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.

在这项修订后的Ninds Pilot临床试验授予神经系统疾病中，我们建议对静脉内人类血清白蛋白治疗（HSALB）进行I期研究，以治疗急性缺血性中风。该研究的结构是一项开放标签的非随机剂量调查试验，该试验将在两个临床场所进行 - 迈阿密/杰克逊大学纪念医院和加拿大卡尔加里大学/foothills医学中心。这两个地点都是具有积极的中风服务和最先进设施的大学附属教学医院。查尔斯顿南卡罗来纳州医科大学生物特征和流行病学系将提供数据管理和统计分析。该研究的主要目标是采用多层剂量降低设计，以辨别急性缺血性脑梗塞持续8小时或更短的急性缺血性脑梗塞患者的安全耐受剂量和静脉内HSALB的给药；并实施标准化程序来监测心血管功能并评估神经系统结果。我们的次要目标是在出院后1和3个月内评估神经系统和功能结果，以便获得该药物的未来随机，多中心II-III期试验的试验经验。两个患者亚组将分别进行独立研究：那些接受组织纤溶酶原激活剂疗法的3小时，而未接受TPA的纤溶酶原激活剂治疗。该研究的假设是急性缺血性中风的患者将耐受中等剂量的HSALB，而不会患有心血管并发症或其他不良事件。资格标准包括在8小时内进入；最初的NIH中风量表为6或更高；年龄=大于18岁。主要的排除标准包括充血性心力衰竭，超声心动图，颅内出血，严重的高血压和严重的全身性疾病减少心脏射血分数。在广泛的临床前研究中，我们记录了人白蛋白疗法在局灶性和全球脑部缺血以及急性脑外伤中均一致的神经保护一致。我们已经表明，中等剂量白蛋白（1.25 g/kg）神经保护的治疗窗口延伸至MCA闭塞发作后四个小时，并且该白蛋白剂量在中风发作后2小时给予该白蛋白剂量，即使在永久性MCA遮挡中也会减少插图大小。这项拟议的临床试验在允许有机会研究这种高效的药物的剂量和给药的机会非常独特，与已经证明其功效的实验环境非常相似。在我们看来，白蛋白分子的多种独特的生理化学特性是其神经保护作用不可或缺的，并使其独特地作为对抗缺血性脑损伤的治疗剂。