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: 9405683
• 负责人: Sally E Wenzel
• 金额: $ 33.6万
• 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/9405683
• 关键词: Adrenal Cortex Hormones; Agonist; Alleles; Alternative Therapies; Antibodies; Asthma; Biological Markers; Biological Response Modifier Therapy; Biology; Blood; Breathing; 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; 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; Specific qualifier value; Sputum; Standardization; Symptoms; TNFR-Fc fusion protein; TNFRSF1A gene; Time; Treatment Efficacy; Treatment Failure; arm; asthmatic; asthmatic patient; base; bioimaging; clinically relevant; cost; economic impact; eosinophil; imaging biomarker; improved; indexing; individual patient; mast cell; molecular phenotype; precision medicine; predicting response; predictive modeling; programs; response; safety testing; specific biomarkers; targeted treatment; 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.

严重的易加重哮喘影响了5%-10%的哮喘人口，并继续 重大的人力和经济影响，有近200万次急诊室就诊和50万人次 每年的住院人数。来自重症哮喘研究计划(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个 基于存在/不存在与(T)-2(IL-4、5、-13)相关的生物标志物证据的广泛类别 发炎。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， 有证据表明T2靶向生物疗法的实质性疗效，包括那些针对IL-4/13和 T2Hi哮喘患者IL-5途径的研究然而，预测T2靶向反应的最佳生物标志物 治疗方法尚不清楚。考虑到它们的巨大成本，更好地理解和识别这些问题至关重要 谁最需要这些药物，哪些药物应该首先使用，哪些患者需要。更不清楚的是 在没有T2炎症证据的患者中是否存在特定的生物标记物(使用当前的生物标记物)或 他们是否预测了针对这些患者的有针对性的生物方法。这里提出的适应性设计试验 将利用目前接受的生物标记物以及其他探索性生物成像和遗传标记物来 对于这些广泛的(但更具体的)T2表型，预测最有效和安全的方法。我们 因此，假设一项整合T2(和非T2)生物标记物、靶向治疗的适应性试验设计 临床上相关的结果将提高对重症哮喘病理生物学的理解。 使用或不使用长效𝛽𝛽2激动剂(LABA)的患者使用中到大剂量吸入皮质类固醇(ICS) 并为每个严重哮喘患者提供最有效(和最安全)的药物。我们 建议对800例控制不良、加重和/或严重哮喘患者进行多期适应性试验设计 和/或口服皮质类固醇(OCS)。第一个(磨合)阶段将建立每个参与者的基准3-6 一个月的时间段，同时重复测量已建立的和探索性的生物标志物。来自这里的数据 磨合期将用于将患者分配到T2Hi或-Lo分子表型，并告知建模 在靶向治疗阶段应用的预测因素。靶向治疗阶段将 由3个处理组成，自适应地应用于两个广泛的T2表型，目的是支持 潜在T2亚型的重要性，如T2Hi/肥大细胞-Hi和T2Lo/代谢。三人组 治疗会因开始T2表型而有所不同，但每个干预的主要终点将是治疗 失败由生物标记物和临床指标定义。T2Hi干预将按顺序包括CRTH2 拮抗剂，抗IL-4受体(R)抗体和可溶性肿瘤坏死因子-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。这些研究将大大扩展到 改善严重、易加重哮喘的护理的精准医学路径。