This was a randomized, double-blind, placebo-controlled, parallel-group, multinational (Japan, Romania, Russia and Ukraine) phase III study (Study code: D5122C00001; ClinicalTrials.gov identifier: NCT00628862) conducted at 65 centers in Japan and Europe. The study protocol was approved by the Institutional Review Board/Ethics Committee at all participating sites and the study was performed in accordance with the Declaration of Helsinki and the AstraZeneca policy on Bioethics and Human Biological Samples. All patients provided written informed consent prior to enrolment into the study.
The primary objective was to show that formoterol 4.5 and 9 μg bid for 12 weeks were superior to placebo in Japanese and European patients with COPD using forced expiratory volume in 1 second (FEV1) 60-min post-dose as the primary outcome variable.
The study consisted of an enrolment period for withdrawal of pre-study medication, a 2-week run-in period and a 12-week treatment period. Clinic visits took place at baseline (on completion of the 2-week run-in period), and at weeks 4, 8, and 12 of the treatment period.
Male and female patients ≥ 40 years of age with a clinical diagnosis of COPD (post-bronchodilator FEV1 < 80% of predicted normal, and post-bronchodilator FEV1/forced vital capacity [FVC] < 70%) and current COPD symptoms were eligible for inclusion. Patients were also required to have a current or previous smoking history of ≥ 10 pack-years and a symptom score of at least 2 points (combination of breathlessness, cough, and/or night time awakenings due to symptoms; each assessed by the patients on a scale of 0-4 where 0 = no symptoms and 4 = severe symptoms) on at least 6 of the last 10 days of the run-in period.
Patients with a history and/or current clinical diagnosis of asthma were excluded from participating, as were those with a history and/or current clinical diagnosis of atopic disease such as allergic rhinitis. Additional exclusion criteria included use of an ICS within 4 weeks of the run-in period, COPD exacerbation requiring hospitalization and/or a course of antibiotics and/or systemic steroid therapy within 4 weeks of the run-in period, significant or unstable ischemic heart disease, or other relevant cardiovascular conditions, any other respiratory tract disorders or significant disease likely to place the patient at risk during the study.
Patients received inhaled formoterol 4.5 or 9 μg twice daily (bid) via Turbuhaler® or matching placebo for 12 weeks. Study treatments were taken at approximately the same time every morning and evening and immediately after measuring peak expiratory flow (PEF).
Salbutamol 100 μg/actuation via a pressurized metered-dose inhaler (pMDI) was available to relieve symptoms throughout the study period and patients could continue to take short-acting anticholinergics. Patients previously receiving long-acting anticholinergics were switched to short-acting anticholinergics at the start of the enrolment period. Glucocorticosteroid treatment was not permitted at any time during the study.
The primary outcome variable was change (ratio) from baseline to the end of treatment period in FEV1 60-min post-dose. Secondary outcome variables included spirometry, diary variables, and assessment of health-related quality-of-life (HRQL). Spirometry endpoints were FVC 60-min post-dose, FEV1 and FVC pre-dose and 5-min post-dose. Diary variables were morning and evening PEF, COPD symptom scores (night-time awakenings due to symptoms, breathlessness, and cough), and use of salbutamol as reliever medication (measured as inhalations/day). HRQL was assessed using the St George's Respiratory Questionnaire (SGRQ).
Safety and tolerability were assessed by evaluation of the nature, incidence and severity of adverse events, clinical laboratory variables including clinical chemistry, hematology, and urinalysis, 12-lead electrocardiogram (ECG), blood pressure and pulse rate.
Sample size selection was based on clinical data derived from a published 6-month study . With a two-sided test at level 0.05 and 176 patients per treatment group, the study was determined to have 80% power to detect a difference between the treatment groups of at least 0.06 L in the change from baseline FEV1 value.
A last-observation-carried-forward (LOCF) approach was used to account for any missing week 6 data. The comparison of formoterol 4.5 and 9 μg bid with placebo was performed on the primary endpoint, mean change from baseline in FEV1 60-min post-dose, using an analysis of covariance (ANCOVA) model including country and treatment as fixed factors and the baseline value as covariate. A two-sided 5% significance level was used and 95% confidence intervals (CIs) for the mean difference between each dose of formoterol and placebo were calculated. The multiplicity of statistical tests was adjusted by a "closed testing procedure" under which the null hypothesis that 9 μg bid was equal to placebo was tested; if this null hypothesis was rejected then the 4.5 μg bid dose versus placebo was tested.
As for FEV1, the comparison of active treatments (formoterol 4.5 μg and 9 μg bid) with placebo for the secondary variables was performed using an ANCOVA model including country and treatment as fixed factors and the baseline value as covariate. The ANCOVA model used in the analysis was multiplicative. A two-sided 5% significance level was used and the "closed testing procedure" was applied.
The incidence of adverse events was calculated, and results from laboratory safety measurements, vital signs, and ECG, were analyzed primarily by means of descriptive statistics.