Intravenous Thrombolysis Plus Hypothermia for Acute Treatment of Ischemic Stroke

• Safety: Mortality at 90 days, hemorrhage rate, number of serious adverse events.
• Efficacy: NIHSS at 24 hours, Modified Ranking and NIHSS at 30 days, Stroke Volume on day 30 CT, incidence and volume of hemorrhage on CT scans.

• Incidence of AE and SAE [ Time Frame: 90 days post onset ] [ Designated as safety issue: Yes ]
• Mortality in both groups testing whether hypothermia improves mortality after stroke [ Time Frame: 90 Day ] [ Designated as safety issue: Yes ]
• NIHSS at the end of hypothermia [ Time Frame: Hour 23.5 +/- 30 minutes of hypothermia ] [ Designated as safety issue: No ]
• Modified Rankin and NIHSS [ Time Frame: 30 and 90days ] [ Designated as safety issue: No ]
• CT lesion volume [ Time Frame: 30 days ] [ Designated as safety issue: No ]

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.

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.

• Procedure: hypothermia

  Hypothermia with or without tPA for stroke. Hypothermia is induced using the Celsius Control™ System.

  Subjects are stratified by time to six groups.

• Drug: tissue plasminogen activator
  tPA is a naturally occurring protein that opens blocked arteries by dissolving blood clots

• Active Comparator: Group 1
  Groups 1 and 2: Parallel groups, randomized to hypothermia or no hypothermia. Both groups receive tPA as a part of standard of care.
  Intervention: Drug: tissue plasminogen activator
• Active Comparator: Group 2
  Groups 1 and 2: Parallel groups, randomized to hypothermia or no hypothermia. Both groups receive tPA as a part of standard of care.
  Interventions:

  • Procedure: hypothermia
  • Drug: tissue plasminogen activator
• No Intervention: Group 3
  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
  Groups 3, 4, 5 and 6: Factorial groups, randomized to hypothermia plus tPA, hypothermia alone, tPA alone, or no treatment assignment (standard of care).
  Intervention: Drug: tissue plasminogen activator
• Active Comparator: Group 5
  Groups 3, 4, 5 and 6: Factorial groups, randomized to hypothermia plus tPA, hypothermia alone, tPA alone, or no treatment assignment (standard of care).
  Intervention: Procedure: hypothermia
• Active Comparator: Group 6
  Groups 3, 4, 5 and 6: Factorial groups, randomized to hypothermia plus tPA, hypothermia alone, tPA alone, or no treatment assignment (standard of care).
  Interventions:

  • Procedure: hypothermia
  • Drug: tissue plasminogen activator

• Hemmen TM, Raman R, Guluma KZ, Meyer BC, Gomes JA, Cruz-Flores S, Wijman CA, Rapp KS, Grotta JC, Lyden PD; ICTuS-L Investigators. Intravenous thrombolysis plus hypothermia for acute treatment of ischemic stroke (ICTuS-L): final results. Stroke. 2010 Oct;41(10):2265-70. Epub 2010 Aug 19.
• Lyden Patrick D., Allgren Robin L., Ng Ken, Akins Paul, Meyer Brett, Fahmi Al-Sanani, Lutsep Helmi, Dobak John, Matsubara Bradley S., Zivin Justin; Intravascular Cooling in the Treatment of Stroke (ICTuS): Early Clinical Experience: Journal of Stroke and Cerebrovascular Diseases, Vol. 14, No. 3 (May - June), 2005: pp 107 - 114.
• Guluma KZ, Hemmen TM, Olsen SE, Rapp KS, Lyden PD. A trial of therapeutic hypothermia via endovascular approach in awake patients with acute ischemic stroke: methodology. Acad Emerg Med. 2006 Aug;13(8):820-7. Epub 2006 Jun 9.
• Hemmen TM, Guluma KZ, Wijman CA, Cruz-Flores S, Meyer BC, Rapp KS, Klos BR, Raman R, Lyden PD. Intravenous Thrombolysis Plus Hypothermia for acute Treatment of Ischemic Stroke (ICTuS-L) Stroke 37:706, 2006.
• Hemmen TM, Lyden PD. Induced hypothermia for acute stroke. Stroke. 2007 Feb;38(2 Suppl):794-9. Review.

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.