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，几种他汀类药物在动物中风模型中显示出剂量依赖性，通过上调内皮一氧化氮合酶增加脑血流量和减少炎症来减少梗死面积。在一项采用适应性研究设计的1B期剂量递增和剂量发现研究中，我们证明洛伐他汀可以安全地用于急性缺血性卒中患者，剂量高达目前FDA批准的剂量的8倍（8mg /kg/天，持续3天）。提出了一项多中心、随机、安慰剂对照的2A期临床试验，对168例急性缺血性卒中患者进行短期高剂量洛伐他汀治疗，固定剂量为640mg /天，持续3天。随机分组将根据既往使用他汀类药物进行分层。主要终点将是安全性，由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倍正常值上限来定义。安全监测委员会将审查血压、神经系统状况、出血性转化率和感染率，以寻找额外或意外毒性的证据。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一年进行，为纳入接受静脉或动脉溶栓治疗的患者做准备。这项研究的数据将对计划和设计一项测试大剂量他汀类药物治疗急性缺血性卒中疗效的3期试验至关重要。

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.