The Intravascular Cooling in the Treatment of Stroke 2/3 Trial (ICTuS2/3)

• ClinicalTrials.gov Identifier: NCT01123161
• Recruitment Status: Terminated
• First Posted: May 14, 2010
• Results First Posted: April 5, 2017
• Last Update Posted: April 5, 2017
• Sponsor: University of California, San Diego
• Collaborators: National Institute of Neurological Disorders and Stroke (NINDS); The University of Texas Health Science Center, Houston
• Information provided by (Responsible Party): Patrick Lyden, Cedars-Sinai Medical Center

Study Description

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.

Condition or disease	Intervention/treatment	Phase
Stroke, Acute	Device: hypothermia and anti-shivering treatment; Drug: Group1: IV t-PA and normothermia	Phase 2; Phase 3

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.

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 120 participants
• Allocation: Randomized
• Intervention Model: Factorial Assignment
• Intervention Model Description: Randomized to normothermia or hypothermia
• Masking: Single (Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: Phase 2/3 Study of Intravenous Thrombolysis and Hypothermia for Acute Treatment of Ischemic Stroke
• Study Start Date: June 2010
• Actual Primary Completion Date: January 2015
• Actual Study Completion Date: May 2015

Arms and Interventions

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

Outcome Measures

Primary Outcome Measures :

1. 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. [ Time Frame: 90 days ]
   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
2. Incidence of Any Intracranial Hemorrhage (ICH) Within 48 Hours of Stroke Onset [ Time Frame: 48 hours ]
   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.
3. Incidence of Any Symptomatic Intracranial Hemorrhage (sICH) Within 48 Hours of Stroke Onset [ Time Frame: 48 hours ]
   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.
4. Incidence of Pneumonia [ Time Frame: 7 days or discharge whichever comes first ]
   Number subjects diagnosed with pneumonia according to CDC criteria will be presented by treatment group and overall, regardless of seriousness
5. 90 Day Mortality [ Time Frame: 90 days ]
   Mortality prior to the 90-day evaluation.

Secondary Outcome Measures :

1. The Barthel Index Measure of Activities of Daily Living; [ Time Frame: 90 days ]
   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.
2. NIHSS Scores at 90 Days [ Time Frame: 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.

Eligibility Criteria

• Ages Eligible for Study: 22 Years to 82 Years (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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

Contacts and Locations

Locations

United States, Alabama

University of Alabama Hospital

Birmingham, Alabama, United States, 35249

United States, California

Cedars-Sinai Medical Center

Los Angeles, California, United States, 90048

Hoag Memorial Hospital Presbyterian

Newport Beach, California, United States, 92658

University of California San Diego Health System

San Diego, California, United States, 92093

Scripps Mercy Medical Center

San Diego, California, United States, 92103

United States, Colorado

University of Colorado Hospital

Aurora, Colorado, United States, 80045

Swedish Medical Center

Englewood, Colorado, United States, 80113

United States, Connecticut

Hartford Hospital

Hartford, Connecticut, United States, 06102

Yale University

New Haven, Connecticut, United States, 06510

United States, Florida

Gulf Coast Medical Center

Fort Myers, Florida, United States, 33912

University of Florida

Gainesville, Florida, United States, 32608

University of Miami, Jackson Memorial Hospital

Miami, Florida, United States, 33136

Intercoastal Medical Group

Sarasota, Florida, United States, 34232

St. Joseph's Hospital

Tampa, Florida, United States, 33607

United States, Illinois

Alexian Brothers Medical Center

Elk Grove Village, Illinois, United States, 60007

United States, Indiana

Parkview Hospital

Fort Wayne, Indiana, United States, 46805

United States, Iowa

Ruan Neurology Clinic and Research Center

Des Moines, Iowa, United States, 50314

United States, Kentucky

University of Louisville

Louisville, Kentucky, United States, 40202

United States, Michigan

Henry Ford Health System

Detroit, Michigan, United States, 48202

Michigan State University

East Lansing, Michigan, United States, 48824

United States, Minnesota

North Memorial Medical Center

Robbinsdale, Minnesota, United States, 55422

United States, Missouri

Saint Louis University Medical Center

St. Louis, Missouri, United States, 63110

United States, New York

Columbia University Medical Center

New York, New York, United States, 10032

United States, Ohio

University of Toledo Medical Center

Toledo, Ohio, United States, 43614

United States, Pennsylvania

Abington Memorial Hospital

Abington, Pennsylvania, United States, 19001

Lehigh Valley Health Network

Allentown, Pennsylvania, United States, 18103

United States, Texas

Seton Medical Center Austin

Austin, Texas, United States, 78705

UT Southwestern

Dallas, Texas, United States, 75390

University of Texas Health Science Center

Houston, Texas, United States, 77030

Austria

Medical University Innsbruck

Innsbruck, Austria

Switzerland

CHUV

Lausanne, Switzerland

Sponsors and Collaborators

University of California, San Diego

National Institute of Neurological Disorders and Stroke (NINDS)

The University of Texas Health Science Center, Houston

Investigators

• Principal Investigator: Patrick D. Lyden, MD; Cedars-Sinai Medical Center
• Study Director: Thomas M. Hemmen, MD, PhD; University of California, San Diego
• Study Director: James C. Grotta, MD; The University of Texas Health Science Center, Houston

More Information

Publications:

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.

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.

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.

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.

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.

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.

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

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.

• Responsible Party: Patrick Lyden, Principal Investigator, Cedars-Sinai Medical Center
• ClinicalTrials.gov Identifier: NCT01123161
• Other Study ID Numbers: ICTuS2/3; P50NS044148 ( U.S. NIH Grant/Contract ); P50NS044227 ( U.S. NIH Grant/Contract )
• First Posted: May 14, 2010
• Results First Posted: April 5, 2017
• Last Update Posted: April 5, 2017
• Last Verified: February 2017

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: Undecided

Keywords provided by Patrick Lyden, Cedars-Sinai Medical Center:

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

Additional relevant MeSH terms:

Stroke; Cerebrovascular Disorders; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Vascular Diseases; Cardiovascular Diseases