San Diego Team Asthma Management using Phenotypes (STAMP)

项目总结/摘要 在过去的几年里，人们越来越多地认识到病理生物学的异质性。 哮喘的基础以及表型和内型在决定对 疗法例如，只有在选择痰（和后来的血液）嗜酸性粒细胞增多的患者并使用 急性发作率作为主要结果，是临床试验中发现的美泊利珠单抗在哮喘中的效用 设置.随着多种免疫调节生物制剂已经可用，并与更多的来在非常 在不久的将来，我们将了解如何以精确的方式将这些药物最好地应用于严重 和/或有加重倾向的哮喘（最有可能使用生物制剂的患者）必须 完善. Precise网络将使用连续的，自适应的临床试验设计，这代表了一种新的 哮喘临床研究的方法，回答这些问题，同时也提供了一个机会， 表型分型和内型分型应用于重症肌无力患者的临床管理的重大进展 哮喘在此申请中，我们提出以下具体目标：1）建立圣地亚哥团队 哮喘管理计划（STAMP）作为NHLBI Precise网络的临床中心：我们已经将 一个团队，利用UCSD和圣地亚哥地区的大量资源， Precise临床中心将以最佳方式招募受试者并按原样执行Precise网络方案 制定并实施。2)使用顺序的、自适应的、 IIb期/概念设计验证：根据Precise网络的目标，我们提议的试验 设计将集中在基于严重哮喘受试者分层的精确干预的使用， 表型/内型。使用已经建立的生物标志物，包括血液/痰嗜酸性粒细胞增多，血清 根据骨膜蛋白、血清IgE和呼出的NO，我们提出将受试者分层为Th 2高（“Th 2 H”）、非Th 2高（“Th 2 H”）、非Th 2高（“Th 2 H”）和非Th 2高（“Th 2 H”）。 （“NTh 2 H”）和MIXED内型来指示实验干预。Th 2 H和MIXED受试者 随机分配至安慰剂、Allakos（抗Siglec-8单克隆抗体）或dupilumab（抗IL 4/IL 13受体）。 同时，NTh 2 H受试者将随机分配至安慰剂、依那西普（TNF抑制剂）或dupilumab组。 在试验期间，这些干预措施中的一些可能显示出缺乏足够的活性，并且这些干预措施将被 在中期分析后退出，并由新药物或新生物标志物定义的组取代。成功 中期分析阶段的治疗将进入下一阶段。3)鉴定新的生物标志物， 对靶向治疗的反应者进行分层：我们的团队拥有科学的专业知识来执行和分析新的治疗方法。 与PrecISE方案相关的生物标志物研究。我们建议利用这些微型基因组 和免疫学工具，从患者的痰和血液样本中识别治疗反应的新型生物标志物 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.