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

• 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
• 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

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.

添加 尽管适当的IVIG治疗，川崎疾病（KD）的四分之一仍有冠状动脉动脉 动脉瘤（CAA）和1％的巨型CAA有巨大的CAA，这有不良心脏事件的风险，包括心肌 梗塞和猝死。为了降低CAA发病率和相关的发病率，2017年美国心脏 协会KD指南建议考虑针对患者的主要辅助抗炎疗法 CAA的高风险。但是，尚无临床试验比较辅助抗炎的功效 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强的候选者 高风险KD的辅助疗法，因为它们的功效具有生理原理，也是最大的 支持结果有益影响的数据量。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对主要辅助KD的类固醇的安全性和功效 治疗。鉴于KD相关的CAA的发病率和死亡率，缩小此知识差距是一个关键的未得到的 需要。川崎病是一种罕见的疾病，使得无法获得足够的样本量 具有单一主要结果度量的动力，传统，受控的III期试验。而且，如果这两个 疗法对于减少CAA，其他结果，例如发烧持续时间，住院时间长度，同样有效 并需要其他疗法，可以指导代理的选择。因此，该提议的总体目标和 申请该特定U34的理由是完善可行的创新临床试验的设计 高风险KD患者的最佳急性辅助治疗与创新临床试验协商 资源（ICTR）。具体而言，我们提出了一项使用全球等级的前瞻性，随机，第三阶段的试验 端点将多种临床相关的结果度量纳入单个主要终点。这 临床试验的预期结果是，新型的主要终点将提供足够的统计能力 检测用英夫利昔单抗或类固醇的辅助性原发治疗之间的临床重要差异。具体 计划期的目标是：1）与ICTR协商，以开发结合的最佳实践 单个患者的结果创建一个新颖的，分层的全球排名端点； 2）召集咨询面板 KD专家的指导选择终点以纳入终点及其相对临床重要性以允许 变量的加权。我们在计划期间的预期结果是对该阶段的最终设计 III辅助治疗用英夫利昔单抗与类固醇急性，高风险KD患者的试验。这将有一个 对KD和CAA儿童的护理的积极影响，因为这将是足够动力的基础 III期KD试验将解决定义最佳辅助疗法的紧急临床需求以防止 CAA的进展。