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（MI）、中风和其他血管事件方面具有巨大益处。(1)他汀类药物在预防方面的益处至少部分独立于其降低胆固醇的作用。(2)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，包括类异戊二烯，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。最近，几种他汀类药物在急性缺血性中风的啮齿动物模型中显示出减少神经元损伤和梗死面积，增加中风后的血管生成和突触发生，并改善行为结果。在这些模型中， 在实验性中风前和中风后的急性治疗（长达24小时）中给予。这种神经保护的机制也不依赖于胆固醇，并且似乎主要与改善的内皮功能、增加的脑血流量和减少的炎症有关，而不是与直接的神经元细胞保护益处有关。这些实验研究中使用的最有效的他汀类药物剂量远高于目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，以及我们自己的下述1期经验（3，4）表明，这些剂量在短时间内可能耐受良好。 尽管存在大量的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卒中（SPARCL）试验（5），但很少进行转化研究来测试大剂量他汀类药物作为卒中患者早期治疗的作用。关于他汀类药物在卒中治疗中的作用的突出问题是： 1.短期大剂量他汀类药物治疗是否可以安全地使用 神经保护？ 2.急性卒中后早期短期大剂量他汀类药物治疗是否能显著改善功能预后？ 3.短期大剂量他汀类药物治疗神经保护的作用机制是什么？ 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）是一种急性中风药物 一项旨在检验短期他汀类药物治疗（剂量高于美国食品药品监督管理局（FDA）目前批准的剂量）在急性缺血性卒中患者中可行且安全的假设的开发计划。NeuSTART IB期剂量递增和剂量探索研究通过该纽约哥伦比亚合作SPOTRIAS的第一个周期资助，并利用了既往卒中试验的适应性临床试验设计，证明急性缺血性卒中后3天每天口服剂量高达8 mg/kg的洛伐他汀是可行和安全的。（3，4）本方案描述了多中心、随机、双盲、安慰剂对照、2A期安全性和初步疗效试验的原理和设计。由于近年来他汀类药物使用的增加，2期研究也有一些独特的设计特点，包括基于既往使用他汀类药物治疗的分层随机化。 这项研究是在我们目前的SPOTRIAS周期下开始的，但由于获得FDA批准的延迟和低于预期的患者招募而尚未完成。因为我们在提交竞争性续约的能力上的非自愿延迟（由于合理的愿望，以同步提交的合作伙伴计划和纽约哥伦比亚合作SPOTRIAS），我们最近申请并收到了行政补充NINDS通过美国复苏和再投资法案（ARRA），这将资助我们准备扩大我们的2期研究从两个中心，一项基于纽约的研究，一项跨越SPOTRIAS和其他中心的多中心研究。该ARRA资金将不包括这些研究中心的患者招募费用，而是用于招募的药房准备和行政程序。 NeuSTART 2从一家双中心、单一医院的转换（哥伦比亚和康奈尔是一个医院系统的一部分，纽约长老会医院）进行多中心临床试验将（1）使我们能够达到患者招募目标;（2）增加SPOTRIAS网站联盟之间的凝聚力，包括正在提交SPOTRIAS申请的迈阿密大学，和（3）促进SPOTRIAS计划开发的合作研究。它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.