Chicago Metropolitan Asthma Consortium for severe / exacerbation-prone asthma

项目摘要 来自芝加哥大都会哮喘联盟（CMAC）的这份申请是对RFA的回应 名为“NHLBI对重度和/或急性发作倾向哮喘的精确干预临床中心 （Precise）Network”。芝加哥大都市区有近1000万居民，他们是种族和种族- nically多样.芝加哥市，代表了大约三分之一的人口，有一个哮喘preva- 儿童和成人的哮喘发病率超过10%，是世界上哮喘死亡率最高的国家之一。 美国的重度和/或易加重（S/EP）哮喘影响超过10%的哮喘患者， 占哮喘相关费用的大部分。虽然取得了实质性进展， 在帮助患者控制哮喘症状方面取得了进展，如何使用目前的疗法来靶向特定的phe- 不准确的类型和防止疾病进展，以及何时以及如何改变这些治疗， 失败，还不清楚。CMAC包括学术医疗中心合作伙伴：西北大学， 芝加哥大学、鲁瑞儿童医院、拉什大学和约翰H。斯特罗格医院，和一个扩展- 社区合作伙伴网络。CMAC是唯一有资格参与Precise网络的机构 并为网络临床试验的开发和成功完成做出贡献， cept/mechanistic研究。我们的主要人员在哮喘临床和翻译方面具有丰富的经验 研究，包括探索其病理生理学、发病机制（遗传和环境因素）的研究， 流行病学和治疗;领导作用的关键研究支持和CTSA计划在各自的 机构;在哮喘研究方面与多个机构和网络成功合作 项目;获得大量不同的哮喘人群;以及记录在案的成功招募患者的能力 在美国国立卫生研究院，基金会和企业赞助哮喘研究和临床试验。我们提出了一个模型 干预顺序，适应性临床试验方案，三个有针对性的，精确的干预措施， 通过生物标志物的重复评估指导，以告知初始治疗选择和随后的间 ventions。此外，我们的建议利用了最新的适应性临床试验设计，仔细的纵向随访， 并将使用早期招募患者的反应来指导随后招募的亚组患者的靶向治疗， - 是的我们的针对性干预包括三种不同的抗细胞因子和前列腺素治疗， Th 2-高患者，以及针对Th 2-低、肥胖和瘦型患者的三种不同疗法。参与 CMAC将加强Precise网络，以便早日实现成功完成的目标- 阶段临床试验，测试S/EP哮喘患者的靶向干预措施，产生新的知识， 关注哮喘表型、预测性生物标志物和治疗反应性，并积极告知临床 严重哮喘患者的治疗方法。

PROJECT SUMMARY This application from the Chicagoland Metropolitan Asthma Consortium (CMAC) is in response to the RFA entitled “Clinical Centers for the NHLBI's Precision Interventions for Severe and/or Exacerbation Prone Asthma (PrecISE) Network”. The Chicago metropolitan area has almost 10 million inhabitants who are racially and eth- nically diverse. The City of Chicago, which represents about one-third of this population, has an asthma preva- lence rates in both children and adults exceeding 10% and has one of the highest asthma mortality rates in the United States. Severe and/or exacerbation prone (S/EP) asthma affects over 10% of asthmatic patients and accounts for both substantial morbidity and a majority of asthma-related costs. While substantial progress has been made in helping patients control asthma symptoms, how to use current therapies to target specific phe- notypes precisely and prevent disease progression, and when and how to change these therapies in the event of failure, remain unclear. The CMAC includes academic medical center partners: Northwestern University, the University of Chicago, Lurie Children's Hospital, Rush University, and John H. Stroger Hospital, and an expan- sive network of Community Partners. The CMAC is uniquely qualified to participate in the PrecISE Network and contribute to the development and successful completion of the network clinical trials and proof of con- cept/mechanistic studies. Our key personnel have extensive experience in asthma clinical and translational research, including studies exploring its pathophysiology, pathogenesis (genetic and environmental factors), epidemiology and treatment; leadership roles in key research support and CTSA programs at their respective institutions; successful collaborations together and with multiple institutions and networks on asthma research programs; access to a large, diverse asthma population; and documented, successful ability to enroll patients in NIH, foundation and industry sponsored asthma research studies and clinical trials. We propose a model intervention sequential, adaptive clinical trial protocol with three targeted, precise interventions that will be guided by repeated assessment of biomarkers to inform both the initial therapy choice and subsequent inter- ventions. Further, our proposal utilizes the latest adaptive clinical trial design, careful longitudinal follow-up, and will use the responses of early-recruited patients to guide targeted therapy in subsequently-enrolled sub- jects. Our targeted interventions include three different anti-cytokine and prostaglandin therapies directed to Th2-high patients, and three different therapies directed to Th2-low, obese and lean patients. Participation by the CMAC will strengthen the PrecISE Network so that it will achieve its goal to complete successfully early- phase clinical trials to test targeted interventions in patients with S/EP asthma, generate new knowledge re- garding asthma phenotypes, predictive biomarkers and therapeutic responsiveness, and positively inform clini- cal practice in the treatment of patients with severe asthma.