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

作者：Singh Dave^*; Ciurlia Giorgia; Piccinno Annalisa; Muraro Annamaria; Bocchi Maria; Scuri Mario

来源：Pulmonary Pharmacology & Therapeutics, 2017, 42: 43-51.

DOI：10.1016/j.pupt.2016.12.004

• beta(2)-agonist
• Cardiovascular
• Safety
• COPD

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 FEV1 40-80% predicted, FEV1/FVC <0.7). Patients received BDP/FF 200/12, 800/48 mu g and placebo via DPI, and BDP/FF 200/12 and 800/48 mu g via pMDI. In both devices, 200/12 mu g is the therapeutic dose; 800/48 mu g is supratherapeutic.
Primary objective: to demonstrate non-inferiority between BDP/FF DPI and pMDI in average 4-h heart rate (HR0-4h) at each dose level. Secondary variables included: HR1-12h, HR peak and individual time point; QTcF interval; SBP and DBP AUC(0-12h); and potassium and glucose AUC(0-4h). 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 mu,g and 0.6 bpm [-0.5,1.7] for 800/48 mu beta). 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 mu g 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.

• 出版日期2017-2