Influence of Cooling Duration on Efficacy in Cardiac Arrest Patients

Hypoxia-Ischemia, Brain Clinical Trial

— ICECAP  

Official title:

Influence of Cooling Duration on Efficacy in Cardiac Arrest Patients - A Multicenter, Randomized, Adaptive Clinical Trial to Identify the Optimal Duration of Induced Hypothermia for Neuroprotection in Comatose Survivors of Cardiac Arrest

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT04217551
• Other study ID #: G160072
• Secondary ID: U01NS073476
• Status: Recruiting
• Phase: N/A
• 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
• 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

Related Conditions & MeSH terms

• Brain Ischemia
• Cardiac Arrest, Out-Of-Hospital
• Heart Arrest
• Hypothermia
• Hypothermia, Induced
• Hypoxia
• Hypoxia-Ischemia, Brain
• Out-of-Hospital Cardiac Arrest

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