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

Abstract

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 (FEV(1)) over 0-12 hours (AUC(0-12 h) FEV(1)) with MF/F versus MF, and in morning (AM) pre-dose (trough) FEV(1) 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) FEV(1) 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 FEV(1), for which effects were further investigated, excluding subjects whose AM FEV(1) 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.

Trial registration: ClinicalTrials.gov NCT00383721.

Keywords: COPD; FEV1; bronchodilator; exacerbation; inhaled corticosteroid; spirometry.

Figure 1

Subject disposition. Notes: Total doses were delivered after two inhalations BID of the following actuated doses: MF/F 200/5 μg, MF/F 100/5 μg, MF 200 μg, F 5 μg, or placebo. Abbreviations: AE, adverse event; BID, twice daily; F, formoterol; MF, mometasone furoate; MF/F, mometasone furoate/formoterol fixed-dose combination formulation.

Figure 2

FEV₁ AUC_{0–12 h} at week 13 endpoint (LOCF). Abbreviations: AUC_{0–12 h}, area under the curve from 0 to 12 hours post-dose; BID, twice daily; FEV₁, forced expiratory volume in 1 second; LOCF, last observation carried forward; F, formoterol; MF, mometasone furoate; MF/F, mometasone furoate/formoterol fixed-dose combination formulation.

Figure 3

Serial FEV₁ post-dose at day 1 (A) and week 26 (B). Notes: Significantly greater increases in FEV₁ occurred with both MF/F treatments compared with MF at all time points on day 1 (P < 0.001), as well as week 26 (P ≤ 0.035). Compared with F 10 μg, MF/F 400/10 μg had significantly greater increases in FEV₁ at all time points on week 26 (P ≤ 0.016), whereas MF/F 200/10 μg had significantly greater increases versus F only at the 4 and 8 hour post-dose time points (P ≤ 0.022). Abbreviations: BID, twice daily; FEV₁, forced expiratory volume in 1 second; F, formoterol; MF, mometasone furoate; MF/F, mometasone furoate/formoterol fixed-dose combination formulation.

Figure 4

AM pre-dose (trough) FEV₁ at week 13 endpoint. Abbreviations: AM, morning; BID, twice daily; FEV₁, forced expiratory volume in 1 second; F, formoterol; MF, mometasone furoate; MF/F, mometasone furoate/formoterol fixed-dose combination formulation.

Figure 5

SGRQ total score change from baseline at week 26 endpoint. Notes: Compared with placebo, significantly greater improvements in SGRQ total scores occurred with MF/F 400/10 μg (P = 0.020) and MF 400 μg (P = 0.023), as well as with MF/F 200/10 μg. The difference between MF/F 200/10 μg and F 10 μg was also significant (P = 0.020) at the week 26 endpoint. Abbreviations: BID, twice daily; SGRQ, St George’s Respiratory Questionnaire; FEV₁, forced expiratory volume in 1 second; F, formoterol; MF, mometasone furoate; MF/F, mometasone furoate/formoterol fixed-dose combination formulation.

Figure 6

Time to first moderate or severe exacerbation over the 26-week treatment period. Notes: *P < 0.001 versus placebo; ^†P = 0.027 versus placebo; ^‡P = 0.003 versus placebo. Abbreviations: F, formoterol; MF, mometasone furoate; MF/F, mometasone furoate/formoterol fixed-dose combination formulation.