Refining an Innovative Phase III Trial of Adjunctive Therapy in Acute Kawasaki Disease with Coronary Artery Aneurysms

减去 尽管接受了适当的静脉注射免疫球蛋白治疗，每四名川崎病(KD)儿童中就有一人发展为冠状动脉。 动脉瘤(CAA)和1%的人发展为巨大的CAA，有发生包括心肌梗死在内的不良心脏事件的风险 脑梗塞和猝死。为了减少CAA的发病率和相关的发病率，2017美国心脏 KD协会指南建议患者考虑进行主要的辅助抗炎治疗 对CAA来说风险很高。然而，还没有临床试验比较辅助抗炎的疗效。 养生法，导致了广泛的实践差异。英夫利昔单抗和皮质类固醇是最强的候选药物 高危KD的辅助治疗，因为它们既有疗效的生理基础，也有最大的 支持对结果产生有益影响的数据量。拟议的临床试验的理由是 需要临床试验数据来比较英夫利昔单抗和类固醇治疗主要辅助性KD的安全性和有效性 心理治疗。鉴于KD相关的CAA的发病率和死亡率，弥合这一知识差距是一个关键的未满足的问题 需要。川崎病是一种罕见的疾病，因此无法获得足够的样本量来进行充分的 有动力的、传统的、对照的第三阶段试验，只有一个主要结果衡量标准。而且，如果两个人 治疗对减少CAA、其他结果，如发烧持续时间、住院时间、 并需要额外的治疗方法，可指导药物的选择。因此，这项提案的总体目标是 申请这种特殊的U34的基本原理是完善可行的、创新的临床试验的设计，以确定 结合创新临床试验探讨高危KD患者的最佳急性辅助治疗 资源(卢旺达问题国际法庭)。具体地说，我们提出了一项利用全球排名的前瞻性、随机化的第三阶段试验 将多个临床相关的结果测量合并到单个主要终点的终点。这个 临床试验的预期结果是，新的主要终点将提供足够的统计能力 检测英夫利昔单抗或类固醇辅助初次治疗在临床上的重要区别。具体的 规划期的目标是：1)与卢旺达问题国际法庭协商，制定最佳做法 个人患者结果，以创建新的、分层的全球排名终点；2)召开咨询小组 KD专家指导选择纳入的终点，以及它们的相对临床重要性 变量的权重。我们预计规划期的结果是有一个最终的阶段设计。 英夫利昔单抗与类固醇辅助治疗急性高危KD患者的试验。这将会有一个 对KD和CAA儿童的护理产生积极影响，因为这将是充分动力的基础 第三阶段KD试验将解决确定最佳辅助治疗以预防的紧迫临床需求 CAA的进展。

ABTRACT Despite appropriate IVIG therapy, one in four children with Kawasaki disease (KD) develops coronary artery aneurysms (CAA) and 1% develop giant CAA which are at risk for adverse cardiac events including myocardial infarction and sudden death. To decrease CAA incidence and associated morbidity, the 2017 American Heart Association KD guidelines recommend consideration of primary adjunctive anti-inflammatory therapy for patients at high risk for CAA. However, no clinical trials have compared the efficacy of adjunctive anti-inflammatory regimens, leading to wide practice variation. Infliximab and corticosteroids are the strongest candidates for adjunctive therapy in high-risk KD, as they have both physiological rationale for their efficacy and the greatest amount of data supporting a beneficial effect on outcomes. The rationale for the proposed clinical trial is that clinical trial data are needed to compare the safety and efficacy of infliximab to steroids for primary adjunctive KD therapy. Given the morbidity and mortality of KD-associated CAA, closing this knowledge gap is a critical unmet need. Kawasaki disease is a rare disease, making it impossible to attain sufficient sample size for an adequately powered, traditional, controlled Phase III trial with a single primary outcome measure. Moreover, if the two therapies are similarly effective for reducing CAA, other outcomes such as fever duration, hospital length of stay, and need for additional therapies, may guide the choice of agent. Thus the overall objective of this proposal and the rationale to apply for this specific U34 is to refine the design of a feasible, innovative clinical trial to determine the optimal acute adjunctive therapy for high risk KD patients in consultation with the Innovative Clinical Trials Resource (ICTR). Specifically, we propose a prospective, randomized, Phase III trial utilizing a global rank endpoint that incorporates multiple clinically relevant outcome measures into a single primary endpoint. The expected outcome of the clinical trial is that the novel primary endpoint will provide sufficient statistical power to detect a clinically important difference between adjunctive primary therapy with infliximab or steroids. The specific objectives of the planning period are: 1) in consultation with ICTR, to develop best practices for combining individual patient outcomes to create a novel, hierarchical global rank endpoint; 2) to convene an advisory panel of KD experts to guide selection of the endpoints for inclusion, and their relative clinical importance to allow weighting of the variables. Our expected outcome of the planning period is to have a finalized design of the Phase III trial of adjunctive therapy with infliximab versus steroids for acute, high risk KD patients. This will have a positive impact on the care of children with KD and CAA as it will be the foundation for an adequately powered Phase III KD trial that will address the urgent clinical need of defining the best adjunctive therapy to prevent progression of CAA.