATS)/European Respiratory Society (ERS) recommendations over 24 hours following morning treatment on day one and at week six. Three manoeuvres were performed at each time point. Additional measurements (up to a total of eight tests) were made if the first three were not acceptable
Notes	Full text publication Source of funding: Almirall, SA, Barcelona, Spain, and Forest Laboratories, Inc, New York, USA Study number: ClinicalTrials.gov NCT01462929
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Quote (from report): "random sequence generation was by computer‐generated schedule" 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 report): "allocation via an interactive voice‐response system" 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), double‐dummy Quote (from report): "patients and study personnel remained blinded to treatment allocation throughout the study" 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, double‐dummy
Incomplete outcome data (attrition bias) All outcomes	Low risk	Comment: number of withdrawals and reasons were clearly mentioned for intervention and placebo arms Withdrawals were low and balanced across the groups (aclidinium 2.9%, tiotropium 2.5%, placebo 5.9%). Efficacy analyses and safety summaries were based on the intent‐to‐treat population, which included 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 value Quote (from report): "no patients were lost to follow‐up"
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