The Neuroprotection with Statin Therapy for Acute Recovery Trial (NeuSTART): an adaptive design phase I dose-escalation study of high-dose lovastatin in acute ischemic stroke
The Neuroprotection with Statin Therapy for Acute Recovery Trial (NeuSTART): an adaptive design phase I dose-escalation study of high-dose lovastatin in acute ischemic stroke
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DOI：
10.1111/j.1747-4949.2008.00200.x
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发表时间：
2008-08-01
影响因子：
6.7
通讯作者：
Cheung, Ken
中科院分区：
文献类型：
--
作者：
Elkind, Mitchell S. V.;Sacco, Ralph L.;Cheung, Ken
越来越多的实验和临床证据表明，通过减少甲羟戊酸途径的下游产物而不是胆固醇，HMG-CoA还原酶抑制剂（“他汀类药物”）对内皮功能、冠状动脉和脑血流、炎症和止血具有有益作用。他汀类药物在急性缺血性卒中的啮齿动物模型中显示出以剂量依赖性方式减少神经元损伤和梗死面积。这项早期试验的目的是确定短期急性卒中治疗中洛伐他汀的最大耐受剂量。在这项多中心1B期剂量递增和剂量探索研究中，33例急性缺血性卒中患者将在症状发作后24小时内开始接受洛伐他汀给药，剂量从每日1 mg/kg增加至10 mg/kg，持续3天。主要安全性结果将是发生由临床和实验室标准定义的肌毒性或肝毒性，并且该研究旨在确定可以以< 10%的肌毒性或肝毒性风险施用的洛伐他汀的最高剂量。本研究的统计学设计采用了适应性设计，即连续再评估方法，该方法对卒中试验来说是新颖的，以找到最佳剂量。对剂量-毒性模型进行校准，使得该方法最终将选择引起7-13%剂量限制性毒性（在目标的3%内）的剂量。样本量为33将确保任何二进制变量的估计值具有宽度的95%置信区间
There is growing experimental and clinical evidence that by reducing downstream products of the mevalonate pathway other than cholesterol, HMG-CoA reductase inhibitors ('statins') have beneficial effects on endothelial function, coronary and cerebral blood flow, inflammation, and hemostasis. Statins have been shown in rodent models of acute ischemic stroke to reduce neuronal injury and infarct size in a dose-dependent fashion. The objective of this early phase trial will be to determine the maximal-tolerated dose of lovastatin for short-term acute stroke therapy. In this multicenter phase 1B dose-escalation and dose-finding study, 33 patients with acute ischemic stroke will be administered lovastatin in increasing doses from one to 10 mg/kg daily for 3 days beginning within 24 hours after symptom onset. The primary safety outcome will be occurrence of myotoxicity or hepatotoxicity, defined by clinical and laboratory criteria, and the study is designed to determine the highest dose of lovastatin that can be administered with < 10% risk of myotoxicity or hepatotoxicity. The statistical design of the study utilizes an adaptive design, the Continual Reassessment Method, which is novel to stroke trials, to find the optimal dosage. The dose-toxicity model is calibrated such that the method will eventually select a dose that causes 7-13% dose-limiting toxicity (within 3% of target). A sample size of 33 will ensure that estimates of any binary variables will have a 95% confidence interval of width