title: Acute cardiovascular safety of two formulations of beclometasone dipropionate/formoterol fumarate in COPD patients: A single-dose, randomised, placebo-controlled crossover study.
abstract: 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.
  
  
  
  Single-dose, partially-blind, randomised, placebo-controlled, 5-period crossover study. Main inclusion criteria: aged 40-75 years; moderate to severe COPD (post-bronchodilator FEV140-80% predicted, FEV1/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.
  
  
  
  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: HR0-12h, HR peak and individual timepoint; QTcF interval; SBP and DBP AUC0-12h; and potassium and glucose AUC0-4h. Adverse events (AEs) were collected.
  
  
  
  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.
  
  
  
  Overall, this study provides reassurance over the cardiovascular safety of extrafine BDP/FF, both in a DPI and a pMDI formulation.
authors.affiliation: University of Manchester, Medicines Evaluation Unit, The Langley Building, University Hospital of South Manchester, Southmoor Rd, Wythenshawe M23 9QZ, United Kingdom. Electronic address: DSingh@meu.org.uk.
authors.forename: Dave
authors.initials: D
authors.lastname: Singh
authors.affiliation: Chiesi Farmaceutici SpA, Via Palermo 26/A, 43122 Parma, Italy.
authors.forename: Giorgia
authors.initials: G
authors.lastname: Ciurlia
authors.affiliation: Chiesi Farmaceutici SpA, Via Palermo 26/A, 43122 Parma, Italy.
authors.forename: Annalisa
authors.initials: A
authors.lastname: Piccinno
authors.affiliation: Chiesi Farmaceutici SpA, Via Palermo 26/A, 43122 Parma, Italy.
authors.forename: Annamaria
authors.initials: A
authors.lastname: Muraro
authors.affiliation: Chiesi Farmaceutici SpA, Via Palermo 26/A, 43122 Parma, Italy.
authors.forename: Maria
authors.initials: M
authors.lastname: Bocchi
authors.affiliation: Chiesi Farmaceutici SpA, Via Palermo 26/A, 43122 Parma, Italy.
authors.forename: Mario
authors.initials: M
authors.lastname: Scuri
mesh_terms: D000280:Administration, Inhalation; D000368:Aged; D001507:Beclomethasone / Q000008:administration & dosage* / Q000009:adverse effects; D001993:Bronchodilator Agents / Q000008:administration & dosage* / Q000009:adverse effects; D018592:Cross-Over Studies; D004338:Drug Combinations; D058995:Dry Powder Inhalers; D004562:Electrocardiography; D005260:Female; D005541:Forced Expiratory Volume; D000068759:Formoterol Fumarate / Q000008:administration & dosage* / Q000009:adverse effects; D006339:Heart Rate / Q000187:drug effects; D006801:Humans; D008297:Male; D036501:Metered Dose Inhalers; D008875:Middle Aged; D029424:Pulmonary Disease, Chronic Obstructive / Q000188:drug therapy* / Q000503:physiopathology; D012720:Severity of Illness Index; D016037:Single-Blind Method
chemical_list: D001993:Bronchodilator Agents; D004338:Drug Combinations; D001507:Beclomethasone; D000068759:Formoterol Fumarate
keywords: COPD; Cardiovascular; Safety; β(2)-agonist