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Craig LaForce,1 Frank C Albers,2 Mark Cooper,3 Anna Danilewicz,4 Lynn Dunsire,3 Robert Rees,4 Christy Cappelletti5 1North Carolina Clinical Research, Chapel Hill, NC, USA; 2Avillion, Northbrook, IL, USA; 3BioPharmaceuticals Research and Development, AstraZeneca, Cambridge, UK; 4Avillion, London, UK; 5BioPharmaceuticals Research and Development, AstraZeneca, Durham, NC, USACorrespondence: Mark Cooper, BioPharmaceuticals Reseach and Development, AstraZeneca, Cambridge, UK, Email mark.cooper1@astrazeneca.comPurpose: Decentralized clinical trials, where trial-related activities occur at locations other than traditional clinical sites(eg participant homes, local healthcare facilities), have the potential to improve trial access for people for whom time and/or distance constraints may impede participation. Albuterol–budesonide 180/160 μg pressurized metered-dose inhaler (pMDI) is FDA approved for the as-needed treatment or prevention of bronchoconstriction and to reduce the risk of exacerbations in patients with asthma 18 years or older. BATURA (NCT05505734) is a fully decentralized study, investigating as-needed albuterol–budesonide in participants with mild asthma.Methods: BATURA is a fully decentralized, phase 3b, randomized, double-blind, event-driven exacerbation study conducted in the United States. Participants aged ≥ 12 years using as-needed short-acting β2-agonist (SABA), alone or with low-dose inhaled corticosteroid or leukotriene receptor antagonist maintenance, are randomized 1:1 to as-needed albuterol–budesonide 180/160 μg or albuterol 180 μg pMDI for up to 52 weeks (minimum 12 weeks). Participants continue their current maintenance therapy, if applicable. Participants must have used SABA for ≥ 2 days in the 2 weeks pre-enrollment and have an Asthma Impairment Risk Questionnaire score ≥ 2 at screening and randomization. All trial-related visits, including screening and consent, are conducted virtually, with study medication shipped directly to each participant’s residence. The primary objective is to evaluate the efficacy of as-needed albuterol–budesonide versus albuterol on severe asthma exacerbation risk, measured by time-to-first severe asthma exacerbation (primary endpoint). Secondary endpoints include annualized rate of severe asthma exacerbation and total systemic corticosteroid exposure. Study medication use is captured via a Hailie sensor attached to the study medication pMDI. The intended sample size is 2500 participants.Conclusion: BATURA evaluates as-needed albuterol–budesonide in participants with mild asthma. The decentralized study model enables the trial to move out of research sites into participant homes, reducing participant burden and improving access.Keywords: decentralized clinical trials, trial design, albuterol–budesonide, SABA–ICS

What is this summary about? This summary describes the results of a clinical study called MANDALA that was published in the New England Journal of Medicine in 2022. In the MANDALA study, researchers looked at a new asthma rescue inhaler that contains both albuterol and budesonide in a single inhaler (known as albuterol-budesonide , AIRSUPRA™). This summary describes the results for people aged 18 yearsand older who took part in the study.

Background: In the phase 3 MANDALA trial, as-needed albuterol-budesonide pressurized metered-dose inhaler significantly reduced severe exacerbation risk vs as-needed albuterol in patients with moderate-to-severe asthma receiving inhaled corticosteroid-containing maintenance therapy. This study (DENALI) was conducted to address the US Food and Drug Administration combination rule, which requires a combination product to demonstrate that each component contributes to its efficacy., Research Question: Do both albuterol and budesonide contribute to the efficacy of the albuterol-budesonide combination pressurized metered-dose inhaler in patients with asthma?, Study Design and Methods: This phase 3 double-blind trial randomized patients aged ≥ 12 years with mild-to-moderate asthma 1:1:1:1:1 to four-times-daily albuterol-budesonide 180/160 μg or 180/80 μg, albuterol 180 μg, budesonide 160 μg, or placebo for 12 weeks. Dual-primary efficacy end points included change from baseline in FEV 1 area under the curve from 0 to 6 h (FEV 1 AUC 0-6h ) over 12 weeks (assessing albuterol effect) and trough FEV 1 at week 12 (assessing budesonide effect)., Results: Of 1,001 patients randomized, 989 were ≥ 12 years old and evaluable for efficacy. Change from baseline in FEV 1 AUC 0-6h over 12 weeks was greater with albuterol-budesonide 180/160 μg vs budesonide 160 μg (least-squares mean [LSM] difference, 80.7 [95% CI, 28.4-132.9] mL; P = .003). Change in trough FEV 1 at week 12 was greater with albuterol-budesonide 180/160 and 180/80 μg vs albuterol 180 μg (LSM difference, 132.8 [95% CI, 63.6-201.9] mL and 120.8 [95% CI, 51.5-190.1] mL, respectively; both P < .001). Day 1 time to onset and duration of bronchodilation with albuterol-budesonide were similar to those with albuterol. The albuterol-budesonide adverse event profile was similar to that of the monocomponents., Interpretation: Both monocomponents contributed to albuterol-budesonide lung function efficacy. Albuterol-budesonide was well tolerated, even at regular, relatively high daily doses for 12 weeks, with no new safety findings, supporting its use as a novel rescue therapy., Clinical Trial Registration: ClinicalTrials.gov; No.: NCT03847896; URL: www., Clinicaltrials: gov., (Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.)

Background: As asthma symptoms worsen, patients typically rely on short-acting β 2 -agonist (SABA) rescue therapy, but SABAs do not address worsening inflammation, which leaves patients at risk for severe asthma exacerbations. The use of a fixed-dose combination of albuterol and budesonide, as compared with albuterol alone, as rescue medication might reduce the risk of severe asthma exacerbation., Methods: We conducted a multinational, phase 3, double-blind, randomized, event-driven trial to evaluate the efficacy and safety of albuterol-budesonide, as compared with albuterol alone, as rescue medication in patients with uncontrolled moderate-to-severe asthma who were receiving inhaled glucocorticoid-containing maintenance therapies, which were continued throughout the trial. Adults and adolescents (≥12 years of age) were randomly assigned in a 1:1:1 ratio to one of three trial groups: a fixed-dose combination of 180 μg of albuterol and 160 μg of budesonide (with each dose consisting of two actuations of 90 μg and 80 μg, respectively [the higher-dose combination group]), a fixed-dose combination of 180 μg of albuterol and 80 μg of budesonide (with each dose consisting of two actuations of 90 μg and 40 μg, respectively [the lower-dose combination group]), or 180 μg of albuterol (with each dose consisting of two actuations of 90 μg [the albuterol-alone group]). Children 4 to 11 years of age were randomly assigned to only the lower-dose combination group or the albuterol-alone group. The primary efficacy end point was the first event of severe asthma exacerbation in a time-to-event analysis, which was performed in the intention-to-treat population., Results: A total of 3132 patients underwent randomization, among whom 97% were 12 years of age or older. The risk of severe asthma exacerbation was significantly lower, by 26%, in the higher-dose combination group than in the albuterol-alone group (hazard ratio, 0.74; 95% confidence interval [CI], 0.62 to 0.89; P = 0.001). The hazard ratio in the lower-dose combination group, as compared with the albuterol-alone group, was 0.84 (95% CI, 0.71 to 1.00; P = 0.052). The incidence of adverse events was similar in the three trial groups., Conclusions: The risk of severe asthma exacerbation was significantly lower with as-needed use of a fixed-dose combination of 180 μg of albuterol and 160 μg of budesonide than with as-needed use of albuterol alone among patients with uncontrolled moderate-to-severe asthma who were receiving a wide range of inhaled glucocorticoid-containing maintenance therapies. (Funded by Avillion; MANDALA ClinicalTrials.gov number, NCT03769090.)., (Copyright © 2022 Massachusetts Medical Society.)