Study of Aspirin and TPA in Acute Ischemic Stroke

The recruitment status of this study is unknown because the information has not been verified recently.
Verified January 2007 by Hadassah Medical Organization.
Recruitment status was  Not yet recruiting
Sponsor:
Information provided by:
Hadassah Medical Organization
ClinicalTrials.gov Identifier:
NCT00417898
First received: January 2, 2007
Last updated: January 3, 2007
Last verified: January 2007
  Purpose

This study will determine the safety of 500mg of aspirin added to IV TPA at standard doses to prevent re-occlusion of cerebral vessels after successful reperfusion. In ischemic stroke brain arteries are occluded either by an embolus originating in the heart or large vessels leading to the brain or by a process of acute thrombosis of the cerebral arteries over a ruptured atherosclerotic plaque. Rupture of the plaque exposes thrombogenic elements within the plaque and leads to accumulation and activation of platelets and induction of the clotting cascade eventually leading to acute thrombosis and occlusion of the artery. TPA is currently approved by the Food and Drug Administration to treat heart and brain problems caused by blockage of arteries. It activates plasminogen and leads to disintegration of the thrombus/embolus. It is effective only if begun within 3 to 4.5 hours of onset of the stroke because of potential deleterious side effects including life threatening symptomatic intracranial hemorrhage (sICH) when the drug is administered outside of this time window.

Reperfusion of the ischemic brain (i.e. timely opening of the occluded artery) with TPA is associated with improved outcome. However, in about 33% of patients that have successfully reperfused after TPA the artery re-occludes within the first few hours resulting in worsening neurological symptoms and worse functional outcome. This re-occlusion is speculated to result from re-thrombosis over an existing ruptured atherosclerotic plaque. This is explained by the relatively short half life of TPA leaving the exposed ruptured plaque intact which leads to re-activation of platelets and clotting factors and re-thrombosis. Thus, we hypothesize that the addition of an antiplatelet agent to TPA would result in lower rates of re-occlusion after AIS. The FDA approved TPA for patients with AIS but discouraged the concomitant use of anti-platelet or anti-thrombotic drugs for the first 24hours after administration of TPA because of concerns that such therapy may result in increased rates of intracerebral hemorrhage. Aspirin is a well known platelet anti-aggregant that works by inhibition of cycloxygenase 1 and reduction in thromboxane A levels. It has a rapid onset of action and additional potential beneficial anti-inflammatory effects in patients with AIS. The international stroke study showed that acute treatment of stroke patients with 500mg of aspirin is safe and feasible and results in better outcome. Furthermore, the drug was safe in these circumstances with an ICH rate of only .

Therefore, the purpose of this clinical trial is to examine the safety and efficacy of the combination of aspirin with rt-TPA in patients with AIS.

Patients between 18 and 80 years of age who have had a mild or moderate acute stroke involving the middle cerebral artery territory up to 4.5 hours before starting study drugs may be eligible for this study. Candidates will be screened with a medical history and physical examination, blood tests, rating of neurological deficits such as cognition deficits or problems walking that resulted from the stroke, and a computed tomography (CT) or a magnetic resonance (MRI) scan of the head. CT involves the use of specialized X-rays and MRI involves a magnetic field to obtain images of the brain. The patient lies on a table that is moved into a cylindrical machine (the scanner) for the imaging study, which usually takes about 5 to 10 minutes.

All participants will receive 0.9mg/kg of TPA. The drug is infused into the vein over 1hour with 10% of the total dose given as a bolus. Half of the patients will also receive 500mg of aspirin (one tablet P.O) which may reduce the likelihood of arterial re-occlusion. And possibly also increase the effectiveness of TPA in opening the blocked blood vessel. Patients will be monitored daily until discharge from the hospital, or until day 5, whichever is earlier. Assessments will include physical examinations, blood tests to examine factors involved in blood clotting, and transcranial Doppler (TCD) to evaluate the patency rate achieved after treatment. MRI or CT scans will be performed at 5 days (or sooner as needed) to evaluate both the response to treatment and drug side effects. Patients will return for a follow-up examination and MRI/CT scan 30 days after treatment.


Condition Intervention Phase
Acute Ischemic Stroke
Drug: Aspirin
Phase 1

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Parallel Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: Phase 1 Study to Assess the Safety of 500mg of Aspirin Added to IV TPA at Standard Doses to Prevent re-Occlusion of Cerebral Vessels After Successful Reperfusion.

Resource links provided by NLM:


Further study details as provided by Hadassah Medical Organization:

Primary Outcome Measures:
  • PRIMARY ENDPOINT
  • Safety (mortality, symptomatic ICH, asymptomatic ICH).

Secondary Outcome Measures:
  • Proportion of patients achieving excellent functional outcome as determined by a modified Rankin score (mRS) < 2 and Barthel index (BI) > 85 obtained at 3 months after stroke onset.
  • Good neurological outcome as assessed by NIH stroke scale score at discharge < 5 or showing improvement of at least 8 points from the initial stroke score.
  • Good neurological outcome as assessed by NIH stroke scale score at 3 months < 5 or showing improvement of at least 8 points from the initial stroke score.

Estimated Enrollment: 40
Study Start Date: March 2007
Estimated Study Completion Date: December 2012
  Show Detailed Description

  Eligibility

Ages Eligible for Study:   18 Years to 85 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

Patients must meet all of the inclusion criteria.

  1. Diagnosis of acute ischemic stroke with onset less than 4.5 hours prior to the planned start of intravenous alteplase. 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 4.5 hours are not eligible if their first symptoms started more than 4.5 hours before. 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 in the middle cerebral artery territory.
  3. NIHSS less than or equal to 18 for left hemisphere strokes, NIHSS less than or equal to 16 for others.
  4. Evidence of MCA occlusion (stem or branch) prior to drug administration by TCD, CTA or MRA.
  5. Age 18-85 years, inclusive.
  6. Able to sign informed consent.

    For MRI Arm only:

  7. Screening MRI diagnostic of focal cerebral ischemia 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.
  8. Evidence on 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 rt-TPA 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. Absence of acoustic window to insonate the MCA on the involved side.
  3. Time interval since stroke onset of less than 3 hours is impossible to determine with high degree of confidence.
  4. Symptoms suggestive of subarachnoid hemorrhage, even if CT or MRI scan is negative for hemorrhage.
  5. 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.
  6. Acute Pericarditis.
  7. Women known to be pregnant, lactating or having a positive or indeterminate pregnancy test.
  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 18 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.
  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. Platelet counts less than 100,000 cells/micro L.
  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 XII deficiency.
    2. 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. AST or 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 GPIIbIIIa inhibitor 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 TPA.
  41. Anticoagulation (evidenced by abnormal INR, aPTT, or platelet count) caused by herbal therapy.

    FOR non-MRI arm only (#42-43):

  42. Ischemic changes on screening CT of greater than approximately one third of the territory of the middle cerebral artery territory by qualitative assessment.
  43. Patients who were excluded by screening MRI, except for exclusions #45 (contraindication to MRI) and #46 (PWI was not obtained or is uninterpretable) and #50 (MRI not obtainable because it would have put the patient out of the 3 hour time window for alteplase).

    FOR MRI arm only (#44-51):

  44. Contraindication to MRI scan.
  45. PWI not obtained or uninterpretable.
  46. No MTT defect corresponding to acute stroke deficit.
  47. DWI abnormality larger than approximately one third of the territory of the middle cerebral artery territory by qualitative assessment.
  48. 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).
  49. Evidence of multiple microbleeds on gradient echo MRI (GRE).
  50. MRI not obtained because it would have put the patient out of the 3 hour time window for alteplase.
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT00417898

Contacts
Contact: Ronen R Leker, MD 011-972-2-6776192 leker@cc.huji.ac.il
Contact: Tamir Ben Hur, MD, PhD 011-972-2-6777741 tamir@hadassah.org.il

Locations
Israel
Hadassah University Medical Center Not yet recruiting
Jerusalem, Israel, 91120
Contact: Arik Tzukert, DMD    : 00 972 2 6776095    arik@hadassah.org.il   
Contact: Hadas Lemberg, PhD    : 00 972 2 6777572    lhadas@hadassah.org.il   
Sponsors and Collaborators
Hadassah Medical Organization
Investigators
Principal Investigator: Ronen R Leker, MD Hadassah Medical Organization
  More Information

No publications provided

ClinicalTrials.gov Identifier: NCT00417898     History of Changes
Other Study ID Numbers: ATPA-HMO-CTIL
Study First Received: January 2, 2007
Last Updated: January 3, 2007
Health Authority: Israel: Israeli Health Ministry Pharmaceutical Administration

Keywords provided by Hadassah Medical Organization:
Stroke
Cerebral Ischemia
Tissue Plasminogen Activator
Aspirin
Human
Cerebral Reperfusion

Additional relevant MeSH terms:
Cerebral Infarction
Ischemia
Stroke
Brain Diseases
Brain Infarction
Brain Ischemia
Cardiovascular Diseases
Central Nervous System Diseases
Cerebrovascular Disorders
Nervous System Diseases
Pathologic Processes
Vascular Diseases
Aspirin
Analgesics
Analgesics, Non-Narcotic
Anti-Inflammatory Agents
Anti-Inflammatory Agents, Non-Steroidal
Antipyretics
Antirheumatic Agents
Cardiovascular Agents
Central Nervous System Agents
Cyclooxygenase Inhibitors
Enzyme Inhibitors
Fibrin Modulating Agents
Fibrinolytic Agents
Hematologic Agents
Molecular Mechanisms of Pharmacological Action
Peripheral Nervous System Agents
Pharmacologic Actions
Physiological Effects of Drugs

ClinicalTrials.gov processed this record on October 23, 2014