In patients with uncontrolled moderate-to-severe asthma, the risk of asthmatic exacerbation was significantly reduced when patients used a fixed-dose inhaler with a combination of albuterol and budesonide as-needed compared with the use of an inhaler with albuterol alone as-needed, in a dose-dependent manner.

The phase III, double-blind, randomized, event-driven MANDALA trial (NCT03769090) looked at patients with uncontrolled moderate-to-severe asthma, and asked whether a fixed-dose combination of short-acting beta-2 agonist albuterol (180 μg) and the inhaled corticosteroid budesonide (160 μg) could be used as an as-needed rescue medication to lower the risk for severe asthma exacerbations compared with albuterol monotherapy used as an as-needed rescue inhaler. Prof. Alberto Papi (University of Ferrara, Italy) presented the results, which were simultaneously published in the New England Journal of Medicine [1,2]. MANDALA enrolled patients with moderate to severe asthma of >3 years old, and who had had ³1 severe exacerbation in the prior 12 months. Despite allowing children, only 183 of 3,132 randomized patients were pediatric patients; the mean age of the intention-to-treat population was 49 years. Participants were allocated to 1 of 3 arms: an arm receiving the combination with a high-dose of budesonide (albuterol 180 µg/budesonide 160 µg), a lower-dose arm (albuterol 180 µg/budesonide 800 µg), or albuterol 180 µg alone. Study medication was administered through blinded, pressurized metered-dose inhalers. All patients continued receiving maintenance inhaled corticosteroids either with or without other medications for their asthma. The primary endpoint was time to first severe asthma exacerbation, which reported a 27% reduction among patients assigned a fixed-dose combination of the higher dose combination compared with albuterol 180 µg alone (HR 0.73; 95% CI 0.61–0.88; P<0.001). Similarly, a 17% reduction was observed with the lower-dose combination arm (HR 0.83; 95% CI 0.7–0.99; P=0.041), but the data did suggest a dose-response. In an additional intention-to-treat analysis, risk was reduced by 26% with the higher-dose combination (HR 0.74; 95% CI 0.62–0.89; P=0.001) and 16% with the lower-dose combination (HR 0.84; 95% CI 0.71–1.0; P=0.052). With regard to safety, the incidence of any adverse event was nearly identical across all 3 groups, with 46.2% in the higher-dose combination group, 47.1% in the lower-dose combination group, and 46.4% in the albuterol-only group. Similarly, serious adverse events occurred in 5.2%, 3.8%, and 4.5%, respectively. Adverse events were consistent with the known safety profiles of the individual components; the most common adverse events were nasopharyngitis, headache, and upper respiratory tract infection. “Given the efficacy of adding budesonide to albuterol as a rescue medication and the duration of the treatment, we believe that this is going to be a potential change in the paradigm of the use of rescue medication,” Prof. Papi concluded.

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