Efficacy and safety of fluticasone furoate/vilanterol (50/25 mcg; 100/25 mcg; 200/25 mcg) in Asian patients with chronic obstructive pulmonary disease: a randomized placebo-controlled trial.

BACKGROUND AND OBJECTIVE
Three strengths of fluticasone furoate/vilanterol (FF/VI) were previously evaluated for the treatment of chronic obstructive pulmonary disease (COPD) in a program of global Phase 3 studies that included only a small subgroup of Asian patients. This study further evaluated the efficacy and safety of the same three strengths of FF/VI exclusively in Asian patients.


METHODS
A randomized, double-blind, placebo-controlled, parallel-group, multicenter study. Patients with post-bronchodilator FEV1/FVC ≤0.70, FEV1 ≤70% predicted and modified Medical Research Council score ≥2 were randomized (1:1:1:1) to placebo, FF/VI 50/25 mcg, 100/25 mcg or 200/25 mcg once daily via the ELLIPTA dry powder inhaler. The primary efficacy endpoint was change from baseline in trough FEV1 at Week 24.


RESULTS
The intent-to-treat population comprised 643 patients. Statistically significant (p < 0.001) improvements in trough FEV1 were observed with all strengths of FF/VI versus placebo at Week 24 (0.14-0.19 L). Reduction of supplemental albuterol use was observed with all strengths of FF/VI versus placebo. The incidence of on-treatment adverse events (AEs) was 48% with FF/VI 200/25 mcg and 37-40% with other treatments. The incidence of on-treatment serious AEs was 4-9% with FF/VI treatments versus 9% with placebo; however, the study only covered a 6 month treatment period and was not powered to assess effects on exacerbations. No clinically significant treatment effects versus placebo were identified for electrocardiogram, vital signs, 24 hour urinary cortisol excretion and pneumonia.


CONCLUSIONS
All strengths of FF/VI improved lung function with an acceptable safety profile. There is no evidence to suggest that dose adjustment may be required in Asian patients using FF/VI 100/25 mcg for the treatment of COPD.


CLINICAL TRIAL REGISTRATION
NCT01376245.

2 performed at screening and pre-dose on the randomisation visit; failure to demonstrate adequate compliance with study procedures including taking the run-in medication.
Supplementary Appendix 2 Other permitted and prohibited concomitant medications.
Permitted non-COPD medications included: cardioselective beta-blockers (stable dose) and ophthalmic beta-blockers; antihistamines and nasal decongestants; over-the-counter cough suppressants (for ≤7days); intranasal sodium cromoglycate or nedocromil sodium; intranasal corticosteroids (stable daily dose for ≥4 weeks prior to screening and throughout the study); topical (≤1% hydrocortisone in strength) or ophthalmic corticosteroids; antibiotics that are not strong inhibitors of cytochrome P450 3A4 for treatment (≤14 days) of acute non-respiratory tract infections; influenza and/or pneumonia vaccination; tricyclic antidepressants and monoamine oxidase inhibitors (MAOIs); diuretics; treatment(s) for smoking cessation; and all medications for other disorders as long as the dose remained constant wherever possible and their use was not expected to affect lung function. analyses COPD symptoms were scored as follows: breathlessness on a scale of 0 (not breathless at rest or exertion) to 4 (breathless), cough scale 0 (none) to 3 (severe), and sputum production scale 0 (none) to 3 (severe). Total symptom-free 24 hour periods were defined as days on which cough, sputum and breathlessness were all scored as zero. The percentage of symptom-free 24 hour periods (cough, sputum, breathlessness, and combined total) during each month of treatment, over the 24-week treatment period and as change from baseline (percentage of symptom-free 24 hour periods during the run-in) were summarised. Mean symptom scores were summarised in the same way, and the percentage of night-time awakenings (requiring rescue use) free days were summarised. The mean symptom score averaged over the entire 24-week treatment period was analysed for cough, sputum and breathlessness separately, mean night-time awakenings requiring rescue use, percentage of rescue-free 24 hour periods, and mean rescue use were summarised and analysed using an analysis of covariance (ANCOVA) model with covariates of baseline symptom score, smoking status at screening and treatment. In addition, a sensitivity analysis was performed for those patients who had at least one night-time awakening during baseline.
The incidence of AEs, COPD exacerbations and pneumonia, vital signs and ECG parameters, oropharyngeal examination data, urine cortisol and data for clinical laboratory parameters were summarised. All actual and change from baseline values for pulse rate, systolic and diastolic blood pressure were summarised by treatment using summary statistics together with maximum (pulse rate and systolic blood pressure) or minimum (diastolic blood pressure) post baseline values, including any recorded at scheduled, unscheduled and early withdrawal visits. From treatment day 2, pre-dose pulse rate, systolic and diastolic blood pressure were analysed using a repeated measures model, with a repeated effect of day within each patient and an associated unstructured covariance structure.
For each endpoint, the model was fitted with a response variable of change from baseline value. The explanatory variables were treatment group, smoking status at screening, baseline (pulse rate, systolic or diastolic blood pressure) and day (as a categorical variable), in addition to day by baseline and day by treatment interaction terms. In addition, the 10 min post-dose assessment made on Day 1 was analysed using an ANCOVA model with treatment group, smoking status and baseline pulse rate, systolic blood pressure or diastolic blood pressure as the explanatory variables. Actual and change from baseline values for QTc(F), QTc(B) and heart rate were summarised by treatment using summary statistics together with maximum post baseline values, including any recorded at scheduled, unscheduled and early withdrawal visits.
Pre-dose QTc(F) and heart rate were analysed using a repeated measures model as described for the primary endpoint. In addition, the 10 minute post-dose assessment made on Day 1 was analysed using an ANCOVA, using the same model as described for vital signs. 24 hour UC excretion was log transformed, summarised and analysed for the UC population. Data were analysed using an ANCOVA model with covariates of log baseline, smoking status and treatment.