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: 10454973
• 负责人: Stanley J Szefler
• 金额: $ 35.03万
• 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 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10454973
• 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.

项目摘要/摘要 严重/易受加剧的哮喘仍然是一个重大发病率和死亡率目的地的主要问题 新靶向疗法的发展。 NHLBI对严重和严重和 恶化哮喘（精确）网络的加重是要进行顺序，适应性，临床试验精确 使用患者表型/内型在分层患者人群中进行干预。我们假设一个 在自适应试验中应用的生物标志物指导方法可用于定义表型/内型特征 严重/易发性哮喘，预测对特定精度干预措施的反应，并在 选择一种精确的干预疗法而不是另一种。因此，我们提出以下特定目标： 1。对成人和青少年的精确网络进行顺序的自适应临床试验 患有严重/恶化的哮喘，使用当前可用的患者表型/内型， 并监视生物标志物以验证其在预测精度干预响应的效用 包括抗IL5，抗IL4/13，抗IGE和抗IL6在内的策略。 2。证明了利用血液嗜酸性粒细胞，呼出一氧化氮和的生物标志物驱动的策略 血浆IL6或CRP级别以层次的方式使用自适应设计，可用于 为患有特定表型/内型的患者选择最佳的精度干预措施。 3。评估下一代生物标志物（包括细胞因子分析，RNA SEQ，途径分析和 立体反应基因在血液，痰液和/或鼻刷中的表达）作为预测因子 对特定哮喘干预措施的反应。 我们提出了一个800个受试者的临床试验，该试验使用顺序的自适应试验设计模型来选择精度 在严重/易于哮喘的情况下，包括抗IL5，抗IL4/13，抗IGE和抗IL6在内的干预措施 具有特定内型的患者。我们将探索当前的生物标志物（包括血液嗜酸性粒细胞，呼出的一氮 氧化物，血清IL-6，CRP），以分层方法以及下一代生物标志物应用。我们将 确定指定生物标志物的更改是否与对精度的响应有关 干预疗法。对于那些未能应对我们的干预措施的人，我们将获得胸部/鼻窦CT扫描 和支气管镜检查进行活检和灌洗，以定义组织特异性策略的精确干预措施。 我们将利用丹佛网站的经验并建立了临床试验计划，并具有专业知识 表型/内型，生物标志物发展和分析方法，以实现我们使用的最终目标 自适应试验设计作为临床护理的模型，以填补管理严重/恶化哮喘的空白 并根据个人治疗反应的评估和 研究人群的失败。

项目成果

Legends of allergy and immunology: Donald Y. M. Leung.

过敏和免疫学传奇人物：Donald Y. M. Leung。

• DOI: 10.1111/all.14031
• 发表时间: 2020
• 期刊: Allergy
• 影响因子: 12.4
• 作者: Szefler,StanleyJ