Randomized controlled trials (RCTs) underpin evidence-based medicine, but a growing proportion of trials contain implausible, inaccurate, or fabricated data. When such studies are incorporated into systematic reviews, they distort effects estimates, inflate evidence certainty, and can mislead the guideline recommendations that the reviews aim to inform. Within eight recent American Academy of Allergy, Asthma & Immunology (AAAAI) and American College of Allergy, Asthma and Immunology (ACAAI) Joint Task Force on Practice Parameters (JTFPP) systematic reviews, 17% of trials published between 2021-2024 were problematic, and in a network meta-analysis of antihistamines for chronic urticaria, 39% of recent trials were excluded due to implausible data, statistical anomalies, and discrepancies between protocols and the final publication. The proliferation of generative AI further facilitates the ability to produce superficially credible, but flawed reports. Standardized tools have been developed to offer systematic approaches to detecting problematic trials, but robust safeguards such as verifiable ethics approval, prospective protocol registration, and adherence to structure reporting guidelines remain essential. As part of efforts to ensure quality research, the JTFPP will continue to update our systematic reviews to remove problematic trials as they are identified. We believe that this approach will promote the development of trustworthy guideline recommendations.

Network meta-analyses (NMAs) are an increasingly popular method in allergy, asthma, and immunology to inform comparative effectiveness among competing treatment options. They enable comparisons among treatments when no direct comparisons (ie, head-to-head randomized control trials) exist and strengthen inferences among direct comparisons by incorporating data from indirect comparisons. To inform optimal decision-making, allergy, asthma, and immunology clinicians, peer reviewers, journal editors, and policymakers must understand the fundamentals of how to assess NMA credibility. Through worked examples supporting American Academy of Allergy, Asthma & Immunology/American College of Allergy, Asthma and Immunology Task Force on Practice Parameters guidelines, we summarize the process of conducting an NMA and how to interpret results to inform clinical decision-making.

RATIONALE:The clinical characteristics of persistent airflow limitation (PAL) were explored in patients aged ≥12 years with physician-assigned diagnoses of asthma, asthma plus chronic obstructive pulmonary disease (COPD), or COPD in the NOVEL Observational longiTudinal studY (NOVELTY) cohort. The NOVELTY study is a prospective study conducted in primary and secondary care in 18 countries. OBJECTIVES:To determine the proportion of patients with PAL at baseline, their baseline characteristics, and the stability and prognostic utility of PAL during follow-up. METHODS:PAL was defined as post-bronchodilator forced expiratory volume in 1 second/forced vital capacity (FEV1/FVC) ratio less than the lower limit of the normal range (European Respiratory Society [ERS]/American Thoracic Society [ATS]) or as <0.7 (Global Initiative for Chronic Obstructive Lung Disease [GOLD] criteria). RESULTS:We studied 9081 patients over 3 years (asthma: 4754; asthma + COPD; 1147; COPD: 3180). Baseline prevalence of PAL was 24.2% and 29.2% (asthma), 63.3% and 74.1% (asthma + COPD), and 65.4% and 75.8% (COPD) using ERS/ATS and GOLD criteria, respectively. Patients with PAL had markedly worse symptom burden and a history of more frequent moderate and severe exacerbations. In patients with asthma, PAL was associated with higher blood eosinophils and fractional exhaled nitric oxide (FeNO) values; 60% had never smoked. Of patients with PAL at baseline 84% continued to meet PAL criteria at Year 3. Irrespective of physician diagnosis, PAL was a marker of increased risk of moderate and severe exacerbations and poor symptom control during the 3-year follow-up. CONCLUSIONS:PAL is a stable trait associated with more severe disease and poor outcomes in adults with a physician-assigned diagnosis of asthma and/or COPD. CLINICAL TRIAL REGISTRATION (IF ANY):NOVELTY: NCT02760329.

BACKGROUND:The benefits and harms of using macrolides for asthma remain unclear. OBJECTIVE:As part of upcoming Academy of Allergy, Asthma and Immunology/American College of Allergy, Asthma and Immunology Joint Task Force on Practice Parameters guidelines addressing severe asthma, we systematically reviewed the efficacy and safety of macrolides for asthma. METHODS:We systematically searched MEDLINE, Embase, and CENTRAL to April 12, 2025, for randomized trials comparing macrolides with placebo or standard care for asthma. Paired reviewers independently screened records and extracted data. Individual patient-level data in random effects analysis of covariance models addressed asthma control and asthma-related quality of life. Random effects meta-analyses addressed severe exacerbations and harms. We used the Grading of Recommendations Assessment, Development and Evaluation approach to evaluate certainty of evidence. Our study protocol is registered in PROSPERO (CRD42023408677). RESULTS:Our meta-analysis comprised 19 trials enrolling 1825 participants. Compared with placebo, macrolides improve asthma control (6-item Asthma Control Questionnaire; score range 0-6, lower better; between-group mean difference: -0.23 [95% CI -0.32 to -0.13]; 40.6% vs 21.6% improving by minimally important difference of 0.5 point; high certainty), likely reduce severe exacerbations (incidence rate ratio: 0.75 [95% CI 0.57 to 0.98]; rate difference: 0.26 fewer events per patient-year [95% CI 0.45 to 0.02 fewer events]; moderate certainty), and likely modestly improve quality of life (Asthma Quality of Life Questionnaire; score range 1-7, higher better; mean difference: 0.11 [95% CI -0.06 to 0.29]; 47.6% vs 42.4% improving by minimally important difference of 0.5 points; moderate certainty) with little to no effect on serious adverse events and mortality (high certainty). Relative effects were similar among patients with type 2 high inflammation versus type 2 low inflammation asthma. CONCLUSIONS:Macrolides likely reduce severe exacerbations and improve asthma control and quality of life with little to no difference in serious harms among patients with type 2 high inflammation or type 2 low inflammation asthma.

Background:The efficacy and safety of bronchial thermoplasty (BT) for severe asthma remains unclear. Objective:We systematically synthesized the efficacy and safety of BT in patients with severe asthma. Methods:As part of the upcoming American Academy of Allergy, Asthma & Immunology/American College of Allergy, Asthma & Immunology Joint Task Force on Practice Parameters severe asthma guidelines, we searched the Medline, Embase, and Central databases to July 29, 2025, for randomized trials comparing BT to control for asthma. Paired reviewers independently screened records and extracted data. Random-effects meta-analyses addressed asthma control (Asthma Control Questionnaire 6 [scale, 0-6; lower better]), asthma-related quality of life (Asthma Quality of Life Questionnaire [range, 1-7; higher better]), severe asthma exacerbations, and harms, stratified by procedural, postprocedural, and overall. The GRADE approach informed certainty-of-evidence ratings (PROSPERO: CRD42023408565). Results:Six trials randomized 573 adults. Procedurally, BT likely increases severe exacerbations (incidence rate ratio [IRR] 2.95; 95% CI, 1.20-7.25; risk difference [RD] 0.08 more events per patient-year; moderate certainty) and serious respiratory adverse events (IRR 5.98; 95% CI, 1.07-33.29; RD 0.18 more events per patient-year; moderate certainty). Postprocedurally, BT may reduce severe exacerbations (IRR 0.67; 95% CI, 0.50-0.89; RD 0.67 fewer events per patient-year; low certainty). Overall, BT may improve asthma control (mean difference -0.37; 95% CI, -0.67 to -0.07; RD for 0.5-point decrease: 15.9% more; low certainty), asthma-related quality of life (mean difference 0.55; 95% CI, 0.28-0.82; RD for 0.5-point increase: 19.1% more; low certainty), and severe exacerbations (IRR 0.81; 95% CI, 0.68-0.97; RD 0.11 fewer events per patient-year; low certainty). Conclusion:Among adults with severe asthma, BT may improve asthma control and asthma-related quality of life and may reduce overall severe exacerbations, but it likely increases procedural severe exacerbations and serious respiratory harms.

BACKGROUND:Uncontrolled asthma in childhood is associated with exacerbations and impaired health-related quality of life. Commonly used control tools for children aged 5 to 11 years assess asthma symptoms but not exacerbations, potentially leading to overestimation of control and suboptimal management. OBJECTIVE:This cross-sectional observational study aimed to validate the Pediatric Asthma Impairment and Risk Questionnaire (Peds-AIRQ), a novel control tool assessing symptom impairment and exacerbation risk. METHODS:A total of 399 children aged 5 to 11 years with physician-diagnosed asthma were recruited from one primary care and seven specialty care sites across the United States. Parents and caregivers, with input from their child, answered 18 yes/no questions about asthma symptoms and exacerbations. Children were categorized as having well-controlled (WC), not well-controlled (NWC), or very poorly controlled (VPC) asthma according to a validation standard using Global Initiative for Asthma symptom control questions plus prior-year exacerbations. Items with the greatest ability to discriminate among control categories and cut points were determined through logistic regression analyses. RESULTS:Models yielded a Peds-AIRQ composed of five impairment-based and three risk-based questions. The Peds-AIRQ yielded areas under receiver-operating characteristic curves of 0.85 to differentiate WC versus NWC/VPC asthma and 0.83 to differentiate WC/NWC versus VPC asthma. Score cut points of 0 to 1, 2 to 4, and 5 to 8 yes responses were determined to best represent WC, NWC, and VPC asthma, respectively. CONCLUSIONS:The Peds-AIRQ is a validated numerical assessment tool for children aged 5 to 11 years that can be used at point-of-care to evaluate asthma control based on current symptoms and exacerbation history.

Rationale Approximately half of US children with asthma aged 5-11 years have uncontrolled disease, placing them at risk for missed school days, emergency department visits, and hospitalizations, and negatively impacting quality of life for both child and parent/caregiver. The Pediatric AIRQ (Peds-AIRQ) was recently validated against a standard of GINA symptom control (impairment) and prior-year exacerbations (risk) and offers an equally weighted, 8-item (5 impairment and 3 risk), yes/no composite tool for children aged 5-11 years (well-controlled 0-1, not well-controlled 2-3, very poorly controlled 4-8 yes responses). The relationship of asthma control as measured by the Peds-AIRQ to the Pediatric Quality of Life Inventory (PedsQL) and parent/caregiver impression of their child's asthma control, risk, and severity was evaluated. Methods The validated PedsQL Acute Version for Parents (for children aged 5-7 years) and the PedsQL Acute Version for Children (for children aged 8-11 years) were used to assess HRQoL in children enrolled in the Peds-AIRQ validation study. Parents/caregivers were asked to rate their child's asthma control, risk, and severity on a 5-point Likert scale, where higher scores indicated more risk and worse control/greater severity (ie, 1=completely controlled, 2=well-controlled, 3=somewhat controlled, 4=poorly controlled, 5=not controlled). Scores of 4 and 5 were combined due to low numbers of patients in the not-controlled category. Generalized linear models were used to compare mean PedsQL scores across Peds-AIRQ control groups and Peds-AIRQ scores across parent/caregiver impression of asthma control, risk, and severity. Results This analysis included 399 children: mean(SD) age was 7.9(1.9) years (107 were aged 5-6 years, 136 7-8 years, 156 9-11 years); 63% male; 69% White children, 15% Black or Black-mixed race children; 33% Hispanic or Latino children; and 39% had public insurance. Among these children, 183 (46%) had ≥1 exacerbation within the past year. Overall, PedsQL scores decreased (indicating worse quality of life) with worsening asthma control as indicated by Peds-AIRQ control category (overall P<0.001). Higher Peds-AIRQ scores (worse asthma control) were significantly associated with worsening parent/caregiver impression of their child's asthma control, risk, and severity (P<0.001, for each). Conclusions At point of care, the Peds-AIRQ reflects patient health-related quality of life and may be beneficial as a parent/caregiver-clinician shared decision-making tool, as it mirrors parent/caregiver impression of their child's asthma control, risk to health, and symptom severity.

BACKGROUND:Long-acting muscarinic antagonists are typically added to inhaled corticosteroids (ICS) and long-acting β-agonists (LABA) for asthma management. OBJECTIVE:To systematically synthesize the benefits and harms of triple therapy (ICS/LABA/long-acting muscarinic antagonists) compared with dual therapy (ICS/LABA) for asthma management across key subpopulations as part of developing linked American Academy of Allergy, Asthma, and Immunology/American College of Allergy, Asthma, and Immunology guidelines. METHODS:We searched MEDLINE, EMBASE, the Cochrane Controlled Register of Trials, and the International Clinical Trials Registry Platform from January 1, 2020 to February 1, 2025, for randomized trials comparing inhaled triple therapy to dual therapy for asthma to update our previous systematic review. Paired reviewers independently screened citations, extracted data, and assessed the risk of bias. Random effects meta-analyses assessed asthma control (asthma control questionnaire-7; 0-6), asthma-related quality of life (asthma quality of life questionnaire; 1-7), prebronchodilator forced expiratory volume in 1 second, severe exacerbations, and serious adverse events. The Grading of Recommendations, Assessment, Development, and Evaluation approach informed the certainty of evidence. Open Science Framework Registration (https://osf.io/u8t4q/). RESULTS:A total of 26 trials randomized 12,431 participants. Compared with dual therapy, triple therapy reduces severe exacerbations in patients at high risk for future exacerbation (relative risk 0.83, 95% CI 0.76-0.90; risk difference 5.3% fewer; high certainty), with trivial improvement in asthma control (mean difference [MD] -0.04, 95% CI -0.07 to 0.00, moderate certainty; lower better), quality of life (MD 0.05, 95% CI -0.03 to 0.14, moderate certainty; higher better), and prebronchodilator forced expiratory volume in 1 second (MD 0.07, 95% CI 0.05-0.09; high certainty), without increase in serious adverse events (moderate certainty). The effects were consistent across age, body mass index, and exacerbation history. CONCLUSION:In patients with moderate-to-severe asthma, triple therapy, compared with dual therapy, reduces severe exacerbations in patients at high risk for future exacerbation with minimal harm.

BACKGROUND:Understanding patient values and preferences can inform optimal care of moderate-to-severe asthma. OBJECTIVE:To systematically synthesize studies addressing the values and preferences of patients with moderate-to-severe asthma and their caregivers toward the management of asthma. METHODS:As part of updating the American Academy of Allergy, Asthma & Immunology/American College of Allergy, Asthma, and Immunology (AAAAI/ACAAI) Joint Task Force on Practice Parameters severe asthma guidelines, we searched MEDLINE, Embase, PsycINFO, and CINAHL from inception to June 1, 2025, for studies addressing the values and preferences of patients with moderate-to-severe asthma or their caregivers. Paired reviewers independently screened citations, extracted data, and assessed risk of bias. We used iterative thematic content analysis to qualitatively synthesize findings and the Grading of Recommendations Assessment, Development and Evaluation-Confidence in the Evidence from Reviews of Quantitative Research (GRADE-CERQual) approach to rate the confidence of the evidence. We prospectively registered our review in PROSPERO (CRD42024572812). RESULTS:Synthesizing 88 studies enrolling 9,593 patients and 274 caregivers, we identified 5 key themes: (1) Patients and their caregivers place high value on avoiding potential adverse effects of asthma treatment (high confidence). Patients probably place high value toward (2) avoiding severe asthma exacerbations, (3) having autonomy in the administration of advanced therapies, such as biologics, and (4) are probably more willing to accept treatment if provided counselling by clinicians knowledgeable in asthma (moderate confidence). (5) Patients may place a high value on asthma treatments that are practical and logistically simple to implement (low confidence). CONCLUSIONS:We identified 5 key themes on the values and preferences of patients with moderate-to-severe asthma and their caregivers to inform optimal clinical care, practice guidelines, and future research.

BACKGROUND:In the United States (US), Black patients with asthma experience higher exacerbation rates compared with non-Black patients. OBJECTIVE:To identify factors that might explain the exacerbation rate association with race in a cohort of patients with severe asthma (SA). METHODS:CHRONICLE was an observational study of US adults with SA treated by allergists-immunologists or pulmonologists. The analysis population was patients not receiving biologic treatment. We used propensity score (PS) methods to identify factors associated with Black race. Non-Black-non-Hispanic or Latino patients (non-Black) were the control group. A generalized linear model (GLM) assessed the association between Black race and exacerbation rate, adjusted for the PS. RESULTS:Between February 2018 and July 2022, 180 Black and 574 non-Black patients were eligible for PS analysis. Socioeconomic status was the strongest discriminator of race (C statistic of 0.75), followed by environment (0.65), demographics (0.64), smoking status (0.55), and comorbidities (0.55). Before adjusting for PS, the GLM showed a 1.28-fold higher exacerbation rate among Black patients compared with non-Black patients (rate ratio = 1.28; 95% CI, 1.01-1.62; P = .039). In the PS-adjusted GLM, Black race was no longer associated with the exacerbation rate (rate ratio = 0.87; 95% CI, 0.56-1.35; P = .522). Results were similar for asthma-related emergency department visit and hospitalization rates. CONCLUSIONS:Higher exacerbation rates in Black patients with SA may be explained by factors associated with Black race, such as socioeconomic status. Addressing socioeconomic disparities and social determinants of health may help reduce the exacerbation risk difference observed between Black and non-Black patients with SA.

BACKGROUND:The benefits and harms of patient-facing digital inhalers (inhalers with a sensor providing patients immediate feedback on adherence and technique) for asthma remain unclear. OBJECTIVE:To systematically synthesize treatment outcomes of patient-facing digital inhalers for asthma. METHODS:As part of developing upcoming American Academy of Allergy, Asthma & Immunology and American College of Allergy, Asthma, and Immunology Joint Task Force on Practice Parameters severe and difficult-to-control asthma guidelines, we searched MEDLINE, Embase, CENTRAL, CINAHL, PsycINFO, International Clinical Trials Registry Platform (ICTRP), and Latin American and Caribbean Literature on Health Sciences (LILACS), and monitored for additional studies to April 1, 2025, for randomized controlled trials evaluating patient-facing digital inhalers in asthma. Paired reviewers independently screened records and extracted data. Individual patient-level data in random effects analysis of covariance models addressed asthma control and asthma-related quality of life. Random-effects meta-analyses addressed severe exacerbations and harms. We used the Grading of Recommendations Assessment, Development and Evaluations (GRADE) approach to assess certainty of evidence (PROSPERO CRD42024525051). RESULTS:Twelve trials enrolled 2,483 children (aged 4-17 y) and adults with asthma. Patient-facing digital inhalers probably improve asthma control (Asthma Control Test, mean difference 0.63 [95% confidence interval {95% CI} 0.29-0.96]; 44.3% vs 39.8% achieving a 3-point increase, moderate certainty) and may reduce severe exacerbations in patients at high risk for future exacerbations (risk ratio 0.89 [95% CI 0.69-1.16]; risk difference 45 fewer per 1,000 [95% CI 127 fewer to 66 more per 1,000], low certainty), with little to no difference in asthma-related quality of life (low certainty). The median of mean device failure rate was 12%, with trials reporting issues regarding sensor synchronization with smartphones (very low certainty). One trial reported a protected health information exposure while using patient-facing digital inhalers. CONCLUSIONS:Patient-facing digital inhalers probably improve asthma control and may reduce severe asthma exacerbations in patients at high risk for future exacerbations with minimal harm.

BACKGROUND:The MANDALA study (NCT03769090) in moderate-to-severe asthma served as the basis of the Food and Drug Administration's 2023 approval of albuterol-budesonide 180/160 µg pressurized metered-dose inhaler for the as-needed treatment or prevention of bronchoconstriction and to reduce exacerbation risk in patients with asthma aged 18 years or older. Clinicians would benefit from an understanding of the patterns of use of albuterol-budesonide vs albuterol and overall inhaled corticosteroid (ICS) exposure when ICS-containing rescue therapies are used alongside ICS-based maintenance therapies. OBJECTIVE:To evaluate patterns of as-needed use and safety profiles of albuterol-budesonide 180/160 µg vs albuterol 180 µg, using data from MANDALA. METHODS:Study medication use was patient-documented using an electronic diary. Safety was assessed as adverse events. Patterns of study medication use (2 inhalations = 1 dose) were summarized as mean percentages of days in which inhalations per day fell within predefined categories (0, 1-2, 3-4, 5-6, 7-8, 9-10, 11-12, and >12). RESULTS:The safety population included 981 patients randomized to as-needed albuterol-budesonide and 981 to as-needed albuterol. Patients adhered to maintenance therapy regimens on a mean of more than or equal to 75% of days. Use of as-needed study drug was similar in both groups (mean of 2.6 and 2.8 inhalations/d of albuterol-budesonide and albuterol, respectively). High daily use (≥8 inhalations/d) or long-term high daily use (≥7 consecutive days) was rare. Adverse event frequencies (ICS-associated and not) were low and comparable between groups, regardless of mean daily as-needed use. CONCLUSION:Patterns of use and safety profiles were similar between as-needed albuterol-budesonide and albuterol. TRIAL REGISTRATION:ClinicalTrials.gov Identifier: NCT03769090.

Importance:The optimal inhaled reliever therapy for asthma remains unclear. Objective:To compare short-acting β agonists (SABA) alone with SABA combined with inhaled corticosteroids (ICS) and with the fast-onset, long-acting β agonist formoterol combined with ICS for asthma. Data Sources:The MEDLINE, Embase, and CENTRAL databases were searched from January 1, 2020, to September 27, 2024, without language restrictions. Study Selection:Pairs of reviewers independently selected randomized clinical trials evaluating (1) SABA alone, (2) ICS with formoterol, and (3) ICS with SABA (combined or separate inhalers). Data Extraction and Synthesis:Two reviewers independently extracted data and assessed risk of bias. Random-effects meta-analyses synthesized outcomes. GRADE (Grading of Recommendations Assessment, Development, and Evaluation) was used to evaluate the certainty of evidence. Main Outcomes and Measures:Asthma symptom control (5-item Asthma Control Questionnaire; range, 0-6, lower scores indicate better asthma control; minimum important difference [MID], 0.5 points), asthma-related quality of life (Asthma Quality of Life Questionnaire; range, 1-7, higher scores indicate better quality of life; MID, 0.5 points), risk of severe exacerbations, and risk of serious adverse events. Results:A total of 27 randomized clinical trials (N = 50 496 adult and pediatric patients; mean age, 41.0 years; 20 288 male [40%]) were included. Compared with SABA alone, both ICS-containing relievers were associated with fewer severe exacerbations (ICS-formoterol risk ratio [RR], 0.65 [95% CI, 0.60-0.72]; risk difference [RD], -10.3% [95% CI, -11.8% to -8.3%]; ICS-SABA RR, 0.84 [95% CI, 0.73-0.95]; RD, -4.7% [95% CI, -8.0% to -1.5%]) with high certainty. Compared with SABA alone, both ICS-containing relievers were associated with improved asthma control (ICS-formoterol RR improvement [MID] in total score, 1.07 [95% CI, 1.04-1.10]; RD, 4.1% [95% CI, 2.3%-5.9%]; ICS-SABA RR, 1.09 [95% CI, 1.03-1.15]; RD, 5.4% [95% CI, 1.8%-8.5%]) with high certainty. In an indirect comparison with ICS-SABA, ICS-formoterol was associated with fewer severe exacerbations (RR, 0.78 [95% CI, 0.66-0.92]; RD, -5.5% [95% CI, -8.4% to -2.0%]) with moderate certainty. Compared with SABA alone, ICS-formoterol (RD, -0.6% [95% CI, -1.3% to 0%]) was not associated with increased risk of serious adverse events (high certainty) and ICS-SABA (RD, 0% [95% CI, -1.1% to 1.2%]) was not associated with increased risk of serious adverse events (moderate certainty). Conclusions and Relevance:In this network meta-analysis of patients with asthma, ICS combined with formoterol and ICS combined with SABA were each associated with reduced asthma exacerbations and improved asthma control compared with SABA alone.

Rationale In MANDALA (NCT03769090), as-needed albuterol−budesonide 180/160 µg reduced severe asthma exacerbation risk by 27% versus as-needed albuterol 180 µg (time-to-first exacerbation) and decreased annualized severe asthma exacerbation rates by 24% in patients ≥12 years. Minimum enrolment was 24 weeks. This analysis explored the benefit of as-needed albuterol−budesonide versus albuterol early after the initiation of the tested rescue treatments and compared the magnitude of shorter-versus longer-term exacerbation risk reduction. Methods MANDALA enrolled symptomatic patients ≥4 years with ≥1 prior-year severe exacerbation, receiving inhaled corticosteroid (ICS)-containing GINA 3−5 maintenance therapy. This post-hoc analysis assessed time-to-first severe exacerbation in the first 3 months post-randomization and annualized exacerbation rate based on 3-month exacerbation occurrence in patients ≥12 years receiving their maintenance therapy and as-needed albuterol−budesonide 180/160 µg versus albuterol 180 µg. Time-to-first severe exacerbation was analyzed using a Cox proportional hazards model, and annualized exacerbation rate by a negative binomial regression model (both adjusted for age, region, and prior-year exacerbations). Results Of 2027 patients, 1013 received albuterol−budesonide 180/160 µg (mean [SD] age=50.6 [15.1]; 63.7% female; 22.2% with ≥2 prior-year severe exacerbations) and 1014 received albuterol 180 µg (age=50.7 [15.5]; 67.2% female; 20.3% with ≥2 prior-year severe exacerbations). Average exposure to randomized treatment was 44 weeks and maximum duration on study was 108 weeks. For patients using as-needed albuterol−budesonide versus albuterol, the risk of a first severe exacerbation was reduced by 28% in the first 3 months (hazard ratio [95% CI]: 0.72 [0.56, 0.92]; p=0.009) and by 27% during the study duration (0.73 [0.61, 0.88]; p<0.001) (Figure). Annualized rates of severe exacerbations based on exacerbation occurrence in the first 3 months were 0.61 (0.43, 0.85) for patients on albuterol−budesonide and 0.81 (0.58, 1.11) for those on albuterol. This represents a 25% reduction in the annualized rate of exacerbations in the first three months (rate ratio [95% CI]: 0.75 [0.58, 0.98]; p=0.033; Figure), versus a 24% reduction for the study duration (0.76 [0.62, 0.93]; p=0.008). Conclusions In patients aged ≥12 years with moderate-to-severe asthma, on as-needed albuterol−budesonide 180/160 µg versus albuterol 180 µg, severe exacerbation risk and annualized exacerbation rates were significantly decreased already in the first 3 months, similar to those seen long-term, indicating a rapid protective effect of the albuterol−budesonide combination. Clinicians and patients switching from albuterol to albuterol−budesonide rescue can anticipate reduction in severe exacerbation risk within 3 months of albuterol−budesonide initiation, which is sustained long-term.