Sequential, Multiple Assignment, Randomized Trial in Severe Asthma Protocol (SMART-SA)

总结/摘要 NHLBI针对重度和急性发作倾向哮喘的精确干预（Precise）网络将开展 适应性临床试验在严重和急性发作倾向的哮喘。在目标1中，我们建议建立一个国际 作为Precise临床中心的四个学术研究中心的联盟。该联盟将由大学领导 加州（UC）旧金山弗朗西斯科研究小组（联合会和研究中心PI：John Fahy）与三个 其他网站-加州大学戴维斯分校哮喘研究小组（网站PI：尼古拉斯凯尼恩），英国大学 哥伦比亚哮喘研究小组（研究中心PI：Mark FitzGerald）和莱斯特哮喘大学 研究小组（研究中心PI：Chris Billing）。所有这些都是在开展临床研究方面经验丰富的学术研究中心。 所有这些研究都对当前关于疾病的知识做出了重要贡献 哮喘的机制我们共同建议快速招募100名重度和急性发作患者， 易患哮喘的患者入组Precise，我们将实施 指导委员会。在目标2中，我们建议Precise应采用顺序多重分配 随机试验（SMART）方法，在哮喘患者亚组中进行适应性试验， 存在或不存在全身性IL 6炎症或全身性嗜酸性粒细胞增多。我们特别提出三个 临床试验，每项试验约占800人Precise队列的三分之一。试验1将按顺序测试 托珠单抗和阿那白滞素治疗IL-6高水平哮喘的疗效。试验#2将依次测试 美泊利单抗和Dupilumab逆转“2型高”哮喘患者的气流阻塞。试验#3将 序贯测试强力霉素和类固醇停药对“2型- 低”哮喘。在所有这些试验中，我们的首要目标是为患有更多疾病的患者推进精准医学 严重的哮喘。

Summary/Abstract The NHLBI Precision Interventions for Severe and Exacerbation Prone Asthma (PrecISE) Network will conduct adaptive clinical trials in severe and exacerbation prone asthma. In Aim 1 we propose to form an international consortium of four academic sites as a clinical center for PrecISE. The consortium will be led by the University of California (UC) San Francisco asthma group (consortium and site PI: John Fahy) in partnership with three other sites - the UC Davis Asthma Research Group (site PI: Nicholas Kenyon), the University of British Columbia Asthma Research Group (site PI: Mark FitzGerald), and the University of Leicester Asthma Research Group (site PI: Chris Brightling). All are academic sites highly experienced in conducting clinical studies in severe asthma, and all have made important contributions to current knowledge about disease mechanisms in asthma. Together, we propose to quickly recruit 100 patients with severe and exacerbation prone asthma for enrollment in PrecISE, and we will implement each network-wide protocol approved by the Steering Committee. In Aim 2 we propose that PrecISE should adopt the sequential multiple assignment randomized trial (SMART) approach to conduct adaptive trials in subgroups of asthmatics defined by the presence or absence of systemic IL6 inflammation or systemic eosinophilia. We specifically propose three clinical trials, each in approximately one third of the 800 person PrecISE cohort. Trial #1 will sequentially test the efficacy of Tocilizumab and Anakinra in IL6-high asthma. Trial #2 will sequentially test the efficacy of Mepolizumab and Dupilumab in reversing airflow obstruction in patients with “type 2-high” asthma. Trial #3 will sequentially test the efficacy of Doxycycline and steroid withdrawal on asthma control in patients with “type 2- low” asthma. In all of these trials, our overarching goal is to advance precision medicine for patients with more severe forms of asthma.