Clinical trial NCT00061373
Conditions: Ischemic Stroke
Keywords: Alteplase Recombinant tissue plasminogen activator Reperfusion therapy Magnetic Resonance Imaging Clinical Trial Tinzaparin Eptifibatide Ischemic Stroke
Sponsor: National Institute of Neurological Disorders and Stroke (NINDS)
Start date: 2003-05-01; Completion date: 2011-07-01
Enrollment: 18 participants; Allocation: NON_RANDOMIZED; Intervention model: SINGLE_GROUP

Brief summary:
Ischemic stroke is caused by a blood clot that blocks the flow of blood to the brain and damages brain cells. The clot, or thrombus, is made up of platelets and fibrin. The medicine alteplase, also known as tPA , is the standard drug used to treat patients with acute ischemic stroke. tPA attacks the fibrin portion of the blood clot. While intravenous (iv) tPA alone is effective in treating the fibrin part of the clot approximately 30% of the time, adding other commercially available drugs such eptifibatide to treat other clot components may improve the effectiveness of iv tPA therapy.

This is a clinical trial to determine an acceptable dose of eptifibatide in combination with aspirin, the low molecular weight heparin tinzaparin, and standard iv tPA therapy for the treatment of acute ischemic stroke. Use of clinical and imaging based selection criteria are hypothesized to contribute to treatment safety by selecting patients at lower risk of intracerebral hemorrhage. Also,selection and evaluation of patients by magnetic resonance imaging (MRI) criteria will result in a different risk to benefit ratio than selecting patients without MRI criteria and will lead to a different acceptable dose.

Detailed description:
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.

Arms: arm 1: Patients are eligible for the MRI arm if all clinical and all MRI inclusion and exclusion criteria are met.

A single dose of aspirin 81 mg orally (or rectal dose equivalent), a single weight-based dose of subcutaneous tinzaparin sodium. Possible dose escalated iv eptifibatide. arm 2: Patients are eligible for the non-MRI arm if all clinical inclusion-exclusion criteria are met, if MRI is contraindicated or if MRI compromises iv tPA delivery within 3-hours of symptom onset.

A single dose of aspirin 81 mg orally (or rectal dose equivalent) and a single weight-based dose of subcutaneous tinzaparin sodium. Possible dose escalated iv eptifibatide.

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Interventions: intervention 1: Aspirin intervention 2: tinzaparin sodium intervention 3: eptifibatide
Intervention descriptions: intervention 1: A single 81 mg aspirin tablet orally (or rectal suppository equivalent dose) given as soon as possible after start of standard iv tPA and consent. intervention 2: A single weight-based dose of 80 anti-Xa International Units/kilogram (IU/kg)administered by subcutaneous (SQ) injection. intervention 3: Eptifibatide administered iv according to dose escalation group. The five dosing groups for eptifibatide are 0, 45 µg/kg bolus, 90 µg/kg bolus, 90 µg/kg bolus plus 0.25 µg/kg/min infusion for 24 hours, and 90 µg/kg bolus plus 0.5 µg/kg/min infusion for 24 hours.

Protocol documents: