New York Columbia Collaborative SPOTRIAS

羟甲基戊二酰辅酶A还原酶抑制剂（他汀类药物）通过降低胆固醇水平和炎症来降低中风和心肌梗死的风险。最近，几种他汀类药物已在动物中风模型中显示出以剂量依赖性方式减少梗死面积，通过上调内皮型一氧化氮合酶增加脑血流量和减少炎症。在一项使用适应性研究设计的1B期剂量递增和剂量探索研究中，我们证明了洛伐他汀可以安全地用于急性缺血性卒中患者，剂量高达FDA目前批准的剂量的8倍（8 mg/kg/天，持续3天）。一项2A期多中心、随机、安慰剂对照试验，在168例急性缺血性脑卒中患者中进行了短期高剂量洛伐他汀治疗，固定剂量为每日640 mg，持续3天。随机化将根据既往他汀类药物使用情况进行分层。主要结局将是安全性，其定义为临床肝脏或肌肉疾病的发展，或肝脏或肌肉酶升高> 3倍或> 10倍正常上限。安全性监测委员会将审查血压、神经系统状态、出血性转化率和感染率，以寻找额外或非预期毒性的证据。本研究还将探讨他汀类药物治疗对功能结局和炎症的影响。FDA要求的体外凝块溶解试验也将在第1年进行，以准备纳入接受静脉或动脉内溶栓的患者。这项研究的数据对于计划和设计III期试验以测试大剂量他汀类药物治疗急性缺血性卒中的疗效至关重要。 相关性：就死亡率、残疾和费用而言，中风是一个主要的公共卫生问题，目前对急性中风的治疗是有限的。中风非常常见，尤其是在少数民族人群中。确定急性卒中的新治疗方法是神经学研究的一个重要目标，并将具有重要的公共卫生意义。

Hydroxymethylglutaryl coenzyme A reductase inhibitors (statins) reduce the risk of stroke and myocardial infarction by reducing cholesterol levels and inflammation. More recently, several statins have been shown in animal stroke models to reduce infarct size in a dose-dependent fashion, by both increasing cerebral blood flow through upregulation of endothelial nitric oxide synthase and reducing Inflammation. In a Phase 1B dose escalation and dose-finding study using an adaptive study design, we demonstrated that lovastatin can be administered safely to acute ischemic stroke patients at doses up to 8 times higher (8 mg/kg/day for 3 days) than those currently approved by the FDA. A Phase 2A multicenter, randomized, placebo-controlled trial of short-term high-dose lovastatin therapy at a fixed dose of 640 mg daily for three days in 168 patients with acute ischemic stroke is proposed. Randomization will be stratified by prior statin use. The primary outcome will be safety, defined by development of clinical liver or muscle disease, or liver or muscle enzyme elevations >3X or >10X upper limit of normal, respectively. A safety monitoring committee will review blood pressure, neurological status, and rates of hemorrhagic conversion and infection for evidence of additional or unexpected toxicity. This study will also explore for effects of statin therapy on functional outcome and inflammation. In vitro clot lysis assays requested by FDA will also be performed in Year 1 preparatory to inclusion of patients receiving intravenous or intra-arterial thrombolysis. Data derived from this study will be essential to the planning and design of a Phase 3 trial to test the efficacy of high-dose statin therapy in acute ischemic stroke. RELEVANCE: Stroke is a major public health problem in terms of mortality, disability, and cost, and treatments for acute stroke are limited at present. Stroke is very common, particularly among minority populations. The identification of new treatments for acute stroke is an important goal of neurological research, and would have important public health implications.