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

针对严重和/或易加重哮喘的精准干预 (PrecISE)

• 批准号: 10219823
• 负责人: Stanley J Szefler
• 金额: $ 38.47万
• 依托单位: NATIONAL JEWISH HEALTH
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-23 至 2023-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10219823
• 关键词: Adherence; Adolescent; Adrenal Cortex Hormones; Adult; Adverse effects; Adverse event; Asthma; Biological Markers; Biopsy; Blood; Bronchoscopy; Chest; Clinical Trials; Clinical trial protocol document; Development; Disease; Dose; Economic Burden; Exhalation; Exhibits; Expenditure; Generations; Genes; Goals; Hospitalization; IL4 gene; IL5 gene; IL6 gene; Individual; Inflammation; Inhalation; Interleukin-6; Intervention; Irrigation; Measures; Modeling; Monitor; Morbidity - disease rate; National Heart, Lung, and Blood Institute; Nitric Oxide; Nose; Pathway Analysis; Patients; Pharmaceutical Preparations; Phenotype; Plasma; Precision therapeutics; Protocols documentation; Quality of life; Refractory; Selection for Treatments; Serum; Sinus; Site; Spirometry; Sputum; Steroids; Symptoms; Therapeutic; Therapeutic Intervention; Time; Tissues; Treatment Failure; Work; X-Ray Computed Tomography; anti-IgE; asthma exacerbation; asthmatic patient; base; biomarker development; biomarker-driven; burden of illness; clinical care; comorbidity; cytokine; design; eosinophil; experience; improved; model design; mortality; new therapeutic target; next generation; non-drug; novel; novel marker; novel therapeutics; patient population; patient stratification; personalized intervention; predicting response; predictive marker; primary outcome; programs; pulmonary function; response; response biomarker; secondary outcome; specific biomarkers; study population; transcriptome sequencing; treatment response; treatment strategy; trial design

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.

项目概要/摘要 尽管严重/易恶化的哮喘仍然是一个具有显着发病率和死亡率的主要问题 开发新的靶向治疗方法是 NHLBI 针对严重和严重疾病的精准干预的目标。 检查性哮喘 (PrecISE) 网络旨在精确地进行连续的、适应性的临床试验 利用患者表型/内型对分层患者群体进行干预。 应用于适应性试验的生物标志物导向方法可用于定义表型/内型特征 严重/易恶化哮喘的预测，预测对特定精准干预措施的反应，并可用于 因此，我们提出以下具体目标： 1. 利用 PrecISE 网络针对成人和青少年进行连续、适应性临床试验 患有严重/易恶化的哮喘，目前利用可用的患者表型/内型， 并监测生物标志物以验证其在预测精准干预反应方面的效用 策略包括抗IL5、抗IL4/13、抗IgE和抗IL6。 2. 证明利用血液嗜酸性粒细胞、呼出的一氧化氮和 血浆 IL6 或 CRP 水平通过适应性设计以分级方式应用，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 seq、通路分析和 血液、痰液和/或鼻刷中类固醇反应基因的表达）作为预测因子 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、自适应试验设计模型来选择精度 针对严重/易加重哮喘的干预措施，包括抗 IL5、抗 IL4/13、抗 IgE 和抗 IL6 我们将探索当前的生物标志物（包括血液嗜酸性粒细胞、呼出的硝酸盐）。 氧化物、血清 IL-6、CRP），以分层方法应用，以及下一代生物标志物。 确定指定生物标志物的变化是否与精度响应相关 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。 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。 我们将利用丹佛基地的经验和既定的临床试验计划以及以下方面的专业知识： 表型/内型、生物标志物开发和分析方法，以满足我们使用的最终目标 适应性试验设计作为临床护理的模型，以填补管理严重/易恶化哮喘的空白 并根据个体治疗反应的评估定义新一代生物标志物 研究人群中的失败。