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/摘要 我们提出了一项高影响力、随机、双盲、安慰剂对照、机制性临床试验，旨在 阐明过敏症患者的严重程度和治疗反应存在广泛异质性的基础 鼻结膜炎（ARC）和过敏性哮喘（AA）。 AA 和 ARC 非常普遍，由环境引发 并且通常存在具有机械相关性的共病。我们将研究患有屋尘螨的人 (HDM) 相关的 PARC 和 AA，称为 HDM+PARC+AA+。 HDMs 对 AA/ARC 发病机制有影响 疾病的严重程度。为了研究可能导致异质性的机制，我们利用了 空气过敏原挑战室 (ACC)，一种独特且相对稀有的资源，可实现受控 暴露于 ARC/AA 疾病触发因素。对 HDM 患者进行固定剂量的 HDM 挑战研究 没有 AA 诱发的相关 PARC (i) 适应不良（持续较高的 ARC 症状），(ii) 适应性 （通过反复挑战逐渐减少症状），以及（ii）有弹性（对症状诱导的抵抗力） 表型。自然环境中症状的严重程度与表型的相关性不精确。 一致地，对 ACC 中具有 HDM 的 HDM+PARC+AA+ 人进行的挑战研究也引发了这些 表型。机制研究表明，这些表型可能与不同水平之间的不平衡有关。 气道上皮完整性和炎症。为了进一步测试这个概念，我们将评估 88 HDM+PARC+AA+ 患有持续性轻至中度哮喘的人。 ACC 将用于识别适应不良的人 和适应性表型，定义为响应 HDM 暴露而引发的较高和较低症状严重程度 在 ACC 中。每个表型层将按 1:1 随机分配，并接受为期 22 周的 dupilumab 疗程 （针对 IL-4 受体 α 的单克隆抗体）或安慰剂。在 ACC 中接触 HDM，每天 1 次，每次 5 小时 将出现以下挑战：1) 表型分析和症状基线评估（预随机化），2) 在使用 dupilumab/安慰剂时间歇性地评估药物反应的异质性， 3) 在停用 dupilumab/安慰剂时间歇性评估复发的异质性 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，这项临床试验将检验这一假设 22 周的 dupilumab 疗程将减轻持续性轻度至中度过敏的 AA/ARC 症状 通过减轻炎症来治疗哮喘受试者，无论是否完全恢复上皮完整性。然而，率 对于适应不良的人来说，症状减弱和复发的程度分别会更少和更大。 与适应性表型相比。这一假设的证实将为该机制提供新的见解 支撑疾病严重程度和治疗反应的异质性，并提供考虑的基础 多模式治疗干预以实现 AA/ARC 症状的持久抑制。