Albuterol-Budesonide Fixed Dose Combination Rescue Inhaler for Asthma – The MANDALA Trial

Albuterol-Budesonide Fixed Dose Combination Rescue Inhaler for Asthma – The MANDALA Trial
Toua Chang, PharmD
Minnesota Community Care

Background: Patients with asthma typically rely on a short-acting β2-agonist (SABA) for rescue therapy when experiencing symptoms such as cough, wheezing, or shortness of breath. However, SABAs are not effective at treating the underlying airway inflammation associated with asthma. An overreliance on SABAs alone may leave patients at risk for severe asthma exacerbations. The Global Initiative for Asthma (GINA) has recently updated their recommendations to include inhaled corticosteroid (ICS)/formoterol therapy as the preferred rescue therapy in patients with a range of asthma severities. However, data regarding use of ICS/SABA rescue therapy in patients with moderate-to-severe asthma is still limited. 

Purpose: The primary objective of this trial was to evaluate the safety and efficacy of albuterol-budesonide combination rescue therapy versus use of albuterol-alone rescue therapy in patients with uncontrolled moderate-to-severe asthma. 

Study Design: This multinational, double-blind, event-driven, phase 3 study was designed to take place for a minimum of 24 weeks and continue until ≥570 first events of severe asthma exacerbation had been reported. Inclusion criteria was as follows: ≥4 years of age, ≥1 severe asthma exacerbation in the previous 12 month, and moderate-to-severe asthma (defined as previous treatment with medium-to-high doses of ICS or low-to-high doses of ICS/LABA combination for ≥3 months, with stable dosing for at least 4 weeks). Adults and adolescents (≥12 years of age) were randomly assigned in a 1:1:1 ratio to one of the three treatment groups: high-dose combination inhaler (180 μg albuterol and 160 μg budesonide), low-dose combination inhaler (90 μg albuterol and 40 μg budesonide), or albuterol-alone inhaler (180 μg). Children 4 to 11 years of age were not assigned to the high-dose combination treatment group due to concerns regarding high-dose ICS use in younger populations. Patients were assessed for inhaler competency and instructed to only use trial medications for rescue therapy. The primary efficacy endpoint was the first event of severe asthma exacerbation. Secondary efficacy endpoints were the annualized rate of severe asthma exacerbations, total systemic glucocorticoid exposure for asthma during the treatment period, and treatment response via various asthma evaluation questionnaires. Safety endpoints included incidence of adverse events and serious adverse events. 

Results: Between December 27, 2018 and July 30, 2021, a total of 3132 patients underwent randomization, of which 3123 were evaluated for efficacy endpoints and 3127 were evaluated for safety endpoints. The trial had a low dropout rate, with 93% of patients completing the 24-week treatment period. Intention-to-treat analysis of the primary endpoint showed that for adults and adolescents ≥12 years, the risk of a severe asthma exacerbation was significantly lower in the high-dose combination group than in the albuterol-alone group (HR 0.74; 95% CI, 0.62 to 0.89; P=0.001). The hazard ratio in the lower-dose combination group, which included children 4 to 12 years of age, versus the albuterol-alone group was 0.84 (95% CI, 0.71 to 1.00; P=0.052), which was insignificant. Secondary endpoints showed similar results in that the high-dose combination therapy was numerically superior to albuterol-alone. The rate of any adverse event was similar among the three trial groups (46.2% in the higher-dose combination group, 47.1% in the lower-dose combination group, and 46.4% in the albuterol-alone group). 

Conclusion: In patients with uncontrolled moderate-to-severe asthma receiving ICS-containing maintenance therapy, risk of severe asthma exacerbation was significantly lower for those using the high-dose combination inhaler as rescue therapy compared to albuterol-alone inhaler. The use of the trial medications were consistent among all three groups, which limits potential bias and adds validity to the results. Children between 4 and <12 years of age only made up 2.7% of all patients and the next age bracket (patients ≥12 to <18 years) at 3.2% respectively, limiting the external validity to children. 

Key Points/Clinical Impact: The primary endpoint (first event of severe asthma exacerbation) was significantly lower for the high-dose combination group compared to the albuterol-alone group in both the pre-specified and pre-planned analyses. The results of this trial may lead to a shift in practice for adult patients with uncontrolled moderate-to-severe asthma who are receiving ICS-containing therapy. Patients may now see more benefit with an ICS/SABA combination rescue therapy versus an albuterol-alone therapy. Astra-Zeneca and Avillion were major funders of this trial and they have filed a New Drug Application for this combination product.

Reference:

  1. Papi A, Chipps BE, Beasley R, et al. Albuterol-Budesonide Fixed-Dose Combination Rescue Inhaler for Asthma. N Engl J Med. 2022;386(22):2071-2083. doi:10.1056/NEJMoa2203163