A32-41 As-needed Albuterol-budesonide Decreases Risk of Severe Asthma Exacerbation in Patients ≥18 Years of Age Using Either GINA Step-3 or GINA Step 4 + 5 Maintenance Therapies: MANDALA Post-hoc Analysis

Rationale

MANDALA showed as-needed albuterol−budesonide 180/160 μg reduced severe asthma exacerbation risk (time-to-first severe exacerbation) in moderate-to-severe disease by 27% versus albuterol 180 μg in the on-treatment population ≥12 years old, with patient data up to 85 weeks included. Although the study was not powered to assess risk reduction for maintenance therapy subpopulations, participants utilizing Global Initiative for Asthma (GINA 2018) Step-3-containing therapies (low-dose inhaled corticosteroid [ICS]/long-acting β2-agonist [LABA] or medium-dose ICS) showed a significant risk reduction of 40%, whereas those taking GINA Step-4 (medium-dose ICS-LABA or high-dose ICS) or Step-5 (high-dose ICS-LABA) maintenance showed numerical but non-significant risk reduction (20% and 23%, respectively). This post-hoc analysis explored albuterol−budesonide risk reduction efficacy in the on-treatment subpopulations ≥18 years utilizing GINA Step-3 (moderate disease) and combining Step 4 + 5 (severe disease) therapies.

Methods

MANDALA was an event-driven study in symptomatic patients with ≥1 prior-year severe exacerbation, receiving ICS-containing GINA 3 − 5 maintenance therapies. This analysis assessed exacerbation risk reduction over the course of the study, time-to-first day of significant risk reduction, time-to-sustained risk reduction, and subject-based number needed to treat (NNT) at 1-year follow-up in the as-needed albuterol−budesonide versus albuterol arms based on disease severity maintenance therapy. Time-to-first exacerbation was analyzed using a Cox proportional hazards model. To determine day when risk reduction was sustained, we examined the time point at which the upper bounds of the treatment confidence interval (CI) remained below unity for the remainder of the trial.

Results

963 participants in the albuterol−budesonide arm (mean[SD] age=51.9[13.7] years, 65% female; 31.3% GINA 3, 68.7% GINA 4 + 5) and 962 in the albuterol arm (51.9[14.2] years, 68% female; 29.5% GINA 3, 70.5% GINA 4 + 5) were included. Over the course of the study, albuterol−budesonide versus albuterol decreased exacerbation risk by 29% for the total population (p < 0.001) and 41% (p = 0.005) and 24% (p = 0.012) for the GINA 3 and GINA 4 + 5 subpopulations, respectively (Figure). First significant risk reduction with as-needed albuterol−budesonide for the total, GINA 3, and GINA 4 + 5 subpopulations occurred at day 29, 41, and 31, with first day of sustained risk reduction occurring at day 84 (25% risk reduction, p = 0.037), 147 (36% risk reduction, p = 0.046), and 111 (25% risk reduction, p = 0.041), respectively. NNT for the total, GINA 3, and GINA 4 + 5 subpopulations was 13, 10 and 16, respectively.

Conclusions

In patients aged ≥18 years with uncontrolled asthma using daily therapies for moderate or severe disease, as-needed albuterol−budesonide reduces severe exacerbation risk compared to albuterol.

This abstract is funded by: The study was funded by Bond Avillion 2 Development LP. Statistical analyses presented here and medical writing support were funded by AstraZeneca.