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

项目摘要/摘要 严重/易加重的哮喘仍然是一个严重的问题，发病率和死亡率很高，尽管 开发新的靶向疗法。NHLBI对重症和非传染性疾病的精确干预的目标 易加重哮喘(PRECISH)网络将精确地进行序贯、适应性、临床试验 对分层患者人群的干预，利用患者表型/内型。我们假设一个 生物标记物导向的方法，应用于适应性试验，可用于定义表型/内型特征 预测对特定精确干预措施的反应，并在 选择一种精准干预疗法而不是另一种。因此，我们提出以下具体目标： 1.与成人和青少年精确网络进行序贯、适应性临床试验 对于严重/易加重的哮喘，利用目前可用的患者表型/内型， 以及监测生物标志物，以验证它们在预测对精确干预的反应方面的有效性 治疗策略包括抗IL5、抗IL4/13、抗IgE、抗IL6。 2.证明生物标记物驱动的策略利用血液中的嗜酸性粒细胞，呼出的一氧化氮和 血浆IL6或CRP水平，通过自适应设计以分层方式应用，可用于 为具有特定表型/内型的患者选择最佳的精确干预措施。 3.评估下一代生物标志物(包括细胞因子分析、RNA序列、途径分析和 血液、痰和/或鼻刷中类固醇反应基因的表达)可作为预测 对特定哮喘干预措施的反应。 我们提出了一项800名受试者的临床试验，该试验使用序贯、适应性试验设计模型来选择精确度 严重/易加重哮喘的干预措施，包括抗IL5、抗IL4/13、抗IgE和抗IL6 有特定内型的患者。我们将探索当前的生物标志物(包括血液中的嗜酸性粒细胞、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。我们会 确定指定生物标志物的变化是否将与对精密度的响应相关联 介入疗法。对于对我们的干预无效的患者，我们将进行胸部/鼻窦CT扫描 支气管镜检查结合活检和灌洗，以确定精确干预的组织特异性策略。 我们将利用丹佛工厂的经验和既定的临床试验计划，在以下方面拥有专业知识 表型分型/内分型、生物标记物开发和分析方法，以满足我们使用 作为临床护理模式的适应性试验设计，以填补管理严重/易加重哮喘的空白 并根据个体治疗反应和评估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.