Study of Aspirin and TPA in Acute Ischemic Stroke

NCT00417898 | Withdrawn Phase 1

• 1 other identifier: ATPA-HMO-CTIL
• Study Type: interventional
• Target: N/A
• Locations: 1 country
• Sites: 1

Brief Summary

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.

Conditions

Acute Ischemic Stroke

Keywords

Stroke; Cerebral Ischemia; Tissue Plasminogen Activator; Aspirin; Human; Cerebral Reperfusion

Outcome Measures

Primary Outcomes (2)

• PRIMARY ENDPOINT

• Safety (mortality, symptomatic ICH, asymptomatic ICH).

Secondary Outcomes (3)

• 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.

Interventions

Aspirin DRUG

Eligibility Criteria

• Age: 18 Years - 85 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.
• Disabling neurological deficit attributable to acute ischemic stroke in the middle cerebral artery territory.
• NIHSS less than or equal to 18 for left hemisphere strokes, NIHSS less than or equal to 16 for others.
• Evidence of MCA occlusion (stem or branch) prior to drug administration by TCD, CTA or MRA.
• Age 18-85 years, inclusive.
• Able to sign informed consent.
• For MRI Arm only:
• 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.
• 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.

You may not qualify if:

• Patients will be excluded from study participation for any of the following reasons:
• 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.
• Absence of acoustic window to insonate the MCA on the involved side.
• Time interval since stroke onset of less than 3 hours is impossible to determine with high degree of confidence.
• Symptoms suggestive of subarachnoid hemorrhage, even if CT or MRI scan is negative for hemorrhage.
• 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.
• Acute Pericarditis.
• Women known to be pregnant, lactating or having a positive or indeterminate pregnancy test.
• Neurological deficit that has led to stupor or coma (NIHSS level of consciousness \[item I a\] score greater than or equal to 2).
• High clinical suspicion of septic embolus.
• Minor stroke with non-disabling deficit or rapidly improving neurological symptoms.
• Baseline NIHSS greater than 18 for left hemisphere stroke or greater than 16 for others.
• Evidence of acute or chronic ICH by head CT or MRI.
• CT or MRI evidence of non-vascular cause for the neurological symptoms.
• Signs of mass effect causing shift of midline structures on CT or MRI.

Sponsors & Collaborators

• Hadassah Medical Organization: lead

Study Sites (1)

Hadassah University Medical Center

Jerusalem, 91120, Israel

Location

MeSH Terms

Conditions

Ischemic Stroke; Stroke; Brain Ischemia

Interventions

Aspirin

Condition Hierarchy (Ancestors)

Cerebrovascular Disorders; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Vascular Diseases; Cardiovascular Diseases

Intervention Hierarchy (Ancestors)

Salicylates; Hydroxybenzoates; Phenols; Benzene Derivatives; Hydrocarbons, Aromatic; Hydrocarbons, Cyclic; Hydrocarbons; Organic Chemicals

Study Officials

• Ronen R Leker, MD

  Hadassah Medical Organization

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER

Study Record Dates

• First Submitted: January 2, 2007
• First Posted: January 4, 2007
• Study Start: March 1, 2007
• Study Completion: December 1, 2012
• Last Updated: September 2, 2016

Record last verified: 2007-01

Locations

IL (1)