University of Kansas' Precision Biologic Interventions for Severe Exacerbation Prone Asthma (PrecISE) Clinical Center

摘要-华盛顿大学精密临床中心 严重哮喘对受这种疾病影响的个人和社会的总体影响是 相当可观。重症哮喘的治疗现在侧重于针对特定表型进行量身定制的治疗。 然而，在内型的推动下，这种方法缺乏证据。主要的表型有 支持合适的生物标记物和基于其内型的治疗的证据包括嗜酸性粒细胞， T2和粘蛋白驱动的疾病状态。这一提案包含了精准医学、生物标记物驱动、高度 新的适应性对照试验将建立由世界卫生组织提出的治疗重症哮喘的新范式 NHLBI对严重和/或易加重哮喘(精确)网络RFA的精确干预。在……里面 目前的建议，我们的总体假设是，特定的表型(嗜酸性、T2或粘蛋白)将 对针对该表型的生物疗法的反应比经验方法更好。 具体地说，我们假设具有以下表型的患者的治疗反应会不同：i) 用抗IL_5或抗IL_4Rα单抗治疗嗜酸性粒细胞优于抗IgE，II)T_2- 用抗IL4Rα或-IL5治疗优于抗-IgE和iii)用抗IL4Rα或-IL5治疗粘液 IL5优于抗-IgE。在这项适应性试验设计中，我们将使用两个短期反应指标， FEV1较基线改善100毫升或以上和/或哮喘控制(ACQ)评分改善 0.5或更大，以确定患者是否有反应。主要终点将是哮喘 加重率。因此，我们的具体目标是研究青少年和成人重症患者。 易持续加重的哮喘： 目的一、评价抗白介素4受体α、抗白介素5或抗IgEmAb哪种生物疗法最有效。 嗜酸性哮喘患者(血嗜酸性粒细胞≥300cell/µL)表现为短期- 反应，并证明了一个可接受的安全概况。 目的II.评价抗白介素4受体α、抗白介素5或抗Ig E单抗中的哪种生物疗法最有效 表现为短期反应的T2哮喘(高T2痰征象)患者 展示了可接受的安全配置文件。 目的三、评价抗白介素4受体α、抗白介素5或抗Ig E单抗哪种生物疗法最有效 粘液驱动哮喘(QCT胸片上粘液评分高)患者表现为短期- 反应，并证明了一个可接受的安全概况。 目的：确定生物治疗是否改善了气道重塑(QCT室壁面积的改变)。 目标IV.b.评估每种生物疗法中的积极短期反应预测的能力 病情恶化和呼吸道重塑。

Abstract – Washington University's PrecISE Clinical Center The overall impact of severe asthma on individuals affected by this disease as well as society is substantial. Treatment for severe asthma is now focusing on tailoring treatment to particular phenotypes driven by the endotypes yet the evidence for this approach is lacking. Key phenotypes which have supporting evidence for appropriate biomarkers and therapy based on their endotype include eosinophilic-, T2- and mucin-driven disease states. This proposal contains a precision-medicine, biomarker-driven, highly novel adaptive controlled trial to establish a new treatment paradigm for severe asthma as proposed by the NHLBI's Precision Interventions for Severe and/or Exacerbation Prone Asthma (PrecISE) Network RFA. In the current proposal, our overall hypothesis is that a specific phenotype (eosinophilic, T2 or mucin) will respond better to a biologic therapy targeted specifically to that phenotype than an empirical approach. Specifically, we hypothesize that patients with the following phenotypes will differ in treatment responses: i) eosinophilic - treatment with anti-IL5 or anti-IL4Rα monoclonal antibody (mAb) is superior to anti-IgE, ii) T2 - treatment with anti-IL4Rα or –IL5 is superior to anti-IgE and iii) mucus - treatment with either anti-IL4Rα or - IL5 is superior to anti-IgE. In this adaptive trial design, we will use two short-term response indicators, improvement in FEV1 of 100 ml or greater from baseline and/or improvement in asthma control (ACQ) score of 0.5 or greater, to determine if the patient is responding or not. The primary endpoint will be the asthma exacerbation rate. Accordingly, our specific aims are to study adolescent and adult patients with severe persistent exacerbation-prone asthma to: Aim I. Evaluate which biologic therapy, anti-IL4Rα, anti-IL5 or anti-IgE mAb, is most effective among patients with eosinophilic asthma (blood eosinophil ≥300 cells/µL) who demonstrate a short term- response and which demonstrates an acceptable safety profile. Aim II. Evaluate which biologic therapy, anti-IL4Rα, anti-IL5 or anti-IgE mAb, is most effective among patients with T2 asthma (high T2 sputum signature) who demonstrate a short term-response and which demonstrates an acceptable safety profile. Aim III. Evaluate which biologic therapy, anti-IL4Rα, anti-IL5 or anti-IgE mAb, is most effective among patients with mucus-driven asthma (high mucus score on qCT chest) who demonstrate a short term- response and which demonstrates an acceptable safety profile. Aim IV. a. Determine whether airway remodeling (change in qCT wall area) is modified by biologic therapy. Aim IV. b. Evaluate the ability of a positive short-term response within each biologic therapy to predict exacerbations and airway remodeling.