Clinical trial NCT01123161: The Intravascular Cooling in the Treatment of Stroke 2/3 Trial
Official title: Phase 2/3 Study of Intravenous Thrombolysis and Hypothermia for Acute Treatment of Ischemic Stroke
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE2
PHASE3
Conditions: Stroke, Acute
Keywords: 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
Plasminogen
cooling
tPA
thrombolysis
Lead sponsor: University of California, San Diego
Sponsor class: OTHER
Collaborators: name: National Institute of Neurological Disorders and Stroke (NINDS)
name: The University of Texas Health Science Center, Houston
First posted: 2010-05-14
Enrollment: 120
Sex: ALL
Minimum age (years): 22
Maximum age (years): 82
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: FACTORIAL
Intervention model description: Randomized to normothermia or hypothermia
Primary purpose: TREATMENT

Brief summary: 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: 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.

Eligibility criteria: Inclusion Criteria:

1. Age 22 to 82 years old inclusive
2. Patient receiving IV rt-PA using standard guidelines
3. NIHSS score ≥ 7 and ≤ 20 (right hemisphere) or ≥ 7 and ≤ 24 (left hemisphere) at the time of randomization
4. Pre-stroke mRS 0-1
5. Able to begin endovascular phase of hypothermia within 2 hours of tPA completion
6. Written Informed Consent, signed and dated by the patient (or patient's authorized representative)

Exclusion Criteria:

1. Etiology other than ischemic stroke
2. Item 1a on NIHSS \> 1 at the time of randomization
3. Clinical symptoms consistent with brainstem or cerebellar stroke
4. 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
5. 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
6. 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)
7. Pregnancy (All women of child-bearing potential must have a negative pregnancy test, urine or blood, prior to therapy.)
8. Medical conditions likely to interfere with patient assessment.
9. Known allergy to meperidine or buspirone
10. Currently taking or used within previous 14 days MAO-I class of medication.
11. Life expectancy \< 6 months
12. Not likely to be available for long-term follow-up
13. Use, or planned use, of intra-arterial thrombolysis, mechanical clot removal, or other experimental or approved acute therapy for this stroke event
14. Chest radiograph or clinical presentation suggestive of pneumonia or clinically significant pulmonary edema at baseline.
15. Temperature upon admission greater than or equal to 38°C

Primary outcomes:
measure: 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.
timeFrame: 90 days
measure: Incidence of Any Intracranial Hemorrhage (ICH) Within 48 Hours of Stroke Onset
timeFrame: 48 hours
measure: Incidence of Any Symptomatic Intracranial Hemorrhage (sICH) Within 48 Hours of Stroke Onset
timeFrame: 48 hours
measure: Incidence of Pneumonia
timeFrame: 7 days or discharge whichever comes first
measure: 90 Day Mortality
timeFrame: 90 days
Secondary outcomes:
measure: The Barthel Index Measure of Activities of Daily Living;
timeFrame: 90 days
measure: NIHSS Scores at 90 Days
timeFrame: 90 days
Other outcomes:
Locations:
city: Birmingham
country: United States
facility: University of Alabama Hospital
state: Alabama
city: Los Angeles
country: United States
facility: Cedars-Sinai Medical Center
state: California
city: Newport Beach
country: United States
facility: Hoag Memorial Hospital Presbyterian
state: California
city: San Diego
country: United States
facility: University of California San Diego Health System
state: California
city: San Diego
country: United States
facility: Scripps Mercy Medical Center
state: California
city: Aurora
country: United States
facility: University of Colorado Hospital
state: Colorado
city: Englewood
country: United States
facility: Swedish Medical Center
state: Colorado
city: Hartford
country: United States
facility: Hartford Hospital
state: Connecticut
city: New Haven
country: United States
facility: Yale University
state: Connecticut
city: Fort Myers
country: United States
facility: Gulf Coast Medical Center
state: Florida
city: Gainesville
country: United States
facility: University of Florida
state: Florida
city: Miami
country: United States
facility: University of Miami, Jackson Memorial Hospital
state: Florida
city: Sarasota
country: United States
facility: Intercoastal Medical Group
state: Florida
city: Tampa
country: United States
facility: St. Joseph's Hospital
state: Florida
city: Elk Grove Village
country: United States
facility: Alexian Brothers Medical Center
state: Illinois
city: Fort Wayne
country: United States
facility: Parkview Hospital
state: Indiana
city: Des Moines
country: United States
facility: Ruan Neurology Clinic and Research Center
state: Iowa
city: Louisville
country: United States
facility: University of Louisville
state: Kentucky
city: Detroit
country: United States
facility: Henry Ford Health System
state: Michigan
city: East Lansing
country: United States
facility: Michigan State University
state: Michigan
city: Robbinsdale
country: United States
facility: North Memorial Medical Center
state: Minnesota
city: St. Louis
country: United States
facility: Saint Louis University Medical Center
state: Missouri
city: New York
country: United States
facility: Columbia University Medical Center
state: New York
city: Toledo
country: United States
facility: University of Toledo Medical Center
state: Ohio
city: Abington
country: United States
facility: Abington Memorial Hospital
state: Pennsylvania
city: Allentown
country: United States
facility: Lehigh Valley Health Network
state: Pennsylvania
city: Austin
country: United States
facility: Seton Medical Center Austin
state: Texas
city: Dallas
country: United States
facility: UT Southwestern
state: Texas
city: Houston
country: United States
facility: University of Texas Health Science Center
state: Texas
city: Innsbruck
country: Austria
facility: Medical University Innsbruck
city: Lausanne
country: Switzerland
facility: CHUV
Study officials:
affiliation: Cedars-Sinai Medical Center
name: Patrick D. Lyden, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: University of California, San Diego
name: Thomas M. Hemmen, MD, PhD
role: STUDY_DIRECTOR
affiliation: The University of Texas Health Science Center, Houston
name: James C. Grotta, MD
role: STUDY_DIRECTOR
References:
citation: Lyden PD, Allgren RL, Ng K, Akins P, Meyer B, Al-Sanani F, Lutsep H, Dobak J, Matsubara BS, Zivin J. Intravascular Cooling in the Treatment of Stroke (ICTuS): early clinical experience. J Stroke Cerebrovasc Dis. 2005 May-Jun;14(3):107-14. doi: 10.1016/j.jstrokecerebrovasdis.2005.01.001.
citation: 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. doi: 10.1161/STROKEAHA.110.592295. Epub 2010 Aug 19.
citation: Lyden P, Ernstrom K, Raman R. Determinants of Pneumonia Risk During Endovascular Hypothermia. Ther Hypothermia Temp Manag. 2013 Mar;3(1):24-27. doi: 10.1089/ther.2012.0021.
citation: Lyden P, Ernstrom K, Cruz-Flores S, Gomes J, Grotta J, Mullin A, Rapp K, Raman R, Wijman C, Hemmen T. Determinants of effective cooling during endovascular hypothermia. Neurocrit Care. 2012 Jun;16(3):413-20. doi: 10.1007/s12028-012-9688-y.
citation: Guluma KZ, Liu L, Hemmen TM, Acharya AB, Rapp KS, Raman R, Lyden PD. Therapeutic hypothermia is associated with a decrease in urine output in acute stroke patients. Resuscitation. 2010 Dec;81(12):1642-7. doi: 10.1016/j.resuscitation.2010.08.003.
citation: 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. doi: 10.1197/j.aem.2006.03.559. Epub 2006 Jun 9.
citation: Lyden P, Hemmen T, Grotta J, Rapp K, Ernstrom K, Rzesiewicz T, Parker S, Concha M, Hussain S, Agarwal S, Meyer B, Jurf J, Altafullah I, Raman R; Collaborators. Results of the ICTuS 2 Trial (Intravascular Cooling in the Treatment of Stroke 2). Stroke. 2016 Dec;47(12):2888-2895. doi: 10.1161/STROKEAHA.116.014200. Epub 2016 Nov 10.