Alberto Papi,et al.

Background:As 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 fixeddose combination of albuterol and budesonide,as compared with albuterol alone,as rescue medication might reduce the risk of severe asthma exacerbation.

Methods:We 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-tosevere 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.

Results:A 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.

Conclusions:The 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.).