Clinical Trial: Adjunctive Drug Treatment for Ischemic Stroke Patients

Official Title: Reperfusion of Stroke Safety Study Imaging Evaluation-2 (ROSIE 2) Adjunctive Treatment to Standard Alteplase Therapy of Ischemic Stroke


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Sponsored by:	National Institute of Neurological Disorders and Stroke (NINDS)
Information provided by:	Warren G Magnuson Clinical Center (CC)

Condition	Treatment or Intervention	Phase
Cerebrovascular Accident	Drug: Eptifibatide in combinatin w Aspirin, Tinzaparin sodium	Phase II

Objectives: This is a clinical trial to determine an acceptable dose of eptifibatide in combination with aspirin, the low molecular weight heparin tinzaparin, and standard alteplase therapy in ischemic stroke.

Study Population: All patients will be eligible for this study if they are eligible for and will be receiving standard intravenous alteplase initiated less than 3 hours from stroke onset. Patients will be selected by criteria to minimize likelihood of toxicity and maximize likehood of response. These criteria include age 18-80 years old, acute ischemic stroke of moderate severity (NIH Stroke Scale 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 hypoerfusion 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 intravenous alteplase therapy plus 81 mg aspirin orally (or 120 mg rectally) and 80 anti Xa IU/kg tinzaparin subcutaneously. 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 should begin as early as possible but no later than the end of the alteplase infusion. Two independent arms - an MRI and a non-MRI arm - will be studied, and dose escalation will proceed independently in either arm. Non-investigational patient management will be standardized across all patients according to the NIH Stroke Center Clinical Care Pathway.

A maximum of 100 patients in each arm will be studied, a maximum of 15 patients treated at each dose level. The outcomes will be monitored by a Data and Safety Monitoring Committee (DSMC), which will have the authority to stop or recommended modifications of the trial for safety concerns after each SAE. Dose escalation from one dose level to the next will be contingent on DSMC 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 serious adverse event 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 will be reperfusion by MRI (at both 2 hours and 24 hours after start of therapy) for the MRI arm of the trial, 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 is identified, then that will be investigated in a subsequent randomized placebo-controlled trial.

INCLUSION CRITERIA:
Patients must meet all of the inclusion criteria.
1. Diagnosis of acute ischemic stroke with onset less than 3 hours prior to the planned start of intravenous alterplase. 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. Patients whose deficits have worsened in the last 3 hours are not eligible if their first symptoms started more than 3 hours before. If the stroke started during sleep, stroke onset will be recorded as the time the patient was last known to be intact.
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 18-80 years, inclusive.
5. Body weight greater than 50 kg.
For MRI Arm only:
6. Screening MRI diagnostic of acute ischemic stroke corresponding to the clinical deficits. The MRI evaluation must involve echo planar diffusion weighted imaging, 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 DWI are eligible.
7. Evidence of 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 alteplase therapy.
EXCLUSION CRITERIA:
Patients will be excluded from study participation for any of the following reasons:
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. 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 CT or MRI scan is negative for hemorrhage.
4. 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 mV in 2 contiguous leads, new onset left bundle branch block, ST segment depression, or T-wave inversion; 3) Elevated troponin I.
5. Acute Pericarditis.
6. Women known to be pregnant, lactating or having a positive or indeterminate pregnancy test.
7. Patients who would refuse blood transfusions if medically indicated.
8. Neurological deficit that has led to stupor or coma (NIHSS level of consciousness [item I a] score greater than or equal to 2).
9. High clinical suspicion of septic embolus.
10. Minor stroke with non-disabling deficit or rapidly improving neurological symptoms.
11. Baseline NIHSS greater than 21 for left hemisphere stroke or greater than 16 for others.
12. Evidence of acute or chronic ICH by head CT or MRI.
13. CT or MRI evidence of non-vascular cause for the neurological symptoms.
14. Signs of mass effect causing shift of midline structures on CT or MRI.
15. 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.
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. Stroke within the past 3 months.
19. History of ICH at any time in the past.
20. Major trauma at the time of stroke, e.g., hip fracture.
21. Blood glucose greater than 200 mg/dl or history of diabetes mellitus.
22. Presence or history of intracranial neoplasm (except small meninigiomas) or arteriovenous malformation.
23. Intracranial aneurysm, unless surgically or endovascularly treated more than 3 months before.
24. Seizure at the onset of stroke.
25. Active internal bleeding.
26. Major hemorrhage (requiring transfusion, surgery or hospitalization) in the past 21 days.
27. 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.
28. Presumed or documented history of vasculitis.
29. Known systemic bleeding or platelet disorder, e.g., von Willebrand's disease, hemophilia, ITP, TTP, others.
30. History of heparin induced thrombocytopenia.
31. Platelet count less than 100,000 cells/micro L.
32. Congenital or acquired coagulopathy (e.g. , secondary to anticoagulants) causing either of the following:
a. 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 XII deficiency.
b. 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.
33. Life expectancy less than 3 months.
34. Other serious illness, e.g., severe hepatic, cardiac, or renal failure; acute myocardial infarction; or complex disease that may confound treatment assessment.
35. Severe renal failure: Serum creatinine greater than 4.0 mg/dL or dependency on renal dialysis.
36. AST or ALT greater than 3 times the upper limit of normal for the local laboratory.
37. Treatment of the qualifying stroke with any thrombolytic, anti-thrombotic or GPIIbIIIa inhibitor outside of this protocol.
38. Any administration of a thrombolytic drug in the prior 7 days.
39. 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.
40. Treatment of the qualifying stroke with a low molecular weight heparin or heparinoid.
41. Known hypersensitivity to alteplase, aspirin, tinzaparin, eptifibatide, heparin, sulfites, benzyl alcohol, or pork products.
42. Anticoagulation (evidenced by PT, aPTT, or platelet count) caused by herbal therapy.
FOR non-MRI arm only (#41-42):
43. Ischemic changes on screening CT or 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 #43 (contraindication to MRI) and #44 (PWI was not obtained or is uninterpretable) and #51 (MRI not obtainable because it would have put the patient out of the 3 hour time window for alteplase).
FOR MRI arm only (#43-49):
45. Contraindication to MRI scan.
46. PWI not obtained or uninterpretable.
47. No MTT defect corresponding to acute stroke deficit.
48. DWI abnormality larger than approximately one third of the territory of the middle cerebral artery territory by qualitative assessment.
49. Satellite DWI hyperintensity with corresponding hyperintensity on T2 weighted image or FLAIR in a vascular territory different than the index stroke (this is evidence of a new ischemic lesion greater than 3 hours in duration).
50. Evidence of microbleed on gradient echo MRI (GRE).
51. MRI not obtained because it would have put the patient out of the 3 hour time window for alteplase.