The Intravascular Cooling in the Treatment of Stroke 2/3 Trial

Study Overview
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Brief Summary
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The purpose of this trial is to determine whether the combination of thrombolysis and hypothermia is superior to thrombolysis alone for the treatment of acute ischemic stroke.

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. 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. 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. There are two study groups - tPA alone or tPA with cooling (hypothermia). Participants will be randomly assigned to one of the two study groups. 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 2/3 Study of Intravenous Thrombolysis and Hypothermia for Acute Treatment of Ischemic Stroke

Conditions
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Stroke, Acute

Intervention / Treatment
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* Device: hypothermia and anti-shivering treatment
* Drug: Group1: IV t-PA and normothermia


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age 22 to 82 years old inclusive Patient receiving IV rt-PA using standard guidelines NIHSS score ≥ 7 and ≤ 20 (right hemisphere) or ≥ 7 and ≤ 24 (left hemisphere) at the time of randomization Pre-stroke mRS 0-1 Able to begin endovascular phase of hypothermia within 2 hours of tPA completion Written Informed Consent, signed and dated by the patient (or patient's authorized representative) Exclusion Criteria: Etiology other than ischemic stroke Item 1a on NIHSS > 1 at the time of randomization Clinical symptoms consistent with brainstem or cerebellar stroke Classic lacunar syndrome with imaging confirmation of small deep ischemia, but randomization will not be delayed for neuroimaging other than initial scan to exclude hemorrhage Known contraindications to hypothermia, such as known hematologic dyscrasias that affect thrombosis (cryoglobulinemia, Sickle cell disease, serum cold agglutinins), or vasospastic disorders such as Raynaud's or thromboangiitis obliterans Known co-morbid conditions that are likely to complicate therapy in the opinion of the investigator, e.g., i. Heart failure (NYHA class III and IV)* ii. Uncompensated arrhythmia iii. Severe Liver disease iv. History of pelvic or abdominal mass likely to compress inferior vena cava v. IVC filters vi. HIV positive vii. Clinically active hypo or hyperthyroidism viii. Renal insufficiency likely to impair meperidine clearance ix. Chronic ethanol abuse x. History of HIT (heparin induced thrombocytopenia) Pregnancy (All women of child-bearing potential must have a negative pregnancy test, urine or blood, prior to therapy.) Medical conditions likely to interfere with patient assessment. Known allergy to meperidine or buspirone Currently taking or used within previous 14 days MAO-I class of medication. Life expectancy < 6 months Not likely to be available for long-term follow-up Use, or planned use, of intra-arterial thrombolysis, mechanical clot removal, or other experimental or approved acute therapy for this stroke event Chest radiograph or clinical presentation suggestive of pneumonia or clinically significant pulmonary edema at baseline. Temperature upon admission greater than or equal to 38°C

Ages Eligible for Study
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Minimum Age: 22 Years
Maximum Age: 82 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
Interventional Model Description: Randomized to normothermia or hypothermia
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Group1: IV t-PA and normothermia<br>IV tpa and normothermia | Drug: Group1: IV t-PA and normothermia<br>* Group 1 will t-PA as standard of care and normothermia<br>|
| Active Comparator: Group 2 : IV t-PA and hypothermia and anti-shivering treatment<br>IV tpa and hypothermia and anti-shivering treatment | Device: hypothermia and anti-shivering treatment<br>* Hypothermia is induced using the Celsius Control™ System. Shivering is treated with buspirone, meperidine and surface warming<br>* Other names: cooling;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The Primary Outcome is the Proportion of Patients Achieving a Favorable Outcome Defined as Modified Rankin Scale Score of 0 or 1, Assessed 90 Days After Treatment. | Modified Rankin describes disability: 0 is free of any disability or symptoms, 6 is death, and higher grades between 0 and 6 reflect progressively greater disability | 90 days | 
| Incidence of Any Intracranial Hemorrhage (ICH) Within 48 Hours of Stroke Onset | Incidence (number) of any intracranial hemorrhage (ICH) (whether or not symptomatic) within 48 hours of stroke onset will be presented by treatment group and overall. | 48 hours | 
| Incidence of Any Symptomatic Intracranial Hemorrhage (sICH) Within 48 Hours of Stroke Onset | Incidence (number) of Symptomatic ICH (sICH) within 48 hours of stroke onset will be presented by treatment group and overall. Patients with neuroworsening (4 or more point increase in NIHSS , or a decline in the NIHSS consciousness item 1A score of more than 1 point, or a motor deterioration lasting more than 8 hours, all not due to iatrogenic cause) and hemorrhage seen on brain images in whom the investigator attributes the clinical change to the hemorrhage. | 48 hours | 
| Incidence of Pneumonia | Number subjects diagnosed with pneumonia according to CDC criteria will be presented by treatment group and overall, regardless of seriousness | 7 days or discharge whichever comes first | 
| 90 Day Mortality | Mortality prior to the 90-day evaluation. | 90 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The Barthel Index Measure of Activities of Daily Living; | The Barthel index measures independence in activities of daily living from 0 (worst) to 100 (best) in 5 point increments. Higher scores between 0 and 100 reflect progressively greater levels of independence. Scores were dichotomized at 90 so that a score of 95 or 100 was considered a successful treatment. | 90 days | 
| NIHSS Scores at 90 Days | The National Institutes of Health Stroke Scale (NIHSS) is used to quantify neurological deficit. The scale ranges from 0 (best) to 42 points (worst). Between scores of 0 to 42, higher values reflect progressively greater deficit. | 90 days | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Plasminogen, Hypothermia, Molecular Mechanisms of Pharmacological Action, Cerebral Infarction, Hematologic Agents, Stroke, Nervous System Diseases, Vascular Diseases, Tissue Plasminogen Activator, Central Nervous System Diseases, Fibrinolytic Agents, Cardiovascular Agents, Body Temperature Changes, Brain Diseases, Cerebrovascular Disorders, Pharmacologic Actions, Signs and Symptoms, Fibrin Modulating Agents, Therapeutic Uses, Brain Ischemia, Cardiovascular Diseases, Brain Infarction, cooling, tPA, thrombolysis