Type-2 or Not Type-2: That is the (Therapeutic) Question

Type-2 或非 Type-2：这是（治疗）问题

• 批准号: 10221034
• 负责人: Sally E Wenzel
• 金额: $ 40.85万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 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/10221034
• 关键词: Adrenal Cortex Hormones; Agonist; Alleles; Alternative Therapies; Antibodies; Asthma; Biological; Biological Markers; Biological Response Modifier Therapy; Biology; Blood; Bronchodilator Agents; Caring; Categories; Cells; Clinical; Clinical Trials; Combined Modality Therapy; Data; Dose; Emergency department visit; Etanercept; Exhalation; Failure; Genetic Markers; Genotype; Goals; Heterogeneity; Hospitalization; Human; Industry; Inflammation; Inhalation; Intention; Interleukin-4; Interleukin-5; Interleukin-6; Intervention; Measurement; Measures; Metabolic; Oral; Outcome; Participant; Pathway interactions; Patients; Pharmaceutical Preparations; Phase; Phenotype; Population; Predictive Factor; Pulmonary Function Test/Forced Expiratory Volume 1; Research; Running; Safety; Smooth Muscle; Specific qualifier value; Sputum; Standardization; Symptoms; TNFR-Fc fusion protein; TNFRSF1A gene; Therapeutic; Time; Treatment Efficacy; Treatment Failure; asthma exacerbation; asthmatic; asthmatic patient; base; bioimaging; clinically relevant; cost; early phase clinical trial; economic impact; eosinophil; imaging biomarker; improved; indexing; individual patient; mast cell; molecular phenotype; precision medicine; predicting response; predictive modeling; primary endpoint; programs; response; safety testing; specific biomarkers; targeted treatment; treatment arm; treatment response; trial design

Severe, exacerbation-prone asthma impacts 5-10% of the asthma population and continues to have substantial human and economic impact, with nearly 2 million emergency room visits and 0.5 million hospitalizations per year. Evidence from the Severe Asthma Research Program (SARP) supports the heterogeneity of severe asthma, with substantial evidence to suggest differentiation of these patients into 2 broad categories based on biomarker evidence for the presence/absence of Type(T)-2 (IL-4, 5, -13) associated inflammation. Concurrent industry sponsored clinical trials have further supported this broad differentiation, with evidence for substantial efficacy of T2-targeted biologic therapies including those targeted to IL-4/13 and IL-5 pathways in T2Hi asthma patients. However, the best biomarkers to predict response to T2-targeted therapies are not yet clear. Given their enormous costs, it is critical to better understand and identify those who most need these medications, which ones to utilize first and in which patients. It is even more unclear whether specific biomarkers in patients with no (using current biomarker) evidence for T2 inflammation exist or whether they predict targeted biologic approaches for these patients. The adaptive design trial proposed here will utilize currently accepted biomarkers, as well as additional exploratory bio-imaging and genetic markers to predict the most efficacious and safe approaches for these broad (but then more specific) T2-phenotypes. We therefore hypothesize that an adaptive trial design integrating T2 (and non-T2) biomarkers, targeted therapies and clinically relevant outcomes will improve the understanding of the pathobiology of severe asthma patients on medium to high dose inhaled corticosteroids (ICS), with or without long acting 𝛽𝛽2 agonists (LABA) phenotypes and bring the most efficacious (and safest) medication to each severe asthma patient. We propose a multiphase adaptive trial design in 800 poorly controlled, exacerbating and/or severe asthmatic and/or oral corticosteroids (OCS). The 1st (run-in) phase will establish each participant's baseline over a 3-6 month period of time, while repeatedly measuring established and exploratory biomarkers. The data from this run-in phase will be used to assign the patient to a T2Hi or -Lo molecular phenotype and inform the modeling of predictive factors to be applied during the targeted treatment phase. The targeted treatment phase will consist of 3 treatments, adaptively applied to the two broad T2 phenotypes, with the intention to support the importance of potential T2 sub-phenotypes, such as a T2Hi/Mast cell-Hi and T2Lo/Metabolic. The 3 treatments will differ by starting T2 phenotype, but the primary endpoint for each intervention will be treatment failure defined by a biomarker and clinical index. T2Hi interventions will sequentially include a CRTH2 antagonist, an anti-IL-4Receptor(R) antibody and a soluble TNF-α receptor, while T2Lo interventions will include anti-IL-4R, an anti-IL-6/6Rreceptor and bronchial thermoplasty. These studies will greatly expand on the precision medicine pathway to improve the care of severe, exacerbation-prone asthma.

严重、易恶化的哮喘影响了 5-10% 的哮喘人群，并且这种情况持续存在 巨大的人力和经济影响，急诊室就诊次数近 200 万人次，急诊就诊人数 50 万人次 每年住院次数。严重哮喘研究计划 (SARP) 的证据支持 严重哮喘的异质性，有大量证据表明这些患者分为 2 类 基于存在/不存在 Type(T)-2（IL-4、5、-13）相关生物标志物证据的广泛类别 炎。同时进行的行业赞助的临床试验进一步支持了这种广泛的差异化， 有证据表明 T2 靶向生物疗法（包括针对 IL-4/13 和 T2Hi 哮喘患者的 IL-5 通路。然而，预测 T2 靶向反应的最佳生物标志物 治疗方法尚不清楚。鉴于其巨大的成本，更好地理解和识别这些问题至关重要 谁最需要这些药物，首先使用哪些药物以及哪些患者。更是不清楚 没有（使用当前生物标志物）T2 炎症证据的患者是否存在特定生物标志物，或者 他们是否预测这些患者的靶向生物方法。这里提出的适应性设计试验 将利用目前公认的生物标记以及其他探索性生物成像和遗传标记来 预测针对这些广泛（但随后更具体）T2 表型的最有效和安全的方法。我们 因此假设整合 T2（和非 T2）生物标志物、靶向治疗的适应性试验设计 和临床相关的结果将提高对严重哮喘病理学的理解 接受中至高剂量吸入皮质类固醇 (ICS) 并联合或不联合长效 𝛽𝛽2 激动剂 (LABA) 的患者 表型并为每位严重哮喘患者提供最有效（且最安全）的药物。我们 提出对 800 名控制不良、恶化和/或严重哮喘患者进行多阶段适应性试验设计 和/或口服皮质类固醇（OCS）。第一（磨合）阶段将在 3-6 年内建立每个参与者的基线 一个月的时间，同时重复测量已建立的和探索性的生物标志物。数据来自于此 磨合阶段将用于将患者分配到 T2Hi 或 -Lo 分子表型并为建模提供信息 在靶向治疗阶段应用的预测因素。目标治疗阶段将 由 3 种治疗方法组成，适应性地应用于两种广泛的 T2 表型，旨在支持 潜在 T2 亚表型的重要性，例如 T2Hi/肥大细胞-Hi 和 T2Lo/代谢。 3号 治疗会因开始 T2 表型而异，但每次干预的主要终点都是治疗 由生物标志物和临床指数定义的失败。 T2Hi 干预措施将依次包括 CRTH2 拮抗剂、抗 IL-4Receptor(R) 抗体和可溶性 TNF-α 受体，而 T2Lo 干预将 包括抗 IL-4R、抗 IL-6/6R 受体和支气管热成形术。这些研究将极大地扩展 改善严重、易加重哮喘护理的精准医学途径。