Specialized Program of Translational Research in Acute Stroke- Project 1

描述(申请人提供)：尽管在中风预防及其急性治疗方面取得了重大进展，但中风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“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，并证明中风实际上是在真正中风发作的前几个小时内发生的，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尔替普斯治疗，如果符合纳入和排除标准，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。我们建议在一项多中心、开放标签、单臂2a期溶栓安全试验中，使用先进的磁共振成像作为“证人”，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eCASS 3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对症状性颅内出血(ICH)的定义。这被定义为任何伴有神经恶化的出血，如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。 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): 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 within the first few hours of true stroke onset, 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 a multi-center, open-label, single-arm Phase 2a safety trial of thrombolysis in these patients. We have modeled the other eligibility criteria after the ECASS 3 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 intracranial hemorrhage (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. 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.