Specialized Programs of Translational Research in Acute Stroke at the Partners

描述(由申请人提供)： 在这份合作伙伴SPOTRIAS续签申请中，我们提出了三项极具创新性的中风研究。两项是临床试验，一项是将tPA的使用扩大到缺乏明确中风发病时间的患者的第二阶段安全性研究，该研究使用MRI信号来预测发病时间，以及一项翻译研究，该研究最终完成了一种新的治疗方法-SLX-2119摇滚抑制-的1B阶段试验。这两项研究都建立在MGH和BWH进行的翻译性临床前和影像研究基础上。第三个项目是功能磁共振恢复项目，该项目正在与哥伦比亚大学合作进行。这些独特的项目寻求扩大急性中风疗法的使用，并改善对结果的预测。我们已经申请更新四个必要的核心，并从我们的第一个SPOTRIAS周期可选的神经成像核心。准入和管理核心(核心A)利用合作伙伴的大量临床资源，以尽可能快的速度对急性中风患者进行溶栓治疗，并招募受试者参加SPOTRIAS项目。神经成像核心(核心B)已经建立了标准化成像数据检索、分析和存档的机制。血液和组织核心(核心C)将支持项目2和SPOTRIAS血浆库样本提交的血液样本收集和处理。生物统计和数据管理核心(核心D)将继续为SPOTRIAS项目提供最先进的支持，以确保高质量的数据和统计分析。此外，作为本报告的一部分，我们增加了一个新的独立培训核心(核心E)。这一新的核心将加强临床和研究急性卒中奖学金之间的整合，并协调SPOTRIAS研究员的培训经验。 相关性：中风是美国人口的主要健康负担。由于只批准了一种急性卒中疗法(静脉注射tPA)，而且该疗法的使用有限，迫切需要进行更多的翻译研究，以开发新的治疗方法和新的范例来提供急性卒中护理。 2P50NS051343-06/项目1施瓦姆，李 描述(由申请人提供)： 尽管在卒中预防及其急性治疗方面取得了重大进展，但卒中仍然是世界范围内第三大死亡原因和成人发病率的主要原因。通过以最保守的方式定义“中风症状发作”，即患者最后一次出现良好的时间，许多发病没有目击的患者自动没有资格接受溶栓治疗，即使他们的真实发病时间允许他们符合条件。如果有一种技术可以取代人类证人，并证明中风的持续时间实际上少于3.5小时，那么根据当前的美国心脏协会(AHA)指南，这些患者可以考虑接受阿替普斯治疗，如果根据纳入和排除标准符合条件，则可以接受治疗。许多中风患者在症状发现后3小时内被迅速送往医院，但FDA的适应症将他们排除在自他们最后一次被发现良好以来超过3小时的静脉注射阿尔替普酶的考虑范围之外。我们建议使用先进的磁共振成像作为“证人”，在开放式标签的Ha期溶栓安全性研究中，为那些没有人类证人的患者提供中风持续时间的证据。我们根据ECASS3试验设计和当前的AHA指南模拟了其他资格标准，以便将感兴趣的变量限制为使用MR作为卒中发病时间的决定因素。我们将排除那些在最后一次见到Well后3小时内到达的患者，因为这些患者有资格接受溶栓治疗。因为这项研究是开放标签的，研究人员是非盲目的，我们将使用更保守的eCASS-2对症状性脑出血的定义。这被定义为任何伴有神经恶化的出血，NIHSS评分高于基线或前7天最低值4分或以上，或任何导致死亡的出血，并不要求将脑出血归类为与神经恶化有因果关系。如果我们的研究成功，我们可能会将溶栓的使用扩大到目前几乎没有提供急性干预的中风患者群体。 公共卫生相关性： 在美国，中风是导致死亡和发病的主要原因。FDA批准在患者最后一次痊愈后180分钟内进行溶栓治疗。大约25%的中风患者有未见过的发病时间。这项研究试图将静脉溶栓扩大到这些患者，使用神经成像作为“证人”，以确定当没有人类证人时中风的持续时间。

DESCRIPTION (provided by applicant): In this Partners SPOTRIAS renewal application, we propose three highly innovative stroke studies. Two are clinical trials, a phase II safety study to expand the use of tPA to patients lacking a clear stroke onset time using the MRI signature to predict time of onset, and a translational study which culminates in a Phase 1B trial of a novel therapeutic approach, ROCK inhibition with SLx-2119. Both studies build upon translational preclinical and imaging studies performed at the MGH and BWH. The third project is an fMRI recovery project, which is being performed in collaboration with Columbia University. These unique projects seek to expand the use of acute stroke therapies and improve prediction of outcome. We have applied to renew the four requisite Cores, and an optional Neuroimaging Core from our first SPOTRIAS cycle. The Access and Administrative Core (Core A) leverages the considerable clinical resources at Partners to treat acute stroke patients with thrombolytic therapy as rapidly as possible, and enroll subjects in SPOTRIAS projects. The Neuroimaging Core (Core B) has established mechanisms for standardized imaging data retrieval, analysis, and archiving. The Blood and Tissue Core (Core C) will support blood sample collection and processing for Project 2 and SPOTRIAS plasma repository sample submission. The Biostatistics and Data Management Core (Core D) will continue to provide state-of-the- art support for the SPOTRIAS projects to ensure high quality data and statistical analyses. In addition, we have added a new, discrete Training Core (Core E) as part of this submission. This new Core will strengthen the integration between the clinical and research acute stroke fellowships and coordinate the training experience for the SPOTRIAS fellows. RELEVANCE: Stroke poses a major health burden on the population of the United States. With only one approved acute stroke therapy (intravenous tPA), and limited use of that treatment, there is a dire need for additional translational research to develop new therapeutic approaches and novel paradigms for the delivery of acute stroke care. 2P50NS051343-06/Project 1 Schwamm, Lee DESCRIPTION (provided by applicant): Despite significant progress in stroke prevention and its acute treatment, stroke remains the third leading cause of death and a leading cause of adult morbidity worldwide. By defining "stroke symptom onset" in the most conservative manner, namely the time the patient was last seen well, many patients whose onset is unwitnessed are automatically ineligible for thrombolytic therapy even if their true time of onset would allow them to qualify. If a technique existed that could replace the human witness and testify that the stroke was in fact less than 3.5 hours duration, then these patients could be considered for alteplase treatment under current American Heart Association (AHA) guidelines, and be treated if eligible according to the inclusion and exclusion criteria. Many stroke patients are rapidly brought to the hospital within 3 hours of the time of symptom discovery, but FDA indications exclude them from consideration for intravenous alteplase if it has been greater than 3 hours since the time they were last known to be well. We propose to use advanced MR imaging as the "witness" to testify as to stroke duration in those patients who do not have a human witness in an open label Phase Ha safety study of thrombolysis in these patients. We have modeled the other eligibility criteria after the ECASS3 trial design and the current AHA guidelines in order to limit the variable of interest to the use of MR as the determinant of time of stroke onset. We will exclude patients from the study who arrive within 3 hours from last seen well since these patients are eligible for on-label treatment with thrombolysis. Because the study is open-label and investigators are unblinded, we will use the more conservative ECASS-2 definition of symptomatic ICH. This is defined as any hemorrhage with neurologic deterioration, as indicated by an NIHSS score that was higher by 4 points or more than the value at baseline or the lowest value in the first 7 days or any hemorrhage leading to death, and does not require that the ICH be classified as causally linked to the neurologic deterioration. If our study is successful, we can potentially expand use of lytics to a stroke patient population for whom little acute intervention is currently offered. PUBLIC HEALTH RELEVANCE: Stroke is a leading cause of death and morbidity in the US. Thrombolysis is approved by the FDA for treatment within 180 minutes from when a patient was last seen well. Approximately 25% of stroke patients have unwitnessed onset times. This study seeks to expand IV thrombolysis to these patients using neuroimaging as the "witness" to establish the stroke duration when a human witness is unavailable.