Rationale Rescue therapy with as-needed albuterol−budesonide 180/160 µg (ALB−BUD) reduced the risk of a severe exacerbation by 47% compared with albuterol 180 µg (ALB) in participants with mild asthma in the BATURA trial. Limited but growing evidence in the literature suggests that even very brief dosing periods (3−7 days) of systemic corticosteroids (SCS) are enough to cause clinically important systemic adverse effects for patients. The efficacy of ALB-BUD to reduce SCS exposure compared with ALB is presented in this prespecified analysis of BATURA. Methods BATURA (NCT05505734), a phase 3b, double-blind, event-driven study, randomized participants ≥12 years of age with mild asthma (using as-needed short-acting β2-agonists ± low-dose inhaled corticosteroids or leukotriene modifiers) 1:1 to ALB−BUD or ALB, as-needed for 12−52 weeks. Severe exacerbations were defined as an exacerbation resulting in ≥3 days SCS use, an emergency-room/urgent care visit for asthma requiring SCS, hospitalization, or death. Here, we report the difference in total SCS exposure between treatment groups in prednisone equivalents. Results BATURA enrolled 2,421 participants (1,209 randomized to ALB−BUD, 1,212 to ALB). The median (interquartile range [IQR]) days on SCS per exacerbation was the same for both groups (6 [5, 8] days). The median (IQR) daily dose of SCS per exacerbation was 26.7 (20, 40) mg for ALB-BUD, and 28.7 (20, 41.2) mg for ALB. A total (annualized) of 263.4 and 549.0 courses of SCS were administered during the trial to the ALB-BUD and ALB groups, respectively, corresponding to a total (annualized) of 928.9 and 2066.8 days of SCS exposure, respectively. Mean annualized SCS exposure per patient was 23.2 mg in the ALB-BUD group and 61.9 mg in the ALB group, a difference of 38.7 mg and a 62.5% reduction (p<0.001; Wilcoxon rank sum test). In the subgroup of participants aged ≥18 years, the mean annualized SCS exposure per patient was 23.0 mg in the ALB-BUD group and 63.0 mg in the ALB group, a difference of 40.0 mg and a 63.5% reduction (p<0.001; Wilcoxon rank sum test). Total SCS exposure for the overall population was 2.7-fold greater in the ALB group compared to the ALB-BUD group (Figure). Conclusions In participants with mild asthma in the BATURA trial, rescue therapy with as-needed ALB-BUD reduced the total SCS exposure compared with ALB, reducing known risks from cumulative exposure to SCS.

BACKGROUND:As-needed use of albuterol-budesonide has been shown to result in a significantly lower risk of severe asthma exacerbation than as-needed use of albuterol alone among patients with moderate-to-severe asthma. Data on albuterol-budesonide in mild asthma are needed. METHODS:We conducted a fully virtual, decentralized, phase 3b, multicenter, double-blind, event-driven trial involving persons 12 years of age or older with disease that was uncontrolled despite treatment for mild asthma with a short-acting β2-agonist (SABA) with or without a low-dose inhaled glucocorticoid or leukotriene-receptor antagonist. Participants were randomly assigned in a 1:1 ratio to a fixed-dose combination of 180 μg of albuterol and 160 μg of budesonide (with each dose consisting of two inhaler actuations of 90 μg and 80 μg, respectively) or 180 μg of albuterol (with each dose consisting of two inhaler actuations of 90 μg) on an as-needed basis for up to 52 weeks. The primary end point was the first severe asthma exacerbation, assessed in a time-to-event analysis, in the on-treatment efficacy population, and the key secondary end point was the first severe exacerbation in the intention-to-treat population. Secondary end points included the annualized rate of severe asthma exacerbations and exposure to systemic glucocorticoids. RESULTS:A total of 2516 participants underwent randomization; 1797 (71.4%) completed the trial. Of 2421 participants in the full analysis population (1209 assigned to the albuterol-budesonide group and 1212 to the albuterol group), 97.2% were 18 years of age or older; 74.4% used a SABA alone at baseline. The trial was stopped for efficacy at a prespecified interim analysis. A severe exacerbation occurred in 5.1% of the participants in the albuterol-budesonide group and in 9.1% of those in the albuterol group in the on-treatment efficacy population (hazard ratio, 0.53; 95% confidence interval [CI], 0.39 to 0.73) and in 5.3% and 9.4%, respectively, in the intention-to-treat population (hazard ratio, 0.54; 95% CI, 0.40 to 0.73) (P<0.001 for both comparisons). The annualized rate of severe asthma exacerbations was lower with albuterol-budesonide than with albuterol (0.15 vs. 0.32; rate ratio, 0.47; 95% CI, 0.34 to 0.64), as was the mean annualized total dose of systemic glucocorticoids (23.2 vs. 61.9 mg per year). Adverse events were similar in the two treatment groups. CONCLUSIONS:As-needed use of albuterol-budesonide resulted in a lower risk of a severe asthma exacerbation than as-needed use of albuterol alone among participants with disease that was uncontrolled despite treatment for mild asthma. (Funded by Bond Avillion 2 Development and AstraZeneca; BATURA ClinicalTrials.gov number, NCT05505734.)See also in NEJM Evidence: Participants as Partners in Decentralized Clinical Trials.

Purpose: 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 β 2 -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.

Evaluate pulmonary safety of repeat dosing of Staccato® alprazolam (STAP) in healthy participants and those with mild asthma.

SESSION TITLE: Allergy and Airway Posters 2 SESSION TYPE: Original Investigation Posters PRESENTED ON: 10/10/2023 12:00 pm - 12:45 pm PURPOSE: Albuterol–budesonide pMDI was FDA-approved January 2023 for as-needed (prn) treatment or prevention of bronchoconstriction and to reduce exacerbation risk in patients ≥18yr with asthma. Approval relied on the MANDALA study, where prn albuterol–budesonide 180/160µg significantly reduced severe exacerbation risk by 27% vs albuterol in symptomatic patients ≥12yr with moderate-to-severe asthma and ≥1 severe exacerbation in the prior year receiving inhaled corticosteroid (ICS)-containing maintenance therapy. Here we describe BATURA, an ongoing Phase 3b study evaluating prn albuterol–budesonide safety and efficacy in participants with mild asthma. METHODS: BATURA is a fully decentralized, US, multicenter, randomized, double-blind, event-driven, asthma exacerbation study (NCT05505734). Participants aged ≥12yr using prn short-acting β2-agonist (SABA) alone or with low-dose ICS or leukotriene receptor agonist maintenance are randomized to prn albuterol–budesonide 180/160µg or albuterol 180µg for ≥12 weeks (max. 52 weeks). Participants must have used SABA on ≥2 days in the 2 weeks pre–enrollment and have an Asthma Impairment and Risk Questionnaire (AIRQTM) score ≥2. Participants continue their own maintenance therapy, if applicable. All visits, including screening and consent, are conducted virtually with study medication directly shipped to the participant. The primary objective is to evaluate the efficacy of prn albuterol–budesonide vs albuterol on severe asthma exacerbation risk; primary endpoint is time to first severe exacerbation, as in MANDALA. Secondary endpoints are annualized severe exacerbation rates and total systemic corticosteroid exposure. Safety endpoints are adverse events. Study medication use is captured electronically (Hailie® sensor). Intended sample size is 1910 (max. 2500), with a planned unblinded interim analysis when 172 severe exacerbation events (50% of target number) have occurred, to assess if the study may be stopped early for success. RESULTS: The first participant enrolled in September 2022. The study will continue (unless stopped at interim analysis for overwhelming efficacy) until either 350 severe exacerbations have occurred or the last randomized participant completes 12 months’ treatment. CONCLUSIONS: BATURA evaluates prn albuterol–budesonide efficacy and safety in participants ≥12yr with mild asthma. The decentralized virtual study model enables the trial to move out of the research site and into the participant’s home, thus reducing participant burden. CLINICAL IMPLICATIONS: Using a decentralized delivery model, BATURA aims to reach people who may not consider participating in clinical studies due to time/distance constraints, improving access for typically under-represented populations. Although albuterol–budesonide is approved across all asthma severities, BATURA will provide data from those with mild disease. DISCLOSURES: Employee relationship with Avillion LLP Please note: since 06/03/2019 Added 04 /03 /2023 by Frank Albers, source=Web Response, value=Salary Employee relationship with AstraZeneca Please note: July 2000 Added 04/04/2023 by Christy Cappelletti, source=Web Response, value=hold stock Employee relationship with AstraZeneca Please note: 2015 to date Added 04/03/2023 by Mark Cooper, source=Web Response, value=Salary No relevant relationships by Anna Danilewicz Employee relationship with AstraZeneca Please note: 01/05/2019 Added 04/03/2023 by Lynn Dunsire, source=Web Response, value=Shareholder Conduct Clinical Trials relationship with Avillion Please note: 2020-current Added 04/03/2023 by Craig LaForce, source=Web Response, value=Grant/Research Conduct Clinical Trial relationship with Amphastar Please note: 2020-Current Added 04/03/2023 by Craig LaForce, source=Web Response, value=Grant/Research Support Conduct Clinical Trial relationship with Chiesi Please note: 2020-Current Added 04/03/2023 by Craig LaForce, source=Web Response, value=Grant/Research Support Conduct Clinical Trial relationship with Novartis Please note: 2020-2022 Added 04/03/2023 by Craig LaForce, source=Web Response, value=Grant/Research Support Conduct Clinical Trial relationship with AstraZeneca Please note: 2020-Current Added 04/03/2023 by Craig LaForce, source=Web Response, value=Grant/Research Support No relevant relationships by Robert Rees

Background: PT027 is a fixed-dose combination of albuterol (salbutamol) and budesonide in a single pressurized metered-dose inhaler. Objective: To evaluate the efficacy and safety of albuterol/budesonide compared with placebo in patients with asthma and exercise-induced bronchoconstriction (EIB). Methods: In this randomized, double-blind, 2-period, single-dose crossover study, adolescents and adults with asthma and EIB (defined by >= 20% decrease from pre-exercise challenge forced expiratory volume in 1 second [FEV1]) were randomized to albuterol/budesonide (180/160 mu g) followed by placebo (n = 29) or the reverse sequence (n = 31). Subjects were stratified by background therapy (as-needed short-acting beta(2)-agonist alone or low-to-medium dose inhaled corticosteroid plus as-needed short-acting beta(2)-agonist). FEV1 was measured 5 minutes pre-dose, 30 minutes postdose (5 minutes pre-exercise challenge [baseline]), and 5, 10, 15, 30, and 60 minutes postexercise. The primary end point was maximum percentage fall from baseline in FEV1 up to 60 minutes postexercise challenge. Results: Least squares mean maximum percentage fall in FEV1 up to 60 minutes postexercise challenge was 5.45% with albuterol/budesonide vs 18.97% with placebo (difference, -13.51% [95% confidence interval, -16.94% to -10.09%]; P < .001). More subjects were fully protected (maximum percentage fall in FEV1 post-exercise challenge < 10%) with albuterol/budesonide than with placebo (78.3% vs 28.3%; P < .001). The treatment effect was consistent irrespective of background inhaled corticosteroid therapy, and albuterol/budesonide was well tolerated. Conclusion: In adolescents and adults with asthma and EIB, a single dose of albuterol/budesonide 180/160 mg taken approximately 30 minutes before exercise was significantly more effective than placebo in preventing EIB. (C) 2021 American College of Allergy, Asthma & Immunology. Published by Elsevier Inc.

Co-suspension Delivery™ Technology has been developed for the administration of albuterol sulfate pressurised inhalation suspension via metered-dose inhaler (AS MDI, PT007). We assessed the efficacy and safety of AS MDI versus Proventil® in order to determine the optimal dose of AS MDI to take to Phase III clinical trials. ASPEN (NCT03371459) and ANTORA (NCT03364608) were Phase II, randomised, crossover, multicentre studies of AS MDI versus Proventil® in patients with persistent asthma. In ASPEN, 46 patients received cumulative-dose treatments (90 μg/inhalation using 1 + 1 + 2 + 4 + 8 inhalations at 30-minute intervals) in 1 of 2 possible sequences: AS MDI/Proventil or Proventil/AS MDI. In ANTORA, 86 patients were randomised to one of 10 treatment sequences of AS MDI (90 μg or 180 μg), placebo MDI, or Proventil (90 μg or 180 μg). The primary endpoints were baseline-adjusted forced expiratory volume in 1 second (FEV1) 30 minutes after each cumulative dose (ASPEN) and change from baseline in FEV1 area under the curve from 0 to 6 h (ANTORA). Safety was assessed in both studies. In ASPEN, AS MDI was equivalent to Proventil (within pre-specified bounds of ± 200 mL) following cumulative doses of albuterol up to 1440 μg for the primary endpoint. In ANTORA, 90 μg and 180 μg doses of AS MDI and Proventil were significantly superior to placebo MDI (p < 0.0001), and AS MDI was non-inferior to Proventil at both doses, based on a margin of 100 mL. No new safety concerns were identified. The effects of albuterol delivered via AS MDI and Proventil on bronchodilation were equivalent, supporting the selection of AS MDI 180 µg to be taken into Phase III clinical trials, either alone or in combination with an inhaled corticosteroid. ASPEN (NCT03371459); Date of registration: 29/12/2017. ANTORA (NCT03364608); Date of registration: 15/12/2017.

BACKGROUND:Morbidity from asthma is disproportionately higher among black patients than among white patients, and black patients constitute the minority of participants in trials informing treatment. Data indicate that patients with inadequately controlled asthma benefit more from addition of a long-acting beta-agonist (LABA) than from increased glucocorticoids; however, these data may not be informative for treatment in black patients. METHODS:We conducted two prospective, randomized, double-blind trials: one involving children and the other involving adolescents and adults. In both trials, the patients had at least one grandparent who identified as black and had asthma that was inadequately controlled with low-dose inhaled glucocorticoids. We compared combinations of therapy, which included the addition of a LABA (salmeterol) to an inhaled glucocorticoid (fluticasone propionate), a step-up to double to quintuple the dose of fluticasone, or both. The treatments were compared with the use of a composite measure that evaluated asthma exacerbations, asthma-control days, and lung function; data were stratified according to genotypic African ancestry. RESULTS:When quintupling the dose of fluticasone (to 250 μg twice a day) was compared with adding salmeterol (50 μg twice a day) and doubling the fluticasone (to 100 μg twice a day), a superior response occurred in 46% of the children with quintupling the fluticasone and in 46% of the children with doubling the fluticasone and adding salmeterol (P = 0.99). In contrast, more adolescents and adults had a superior response to added salmeterol than to an increase in fluticasone (salmeterol-low-dose fluticasone vs. medium-dose fluticasone, 49% vs. 28% [P = 0.003]; salmeterol-medium-dose fluticasone vs. high-dose fluticasone, 49% vs. 31% [P = 0.02]). Neither the degree of African ancestry nor baseline biomarkers predicted a superior response to specific treatments. The increased dose of inhaled glucocorticoids was associated with a decrease in the ratio of urinary cortisol to creatinine in children younger than 8 years of age. CONCLUSIONS:In contrast to black adolescents and adults, almost half the black children with poorly controlled asthma had a superior response to an increase in the dose of an inhaled glucocorticoid and almost half had a superior response to the addition of a LABA. (Funded by the National Heart, Lung, and Blood Institute; BARD ClinicalTrials.gov number, NCT01967173.).

BACKGROUND In many patients with mild, persistent asthma, the percentage of eosinophils in sputum is less than 2% (low eosinophil level). The appropriate treatment for these patients is unknown. METHODS In this 42-week, double-blind, crossover trial, we assigned 295 patients who were at least 12 years of age and who had mild, persistent asthma to receive mometasone (an inhaled glucocorticoid), tiotropium (a long-acting muscarinic antagonist), or placebo. The patients were categorized according to the sputum eosinophil level (<2% or ≥2%). The primary outcome was the response to mometasone as compared with placebo and to tiotropium as compared with placebo among patients with a low sputum eosinophil level who had a prespecified differential response to one of the trial agents. The response was determined according to a hierarchical composite outcome that incorporated treatment failure, asthma control days, and the forced expiratory volume in 1 second; a two-sided P value of less than 0.025 denoted statistical significance. A secondary outcome was a comparison of results in patients with a high sputum eosinophil level and those with a low level. RESULTS A total of 73% of the patients had a low eosinophil level; of these patients, 59% had a differential response to a trial agent. However, there was no significant difference in the response to mometasone or tiotropium, as compared with placebo. Among the patients with a low eosinophil level who had a differential treatment response, 57% (95% confidence interval [CI], 48 to 66) had a better response to mometasone, and 43% (95% CI, 34 to 52) had a better response to placebo (P = 0.14). In contrast 60% (95% CI, 51 to 68) had a better response to tiotropium, whereas 40% (95% CI, 32 to 49) had a better response to placebo (P = 0.029). Among patients with a high eosinophil level, the response to mometasone was significantly better than the response to placebo (74% vs. 26%) but the response to tiotropium was not (57% vs. 43%). CONCLUSIONS The majority of patients with mild, persistent asthma had a low sputum eosinophil level and had no significant difference in their response to either mometasone or tiotropium as compared with placebo. These data provide equipoise for a clinically directive trial to compare an inhaled glucocorticoid with other treatments in patients with a low eosinophil level. (Funded by the National Heart, Lung, and Blood Institute; SIENA ClinicalTrials.gov number, NCT02066298.).

Introduction Seasonal allergic rhinitis (SAR) symptoms often impair quality of life (QoL). In two randomized, double-blind phase 3 studies, twice-daily GSP301 nasal spray, a fixed-dose combination of olopatadine hydrochloride/mometasone furoate, significantly improved reflective and instantaneous Total Nasal Symptom Scores (rTNSS, primary endpoint; iTNSS, secondary endpoint) vs placebo (presented elsewhere). Results of additional endpoints comparing the efficacy and QoL of GSP301 vs placebo are reported here. Methods In study 1 (NCT02631551; N=1,180) and study 2 (NCT02870205; N=1,176), patients with SAR (≥12 years) were randomized 1:1:1:1 to GSP301 (olopatadine 665μg/mometasone 25μg BID), olopatadine (665μg BID), mometasone (25μg BID), or placebo for 14 days. Mean changes from baseline in Physician-assessed Nasal Symptom Score (PNSS) and Rhinoconjunctivitis Quality of Life Questionnaire–Standardized Activities [RQLQ(S)] for GSP301 vs placebo were analyzed using mixed-effect model repeated measures (P Results GSP301 significantly improved PNSS vs placebo in study 1 (least squares mean difference [95% CI]: -0.82 [-1.26, -0.38], PPPPP Conclusions In two phase 3 SAR studies, twice-daily GSP301 treatment provided significant improvements in nasal symptoms and QoL vs placebo and was well tolerated.

Introduction:The safety, lung function efficacy, and symptomatic benefits of combined tiotropium and olodaterol in patients with COPD were established in the 1-year TONADO® studies (NCT01431274; NCT01431287). As tiotropium is predominantly excreted by the kidneys, the long-term safety profile of tiotropium/olodaterol was investigated in patients with renal impairment in a prespecified safety analysis of the TONADO studies. Methods:These were 2 replicate, randomized, double-blind, parallel-group, 52-week Phase III studies that assessed tiotropium/olodaterol compared with tiotropium or olodaterol alone (all via Respimat®) in patients with moderate-to-very severe COPD. In this analysis, renal impairment was defined as mild (creatinine clearance [CLcr] 60-89 mL/min), moderate (CLcr 30-59 mL/min) or severe (CLcr 15-29 mL/min). Adverse events (AEs) were pooled from both studies. Results:Of 3,041 patients included in this analysis, 1,333 (43.8%) had mild, 404 (13.3%) had moderate, and 5 (0.2%) had severe renal impairment; these were distributed equally between treatment groups. Almost one-quarter of all treated patients (23.4%) had a history of cardiac disorder, 45.6% had hypertension, and 13.3% had glucose metabolism disorders, including diabetes. AEs with olodaterol, tiotropium, and tiotropium/olodaterol occurred in 75.1%, 70.8%, and 72.0% of patients with no renal impairment, 75.7%, 74.0%, and 73.3% with mild renal impairment, and 84.3%, 79.5%, and 79.7% with moderate renal impairment, respectively. There was no notable effect of renal impairment on the proportion of patients with an AE, and no differences were observed between tiotropium/olodaterol versus the monocomponents. There was no difference in the incidence of major adverse cardiac events, renal and urinary tract AEs, or potential anticholinergic effects with increasing severity of renal impairment. Conclusion:Over half the patients enrolled in the TONADO studies had renal impairment, and there was a high level of pre-existing cardiovascular comorbidity. The safety and tolerability of tiotropium/olodaterol is comparable to the monocomponents, irrespective of the level of renal impairment.