Date Published: December 7, 2011
Publisher: BioMed Central
Author(s): David I Bernstein, Jacques Hébert, Amarjit Cheema, Kevin R Murphy, Ivan Chérrez-Ojeda, Carlos Eduardo Matiz-Bueno, Wen-Ling Kuo, Hendrik Nolte.
Mometasone furoate/formoterol (MF/F) is a novel combination therapy for treatment of persistent asthma. This noninferiority trial compared the effects of MF/F and fluticasone propionate/salmeterol (FP/S) combination therapies on pulmonary function and onset of action in subjects with persistent asthma.
Following a 2- to 4-week run-in period with MF administered via a metered-dose inhaler (MDI) 200 μg (delivered as 2 inhalations of MF-MDI 100 μg) twice daily (BID), subjects (aged ≥12 y) were randomized to MF/F-MDI 200/10 μg BID (delivered as 2 inhalations of MF/F-MDI 100/5 μg) or FP/S administered via a dry powder inhaler (DPI) 250/50 μg (delivered as 1 inhalation) BID for 12 weeks. The primary assessment was change from baseline to week 12 in area under the curve for forced expiratory volume in 1 second measured serially for 0-12 hours postdose (FEV1 AUC0-12 h). Secondary assessments included onset of action (change from baseline in FEV1 at 5 minutes postdose on day 1) and patient-reported outcomes.
722 subjects were randomized to MF/F-MDI (n = 371) or FP/S-DPI (n = 351). Mean FEV1 AUC0-12 h change from baseline at week 12 for MF/F-MDI and FP/S-DPI was 3.43 and 3.24 L × h, respectively (95% CI, -0.40 to 0.76). MF/F-MDI was associated with a 200-mL mean increase from baseline in FEV1 at 5 minutes postdose on day 1, which was significantly larger than the 90-mL increase for FP/S-DPI (P < 0.001). The overall incidence of adverse events during the 12-week treatment period that were considered related to study therapy was similar in both groups (MF/F-MDI, 7.8% [n = 29]; FP/S-DPI, 8.3% [n = 29]). The results of this 12-week study indicated that MF/F improves pulmonary function and asthma control similar to FP/S with a superior onset of action compared with FP/S. Both drugs were safe, improved asthma control, and demonstrated similar results for other secondary study endpoints. ClinicalTrials.gov: NCT00424008
Asthma is a chronic inflammatory disorder of the airways that results in recurrent coughing, chest tightness, wheezing, and breathlessness . The first line of therapy to relieve symptoms of persistent asthma is inhaled corticosteroids (ICSs) [1,2]. However, when an ICS alone is unable to control persistent asthma, the Global Initiative for Asthma (GINA)  and the National Asthma Education and Prevention Program (NAEPP)  guidelines recommend step-up treatment with an ICS combined with a long-acting β2-agonist (LABA).
This was a multicenter, 12-week,1 open-label, evaluator-blinded, active-controlled, noninferiority efficacy and safety trial in subjects (aged ≥12 y) with uncontrolled persistent asthma previously treated with medium-dose ICS with or without a LABA. Following a 2- to 4-week run-in treatment period with MF-MDI 200 μg (delivered as 2 inhalations of MF-MDI 100 μg) BID monotherapy, eligible subjects were randomized in a 1:1 ratio according to a computer-generated randomization schedule to MF/F-MDI 200/10 μg (delivered as 2 inhalations of MF/F-MDI 100/5 μg) BID or FP/S-DPI 250/50 μg (delivered as 1 inhalation) BID for 12 weeks (Figure 1). Study visits were scheduled at screening (days -28 to -14), prebaseline (days -14 to -7), baseline (day 1), and weeks 1, 2, 4, 8, and 12. The first dose of study drug was to be taken in the office under the supervision of a third-party dispenser. Written instructions on the proper use of the MDI or FP/S-DPI were provided to subjects. Subjects assigned to the MDI also used a placebo training inhaler (no DPI placebo training inhaler matching the FP/S-DPI was available for the study). The study protocol and amendments received institutional review board approval and all subjects (or subject’s legal representation for those under the age of legal consent) provided written informed consent.
This study in adult and adolescent subjects with persistent asthma uncontrolled on medium-dose ICS monotherapy demonstrated that treatment with MF/F-MDI 200/10 μg BID improved lung function and other patient-reported outcomes similar to FP/S-DPI 250/50 μg BID with an onset of action superior to FP/S-DPI. Although stable lung function was demonstrated during the open-label run-in period, subjects were still uncontrolled at baseline (ie, total ACQ score ≥1.5), indicating that medium-dose MF alone was suboptimal for treating this subject population. Two key observations can be taken from the lung function results regarding the efficacy of MF/F over 12 weeks of treatment. First, treatment with MF/F-MDI 200/10 μg BID was noninferior compared with FP/S-DPI 250/50 μg BID based on FEV1 AUC0-12 h at week 12 (LOCF). Second, a significant (≥200 mL from baseline) bronchodilator effect of the MF/F combination was observed as early as 5 minutes postdose, which was superior to FP/S through 30 minutes on day 1. This result was expected given the known characteristics of these ICS/LABA combination constituents. Previous studies have demonstrated the efficacy of MF [11-14] and FP [15-17] monotherapy in improving lung function outcomes in patients with asthma. Although LABA monotherapy should not be used to treat asthma , formoterol and salmeterol have also been shown to be effective in improving lung function outcomes . However, formoterol is associated with a faster onset of action than salmeterol [20,21]. As such, it does not seem surprising that MF/F was associated with a faster onset of action than FP/S in the current study.
In conclusion, the results of this study indicated that MF/F-MDI 200/10 μg BID is noninferior based on FEV1 AUC0-12 h and superior in onset of action to FP/S-DPI 250/50 μg BID over 12 weeks of treatment. Both combinations were safe, improved asthma control, and demonstrated similar results for other secondary study endpoints.
David I. Bernstein has received honoraria as a member of Merck & Co., Inc. advisory boards, served as a consultant for GlaxoSmithKline, and has been a clinical investigator for clinical trials sponsored by Merck & Co, Inc. and GlaxoSmithKline. Jacques Hébert has received speaker/consultancy fees and research support from Merck Canada. Amarjit Cheema has received speaker fees and research support from Merck & Co., Inc. Kevin R. Murphy has received speaker/consultancy fees and research support from AstraZeneca, Boehringer Ingelheim, Dey, Merck& Co., Inc, Genentech, GlaxoSmithKline, and Novartis. Ivan Chérrez-Ojeda has received lecture fees from Merck & Co., Inc. Carlos Eduardo Matiz Bueno’s spouse is an employee of Merck & Co., Inc. Wen-Ling Kuo and Hendrik Nolte are employees of Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Whitehouse Station, NJ.
All authors made substantial contributions to the study conception and design, or acquisition of data, or analysis and interpretation of data; have been involved in drafting the manuscript and/or revising it critically; and have given final approval of the published version.