Phase I and IIa trial of atorvastatin in children with acute Kawasaki disease

描述(申请人提供)：我们建议阿托伐他汀“重新应用”，以减少促炎宿主反应，改善急性川崎病(KD)儿童的心血管结局，KD是一种自限性脉管炎，是儿童获得性心脏病的最常见原因。尽管大剂量静脉注射免疫球蛋白(IVIG)加阿司匹林可降低冠状动脉损伤的风险，但5-10%的KD儿童会继续发展为冠状动脉动脉瘤，可能导致心肌缺血、梗塞或死亡。一旦形成动脉瘤，对动脉壁的损害是不可逆转的，尽管肌内膜增殖可以使管腔恢复到更正常的管径，但这些动脉永远不会正常，随着时间的推移，狭窄和钙化会导致缺血性并发症。因此，治疗的目标应该是预防或减轻冠状动脉损伤。根据我们实验室的初步数据，KD的动脉损伤是由于肌成纤维细胞、中性粒细胞和分泌促炎细胞因子、弹性蛋白酶和基质金属蛋白酶(MMPs)的T细胞的免疫激活和血管壁浸润所致。炎症的消退和急性疾病的恢复是通过T细胞调节实现的。3-羟基-3-甲基戊二酰辅酶A(HMG-CoA)还原酶抑制剂，也被称为他汀类药物，具有广泛的抗炎作用，针对所有这些途径，并不依赖于它们的降胆固醇作用。他汀类药物可以抑制细胞因子诱导的T细胞活化所必需的共刺激分子的表达，增加调节性T细胞的数量和抑制功能，减少上皮/内皮细胞向间质的转变，抑制肌成纤维细胞分泌MMPs，并增加循环内皮祖细胞的数量。在KD的小鼠模型中，阿托伐他汀最近被证明减少了基质金属蛋白酶-9的分泌，基质金属蛋白酶是一种促成动脉瘤形成的有效胶原酶。考虑到这些抗炎作用，他汀类药物将是阻止KD患者CAA进展的合理疗法。拟议的第一阶段研究将在标准剂量递增研究设计(特定目标1)中评估阿托伐他汀的安全性，并在第一次口服剂量(特定目标2)前后密集采样的药代动力学。随之而来的一项IIa期研究将评估药物活性，包括氧化应激和炎症测量的变化，调节性T细胞的计数和特征，以及发烧后头6周冠状动脉内径的超声心动图变化(特定目标3)。这些研究将确定阿托伐他汀的非降脂作用在减少急性KD儿童动脉壁炎方面是否有希望。

DESCRIPTION (provided by applicant): We propose here the "re-purposing" of atorvastatin to reduce pro-inflammatory host responses and improve cardiovascular outcome in children with acute Kawasaki disease (KD), a self-limited vasculitis that is the most common cause of acquired heart disease in children. Although high-dose intravenous immunoglobulin (IVIG) plus aspirin reduces the risk of coronary artery damage, 5-10% of children with KD will go on to develop coronary artery aneurysms that may result in myocardial ischemia, infarction, or death. Once aneurysms have formed, the damage to the arterial wall is irreversible and although myointimal proliferation can restore the lumen to a more normal caliber, these arteries are never normal and over time stenoses and calcification lead to ischemic complications. Thus, the goal of treatment should be prevention or attenuation of coronary artery damage. Based on preliminary data from our laboratory, arterial damage in KD results from immune activation and vessel wall infiltration by myofibroblasts, neutrophils, and T-cells with secretion of pro-inflammatory cytokines, elastases, and matrix metalloproteinases (MMPs). Resolution of inflammation and recovery from the acute illness occurs through T-cell regulation. The 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors, also known as statins, have extensive anti-inflammatory effects that target all of these pathways and are independent of their cholesterol-lowering effect. Statins have been shown to inhibit cytokine-inducible expression of the co-stimulatory molecules necessary for T-cell activation, to increase the number and suppressive function of regulatory T-cells, to reduce epithelial/endothelial to mesenchymal transition, to inhibit the secretion of MMPs by myofibroblasts, and to increase the number of circulating endothelial progenitor cells. In a mouse model of KD, atorvastatin was recently shown to reduce secretion of MMP-9, a potent collagenase that contributes to aneurysm formation. Given these anti-inflammatory effects, statins would be a reasonable therapy to block CAA progression in KD. The proposed Phase I study will assess the safety of atorvastatin in a standard dose-escalation study design (Specific Aim 1) and pharmacokinetics with intensive sampling around the first oral dose (Specific Aim 2). A concomitant Phase IIa study will evaluate drug activity including changes in measures of oxidative stress and inflammation, enumeration and characterization of regulatory T-cells, and echocardiographic changes in the internal diameter of the coronary arteries over the first 6 weeks after fever onset (Specific Aim 3). These studies will determine if the non-lipid lowering effects of atorvastatin show promise in reducing arterial wall inflammation in children with acute KD.