• Alberto Papi, Bradley E Chipps, Richard Beasley, Reynold A Panettieri, Elliot Israel, Mark Cooper, Lynn Dunsire, Allison Jeynes-Ellis, Eva Johnsson, Robert Rees, Christy Cappelletti, and Frank C Albers.
• From the Department of Respiratory Medicine, University of Ferrara Medical School, Ferrara, Italy (A.P.); the Capital Allergy and Respiratory Disease Center, Sacramento, CA (B.E.C.); the Medical Research Institute of New Zealand, Capital and Coast District Health Board, and Victoria University Wellington - all in Wellington, New Zealand (R.B.); Rutgers Institute for Translational Medicine and Science, Child Health Institute of New Jersey, Rutgers, the State University of New Jersey, New Brunswick (R.A.P.); Brigham and Women's Hospital, Harvard Medical School, Boston (E.I.); BioPharmaceuticals Research and Development, AstraZeneca, Cambridge (M.C., L.D.), and Avillion, London (A.J.-E., R.R.) - both in the United Kingdom; BioPharmaceuticals Research and Development, AstraZeneca, Gothenburg, Sweden (E.J.); BioPharmaceuticals Research and Development, AstraZeneca, Durham, NC (C.C.); and Avillion, Northbrook, IL (F.C.A.).
• N. Engl. J. Med. 2022 Jun 2; 386 (22): 207120832071-2083.

BackgroundAs asthma symptoms worsen, patients typically rely on short-acting β2-agonist (SABA) rescue therapy, but SABAs do not address worsening inflammation, which leaves patients at risk for severe asthma exacerbations. The use of a fixed-dose combination of albuterol and budesonide, as compared with albuterol alone, as rescue medication might reduce the risk of severe asthma exacerbation.MethodsWe conducted a multinational, phase 3, double-blind, randomized, event-driven trial to evaluate the efficacy and safety of albuterol-budesonide, as compared with albuterol alone, as rescue medication in patients with uncontrolled moderate-to-severe asthma who were receiving inhaled glucocorticoid-containing maintenance therapies, which were continued throughout the trial. Adults and adolescents (≥12 years of age) were randomly assigned in a 1:1:1 ratio to one of three trial groups: a fixed-dose combination of 180 μg of albuterol and 160 μg of budesonide (with each dose consisting of two actuations of 90 μg and 80 μg, respectively [the higher-dose combination group]), a fixed-dose combination of 180 μg of albuterol and 80 μg of budesonide (with each dose consisting of two actuations of 90 μg and 40 μg, respectively [the lower-dose combination group]), or 180 μg of albuterol (with each dose consisting of two actuations of 90 μg [the albuterol-alone group]). Children 4 to 11 years of age were randomly assigned to only the lower-dose combination group or the albuterol-alone group. The primary efficacy end point was the first event of severe asthma exacerbation in a time-to-event analysis, which was performed in the intention-to-treat population.ResultsA total of 3132 patients underwent randomization, among whom 97% were 12 years of age or older. The risk of severe asthma exacerbation was significantly lower, by 26%, in the higher-dose combination group than in the albuterol-alone group (hazard ratio, 0.74; 95% confidence interval [CI], 0.62 to 0.89; P = 0.001). The hazard ratio in the lower-dose combination group, as compared with the albuterol-alone group, was 0.84 (95% CI, 0.71 to 1.00; P = 0.052). The incidence of adverse events was similar in the three trial groups.ConclusionsThe risk of severe asthma exacerbation was significantly lower with as-needed use of a fixed-dose combination of 180 μg of albuterol and 160 μg of budesonide than with as-needed use of albuterol alone among patients with uncontrolled moderate-to-severe asthma who were receiving a wide range of inhaled glucocorticoid-containing maintenance therapies. (Funded by Avillion; MANDALA ClinicalTrials.gov number, NCT03769090.).Copyright © 2022 Massachusetts Medical Society.

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