Study to Assess the Safety and Efficacy of THR-18 When Administered to Patients Suffering Acute Ischemic Stroke and Treated With Tissue Plasminogen Activator (tPA)
Study to Assess the Safety and Efficacy of THR-18 When Administered to Patients Suffering Acute Ischemic Stroke and Treated With Tissue Plasminogen Activator (tPA)
This will be a randomized, double-blind, placebo-controlled, multi-center, multi-national,
 escalating dose, pilot study comparing two doses of THR-18 to placebo when administered to
 patients suffering acute ischemic stroke and treated with Tissue Plasminogen Activator (tPA).

 The study hypothesis is that THR-18 will be safe and well tolerated in subjects suffering
 acute ischemic stroke and treated with Thrombolysis.
This will be a randomized, double-blind, placebo-controlled, multi-center, multi-national,
 escalating dose, pilot study comparing two doses of THR-18 (0.25 and 0.5 mg/kg) to placebo
 when administered to patients suffering acute ischemic stroke and treated with Tissue
 Plasminogen Activator (tPA).

 A total of 22 subjects suffering from acute ischemic stroke that are eligible for tPA
 treatment will be recruited into the study. Eligible for recruitment are patients with an
 entry National Institutes of Health Stroke Scale (NIHSS) score of 5-18 and a clinical
 syndrome that includes at least 1 of the following: language dysfunction, visual field defect
 or neglect (specifically, at least 1 point on NIHSS items 3 or 9 or 11). Alternatively,
 patients without at least 1 point on NIHSS items 3, 9 or 11 may be enrolled if routine
 diffusion-weighted magnetic resonance imaging (MRI) or computed tomography perfusion scan
 (CT) indicates that the acute stroke involves the cerebral cortex, and as long as the overall
 acute neurological deficit is within the range of 5-18 NIHSS points.

 Stroke onset will be defined as the time the patient was last known to be without a new
 clinical deficit. Patients whose symptoms started more than 3 hours before presentation are
 not eligible for the study. If the stroke started during sleep, stroke onset will be recorded
 as the time the patient was last known to be normal.

 Patients will be recruited after obtaining informed consent. Female subjects of childbearing
 potential (less than 2 years' postmenopausal or not surgically sterilized) will have a urine
 pregnancy test at baseline and will be required to use adequate and effective birth control
 measures for the duration of the trial. Effective birth control measures include hormonal
 contraception, a barrier method such as a diaphragm, intrauterine device (IUD) and/or condom
 with spermicide (IUD, diaphragm, condoms alone or the rhythm method are not considered
 reliable methods).

 Patients will be randomized to receive either 0.25 or 0.5 mg/kg of THR-18 or placebo in an
 escalating manner. tPA should be administered as 0.9 mg/kg (10% of the total dose as an Intra
 Venous(IV) bolus and the reminder infused IV over 60 minutes). THR-18 bolus should be given
 immediately prior to the tPA bolus, and the 60 min infusion of both THR-18 and tPA will be
 done in parallel.
Inclusion Criteria:

 1. Male or female.

 2. Diagnosis of acute ischemic stroke onset less than 3 hours prior to the planned start
 of intravenous Tissue Plasminogen Activator (tPA).

 3. Have suffered an acute hemispheric ischemic stroke, defined as acute, focal,
 neurological deficit(s) and secondary to a presumed vascular event.

 4. Age 18-85 years both inclusive.

 5. Able to sign informed consent.

 Exclusion Criteria:

 1. Participation in another study with an investigational drug or device within 30 days
 of study entry, prior participation in the present study, or planned participation in
 another therapeutic trial, prior to the final (day 30) assessment in this trial.

 2. Time interval since stroke onset of less than 3 hours is impossible to determine with
 high degree of confidence.

 3. Symptoms suggestive of subarachnoid hemorrhage, even if computed tomography perfusion
 scan(CT)or magnetic resonance imaging (MRI) scan is negative for hemorrhage.

 4. Evidence of acute myocardial infarction.

 5. Acute Pericarditis

 6. Patients who would refuse blood transfusions if medically indicated.

 7. Neurological deficit that has led to stupor or coma (National Institutes of Health
 Stroke Scale (NIHSS) level of consciousness 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 18 for left hemisphere stroke or greater than 15 for
 others.

 11. Evidence of acute or chronic Intra cranial Hemorrhage (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 not controlled by antihypertensive therapy or requiring nitroprusside
 for control.

 15. Blood glucose greater than 200 mg/dl.

 16. Anticipated need for major surgery within 72 hours after start of study drugs, e.g.,
 carotid endarterectomy, hip fracture repair.

 17. Any intracranial surgery, intraspinal surgery, or serious head trauma (any head injury
 that required hospitalization) within the past 3 months.

 18. Have suffered a stroke within 90 days of the screening/baseline assessments that is
 either diagnostically confirmed or assumed to be in the same cerebral territory as is
 the current acute stroke.

 19. History of ICH at any time in the past.

 20. Major trauma at the time of stroke, e.g., hip fracture.

 21. Presence or history of intracranial neoplasm (except small meninigiomas) or
 arteriovenous malformation.

 22. Intracranial aneurysm, unless surgically or endovascularly treated more than 3 months
 before the current acute stroke.

 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, ITP, TTP, others.

 29. Platelet counts less than 100,000 cells/micro L.

 30. Congenital or acquired coagulopathy (e.g., secondary to anticoagulants).

 31. Life expectancy less than 3 months.

 32. Severe renal failure.

 33. AST or ALT greater than 3 times the upper limit of normal for the local laboratory.

 34. Any administration of a thrombolytic drug in the prior 7 days.

 35. 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.

 36. Treatment of the qualifying stroke with a low molecular weight heparin or heparinoid.

 37. Known hypersensitivity to tPA.

 38. Anticoagulation (evidenced by abnormal INR, aPTT, or platelet count) caused by herbal
 therapy.

 39. Ischemic changes on screening CT of greater than approximately one third of the
 territory of the middle cerebral artery territory by qualitative assessment.

 40. Female of childbearing potential (less than 2 years' postmenopausal or not surgically
 sterilized) who is not willing to use adequate and effective birth control measures
 for the duration of the trial. Effective birth control measures include hormonal
 contraception, a barrier method such as a diaphragm, intrauterine device (IUD) and/or
 condom with spermicide (IUD, diaphragm, condoms alone or the rhythm method are not
 considered reliable methods).

 41. Have a positive urine pregnancy test at screening/baseline or be a lactating female.

 42. Any condition that in the investigator's judgement precludes participation in the
 study.