Influence of Cooling duration on Efficacy in Cardiac Arrest Patients (ICECAP): study protocol for a multicenter, randomized, adaptive allocation clinical trial to identify the optimal duration of induced hypothermia for neuroprotection in comatose, adult survivors of after out-of-hospital cardiac arrest

doi:10.1186/s13063-024-08280-w

Influence of Cooling duration on Efficacy in Cardiac Arrest Patients (ICECAP): study protocol for a multicenter, randomized, adaptive allocation clinical trial to identify the optimal duration of induced hypothermia for neuroprotection in comatose, adult survivors of after out-of-hospital cardiac arrest

Research output: Contribution to journal › Article › peer-review

5 Scopus citations

Abstract

Background: Cardiac arrest is a common and devastating emergency of both the heart and brain. More than 380,000 patients suffer out-of-hospital cardiac arrest annually in the USA. Induced cooling of comatose patients markedly improved neurological and functional outcomes in pivotal randomized clinical trials, but the optimal duration of therapeutic hypothermia has not yet been established. Methods: This study is a multi-center randomized, response-adaptive, duration (dose) finding, comparative effectiveness clinical trial with blinded outcome assessment. We investigate two populations of adult comatose survivors of cardiac arrest to ascertain the shortest duration of cooling that provides the maximum treatment effect. The design is based on a statistical model of response as defined by the primary endpoint, a weighted 90-day mRS (modified Rankin Scale, a measure of neurologic disability), across the treatment arms. Subjects will initially be equally randomized between 12, 24, and 48 h of therapeutic cooling. After the first 200 subjects have been randomized, additional treatment arms between 12 and 48 h will be opened and patients will be allocated, within each initial cardiac rhythm type (shockable or non-shockable), by response adaptive randomization. As the trial continues, shorter and longer duration arms may be opened. A maximum sample size of 1800 subjects is proposed. Secondary objectives are to characterize: the overall safety and adverse events associated with duration of cooling, the effect on neuropsychological outcomes, and the effect on patient-reported quality of life measures. Discussion: In vitro and in vivo studies have shown the neuroprotective effects of therapeutic hypothermia for 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 a good outcome. If the treatment effect of cooling is increasing across duration, for at least some set of durations, then this provides evidence of the efficacy of cooling itself versus normothermia, even in the absence of a normothermia control arm, confirming previous RCTs for OHCA survivors of shockable rhythms and provides the first prospective controlled evidence of efficacy in those without initial shockable rhythms. Trial registration: ClinicalTrials.gov NCT04217551. Registered on 30 December 2019.

Original language	English
Article number	502
Journal	Trials
Volume	25
Issue number	1
DOIs	https://doi.org/10.1186/s13063-024-08280-w
State	Published - Dec 2024

Bibliographical note

Publisher Copyright:
© The Author(s) 2024.

Funding

We would like to acknowledge the work of the data safety and monitoring board. ICECAP trial investigators (to be named): Sarah Abdallah, BS, [email protected], Medical College of Wisconsin, Emergency Medicine, Milwaukee, WI David Adler, MD, MPH, [email protected], University of Rochester, Emergency Medicine, Rochester, NY Sachin Agarwal, MD, MPH, [email protected], Columbia University Medical Center, Neurology, Neurocritical care, New York Rachel Ambroch, BS, [email protected], Medical College of Wisconsin, Medicine Cardiology, Milwaukee, WI Amer Ardati, MD MSc, [email protected], Univ Illinois Chicago, Medicine Cardiology, Chicago IL Farhan Ayaz, MD, [email protected], Wayne State University, Emergency Medicine, Detroit, MI Maranatha Ayodele, MD, [email protected], Cedars-Sinai Medical Center, Neurology, Los Angeles, CA Meenakshi Balakrishnan, PhD, MPH, [email protected], University of Florida, Emergency Medicine, Gainesville, FL Aaron Barksdale, MD, [email protected], University of Nebraska Medical Center, Emergency medicine, Omaha, NE Torben K Becker, MD, PhD, [email protected], University of Florida, Emergency Medicine, Gainesville, FL David Beiser, MD, MS, [email protected], University of Chicago, Section of Emergency Medicine, Chicago, IL Margaret Beyer, BS, [email protected], Henry Ford Hospital, Emergency Medicine Research, Detroit, MI Ethan Brandler, MD, MPH, [email protected], SUNY Stony Brook, Emergency Medicine, Stony Brook, NY Lauren Buck, [email protected], Wayne state university, Detroit, MI Margaret Carlson, MPH, [email protected], University of Utah, Surgery\u2014Division of Cardiothoracic Surgery, Salt Lake City, UT Jeffrey Caterino, MD, MPH, [email protected], The Ohio State University Wexner Medical Center, Emergency Medicine, Columbus, OH Dong Chang, MD, MS, [email protected], Lundquist Institute at Harbor-UCLA Medical Center, Medicine, Torrance, CA Wan-Tsu Chang, MD, [email protected], University of Maryland School of Medicine, Emergency Medicine, Neurology, Program in Trauma, Baltimore, MD M. Riccardo Colella, DO, [email protected], Medical College of Wisconsin, Emergency Medicine, Milwaukee, WI Alexandrea Cronin, MPH, [email protected], University of California, San Diego, Emergency Medicine, San Diego, CA Anna Curtis, BS, [email protected], The Medical College of Wisconsin, Emergency Medicine, Wauwatosa, WI Marina Del Rios, MD, MS, [email protected], University of Illinois at Chicago, Emergency Medicine, Chicago, IL Alan Denney, MD, [email protected], Regions Hospital, Critical Care Research, Saint Paul, MI Kenneth W. Dodd, MD, [email protected], #1 Advocate Christ Medical Center, #2 University of Illinois, Emergency Medicine, Oak Lawn, IL Brian Driver, MD, [email protected], Hennepin County Medical Center, Emergency Medicine, Minneapolis, MN Timothy Ellender, MD, BSN, [email protected], Indiana University, Emergency Medicine, Indianapolis, IN Jonathan Elmer, MD, MS, [email protected], University of Pittsburgh, Emergency Medicine, Critical Care Medicine and Neurology, Pittsburgh, PA Dominique Evans, BS, [email protected], Medical College of Wisconsin, Emergency Medicine, Milwaukee, WI Octavio Falcucci, MD, [email protected], Medical College of Wisconsin, Anesthesiology, Milwaukee, WI Jennifer Fowler, BSN, [email protected], University of Michigan, Emergency Medicine Research, Ann Arbor, MI Madison Frazier, BS, [email protected], Duke University, Department of Surgery, Durham, NC Megan Fuentes, BS, [email protected], University of Washington, Emergency Medicine, Seattle, WA David Gaieski, MD, [email protected], Thomas Jefferson University, Emergency Medicine, Philadelphia, PA Nina Gentile, MD, [email protected], Lewis Katz School of Medicine at Temple University, Emergency Medicine, Philadelphia, PA Emily Gilmore, MD, MS, [email protected], Yale University, Neurology, New Haven, CT Adit Ginde, MD, MPH, [email protected], University of Colorado School of Medicine, Emergency Medicine, Aurora, CO Joshua Goldstein, MD, PhD, [email protected], Massachusetts General Hospital, Emergency Medicine, Boston, MA Gillian Grafton, DO, [email protected], Henry Ford Hospital, Cardiovascular Medicine, Detroit, MI Matthew Greer, MD, [email protected], University of California Davis, Emergency Medicine, Sacramento, CA Valerie Griffeth, MD, PhD, [email protected], Advocate Aurora Health, Critical Care Medicine, Chicago, IL Vedant Gupta, MD, [email protected], University of Kentucky, Internal Medicine\u2014Cardiovascular Medicine, Lexington, KY Alex Hall, DHSc, MS, RN, [email protected], Emory University, Emergency Medicine, Atlanta, GA Grace Hall, MS, [email protected], Duke University, Emergency Medicine, Durham NC Christopher Harden, MD, [email protected], University of Florida, Pulmonary Critical Care and Sleep Medicine, Gainesville, FL Robert Harrison, MD, [email protected], Duke University, Medicine Cardiology, Durham NC Jason Haukoos, MD, MSc, [email protected], Denver Health Medical Center, Emergency Medicine, Denver, CO J. Claude Hemphill, MD,MAS, [email protected], University of California, San Francisco, Neurology, San Francisco, CA Terra Hiller, MSN, RN, CNL, [email protected], Denver Health Medical Center, Medicine, Denver, CO Karen Hirsch, MD, [email protected], Stanford University, Neurology, Stanford, CA Benton Hunter, MD, [email protected], Indiana University, Emergency, Indianapolis, IN Cameron Hypes, MD MPH, [email protected], University of Arizona, Emergency Medicine, Tucson, AZ Ahamed Idris, MD, [email protected], University of Texas Southwestern Medical Center, Emergency Medicine, Dallas, TX Nastasia James, MS, [email protected], University of Florida, Emergency Medicine, Gainesville, FL Namita Jayaprakash, MB Bch BAO, MRCEM, [email protected], Henry Ford Health System, Emergency Medicine, Pulmonary and Critical Care Medicine, Detroit, MI Elizabeth Jones, MD, [email protected], University of Texas Health Science Center at Houston, Emergency Medicine, Houston, TX Christopher Jones, MD, [email protected], Cooper University Health System, Emergency Medicine, Camden, NJ Gregory Kapinos, MD, MS, [email protected], New York City Health + Hospitals & State University of New York, Neurology, Neurosurgery, Emergency Medicine, Surgery, New York, NY Sarah Katsandres, [email protected], University of Washington, Emergency Medicine, Seattle, WA Adam Kessler, DO, [email protected], UAB, Emergency Medicine, Birmingham, AL Joy Kim, BS, [email protected], OHSU, Emergency Medicine, Portland, OR Kathryn Kisken, MS, MPH, [email protected], Yale School of Medicine, Emergency Medicine, New Haven, CT Howard Klausner, MD, [email protected], Henry Ford Hospital, Emergency Medicine, Detroit, MI Jennifer Klavens, Bachelor of Science, [email protected], Cooper University Hospital,, Camden, NJ William Knight, MD, [email protected], University of Cincinnati, Emergency Medicine, Neurology, Neurosurgery, Cincinnati, OH Michael Christopher Kurz, MD MS, [email protected], University of Alabama at Birmingham, Emergency Medicine, Birmingham, AL Jacob Labinski, BA, [email protected], Medical College of Wisconsin, Emergency Medicine, Milwaukee, WI Nancy Le, BA, MSN, [email protected], Oregon Health & Science University, Emergency Medicine, Portland, OR Christopher Lewandowski, MD, [email protected], Henry Ford Health System, Emergency Medicine, Detroit, MI Alexander Limkakeng, MD, MHSc, [email protected], Duke University, Emergency Medicine, Durham NC Carol Lynn Lyle, PA-C, MPH, [email protected], Denver Health Hospital and Authority,, Denver, CO David Marks, MD, MBA, [email protected], Medical College of Wisconsin, Medicine, Milwaukee, WI Ellen Maruggi, BS, [email protected], Hennepin County Medical Center, Emergency Medicine, Minneapolis, MN Linda Mattrisch, BS, [email protected], MCW, Research, Milwaukee, WI Teresa May, DO MS, [email protected], Maine Medical Center, Critical Care, Portland ME Thomas Mazzocco, BSN, [email protected], Wayne State University, Emergency Medicine Research, Detroit, MI Brenna McKaig, BS, [email protected], Massachusetts General Hospital, Emergency Medicine, Boston, MA Eric Melnychuk, DO, [email protected], Geisinger Medical Center, Emergency Medicine and Critical Care, Mechanicsville, PA Lisa H. Merck, MD MPH MA FACEP, [email protected], University of Florida, Emergency Medicine, Neurology,Neurocritical Care, Gainesville, FL Valerie Mika, MS, [email protected], Wayne State University, Emergency Medicine, Detroit, MI Joseph Miller, MD, MS, [email protected], Henry Ford Hospital, Emergency Medicine, Detroit, MI Benjamin Miller, MD, [email protected], University of Minnesota, Neurology, Minneapolis, MN James Miner, MD, [email protected], University of Minnesota, Emergency Medicine, Minnetrista, MN Wazim Mohamed, MD, [email protected], Wayne State University, Neurology, Detroit, MI Karli Molignoni, [email protected], University of Chicago, Emergency Medicine, Chicago, Il Cindy Montero, MS, [email protected], University of Florida, Emergency Medicine, Gainesville, FL Kayla Muschong, BS, [email protected], Northwestern University Feinberg School of Medicine, Emergency Medicine, Chicago, IL Sung Min Na, BS, [email protected], Cedars-Sinai Medical Center, Neurosciences, Los Angeles, CA Rahul Nanchal, MD, [email protected], Medical College of Wisconsin, Pulmonary Medicine, Milwaukee, WI Robert Neumar, MD, PhD, [email protected], University of Michigan, Emergency Medicine, Ann Arbor, MI Daniel Nishijima, MD, MAS, [email protected], University of California, Davis, Emergency Medicine, Sacramento, CA Katherine Nugent, MD, [email protected], Emory University, Emergency Medicine; Anesthesiology, Atlanta, GA Robert E. O\u2019Connor, M.D., MPH, [email protected], University of Virginia, Emergency Medicine, Charlottesville, VA Gloria Obialisi, MS, [email protected], Cedars-Sinai Medical Center, Neurosciences, Los Angeles, CA Joseph Ornato, MD, [email protected], Virginia Commonwealth University, Emergency Medicine, Richmond, VI Alex Parker, MD, [email protected], University of Florida, Medicine, Gainesville, FL Blair Alden Parry, CCRC, BA, [email protected], Massachusetts General Hospital, Emergency Medicine, Boston, MA Nivedita Patkar, MD, MSPH, [email protected], University of Alabama at Birmingham, Emergency Medicine, Birmingham, AL Jonathan Paul, MD, [email protected], University of Chicago, Medicine, Section of Cardiology, Chicago, IL MaryAnn Peberdy, MD, [email protected], Virginia Commonwealth University, Internal Medicine, Richmond, VI Lars-Kristofer Peterson, MD, [email protected], Cooper University Hospital, Emergency Medicine, Critical Care Medicine, Camden, NJ Tedra Porter, MHA, [email protected], Duke University Health System, Surgery, Durham, NC Matthew Prekker, MD, MPH, [email protected], Hennepin County Medical Center, Medicine, Minneapolis, MN Peter Pruitt, MD, MS, [email protected], Northwestern University Feinberg School of Medicine, Emergency Medicine, Chicago, IL Yanina Purim-Shem-Tov, MD, MS, [email protected], Rush University Medical Center, Emergency Medicine, Chicago, IL Michael Puskarich, MD MSCR, [email protected], University of Minnesota / Hennepin County Medical Center, Emergency Medicine, Minneapolis, MN Dominica Randazzo, BS, CCRP, [email protected], University of California, San Francisco, Neurology, San Francisco, CA Lauren Remboski, MS, [email protected], Cooper University Hospital, Emergency Medicine, Camden, NJ Joshua Reynolds, MD, MS, [email protected], Michigan State University, Emergency Medicine, Grand Rapids, MI Jon Rittenberger, MD, MS, [email protected], Guthrie Robert Packer Hospital, Emergency Medicine, Sayre, PA Christopher Roberts, MD, PhD, [email protected], Medical College of Wisconsin, Anesthesiology, Milwaukee, WI Robert Rodriguez, MD, [email protected], University of California San Francisco, Emergency Medicine, San Francisco, CA Birendra Sah, MD, FCCP, [email protected], Upstate Medical University, Pulmonary, Critical Medicine, Syracuse, NY Christian Sebat, DO, [email protected], University of California, Davis, Internal Medicine, Sacramento, CA Rebecca Sell, MD, [email protected], University of California, San Diego, Medicine, San Diego, CA Reza Shaker, MD, [email protected], Medical College of Wisconsin, Medicine, Milwaukee, WI Shelby Shelton, MPH, [email protected], University of Colorado School of Medicine, Emergency Medicine, Aurora, CO Arun Sherma, MD, [email protected], Wayne State University School of Medicine, Neurology, Detroit, MI Michael Silverman, MD, MPH, [email protected], Massachusetts General Hospital, Cardiology, Boston, MA Bonnie Siry, MSS, [email protected], University of Colorado, Emergency Medicine, Aurora, CO Bill Spurlock, DO, [email protected], Portland Adventist Medical Center/OHSU, Hospitalist, Portland, OR Vasisht Srinivasan, MD, [email protected], University of Washington, Emergency Medicine, Seattle, WA Nicholas Stanley, MS, [email protected], Emory University,, Atlanta, GA Sidney Starkman, MD, [email protected], UCLA, Emergency Medicine, Neurology, Los Angeles, CA Edward Suh, MD, [email protected], Columbia University, Emergency Medicine, New York, NY Timothy Thayer, MD, [email protected], Vanderbilt University Medical Center, Internal Medicine, Division of Cardiovascular Medicine, Nashville, TN Michael Thomas, MD, [email protected], University of Michigan, Cardiovascular Medicine, Ann Arbor, MI Kathryn Thompson, BS, [email protected], University of Washington-Harborview Medical Center, Emergency Medicine, Seattle, WA Juliana Tolles, MD, MHS, [email protected], Harbor-ucla medical center, Emergency Medicine, Torrance, CA Shahed Toossi, MD, [email protected], Cedars-Sinai Medical Center, Neurology, Neurosurgery, Los Angeles, CA Sam Torbati, MD, [email protected], Cedars-Sinai Medical Center, Emergency Medicine, Los Angeles, CA Abigail Vollmer, BA, [email protected], University of Cincinnati, Emergency Medicine, Cincinnati, OH Henry Wang, MD, MS, [email protected], The Ohio State University, Emergency Medicine, Columbus, OH Gabriel Wardi, MD, MPH, [email protected], University of California, San Diego, Emergency Medicine, San Diego, CA Nicholas Wesner, [email protected], Wayne State University,, Detroit, MI Kathleen Wilson, RN, BSN, MS, [email protected], Henry Ford Health System, Emergency Medicine, Detroit, MI Charles Wira, MD, [email protected], Yale School of Medicine, Emergency Medicine, New Haven, CT Nancy Wood, MS, [email protected], University of Rochester, Emergency Medicine, Rochester, NY Kabir Yadav, MDCM MS MSHS, [email protected], Harbor-UCLA Medical Center, Emergency Medicine, Torrance, CA Jenny Yang, MD, [email protected], University of California San Diego, Medicine, Division of Pulmonary, Critical Care and Sleep Medicine, San Diego, CA Lara Zimmermann, MD, [email protected], UC Davis Medical Center, Neurosurgery, Sacramento, CA Michael D. Zwank, MD, [email protected], Regions Hospital, Saint Paul, MN T Aufderheide: Unrestricted research grant from ZOLL Medical, Inc. \u201CResearch reported in this publication was supported by the National Institutes of Health under Awards U24NS100659 and U24NS100655. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

Funders	Funder number
University of Minnesota Rochester
ZOLL Medical, Inc.
Minnesota State University-Mankato
Emergency Medicine, Detroit, MI Charles Wira
University of Colorado School of Medicine, Anschutz Medical Campus
Mental Health Association of Westchester County
University of Alabama
Michigan State University
Wayne State University, Neurology, Detroit, MI Karli Molignoni
Hennepin County Medical Center, Medicine, Minneapolis
University of Colorado Hospital Denver
Henry Ford Hospital
University of Cincinnati University Research Council
Thomas Jefferson University Hospital
Harborview Medical Center Department of Emergency Medicine The University of Washington Seattle WA.
University of Texas Southwestern Medical Center
Department of Emergency Medicine Denver Health and Hospital Authority Denver CO.
University of Alabama, Birmingham
Oregon Institute of Occupational Health Sciences, Oregon Health and Science University
State University of New York Upstate Medical University
Virginia Commonwealth University
MI Brenna McKaig
Ohio Water Resources Center, Ohio State University
Oregon Health and Science University
Stanford Cardiovascular Institute, School of Medicine, Stanford University
Ohio State University Wexner Medical Center
The University of Chicago
University of California, Los Angeles
University of California San Diego Health
Cedars-Sinai Medical Center
Canadian Nuclear Laboratories
University of Kentucky
Duke-Kunshan University
University of Southern Indiana
The University of Texas Health Science Center at San Antonio
LABioMed at Harbor-UCLA Medical Center
Massachusetts General Hospital
University of Utah Health
Yale University School of Medicine
University of Nebraska Medical Center
Cooper University Hospital
University of Maryland School of Medicine, University of Maryland ALS Clinic
Lewis Katz School of Medicine at Temple University
Florida AandM University and Florida State University
University of Northern Arizona
University of California Davis
University of Pittsburgh Medical Center, Children's Hospital of Pittsburgh
Hospitals & State University of New York
Department of Psychiatry, Columbia University Irving Medical Center, New York, USA; New York State Psychiatric Institute, New York, USA
Virginia Agricultural Experiment Station, Virginia Polytechnic Institute and State University
Cooper University Hospital
Yale University
Henry Ford Health System
Hennepin County Medical Center
Vanderbilt Digestive Diseases Research Center, Vanderbilt University Medical Center
The George Washington University
Wayne State University School of Medicine, Neurology, Detroit, MI Michael Silverman
Michigan Retirement Research Center, University of Michigan
Wayne State University
Critical Care Medicine, Detroit, MI Elizabeth Jones
Denver Health Medical Center
National Institutes of Health (NIH)	U24NS100659, U24NS100655
National Institutes of Health (NIH)

Keywords

Bayesian adaptive trial
Cardiopulmonary Resuscitation
Hypothermia
Induced
Neuroprotection; Out-of-Hospital Cardiac Arrest

ASJC Scopus subject areas

Medicine (miscellaneous)
Pharmacology (medical)

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(2024). Influence of Cooling duration on Efficacy in Cardiac Arrest Patients (ICECAP): study protocol for a multicenter, randomized, adaptive allocation clinical trial to identify the optimal duration of induced hypothermia for neuroprotection in comatose, adult survivors of after out-of-hospital cardiac arrest. Trials, 25(1), Article 502. https://doi.org/10.1186/s13063-024-08280-w

@article{0765264ac7464906971a7e3224c1ab6d,

title = "Influence of Cooling duration on Efficacy in Cardiac Arrest Patients (ICECAP): study protocol for a multicenter, randomized, adaptive allocation clinical trial to identify the optimal duration of induced hypothermia for neuroprotection in comatose, adult survivors of after out-of-hospital cardiac arrest",

abstract = "Background: Cardiac arrest is a common and devastating emergency of both the heart and brain. More than 380,000 patients suffer out-of-hospital cardiac arrest annually in the USA. Induced cooling of comatose patients markedly improved neurological and functional outcomes in pivotal randomized clinical trials, but the optimal duration of therapeutic hypothermia has not yet been established. Methods: This study is a multi-center randomized, response-adaptive, duration (dose) finding, comparative effectiveness clinical trial with blinded outcome assessment. We investigate two populations of adult comatose survivors of cardiac arrest to ascertain the shortest duration of cooling that provides the maximum treatment effect. The design is based on a statistical model of response as defined by the primary endpoint, a weighted 90-day mRS (modified Rankin Scale, a measure of neurologic disability), across the treatment arms. Subjects will initially be equally randomized between 12, 24, and 48 h of therapeutic cooling. After the first 200 subjects have been randomized, additional treatment arms between 12 and 48 h will be opened and patients will be allocated, within each initial cardiac rhythm type (shockable or non-shockable), by response adaptive randomization. As the trial continues, shorter and longer duration arms may be opened. A maximum sample size of 1800 subjects is proposed. Secondary objectives are to characterize: the overall safety and adverse events associated with duration of cooling, the effect on neuropsychological outcomes, and the effect on patient-reported quality of life measures. Discussion: In vitro and in vivo studies have shown the neuroprotective effects of therapeutic hypothermia for 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 a good outcome. If the treatment effect of cooling is increasing across duration, for at least some set of durations, then this provides evidence of the efficacy of cooling itself versus normothermia, even in the absence of a normothermia control arm, confirming previous RCTs for OHCA survivors of shockable rhythms and provides the first prospective controlled evidence of efficacy in those without initial shockable rhythms. Trial registration: ClinicalTrials.gov NCT04217551. Registered on 30 December 2019.",

keywords = "Bayesian adaptive trial, Cardiopulmonary Resuscitation, Hypothermia, Induced, Neuroprotection; Out-of-Hospital Cardiac Arrest",

author = "Meurer, \{William J.\} and Schmitzberger, \{Florian F.\} and Sharon Yeatts and Viswanathan Ramakrishnan and Benjamin Abella and Tom Aufderheide and William Barsan and Justin Benoit and Scott Berry and Joy Black and Nia Bozeman and Kristine Broglio and Jeremy Brown and Kimberly Brown and Noelle Carlozzi and Angela Caveney and Cho, \{Sung Min\} and Hangyul Chung-Esaki and Robert Clevenger and Robin Conwit and Richelle Cooper and Valentina Crudo and Mohamud Daya and Deneil Harney and Cindy Hsu and Johnson, \{Nicholas J.\} and Imad Khan and Shaveta Khosla and Peyton Kline and Anna Kratz and Peter Kudenchuk and Lewis, \{Roger J.\} and Chaitra Madiyal and Sara Meyer and Jarrod Mosier and Marwan Mouammar and Matthew Neth and Brian O{\textquoteright}Neil and James Paxton and Sofia Perez and Sarah Perman and Cemal Sozener and Mickie Speers and Aimee Spiteri and Valerie Stevenson and Kavita Sunthankar and Joseph Tonna and Scott Youngquist and Romergryko Geocadin and Vedant Gupta",

note = "Publisher Copyright: {\textcopyright} The Author(s) 2024.",

year = "2024",

month = dec,

doi = "10.1186/s13063-024-08280-w",

language = "English",

volume = "25",

number = "1",

}

2024, 'Influence of Cooling duration on Efficacy in Cardiac Arrest Patients (ICECAP): study protocol for a multicenter, randomized, adaptive allocation clinical trial to identify the optimal duration of induced hypothermia for neuroprotection in comatose, adult survivors of after out-of-hospital cardiac arrest', Trials, vol. 25, no. 1, 502. https://doi.org/10.1186/s13063-024-08280-w

Influence of Cooling duration on Efficacy in Cardiac Arrest Patients (ICECAP): study protocol for a multicenter, randomized, adaptive allocation clinical trial to identify the optimal duration of induced hypothermia for neuroprotection in comatose, adult survivors of after out-of-hospital cardiac arrest. /.
In: Trials, Vol. 25, No. 1, 502, 12.2024.

Research output: Contribution to journal › Article › peer-review

TY - JOUR

T1 - Influence of Cooling duration on Efficacy in Cardiac Arrest Patients (ICECAP)

T2 - study protocol for a multicenter, randomized, adaptive allocation clinical trial to identify the optimal duration of induced hypothermia for neuroprotection in comatose, adult survivors of after out-of-hospital cardiac arrest

AU - Meurer, William J.

AU - Schmitzberger, Florian F.

AU - Yeatts, Sharon

AU - Ramakrishnan, Viswanathan

AU - Abella, Benjamin

AU - Aufderheide, Tom

AU - Barsan, William

AU - Benoit, Justin

AU - Berry, Scott

AU - Black, Joy

AU - Bozeman, Nia

AU - Broglio, Kristine

AU - Brown, Jeremy

AU - Brown, Kimberly

AU - Carlozzi, Noelle

AU - Caveney, Angela

AU - Cho, Sung Min

AU - Chung-Esaki, Hangyul

AU - Clevenger, Robert

AU - Conwit, Robin

AU - Cooper, Richelle

AU - Crudo, Valentina

AU - Daya, Mohamud

AU - Harney, Deneil

AU - Hsu, Cindy

AU - Johnson, Nicholas J.

AU - Khan, Imad

AU - Khosla, Shaveta

AU - Kline, Peyton

AU - Kratz, Anna

AU - Kudenchuk, Peter

AU - Lewis, Roger J.

AU - Madiyal, Chaitra

AU - Meyer, Sara

AU - Mosier, Jarrod

AU - Mouammar, Marwan

AU - Neth, Matthew

AU - O’Neil, Brian

AU - Paxton, James

AU - Perez, Sofia

AU - Perman, Sarah

AU - Sozener, Cemal

AU - Speers, Mickie

AU - Spiteri, Aimee

AU - Stevenson, Valerie

AU - Sunthankar, Kavita

AU - Tonna, Joseph

AU - Youngquist, Scott

AU - Geocadin, Romergryko

AU - Gupta, Vedant

PY - 2024/12

Y1 - 2024/12

N2 - Background: Cardiac arrest is a common and devastating emergency of both the heart and brain. More than 380,000 patients suffer out-of-hospital cardiac arrest annually in the USA. Induced cooling of comatose patients markedly improved neurological and functional outcomes in pivotal randomized clinical trials, but the optimal duration of therapeutic hypothermia has not yet been established. Methods: This study is a multi-center randomized, response-adaptive, duration (dose) finding, comparative effectiveness clinical trial with blinded outcome assessment. We investigate two populations of adult comatose survivors of cardiac arrest to ascertain the shortest duration of cooling that provides the maximum treatment effect. The design is based on a statistical model of response as defined by the primary endpoint, a weighted 90-day mRS (modified Rankin Scale, a measure of neurologic disability), across the treatment arms. Subjects will initially be equally randomized between 12, 24, and 48 h of therapeutic cooling. After the first 200 subjects have been randomized, additional treatment arms between 12 and 48 h will be opened and patients will be allocated, within each initial cardiac rhythm type (shockable or non-shockable), by response adaptive randomization. As the trial continues, shorter and longer duration arms may be opened. A maximum sample size of 1800 subjects is proposed. Secondary objectives are to characterize: the overall safety and adverse events associated with duration of cooling, the effect on neuropsychological outcomes, and the effect on patient-reported quality of life measures. Discussion: In vitro and in vivo studies have shown the neuroprotective effects of therapeutic hypothermia for 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 a good outcome. If the treatment effect of cooling is increasing across duration, for at least some set of durations, then this provides evidence of the efficacy of cooling itself versus normothermia, even in the absence of a normothermia control arm, confirming previous RCTs for OHCA survivors of shockable rhythms and provides the first prospective controlled evidence of efficacy in those without initial shockable rhythms. Trial registration: ClinicalTrials.gov NCT04217551. Registered on 30 December 2019.

AB - Background: Cardiac arrest is a common and devastating emergency of both the heart and brain. More than 380,000 patients suffer out-of-hospital cardiac arrest annually in the USA. Induced cooling of comatose patients markedly improved neurological and functional outcomes in pivotal randomized clinical trials, but the optimal duration of therapeutic hypothermia has not yet been established. Methods: This study is a multi-center randomized, response-adaptive, duration (dose) finding, comparative effectiveness clinical trial with blinded outcome assessment. We investigate two populations of adult comatose survivors of cardiac arrest to ascertain the shortest duration of cooling that provides the maximum treatment effect. The design is based on a statistical model of response as defined by the primary endpoint, a weighted 90-day mRS (modified Rankin Scale, a measure of neurologic disability), across the treatment arms. Subjects will initially be equally randomized between 12, 24, and 48 h of therapeutic cooling. After the first 200 subjects have been randomized, additional treatment arms between 12 and 48 h will be opened and patients will be allocated, within each initial cardiac rhythm type (shockable or non-shockable), by response adaptive randomization. As the trial continues, shorter and longer duration arms may be opened. A maximum sample size of 1800 subjects is proposed. Secondary objectives are to characterize: the overall safety and adverse events associated with duration of cooling, the effect on neuropsychological outcomes, and the effect on patient-reported quality of life measures. Discussion: In vitro and in vivo studies have shown the neuroprotective effects of therapeutic hypothermia for 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 a good outcome. If the treatment effect of cooling is increasing across duration, for at least some set of durations, then this provides evidence of the efficacy of cooling itself versus normothermia, even in the absence of a normothermia control arm, confirming previous RCTs for OHCA survivors of shockable rhythms and provides the first prospective controlled evidence of efficacy in those without initial shockable rhythms. Trial registration: ClinicalTrials.gov NCT04217551. Registered on 30 December 2019.

KW - Bayesian adaptive trial

KW - Cardiopulmonary Resuscitation

KW - Hypothermia

KW - Induced

KW - Neuroprotection; Out-of-Hospital Cardiac Arrest

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