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

提取 尽管有适当的IVIG治疗，四分之一的川崎病（KD）儿童仍会发生冠状动脉粥样硬化。 动脉瘤（CAA）和1%的发展巨大CAA，这是在不良心脏事件的风险，包括心肌 梗塞和猝死。为了降低CAA的发病率和相关的发病率，2017年美国心脏 KD协会指南建议考虑对患者进行初级连续抗炎治疗 CAA的高风险。然而，还没有临床试验比较了连续性抗炎的功效。 方案，导致广泛的实践变化。英夫利昔单抗和皮质类固醇是最有力的候选人， 高风险KD的连续治疗，因为它们既有其疗效的生理学原理， 支持对结果产生有益影响的数据量。拟定临床试验的依据是， 需要临床试验数据来比较英夫利西单抗与类固醇治疗原发性川崎病的安全性和有效性 疗法鉴于KD相关CAA的发病率和死亡率， 需要的川崎是一种罕见的疾病，因此不可能获得足够的样本量进行充分的研究。 有把握的、传统的、对照的III期试验，具有单一的主要结局指标。此外，如果两人 治疗对于减少CAA、其他结果如发热持续时间、住院时间 以及需要额外的治疗，可以指导药物的选择。因此，本建议的总体目标和 申请这一特定U34的基本原理是改进可行的、创新的临床试验的设计，以确定 与创新临床试验协商高危KD患者的最佳急性预防治疗 资源（卢旺达问题国际法庭）。具体来说，我们提出了一个前瞻性的，随机的，III期试验利用全球排名 将多个临床相关结局指标纳入单个主要终点。的 临床试验的预期结局是，新的主要终点将提供足够的统计学把握度， 检测使用英夫利西单抗或类固醇的连续性主要治疗之间的临床重要差异。具体 规划期间的目标是：（1）与卢旺达问题国际法庭协商， 个体患者结局，以创建一个新的、分层的全球排名终点; 2）召集一个顾问小组 KD专家指导纳入终点的选择，以及其相对临床重要性， 变量的权重。我们预期在规划期内， 英夫利西单抗与类固醇联合治疗急性高危KD患者的III期临床试验这将产生 对KD和CAA儿童的护理产生积极影响，因为这将是一个充分动力的基础。 III期KD试验，将解决确定最佳预防性治疗的迫切临床需求， 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.