San Diego Team Asthma Management using Phenotypes (STAMP)

项目摘要/摘要 在过去的几年里，人们越来越多地认识到病理生物学中的异质性 哮喘的基础以及表型和内型在口述反应中的关键重要性 心理治疗。例如，只有在选择了痰(和后来的血液)嗜酸性粒细胞增多症患者并使用 作为主要结果的加重率，是临床试验中发现的甲波利单抗对哮喘的有效性 布景。多种免疫调节生物制剂已经可用，而且还会有更多的生物制剂问世 在不久的将来，我们了解如何以精确的方式最好地将这些药物部署到重症患者 和/或易加重的哮喘(那些最有可能服用生物制剂的人)必须 精致的。精密网络将使用顺序的、适应性的临床试验设计，这代表了一种新的 哮喘临床研究中的方法，以回答这些问题，同时也为 表型和内源性分型在重型肝炎患者临床治疗中的重要进展 哮喘。在本申请中，我们提出了以下具体目标：1)建立圣地亚哥团队 哮喘管理项目(STAMP)作为NHLBI精确网络中的临床中心：我们已经 一个团队，利用加州大学圣地亚哥分校和圣地亚哥地区的大量资源，共同创建 精确的临床中心，将以最佳方式招募受试者并按原样执行精确的网络协议 制定并实施了。2)提出了使用序贯的、自适应的、 阶段IIb/概念设计验证：根据精确网络的目标，我们拟议的试验 设计的中心将是基于对严重哮喘患者进行分层的精确干预措施的使用 表型/内型。使用已经建立的生物标记物，包括血/痰嗜酸性粒细胞增多症、血清 Periostin、血清IgE和呼出的NO，我们建议将受试者分为Th2高(“Th2H”)和非Th2高 (“NTh2H”)，以及指示实验干预的混合内型。Th2H和混合科目将是 随机分为安慰剂、Allakos(抗Siglec-8单抗)或dupilumab(抗IL4/IL13受体)。 同时，NTh2H受试者将被随机分为安慰剂、依那西普(肿瘤坏死因子抑制剂)或dupilumab。 在试验期间，这些干预措施中的一些可能被证明缺乏足够的活动，这些将是 在中期分析后撤回，并由新的试剂或新的生物标记物定义的基团取代。成功 中期分析阶段的治疗将进入下一阶段。3)新的生物标志物的鉴定 对靶向治疗的应答者进行分层：我们的团队拥有执行和分析新的 与精确方案相关的生物标记物研究。我们建议利用这些微尺度的基因组 和免疫学工具，以确定新的生物标记物的治疗反应从痰和血液样本 我们的研究对象。

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.