The Great Lakes PrecISE Partnership

五大湖 PrecISE 合作伙伴关系

• 批准号: 9979943
• 负责人: Loren C Denlinger
• 金额: $ 38.41万
• 依托单位: UNIVERSITY OF WISCONSIN-MADISON
• 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 2023-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9979943
• 关键词: Adherence; Affect; Air; Antibodies; Asthma; Biological Markers; Blinded; Blood; C-reactive protein; Clinical Trials Design; Community Healthcare; Community Practice; Data; Development; Disease; Disease Progression; Dose; Evaluation; FDA approved; Fc Receptor; Free Will; Frequencies; Guidelines; HIV; Heterogeneity; Illinois; Image; Impairment; Interleukin 6 Receptor; Interleukin-5; Interleukin-6; Intervention; Investigation; Malignant Neoplasms; Measures; Methods; Molecular; Monitor; Morbidity - disease rate; Muscarinic Antagonists; Oncology; Outcome; Participant; Pathogenesis; Patients; Pharmacopoeias; Phenotype; Plasma; Population; Population Heterogeneity; Prediction of Response to Therapy; Predictive Value; Prevention; Probability; Process; Protocols documentation; Public Health; Pulmonary Function Test/Forced Expiratory Volume 1; Randomized; Research; Research Personnel; Risk; Risk Factors; Sampling; Severities; Sputum; Standardization; Symptoms; Testing; Therapeutic; Therapeutic Intervention; Translational Research; Treatment Efficacy; Urine; Validation; Vision; Wisconsin; X-Ray Computed Tomography; asthma exacerbation; base; chest computed tomography; comorbidity; design; disease phenotype; effective therapy; eosinophil; eosinophilic inflammation; flexibility; health care settings; heart rate variability; high risk; indexing; innovation; multidisciplinary; oxidant stress; patient population; patient subsets; personalized medicine; precision medicine; predictive tools; programs; randomized placebo-controlled clinical trial; respiratory; success; targeted treatment; therapeutic development; treatment duration; treatment guidelines; treatment response; trial design

Abstract: The lack of data to inform treatment guidelines in patients with severe asthma remains a major unmet need. Our vision is to develop a personalized medicine approach for the treatment of severe asthma, directed at its pathogenesis and ultimately translatable to the community health care setting for implementation. Because traditional clinical trial designs are inefficient for diseases with multiple phenotypes, our central hypothesis is that the application of an adaptive trial design will identify subtypes of severe asthma that will be most responsive to precise interventions. The scientific rationale for this proposal includes recent data showing that elevated blood eosinophils, maximum FEV1 reversal, and plasma IL-6 concentrations are risk factors for frequent exacerbations which are a major component of severe asthma. Each of these phenotypes has precise interventions that are FDA approved for asthma or other diseases, namely anti-IL-5 antibodies, long acting muscarinic antagonists, and anti-IL6 receptor antibodies. We propose the following Specific Aims to test this hypothesis: 1) To determine the impact of phenotype-directed interventions on the frequency of asthma exacerbations using a sequential Bayesian adaptive clinical trial design, stratified by blood eosinophils, maximum FEV1 reversal, and plasma IL-6 concentrations; and 2) To validate the predictive value of monitoring biomarkers assessed at baseline and after three months of treatment. These biomarkers include sputum eosinophils, heart rate variability, C-reactive protein levels, air trapping and other imaging metrics assessed by low dose chest CT scan, and measures of airway oxidant stress. Our team of multi-disciplinary investigators and translational science clinicians in the Great Lakes PrecISE Partnership has access to a diverse population of patients with severe asthma from Wisconsin and Northern Illinois which will enable us to be a very active partner in this collaborative network. We expect to rapidly identify patient subsets that benefit from therapies not currently considered as part of the asthma pharmacopoeia. The efficient assessment of these biomarkers and precise treatments would not be possible without this departure from the typical therapeutic development process.

抽象的： 缺乏数据来指导严重哮喘患者的治疗指南仍然是一个未得到满足的重大需求。 我们的愿景是开发一种治疗严重哮喘的个性化医疗方法，针对其 发病机制并最终转化为社区卫生保健机构实施。因为 传统的临床试验设计对于具有多种表型的疾病效率低下，我们的中心假设是 适应性试验设计的应用将确定最常见的严重哮喘亚型 对精确干预做出反应。该提案的科学依据包括最近的数据表明 血液嗜酸性粒细胞升高、最大 FEV1 逆转和血浆 IL-6 浓度是以下危险因素： 频繁恶化，这是严重哮喘的一个主要组成部分。这些表型中的每一个都有精确的 FDA 批准用于治疗哮喘或其他疾病的干预措施，即抗 IL-5 抗体，长效 毒蕈碱拮抗剂和抗IL6受体抗体。我们提出以下具体目标来测试这一点 假设：1) 确定表型干预措施对哮喘频率的影响 使用序贯贝叶斯适应性临床试验设计，按血液嗜酸性粒细胞分层， 最大 FEV1 逆转和血浆 IL-6 浓度； 2) 验证监测的预测价值 在基线和治疗三个月后评估生物标志物。这些生物标志物包括痰 嗜酸性粒细胞、心率变异性、C反应蛋白水平、空气滞留和其他成像指标评估 低剂量胸部 CT 扫描以及气道氧化应激测量。我们的多学科研究团队 五大湖 PrecISE 合作伙伴关系的转化科学临床医生可以接触到不同的人群 来自威斯康星州和伊利诺伊州北部的严重哮喘患者，这将使我们能够成为一个非常活跃的 该协作网络中的合作伙伴。我们期望快速识别受益于治疗的患者亚群 目前不被视为哮喘药典的一部分。这些生物标志物的有效评估 如果不偏离典型的治疗发展，精确的治疗就不可能实现 过程。