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

NHLBI 重度和/或易加重哮喘的精准干预临床中心 (PrecISE) 网络 (UG1)

• 批准号: 10455086
• 负责人: Serpil C. Erzurum
• 金额: $ 38.49万
• 依托单位: INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS
• 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 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10455086
• 关键词: Accounting; Adult; Aftercare; Androgens; Antioxidants; Ants; Asthma; Biological Markers; Biology; Child; Childhood; Clinical; Clinical Trials; Coenzyme A; Collaborations; Cost Savings; Data; Dehydroepiandrosterone Sulfate; Economic Burden; Enrollment; Equilibrium; Goals; Industry; Interleukin-5; Interleukins; Intervention; Male Adolescents; Measures; Morbidity - disease rate; National Heart, Lung, and Blood Institute; Oral; Oxidative Stress; Oxides; Patient Rights; Patients; Precision therapeutics; Probability; Pulmonary Function Test/Forced Expiratory Volume 1; Randomized; Research Design; Research Infrastructure; Research Personnel; Running; Sequential Multiple Assignment Randomized Trial; Serum; Site; Superoxide Dismutase; Supplementation; System; Testing; Treatment Effectiveness; Ubiquinone; United States National Institutes of Health; Urine; airway obstruction; arm; asthma exacerbation; asthmatic patient; base; clinical biomarkers; clinical center; cost; dehydroepiandrosterone; design; eosinophil; experience; follow-up; improved; mepolizumab; mortality; non-smoker; older women; patient subsets; personalized intervention; phenotypic biomarker; predicting response; predictive marker; primary outcome; programs; pulmonary function; response; response biomarker; secondary outcome; targeted treatment; treatment arm; treatment response; trial design; urinary

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.

抽象的。 传统的哮喘治疗对于重症和易恶化的患者通常无效 哮喘，占哮喘发病率、死亡率和经济负担的一半。我们和 其他人已经确定了这些患者的子集（内型），他们有可治疗的机制 造成气流阻塞。我们提案中的研究人员已经合作了近二十年 定义严重和恶化倾向内型的生物学。我们还开发了生物标志物 可能预测针对每种内型的特定治疗的反应。其中许多生物标志物/内型 这些对最终可能会由 PrecISE 联盟进行研究。在这里，我们重点治疗其中三个 我们的数据表明，彼此之间的重叠程度最低，并且安全、有效且节省成本。这些 1) 尿溴酪氨酸，以确定 70% 的嗜酸性粒细胞患者，ant-IL5 对这些患者有效； 2） 血清超氧化物歧化酶活性以确定对口服辅酶 Q 有反应的患者； 3) 血清 硫酸脱氢表雄酮 (DHEA) 以确定对口服 DHEA 有反应的患者。我们建议使用 适应性试验设计，用于测试和改进所有三种内型的预测和反应生物标志物。 这些研究符合序贯多重分配随机试验（SMART）或同等试验的框架， 每个患者将根据基线生物标志物概况开始初始治疗，然后重新治疗 在每个后续阶段将无反应者分配给其他治疗（图 1）。我们的主要目标是 概括为三个目标。精准治疗目的 1. 检验抗白细胞介素 5 的假设 （美泊利单抗）会降低 Th2-high 中通过尿溴酪氨酸 (BrTyr) 测量的嗜酸性粒细胞活化 严重哮喘患者，从而改善肺功能和哮喘控制。精准治疗目的 2. 检验补充 CoQ 会恢复抗氧化能力和还原氧化能力的假设 血清 SOD 活性降低的严重哮喘患者的平衡，从而改善肺功能 功能和哮喘控制。精准治疗目标 3. 检验补充 DHEA 能够改善这一假设 改善患有SA和年轻男性青少年的FEV1、哮喘控制和DHEAS水平 EPA。为了实现这些目标，我们计划参与 PrecISE 网络，招募 100 名受试者 严重和/或易恶化的哮喘。其中包括儿童（12-18 岁）和成人，这反映了我们的 长期的儿科/成人合作。我们在三个地点都拥有研究基础设施 合作已有十多年，在 NIH 和基于行业的试验方面拥有丰富的经验。

项目成果

Novel insights into pathogenic mechanisms of severe exacerbation-prone asthma and their impact on clinical management.

对严重易发作哮喘的致病机制及其对临床管理的影响的新见解。

• 发表时间: 2022-12
• 作者: Makin, Thomas;Breidenbaugh, Marc;Borish, Larry
• 通讯作者: Borish, Larry

Recent discoveries regarding the pathogenesis of chronic rhinosinusitis and their implications for future therapies.

关于慢性鼻窦炎发病机制的最新发现及其对未来治疗的影响。

• 发表时间: 2021
• 作者: Eschenbacher, William;Eid, Ryan;Borish, Larry
• 通讯作者: Borish, Larry

Innate immune cell dysregulation drives inflammation and disease in aspirin-exacerbated respiratory disease.

先天免疫细胞失调会导致阿司匹林加剧的呼吸道疾病的炎症和疾病。

• 发表时间: 2021
• 作者: Eid, Ryan;Yan, Carol H;Stevens, Whitney;Doherty, Taylor A;Borish, Larry
• 通讯作者: Borish, Larry

A novel, noninvasive assay shows that distal airway oxygen tension is low in cystic fibrosis, but not in primary ciliary dyskinesia.

一项新颖的无创检测表明，囊性纤维化患者的远端气道氧分压较低，但原发性纤毛运动障碍则不然。

• 发表时间: 2019
• 影响因子: 3.1
• 作者: Mendelsohn, Lori;Wijers, Christiaan;Gupta, Ritika;Marozkina, Nadzeya;Li, Chun;Gaston, Benjamin
• 通讯作者: Gaston, Benjamin

Interleukin-5 receptor alpha (CD125) expression on human blood and lung neutrophils.

白细胞介素 5 受体 α (CD125) 在人血液和肺中性粒细胞上的表达。

• 发表时间: 2022-01
• 作者: Lawrence, Monica G;Teague, W Gerald;Feng, Xin;Welch, Caitlin;Etter, Elaine;Negri, Julie;Spano, Marthajoy;Wavell, Kristin;Braciale, Thomas;Steinke, John W;Borish, Larry
• 通讯作者: Borish, Larry