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

阿托伐他汀治疗急性川崎病儿童的 I 期和 IIa 期试验

基本信息

批准号：
9096853
负责人：
ADRIANA H TREMOULET
金额：
$ 32.19万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN DIEGO
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-09-23 至 2018-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9096853
关键词：
Acute Adolescent Adult Age Age-Months Albumins Aneurysm Anti-Inflammatory Agents Anti-inflammatory Arteries Aspirin Attenuated Binding Proteins Blood Blood specimen CYP3A4 gene Caliber Cardiovascular system Case-Control Studies Cessation of life Child Cholesterol Clinical Clinical Trials Coenzyme A Coronary artery Data Development Dose Drug Kinetics Echocardiography Elastases Endothelial Cells Enrollment Epithelial Etiology Evaluation Family Fever Future Gelatinase B Goals Health Heart Diseases Hepatic Hour Human Immune response Infarction Infectious Agent Infiltration Inflammation Inflammatory Inflammatory Response Intercellular Junctions Intravenous Immunoglobulins Knowledge Laboratories Lead Life Matrilysin Matrix Metalloproteinases Measures Mesenchymal Methods Mission Monitor Mucocutaneous Lymph Node Syndrome Muscle Myocardial Infarction Myocardial Ischemia Myofibroblast Oral Outcome Oxidative Stress Oxidoreductase Pathway interactions Patients Pharmaceutical Preparations Phase Population Prevention Public Health Publishing Recovery Regulatory T-Lymphocyte Research Research Design Resolution Risk Safety Sampling Societies Stem cells Stenosis T cell regulation T-Cell Activation T-Lymphocyte TNF gene Testing Thrombosis Time Toxic effect Urine Vasculitis atorvastatin attenuation base calcification collagenase cytokine disability disorder control dosage efficacy trial epithelial to mesenchymal transition immune activation improved inducible gene expression inflammatory marker infliximab inhibitor/antagonist mouse model neutrophil novel therapeutics phase 1 study phase III trial prevent safety study sex study population therapy design

项目摘要

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.

描述（由申请人提供）：我们在这里提出了对阿托伐他汀的“重新点化”，以减少促炎性宿主反应并改善急性川崎病（KD）儿童的心血管结局，这是一种自我限制的血管炎，是儿童获得性心脏病的最常见原因。尽管高剂量的静脉免疫球蛋白（IVIG）加上阿司匹林降低了冠状动脉损伤的风险，但有5-10％的KD儿童将继续发展冠状动脉动脉瘤，这可能导致心肌缺血，感染或死亡。一旦形成大动脉瘤，动脉壁的损害是不可逆的，尽管肌后增殖可以使腔恢复到更正常的能力，但这些动脉永远是正常的，随着时间的推移，steNoses和钙化导致缺血并发症。因此，治疗的目标应是预防或衰减冠状动脉损伤。基于我们实验室的初步数据，KD中的动脉损伤是由肌纤维细胞，中性粒细胞和T细胞浸润的免疫激活和血管壁浸润，并分泌了促炎细胞因子，弹性酶，弹性酶和基质金属蛋白酶（MMPS）。通过T细胞调节，从急性疾病中解决炎症和恢复。 3-羟基-3-甲基戊二酰辅酶A（HMG-COA）还原酶抑制剂（也称为他汀类药物）具有广泛的抗炎作用，可针对所有这些途径，并且独立于其胆固醇降低胆固醇。汀类药物已被证明可以抑制T细胞激活所必需的共刺激分子的细胞因子诱导表达，以增加调节T细胞的数量和抑制功能，以减少对间质的过渡的上皮/内皮过渡，以抑制MMP的分泌肌纤维细胞和循环的数量，以抑制MMP的分泌。在KD的小鼠模型中，最近证明了阿托伐他汀可以减少MMP-9的分泌，MMP-9是一种有效的胶原酶，有助于动脉瘤形成。鉴于这些抗炎作用，他汀类药物将是阻止KD中CAA进展的合理疗法。拟议的I期研究将评估阿托伐他汀在标准剂量降低研究设计中的安全性（特定目标1）和药代动力学，并在第一个口服剂量附近进行大量采样（特定的目标2）。一项伴随的IIA研究将评估药物活性，包括在发烧后的前6周内冠状动脉内径的氧化应激和炎症，调节性T细胞的枚举和表征以及超声心动图的变化（特定目标3）。这些研究将确定阿托伐他汀的非脂质降低作用是否在减少急性KD儿童的动脉壁炎症方面有望。