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; 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。项目摘要/摘要 我们提出了一项针对针对的高影响，随机，双盲，安慰剂对照的机械临床试验 阐明过敏患者的严重性和治疗反应的广泛异质性的基础 鼻连接炎（ARC）和过敏性哮喘（AA）。 AA和ARC非常普遍，环境触发 共享机理的合并条件通常与之相关。我们将与房屋尘螨一起学习 （HDM）相关的PARC和AA，称为HDM+PARC+AA+。 HDM在AA/ARC发病机理和 疾病的严重程度。为了调查可能导致异质性的机制，我们利用了 Aeroalroergen挑战室（ACC），一种独特且相对罕见的资源，可以控制 暴露于ARC/AA疾病触发因素。 HDM的患者的固定剂量HDM挑战研究 没有AA的相关PARC（i）适应不良（持续更高的ARC症状），（ii）自适应 （随着反复挑战的进行性症状减轻）和（ii）弹性（抵抗症状诱导） 表型。自然环境中的症状严重程度是表型的不精确关联。 一致，HDM+PARC+AA+HDMS中的挑战研究也唤起了这些 表型。机械研究表明，这些表型可能与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+ 持续性轻度至中度哮喘的人。 ACC将用于识别适应不良的人 和自适应表型，由响应HDM暴露的较高和较低的症状严重程度定义 在ACC中。每个表型地层将被随机分为1：1，并给予22周的杜皮鲁姆布（Dupilumab）疗程 （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15小时 挑战将发生：1）用于表型和症状的基线评估（随机化前），2） 间歇性地进行杜皮鲁姆（Dupilumab）/安慰剂给药，以评估对药物反应的异质性， 3）间歇性地在dupilumab/安慰剂之外，以评估复发性的异质性 症状。上呼吸道（鼻）和全身性（外围血液）隔室的机械相关性 将确定预处理，治疗和非治疗。因此，该临床试验将检验假设 22周的Dupilumab课程会减轻持续的轻度至中等过敏性的AA/ARC症状 通过或不完全恢复上皮完整性，通过缓解炎症来缓解哮喘受试者。但是，费率 症状衰减和复发的人会分别较少和更大。 与自适应表型相比。对该假设的肯定将为机制提供新的见解 疾病严重性和治疗反应的异质性的基础，并提供了考虑的基础 多模式治疗干预措施，以抑制AA/ARC症状。