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.

严重的，恶化的哮喘会影响5-10％的哮喘人群，并继续 人类和经济影响很大，近200万次急诊室和50万 每年住院。严重哮喘研究计划（SARP）的证据支持 严重哮喘的异质性，有大量证据表明将这些患者分化为2 基于生物标志物证据的广泛类别证明（t）-2（IL-4，5，-13）的存在/不存在 炎。并发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靶向生物疗法的效率很高，包括针对IL-4/13的生物疗法 T2HI哮喘患者的IL-5途径。但是，预测对T2靶向反应的最佳生物标志物 疗法尚不清楚。鉴于他们的巨大成本，至关重要的是要更好地理解和识别那些 谁最需要这些药物，哪种药物首先要利用哪种药物。甚至更不清楚 NO（使用当前生物标志物）T2炎症的患者中是否存在或 他们是否预测了这些患者的靶向生物学方法。这里提出的自适应设计试验 将利用当前接受的生物标志物，以及其他探索性生物成像和遗传标记 预测这些广泛（但更具体的）T2型型的最有效，最安全的方法。我们 因此，假设一种自适应试验设计整合了T2（和非T2）生物标志物，有针对性的疗法 临床上相关的结果将提高对严重哮喘病理生物学的理解 中等剂量遗传性皮质类固醇（ICS）的患者，有或没有长期作用𝛽𝛽2激动剂（LABA） 表型并将最有效（最安全的）药物带到每个严重的哮喘患者。我们 提议在800个受良好控制，恶化和/或严重哮喘的800个多相自适应试验设计中 和/或口服皮质类固醇（OCS）。第一阶段将在3-6上建立每个参与者的基线 一个月的时间段，同时反复测量建立和探索性生物标志物。来自此的数据 磨合阶段将用于将患者分配到T2HI或-LO分子表型并告知建模 在目标治疗阶段要应用的预测因素。目标治疗阶段将 由3种治疗组成，适应于两种广泛的T2表型，目的是支持 潜在的T2亚表现型的重要性，例如T2HI/MAST细胞-HI和T2LO/代谢。 3 治疗将通过启动T2表型而有所不同，但是每种干预的主要终点将是治疗 由生物标志物和临床指数定义的失败。 T2HI干预将依次包括CRTH2 拮抗剂，一种抗IL-4受体（R）抗体和可溶性TNF-α受体，而T2LO干预将 包括抗IL-4R，抗IL-6/6RECEPTOR和支气管热成形术。这些研究将大大扩展 改善严重，恶化的哮喘护理的精确医学途径。