Acute cardiovascular safety of two formulations of beclometasone dipropionate/formoterol fumarate in COPD patients: A single-dose, randomised, placebo-controlled crossover study.

INTRODUCTION

An extrafine combination of beclometasone dipropionate (BDP) and formoterol fumarate (FF) via a pressurised metered-dose inhaler (pMDI) has been commercially available for some years for the management of asthma and chronic obstructive pulmonary disease (COPD). A dry powder inhaler (DPI) formulation of extrafine BDP/FF is now also available. This study evaluated the cardiovascular safety of BDP/FF DPI in comparison to BDP/FF pMDI and placebo.

METHODS

Single-dose, partially-blind, randomised, placebo-controlled, 5-period crossover study. Main inclusion criteria: aged 40-75 years; moderate to severe COPD (post-bronchodilator FEV 40-80% predicted, FEV/FVC <0.7). Patients received BDP/FF 200/12, 800/48 μg and placebo via DPI, and BDP/FF 200/12 and 800/48 μg via pMDI. In both devices, 200/12 μg is the therapeutic dose; 800/48 μg is supratherapeutic.

PRIMARY OBJECTIVE

to demonstrate non-inferiority between BDP/FF DPI and pMDI in average 4-h heart rate (HR) at each dose level. Secondary variables included: HR, HR peak and individual timepoint; QTcF interval; SBP and DBP AUC; and potassium and glucose AUC. Adverse events (AEs) were collected.

RESULTS

Forty-nine patients were randomised; 45 (92%) received all five treatments. Non-inferiority was demonstrated between the DPI and pMDI formulations at both doses (-0.2 bpm [95% CI -1.3, 0.9] for 200/12 μg and 0.6 bpm [-0.5, 1.7] for 800/48 μg). Although there were statistically significant treatment-placebo differences at both doses and with both devices (thus confirming assay sensitivity), these differences were small and well below 5 bpm for the 200/12 μg dose. The results for the secondary parameters (QTcF, glucose and potassium) further supported the therapeutic equivalence of the two treatments. At the therapeutic dose, there were no clinically relevant treatment-placebo differences in any parameter with either formulation. There was no increase in the proportion of patients reporting AEs whilst receiving therapeutic doses of BDF/FF (either formulation) compared with placebo.

CONCLUSIONS

Overall, this study provides reassurance over the cardiovascular safety of extrafine BDP/FF, both in a DPI and a pMDI formulation.