Efficacy and safety characteristics of mometasone furoate/formoterol fumarate fixed-dose combination in subjects with moderate to very severe COPD: findings from pooled analysis of two randomized, 52-week placebo-controlled trials

Abstract

Background: The clinical efficacy and safety of a mometasone furoate/formoterol fumarate (MF/F) fixed-dose combination formulation administered via a metered-dose inhaler was investigated in patients with moderate to very severe chronic obstructive pulmonary disease (COPD).

Methods: Two 52-week, multicenter, double-blind, placebo-controlled trials with identical study designs were conducted in current or ex-smokers (aged ≥40 years), and pooled study results are presented herein. Subjects (n = 2251) were randomized to 26 weeks of twice-daily treatment with MF/F 400/10 μg, MF/F 200/10 μg, MF 400 μg, F 10 μg, or placebo. After the 26-week treatment period, placebo subjects completed the trial and 75% of subjects on active treatment entered a 26-week safety extension. Coprimary efficacy variables were mean changes in forced expiratory volume in one second (FEV(1)), area under the curve from 0 to 12 hours postdose (AUC(0-12 h)), and morning predose/trough FEV(1) from baseline to the week 13 endpoint. Key secondary efficacy variables were St George's Respiratory Questionnaire scores, symptom-free nights, time-to-first exacerbation, and partly stable COPD at the week 26 endpoint.

Results: In the 26-week treatment period, significantly greater increases in FEV(1) AUC(0-12 h) occurred with MF/F 400/10 versus MF 400 and placebo at the week 13 and week 26 endpoints (P ≤ 0.032). These increases were over three-fold greater with MF/F 400/10 than with MF 400. Also, significantly greater increases in morning predose/trough FEV(1) occurred with MF/F 400/10 versus F 10 and placebo at the week 13 endpoint (P < 0.05). The increase was four-fold greater with MF/F 400/10 than with F 10. All active treatment groups achieved minimum clinically important differences from baseline (>4 units) in St George's Respiratory Questionnaire scores at week 26. Symptom-free nights increased by ≥14% in the MF/F 400/10, MF 400, and F 10 groups (P ≤ 0.033 versus placebo). The incidence of exacerbations was lower in the MF/F groups (≤33.3%) than it was in the MF, formoterol, and placebo groups (≥33.8%) over the 26-week treatment period. The incidence of adverse events was similar in the active-treated and placebo-treated subjects across 26 weeks of treatment. Over the 1-year study period, there were no notable differences in the incidence or types of adverse events between the MF/F 400/10 and MF/F 200/10 groups compared with the MF or formoterol groups. Differences in rates of individual treatment-emergent adverse events were <3% between treatment groups. Rates of pneumonia were low (≤2%) across all treatment groups.

Conclusion: Patients treated with MF/F demonstrated significant improvements in lung function, health status, and exacerbation rates. Although significant improvements were seen with both doses, a trend showing a dose-response effect was observed in the lung function measurements.

Trial registration: ClinicalTrials.gov NCT00383435 NCT00383721.

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

Figure 1

Study design. Notes: Total doses were delivered after two inhalations twice daily of the following actuated doses: MF/F 200/5 μg, MF/F 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; FDC, fixed-dose combination; MDI, metered-dose inhaler; MF, mometasone furoate; MF/F, mometasone furoate/formoterol fumarate fixed-dose combination formulation; SABA, short-acting β₂-agonist.

Figure 2

Change from baseline in FEV₁ AUC_{0–12 h} (L × hour) at week 13 (last observation carried forward). Notes: *P < 0.001 versus placebo; ^†P < 0.001 versus MF 400; ^‡P ≤ 0.011 versus F 10; ^¶P = 0.031 versus MF/F 200/10. Abbreviations: AUC_{0–12 h}, area under the curve from 0 to 12 h postdose; FEV₁, forced expiratory volume in 1 second; F, formoterol; MF, mometasone furoate; MF/F, mometasone furoate/formoterol fumarate fixed-dose combination formulation.

Figure 3

Morning predose/trough FEV₁ at week 13 endpoint (last observation carried forward). Notes: *P < 0.001 versus placebo; ^†P < 0.001 versus MF 400; ^‡P < 0.001 versus F 10; ^¶P = 0.018 versus MF/F 200/10. Abbreviations: FEV₁, forced expiratory volume in 1 second; F, formoterol; MF, mometasone furoate; MF/F, mometasone furoate/formoterol fumarate fixed-dose combination formulation.

Figure 4

Changes from baseline in morning predose/trough FEV₁ over the study period (last observation carried forward). Note: Subjects randomized to placebo were only enrolled up to week 26. Abbreviations: F, formoterol; FEV₁, forced expiratory volume in 1 second; MF, mometasone furoate; MF/F, mometasone furoate/formoterol fixed-dose combination formulation.

Figure 5

St George’s Respiratory Questionnaire total score change from baseline at week 26 endpoint. Notes: *P < 0.001 versus placebo; ^†P = 0.007 versus placebo. Abbreviations: F, formoterol; MF, mometasone furoate; MF/F, mometasone furoate/formoterol fumarate fixed-dose combination formulation; SGRQ, St George’s Respiratory Questionnaire.

Figure 6

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: F, formoterol; MF, mometasone furoate; MF/F, mometasone furoate/formoterol fumarate fixed-dose combination formulation.