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Clinical Trial Details — Status: Recruiting

Administrative data

NCT number NCT04217551
Other study ID # G160072
Secondary ID U01NS073476
Status Recruiting
Phase N/A
First received
Last updated
Start date May 18, 2020
Est. completion date August 31, 2025

Study information

Verified date May 2024
Source University of Michigan
Contact William Meurer
Phone 734-232-2142
Email wmeurer@med.umich.edu
Is FDA regulated No
Health authority
Study type Interventional

Clinical Trial Summary

A multicenter, randomized, adaptive allocation clinical trial to determine if increasing durations of induced hypothermia are associated with an increasing rate of good neurological outcomes and to identify the optimal duration of induced hypothermia for neuroprotection in comatose survivors of cardiac arrest.


Description:

A multicenter, randomized, adaptive allocation clinical trial to determine if increasing durations of induced hypothermia are associated with an increasing rate of good neurological outcomes and to identify the optimal duration of induced hypothermia for neuroprotection in comatose survivors of cardiac arrest. Cardiac arrest is a common and devastating emergency of the heart and the brain. More than 380,000 patients suffer out of hospital cardiac arrest (OHCA) each year in the US. Improvements in cardiac resuscitation (the early links in the "chain of survival" for patients with OHCA) are tempered by our limited ability to resuscitate and protect the brain from global cerebral ischemia. Neurological death and disability are common outcomes in survivors of cardiac arrest. Therapeutic cooling of comatose patients resuscitated from shockable rhythms markedly increases the rate of good neurological outcome, but poor outcomes still occur in as many as 50%, and the benefit of cooling in those resuscitated from asystole and pulseless electrical activity has not been shown in a randomized study. Objectives: The overarching goal of this project is to identify clinical strategies that will increase the number of patients with good neurological recovery from cardiac arrest. We hypothesize that longer durations of cooling may improve either the proportion of patients that attain a good neurological recovery or may result in better recovery among the proportion already categorized as having good outcomes. Primary Objectives: A. To determine, in each of two populations of adult comatose survivors of cardiac arrest (those with initial shockable rhythms and those with pulseless electrical activity (PEA)/asystole), the shortest duration of cooling that provides the maximum treatment effect as determined by a weighted 90 day modified Rankin score B. To determine, in each of two populations of adult comatose survivors of cardiac arrest (those with initial shockable rhythms and those with PEA/asystole), whether increasing durations of cooling are associated with better outcomes or recovery implying efficacy of hypothermia to no cooling. Secondary Objectives: To characterize the overall safety and adverse events associated with duration of cooling To characterize the effect of duration of cooling on neuropsychological outcomes To characterize the effect of duration of cooling on patient reported quality of life Design: This study is a randomized, response-adaptive, duration (dose) finding, comparative effectiveness clinical trial with blinded outcome assessment. The design is based on a statistical model of response as defined by the primary endpoint, a weighted 90-day mRS, across the treatment arms. The design will fit patient outcome data to a duration response model (separately for shockable and non-shockable rhythms), in which the potentially non-linear association between durations of cooling and the primary endpoint are estimated. All conclusions about the treatment arms are based on this model. The functional form of the duration-response model is flexible and able to fit many different shapes for the duration-response curve. Specifically it is parameterized to identify up to two change-points in the treatment effect across arms, allowing it to fit an increasing, decreasing, flat, plateau, or U-shape duration-response curve. Subjects will initially be equally randomized between 12, 24, and 48 hours of cooling. After the first 200 subjects have been randomized, additional treatment arms between 12 and 48 hours will be opened and patients will be allocated, within each rhythm type, by response adaptive randomization. As the trial continues, shorter and longer duration arms may be opened. Specifically, a 6-hour duration arm will be opened if the emerging duration-response curve from 12 hours is flat. Similarly, a 60-hour or 72-hour duration arm will be opened if the emerging duration response curve shows an increasing treatment benefit through 48 hours. This trial will have frequent interim analyses to stop the trial early for futility if it is highly likely that no treatment arm offers a greater benefit then the 6-hour duration arm. Primary Outcome Measure: The primary outcome measure will be the modified Rankin scale at 90 days after return of spontaneous circulation. The mRS will be analyzed as a weighted score incorporating both the proportion of subjects achieving a good neurological outcome and degree of residual functional impairment among those with good neurological outcomes. Study Population: Comatose adult survivors of out of hospital cardiac arrest that have already been rapidly cooled using a definitive temperature control method (endovascular or surface) will be enrolled in the emergency department or intensive care unit. Hub and spoke hospitals from the SIREN network will be enriched with high potential ancillary Hubs. Approximately 50 hospitals are anticipated to each enroll an average of 9 subjects per year. Randomization: Central computerized randomization by web-based interface will be used. Subjects will be potentially randomized over the course of the trial to the following possible durations of cooling (in hours): 6, 12, 18, 24, 30, 36, 42, 48, 60, and 72. The first 200 patients will be randomized 1:1:1 to the 12, 24, and 48-hour durations only. After this initial "burn in" period, response adaptive randomization will be used to allocate subjects to durations inclusive of 12 to 48 hours initially, and then subsequently to the 6, 60 or 72 hour durations if specified conditions are met and the emerging duration-response curve suggests that the maximum treatment benefit might be on those durations. The response adaptive randomization probabilities for each arm will be determined separately for the two rhythm type populations. Randomization probabilities will be updated monthly, or approximately every 38 patients based on the expected accrual rate. Consent: Eligible patients for this trial will not have capacity to provide informed consent. Written informed consent from a legally authorized representative will be required. Intervention: The intervention will be random allocation to duration of cooling after cardiac arrest. Cooling in the study will be by a definitive temperature control method to a target temperature of 33 deg C. Any endovascular or surface cooling system with closed loop feedback will be allowed. Duration of cooling will be measured from the time that cooling with a definitive device is initiated in the hospital. As part of routine medical care, cooling may be initiated by emergency medical service (EMS) or in the emergency department. Eligibility will require that a temperature of <34 degrees C be obtained by 240 minutes after cardiac arrest. After the allocated duration of cooling is completed, controlled rewarming will be performed. Rewarming to a temperature of 36.5 deg C will occur over the shorter of 24 hours or a rewarming period equal to the allocated duration of cooling. Definitive cooling devices may be used for maintenance of normothermia after rewarming is complete. A clinical standardization guideline will be followed to reduce the effects of practice variability. Key physiologic and practice variables will be tracked and compliance with clinical standardization and deviation from physiologic targets reported back to study teams. Statistical Analysis for the Primary Outcome Measure: We will model the mean weighted mRS at 90 days across the treatment arms. The weighted mRS incorporates both the proportion of subjects achieving a good neurological outcome and degree of impairment among those with good neurological outcomes. The primary analysis is conducted separately for each rhythm type, allowing for a different treatment effect by rhythm type, and has two components. First, we identify the most likely target duration, where the target duration is the shortest duration that achieves the maximum treatment effect (Objective A). Second, we calculate whether the efficacy of any duration is superior to any shorter duration of cooling indicating a positive duration response (Objective B). Establishing a positive duration response implies confirmation that cooling is effective in improving outcome or recovery versus normothermia, when a normothermia control arm is not clinically acceptable. A maximal sample size of 1800 subjects enrolled over 4 years (estimated accrual rate of 37.5 subjects/month) is anticipated. Investigational Device Exemption


Recruitment information / eligibility

Status Recruiting
Enrollment 1800
Est. completion date August 31, 2025
Est. primary completion date July 15, 2025
Accepts healthy volunteers No
Gender All
Age group 18 Years and older
Eligibility Inclusion Criteria: - Coma after resuscitation from out of hospital cardiac arrest - Cooled to <34 deg C with 240 minutes of cardiac arrest - Definitive temperature control applied - Age = 18 years - Informed consent from legal authorized representative (LAR) including intent to maintain life support for 96 hours - Enrollment within 6 hours of initiation of cooling Exclusion Criteria: - Hemodynamic instability - Pre-existing neurological disability or condition that confounds outcome determination - Pre-existing terminal illness, unlikely to survive to outcome determination - Planned early withdrawal of life support - Presumed sepsis as etiology of arrest - Prisoner

Study Design


Intervention

Device:
Therapeutic Hypothermia
Participants will receive therapeutic hypothermia for the assigned number of hours with controlled rewarming, using a closed-loop temperature control device.

Locations

Country Name City State
United States University of Michigan Hospital Ann Arbor Michigan
United States Grady Memorial Hospital Atlanta Georgia
United States University of Colorado Hospital Aurora Colorado
United States Johns Hopkins Hospital Baltimore Maryland
United States University of Maryland Medical Center Baltimore Maryland
United States University of Alabama Hospital Birmingham Alabama
United States Beth Israel Deaconess Medical Center Boston Massachusetts
United States Brigham & Women's Hospital Boston Massachusetts
United States Massachusetts General Hospital Boston Massachusetts
United States Kings County Hospital Center Brooklyn New York
United States Cooper University Hospital Camden New Jersey
United States University of Virginia Medical Center Charlottesville Virginia
United States Northwestern Memorial Hospital Chicago Illinois
United States Rush University Medical Center Chicago Illinois
United States University of Chicago Medical Center Chicago Illinois
United States University of Illinois-Chicago Hosptial Chicago Illinois
United States University of Cincinnati Cincinnati Ohio
United States OSU East Hospital Columbus Ohio
United States OSU Wexner Medical Center Columbus Ohio
United States Parkland Hospital Dallas Texas
United States Geisinger Medical Center Danville Pennsylvania
United States Denver Health Medical Center Denver Colorado
United States Detroit Receiving Hospital Detroit Michigan
United States DMC Sinai Grace Hospital Detroit Michigan
United States Henry Ford Hospital Detroit Michigan
United States Duke University Hospital Durham North Carolina
United States M Health Fairview Southdale Hospital Edina Minnesota
United States Providence Regional Medical Center Everett Everett Washington
United States UF Health Shands Hospital Gainesville Florida
United States Spectrum Health Butterworth Hospital Grand Rapids Michigan
United States ECU Health Medical Center Greenville North Carolina
United States UPMC Harrisburg Harrisburg Pennsylvania
United States The Queen's Medical Center Honolulu Hawaii
United States Memorial Hermann Hospital Houston Texas
United States IU Health Methodist Hospital Indianapolis Indiana
United States University of Kansas Medical Center Kansas City Kansas
United States University of Kentucky Hospital Lexington Kentucky
United States Cedars-Sinai Medical Center Los Angeles California
United States Ronald Regan UCLA Medical Center Los Angeles California
United States UofL Health - Jewish Hospital Louisville Kentucky
United States Froedtert Hospital Milwaukee Wisconsin
United States Hennepin County Medical Center Minneapolis Minnesota
United States M Health Fairview East Bank Hospital Minneapolis Minnesota
United States Yale New Haven Hospital New Haven Connecticut
United States NYP Columbia University Medical Center New York New York
United States NYU Langone Health - Tisch Hospital New York New York
United States Advocate Christ Medical Center Oak Lawn Illinois
United States University of Nebraska Medical Center Omaha Nebraska
United States Hospital of the University of Pennsylvania Philadelphia Pennsylvania
United States Penn Presbyterian Medical Center Philadelphia Pennsylvania
United States Temple University Hospital Philadelphia Pennsylvania
United States Thomas Jefferson University Hospital Philadelphia Pennsylvania
United States University of Pittsburgh Medical Center Pittsburgh Pennsylvania
United States Adventist Health Portland Oregon
United States Maine Medical Center Portland Maine
United States VCU Medical Center Richmond Virginia
United States Strong Memorial Hospital Rochester New York
United States William Beaumont Hospital Royal Oak Michigan
United States UC Davis Medical Center Sacramento California
United States Regions Hospital Saint Paul Minnesota
United States University of Utah Hospital Salt Lake City Utah
United States UC San Diego Medical Center - Hillcrest San Diego California
United States Zuckerberg San Francisco General Hospital San Francisco California
United States Guthrie Robert Packer Hospital Sayre Pennsylvania
United States Harborview Medical Center Seattle Washington
United States Stanford University Medical Center Stanford California
United States Stony Brook University Hospital Stony Brook New York
United States SUNY Upstate Medical University Syracuse New York
United States Mercy St. Vincent Medical Center Toledo Ohio
United States Harbor-UCLA Medical Center Torrance California
United States Banner University Medical Center Tucson Arizona
United States Wake Forest Baptist Medical Center Winston-Salem North Carolina

Sponsors (5)

Lead Sponsor Collaborator
University of Michigan Johns Hopkins University, Medical University of South Carolina, National Institute of Neurological Disorders and Stroke (NINDS), National Institutes of Health (NIH)

Country where clinical trial is conducted

United States, 

Outcome

Type Measure Description Time frame Safety issue
Primary Weighted Modified Rankin Scale (mRS) The mRS is a 7 level ordinal scale of disability that ranges from 0 (no symptoms at all) to 6 (death). ICECAP uses weighting of mRS states to capture changes in functional status. 90 days after return of spontaneous circulation
Secondary All Cause Mortality All patients who are dead at follow up. 90 days after return of spontaneous circulation
Secondary NIH Toolbox Crystallized Cognition Composite Score Composite T-scores from a subset of study neuropsychological tests evaluating. 90 days after return of spontaneous circulation
Secondary NIH Toolbox Fluid Cognition Composite Score Composite T-scores from a subset of study neuropsychological tests evaluating cognitive functioning in awake survivors collected on the NIH Toolbox platform. The fluid cognition composite score is more reflective of capacity for new learning and information. processing in novel situations 90 days after return of spontaneous circulation
Secondary Pneumonia Determined by simplified Centers for Disease Control and Prevention (CDC) National Healthcare Safety Network (NHSN) definitions of Ventilator-Associated Event (VAE) or Pneumonia. 90 days after return of spontaneous circulation
Secondary Other infection Determined by simplified CDC NHSN (Center for Disease Control National Healthcare Safety Network) definitions of Urinary Tract Infection or Blood Stream Infection. 90 days after return of spontaneous circulation
Secondary Malignant cardiac arrhythmia Defined as any arrhythmia that requires termination with chest compressions, pacing, defibrillation, or electrical cardioversion. Arrhythmias (including atrial fibrillation) managed only with medication are excluded. 90 days after return of spontaneous circulation
Secondary Seizures Defined as unambiguous convulsive or electroencephalographic seizure activity triggering urgent initial or additional anticonvulsant therapy. This definition does not include those given further anticonvulsants as secondary prophylaxis or as treatment for vague or uncertain exam findings or nondiagnostic electroencephalography. It does not include myoclonus. 90 days after return of spontaneous circulation
Secondary Neurological worsening Determined by a decrease in Full Outline of Unresponsiveness (FOUR) score of =4 points that persists on two consecutive days or is associated with a neurological death. It excludes transient fluctuations in neurological examination or changes attributed to pharmacological sedation or paralysis. 90 days after return of spontaneous circulation
Secondary Electrolyte abnormalities Defined as a measured serum Na, K, Mg, or Ca that is either higher or lower than study defined boundaries on at least two sequential measurements and resulting in a change in IV therapy. It excludes deliberate hypernatremia or hypermagnesemia induced to treat intracranial hypertension or shivering. 90 days after return of spontaneous circulation
Secondary Coagulopathies Defined as requiring all 3 of the following parameters: (1) some form of major bleeding associated with (2) laboratory confirmation of an abnormal clotting axis and (3) treatment with blood product transfusion or reversal agent. Laboratory testing may include International Normalized Ratio (INR), partial thromboplastin time (PTT), clotting time, or thromboelastography. 90 days after return of spontaneous circulation
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