Neuroprotection with Statin Therapy for Acute Recovery Trial (NeuSTART)

羟甲基戊二酰辅酶A(HMG-CoA)还原酶抑制剂，或他汀类药物，已被证明在预防心肌梗死(ML)、中风和其他血管事件方面具有巨大的益处。(1)他汀类药物在预防方面的好处至少在一定程度上与它们降低胆固醇的效果无关。(2)越来越多的实验和临床证据表明，他汀类药物通过减少甲戊酸途径中除胆固醇以外的下游产物，包括异戊二烯类化合物，对内皮功能、冠状动脉和脑血流、炎症和止血有好处。最近，在急性缺血性中风的啮齿动物模型中，有几种他汀类药物被证明可以减少神经元损伤和梗塞面积，增加中风后的血管生成和突触生成，并改善行为结果。在这些模型中，他汀类药物 在实验性中风前和中风后作为急性治疗(长达24小时)都给予了治疗。这种神经保护的机制也独立于胆固醇，似乎主要与改善内皮功能、增加脑血流量和减少炎症有关，而不是直接的神经元细胞保护益处。这些实验研究中使用的最有效的他汀类药物剂量远远高于当前临床实践中使用的剂量。来自癌症患者早期临床试验的初步证据，以及我们下面描述的第一阶段经验(3，4)表明，这些剂量可能在短时间内耐受性良好。 尽管存在大量试验证明他汀类药物在血管预防中的益处，(2)和积极降低胆固醇水平预防中风(SPARCL)试验(5)，但很少进行翻译研究来测试大剂量他汀类药物作为中风患者早期治疗的作用。有关他汀类药物在中风治疗中作用的悬而未决的问题包括： 1.短期大剂量他汀类药物能否安全地给予可能提供 神经保护？ 2.急性卒中后早期应用短期、大剂量他汀类药物治疗是否能显著改善患者的功能？ 3.短期大剂量他汀类药物在神经保护中的作用机制是什么？ 4.短期大剂量他汀类药物对急性缺血性卒中后全身炎症标志物的影响有多大？ Neu Start(他汀类药物治疗急性恢复的神经保护疗法)是一种急性卒中药物 开发计划旨在测试短期他汀类药物治疗的假说，剂量高于食品和药物管理局(FDA)目前批准的剂量，对急性缺血性中风患者是可行和安全的。NeuSTART IB期剂量递增和剂量发现研究由纽约哥伦比亚大学合作SPOTRIAS的第一个周期资助，并利用先前对中风试验新颖的适应性临床试验设计，证明在急性缺血性中风后每天口服洛伐他汀高达8毫克/公斤是可行和安全的。(3，4)本方案描述了多中心、随机、双盲、安慰剂对照、第2A期安全性和试点疗效试验的基本原理和设计。由于近年来他汀类药物的使用增加，2期研究也有一些独特的设计特点，包括基于先前使用他汀类药物治疗的分层随机分组。 这项研究开始于我们目前的SPOTRIAS周期，但由于在获得FDA批准方面的延误和患者招募低于预期，该研究尚未完成。由于我们提交竞争续签的能力被无意识地推迟(由于我们合理地希望同步来自合作伙伴计划和纽约哥伦比亚合作SPOTRIAS的提交)，我们最近通过美国复苏和再投资法案(ARRA)申请并获得了NINDS的行政补充，这将为我们准备将我们的第二阶段研究从两个中心的纽约研究扩展到跨SPOTRIAS和其他中心的多中心研究提供资金。ARRA的这笔资金将不包括在这些地点登记病人的费用，而是用于准备药房和招募的行政程序。 NeuSTART 2从双中心、单医院(哥伦比亚和康奈尔是纽约长老会医院系统的一部分)转变为多中心临床试验将：(1)使我们能够实现患者招募目标；(2)增加SPOTRIAS站点联盟之间的凝聚力，包括正在提交SPOTRIAS申请的迈阿密大学；(3)促进SPOTRIAS项目开发所针对的那种合作研究。这将进一步为一项大型、多中心的3期研究铺平道路，以证明疗效。

Hydroxymethylglutaryl coenzyme A (HMG-CoA) reductase inhibitors, or statins, have been proven to be of tremendous benefit in prophylaxis against myocardial infarction (Ml), stroke, and other vascular events.(1) The benefit of statins in prevention is at least partly independent of their effects on lowering cholesterol.(2) There is growing experimental and clinical evidence that by reducing downstream products of the mevalonate pathway other than cholesterol, including isoprenoids, the statins have beneficial effects on endothelial function, coronary and cerebral blood flow, inflammation, and hemostasis. More recently, several statins have been shown in rodent models of acute ischemic stroke to reduce neuronal injury and infarct size, to increase angiogenesis and synaptogenesis after stroke, and to improve behavioral outcomes. In these models, statins have been given both before experimental stroke and as acute treatment (up to 24 hours) after stroke. The mechanism of this neuroprotection is also independent of cholesterol, and appears primarily related to improved endothelial function, increased cerebral blood flow and reduced inflammation, rather than to a direct neuronal cytoprotective benefit. The most effective statin doses used in these experimental studies are much higher than those used in current clinical practice. Preliminary evidence from early phase clinical trials in cancer patients, as well as from our own Phase 1 experience described below,(3,4) suggests that these doses may be well-tolerated for short periods of time. Despite the existence of an abundance of trials demonstrating the benefit of statins in vascular prophylaxis generally,(2) and the Stroke Prevention by Aggressive Reduction in Cholesterol Levels, or SPARCL, trial (5), few translational studies have been performed to test the role of high-dose statins administered as early therapy in stroke patients. Outstanding questions about the role of statins in stroke treatment are: 1. Can short-term high-dose statin therapy be administered safely at doses likely to provide neuroprotection? 2. Does early treatment with short-term, high-dose statin therapy after acute stroke lead to meaningful improvement in functional outcome? 3. What are the mechanisms of action of short-term high-dose statin therapy in neuroprotection? 4. How much effect do short-term high-dose statins have on systemic markers of inflammation after acute ischemic stroke? Neu START (Neuroprotection with Statin Therapy for Acute Recovery Jrial) is an acute stroke drug development program designed to test the hypothesis that short-term statin therapy, at doses that are higher than those currently approved by the Food and Drug Administration (FDA), is feasible and safe in patients with acute ischemic stroke. The NeuSTART phase IB dose-escalation and dose-finding study, funded through the first cycle of this New York Columbia Collaborative SPOTRIAS and utilizing an adaptive clinical trial design previously novel to stroke trials, demonstrated that oral doses of lovastatin up to 8 mg/kg daily administered for three days after acute ischemic stroke were feasible and safe.(3,4) The present protocol describes the rationale and design for a multicenter, randomized, double-blind, placebo-controlled, phase 2A safety and pilot efficacy trial. Because of the increase in use of statins in recent years, the Phase 2 study also has some unique design features, including stratified randomization based on prior use of statin therapy. This study began under our current SPOTRIAS cycle, but has not been completed due to delays in obtaining FDA approval and lower-than-expected patient recruitment. Because of the involuntary delay in our ability to submit our competitive renewal (due to the reasonable desire to synchronize the submissions from the Partners Program and the NY Columbia Collaborative SPOTRIASs), we recently applied for and received an administrative supplement from NINDS through the American Recovery and Reinvestment Act (ARRA) that will fund us to prepare to expand our Phase 2 study from a two-center, New York based study to a multicenter study across SPOTRIAS and other centers. This ARRA funding will not cover the expenses of the patient enrolment at thse sites, but rather the preparation of pharmacy and administrative procedures for recruitment. The conversion of NeuSTART 2 from a two-center, single hospital (Columbia and Cornell are part of one hospital system, the New York-Presbyterian Hospital) to a multicenter clinical trial will (1) enable us to reach patient recruitment goals; (2) increase the cohesion among the consortium of SPOTRIAS sites, including the University of Miami, which is submitting a SPOTRIAS application, and (3) facilitate the kind of collaborative research for which the SPOTRIAS program was developed. It will further pave the way for a large, multicenter Phase 3 study to demonstrate efficacy.