Intravenous Thrombolysis Plus Hypothermia for Acute Treatment of Ischemic Stroke

Study Overview
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Brief Summary
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The purpose of this trial is to evaluate if it is safe to use tissue plasminogen activator (tPA) within 6 hours of stroke onset when combined with hypothermia.

Detailed Description
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A stroke is usually caused by a blockage in one of the arteries that carries blood to the brain. Research has shown that tissue plasminogen activator (tPA)-a naturally occurring protein that opens blocked arteries by dissolving blood clots-activates the body's ability to dissolve recently formed blood clots and reduces or prevents the brain damage caused by a stroke. The Food and Drug Administration (FDA) has approved the use of tPA for people having a stroke when taken within 3 hours of stroke onset, but not for those who arrive at the hospital more than 3 hours after stroke onset. Researchers believe that a lower body temperature (hypothermia) may be beneficial while a stroke is happening because hypothermia may prevent further brain injury, or may make the stroke less damaging. In particular, hypothermia may make it possible to use tPA later than 3 hours after a stroke begins. This study will determine if it is safe to use tPA within 6 hours of the start of a stroke when combined with hypothermia. Patients will receive a standard stroke evaluation, which includes blood tests, a computed tomography (CT) scan, complete physical and neurological examinations, and an electrocardiogram (EKG) to determine eligibility for the study. Participants will be randomly assigned to a study group based on when their stroke began. Those who arrive at the hospital less than 3 hours from stroke onset will receive tPA alone or tPA with cooling (hypothermia). Those who arrive at the hospital 3 to 6 hours after stroke onset will be assigned to 1 of 4 groups-receiving either tPA alone, tPA with cooling, cooling alone, or standard medical care. Length of participation (including observation after the patient leaves the hospital) is 90 days. This study is part of the Specialized Program of Translational Research in Acute Stroke (SPOTRIAS), which allows researchers to enhance and initiate translational research that ultimately will benefit stroke patients by treating more patients in less than 2 hours, and finding ways to treat additional patients later.

Official Title
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Phase 1 Study of Intravenous Thrombolysis Plus Hypothermia for Acute Treatment of Ischemic Stroke

Conditions
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Stroke

Intervention / Treatment
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* Procedure: hypothermia
* Drug: tissue plasminogen activator


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age 18 to 80 All eligibility criteria for t-PA administration for acute ischemic stroke as outlined by the NINDS tPA Guidelines are met with the exception of time from onset Stroke onset within 6 hours prior to planned start of tPA Any subtype of ischemic stroke with NIHSS < 7 at the time hypothermia begins Exclusion Criteria: Etiology other than ischemic stroke Item 1a on NIHSS>1 at the time of enrollment Symptoms resolving or NIHSS < 7 at the time hypothermia begins Contraindications to hypothermia, such as patients with known hematologic dyscrasias which affect thrombosis, (cryoglobulinemia, Sickle cell disease, serum cold agglutinins), or vasospastic disorders such as Raynaud's or thromboangiitis obliterans. Known co-morbid conditions likely to complicate therapy, e.g., end-stage cardiomyopathy, uncompensated arrhythmia, myopathy, liver disease severe enough to elevate bilirubin, history of pelvic or abdominal mass likely to compress inferior vena cava, IVC filters, dementia severe enough to prevent valid consent, end-stage AIDS, known thyroid deficiency, known renal insufficiency likely to impair meperidine (Demerol®) clearance Intracerebral hematoma Any intraventricular hemorrhage SBP > 185 or < 100; DBP > 110 or < 50 mmHg Pregnancy in women of child-bearing potential (must have pregnancy test, urine or blood, prior to therapy). Medical conditions likely to interfere with patient assessment Known allergy to meperidine (Demerol®) Currently taking MAO-I class of medication or used within previous 14 days Life expectancy < 3 months Not likely to be available for long-term follow-up.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 80 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
Allocation: Randomized
Intervention Model: Factorial Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Group 1<br>Groups 1 and 2: Parallel groups, randomized to hypothermia or no hypothermia. Both groups receive tPA as a part of standard of care. | Drug: tissue plasminogen activator<br>* tPA is a naturally occurring protein that opens blocked arteries by dissolving blood clots<br>|
| Active Comparator: Group 2<br>Groups 1 and 2: Parallel groups, randomized to hypothermia or no hypothermia. Both groups receive tPA as a part of standard of care. | Procedure: hypothermia<br>* Hypothermia with or without tPA for stroke. Hypothermia is induced using the Celsius Control™ System. Subjects are stratified by time to six groups.<br>Drug: tissue plasminogen activator<br>* tPA is a naturally occurring protein that opens blocked arteries by dissolving blood clots<br>|
| No Intervention: Group 3<br>Groups 3, 4, 5 and 6: Factorial groups, randomized to hypothermia plus tPA, hypothermia alone, tPA alone, or no treatment assignment (standard of care). | |
| Active Comparator: Group 4<br>Groups 3, 4, 5 and 6: Factorial groups, randomized to hypothermia plus tPA, hypothermia alone, tPA alone, or no treatment assignment (standard of care). | Drug: tissue plasminogen activator<br>* tPA is a naturally occurring protein that opens blocked arteries by dissolving blood clots<br>|
| Active Comparator: Group 5<br>Groups 3, 4, 5 and 6: Factorial groups, randomized to hypothermia plus tPA, hypothermia alone, tPA alone, or no treatment assignment (standard of care). | Procedure: hypothermia<br>* Hypothermia with or without tPA for stroke. Hypothermia is induced using the Celsius Control™ System. Subjects are stratified by time to six groups.<br>|
| Active Comparator: Group 6<br>Groups 3, 4, 5 and 6: Factorial groups, randomized to hypothermia plus tPA, hypothermia alone, tPA alone, or no treatment assignment (standard of care). | Procedure: hypothermia<br>* Hypothermia with or without tPA for stroke. Hypothermia is induced using the Celsius Control™ System. Subjects are stratified by time to six groups.<br>Drug: tissue plasminogen activator<br>* tPA is a naturally occurring protein that opens blocked arteries by dissolving blood clots<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence and volume of hemorrhage on CT |  | 48 hours post onset | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of AE and SAE |  | 90 days post onset | 
| Mortality in both groups testing whether hypothermia improves mortality after stroke |  | 90 Day | 
| NIHSS at the end of hypothermia |  | Hour 23.5 +/- 30 minutes of hypothermia | 
| Modified Rankin and NIHSS |  | 30 and 90days | 
| CT lesion volume |  | 30 days | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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stroke, hypothermia, cooling, tissue plasminogen activator, tPA, thrombolysis