ReoPro and Retavase to Restore Brain Blood Flow After Stroke
Condition: Cerebrovascular Accident
MeSH terms: Stroke
Study type: Interventional
Phase: Phase 2

Summary: 
      This study will evaluate the safety and effectiveness of two types of blood thinners,
      abciximab (ReoPro) and reteplase (Retavase) for restoring normal brain blood flow after
      ischemic stroke (stroke resulting from a blood clot in the brain).

      The only therapy approved by the Food and Drug Administration to treat ischemic stroke is the
      clot buster drug rt-PA. This treatment, however, is effective only if begun within 3 hours of
      onset of the stroke and most patients do not get to the hospital early enough to benefit from
      it. There is thus a pressing need to develop effective stroke treatments that can be
      initiated more than 3 hours after onset.

      Patients between 18 and 80 years of age who have experienced a mild or moderate acute stroke
      between 3 and 24 hours before starting study drugs may be eligible for this study. Candidates
      will be screened with a physical examination, blood tests and a magnetic resonance imaging
      (MRI) scan (if an MRI was not done during the stroke evaluation).

      All participants will receive ReoPro. Some will also receive Retavase, which may boost the
      effectiveness of ReoPro. Retavase is administered in a single dose through a needle in the
      vein over 2 minutes. ReoPro is infused into the vein over 12 hours. Patients will be
      monitored with physical examinations, blood tests, computed tomography (CT) scans, and three
      or four MRI scans of the brain to evaluate both the response to treatment and side effects of
      the drugs. An MRI scan will be done 24 hours, 5 days and 30 days after starting the study
      medication, and possibly during screening for this study.

      CT involves the use of specialized x-rays to obtain images of the brain. The patient lies
      still in the scanner for a short time while the X-ray images are formed. MRI uses a strong
      magnetic field and radio waves to demonstrate structural and chemical changes in tissue. MRI
      is more sensitive than x-ray in evaluating acute stroke. The patient lies on a table in a
      metal cylinder (the scanner) while the pictures are being taken. During part of the MRI, a
      medicine called gadolinium contrast is injected in a vein. This medicine brightens the
      images, creating better pictures of the blood flow.
    

Detailed description: 
      Objectives: This is a clinical trial to determine an acceptable dose of reteplase in
      combination with a fixed dose of abciximab for ischemic stroke 3-24 hours from onset.

      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, acute
      ischemic stroke of moderate severity (NIH Stroke Scale less than or equal to 16 and lesion
      volume on diffusion MRI less than approximately one third of the volume of the middle
      cerebral artery territory), positive MRI evidence of hypoperfusion corresponding to the acute
      stroke symptoms, no MRI evidence of chronic micro-hemorrhages, and no other clinical,
      radiological or laboratory features associated with 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 0 U, 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, in which data on both the
      response and toxicity will be used to determine the dose for subsequent patients, thereby
      minimizing exposure to either ineffective or toxic doses. Non-investigational 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 reperfusion by MRI 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 treated 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.
    

Intervention name(s): Abciximab (ReoPro) and Reteplase (Retavase)
Intervention type(s): Drug
Intervention MeSH terms: Reteplase; Abciximab
Primary purpose: Treatment
Keywords: Stroke; Abciximab; Reteplase; MRI; Cerebral Blood Flow