ReoPro and Retavase to Treat Acute Stroke

Objectives: This is the companion protocol to the ROSIE protocol. This clinical trial will determine an acceptable dose of reteplase in combination with a fixed dose of abciximab for ischemic stroke 3-24 hours from onset in patients screened with brain CT rather than MRI (as required by the ROSIE protocol). The importance of this study relative to ROSIE will be its relevance to the large proportion of acute stroke patients who cannot have a screening MRI, because of contraindications or unavailability of emergency MRI at their hospital. Study Population: Patients will be selected by criteria to minimize likelihood of toxicity and maximize likelihood of response. These criteria include age 18-80 years old, patients who cannot get acute MRI because of contraindication to or unavailability of MRI, acute ischemic stroke of moderate severity (NIH Stroke Scale less than or equal to 16 and ischemic changes on CT scan less than approximately one third of the volume of the middle cerebral artery territory), no evidence of hemorrhage on CT, and no other clinical, radiological or laboratory features associated with increased risk of hemorrhage with thrombolytic therapy. Design: The study is open-label, dose escalation, safety and proof of principle study of the combination of intravenous abciximab and reteplase. A fixed dose of abciximab will be used in all patients: 0.25 mg/kg bolus (to a maximum of 30 mg) followed by a 0.125 microgram/kg/minute infusion (to a maximum of 10.0 microgram/minute) for 12 hours. The five dosing groups for the reteplase dose are 0U, 2.5 U, 5.0 U, 7.5 U, and 10.0 U. A maximum of 72 patients will be treated using an adaptive statistical design. Non-investigation patient management will be standardized across all patients according to the NIH Stroke Center Clinical Care Pathway. Outcome Measures: The primary efficacy endpoint for response will be clinical improvement (complete recovery or improvement of 4 points or more on the NIH Stroke Scale) at 24 hours after start of therapy. The primary safety endpoint for determination of toxicity will be any one of the following: symptomatic intracranial hemorrhage (ICH), major systemic hemorrhage, or other serious adverse event related to study drug administration, including death, within 48 hours from start of therapy. The maximum acceptable rate of toxicity will be 10% of patients treated at any dose level and the minimum acceptable rate of response will be 50% of patients at any dose level. The outcomes will be monitored by a Data and Safety Monitoring Committee, which will have the authority to stop or recommend modifications of the trial for safety concerns. Other clinical outcome variables and imaging variables will be recorded and analyzed in secondary and exploratory analyses. If an acceptable dose is identified, then that will be investigated in a subsequent randomized placebo-controlled trial.