Clinical Centers for the NHLBI's Precision Interventions for Severe and/or Exacerbation Prone Asthma (PrecISE) Network (UG1)

抽象的。 传统的哮喘疗法对病情严重且易加重的患者往往无效。 哮喘，占哮喘发病率、死亡率和经济负担的一半以上的疾病。我们和 其他人已经确定了这些患者的亚群(内型)，这些患者有可治疗的机制 导致气流受阻。我们提案中的调查人员已经合作了近20年 明确重症和易加重内型的生物学特征。我们还开发了生物标记物，将 可能预测针对每种内型的治疗反应。这些生物标志物/内型中的许多 配对最终可能会由精确的联盟进行研究。在这里，我们重点治疗其中的三个 我们的数据表明，它们之间的重叠程度将降至最低，并且将是安全、有效和节省成本的。这些 1)尿溴酪氨酸用于识别ANT-IL5对70%的嗜酸性粒细胞增多症患者有效；2) 血清超氧化物歧化酶活性以确定哪些患者对口服辅酶Q有反应；以及3)血清 脱氢表雄酮(DHEA)硫酸盐用于确定口服脱氢表雄酮(DHEA)有效的患者。我们建议使用 一项适应性试验设计，以测试和改进所有三种内型的预测和反应生物标志物。 这些研究符合顺序多分配随机试验(SMART)或等效物的框架， 每个患者将开始基于基线生物标记物概况的初步治疗，随后重新- 在每个后续阶段将无应答者分配到其他治疗(图1)。我们的主要目标是 概括起来有三个目的。精确治疗目标1.检验抗白介素5的假说 (美波利单抗)会降低Th2-High中以尿溴酪氨酸(BrTyr)测定的嗜酸性粒细胞的激活 治疗严重哮喘患者，从而改善肺功能，控制哮喘。精准治疗目标 2.验证补充辅酶Q可恢复机体抗氧化能力和还原氧化能力的假说 平衡严重哮喘患者血清超氧化物歧化酶活性降低，从而改善肺功能 功能和哮喘控制。精确治疗目标3.检验补充脱氢表雄酮将 改善患有SA和DHEAS的老年女性和年轻男性青少年的FEV1、哮喘控制和DHEAS水平 为了实现这些目标，我们计划参加精确网络，招募100名学科 严重和/或易加重的哮喘。这些人将包括儿童(12-18岁)和成年人，反映出我们的 长期的儿科/成人合作。我们在我们的三个地点都有研究基础设施，已经 合作了十多年，在NIH和基于行业的跟踪方面都有丰富的经验。

Abstract. Conventional asthma therapies are often ineffective for patients with severe and exacerbation-prone asthma, conditions accounting for up to half of the morbidity, mortality and economic burden of asthma. We and others have identified subsets of these patients (endotypes) for whom there are treatable mechanisms contributing to airflow obstruction. The investigators in our proposal have collaborated for the nearly two decades to define the biology of severe and exacerbation prone endotypes. We have also developed biomarkers that will likely predict response to therapy targeted specifically to each endotype. Many of these biomarker/endotype pairs may ultimately be studied by the PrecISE consortium. Here, we have focused on treating three of these that our data suggests will overlap minimally with one another and will be safe, effective and cost-saving. These are 1) urinary bromotyrosine to identify the 70% of eosinophilic patients for whom ant-IL5 will be effective; 2) serum superoxide dismutase activity to identify patients who will respond to oral Coenzyme Q; and 3) serum dehydroepiandrosterone (DHEA) sulfate to identify patients who will respond to oral DHEA. We propose to use an adaptive trial design to test and improve the predictive and response biomarkers for all three endotypes. These studies fit into the framework of a sequential multiple assignment randomized trial (SMART) or equivalent, where each patient will start an initial treatment based on the baseline biomarker profile, followed by re- assignment of non-responders to other treatments at each subsequent stage (Figure 1). Our key objectives are summarized by three Aims. Precision treatment Aim 1. Test the hypothesis that Anti-Interleukin 5 (Mepolizumab) will decrease eosinophil activation as measured by urine bromotyrosine (BrTyr) in the Th2-high severe asthmatic patient and consequently improve lung function and asthma control. Precision treatment Aim 2. Test the hypothesis that CoQ supplementation will restore the antioxidant capacity and reducing-oxidizing balance in severe asthmatic patients with decreased serum SOD activity, and will consequently improve lung function and asthma control. Precision treatment Aim 3. Test the hypothesis that DHEA supplementation will improve FEV1, asthma control and DHEAS levels in older women and younger male adolescents with SA and EPA .To accomplish these Aims, we plan to participate in the PrecISE network, enrolling 100 subjects with severe and/or exacerbation prone asthma. These will include both children (12-18) and adults, reflecting our longstanding Pediatric/adult collaboration. We have research infrastructures at our three sites that have already collaborated for over a decade and have extensive experience both with NIH and industry-based trails.