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.
