Originally published by 2 Minute Medicine® (view original article). Reused on AccessMedicine with permission.

1. Fixed-dose combinations of mometasone furoate and indacaterol acetate showed greater improvements in lung function parameters compared to inhaled corticosteroid monotherapy in patients with poorly-controlled asthma after 26 weeks

2. High dose mometasone furoate and indacterol acetate as a once-daily fixed-dose combination regimen was non-inferior to twice-daily inhaled corticosteroid-long acting beta agonist combination therapy for lung function parameter improvements in patients with poorly-controlled asthma.

Evidence Rating Level: 1 (Excellent)

Study Rundown:

Long-acting B2-adrenoceptor agonists (LABA) are often used in combination with inhaled corticosteroids (ICS) for patients with uncontrolled asthma. This randomised, double-blind, triple-dummy, controlled 52-week phase 3 study compared the efficacy of ICS-LABA dual therapy with mometasone furoate and indacterol maleate (MF-IND) to ICS monotherapy with the former alone (IND), with each regimen evaluated as high and medium dose regimens. The study also compared the efficacy of a once-daily regimen of high dose ICS-LABA to widely-used twice-daily high dose ICS-LABA therapy with fluticasone proprionate and salmeterol xinafoate (FLU-SAL). Eligible participants were between 12 to 75 years of age, with an asthma diagnosis for 1 year or longer and a forced expiratory volume in one second (FEV1) of 50-85% of predicted normal with improvement of at least 12% with 200 mL on salbutamol administration. The study showed that combination therapy with MF-IND at high- and medium dose was superior to corresponding MF doses in terms of FEV1, Asthma Control Questionnaire (ACQ)-7 score, and peak expiratory flow (PEF) at 26 and 52 weeks. In addition, high dose MF-IND resulted in less severe asthma exacerbations compared to high dose MF and, therefore, required less frequent use of a rescue therapy with short acting bronchodilators (SABAs). Among patients in the high dose MF-IND group, the overall incidence of adverse events was substantially lower than those in the medium dose MF group. Finally, high dose MF-IND was non-inferior to high dose twice-daily FLU-SAL in improving trough FEV1 after 26 weeks of therapy. This study was limited by a triple-dummy design which required patients to use three different inhalers, thus increasing its complexity and making it less generalizable. As well, the study was not designed to compare the effect of MF-IND, MF, and FLU-SAL on asthma exacerbation. Nevertheless, this study provides important insights into appropriate asthma step-up management for patients with poorly controlled asthma.

In-depth [randomized controlled trial]:

This randomized, double-blind, phase 3 study funded by Novartis enrolled 3890 patients between Dec 29, 2015 to May 4, 2018, of which 2216 participants were randomly assigned to one of the following groups for 52 weeks of therapy: high dose MF-IND (n=445), medium dose MF-IND (n=439), high dose MF (n=442), medium dose MF (n=444), and high dose FLU-SAL (n=446). Of these, 1,973 participants completed the study treatment.

The mean age of participants was 48±14.78 years, and the majority (69%) did not have an asthma exacerbation in the previous year. At week 26, high dose MF-IND (treatment difference 132 mL, 95% CI 88 to 176, p<0.001) and medium dose MF-IND (treatment difference 211 mL, 95% CI 167 to 255, p<0.001) showed a greater improvement in trough FEV1 compared to similarly dosed MF monotherapy regimens. The change in FEV1 improvement was less apparent between high dose MF-IND and high dose FLU-SAL (treatment difference 36 mL, 95% CI -7 to 80, p=0.101) at 26 weeks from baseline. Moreover, combined doses of MF-IND significantly improved the asthma control questionnaire (ACQ)-7 score compared to combined doses of MF (treatment difference -0.209 mL, 95% CI -0.270 to -0.149, p<0.001), with a greater proportion of patients achieving a clinically important difference of ≥0.5 unit in ACQ-7 score on MF-IND than MF (76.3% vs 69.7%, OR 1.51, 95% CI 1.20 to 1.89, p<0.001). Improvements were also noted in trough forced vital capacity (FVC) and forced expiratory flow at 25 to 75% of pulmonary volume (FEF25-75%) for individuals assigned to the high- and medium dose MF-IND group. Individuals receiving high dose MF-IND experienced significantly fewer moderate or severe exacerbations compared to those receiving high dose MF (RR 0.65, 95% CI 0.48 to 0.89, p=0.008), as did those receiving medium dose MF-IND group versus medium dose MF group (RR 0.47, 95% CI 0.35 to 0.64, p<0.001). When comparing high dose MF-IND to widely used high dose FLU-SAL combination therapy, the former was found to be non-inferior in improving trough FEV1 after 26 weeks of therapy (treatment difference 36 mL, 95% CI -7 to 80, p=0.101). Finally, the incidence of of adverse events, defined as one or more of dysphonia, asthma exacerbation, and oral candidiasis, was substantially lower with high dose MF-IND compared to medium dose MF (122.7/100 patient-years vs 166.3/100 patient-years). In all, this study suggests that mometasone furoate-indacaterol dual therapy is superior to mometasone monotherapy or fluticasone propionate-salmeterol xinafoate in patients with prolonged and uncontrolled asthma.

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