Back to resultsThe Intravascular Cooling in the Treatment of Stroke 2/3 Trial (ICTuS2/3)
Primary Purpose
Stroke, Acute
Status
Terminated
Phase
Phase 2
Locations
International
Study Type
Interventional
Intervention
hypothermia and anti-shivering treatment
Group1: IV t-PA and normothermia
Sponsored by
About this trial
This is an interventional treatment trial for Stroke, Acute focused on measuring 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
Eligibility Criteria
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
Sites / Locations
- University of Alabama Hospital
- Cedars-Sinai Medical Center
- Hoag Memorial Hospital Presbyterian
- University of California San Diego Health System
- Scripps Mercy Medical Center
- University of Colorado Hospital
- Swedish Medical Center
- Hartford Hospital
- Yale University
- Gulf Coast Medical Center
- University of Florida
- University of Miami, Jackson Memorial Hospital
- Intercoastal Medical Group
- St. Joseph's Hospital
- Alexian Brothers Medical Center
- Parkview Hospital
- Ruan Neurology Clinic and Research Center
- University of Louisville
- Henry Ford Health System
- Michigan State University
- North Memorial Medical Center
- Saint Louis University Medical Center
- Columbia University Medical Center
- University of Toledo Medical Center
- Abington Memorial Hospital
- Lehigh Valley Health Network
- Seton Medical Center Austin
- UT Southwestern
- University of Texas Health Science Center
- Medical University Innsbruck
- CHUV
Arms of the Study
Arm 1
Arm 2
Arm Type
Active Comparator
Active Comparator
Arm Label
Group1: IV t-PA and normothermia
Group 2 : IV t-PA and hypothermia and anti-shivering treatment
Arm Description
IV tpa and normothermia
IV tpa and hypothermia and anti-shivering treatment
Outcomes
Primary Outcome Measures
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
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.
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.
Incidence of Pneumonia
Number subjects diagnosed with pneumonia according to CDC criteria will be presented by treatment group and overall, regardless of seriousness
90 Day Mortality
Mortality prior to the 90-day evaluation.
Secondary Outcome Measures
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.
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.
Full Information
NCT ID
NCT01123161
First Posted
April 27, 2010
Last Updated
February 18, 2017
Sponsor
University of California, San Diego
Collaborators
National Institute of Neurological Disorders and Stroke (NINDS), The University of Texas Health Science Center, Houston
1. Study Identification
Unique Protocol Identification Number
NCT01123161
Brief Title
The Intravascular Cooling in the Treatment of Stroke 2/3 Trial
Acronym
ICTuS2/3
Official Title
Phase 2/3 Study of Intravenous Thrombolysis and Hypothermia for Acute Treatment of Ischemic Stroke
Study Type
Interventional
2. Study Status
Record Verification Date
February 2017
Overall Recruitment Status
Terminated
Why Stopped
The ICTuS 2 portion of the trial has been halted and data will be analyzed.
Study Start Date
June 2010 (undefined)
Primary Completion Date
January 2015 (Actual)
Study Completion Date
May 2015 (Actual)
3. Sponsor/Collaborators
Responsible Party, by Official Title
Principal Investigator
Name of the Sponsor
University of California, San Diego
Collaborators
National Institute of Neurological Disorders and Stroke (NINDS), The University of Texas Health Science Center, Houston
4. Oversight
Data Monitoring Committee
Yes
5. 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.
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.
6. Conditions and Keywords
Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
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
7. Study Design
Primary Purpose
Treatment
Study Phase
Phase 2, Phase 3
Interventional Study Model
Factorial Assignment
Model Description
Randomized to normothermia or hypothermia
Masking
Outcomes Assessor
Allocation
Randomized
Enrollment
120 (Actual)
8. Arms, Groups, and Interventions
Arm Title
Group1: IV t-PA and normothermia
Arm Type
Active Comparator
Arm Description
IV tpa and normothermia
Arm Title
Group 2 : IV t-PA and hypothermia and anti-shivering treatment
Arm Type
Active Comparator
Arm Description
IV tpa and hypothermia and anti-shivering treatment
Intervention Type
Device
Intervention Name(s)
hypothermia and anti-shivering treatment
Other Intervention Name(s)
cooling
Intervention Description
Hypothermia is induced using the Celsius Control™ System. Shivering is treated with buspirone, meperidine and surface warming
Intervention Type
Drug
Intervention Name(s)
Group1: IV t-PA and normothermia
Intervention Description
Group 1 will t-PA as standard of care and normothermia
Primary Outcome Measure Information:
Title
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.
Description
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
Time Frame
90 days
Title
Incidence of Any Intracranial Hemorrhage (ICH) Within 48 Hours of Stroke Onset
Description
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.
Time Frame
48 hours
Title
Incidence of Any Symptomatic Intracranial Hemorrhage (sICH) Within 48 Hours of Stroke Onset
Description
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.
Time Frame
48 hours
Title
Incidence of Pneumonia
Description
Number subjects diagnosed with pneumonia according to CDC criteria will be presented by treatment group and overall, regardless of seriousness
Time Frame
7 days or discharge whichever comes first
Title
90 Day Mortality
Description
Mortality prior to the 90-day evaluation.
Time Frame
90 days
Secondary Outcome Measure Information:
Title
The Barthel Index Measure of Activities of Daily Living;
Description
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.
Time Frame
90 days
Title
NIHSS Scores at 90 Days
Description
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.
Time Frame
90 days
10. Eligibility
Sex
All
Minimum Age & Unit of Time
22 Years
Maximum Age & Unit of Time
82 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
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
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Patrick D. Lyden, MD
Organizational Affiliation
Cedars-Sinai Medical Center
Official's Role
Principal Investigator
First Name & Middle Initial & Last Name & Degree
Thomas M. Hemmen, MD, PhD
Organizational Affiliation
University of California, San Diego
Official's Role
Study Director
First Name & Middle Initial & Last Name & Degree
James C. Grotta, MD
Organizational Affiliation
The University of Texas Health Science Center, Houston
Official's Role
Study Director
Facility Information:
Facility Name
University of Alabama Hospital
City
Birmingham
State/Province
Alabama
ZIP/Postal Code
35249
Country
United States
Facility Name
Cedars-Sinai Medical Center
City
Los Angeles
State/Province
California
ZIP/Postal Code
90048
Country
United States
Facility Name
Hoag Memorial Hospital Presbyterian
City
Newport Beach
State/Province
California
ZIP/Postal Code
92658
Country
United States
Facility Name
University of California San Diego Health System
City
San Diego
State/Province
California
ZIP/Postal Code
92093
Country
United States
Facility Name
Scripps Mercy Medical Center
City
San Diego
State/Province
California
ZIP/Postal Code
92103
Country
United States
Facility Name
University of Colorado Hospital
City
Aurora
State/Province
Colorado
ZIP/Postal Code
80045
Country
United States
Facility Name
Swedish Medical Center
City
Englewood
State/Province
Colorado
ZIP/Postal Code
80113
Country
United States
Facility Name
Hartford Hospital
City
Hartford
State/Province
Connecticut
ZIP/Postal Code
06102
Country
United States
Facility Name
Yale University
City
New Haven
State/Province
Connecticut
ZIP/Postal Code
06510
Country
United States
Facility Name
Gulf Coast Medical Center
City
Fort Myers
State/Province
Florida
ZIP/Postal Code
33912
Country
United States
Facility Name
University of Florida
City
Gainesville
State/Province
Florida
ZIP/Postal Code
32608
Country
United States
Facility Name
University of Miami, Jackson Memorial Hospital
City
Miami
State/Province
Florida
ZIP/Postal Code
33136
Country
United States
Facility Name
Intercoastal Medical Group
City
Sarasota
State/Province
Florida
ZIP/Postal Code
34232
Country
United States
Facility Name
St. Joseph's Hospital
City
Tampa
State/Province
Florida
ZIP/Postal Code
33607
Country
United States
Facility Name
Alexian Brothers Medical Center
City
Elk Grove Village
State/Province
Illinois
ZIP/Postal Code
60007
Country
United States
Facility Name
Parkview Hospital
City
Fort Wayne
State/Province
Indiana
ZIP/Postal Code
46805
Country
United States
Facility Name
Ruan Neurology Clinic and Research Center
City
Des Moines
State/Province
Iowa
ZIP/Postal Code
50314
Country
United States
Facility Name
University of Louisville
City
Louisville
State/Province
Kentucky
ZIP/Postal Code
40202
Country
United States
Facility Name
Henry Ford Health System
City
Detroit
State/Province
Michigan
ZIP/Postal Code
48202
Country
United States
Facility Name
Michigan State University
City
East Lansing
State/Province
Michigan
ZIP/Postal Code
48824
Country
United States
Facility Name
North Memorial Medical Center
City
Robbinsdale
State/Province
Minnesota
ZIP/Postal Code
55422
Country
United States
Facility Name
Saint Louis University Medical Center
City
St. Louis
State/Province
Missouri
ZIP/Postal Code
63110
Country
United States
Facility Name
Columbia University Medical Center
City
New York
State/Province
New York
ZIP/Postal Code
10032
Country
United States
Facility Name
University of Toledo Medical Center
City
Toledo
State/Province
Ohio
ZIP/Postal Code
43614
Country
United States
Facility Name
Abington Memorial Hospital
City
Abington
State/Province
Pennsylvania
ZIP/Postal Code
19001
Country
United States
Facility Name
Lehigh Valley Health Network
City
Allentown
State/Province
Pennsylvania
ZIP/Postal Code
18103
Country
United States
Facility Name
Seton Medical Center Austin
City
Austin
State/Province
Texas
ZIP/Postal Code
78705
Country
United States
Facility Name
UT Southwestern
City
Dallas
State/Province
Texas
ZIP/Postal Code
75390
Country
United States
Facility Name
University of Texas Health Science Center
City
Houston
State/Province
Texas
ZIP/Postal Code
77030
Country
United States
Facility Name
Medical University Innsbruck
City
Innsbruck
Country
Austria
Facility Name
CHUV
City
Lausanne
Country
Switzerland
12. IPD Sharing Statement
Plan to Share IPD
Undecided
Citations:
PubMed Identifier
17904009
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.
Results Reference
background
PubMed Identifier
20724711
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.
Results Reference
background
PubMed Identifier
23667781
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.
Results Reference
background
PubMed Identifier
22466971
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.
Results Reference
background
PubMed Identifier
20817376
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.
Results Reference
background
PubMed Identifier
16766740
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.
Results Reference
background
PubMed Identifier
27834742
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.
Results Reference
derived
Learn more about this trial
The Intravascular Cooling in the Treatment of Stroke 2/3 Trial
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