Fixed-dose albuterol/budesonide an effective rescue med in moderate-to-severe asthma
A fixed-dose combination of albuterol and budesonide, delivered as needed, reduced the risk of severe exacerbations in patients with moderate-to-severe asthma inadequately controlled with corticosteroid maintenance therapy, according to results of the phase III MANDALA trial presented at ATS 2022.
This multinational, event-driven, double-blind trial involved 3,123 patients aged ≥4 years (mean age 49.4 years, 64.8 percent female) with symptomatic, uncontrolled moderate-to-severe asthma (≥1 severe exacerbation in the prior 12 months; mean ACQ-5* score 2.6) receiving inhaled corticosteroid maintenance therapies**. Patients aged ≥12 years were randomized 1:1:1 to receive fixed-dose albuterol/budesonide (180 µg/160 µg; each dose comprised two actuations of 90 μg/80 μg [high-dose combination group]), albuterol/budesonide (180 μg/80 µg; each dose comprised two actuations of 90 μg/40 μg [lower-dose combination group]), or albuterol only (180 μg; each dose comprised two actuations of 90 μg). Children aged 4–11 years were randomized to either the lower-dose combination or albuterol-only groups.
The medications were delivered via a pressurized metered-dose inhaler and administered as needed in presence of symptoms or before exercise, with a maximum of six doses/day.
In the intention-to-treat analysis, compared with patients who received albuterol only, those who received the higher-dose combination experienced a significantly reduced risk of severe asthma exacerbation*** (hazard ratio [HR], 0.74, 95 percent confidence interval [CI], 0.62–0.89; p=0.001). [ATS 2022, Session B93; N Engl J Med 2022;doi:10.1056/NEJMoa2203163]
There was a trend toward a reduced risk of severe asthma exacerbation with the lower dose of albuterol/budesonide compared with albuterol only (HR, 0.84, 95 percent CI, 0.71–1.00; p=0.052).
Annualized severe asthma exacerbation rate was 0.43 and 0.58 in the higher-dose combination and albuterol-only groups, respectively (rate ratio [RR], 0.75), and 0.48 and 0.60 in the lower-dose combination and albuterol-only groups, respectively (RR, 0.81).
Annualized total cumulative systemic glucocorticoid exposure (prednisolone equivalent) during the treatment period was a mean 83.6 and 130.0 mg in the higher-dose combination and albuterol-only groups, respectively, and 94.7 and 127.6 mg in the lower-dose combination and albuterol-only groups, respectively.
Incidence of ≥1 severe exacerbation warranting hospitalization was reported in nine, 10, and 17 patients in the higher-dose, lower-dose, and albuterol-only groups, respectively, while incidence warranting emergency department or urgent care was reported in 49, 50, and 66 patients, respectively.
At week 24, response (≥0.5-point improvement from baseline) on ACQ-5 was recorded in 66.8 and 62.1 percent of patients in the higher-dose combination and albuterol-only groups (odds ratio [OR], 1.22), and in 64.7 and 61.6 percent of patients in the lower-dose and albuterol-only groups (OR, 1.13). Response on Asthma Quality of Life Questionnaire (for patients aged ≥12 years; AQLQ+12) was recorded in 51.1, 49.5, and 46.4 percent of patients in the higher-dose, lower-dose, and albuterol-only groups, respectively (ORs, 1.23 and 1.11 for higher and lower dose combination, respectively, vs albuterol only).
As-needed use of trial medication was comparable between groups at approximately 1.3, 1.3, and 1.4 doses/day in the higher-dose, lower-dose, and albuterol-only groups, respectively.
Acceptable safety profile
Adverse events (AEs) were reported in 46.2, 47.1, and 46.4 percent of patients in the higher-dose, lower-dose, and albuterol-only groups, respectively, and serious AEs (including death) in 5.2, 3.8, and 4.5 percent, respectively. None of the seven deaths were considered related to trial medication. AEs led to discontinuation in 1.0, 0.9, and 0.9 percent, respectively.
The most common AEs were nasopharyngitis, headache, COVID-19, and upper respiratory tract infections. The most common inhaled glucocorticoid-related AEs were oral candidiasis, dysphonia, and oropharyngeal candidiasis, all of which occurred at low rates (≤1.0 percent of patients).
“Both doses of albuterol/budesonide had an acceptable safety profile that was consistent with that of the active components, with no safety concerns identified,” said the authors.
A new rescue option
Short-acting β2-agonists (SABAs) are the usual rescue therapy option for asthma symptom exacerbation, said the authors. “However, SABAs have little effect on underlying airway inflammation, and overreliance on SABAs serves as a metric for poor asthma control.”
“Given the risks and limitations of SABA alone as rescue therapy, national and international recommendations call for an inhaled glucocorticoid-containing rescue medication as the preferred as-needed treatment,” they continued.
“Given its acceptable safety profile, the greater efficacy of the fixed-dose combination than of albuterol alone, as well as the absence of a need to change underlying maintenance therapy, indicates that this fixed-dose combination could replace SABA alone as rescue therapy in patients with moderate-to-severe asthma,” the authors concluded.