A Study of Intravenous Thrombolysis With Alteplase in MRI-Selected Patients

Study Overview
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Brief Summary
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This study was jointly developed and is jointly led by investigators at Massachusetts General Hospital and the intramural division of NINDS. We are doing this research study to find out if Activase ® (also called alteplase or rt-PA) can safely be given to people with an acute ischemic stroke when their stroke onset was not witnessed making them ineligible for standard thrombolytic (clot busting) therapy. We also want to find out if rt-PA can help people recover better from their stroke. The purpose of this study is to: 1) see if it is safe to give intravenous (IV) rt-PA to people with unwitnessed stroke but with MRI evidence of early ischemic stroke, 2) see if rt-PA is effective if given to people who are selected for treatment based on MRI evidence of an early stroke, and 3) get information about this new MRI diagnostic methods for guiding stroke treatment.

Detailed Description
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This study was jointly developed and is jointly led by Massachusetts General Hospital and the NINDS. This is a multi-center, open-label, Phase IIa safety study in adult acute ischemic stroke patients to determine if it is safe to extend intravenous thrombolytic treatment to subjects who are evaluated within 24 hours from last known well (stroke onset) and eligible to receive thrombolytic treatment within 4.5 hours from symptom discovery with the assistance of an MRI-based witness when no human witness of stroke onset is available. The study is designed to investigate the safety in using standard diagnostic MRI in selecting patients for thrombolytic therapy when the last known well time places the patient beyond the current IV thrombolytic time-window.

Official Title
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MR WITNESS: A Phase IIa Safety Study of Intravenous Thrombolysis With Alteplase in MRI-Selected Patients

Conditions
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Acute Stroke

Intervention / Treatment
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* Drug: IV rt-PA


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age, 18 to 85 years inclusive Brain MRI findings consistent with early stroke onset Clinical diagnosis of acute ischemic stroke with disabling neurological deficit Stroke symptoms present for at least 30 minutes with no significant improvement before treatment Be last known well (without stroke symptoms) within 24 hours of triage Be able to receive IV rt-PA within 4.5 hours from the time the symptoms were discovered. MRI diagnostic of acute ischemic stroke and consistent with clinical syndrome Time between completion of qualifying MRI studies to treatment initiation ≤ 1 hour Exclusion Criteria: History of intracranial hemorrhage Symptoms rapidly improving or only minor before start of study drug. Severe stroke as assessed clinically (e.g., NIHSS score >25) or by appropriate imaging techniques (lesion volume > one-third of MCA by visual inspection or >100 cm3 using the ellipsoid estimation formula of ABC/2) Stroke or serious head trauma within the previous 3 months Administration of heparin within the 48 hours preceding the onset of stroke, with an activated partial-thromboplastin time at presentation exceeding the upper limit of the normal range Platelet count of less than 100,000 per cubic millimeter Uncontrolled hypertension defined as systolic blood pressure > 185 mm Hg or diastolic blood pressure > 110 mm Hg that cannot be controlled except with continuous parenteral antihypertensive medication Blood glucose less than 50 mg per deciliter or greater than 400 mg per deciliter Symptoms suggestive of subarachnoid hemorrhage, even if CT/MRI scan was normal Oral anticoagulant treatment, regardless of INR. Major surgery or severe trauma within the previous 3 months Other major disorders associated with an increased risk of bleeding Eligible for rt-PA therapy per institutional protocol as part of routine clinical practice Non-ischemic etiology demonstrated by neuroimaging Neuroimaging (CT or gradient echo MRI) evidence of acute or chronic ICH (non-microbleed) Presence of 10 or more microbleeds on GRE (suggestive of amyloid angiopathy) Any contraindication for MRI, e.g. presence of a pacemaker, ferromagnetic aneurysm clip, etc, pre-menopausal women with a positive pregnancy blood test, or severe claustrophobia. Poor quality MRI- images are not interpretable In the opinion of the investigator, the patient is not an appropriate candidate for IV rt-PA Women known to be pregnant, lactating or having a positive or indeterminate pregnancy test.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 85 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: IV rt-PA<br>open-label | Drug: IV rt-PA<br>* open-label<br>* Other names: Alteplase, Activase;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Subjects With Symptomatic Intracerebral Hemorrhage | Safety of IV rt-PA as evident by rates of symptomatic ICH defined by an increase of 4 points or more on the NIHSS . | Within 7 days from tPA administration. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Subjects With Symptomatic Cerebral Edema | Safety of IV rt-PA as evident by rates of symptomatic cerebral edema defined as brain edema with mass effect as the predominant cause of clinical deterioration. | Within 96 hours of tPA administration | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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acute stroke, IV rt-PA, Activase, Alteplase