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

Phase 2/3 Study of Intravenous Thrombolysis and Hypothermia for Acute Treatment of Ischemic Stroke

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.

Study Overview

• Status: Terminated
• Conditions: Stroke, Acute
• Intervention / Treatment: Drug: Group1: IV t-PA and normothermia; Device: hypothermia and anti-shivering treatment

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 Type: Interventional
• Enrollment (Actual): 120
• Phase: Phase 2; Phase 3

Contacts and Locations

Study Locations

• Austria
  • Innsbruck, Austria
    • Medical University Innsbruck
• Switzerland
  • Lausanne, Switzerland
    • CHUV
• United States
  • Alabama
    • Birmingham, Alabama, United States, 35249
      • University of Alabama Hospital
  • California
    • Los Angeles, California, United States, 90048
      • Cedars-Sinai Medical Center
    • Newport Beach, California, United States, 92658
      • Hoag Memorial Hospital Presbyterian
    • San Diego, California, United States, 92093
      • University of California San Diego Health System
    • San Diego, California, United States, 92103
      • Scripps Mercy Medical Center
  • Colorado
    • Aurora, Colorado, United States, 80045
      • University of Colorado Hospital
    • Englewood, Colorado, United States, 80113
      • Swedish Medical Center
  • Connecticut
    • Hartford, Connecticut, United States, 06102
      • Hartford Hospital
    • New Haven, Connecticut, United States, 06510
      • Yale University
  • Florida
    • Fort Myers, Florida, United States, 33912
      • Gulf Coast Medical Center
    • Gainesville, Florida, United States, 32608
      • University of Florida
    • Miami, Florida, United States, 33136
      • University of Miami, Jackson Memorial Hospital
    • Sarasota, Florida, United States, 34232
      • Intercoastal Medical Group
    • Tampa, Florida, United States, 33607
      • St. Joseph's Hospital
  • Illinois
    • Elk Grove Village, Illinois, United States, 60007
      • Alexian Brothers Medical Center
  • Indiana
    • Fort Wayne, Indiana, United States, 46805
      • Parkview Hospital
  • Iowa
    • Des Moines, Iowa, United States, 50314
      • Ruan Neurology Clinic and Research Center
  • Kentucky
    • Louisville, Kentucky, United States, 40202
      • University of Louisville
  • Michigan
    • Detroit, Michigan, United States, 48202
      • Henry Ford Health System
    • East Lansing, Michigan, United States, 48824
      • Michigan State University
  • Minnesota
    • Robbinsdale, Minnesota, United States, 55422
      • North Memorial Medical Center
  • Missouri
    • St. Louis, Missouri, United States, 63110
      • Saint Louis University Medical Center
  • New York
    • New York, New York, United States, 10032
      • Columbia University Medical Center
  • Ohio
    • Toledo, Ohio, United States, 43614
      • University of Toledo Medical Center
  • Pennsylvania
    • Abington, Pennsylvania, United States, 19001
      • Abington Memorial Hospital
    • Allentown, Pennsylvania, United States, 18103
      • Lehigh Valley Health Network
  • Texas
    • Austin, Texas, United States, 78705
      • Seton Medical Center Austin
    • Dallas, Texas, United States, 75390
      • UT Southwestern
    • Houston, Texas, United States, 77030
      • University of Texas Health Science Center

Participation Criteria

Eligibility Criteria

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

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Factorial Assignment
• Masking: Single

Number of Arms

2

Arms and Interventions

Participant Group / 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 Names: cooling

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: University of California, San Diego
• Collaborators: The University of Texas Health Science Center, Houston; National Institute of Neurological Disorders and Stroke (NINDS)
• 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

Publications and helpful links

General Publications

• 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 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.
• 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.
• 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.

Study record dates

Study Major Dates

• Study Start: June 1, 2010
• Primary Completion (Actual): January 1, 2015
• Study Completion (Actual): May 1, 2015

Study Registration Dates

• First Submitted: April 27, 2010
• First Submitted That Met QC Criteria: May 11, 2010
• First Posted (Estimate): May 14, 2010

Study Record Updates

• Last Update Posted (Actual): April 5, 2017
• Last Update Submitted That Met QC Criteria: February 18, 2017
• Last Verified: February 1, 2017

More Information

Terms related to this study

• Keywords: thrombolysis; Stroke; Vascular Diseases; Cardiovascular Diseases; Nervous System Diseases; Central Nervous System Diseases; Hypothermia; tPA; Pharmacologic Actions; Brain Diseases; Therapeutic Uses; Cerebral Infarction; Signs and Symptoms; Cerebrovascular Disorders; cooling; Cardiovascular Agents; Brain Infarction; Brain Ischemia; Molecular Mechanisms of Pharmacological Action; Tissue Plasminogen Activator; Plasminogen; Hematologic Agents; Fibrinolytic Agents; Fibrin Modulating Agents; Body Temperature Changes
• Additional Relevant MeSH Terms: Cardiovascular Diseases; Vascular Diseases; Cerebrovascular Disorders; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Stroke
• Other Study ID Numbers: ICTuS2/3; P50NS044148 (U.S. NIH Grant/Contract); P50NS044227 (U.S. NIH Grant/Contract)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED