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

严重的、易加重的哮喘影响5-10%的哮喘人群，并继续存在 重大的人力和经济影响，近200万急诊室就诊和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，有大量证据表明这些患者可分为2类 基于存在/不存在（T）-2型（IL-4、IL-5、IL-13）相关的生物标志物证据的广泛类别 炎症同时进行的行业申办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（包括靶向IL-4/13的生物疗法）具有实质性疗效， T2 Hi哮喘患者的IL-5通路然而，预测T2靶向治疗反应的最佳生物标志物 治疗方法尚不明确。鉴于其巨大的成本，更好地了解和确定这些因素至关重要。 哪些人最需要这些药物，哪些人应该首先使用，哪些人应该首先使用。更不清楚 在没有（使用当前生物标志物）T2炎症证据的患者中是否存在特异性生物标志物，或 他们是否预测了这些患者的靶向生物治疗方法。这里提出的适应性设计试验 将利用目前公认的生物标志物，以及其他探索性生物成像和遗传标记， 预测这些广泛的（但更具体的）T2表型的最有效和安全的方法。我们 因此，假设一种整合T2（和非T2）生物标志物、靶向治疗 临床相关结果将提高对严重哮喘病理学的理解 接受中等至高剂量吸入性皮质类固醇（ICS）的患者，伴或不伴长效β2受体激动剂（LABA） 表型和带来最有效的（和最安全的）药物治疗每一个严重的哮喘患者。我们 在800例控制不佳、急性发作和/或重度哮喘患者中，提出一项多阶段适应性试验设计 和/或口服皮质类固醇（OCS）。第1（导入）阶段将在3-6天内建立每位参与者的基线 一个月的时间，同时重复测量建立和探索性生物标志物。从这个数据 导入期将用于将患者分配为T2 Hi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。目标治疗阶段将 包括3种处理，适应性地应用于两种广泛的T2表型，目的是支持 潜在的T2亚表型的重要性，如T2 Hi/肥大细胞-Hi和T2 Lo/代谢。的3 治疗将因起始T2表型而异，但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。T2 Hi干预将依次包括CRTH 2 拮抗剂，抗IL-4受体（R）抗体和可溶性TNF-α受体，而T2 Lo干预将 包括抗IL-4 R、抗IL-6/6 R受体和支气管热成形术。这些研究将大大扩展 精准医学路径，以改善严重的，有加重倾向的哮喘的护理。

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.