Efficacy and safety of a fixed-dose combination of mometasone furoate and formoterol fumarate in subjects with moderate to very severe COPD: results from a 52-week Phase III trial

Abstract

Background: A clinical trial 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) investigated the efficacy and safety of a fixed-dose combination of MF/F.

Methods: This multicenter, double-blind, placebo-controlled trial had a 26-week treatment period and a 26-week safety extension. Subjects (n = 1055; ≥40 years) were current or ex- smokers randomized to twice-daily treatment with inhaled MF/F 400/10 μg, MF/F 200/10 μg, MF 400 μg, F 10 μg, or placebo. The coprimary endpoints of the trial were mean changes from baseline in forced expiratory volume in 1 second (FEV(1)) over 0-12 hours (AUC(0-12) FEV(1)) with MF/F versus MF, and in morning predose FEV(1) with MF/F versus F. Key secondary endpoints were quality of life (Saint George's Respiratory Questionnaire [SGRQ]), symptom-free nights, and partly stable COPD at 26 weeks, as well as time to first COPD exacerbation.

Results: Significant improvements in FEV(1) AUC(0-12) occurred at endpoint with MF/F 400/10 and MF/F 200/10 versus MF 400 (P ≤ 0.007). Significant bronchodilation occurred in 5 minutes with MF/F, and serial spirometry demonstrated sustained FEV(1) improvements with MF/F over the treatment period. Significant improvements in morning predose FEV(1) occurred with both MF/F doses, and these effects were further investigated by excluding results for subjects whose morning FEV(1) data were collected >2 days after the last dose of study treatment. Improvements in SGRQ total scores surpassed the minimum clinically important difference of at least 4 units with MF/F 400/10. MF/F 400/10 significantly reduced the time-to-first COPD exacerbation. Similar proportions of subjects in all five treatment groups reported treatment-emergent adverse events. Rates of pneumonia were low (≤1.0%) across treatment groups.

Conclusion: MF/F 400/10 μg twice daily was shown to be an effective therapy for patients with moderate to very severe COPD, and both MF/F 400/10 μg twice daily and MF/F 200/10 μg twice daily were well tolerated.

Trial registration: ClinicalTrials.gov NCT00383435.

Keywords: FEV1; bronchodilator; chronic obstructive pulmonary disease; exacerbation; inhaled corticosteroid; spirometry.

Figure 1

Study design schematic. Note: Total doses were delivered after two inhalations twice daily of the following actuated doses: MF/F 200/5 μg, MF 100/5 μg, MF 200 μg, F 5 μg, or placebo. ^a75% of each group were randomly selected to continue into the safety extension. Abbreviations: bid, twice daily; F, formoterol; MDI, metered-dose inhaler; MF, mometasone furoate; MF/F, mometasone furoate/formoterol fixed-dose combination.

Figure 2

FEV₁ AUC_{0–12 h} week 13 last observation carried forward results (all randomized subjects). Abbreviations: AUC, area under curve; FEV₁, forced expiratory volume in 1 second; F, formoterol; MDI, metered-dose inhaler; MF, mometasone furoate; MF/F, mometasone furoate/formoterol fixed-dose combination.

Figure 3

Serial FEV₁ postdose at day 1 (A) and week 26 (B). Notes: Significantly greater increases in FEV₁ occurred with MF/F 400/10 versus MF 400 at all time points on day 1 (P ≤ 0.009) and week 26 (P ≤ 0.042). Significant increases in FEV₁ with MF/F 200/10 versus MF 400 occurred through 10 hours on day 1 (P ≤ 0.015) and 4 hours on week 26 (P ≤ 0.026). Compared with F 10, MF/F 400/10 had significantly greater increases in FEV₁ at all time points in week 26 (P < 0.05), whereas MF/F 200/10 had significantly greater increases than F 10 at hours 8, 10, and 12 postdose in week 26 (P ≤ 0.025). Abbreviations: bid, twice daily; FEV₁, forced expiratory volume in 1 second; F, formoterol; MF, mometasone furoate; MF/F, mometasone furoate/formoterol fixed-dose combination.

Figure 4

St George’s Respiratory Questionnaire total score change from baseline at week 26 endpoint. Note: Treatment with MF/F 400/10 achieved a statistically significant difference from placebo, which satisfied this key secondary endpoint and surpassed the MCID of 4.0. Abbreviations: F, formoterol; LS, least squares; MCID, minimum clinically important difference; MF, mometasone furoate; MF/F, mometasone furoate/formoterol fixeddose combination; SGRQ, St George’s Respiratory Questionnaire.

Figure 5

Time-to-first mild, moderate or severe COPD exacerbation over the 26-week treatment period: Kaplan-Meier survival curves by treatment (all randomized subjects). Abbreviations: COPD, chronic obstructive pulmonary disease; F, formoterol; MF, mometasone furoate; MF/F, mometasone furoate/formoterol fixed-dose combination.