Mechanistic clinical trial of blocking the IL-4/13 axis in asthmatics precision phenotyped in an aeroallergen challenge chamber before, during and after receipt of dupilumab

在接受 dupilumab 之前、期间和之后在空气过敏原激发室中精确表型的哮喘患者中阻断 IL-4/13 轴的机制临床试验

• 批准号: 10488483
• 负责人: Sunil K Ahuja
• 金额: $ 118.24万
• 依托单位: UNIVERSITY OF TEXAS HLTH SCIENCE CENTER
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-08-18 至 2027-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10488483
• 关键词: Allergic; Allergic rhinitis; Asthma; Attenuated; Automobile Driving; Biological Assay; Biological Products; CCL18 gene; Clinical Trials; Coupling; Data; Depressed mood; Disease; Disease model; Dose; Double-Blind Method; Environment; Epithelial; Exposure to; Extrinsic asthma; FDA approved; Genes; Heterogeneity; Hour; Immune response; Individual; Individual Differences; Inflammation; Inflammatory; Influentials; Interleukin 4 Receptor; Interleukin-13; Interleukin-4; Intervention; Mediating; Mediator of activation protein; Modeling; Monitor; Monoclonal Antibodies; Nose; Outcome; Participant; Pathogenesis; Pathway interactions; Persons; Pharmaceutical Preparations; Phase; Phenotype; Placebo Control; Placebos; Proxy; Pyroglyphidae; Randomized; Recrudescences; Reporting; Resistance; Resources; Role; Sampling Studies; Series; Severities; Severity of illness; Symptoms; System; Testing; Therapeutic Intervention; Time; airborne allergen; airway epithelium; antiviral immunity; asthmatic; attenuation; base; comorbidity; epithelial injury; epithelial repair; experience; filaggrin; gain of function; genome wide association study; immunological status; innovation; insight; loss of function; multidisciplinary; multimodality; novel; peripheral blood; predictive modeling; reduce symptoms; response; rhinoconjunctivitis; systemic inflammatory response; therapeutic target; trait; transcriptomics; treatment response

7. Project Summary/Abstract We propose a high-impact, randomized, double-blind, placebo-controlled, mechanistic clinical trial aimed at elucidating the basis for the wide heterogeneity in severity of and treatment responses in persons with allergic rhinoconjunctivitis (ARC) and allergic asthma (AA). AA and ARC are highly prevalent, environmentally triggered and often comorbid conditions that share mechanistic correlates. We will study persons with house dust mite (HDM)-associated PARC and AA, termed HDM+PARC+AA+. HDMs are influential in AA/ARC pathogenesis and disease severity. To investigate mechanisms that may contribute to heterogeneity, we capitalized on an aeroallergen challenge chamber (ACC), a unique and relatively rare resource, which allows for controlled exposures to disease triggers of ARC/AA. Challenge studies with a fixed dose of HDM in persons with HDM- associated PARC without AA evoked (i) maladaptive (persistently higher ARC symptoms), (ii) adaptive (progressive symptom reduction with repeated challenges), and (ii) resilient (resistance to symptom induction) phenotypes. Symptom severity in the natural environment was an imprecise correlate of the phenotypes. Congruently, challenge studies in HDM+PARC+AA+ persons with HDMs in the ACC also evoked these phenotypes. Mechanistic studies revealed that these phenotypes may relate to an imbalance between levels of airway epithelial integrity and inflammation. To further test this concept, we will evaluate 88 HDM+PARC+AA+ persons with persistent mild-to-moderate asthma. The ACC will be used identify persons with the maladaptive and adaptive phenotypes, defined by higher and lower symptom severity evoked in response to HDM exposures in the ACC. Each phenotype strata will be randomized 1:1 and administered a 22-week course of dupilumab (monoclonal antibody targeting IL-4 receptor alpha) or placebo. Exposure to HDMs in an ACC for 1 daily 5-hour challenge will occur: 1) for phenotyping and baseline assessment of symptoms (pre-randomization), 2) intermittently while on dupilumab/placebo administration for assessment of heterogeneity in responses to drug, and 3) intermittently while off dupilumab/placebo for assessment of heterogeneity in the recrudescence in symptoms. Mechanistic correlates of the upper airway (nasal) and systemic (peripheral blood) compartments will be determined pre-treatment, on-treatment, and off-treatment. Thus, this clinical trial will test the hypothesis that a 22-week course of dupilumab will attenuate AA/ARC symptoms in persistent mild-to-moderate allergic asthmatic subjects by mitigating inflammation with or without fully restoring epithelial integrity. However, the rate of symptom attenuation and recrudescence will be less and greater, respectively, in persons with the maladaptive compared with adaptive phenotypes. Affirmation of this hypothesis will provide new insights into the mechanisms underpinning heterogeneity in disease severity and treatment responses, as well as provide a basis to consider multi-modal therapeutic interventions to achieve durable suppression of AA/ARC symptoms.

7. 项目总结/文摘