Rationale and study design for a phase I/IIa trial of anakinra in children with Kawasaki disease and early coronary artery abnormalities (the ANAKID trial).
Rationale and study design for a phase I/IIa trial of anakinra in children with Kawasaki disease and early coronary artery abnormalities (the ANAKID trial).
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川崎疾病儿童和早期冠状动脉异常的I/IIA期试验的基本原理和研究设计（ANAKID试验）。
DOI：
10.1016/j.cct.2016.04.002
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发表时间：
2016-05
影响因子：
2.2
通讯作者：
Burns JC
中科院分区：
文献类型：
--
作者：
Tremoulet AH;Jain S;Kim S;Newburger J;Arditi M;Franco A;Best B;Burns JC
虽然川崎（KD）是儿童获得性心脏病的最常见原因，并可能导致冠状动脉瘤（CAA），伴随心肌梗死的风险，但没有推荐的治疗方法来阻止动脉壁损伤的进展并预防血管炎急性期的动脉瘤形成。虽然静脉注射免疫球蛋白（IVIG）可以降低CAA的风险，但高达20%的KD患者对IVIG耐药，并且发展CAA的风险更高。IL-1促炎通路在急性KD儿童中上调，并在KD实验动物模型中起关键作用。因此，IL-1是合理的治疗靶点。本研究的目的是确定阿那白滞素（一种重组人IL-1受体拮抗剂）在基线超声心动图显示冠状动脉异常的急性KD患者中的安全性、耐受性、药代动力学和免疫调节作用。这是一项在30例年龄≥8个月、右冠状动脉和/或左前降支冠状动脉Z评分≥3.0或动脉瘤的急性KD患者中开展的双中心剂量递增I/IIa期试验。受试者将通过每日皮下注射接受2- 6周疗程的阿那白滞素，并将评估炎症消退和剂量限制性毒性（白细胞减少症、类过敏反应或重度感染）。将评估阿那白滞素阻断IL-1α和IL-1β的安全性和耐受性，作为预防或减轻急性KD婴儿和儿童冠状动脉损伤的策略。
Although Kawasaki disease (KD) is the most common cause of acquired heart disease in children and may result in coronary artery aneurysms (CAA) with an attendant risk of myocardial infarction, there is no recommended therapy to halt progression of arterial wall damage and prevent aneurysm formation in the acute phase of the vasculitis. While intravenous immunoglobulin (IVIG) reduces the risk of CAA, up to 20% of KD patients are IVIG resistant and have a higher risk for developing CAA. The IL-1 pro-inflammatory pathway is upregulated in children with acute KD and plays a critical role in the experimental animal model of KD. Thus, IL-1 is a logical therapeutic target. The goal of this study is to determine the safety, tolerability, pharmacokinetics, and immunomodulatory effects of anakinra, a recombinant human IL-1 receptor antagonist, in acute KD patients with coronary artery abnormalities on the baseline echocardiogram. This is a two-center dose-escalation Phase I/IIa trial in 30 acute KD patients ≥8 months old with a coronary artery Z score ≥3.0 in the right coronary artery and/or left anterior descending artery or an aneurysm. Subjects will receive a 2- to 6-week course of anakinra by daily subcutaneous injection and will be assessed for resolution of inflammation and dose limiting toxicities (leukopenia, anaphylactoid reaction, or severe infection). The safety and tolerability of blocking both IL-1α and Il-1β by anakinra will be evaluated as a strategy to prevent or attenuate coronary artery damage in infants and children with acute KD.