San Diego Team Asthma Management using Phenotypes (STAMP)

圣地亚哥团队使用表型进行哮喘管理 (STAMP)

• 批准号: 9406023
• 负责人: Praveen Akuthota
• 金额: $ 24.2万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 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/9406023
• 关键词: Adrenal Cortex Hormones; Adrenergic Agents; Adult; Affect; Allergic Disease; American; Asthma; Biological; Biological Assay; Biological Markers; Biological Response Modifier Therapy; Blood; Blood specimen; Breathing; California; Cells; Childhood; Clinical; Clinical Management; Clinical Research; Clinical Trials; Clinical Trials Design; Clinical Trials Network; Development; Disease; Eosinophilia; Etanercept; Exhalation; Failure; Future; Genomics; Goals; Grant; Heterogeneity; Hypersensitivity; IL4 gene; IgE; Immune; Immunology; Inflammation; Institutes; Interleukin-13; Interleukin-4; Interleukin-5; Intervention; Investigational Therapies; Leukotrienes; Modification; Monoclonal Antibodies; Monoclonal Antibody R24; National Heart, Lung, and Blood Institute; New Agents; Patients; Pharmaceutical Preparations; Phase; Phenotype; Placebos; Process; Protocols documentation; Pulmonology; Randomized; Recruitment Activity; Research Institute; Resources; Sampling; Serum; Sputum; Stratification; Study Subject; Surface; TNF gene; Therapeutic; Translational Research; Universities; Work; anti-IgE; arm; asthmatic patient; base; design; drug development; eosinophil; epigenomics; individual patient; inhibitor/antagonist; interest; interleukin-13 receptor; interleukin-5 receptor; mepolizumab; novel marker; novel strategies; novel therapeutics; omalizumab; periostin; personalized intervention; primary outcome; programs; receptor; response; sialic acid binding Ig-like lectin; success; targeted treatment; tool; treatment response; trial design; Adrenal Cortex Hormones; Adrenergic Agents; Adult; Affect; Allergic Disease; American; Asthma; Biological; Biological Assay; Biological Markers; Biological Response Modifier Therapy; Blood; Blood specimen; Breathing; California; Cells; Childhood; Clinical; Clinical Management; Clinical Research; Clinical Trials; Clinical Trials Design; Clinical Trials Network; Development; Disease; Eosinophilia; Etanercept; Exhalation; Failure; Future; Genomics; Goals; Grant; Heterogeneity; Hypersensitivity; IL4 gene; IgE; Immune; Immunology; Inflammation; Institutes; Interleukin-13; Interleukin-4; Interleukin-5; Intervention; Investigational Therapies; Leukotrienes; Modification; Monoclonal Antibodies; Monoclonal Antibody R24; National Heart, Lung, and Blood Institute; New Agents; Patients; Pharmaceutical Preparations; Phase; Phenotype; Placebos; Process; Protocols documentation; Pulmonology; Randomized; Recruitment Activity; Research Institute; Resources; Sampling; Serum; Sputum; Stratification; Study Subject; Surface; TNF gene; Therapeutic; Translational Research; Universities; Work; anti-IgE; arm; asthmatic patient; base; design; drug development; eosinophil; epigenomics; individual patient; inhibitor/antagonist; interest; interleukin-13 receptor; interleukin-5 receptor; mepolizumab; novel marker; novel strategies; novel therapeutics; omalizumab; periostin; personalized intervention; primary outcome; programs; receptor; response; sialic acid binding Ig-like lectin; success; targeted treatment; tool; treatment response; trial design

Project Summary/Abstract There has been increasing recognition over the last several years of the heterogeneity in the pathobiologic underpinnings of asthma and the critical importance of phenotyping and endotyping in dictating response to therapy. For example, it was only after selecting patients with sputum (and later blood) eosinophilia and using exacerbation rate as the primary outcome, was the utility of mepolizumab in asthma uncovered in a clinical trial setting. With multiple immune-modulating biologic agents already available and with more to come in the very near future, our understanding how to best deploy these agents in a precise manner to patients with severe and/or exacerbation-prone asthma (those who would be most likely to be prescribed biologic agents) must be refined. The PrecISE Network will use sequential, adaptive clinical trial designs, which represents a novel approach in asthma clinical research, to answer these questions, while also presenting an opportunity for significant progress in phenotyping and endotyping as applied to clinical management of patients with severe asthma. In this application, we propose the following Specific Aims: 1) Establishment of the San Diego Team Asthma Management Program (STAMP) as a Clinical Center in the NHLBI PrecISE Network: We have put together a team that leverages the substantial resources of UCSD and the San Diego region to create a PreCISE Clinical Center that will optimally recruit subjects and perform PrecISE Network protocols as they are developed and implemented. 2) Proposal of a PrecISE Netowrk Clinical Trial Using a sequential, adaptive, phase IIb/proof of concept design: In accordance with the goals of the PrecISE Network, our proposed trial design will be center on the use of precision interventions based on stratification of severe asthma subjects by phenotype/endotype. Using already established biomarkers, including blood/sputum eosinophilia, serum periostin, serum IgE, and exhaled NO, we propose to stratify subjects into Th2-high (“Th2H”), non-Th2-high (“NTh2H”), and MIXED endotypes to dictate experimental interventions. Th2H and MIXED subjects would be randomized to placebo, Allakos (Anti-Siglec-8 monoclonal antibody), or dupilumab (anti-IL4/IL13 receptor). Concurrently, NTh2H subjects would be randomized into placebo, etanercept (TNF inhibitor), or dupilumab. During the trial, some of these interventions may be shown to have a lack of sufficient activity and these will be withdrawn after interim analysis and replaced by new agents or by new biomarker-defined groups. Successful treatments at the interim analysis stage will proceed to the next stage. 3) Identification of novel biomarkers to stratify responders to targeted treatments: Our group has the scientific expertise to perform and analyze novel biomarker studies associated with PrecISE protocols. We propose to leverage these micro-scaled genomic and immunology tools to identify novel biomarkers for treatment response from sputum and blood samples of our study subjects.

项目摘要/摘要 在病理生物学中的异质性的最后几年中，人们的认识越来越多 哮喘的基础以及表型和内型在决定对反应的重要性 治疗。例如，只有在选择痰液（及以后的血液）嗜酸性粒细胞并使用的患者之后 加剧率是主要结果，是在临床试验中发现的巨脂珠的实用性 环境。有多种免疫调节生物学剂已经可用，并且还有更多 不久的将来，我们的理解如何以精确方式最佳地部署这些代理商 和/或且容易发生的哮喘（最有可能被处方生物学毒剂的哮喘）必须是 精制。精确的网络将使用顺序的自适应临床试验设计，代表一种新颖 哮喘临床研究中的方法，回答这些问题，同时也为 表型和内型的显着进展，适用于严重患者的临床管理 哮喘。在此应用程序中，我们提出以下特定目的：1）建立圣地亚哥团队 哮喘管理计划（邮票）作为NHLBI精确网络中的临床中心：我们已经说明 一支利用UCSD和圣地亚哥地区大量资源来创建的团队 精确的临床中心将最佳招募主题并执行精确的网络协议 开发和实施。 2）使用顺序的自适应，提出精确的NetOwrk临床试验的建议 IIB阶段/概念验证设计：根据精确网络的目标，我们提议的试验 设计将是基于严重哮喘受试者分层的精确干预措施的中心 表型/内型。使用已经建立的生物标志物，包括血/痰嗜酸性粒细胞，系列 骨膜蛋白，血清IgE和呼气不，我们建议将受试者分层为Th2高（“ Th2H”），非Th2高 （“ nth2h”），以及混合式内型来决定实验干预措施。 TH2H和混合主题将是 随机分为安慰剂，allakos（抗Siglec-8单克隆抗体）或dupilumab（抗IL4/IL13受体）。 同时，NTH2H受试者将被随机分为安慰剂，Etanercept（TNF抑制剂）或Dupilumab。 在试验期间，其中一些干预措施可能显示出缺乏足够的活动，这些活动将是 临时分析后撤回，由新代理或新的生物标志物定义的组取代。成功的 临时分析阶段的治疗将继续前进。 3）识别新型生物标志物 分层响应者对有针对性的治疗：我们的小组具有执行和分析新颖的科学专业知识 与精确方案相关的生物标志物研究。我们建议利用这些微刻度基因组 和免疫学工具，以识别新型生物标志物，以用于痰液和血液样本的治疗反应 我们的研究学科。