Effects of mometasone furoate/formoterol fumarate fixed-dose combination formulation on chronic obstructive pulmonary disease (COPD): results from a 52-week Phase III trial in subjects with moderate-to-very severe COPD

Dennis E Doherty¹, Donald P Tashkin², Edward Kerwin³, Barbara A Knorr⁴, Tulin Shekar⁴, Sibabrata Banerjee⁴, Heribert Staudinger^4
1Division of Pulmonary, Critical Care, and Sleep Medicine, University of Kentucky, Lexington, KY, ²David Geffen School of Medicine at UCLA, Los Angeles, CA, ³Clinical Research Institute of Southern Oregon, Medford, OR, ⁴Merck Sharp & Dohme Corp, Whitehouse Station, NJ, USA

Rationale: The purpose of this study was to investigate the clinical efficacy and safety of a fixed-dose combination of mometasone furoate/formoterol fumarate (MF/F) administered via a metered-dose inhaler in subjects with moderate-to-very severe chronic obstructive pulmonary disease (COPD).
Methods: This multicenter, double-blind, placebo-controlled trial had a 26-week treatment period and a 26-week safety extension. Subjects (n = 1196), at least 40 years old, were current or ex-smokers randomized to twice-daily inhaled MF/F 400/10 µg, MF/F 200/10 µg, MF 400 µg, F 10 µg, or placebo. The trial’s co-primary endpoints were mean changes from baseline, as area under the curve (AUC), in forced expiratory volume (FEV₁) over 0–12 hours (AUC_{0-12 h} FEV₁) with MF/F versus MF, and in morning (AM) pre-dose (trough) FEV₁ with MF/F versus F after 13 weeks of treatment. Key secondary endpoints were the effects of MF/F on respiratory health status using the Saint George’s Respiratory Questionnaire (SGRQ), symptom-free nights, partly stable COPD at 26 weeks, and time to first COPD exacerbation.
Results: The largest improvements in AUC_{0-12 h} FEV₁ were observed with MF/F 400/10 µg and MF/F 200/10 µg. Serial spirometry results demonstrated that bronchodilator effects with MF/F occurred rapidly (within 5 minutes), persisted for 12 hours after dosing, and were sustained over the 26-week treatment period. Similar findings were observed for AM pre-dose FEV₁, for which effects were further investigated, excluding subjects whose AM FEV₁ data were incorrectly collected after 2 days from the last dose of study treatment. Improvements in SGRQ scores surpassed the minimum clinically important difference of more than four units with both MF/F treatments. At 26 weeks, no notable between-treatment differences in the occurrence and nature of adverse events (AEs) were reported. No unexpected AEs were observed. Overall, 90 subjects reported AEs considered to be treatment-related, the most common of which were lenticular opacities, dysphonia, and oral candidiasis.
Discussion: In conclusion, MF/F treatments improved lung function and respiratory health status, reduced exacerbations, and were well tolerated in subjects with moderate-to-very severe COPD.

Keywords: COPD, FEV₁, spirometry, exacerbation, inhaled corticosteroid, bronchodilator