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Influence of Cooling Duration on Efficacy in Cardiac Arrest Patients (ICECAP)

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT04217551
Recruitment Status : Recruiting
First Posted : January 3, 2020
Last Update Posted : September 18, 2020
Sponsor:
Collaborators:
Johns Hopkins University
Medical University of South Carolina
National Institutes of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Information provided by (Responsible Party):
William J Meurer, University of Michigan

Tracking Information
First Submitted Date  ICMJE December 30, 2019
First Posted Date  ICMJE January 3, 2020
Last Update Posted Date September 18, 2020
Actual Study Start Date  ICMJE May 18, 2020
Estimated Primary Completion Date June 2024   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: July 3, 2020)
Weighted Modified Rankin Scale (mRS) [ Time Frame: 90 days after return of spontaneous circulation ]
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.
Original Primary Outcome Measures  ICMJE
 (submitted: December 30, 2019)
Modified Rankin Scale [ Time Frame: 90 days after return of spontaneous circulation ]
A 7 level ordinal scale of disability
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: July 3, 2020)
  • All Cause Mortality [ Time Frame: 90 days after return of spontaneous circulation ]
    All patients who are dead at follow up.
  • NIH Toolbox Crystallized Cognition Composite Score [ Time Frame: 90 days after return of spontaneous circulation ]
    Composite T-scores from a subset of study neuropsychological tests evaluating.
  • NIH Toolbox Fluid Cognition Composite Score [ Time Frame: 90 days after return of spontaneous circulation ]
    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
  • Pneumonia [ Time Frame: 90 days after return of spontaneous circulation ]
    Determined by simplified CDC NHSN (Center for Disease Control National Healthcare Safety Network) definitions of Ventilator-Associated Event (VAE) or Pneumonia.
  • Other infection [ Time Frame: 90 days after return of spontaneous circulation ]
    Determined by simplified CDC NHSN (Center for Disease Control National Healthcare Safety Network) definitions of Urinary Tract Infection or Blood Stream Infection.
  • Malignant cardiac arrhythmia [ Time Frame: 90 days after return of spontaneous circulation ]
    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.
  • Seizures [ Time Frame: 90 days after return of spontaneous circulation ]
    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.
  • Neurological worsening [ Time Frame: 90 days after return of spontaneous circulation ]
    Determined by a decrease in 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.
  • Electrolyte abnormalities [ Time Frame: 90 days after return of spontaneous circulation ]
    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.
  • Coagulopathies [ Time Frame: 90 days after return of spontaneous circulation ]
    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 INR, PTT, clotting time, or thromboelastography.
Original Secondary Outcome Measures  ICMJE Not Provided
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Influence of Cooling Duration on Efficacy in Cardiac Arrest Patients
Official Title  ICMJE 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
Brief 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.
Detailed 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 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 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

Study Type  ICMJE Interventional
Study Phase  ICMJE Not Applicable
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Intervention Model Description:
Bayesian Adaptive Design
Masking: Single (Outcomes Assessor)
Masking Description:
The outcomes assessors will be blinded to the treatment assignment of the participant.
Primary Purpose: Treatment
Condition  ICMJE
  • Cardiac Arrest, Out-Of-Hospital
  • Hypothermia, Induced
  • Hypoxia-Ischemia, Brain
Intervention  ICMJE Device: Therapeutic Hypothermia
Participants will receive therapeutic hypothermia for the assigned number of hours with controlled rewarming, using a closed-loop temperature control device.
Study Arms  ICMJE
  • Experimental: 6 hours - shockable
    Participants with shockable initial rhythm will be assigned to receive 6 hours of hypothermia with a target of 33 degrees followed by 6 hours of controlled rewarming.
    Intervention: Device: Therapeutic Hypothermia
  • Experimental: 12 hours - shockable
    Participants with shockable initial rhythm will be assigned to receive 12 hours of hypothermia with a target of 33 degrees followed by 12 hours of controlled rewarming.
    Intervention: Device: Therapeutic Hypothermia
  • Experimental: 18 hours - shockable
    Participants with shockable initial rhythm will be assigned to receive 18 hours of hypothermia with a target of 33 degrees followed by 18 hours of controlled rewarming.
    Intervention: Device: Therapeutic Hypothermia
  • Experimental: 24 hours - shockable
    Participants with shockable initial rhythm will be assigned to receive 24 hours of hypothermia with a target of 33 degrees followed by 24 hours of controlled rewarming.
    Intervention: Device: Therapeutic Hypothermia
  • Experimental: 30 hours - shockable
    Participants with shockable initial rhythm will be assigned to receive 30 hours of hypothermia with a target of 33 degrees followed by 24 hours of controlled rewarming.
    Intervention: Device: Therapeutic Hypothermia
  • Experimental: 36 hours - shockable
    Participants with shockable initial rhythm will be assigned to receive 36 hours of hypothermia with a target of 33 degrees followed by 24 hours of controlled rewarming.
    Intervention: Device: Therapeutic Hypothermia
  • Experimental: 42 Hours - shockable
    Participants with shockable initial rhythm will be assigned to receive 42 hours of hypothermia with a target of 33 degrees followed by 24 hours of controlled rewarming.
    Intervention: Device: Therapeutic Hypothermia
  • Experimental: 48 hours - shockable
    Participants with shockable initial rhythm will be assigned to receive 48 hours of hypothermia with a target of 33 degrees followed by 24 hours of controlled rewarming.
    Intervention: Device: Therapeutic Hypothermia
  • Experimental: 60 hours - shockable
    Participants with shockable initial rhythm will be assigned to receive 60 hours of hypothermia with a target of 33 degrees followed by 24 hours of controlled rewarming.
    Intervention: Device: Therapeutic Hypothermia
  • Experimental: 72 hours - shockable
    Participants with shockable initial rhythm will be assigned to receive 72 hours of hypothermia with a target of 33 degrees followed by 24 hours of controlled rewarming.
    Intervention: Device: Therapeutic Hypothermia
  • Experimental: 6 hours - non shockable
    Participants with non-shockable initial rhythm will be assigned to receive 6 hours of hypothermia with a target of 33 degrees followed by 6 hours of controlled rewarming.
    Intervention: Device: Therapeutic Hypothermia
  • Experimental: 12 hours - non-shockable
    Participants with non-shockable initial rhythm will be assigned to receive 12 hours of hypothermia with a target of 33 degrees followed by 12 hours of controlled rewarming.
    Intervention: Device: Therapeutic Hypothermia
  • Experimental: 18 hours - non-shockable
    Participants with non-shockable initial rhythm will be assigned to receive 18 hours of hypothermia with a target of 33 degrees followed by 18 hours of controlled rewarming.
    Intervention: Device: Therapeutic Hypothermia
  • Experimental: 24 hour - non-shockable
    Participants with non-shockable initial rhythm will be assigned to receive 24 hours of hypothermia with a target of 33 degrees followed by 24 hours of controlled rewarming.
    Intervention: Device: Therapeutic Hypothermia
  • Experimental: 30 hours - non-shockable
    Participants with non-shockable initial rhythm will be assigned to receive 30 hours of hypothermia with a target of 33 degrees followed by 24 hours of controlled rewarming.
    Intervention: Device: Therapeutic Hypothermia
  • Experimental: 36 hours - non-shockable
    Participants with non-shockable initial rhythm will be assigned to receive 36 hours of hypothermia with a target of 33 degrees followed by 24 hours of controlled rewarming.
    Intervention: Device: Therapeutic Hypothermia
  • Experimental: 42 hours - non-shockable
    Participants with non-shockable initial rhythm will be assigned to receive 42 hours of hypothermia with a target of 33 degrees followed by 24 hours of controlled rewarming.
    Intervention: Device: Therapeutic Hypothermia
  • Experimental: 48 hours - non-shockable
    Participants with non-shockable initial rhythm will be assigned to receive 48 hours of hypothermia with a target of 33 degrees followed by 24 hours of controlled rewarming.
    Intervention: Device: Therapeutic Hypothermia
  • Experimental: 60 hours - non-shockable
    Participants with non-shockable initial rhythm will be assigned to receive 60 hours of hypothermia with a target of 33 degrees followed by 24 hours of controlled rewarming.
    Intervention: Device: Therapeutic Hypothermia
  • Experimental: 72 hours - non-shockable
    Participants with non-shockable initial rhythm will be assigned to receive 72 hours of hypothermia with a target of 33 degrees followed by 24 hours of controlled rewarming.
    Intervention: Device: Therapeutic Hypothermia
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Recruiting
Estimated Enrollment  ICMJE
 (submitted: December 30, 2019)
1800
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE July 2024
Estimated Primary Completion Date June 2024   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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 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
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Contact: William Meurer 734-232-2142 wmeurer@med.umich.edu
Contact: Mickie Speers 734-232-2142 lraes@med.umich.edu
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT04217551
Other Study ID Numbers  ICMJE G160072
U01NS073476 ( U.S. NIH Grant/Contract )
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: Yes
IPD Sharing Statement  ICMJE
Plan to Share IPD: Yes
Plan Description: The data will be stored in the NHLBI data repository after trial completion.
Supporting Materials: Study Protocol
Supporting Materials: Statistical Analysis Plan (SAP)
Supporting Materials: Informed Consent Form (ICF)
Time Frame: 1 year after publication on main outcome results paper
Access Criteria: Data use agreement with the appropriate NHLBI repository
Responsible Party William J Meurer, University of Michigan
Study Sponsor  ICMJE University of Michigan
Collaborators  ICMJE
  • Johns Hopkins University
  • Medical University of South Carolina
  • National Institutes of Health (NIH)
  • National Institute of Neurological Disorders and Stroke (NINDS)
Investigators  ICMJE
Principal Investigator: William Meurer University of Michigan
Principal Investigator: Robert Silbergleit University of Michigan
Principal Investigator: Romer Geocadin Johns Hopkins University
PRS Account University of Michigan
Verification Date September 2020

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP