Lebrikizumab in Uncontrolled Asthma: Reanalysis in a Well-Defined Type 2 Population.

BACKGROUND: LAVOLTA (L)I, LII, and ACOUSTICS were randomized, placebo-controlled, Phase 3 trials of lebrikizumab, a monoclonal antibody targeting IL-13 in patients with uncontrolled asthma. Failure to demonstrate efficacy may have been related to patient selection in those trials. OBJECTIVE: To assess the efficacy in a well-defined subpopulation of patients with elevated blood eosinophil counts and a minimum number of prior asthma exacerbations. We performed an additional analysis in a subpopulation of patients with elevated FeNO and prior exacerbations. METHODS: Adult (LI and LII) and adolescent patients (aged 12-17 years weighing ≥40 kg, ACOUSTICS) with uncontrolled asthma received lebrikizumab (125 mg, n = 832; or 37.5 mg, n = 829) or placebo (n = 833) subcutaneously every 4 weeks. Post hoc analysis of the annualized adjusted exacerbation rate (AER) was performed in a subpopulation of patients with baseline blood eosinophils of 300 cells/µL or greater and history of one or more exacerbations. In this subpopulation, there were 227 patients in the placebo group, 222 in the lebrikizumab 37.5-mg group, and 217 in the lebrikizumab 125-mg group. We summarized safety in patients who received at least one dose of lebrikizumab using adverse events. RESULTS: Lebrikizumab significantly reduced AER compared with placebo in adults (AER reduction: 125 mg [38%]; and 37.5 mg [41%]) and adolescents (AER reduction:125 mg [59%]; 37.5 mg [64%]) with baseline blood eosinophils of 300 cells/µL or greater and one or more exacerbations. Most adverse events were mild or moderate in severity and did not lead to treatment discontinuation. CONCLUSION: Lebrikizumab significantly reduced asthma exacerbations in a subpopulation of patients with elevated blood eosinophils, elevated FeNO, and a history of asthma exacerbation.

Fifty Years of Unraveling the Clinical Pharmacology of Corticosteroids.

This review will highlight portions of Dr. William Jusko's and colleagues' work that affected the clinical use and study of corticosteroids in acute and chronic disease management. Selected publications related to corticosteroid pharmacokinetics and pharmacodynamics from the 1970s through today were included in this review, with a focus on the foundational human-based studies conducted in the 1970s-1990s. Dr. Jusko contributed significantly to early corticosteroid pharmacology across several domains including: 1) foundational corticosteroid pharmacokinetic methods and parameter development, 2) disease state-variation in corticosteroid pharmacokinetics, 3) drug interaction effects on corticosteroid pharmacokinetics, and 4) early corticosteroid pharmacodynamic studies. In an era where little was known about the pharmacokinetics and pharmacodynamics of corticosteroids, Dr. Jusko's work opened the eyes of researchers and clinicians to the potential for disease and drug interactions that could reduce or enhance the effects of corticosteroids. This significant body of work paved the way for alternative routes of administration that would be useful in concentrating the activity at the site of action and markedly reduced systemic drug exposure, minimizing the risk of adverse effects through application of the dose-sparing pharmacokinetic and pharmacodynamic principles.

Is the assessment of asthma treatment efficacy sufficiently comprehensive?

The goal of asthma guideline therapy is to achieve disease control, by minimizing impairment and decreasing the risk of exacerbations and adverse effects of the disease and its treatment. The primary objective of most clinical trials of biologics for severe asthma is a reduction in exacerbation rate. Recently, studies with patients at the lower guideline steps have also selected exacerbation reduction as a primary objective. These trials in patients with milder disease frequently demonstrate statistically significantly fewer exacerbations, but their power calculations reflect larger sample size and smaller effect size. Exacerbations have a precise consensus definition, although a minimal clinically important difference has not been established. Reduction of exacerbations in severe asthma is commonly 10-fold greater than in mild disease. Further, reduction in exacerbations is not always associated with reduced impairment. If superior control is the objective, both domains should demonstrate consistent and parallel improvement. The disconnect may reflect the need for alternative tools for measurement of impairment or, possibly, different therapeutic mechanisms of action. Determining response to biologics or discussion of disease remission requires assessing symptoms that may occur daily rather than focusing on exacerbations that occur once or twice a year for patients at the highest steps of care according to the guidelines.

Encouraging adherence in adolescents with asthma using financial incentives: An RCT.

BACKGROUND: Medication adherence in adolescents remains a significant management challenge and innovative strategies are needed to improve medication adherence. Financial incentives have been used to improve outcomes for health behaviors among adults, but have not been well-studied among adolescents. The objective of this study was to test if a modest financial incentive improved medication adherence in adolescents with asthma compared with a control group. METHODS: Participants were randomized to either control (electronic medication monitoring [EMM] with App reminders/feedback for 4 months) or intervention (EMM + $1 per day for perfect medication adherence for 3 months [maximum $84] followed by 1 month of EMM only). A repeated measures mixed model, with a first order autoregressive correlation structure between errors, was used to test the null hypothesis for an interaction of treatment group and week. RESULTS: Fifty-two participants were enrolled, and 48 completed primary analysis. Mean adherence rates declined in both groups over time, and there was no significant difference in the change in adherence rates between the groups (F-statistic = 0.72, ndf = 15, ddf = 625, p = 0.76). Adherence rates (during the 12 weeks when incentives were given) declined from 80% to 64% in the control group, and from 90% to 58% in the incentive group. There was no significant change in the slope of decline in the incentives group in the month following payment discontinuation. CONCLUSION: A modest financial incentive did not lead to significantly different medication adherence rates in adolescents with asthma who were receiving a monitoring and reminder intervention. Further study is needed to determine viable interventions to optimize medication use in this group.

Is Once Versus Twice Daily Dosing Better for Adherence in Asthma and Chronic Obstructive Pulmonary Disease?

BACKGROUND: Patients with asthma and chronic obstructive pulmonary disease (COPD) may be prescribed once- or twice-daily dosing of controller inhalers. OBJECTIVE: To assess differences in controller adherence by dosing schedule and age. METHODS: Electronic medication monitors (EMMs) captured the date and time of inhaler actuations over 90 days in patients using the Propeller Health platform. Prescribed inhaler schedule was self-reported. Once- versus twice-daily schedule comparisons were assessed retrospectively using regressions adjusting for age. RESULTS: A total of 6294 patients with asthma and 1791 patients with COPD were included. On average, once-daily users had significantly higher median (interquartile range [IQR]) daily adherence than twice-daily users (asthma: 63.3 [IQR: 31.1, 86.7]% vs 50.3 [IQR: 21.1, 78.3]%, P < .001; COPD: 83.3 [IQR: 57.2, 95.6]% vs 64.7 [IQR: 32.8, 88.9]%, P < .001). This pattern persisted in all age groups, with the exception of 4- to 17-year-olds in asthma. The lowest adherence was in the young adult population (18- to 29-year-olds). The percentage of patients who achieved ≥80% adherence was significantly higher among once- versus twice-daily users in asthma (34.3% vs 23.6%, P < .001) and COPD (54.8% vs 38.6%, P < .001). The adjusted odds of once- versus twice-daily users achieving ≥80% adherence was 1.36 (95% confidence interval: 1.19-1.56, P < .001) in asthma and 1.73 (95% confidence interval: 1.38-2.17, P < .001) in COPD. Most once-daily patients with COPD took their medication in the morning versus at night; there was no difference in morning versus afternoon/evening administration in all other asthma and COPD groups. CONCLUSION: Patients with asthma and COPD who were prescribed once-daily versus twice-daily medications were more likely to adhere to their inhalers. Patients with COPD had higher adherence than those with asthma, possibly reflecting, in part, the older cohort age. The effect of greater adherence on exacerbations is a topic for future analysis.

Assessment of dupilumab in children with moderate-to-severe type 2 asthma with or without evidence of allergic asthma.

BACKGROUND: Cytokines, such as interleukins (IL)-4/5/13, play a key role in multiple type 2 inflammatory diseases, including allergic asthma. Dupilumab, a human monoclonal antibody, blocks the shared receptor component for IL-4/IL-13, inhibiting signaling. In this post hoc analysis of VOYAGE (NCT02948959), dupilumab efficacy was evaluated in patients aged 6-11 years with type 2 asthma with or without evidence of allergic asthma (baseline serum total IgE ≥30 IU/mL and ≥1 perennial aeroallergen-specific IgE ≥0.35kU/L). METHODS: Annualized severe exacerbation rates (AER) and changes in pre-bronchodilator (Pre-BD) forced expiratory volume in one second (FEV1 ), percent-predicted pre-BD FEV1 (ppFEV1 ), and Asthma Control Score (ACQ)-7 were assessed during the treatment period. RESULTS: 350 children (261 with and 89 without evidence of allergic asthma) were included. Dupilumab versus placebo significantly reduced AER in patients with (0.24 vs. 0.62, relative risk reduction [RRR]: 62% [95% CI, 39-76], P < .0001) and without (0.39 vs. 0.80, RRR: 51% [95% CI, 0-76], P < .05) evidence of allergic asthma. Significant improvements in ppFEV1 , pre-bronchodilator FEV1 , and ACQ-7 scores were observed in dupilumab versus placebo throughout the treatment period in patients with evidence of allergic asthma. In patients without evidence of allergic asthma, numerical improvements in pre-bronchodilator FEV1 and asthma control were observed by Week 52. CONCLUSION: Dupilumab versus placebo reduced asthma exacerbations in children with type 2 asthma irrespective of evidence of allergic asthma; similar trends were observed in changes in lung function. Significant improvement in asthma control was observed in patients with evidence of allergic asthma, but not in those without.

Factors to Consider in Prescribing Asthma Biologic Therapies to Children.

The increasing availability of biologics, both by expanding age indications and by development of new therapies, provides additional options to treat children and adolescents with severe asthma. However, the evidence for these biologics in these populations is limited compared with that for adult studies. As such, before initiation of therapy, possible alternative therapies that can also provide asthma control, confirmation of the diagnosis of asthma, management of comorbidities, and assessment of adherence should be explored. The choice of a biologic should be a shared decision-making process between providers and families, balancing biologic efficacy, goals of care, administration, and ability to treat multiple conditions. Response to treatment should be periodically evaluated not only to ensure an ineffective treatment is not continued but also to consider when to potentially discontinue therapy should it be beneficial. The utilization of biologics in children and adolescents with severe asthma also leads to unanswered questions on their role in disease remission and long-term outcomes.

Treating asthma in the time of COVID.

The Precision Interventions for Severe and/or Exacerbation-Prone Asthma clinical trials network is actively assessing novel treatments for severe asthma during the coronavirus disease (COVID-19) pandemic and has needed to adapt to various clinical dilemmas posed by the COVID-19 pandemic. Pharmacologic interactions between established asthma therapies and novel drug interventions for COVID-19 infection, including antivirals, biologics, and vaccines, have emerged as a critical and unanticipated issue in the clinical care of asthma. In particular, impaired metabolism of some long-acting beta-2 agonists by the cytochrome P4503A4 enzyme in the setting of antiviral treatment using ritonavir-boosted nirmatrelvir (NVM/r, brand name Paxlovid) may increase risk for adverse cardiovascular events. Although available data have documented the potential for such interactions, these issues are largely unappreciated by clinicians who treat asthma, or those dispensing COVID-19 interventions in patients who happen to have asthma. Because these drug-drug interactions have not previously been relevant to patient care, clinicians have had no guidance on management strategies to reduce potentially serious interactions between treatments for asthma and COVID-19. The Precision Interventions for Severe and/or Exacerbation-Prone Asthma network considered the available literature and product information, and herein share our considerations and plans for treating asthma within the context of these novel COVID-19-related therapies.

Understanding Core Community Needs for School-Based Asthma Programming: A Qualitative Assessment in Colorado Communities.

Objectives: Asthma is one of the most prevalent chronic conditions affecting approximately 8.5% of children in Colorado. Our school-based asthma program (SBAP) has effectively improved asthma control and reduced asthma disparities among children but has been largely limited to the Denver area. We interviewed community stakeholders in 5 regions of Colorado to understand community needs for broader dissemination of SBAPs. Methods: In-depth, semistructured key informant interviews were conducted with school nurses, parents, pediatric healthcare providers, public health professionals, and community resource organization representatives. Inductive and deductive analyses were informed by the practical, robust, implementation, and sustainability model, an implementation science framework. Results: Participants (n=52) identified 6 types of needs for successful future implementation of our SBAP: (1) buy-in from stakeholders; (2) asthma prioritization; (3) improved relationships, communication, and coordination among school nurses, healthcare providers, and community organizations that address social determinants of health (SDOH) and children/families; (4) resources to address healthcare and SDOH needs and awareness of existing resources; (5) asthma education for children/families, school staff, and community members; and (6) improved coordination for School Asthma Care Plan completion. These needs mapped to a 3-tiered, progressive structure of foundational, relational, and functional needs for implementation success. Conclusion: These 6 types of needs illuminate factors that will allow this SBAP to work well and program delivery approaches and implementation strategies that may need modification to be successful. Next steps should include tailoring implementation strategies to variations in local context to support fit, effectiveness, and sustainment.

Developing a Social Determinants of Health Needs Assessment for Colorado Kids (SNACK) Tool for a School-Based Asthma Program: Findings from a Pilot Study.

Background: School-based asthma programs effectively address poorly controlled asthma and asthma disparities, especially when coupled with screening for and addressing social determinants of health (SDOH) needs. Existing screening tools are tailored to clinical settings; therefore, we sought to develop a community-based SDOH screening tool. Design/Methods: We used a four-phase iterative design process to develop and pilot a community-based screening tool. We used a modified Delphi process to identify screening tool domains, identified validated items for inclusion, and developed an appropriate tool layout for populations with limited health/general literacy. Community advisory boards reviewed and refined a draft tool. Next, we conducted a qualitative pilot test of acceptability to parents and feasibility for staff in a community health center. Results: Six domains are included in our SDOH screening tool: health care access, transportation, food insecurity, public benefits, housing, and utilities. In the pilot test, 41 screenings were completed, and 36 parents (16.7% Spanish speaking) provided feedback. Most families understood the purpose of the screening; felt that the questions were clear, appropriate, and quick to complete; and liked the pictures. The clinic's care coordinator expressed a preference for the pilot tool compared to their existing screening tool and recommended improvements to encourage honest reporting by patients. Conclusion: This community-based screening tool addresses key SDOH needs that impact asthma and is acceptable to families. The next steps are to implement the tool in school-based asthma programs to support improvements in asthma outcomes and disparities by identifying and addressing families' unmet SDOH needs.

Efficacy, safety, and tolerability of lebrikizumab in adolescent patients with uncontrolled asthma (ACOUSTICS).

Background: Lebrikizumab is a monoclonal antibody that modulates activity of interleukin-13. The Phase 3 ACOUSTICS study assessed lebrikizumab efficacy and safety in adolescents with uncontrolled asthma despite standard-of-care treatment. Methods: Adolescents (aged 12-17 years) with uncontrolled asthma, prebronchodilator forced expiratory volume in 1 s 40%-90% predicted, and stable background therapy were randomised 1:1:1 to receive lebrikizumab 125 or 37.5 mg or placebo subcutaneously once every 4 weeks. Primary efficacy endpoint was asthma exacerbation rate over 52 weeks. Results: Between August 2013 and July 2016, 579 patients were screened and 346 were randomised; 224 (65%) completed the study with 52 weeks of treatment. Lebrikizumab 125 mg (n = 116) reduced the exacerbation rate at 52 weeks versus placebo (n = 117; adjusted rate ratio [RR] 0.49 [95% CI 0.28-0.83]; 51% rate reduction). Lebrikizumab 37.5 mg (n = 113) was less effective at reducing exacerbations (RR 0.60 [95% CI 0.35-1.03]; 40% rate reduction). In patients with blood eosinophil counts ≥300 cells/µl, both lebrikizumab doses reduced exacerbations (125 mg: RR 0.44 [95% CI 0.21-0.89]; 37.5 mg: 0.42 [95% CI 0.19-0.93]). Treatment-emergent adverse events, serious adverse events, and adverse events leading to study discontinuation occurred in 155 (68%), 7 (3%), and 5 (2%) of 229 patients who received lebrikizumab (both 125 and 37.5 mg doses) and in 72 (62%), 4 (3%), and 1 (1%) of 117 who received placebo, respectively. No deaths occurred. Conclusion: Lebrikizumab 125 mg reduced asthma exacerbation rates in adolescents with uncontrolled asthma. However, the study was prematurely terminated (sponsor's decision) potentially limiting interpretation of results. Clinical trial registration: NCT01875003 (www.ClinicalTrials.gov).

Applying dissemination and implementation research methods to translate a school-based asthma program.

Our school-based asthma program has reduced asthma exacerbations for youth with health disparities in the Denver metropolitan area, due partly to addressing social determinants of health, such as access to health care and medications. Dissemination and implementation (D&I) science approaches accelerate the translation of evidence-based programs into routine practice. D&I methods are being applied more commonly to improve health equity. The purpose of this publication was to give an overview of D&I research methods, using our school-based asthma program as an example. To successfully scale out our program across the state of Colorado, we are applying a D&I framework that guides the adaptation of our existing implementation approach to better meet our stakeholders' local context-the Exploration, Preparation, Implementation, Sustainment framework. In a pragmatic trial design, we will evaluate the outcomes of implementing the program across 5 Colorado regions, with attention to health equity, using a second commonly used D&I framework-Reach, Effectiveness, Adoption, Implementation, and Maintenance. Our central hypothesis is that our program will have broad and equitable reach to eligible students (primary outcome) and will reduce asthma attacks and symptoms. This D&I approach accelerates dissemination of our program and is an applicable process for translating other effective allergy/asthma programs to address asthma and allergy-related disparities.

The National Heart Lung and Blood Institute Disparities Elimination through Coordinated Interventions to Prevent and Control Heart and Lung Disease Alliance.

OBJECTIVE: To describe the National Heart Lung and Blood Institute (NHLBI) sponsored Disparities Elimination through Coordinated Interventions to Prevent and Control Heart and Lung Disease (DECIPHeR) Alliance to support late-stage implementation research aimed at reducing disparities in communities with high burdens of cardiovascular and/or pulmonary disease. STUDY SETTING: NHBLI funded seven DECIPHeR studies and a Coordinating Center. Projects target high-risk diverse populations including racial and ethnic minorities, urban, rural, and low-income communities, disadvantaged children, and persons with serious mental illness. Two projects address multiple cardiovascular risk factors, three focus on hypertension, one on tobacco use, and one on pediatric asthma. STUDY DESIGN: The initial phase supports planning activities for sustainable uptake of evidence-based interventions in targeted communities. The second phase tests late-stage evidence-based implementation strategies. DATA COLLECTION/EXTRACTION METHODS: Not applicable. PRINCIPAL FINDINGS: We provide an overview of the DECIPHeR Alliance and individual study designs, populations, and settings, implementation strategies, interventions, and outcomes. We describe the Alliance's organizational structure, designed to promote cross-center partnership and collaboration. CONCLUSIONS: The DECIPHeR Alliance represents an ambitious national effort to develop sustainable implementation of interventions to achieve cardiovascular and pulmonary health equity.

Social Determinants of Health in Asthma Through the Life Course.

There is strong evidence supporting the influence of social determinants of health (SDOH) on the development and progression of asthma. SDOH are defined as conditions in which people are born, grow up, live, work, and age, which influence their opportunity to be healthy, risk of illness, and life expectancy. The goal of this article was to describe 2 case-based approaches (pediatric and adult) to assessing and addressing SDOH in asthma across the life course and in community settings. As asthma providers and specialists, the role of SDOH is complex in our clinical care; however, it is critical to address social needs identified through clinical care for our patients with asthma. Clinical-community partnerships, through grant and cost-sharing mechanisms with resource agencies, are necessary to ameliorate social needs for patients and their communities and have the potential to improve asthma outcomes. Although this is a unique and exciting time in health care to promote individual and population health, knowledge gaps remain, including best practices to integrate holistic SDOH care into the care of patients with asthma.

Prioritising primary care respiratory research needs: results from the 2020 International Primary Care Respiratory Group (IPCRG) global e-Delphi exercise.

Respiratory diseases remain a significant cause of global morbidity and mortality and primary care plays a central role in their prevention, diagnosis and management. An e-Delphi process was employed to identify and prioritise the current respiratory research needs of primary care health professionals worldwide. One hundred and twelve community-based physicians, nurses and other healthcare professionals from 27 high-, middle- and low-income countries suggested 608 initial research questions, reduced after evidence review by 27 academic experts to 176 questions covering diagnosis, management, monitoring, self-management and prognosis of asthma, COPD and other respiratory conditions (including infections, lung cancer, tobacco control, sleep apnoea). Forty-nine questions reached 80% consensus for importance. Cross-cutting themes identified were: a need for more effective training of primary care clinicians; evidence and guidelines specifically relevant to primary care, adaption for local and low-resource settings; empowerment of patients to improve self-management; and the role of the multidisciplinary healthcare team.

The Precision Interventions for Severe and/or Exacerbation-Prone (PrecISE) Asthma Network: An overview of Network organization, procedures, and interventions.

Asthma is a heterogeneous disease, with multiple underlying inflammatory pathways and structural airway abnormalities that impact disease persistence and severity. Recent progress has been made in developing targeted asthma therapeutics, especially for subjects with eosinophilic asthma. However, there is an unmet need for new approaches to treat patients with severe and exacerbation-prone asthma, who contribute disproportionately to disease burden. Extensive deep phenotyping has revealed the heterogeneous nature of severe asthma and identified distinct disease subtypes. A current challenge in the field is to translate new and emerging knowledge about different pathobiologic mechanisms in asthma into patient-specific therapies, with the ultimate goal of modifying the natural history of disease. Here, we describe the Precision Interventions for Severe and/or Exacerbation-Prone Asthma (PrecISE) Network, a groundbreaking collaborative effort of asthma researchers and biostatisticians from around the United States. The PrecISE Network was designed to conduct phase II/proof-of-concept clinical trials of precision interventions in the population with severe asthma, and is supported by the National Heart, Lung, and Blood Institute of the National Institutes of Health. Using an innovative adaptive platform trial design, the PrecISE Network will evaluate up to 6 interventions simultaneously in biomarker-defined subgroups of subjects. We review the development and organizational structure of the PrecISE Network, and choice of interventions being studied. We hope that the PrecISE Network will enhance our understanding of asthma subtypes and accelerate the development of therapeutics for severe asthma.