Combination Anti-Platelet and Anti-Coagulation Treatment After Lysis of Ischemic Stroke Trial (CATALIST)
Condition: Ischemic Stroke
MeSH terms: Stroke; Ischemic Stroke; Cerebral Infarction; Ischemia
Study type: Interventional
Phase: Phase 2

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.
    

Intervention name(s): Aspirin; tinzaparin sodium; eptifibatide
Intervention type(s): Drug; Drug; Drug
Intervention description(s): 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.; A single weight-based dose of 80 anti-Xa International Units/kilogram (IU/kg)administered by subcutaneous (SQ) injection.; 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.
Other intervention name(s): Innohep (registered trademark); Integrilin (registered trademark)
Intervention MeSH terms: Aspirin; Tinzaparin; Heparin, Low-Molecular-Weight; Dalteparin; Eptifibatide
Allocation: Non-Randomized
Intervention model: Single Group Assignment
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: Alteplase; Recombinant tissue plasminogen activator; Reperfusion therapy; Magnetic Resonance Imaging; Clinical Trial; Tinzaparin; Eptifibatide; Ischemic Stroke