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以及社会的总体影响是 相当可观严重哮喘的治疗现在集中在针对特定表型的定制治疗上 由内型驱动，但缺乏这种方法的证据。关键表型， 适当的生物标志物和基于其内型的治疗的支持证据包括嗜酸性粒细胞-， T2和粘蛋白驱动的疾病状态。该提案包含了一个精确的医学，生物标记驱动，高度 一项新的适应性对照试验，以建立一种新的治疗重度哮喘的范例， NHLBI的Precision Interventions for Severe and/or Exacerbation Prone Asthma（Precise）Network RFA。在 目前的建议，我们的总体假设是，一个特定的表型（嗜酸性粒细胞，T2或粘蛋白）将 与经验方法相比，对针对该表型的生物治疗反应更好。 具体而言，我们假设具有以下表型的患者在治疗反应上会有所不同：i） 嗜酸性粒细胞-用抗IL 5或抗IL 4 R α单克隆抗体（mAb）治疗上级抗IgE，ii）T2 - 用抗-IL 4 R α或-IL 5治疗上级抗-IgE，和iii）用抗-IL 4 R α或-IL 5治疗的粘液-治疗 IL-5比抗-IgE强上级。在本适应性试验设计中，我们将使用两个短期反应指标， FEV 1较基线改善≥ 100 ml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。主要终点为哮喘 加重率因此，我们的具体目标是研究青少年和成人患者的严重 持续性易加重哮喘： 艾姆岛评价哪种生物治疗（抗IL 4 R α、抗IL 5或抗IgE mAb）最有效， 嗜酸性粒细胞性哮喘患者（血嗜酸性粒细胞≥300个细胞/µL）， 反应，并证明可接受的安全性。 Aim II.评价哪种生物治疗（抗IL 4 R α、抗IL 5或抗IgE mAb）最有效， T2哮喘患者（高T2痰特征），表现出短期应答， 证明了可接受的安全性。 Aim III.评价哪种生物治疗（抗IL 4 R α、抗IL 5或抗IgE mAb）最有效， 粘液驱动型哮喘患者（qCT胸部粘液评分高）， 反应，并证明可接受的安全性。 目标四。a.确定生物治疗是否改变了气道重塑（qCT壁面积的变化）。 目标四。B.评价每种生物制剂治疗中的阳性短期缓解预测 加重和气道重塑。

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.