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

完善急性川崎病合并冠状动脉瘤辅助治疗的创新 III 期试验

基本信息

批准号：
9811216
负责人：
Kevin Friedman
金额：
$ 23.27万
依托单位：
BOSTON CHILDREN'S HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-08-15 至 2021-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9811216
关键词：
Acute Address Adrenal Cortex Hormones Adverse event American Heart Association Aneurysm Anterior Descending Coronary Artery Anti-Inflammatory Agents Anti-inflammatory Biological Markers Biometry Cardiac Cardiology Cardiovascular Diseases Child Child Care Childhood Clinical Clinical Trials Complication Consultations Coronary Coronary Stenosis Coronary Thrombosis Coronary artery Data Dimensions Double-Blind Method Etiology Event Fever Foundations Goals Guidelines Heart Diseases Immunoglobulin Therapy Incidence Individual Infant Infarction Inflammation Intravenous Immunoglobulins Japan Knowledge Left Length of Stay Measures Mission Monoclonal Antibodies Morbidity - disease rate Mucocutaneous Lymph Node Syndrome Multicenter Trials Myocardial Infarction Myocardial Ischemia Onset of illness Outcome Outcome Measure Parents Patient-Focused Outcomes Patients Pharmacology Phase Physiological Placebos Randomized Rare Diseases Regimen Resistance Resources Risk Safety Sample Size Steroids Sudden Death TNF gene Therapeutic Agents Time Treatment Protocols United States National Institutes of Health Variant Vasculitis Weight base clinically relevant comparative efficacy design disability double-blind placebo controlled trial factor A follow-up high risk improved individual patient inflammatory marker infliximab innovation mortality novel optimal treatments patient subsets phase III trial prednisolone prevent primary endpoint primary outcome prospective secondary endpoint

项目摘要

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.

摘要尽管进行了适当的 IVIG 治疗，四分之一的川崎病 (KD) 儿童仍会出现冠状动脉病变动脉瘤 (CAA) 和 1% 的人会发展成巨大的 CAA，这些动脉瘤有发生不良心脏事件（包括心肌病）的风险梗塞和猝死。为了降低 CAA 发生率和相关发病率，2017 年美国心脏协会 KD 协会指南建议考虑对患者进行主要辅助抗炎治疗 CAA 的高风险。然而，尚无临床试验比较辅助抗炎药的功效。养生法，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药物高危川崎病的辅助治疗，因为它们既有其功效的生理学原理，也有最大的疗效支持对结果产生有益影响的数据量。拟议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与类固醇治疗原发性辅助 KD 的安全性和有效性治疗。鉴于川崎病相关 CAA 的发病率和死亡率，缩小这一知识差距是一个关键的未满足问题需要。川崎病是一种罕见疾病，因此不可能获得足够的样本量来充分研究有动力的、传统的、受控的 III 期试验，具有单一的主要结果指标。而且，如果两个治疗对于减少 CAA 以及其他结果（例如发烧持续时间、住院时间、以及是否需要额外的治疗，可以指导药物的选择。因此，该提案的总体目标和申请此特定 U34 的理由是完善可行的创新临床试验的设计，以确定咨询创新临床试验后，为高危川崎病患者提供最佳的急性辅助治疗资源（卢旺达问题国际法庭）。具体来说，我们提出了一项利用全球排名的前瞻性、随机、III 期试验将多个临床相关结果测量纳入单个主要终点的终点。这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主要治疗之间的临床重要差异。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，将个体患者的结果创建一个新颖的、分层的全球排名终点； 2）召集顾问小组 KD 专家指导纳入终点的选择，以及它们的相对临床重要性，以允许变量的权重。我们在规划期间的预期成果是完成期数的最终设计英夫利昔单抗与类固醇辅助治疗急性高危 KD 患者的 III 期试验。这将有一个对 KD 和 CAA 儿童的护理产生积极影响，因为它将成为充分动力的基础 III 期 KD 试验将解决确定最佳辅助治疗以预防的迫切临床需求 CAA 的进展。