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.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
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Special Emphasis Panel (ZNS1-SRB-R)
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Columbia University (N.Y.)
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