Combination Anti-Platelet and Anti-Coagulation Treatment After Lysis of Ischemic Stroke Trial (CATALIST)

Study Population: All acute ischemic stroke patients treated with standard iv tPA therapy within 3 hours from stroke onset will be considered for study participation. Patient will be selected by criteria to minimize likelihood of toxicity and maximize likelihood of response. These criteria include age 18-85 years old acute ischemic stroke of moderate severity measured using the National Institutes of Health Stroke Scale Stroke Scale (NIHSS) less than 22 for left hemisphere strokes, less than 17 for others) and no other clinical, radiological or laboratory features associated with increased risk of hemorrhage of thrombolytic therapy. In the MRI arm of the trial, patients must have positive MRI evidence of hypoperfusion corresponding to the acute stroke symptoms and no MRI evidence of chronic micro-hemorrhages. Design: This is an open-label, dose escalation, safety and proof of principle clinical trial. All patients will receive iv tPA therapy plus 81 mg aspirin orally (or 150 mg rectally) and 80 anti Xa IU/kg tinzaparin subcutaneously and some patients will receive iv eptifibatide. Intravenous eptifibatide will be given in a dose-escalating manner. The five dosing groups for eptifibatide are 0, 45 micro g/kg bolus, 90 micro g/kg bolus, 90 micro g/kg bolus plus 0.25 micro g/kg/min infusion for 24 hours, and 90 mg/kg bolus plus 0.5 micro g/kg/min infusion for 24 hours. Investigational therapy is to begin as early as possible but no later than 6 hours after the onset of the patient's symptoms. Two arms - an MRI and a non-MRI arm - will receive identical drug regimes,and dose escalation will proceed independently in either arm. A maximum of 100 patients in each arm will be studied, a minimum of 15 patients treated at each dose level. The outcomes will be monitored by a Data and Safety Monitoring Board (DSMB). The DSMB will have the authority to stop or recommend modifications of the trial for safety concerns throughout the trial and after any occurrence of severe adverse events (SAE). Dose escalation from one dose level to the next will be contingent on DSMB approval. Outcome Measures: The primary safety endpoint for determination of toxicity will be any one of the following: symptomatic intracranial hemorrhage (ICH), major systemic hemorrhage, or other SAE related to study drug administration, within 72 hours from start of therapy. Adverse events will be monitored for 30 days. The primary efficacy endpoint for response in the MRI arm will be reperfusion as measured by perfusion weighted imaging (PWI) at both 2 hours and 24 hours after start of therapy and substantial clinical recovery at 24 hours for the non-MRI arm. Clinical outcome variables and imaging variables will be recorded and analyzed in secondary and exploratory analyses. If an acceptable dose of eptifibatide is identified, that dose of eptifibatide will be investigated in a subsequent randomized placebo-controlled trial. MRI and CT are used as radiological measures of brain hemorrhage. The NIH Stroke Scale (NIHSS) is used to measure neurological worsening or recovery. The NIHSS is a 15-item neurologic examination stroke scale used to evaluate the effect of acute stroke on the levels of consciousness, language, neglect, visual-field loss, extra ocular movement, motor strength, ataxia, dysarthria, and sensory loss. A trained observer rates the patient's ability to answer questions and perform activities. Ratings for each of the 15 items are scored. Patients who have a score of 0 are considered to have "normal" examination. Patients with a score of 40 have the most severe stroke symptoms.