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
Intervention: Aspirin; tinzaparin sodium; eptifibatide
Intervention description: 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.
Intervention MeSH terms: Aspirin; Tinzaparin; Heparin, Low-Molecular-Weight; Dalteparin; Eptifibatide
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Allocation: Non-Randomized
Intervention model: Single Group Assignment
Masking: None (Open Label)
Enrollment: 18.0
Sex: All
Minimum age: 18 Years
Maximum age: 85 Years
Healthy volunteers: No
Keywords: Alteplase; Recombinant tissue plasminogen activator; Reperfusion therapy; Magnetic Resonance Imaging; Clinical Trial; Tinzaparin; Eptifibatide; Ischemic Stroke

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.
    

Eligibility criteria:

        INCLUSION CRITERIA:

          1. Diagnosis of acute ischemic stroke with planned start of intravenous tPA. Acute
             ischemic stroke is defined as a measurable neurological deficit of sudden onset,
             presumed secondary to focal cerebral ischemia. Stroke onset will be defined as the
             time the patient was last known to be without the new clinical deficit. If the stroke
             started during sleep, stroke onset will be recorded as the time the patient was last
             known to be at baseline.

          2. Disabling neurological deficit attributable to acute ischemic stroke.

          3. NIHSS less than or equal to 21 for left hemisphere strokes, NIHSS less than or equal
             to 16 for others.

          4. Age 18-85 years, inclusive.

          5. Body weight greater than 50 kg.

             For MRI Arm only:

          6. Screening MRI diagnostic of focal cerebral ischemia corresponding to the clinical
             deficits. The MRI evaluation must involve echo planar diffusion weighted imaging,
             magnetic resonance angiography(MRA),and MRI perfusion. A normal appearing MRA with an
             appropriate perfusion deficit is eligible. An apparent stenosis or occlusion on MRA
             with normal appearing perfusion distally will not be eligible. Poor quality or
             uninterpretable MRA will not make patient ineligible. Patients who have a normal
             appearing diffusion weighted image (DWI) are eligible.

          7. Evidence on perfusion weighted image (PWI) MRI or a perfusion defect corresponding to
             the acute stroke syndrome. The PWI will be assessed by relative mean transit time
             (MTT) images obtained prior to the start of tPA therapy.

        EXCLUSION CRITERIA:

          1. Current participation in another study with an investigational drug or device within,
             prior participation in the present study, or planned participation in another
             therapeutic trial, prior to the final (day 30) assessment in this trial.

          2. Symptoms suggestive of subarachnoid hemorrhage, even if CT or MRI scan is negative for
             hemorrhage.

          3. Evidence of acute myocardial infarction defined as having at least two of the
             following three features: 1) Chest pain suggestive of cardiac ischemia; 2) EKG
             findings of ST elevation of more greater than 0.2 millivolts (mV) in 2 contiguous
             leads, new onset left bundle branch block, ST segment depression, or T-wave inversion;
             3) Elevated troponin I.

          4. Acute Pericarditis.

          5. Women known to be pregnant, lactating or having a positive or indeterminate pregnancy
             test.

          6. Patients who would refuse blood transfusions if medically indicated.

          7. Neurological deficit that has led to stupor or coma (NIHSS level of consciousness
             [item I a] score greater than or equal to 2).

          8. High clinical suspicion of septic embolus.

          9. Minor stroke with non-disabling deficit or rapidly improving neurological symptoms.

         10. Baseline NIHSS greater than 21 for left hemisphere stroke or greater than 16 for
             others.

         11. Evidence of acute or chronic ICH by head CT or MRI.

         12. CT or MRI evidence of non-vascular cause for the neurological symptoms.

         13. Signs of mass effect causing shift of midline structures on CT or MRI.

         14. Persistent hypertension with systolic BP greater than 185 mmHg or diastolic BP greater
             than 110 mmHg (mean of 3 consecutive arm cuff readings over 20-30 minutes), not
             controlled by antihypertensive therapy or requiring nitroprusside for control.

         15. Anticipated need for major surgery within 72 hours after start of study drugs, such as
             a carotid endarterectomy or hip fracture repair.

         16. Any intracranial surgery, intraspinal surgery, or serious head trauma (any head injury
             that required hospitalization) within the past 3 months.

         17. Stroke within the past 3 months.

         18. History of ICH at any time in the past.

         19. Major trauma at the time of stroke, such as a hip fracture.

         20. Blood glucose greater than 200 milligrams per diluent (mg/dl).

         21. Presence or history of intracranial neoplasm (except small meningiomas) or
             arteriovenous malformation.

         22. Intracranial aneurysm, unless surgically or endovascularly treated more than 3 months
             before.

         23. Seizure at the onset of stroke.

         24. Active internal bleeding.

         25. Major hemorrhage (requiring transfusion, surgery or hospitalization) in the past 21
             days.

         26. Major surgery, serious trauma, lumbar puncture, arterial puncture at a
             non-compressible site, or biopsy of a parenchymal organ in last 14 days. Major
             surgical procedures include but are not limited to the following: major thoracic or
             abdominopelvic surgery, neurosurgery, major limb surgery, carotid endarterectomy or
             other vascular surgery, and organ transplantation. For non-listed procedures, the
             operating surgeon should be consulted to assess the risk.

         27. Presumed or documented history of vasculitis.

         28. Known systemic bleeding or platelet disorder, e.g., von Willebrand's disease,
             hemophilia, idiopathic thrombocytopenia purpura (ITP),thrombotic thrombocytopenic
             purpura (TTP), others.

         29. History of heparin induced thrombocytopenia.

         30. Platelet count less than 100,000 cells/microliter.

         31. Congenital or acquired coagulopathy (e.g. , secondary to anticoagulants) causing
             either of the following:

               1. Activated partial thromboplastin time (aPTT) prolongation greater than 2 seconds
                  above the upper limit of normal for local laboratory, except if due to isolated
                  factor twelve (XII) deficiency.

               2. International normalized ratio (INR) greater than or equal to 1.4. Patients
                  receiving warfarin prior to entry are eligible provided INR is less than 1.4 and
                  warfarin can be safely discontinued for at least 48 hours.

         32. Life expectancy less than 3 months.

         33. Other serious illness, e.g., severe hepatic, cardiac, or renal failure; acute
             myocardial infarction; or complex disease that may confound treatment assessment.

         34. Severe renal failure: Serum creatinine greater than 4.0 mg/dL or dependency on renal
             dialysis.

         35. Aspartate aminotransferase (AST) or Alanine transaminase(ALT) greater than 3 times the
             upper limit of normal for the local laboratory.

         36. Treatment of the qualifying stroke with any thrombolytic, anti-thrombotic or
             glycoprotein inhibitor(GPIIbIIIa)outside of this protocol.

         37. Any administration of a thrombolytic drug in the prior 7 days.

         38. Treatment of the qualifying stroke with intravenous heparin unless aPTT prolongation
             is no greater than 2 seconds above the upper limit of normal for local laboratory
             prior to study drug initiation.

         39. Treatment of the qualifying stroke with a low molecular weight heparin or heparinoid.

         40. Known hypersensitivity to alteplase, aspirin, tinzaparin, eptifibatide, heparin,
             sulfites, benzyl alcohol, or pork products.

         41. Anticoagulation (evidenced by abnormal INR, aPTT, or platelet count) caused by herbal
             therapy.

         42. Known history of alcohol or illicit drug use (e.g. prior to study drug administration)

             FOR non-MRI arm only (items 43-44):

         43. Ischemic changes on screening CT of greater than approximately one third of the
             territory of the middle cerebral artery territory by qualitative assessment.

         44. Patients who were excluded by screening MRI, except for exclusions item 45
             (contraindication to MRI) and item 46 (PWI was not obtained or is uninterpretable) and
             item 51 (MRI not obtainable because it would have put the patient out of the 3 hour
             time window for tPA).

             FOR MRI arm only (items 45-51):

         45. Contraindication to MRI scan.

         46. PWI not obtained or uninterpretable.

         47. No MTT defect corresponding to acute stroke deficit.

         48. Satellite DWI hyperintensity with corresponding hyperintensity on T2 weighted image or
             FLAIR in a vascular territory different than the index stroke

         49. DWI abnormality larger than approximately one third of the territory of the middle
             cerebral artery territory by qualitative assessment.

         50. Evidence of multiple microbleeds on gradient echo MRI (GRE).

         51. Patient has a contraindication to gadolinium contrast agent: prior adverse reaction to
             gadolinium or estimated glomerular filtration rate(GFR) less than 60 milliliters per
             minute (mL/min).