Chanez 2010.

Methods	Study design: randomised, parallel‐group, double‐blind (open‐label for patients randomised to tiotropium), phase IIb study Study duration: four weeks Run‐in: two weeks Setting: multicentre trial Number of study centres and location: 42 centres in Europe and Russia Randomisation: yes Blinding: double‐blind (open label for patients randomised to tiotropium) Withdrawals: stated
Participants	Number screened: 694 Number randomised: 464 Number in treatment group: 66 (aclidinium 25 μg), 65 (aclidinium 50 μg), 70 (aclidinium 100 μg), 67 (aclidinium 200 μg), 67 (aclidinium 400 μg), 65 (tiotropium 18 μg) Number in control group: 64 Number of withdrawals (treatment/control): 4 (aclidinium 25 μg), 3 (aclidinium 50 μg), 3 (aclidinium 100 μg), 3 (aclidinium 200 μg), 3 (aclidinium 400 μg), 4 (tiotropium 18 μg)/3 Number completing trial (treatment/control): 62 (aclidinium 25 μg), 62 (aclidinium 50 μg), 67 (aclidinium 100 μg), 64 (aclidinium 200 μg), or 64 (aclidinium 400 μg), 61 (tiotropium 18 μg)/61 Mean age (years): 60.4 (aclidinium 25 μg), 61.1 (aclidinium 50 μg), 61.6 (aclidinium 100 μg), 62.1 (aclidinium 200 μg), 62.0 (aclidinium 400 μg), 62.2 (tiotropium 18 μg), 61.2 (placebo) Gender (male/female): 49/16 (aclidinium 25 μg), 47/18 (aclidinium 50 μg), 54/15 (aclidinium 100 μg), 57/9 (aclidinium 200 μg), 53/14 (aclidinium 400 μg), 56/8 (tiotropium 18 μg), 55/9 (placebo) Ethnicity: not stated Inclusion criteria: male and female patients ≥ 40 years with a diagnosis of stable moderate to severe COPD according to American Thoracic Society criteria with a smoking history of ≥ 10 pack‐years, and FEV1 in the range of 30–65% of predicted normal (Quanjer predicted normal value) at the screening visit; pre‐dose FEV1 at the randomisation visit within 20% of the screening visit value. The ratio between FEV1 and FVC was required to be ≤ 70% at both the screening visit and randomisation visit Exclusion criteria: history of or current asthma, allergic rhinitis, or atopy; reversibility to inhaled salbutamol 400 mg > 20% of pre‐dose value; blood eosinophil count > 400 cells/mm3; respiratory tract infection or COPD exacerbation within one month (or hospitalisation within three months) of the screening visit; clinically significant or relevant cardiovascular conditions, laboratory tests, or electrocardiogram (ECG) parameters; QTc interval > 450 ms; history of narrow‐angle glaucoma, symptomatic prostatic hypertrophy, or bladder neck obstruction Baseline characteristics of treatment/control groups: comparable
Interventions	Intervention: inhaled aclidinium 25 μg, 50 μg, 100 μg, 200 μg, or 400 μg (via multidose dry‐powder inhaler, Genuair) or tiotropium 18 μg (via Handi‐Haler) once daily in the morning between 08.00 and 12.00 Comparison: matching placebo once daily As‐needed therapy: salbutamol 100 mg/puff was allowed as rescue medication, and was discontinued for eight hours prior to any visit Concomitant medications: inhaled corticosteroids, oral sustained release theophyllines (suspended at least 48 hours before each study visit), antihistamines, nedocromil, and ketotifen was permitted, provided the stable dose was administered prior to randomisation. The morning dose of these medications was delayed until the completion of spirometry measurements at each visit. Any other medication used for the treatment of COPD was withdrawn prior to the start of the study, and medications with pro‐arrhythmic effects or that affect heart rate or QTc were not permitted
Outcomes	Primary outcomes: trough FEV1 (the mean value of the three highest readings assessed at 22, 23, and 24 hour following the trial drug administration) on day 29 for aclidinium (all doses) versus placebo Secondary outcomes: trough FEV1 on days 2, 8, and 15; trough FVC (the mean value of the three highest readings assessed at 22, 23, and 24 hour following the trial drug administration) on days 2, 8, 15, and 29; change from baseline in trough and peak FEV1 and FVC; change from baseline in total and component (symptoms, activity, and impact) scores of the St. George’s Respiratory Questionnaire (SGRQ); improvement in Transition Dyspnoea Index (TDI); number of days with COPD symptoms; change from baseline in average morning and evening peak expiratory flow rate (PEFR); and use of rescue medication Time points: Two spirometry measurements at one hour interval at the screening visit and before randomisation on day one, and the averaged values provided the screening and baseline values. Efficacy spirometry measurements were taken at 0.5, 1, 2, 3, 4, 5, and 6 hours after the first and last dose (days 1 and 29 respectively) in addition to 22, 23, and 24 hours after the first dose and at each study visit (i.e. after the 7th, 14th, and 28th day of drug administration). Three acceptable readings were taken for each measurement at each time point according to the ATS/ERS recommendations on spirometric assessments
Notes	Full text publication Source of funding: Almirall, Barcelona, Spain
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	Unclear risk	Quote: "double blind for aclidinium and placebo arms but open label for patients randomised to tiotropium arm" Comment: high risk of bias for comparison with tiotropium but low risk of bias for comparison with placebo
Blinding of outcome assessment (detection bias) All outcomes	Unclear risk	Quote: "double blind for aclidinium and placebo arms but open label for patients randomised to tiotropium arm" Comment: high risk of bias for comparison with tiotropium but low risk of bias for comparison with placebo
Incomplete outcome data (attrition bias) All outcomes	Low risk	Comment: number of withdrawals were low and comparable across the study arms (aclidinium 25 μg 6.1%, aclidinium 50 μg 4.6%, aclidinium 100 μg 4.3%, aclidinium 200 μg 4.5%, aclidinium 400 μg 4.5%, tiotropium 6.2%, placebo 4.7%). Efficacy data are reported for the intention‐to‐treat (ITT) population, defined as all randomised patients who received at least one dose of study medication and who had a baseline and at least one post‐baseline efficacy assessment. The safety population comprised of all randomised patients who received at least one dose of study medication. Quote (from report): "missing spirometry data were handled as follows: for discontinuations because of lack of efficacy, the least favourable value prior to discontinuation was imputed; for other discontinuations, the last value carried forward approach was used. When only some values were missing from a test day, linear interpolation was used to estimate a value missing between two valid measurements. If values were missing for an entire visit or at the beginning or the end of an assessment period (i.e. 0.5, 6, 22, or 24 hour), time‐matched values of the previous available visit were used"
Selective reporting (reporting bias)	High risk	Comment: trough FVC on days 2,8,15 and 29; and change from baseline in average morning and evening peak expiratory flow rate (PEFR) were mentioned as secondary end points of the trial, but no data on these outcomes was reported in the published results
Other bias	Low risk	Comment: no apparent source of bias was observed