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: 10220117
• 负责人: EUGENE ROLAND BLEECKER
• 金额: $ 42.53万
• 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 2023-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10220117
• 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，卫生保健利用率高，生活质量差 并增加了死亡率。我们对这种疾病的病理生物学的理解有了很大的进步， 特别是通过NHLBI重症哮喘研究计划(SARP)。通过多变量聚类 使用客观的生理和生物参数进行分析，无偏的表型分析将 哮喘的谱系分为具有特定疾病特征的亚群，这些特征强烈表明 对皮质类固醇和其他控制疗法的治疗反应。这种异质性尤其是 在病情较重的哮喘患者中很明显。这种方法，基于理解 疾病病理生物学，具有更大的个人化治疗意义，而不仅仅是广义的 将严重哮喘归类为未充分使用皮质类固醇和其他药物控制的哮喘 控制器。这项提案代表了在SARP中取得的谅解的延伸，我们将在SARP中界定 对各种严重哮喘的治疗反应，以进一步确定表型/内型 在开发和测试新的分子和基因组生物标记物时使用已知的生物标记物。而当 对重症哮喘表型/内型病理生物学的认识有所进步，对治疗的反应 在哮喘中，哪些靶向特定的炎症途径还不完全清楚。此外，我们不是 能够根据先验的临床特征和表现明确地预测治疗的反应 已知的生物标志物。要推进重症哮喘的精准医学治疗，关键是要了解 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 对特定哮喘干预措施的药理学反应。我们假设自适应序列 临床试验是解决哮喘异质性和使 重症哮喘治疗取得重大进展。为了验证这一假设，我们将进行临床和 重度和/或易加重哮喘患者的分子表型包括 对皮质类固醇的反应性，以确定参与广泛网络的特定表型/内型 精确的审判。(目标1)。在目标2中，我们将与所有其他临床站点合作，进行创新、循序渐进的 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，我们将改进 目前的生物标志物和开发新的预测性和动态的前后反应生物标志物 通过靶向治疗来提高他们的预测能力，并将新的生物标志物引入到 临床领域。这项提议将允许严重哮喘患者获得新的治疗方法，并改善我们的 使用临床和分子生物标记物预测这种异质性疾病的治疗反应的能力。