HUMAN ALBUMIN THERAPY-TREATMENT OF ACUTE ISCHEMIC STROKE

人类白蛋白疗法-治疗急性缺血性中风

基本信息

批准号：
6650873
负责人：
MYRON DAVID GINSBERG
金额：
$ 53.18万
依托单位：
UNIVERSITY OF MIAMI SCHOOL OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
2001
资助国家：
美国
起止时间：
2001-08-15 至 2005-07-31
项目状态：
已结题

项目摘要

In this revised NINDS Pilot Clinical Trial Grant for Neurological Disease, we propose to conduct a phase I investigation of intravenous human serum albumin therapy (HSAlb) for the treatment of acute ischemic stroke. The study is structured as an open-label, non-randomized dose-finding trial that will be conducted at two clinical sites - the University of Miami/Jackson Memorial Hospital and the University of Calgary/Foothills Medical Centre, Canada. Both sites are major University-affiliated teaching hospitals with active Stroke Services and state-of-the-art facilities. The Department of Biometry and Epidemiology at the Medical University of South Carolina, Charleston, will provide data management and statistical analysis. The study's primary objective is to employ a multiple-tier dose-escalation design to discern the safely tolerated maximum dose and administration of intravenous HSAlb in patients with acute ischemic cerebral infarction of 8 hours' duration or less; and to implement standardized procedures for monitoring cardiovascular function and assessing neurological outcome. Our secondary objective is to evaluate neurological and functional outcome at 1 and 3 months after hospital discharge in order to obtain pilot experience for future randomized, multicenter phase II-III trials of this agent. Two patient subgroups will be separately and independently studied: those admitted with 3 h who also receive tissue plasminogen activator therapy, and those not receiving tPA. The study's hypothesis is that patients with acute ischemic stroke will tolerate moderate doses of HSAlb without suffering cardiovascular complications or other adverse events. Eligibility criteria include entry within 8 hours; initial NIH Stroke Scale of 6 or greater; and age =greater than 18 years. Major exclusion criteria include congestive heart failure, reduced cardiac ejection fraction by echocardiography, intracranial hemorrhage, severe hypertension, and serious systemic disease. In extensive preclinical studies, we have documented that human albumin therapy confers consistent, marked neuroprotection in animal models of both focal and global brain ischemia as well as in acute brain trauma. We have shown that the therapeutic window for neuroprotection with moderate- dose albumin (1.25 g/kg) extends to four hours after onset of MCA occlusion, and that this albumin dose, when given 2 hours after stroke onset, reduces infarct size even in permanent MCA occlusion. This proposed clinical trial is unique in permitting the opportunity to study this highly efficacious agent at a dose and administration that closely resemble the experimental settings in which its efficacy has already been proven. In our view, the multiple unique physiochemical properties of the albumin molecule are integral to its neuroprotective effect and render it uniquely suited as a therapeutic agent to combat ischemic brain injury.

在本次修订后的 NINDS 神经疾病试点临床试验拨款中，我们建议开展静脉人血清白蛋白疗法 (HSAlb) 用于治疗急性缺血性中风的 I 期研究。该研究是一项开放标签、非随机剂量探索试验，将在两个临床中心进行——迈阿密大学/杰克逊纪念医院和加拿大卡尔加里大学/山麓医疗中心。这两个医院都是主要的大学附属教学医院，拥有活跃的中风服务和最先进的设施。查尔斯顿南卡罗来纳医科大学生物统计和流行病学系将提供数据管理和统计分析。该研究的主要目的是采用多层剂量递增设计来确定持续时间不超过 8 小时的急性缺血性脑梗死患者静脉注射 HSAlb 的安全耐受最大剂量和给药方式；并实施监测心血管功能和评估神经系统结果的标准化程序。我们的次要目标是评估出院后 1 个月和 3 个月的神经学和功能结果，以便为该药物未来的随机、多中心 II-III 期试验获得试点经验。将分别独立地研究两个患者亚组：入院 3 小时并接受组织纤溶酶原激活剂治疗的患者，以及未接受 tPA 的患者。该研究的假设是，急性缺血性中风患者能够耐受中等剂量的 HSAlb，而不会出现心血管并发症或其他不良事件。资格标准包括8小时内入场；初始 NIH 中风评分为 6 或更高；并且年龄=大于18岁。主要排除标准包括充血性心力衰竭、超声心动图显示的心脏射血分数降低、颅内出血、严重高血压和严重全身性疾病。在广泛的临床前研究中，我们记录了人白蛋白治疗在局灶性和全脑缺血以及急性脑损伤的动物模型中提供一致、显着的神经保护作用。我们已经证明，中等剂量白蛋白（1.25 g/kg）的神经保护治疗窗可延长至 MCA 闭塞发作后 4 小时，并且在中风发作后 2 小时给予该白蛋白剂量，即使在永久性中风患者中也能减少梗塞面积。 MCA 闭塞。这项拟议的临床试验的独特之处在于，它允许有机会以与已证明其功效的实验环境非常相似的剂量和给药方式来研究这种高效药物。我们认为，白蛋白分子的多种独特的理化特性是其神经保护作用不可或缺的一部分，并使其特别适合作为对抗缺血性脑损伤的治疗剂。