Precision Interventions for Severe and/or Exacerbation Prone Asthma (PrecISE)

项目总结/摘要 重度/易于加重的哮喘仍然是一个主要问题，具有显著的发病率和死亡率， 新的靶向治疗的发展。NHLBI的目标是对严重和 急性发作倾向性哮喘（Precise）网络是进行顺序，适应性，临床试验的精度 利用患者表型/内在型对分层患者人群进行干预。我们假设 在适应性试验中应用的生物标志物导向方法可用于定义表型/内型特征 严重/有加重倾向的哮喘，预测对特定精确干预措施的反应， 选择一种精确的介入治疗而不是另一种。因此，我们提出以下具体目标： 1.使用Precise Network为成人和青少年开展连续的适应性临床试验 严重/易加重哮喘，利用目前可用的患者表型/内在型， 并监测生物标志物，以验证其在预测对精确干预的反应方面的效用 抗IL-5、抗IL-4/13、抗IgE和抗IL-6的免疫治疗策略。 2.证明利用血液嗜酸性粒细胞、呼出的一氧化氮和 血浆IL 6或CRP水平，以适应性设计的分级方式应用，可用于 为具有特定表型/内型的患者选择最佳精确干预。 3.评估下一代生物标志物（包括细胞因子分析、RNA测序、途径分析和 类固醇反应基因在血液、痰和/或鼻刷中的表达）作为 对特定哮喘干预措施的反应。 我们提出了一个800名受试者的临床试验，使用序贯，自适应试验设计模型来选择精度 在重度/易加重哮喘中进行干预，包括抗IL 5、抗IL 4/13、抗IgE和抗IL 6 具有特定内型的患者。我们将探讨目前的生物标志物（包括血液嗜酸性粒细胞，呼出的一氧化氮， 氧化物、血清IL-6、CRP），以及下一代生物标志物。我们将 确定指定生物标志物的变化是否与对精密度的响应相关 介入治疗对于那些对我们的干预措施没有反应的人，我们将进行胸部/鼻窦CT扫描。 以及支气管镜活检和灌洗，以确定精确干预的组织特异性策略。 我们将利用丹佛研究中心的经验和已建立的临床试验计划， 表型分型/内型，生物标志物的开发和分析方法，以满足我们使用 适应性试验设计作为临床护理模式，以填补管理重度/易加重哮喘的差距 以及基于个体治疗反应的评估来定义新一代生物标志物， 在研究人群中失败。

Project Summary/Abstract Severe/exacerbation-prone asthma remains a major problem with significant morbidity and mortality despite the development of new targeted therapies. The goal of the NHLBI’s Precision Interventions for Severe and Exacerbation Prone Asthma (PrecISE) Network is to conduct sequential, adaptive, clinical trials with precision interventions in stratified patient populations, utilizing patient phenotypes/endotypes. We hypothesize that a biomarker-directed approach, applied in an adaptive trial, can be used to define phenotypic/endotypic features of severe/exacerbation-prone asthma, predict response to specific precision interventions, and be useful in selecting one precision intervention therapy over another. We thus propose the following Specific Aims: 1. Conduct a sequential, adaptive clinical trial with the PrecISE Network for adults and adolescents with severe/exacerbation-prone asthma, utilizing currently available patient phenotypes/endotypes, and monitoring biomarkers to validate their utility in predicting response to precision intervention strategies including anti-IL5, anti-IL4/13, anti-IgE, and anti IL6. 2. Demonstrate that a biomarker-driven strategy utilizing blood eosinophils, exhaled nitric oxide and plasma IL6 or CRP levels, applied in a hierarchical manner with an adaptive design, can be used to select the best precision intervention for a patient with a specific phenotype/endotype. 3. Evaluate next generation biomarkers (including cytokine profiling, RNA seq, pathway analysis, and expression of steroid response genes in blood, sputum and/or nasal brushings) as predictors of response to specific asthma interventions. We propose an 800-subject clinical trial that uses a sequential, adaptive trial design model to select precision interventions, including anti-IL5, anti-IL4/13, anti-IgE and anti-IL6, in severe/exacerbation-prone asthma patients with specific endotypes. We will explore current biomarkers (including blood eosinophils, exhaled nitric oxide, serum IL-6, CRP), applied in a hierarchical approach, as well as next generation biomarkers. We will determine whether a change in a designated biomarker will be associated with a response to the precision intervention therapy. For those who fail to respond to our interventions, we will obtain chest/sinus CT scans and bronchoscopy with biopsy and lavage to define tissue-specific strategies for precision interventions. We will leverage the experience and established clinical trial program of the Denver site with expertise in phenotyping/endotyping, biomarker development, and analytic approach, to meet our ultimate goals of using adaptive trial design as a model for clinical care, to fill the gap in managing severe/exacerbation-prone asthma and defining a new generation of biomarkers based on assessment of individual treatment response and failure within the study population.