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: 10686198
• 负责人: Sunil K Ahuja
• 金额: $ 118.35万
• 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/10686198
• 关键词: Allergic; Allergic rhinitis; Asthma; Attenuated; Automobile Driving; Biological Assay; Biological Products; CCL18 gene; Classification; Clinical Trials; Coupling; Data; Depressed mood; Disease; Disease model; Dose; Double-Blind Method; Environment; Epithelium; 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; 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; 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; resilience; 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/摘要 我们提出了一个高影响力，随机，双盲，安慰剂对照，机械临床试验，旨在 阐明了过敏性鼻炎患者的严重程度和治疗反应的广泛异质性的基础， 鼻结膜炎（ARC）和过敏性哮喘（AA）。AA和ARC非常普遍，由环境引发 并且常常是共享机械相关性的共病状况。我们将研究患有屋尘螨的人 （HDM）相关的PARC和AA，称为HDM+PARC+AA+。HDM在AA/ARC发病机制中有影响， 疾病严重程度。为了研究可能导致异质性的机制，我们利用了一个 空气过敏原激发室（ACC），一种独特且相对罕见的资源， 暴露于ARC/AA的疾病触发因素。在HDM患者中进行的固定剂量HDM激发研究- 无AA的相关PARC诱发（i）适应不良（持续较高的ARC症状），（ii）适应性 （反复挑战的渐进性症状减轻）和（ii）弹性（对症状诱导的抵抗力） 表型在自然环境中的症状严重程度是一个不精确的相关表型。 相应地，在ACC中存在HDM的HDM+PARC+AA+患者中进行的激发研究也诱发了这些 表型机制研究表明，这些表型可能与以下水平之间的不平衡有关： 气道上皮完整性和炎症。为了进一步测试这一概念，我们将评估88 HDM+PARC+AA+ 患有持续性轻度至中度哮喘的人。ACC将用于识别适应不良的人 和适应性表型，定义为对HDM暴露的反应引起的较高和较低的症状严重程度 每个表型分层将以1：1随机分配，并给予22周疗程的dupilumab （靶向IL-4受体α的单克隆抗体）或安慰剂。在ACC中暴露于HDM，每天1次，每次5小时 将进行激发：1）用于表型分析和症状基线评估（随机化前），2） 在dupilumab/安慰剂给药期间间歇性评估药物应答异质性， 和3）间歇性停用dupilumab/安慰剂，以评估 症状上气道（鼻）和全身（外周血）室的机制相关性 将在治疗前、治疗中和治疗结束时确定。因此，这项临床试验将测试假设 dupilumab 22周疗程将减轻持续性轻度至中度过敏性鼻炎患者的AA/ARC症状。 哮喘受试者通过减轻炎症而具有或不具有完全恢复上皮完整性。然而， 的症状减轻和复发将分别更少和更大，在人与适应不良 与适应性表型相比。对这一假说的肯定将为研究其作用机制提供新的思路 支持疾病严重程度和治疗反应的异质性，并提供考虑 多模式治疗干预，以实现AA/ARC症状的持久抑制。