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度和有加重倾向的患者通常无效， 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亚群（内型）， 导致气流阻塞。我们提案中的调查人员已经合作了近20年 以定义严重和易加重的内源型的生物学。我们还开发了生物标志物， 可能预测对特异性针对每种内型的治疗的反应。许多这些生物标志物/内型 最终可能由Precise联合体研究。在这里，我们重点讨论了其中的三个问题， 我们的数据表明，它们之间的重叠最小，并且安全，有效和节省成本。这些 是1）尿溴酪氨酸以鉴定抗IL-5将有效的70%嗜酸性粒细胞患者; 2） 血清超氧化物歧化酶活性，以鉴定对口服辅酶Q有反应的患者;和3）血清 脱氢表雄酮（DHEA）硫酸盐，以确定谁将响应于口服DHEA的患者。我们建议使用 适应性试验设计，以测试和改善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分配随机试验（SMART）或等同试验的框架， 其中每名患者将基于基线生物标志物谱开始初始治疗，随后重新治疗。 在每个后续阶段将无应答者分配至其他治疗（图1）。我们的主要目标是 总结为三个目标。精准治疗目标1.检验抗白细胞介素5 （美泊利珠单抗）将减少Th 2-高表达的小鼠中的嗜酸性粒细胞活化，如通过尿溴酪氨酸（BrTyr）所测量的。 从而改善肺功能和哮喘控制。精准治疗目的 2.验证补充辅酶Q将恢复抗氧化能力和还原氧化能力的假设 严重哮喘患者血清SOD活性下降，从而改善肺平衡， 功能和哮喘控制。精准治疗目标3.测试DHEA补充剂将 改善SA老年女性和年轻男性青少年的FEV 1、哮喘控制和DHEAS水平， 为了实现这些目标，我们计划参加Precise网络，招募100名受试者， 严重和/或易加重的哮喘。这些将包括儿童（12-18岁）和成人，反映了我们的 长期的儿科/成人合作。我们在三个基地都有研究基础设施， 合作了十多年，在NIH和行业试验方面都有丰富的经验。

项目成果

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。

• DOI: 10.1002/ppul.24192
• 发表时间: 2019
• 期刊: Pediatric pulmonology
• 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

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。

• DOI: 10.1016/j.anai.2020.11.006
• 发表时间: 2021
• 期刊: Annals of allergy, asthma & immunology : official publication of the American College of Allergy, Asthma, & Immunology
• 作者: Eschenbacher,William;Eid,Ryan;Borish,Larry
• 通讯作者: Borish,Larry

Pediatric Severe Asthma in the Era of Biologic Treatments.

生物治疗时代的小儿严重哮喘。

• DOI: 10.1089/ped.2020.1249
• 发表时间: 2020
• 期刊: Pediatric allergy, immunology, and pulmonology
• 作者: Teague,WGerald

Blood Eosinophil and Neutrophil Categories Can Differentiate Adult Asthma Phenotypes.

血液嗜酸性粒细胞和中性粒细胞类别可以区分成人哮喘表型。

• DOI: 10.1016/j.jaip.2023.01.006
• 发表时间: 2023
• 期刊: The journal of allergy and clinical immunology. In practice
• 作者: Rupani,Hitasha;Teague,WGerald
• 通讯作者: Teague,WGerald

Asthma-related outcomes during the SARS-CoV2 pandemic: A single-center observational study.

• DOI: 10.1016/j.jaip.2021.05.034
• 发表时间: 2021-09
• 期刊: The journal of allergy and clinical immunology. In practice
• 作者: Al-Hazaymeh A;Patrie J;Adams JC;Borish L;McGowan EC
• 通讯作者: McGowan EC