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

7.项目摘要/摘要 我们提出了一项高影响、随机、双盲、安慰剂对照、机械性的临床试验，旨在 阐明过敏症患者严重程度和治疗反应广泛异质性的基础 鼻结膜炎(ARC)和过敏性哮喘(AA)。AA和ARC非常普遍，由环境触发 而且常常是机械相关的共病情况。我们将研究患有屋尘螨的人 (HDM)相关的PARC和AA，称为HDM+PARC+AA+。HDMS在AA/ARC发病机制中的作用 疾病的严重性。为了研究可能导致异质性的机制，我们利用了一个 空气变应原挑战室(ACC)，一种独特而相对稀有的资源，允许受控 暴露于ARC/AA的疾病触发因素。对HDM患者进行固定剂量HDM的挑战研究- 无AA诱发的相关PARC(I)适应不良(持续较高的ARC症状)，(Ii)适应性 (通过反复挑战逐步减少症状)，以及(Ii)弹性(抵抗症状诱导) 表型。自然环境中的症状严重程度与表型之间存在不精确的相关性。 一致的是，对ACC中HDM+PARC+AA+HDMS患者的挑战研究也引发了这些 表型。机械论研究表明，这些表型可能与不同水平的 呼吸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个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 适应性表型，由对HDM暴露的反应引起的更高和更低的症状严重程度定义 在美国中央情报局。每个表型地层将被随机分为1：1，并接受为期22周的dupiumab疗程 (针对IL-4受体α的单抗)或安慰剂。在ACC中暴露于HDMS，每天1次，每次5小时 将面临挑战：1)表型和症状基线评估(随机前)，2) 间歇性地服用杜匹单抗/安慰剂以评估药物反应的异质性， 3)间歇性停用杜匹单抗/安慰剂以评估复发的异质性。 症状。上呼吸道(鼻腔)和全身(外周血液)隔室的机械相关性 将判定为治疗前、治疗中、治疗后。因此，这项临床试验将检验这一假设 持续22周的dupilumab疗程将减轻持续性轻度至中度过敏患者的AA/ARC症状 哮喘受试者通过减轻炎症，无论是否完全恢复上皮完整性。然而，这一比率 在适应不良的人中，症状缓解和复发的可能性分别较小和较大 与适应性表型进行比较。对这一假说的肯定将为我们提供对机制的新见解。 支持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，实现对AA/ARC症状的持久抑制。

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.