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

堪萨斯大学针对重度哮喘易发性哮喘的精准生物干预 (PrecISE) 临床中心

基本信息

批准号：
10223411
负责人：
Mario Castro
金额：
$ 39.43万
依托单位：
UNIVERSITY OF KANSAS MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-09-17 至 2023-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10223411
关键词：
Adolescent Adult Affect Area Asthma Automobile Driving Biological Biological Markers Biological Response Modifier Therapy Caring Cells Child Control Groups Diagnosis Disease Expenditure Functional disorder Gases Guidelines IL5 gene Individual International Intervention Intervention Studies Kansas Lung Magnetic Resonance Imaging Measures Monoclonal Antibodies Mucins Mucous body substance Multicenter Trials National Heart, Lung, and Blood Institute Patients Phenotype Prevalence Pulmonary Function Test/Forced Expiratory Volume 1 Research Safety Smooth Muscle Societies Sputum Therapeutic Translational Research United States National Institutes of Health Universities Washington airway epithelium airway remodeling anti-IgE asthma exacerbation asthmatic base biomarker-driven chest computed tomography clinical center disease phenotype eosinophil eosinophilic asthma evidence base imaging modality individualized medicine insight novel personalized intervention precision medicine primary endpoint programs recruit response response biomarker targeted treatment treatment response trial design

项目摘要

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.

摘要 - 华盛顿大学的精确临床中心严重哮喘对受这种疾病和社会影响的个体的总体影响是重大的。严重哮喘的治疗现在正着重于针对特定表型的治疗在内部型中，这种方法的证据却缺乏。具有的关键表型支持适当的生物标志物和基于其内型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。该提案包含一个精密的中等医学，生物标志物驱动的，高度新型的自适应对照试验，以建立针对严重哮喘的新治疗范式 NHLBI的严重和/或恶化哮喘（精确）网络RFA的精确干预措施。在当前的建议，我们的总体假设是特定的表型（嗜酸性粒细胞，T2或粘蛋白）将对专门针对该表型的生物疗法的反应比经验方法更好。具体而言，我们假设患有以下表型的患者在治疗反应上会有所不同：i）嗜酸性 - 用抗IL5或抗IL4Rα单克隆抗体（MAB）治疗优于抗IgE，ii）T2- 抗IL4Rα或–IL5治疗抗IgE和iii）粘液 - 用抗IL4Rα或–IL5处理抗Il5和iii）粘液 - 用抗IL4Rα或 - 治疗 IL5优于抗IgE。在这种自适应试验设计中，我们将使用两个短期响应指标， FEV1的改进为100 mL或从基线和/或改善哮喘控制（ACQ）评分改善 0.5或更高，以确定患者是否反应。主要终点将是哮喘加重率。据所有人，我们的具体目的是研究青少年和成年患者持续性加重哮喘至： AIM I.评估哪种生物疗法，抗IL4Rα，抗IL5或抗IgE mAB在嗜酸性哮喘（血液嗜酸性≥300细胞/µL）的患者表现出短期 - 响应并显示出可接受的安全性。目标II。评估哪种生物疗法，抗IL4Rα，抗IL5或抗IgE MAB在 T2哮喘患者（高T2痰液签名）表现出短期反应，并且展示可接受的安全性。目标三。评估哪种生物疗法，抗IL4Rα，抗IL5或抗IgE MAB在患有粘液驱动哮喘的患者（QCT胸部粘液评分很高），这些患者表现出短期 - 响应并显示出可接受的安全性。目标IV。一个。确定气道重塑（QCT壁区域的变化）是否通过生物治疗来改变。目标IV。 b。评估每种生物疗法中阳性短期反应预测的能力恶化和气道重塑。