Specialized Programs of Translational Research in Acute Stroke at the Partners

合作伙伴的急性中风转化研究专门项目

• 批准号: 8134850
• 负责人: Karen L Furie
• 金额: $ 121.55万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-09-20 至 2014-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8134850
• 关键词: Specialized; Programs; Translational; Research; Acute

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.

描述（由申请人提供）： 在此次Partners SPOTRIAS续约申请中，我们提出了三项高度创新的卒中研究。其中两项是临床试验，一项II期安全性研究，旨在将tPA的使用扩展到缺乏明确卒中发作时间的患者，使用MRI特征来预测发作时间，另一项转化研究最终导致了一种新型治疗方法的1B期试验，SLx-2119抑制ROCK。这两项研究都建立在MGH和BWH进行的转化临床前和成像研究的基础上。第三个项目是功能磁共振成像恢复项目，该项目正在与哥伦比亚大学合作进行。这些独特的项目旨在扩大急性卒中治疗的使用，并改善预后预测。我们已经申请更新四个必要的核心，和一个可选的神经影像核心从我们的第一个SPOTRIAS周期。访问和管理核心（核心A）利用合作伙伴的大量临床资源，以尽可能快的速度用溶栓疗法治疗急性卒中患者，并在SPOTRIAS项目中招募受试者。神经影像学核心（核心B）已经建立了标准化的影像学数据检索、分析和存档机制。血液和组织核心（核心C）将支持项目2和SPOTRIAS血浆储存库样本提交的血液样本采集和处理。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，我们还增加了一个新的离散培训核心（核心E）作为本次提交的一部分。这个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。由于只有一种获批的急性卒中治疗（静脉注射tPA），并且该治疗的使用有限，因此迫切需要进行额外的转化研究，以开发新的治疗方法和提供急性卒中护理的新范例。 2 P50 NS 051343 -06/项目1 Schwamm，Lee 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，但卒中仍然是全球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“卒中症状发作”，即患者最后一次被观察到良好的时间，许多发作未被观察到的患者自动不符合溶栓治疗的条件，即使他们的真实发作时间允许他们符合条件。如果存在一种技术，可以取代人类证人，并证明中风实际上是小于3.5小时的持续时间，那么这些患者可以考虑根据现行的美国心脏协会（AHA）指南进行阿替普酶治疗，如果符合入选和排除标准，则进行治疗。许多卒中患者在发现症状后3小时内被迅速送往医院，但FDA的适应症将其排除在静脉注射阿替普酶的考虑范围之外，如果自最后一次知道他们身体状况良好后超过3小时。我们建议使用先进的MR成像作为“证人”，在这些患者的开放标签IIa期溶栓安全性研究中证明没有人类证人的患者的卒中持续时间。我们根据ECASS 3试验设计和现行AHA指南对其他合格性标准进行了建模，以将关注变量限制为使用MR作为卒中发作时间的决定因素。我们将从研究中排除在最后一次观察良好后3小时内到达的患者，因为这些患者有资格接受标签内溶栓治疗。由于本研究是开放标签的，研究者是非盲的，我们将使用更保守的ECASS-2症状性ICH定义。这被定义为任何伴有神经功能恶化的出血，如NIHSS评分比基线值或前7天的最低值高4分或以上，或任何导致死亡的出血，并且不要求将ICH归类为与神经功能恶化有因果关系。如果我们的研究是成功的，我们可以潜在地扩大使用溶解剂的中风患者人群，目前很少提供急性干预。 公共卫生相关性： 中风是美国死亡和发病的主要原因。FDA批准在患者最后一次就诊后180分钟内进行溶栓治疗。大约25%的中风患者的发病时间无人目睹。本研究旨在将静脉溶栓扩大到这些患者，使用神经影像学作为“证人”，以确定中风持续时间时，人类证人不可用。