The use of a combination of albuterol and budesonide as rescue medication in patients with uncontrolled moderate to severe asthma markedly reduced the risk of acute exacerbations, according to the MANDALA trial published in the New England Journal of Medicine.¹

The multinational, phase III MANDALA trial aimed to test the efficacy and safety of albuterol–budesonide as a rescue medication in 3132 patients with uncontrolled moderate-to-severe asthma. For this, they enrolled patients who had moderate to severe asthma for the last four years and experienced at least one severe exacerbation episode in the preceding year even with maintenance therapy. The mean age of the participants was about 49 years; nearly 65% were female. All the participants had been taking ICS-containing asthma maintenance therapy, which they continued with all through the trial.

Participants older than 12 years of age were randomized in 1:1:1 ratio to three treatment arms: higher-dose combination group (albuterol/budesonide 180/160 μg with two inhalations of 90/80 μg), lower-dose combination group (albuterol/budesonide 180/80 μg with two inhalations of 90/40 μg) and the albuterol-alone group (180 μg with two inhalations of 90 μg). Those aged 4-11 years were randomized to either the lower-dose combination group or the albuterol-alone group.

Over the follow-up period of two years, the risk of severe exacerbation was reduced by 26% in the higher-dose combination group and by 16% in the lower-dose combination group. The time to first severe exacerbation, which was the primary efficacy endpoint, was significantly prolonged in both higher-dose and lower-dose combination groups with hazard ratios of 0.74 and 0.84, respectively.

Compared to treatment with albuterol alone, a marked decrease in the secondary endpoint of annualized severe exacerbation rate was seen with the two doses of albuterol/budesonide. The rate ratio for the higher dose group was 0.76 and that for the lower dose group was 0.80. Fewer patients in the higher combination group required systemic steroids. This group of patients also had higher Asthma Control Questionnaire (ACQ-5) (66.8% vs 61.6%) and Asthma Quality of Life Questionnaire (AQLQ+12) (51.1% vs 46.4%) responder rates than treatment with albuterol alone. The incidence of adverse events was comparable between the three treatment groups.

Asthma is an inflammatory disease and the degree of inflammation is proportional to the severity of symptoms. Albuterol, a fast-acting bronchodilator, only dilates the airways; it does not address the underlying inflammation. Results of the MANDALA trial show that use of the fixed dose combination of the short-acting beta agonist albuterol and the anti-inflammatory budesonide as “as-needed” rescue medication significantly reduced the risk of severe asthma exacerbations in patients with moderate-to-severe asthma vs albuterol alone. The higher dose of the FDC also reduced the need for systemic steroids. More patients treated with albuterol/budesonide had significant improvement in symptoms and thus quality of life.

Reference

1. Papi A, et al. Albuterol-budesonide fixed-dose combination rescue inhaler for asthma. N Engl J Med. 2022 May 15. doi: 10.1056/NEJMoa2203163.