PrecISE Network: ADAPT (Advancing Severe Asthma Precision Therapy)

PrecISE 网络：ADAPT（推进严重哮喘精准治疗）

• 批准号: 10454134
• 负责人: EUGENE ROLAND BLEECKER
• 金额: $ 38.57万
• 依托单位: UNIVERSITY OF ARIZONA
• 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/10454134
• 关键词: 12 year old; Address; Adrenal Cortex Hormones; Aftercare; Arizona; Asthma; Biological; Biological Markers; Blood; Characteristics; Clinical; Clinical Trials; Cluster Analysis; Collaborations; Complex; Dipeptidases; Disease; Enrollment; Exhalation; Gene Expression; Heterogeneity; IgE; Inflammatory; Intervention; Investigation; Knowledge; Measurement; National Heart, Lung, and Blood Institute; Nitric Oxide; Nose; Outcome; Participant; Pathway interactions; Patients; Performance; Pharmacology; Phenotype; Physiological; Precision therapeutics; Prediction of Response to Therapy; Proteins; Quality of life; Regimen; Research; Running; Sampling; Sputum; Symptoms; Testing; Therapeutic; Therapeutic Intervention; Universities; asthma exacerbation; asthmatic; asthmatic patient; base; clinical biomarkers; clinical phenotype; clinical research site; cytokine; eosinophil peroxidase; forest; genomic biomarker; health care service utilization; improved; innovation; molecular marker; molecular phenotype; mortality; novel; novel therapeutics; periostin; personalized intervention; personalized therapeutic; precision medicine; predicting response; predictive marker; programs; protein biomarkers; pulmonary function; response; response biomarker; targeted treatment; treatment choice; treatment response; trial design

Severe asthma is a complex heterogeneous disease with significant health care utilization, poor quality of life and increased mortality. Our understanding of the disease pathobiology has significantly advanced, particularly through the NHLBI Severe Asthma Research Program (SARP). Through multivariate cluster analyses using objective physiologic and biologic parameters, unbiased phenotypic analyses divides the spectrum of asthma into subpopulations with specific disease characteristics that strongly suggest variability in therapeutic responses to corticosteroid and additional controller therapies. This heterogeneity is particularly apparent among asthmatic patients with more severe disease. This approach, based on understanding disease pathobiology, has greater personalized therapeutic implications than an approach which just broadly classifies severe asthma as asthma that is not adequately controlled using corticosteroids and additional controllers. This proposal represents an extension of the understanding gained in SARP, where we will define therapeutic responses across a spectrum of severe asthma to further define phenotypes/endotypes using known biomarkers while developing and testing novel molecular and genomic biomarkers. While the understanding of severe asthma phenotype/endotype pathobiology has advanced, the response to therapies which target specific inflammatory pathways in asthma is not completely understood. Furthermore, we are not able to definitively predict response to treatments based upon a priori clinical characteristics and expression of known biomarkers. To advance precision medicine approaches in severe asthma, it is crucial to understand the phenotypes and endotypes including cellular, protein and genomic biomarkers that predict asthma pharmacologic responsiveness to specific asthma interventions. We hypothesize that adaptive sequential clinical trials are an important fundamental approach to address asthma heterogeneity and to make major advances in the treatment of severe asthma. To test this hypothesis, we will perform clinical and molecular phenotyping in participants with severe and/or exacerbation prone asthma to include responsiveness to corticosteroids to identify specific phenotypes/endotypes for participation in a network wide PrecISE trial. (Aim 1). In Aim 2, we will collaborate with all other clinical sites to perform innovative, sequential adaptive clinical trials including novel interventions based on predictive biomarkers. In Aim 3, we will refine current biomarkers and develop new predictive and dynamic biomarkers of response before and after treatment with targeted therapies to increase their predictive abilities and introduce new biomarkers to the clinical arena. This proposal will allow patients with severe asthma access to novel therapies and improve our ability to predict therapeutic responses using clinical and molecular biomarkers in this heterogeneous disease.

重症哮喘是一种复杂的异质性疾病，具有严重的医疗保健利用，生活质量差 和死亡率的增加。我们对疾病病理学的理解有了很大的进步， NHLBI严重哮喘研究计划（SARP）。通过多元聚类 使用客观生理和生物学参数进行分析，无偏表型分析将 将哮喘谱分成具有特定疾病特征的亚群，强烈提示 对皮质类固醇的治疗反应和另外的控制剂疗法。这种异质性尤其 在病情更严重的哮喘患者中更明显。这种方法基于对 疾病病理生物学，具有更大的个性化治疗的影响，而不是一种方法， 将严重哮喘归类为使用皮质类固醇和其他药物不能充分控制的哮喘。 控制器。该建议代表了在SARP中获得的理解的扩展，在SARP中，我们将定义 使用以下方法进一步确定表型/内型， 同时开发和测试新的分子和基因组生物标志物。而 对严重哮喘表型/内型病理生物学的理解已经进步， 其靶向哮喘中的特异性炎症途径尚不完全清楚。此外，我们不是 能够基于先验临床特征和以下表达明确预测对治疗的反应： 已知的生物标志物。为了推进重度哮喘的精准医学方法，了解 预测哮喘的表型和内型，包括细胞、蛋白质和基因组生物标志物 对特定哮喘干预的药理学反应性。我们假设适应性顺序 临床试验是解决哮喘异质性的重要基本方法， 严重哮喘治疗的重大进展。为了验证这一假设，我们将进行临床和 重度和/或易发作哮喘受试者的分子表型分析，包括 对皮质类固醇的反应性，以确定参与全网络的特定表型/内型 Precise试验。(Aim 1）。在目标2中，我们将与所有其他临床研究中心合作， 适应性临床试验，包括基于预测性生物标志物的新型干预措施。在目标3中，我们将完善 目前的生物标志物，并开发新的预测和动态生物标志物的反应前后 靶向治疗，以提高其预测能力，并引入新的生物标志物， 临床竞技场。这项提案将使严重哮喘患者获得新的治疗方法，并改善我们的健康状况。 在这种异质性疾病中使用临床和分子生物标志物预测治疗反应的能力。