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
Authors: Meurer William J. , Schmitzberger Florian F. , Yeatts Sharon , Ramakrishnan Viswanathan , Abella Benjamin , Aufderheide Tom , Barsan William , Benoit Justin , Berry Scott , Black Joy , Bozeman Nia , Broglio Kristine , Brown Jeremy , Brown Kimberly , Carlozzi Noelle , Caveney Angela , Cho Sung-Min , Chung-Esaki Hangyul , Clevenger Robert , Conwit Robin , Cooper Richelle , Crudo Valentina , Daya Mohamud , Harney Deneil , Hsu Cindy , Johnson Nicholas J. , Khan Imad , Khosla Shaveta , Kline Peyton , Kratz Anna , Kudenchuk Peter , Lewis Roger J. , Madiyal Chaitra , Meyer Sara , Mosier Jarrod , Mouammar Marwan , Neth Matthew , O’Neil Brian , Paxton James , Perez Sofia , Perman Sarah , Sozener Cemal , Speers Mickie , Spiteri Aimee , Stevenson Valerie , Sunthankar Kavita , Tonna Joseph , Youngquist Scott , Geocadin Romergryko , Silbergleit Robert ,   ICECAP trial investigators, Abdallah Sarah , Adler David , Agarwal Sachin , Ambroch Rachel , Ardati Amer , Ayaz Farhan , Ayodele Maranatha , Balakrishnan Meenakshi , Barksdale Aaron , Becker Torben K. , Beiser David , Beyer Margaret , Brandler Ethan , Buck Lauren , Carlson Margaret , Caterino Jeffrey , Chang Dong , Chang Wan-Tsu , Colella M. Riccardo , Cronin Alexandrea , Curtis Anna , Del Rios Marina , Denney Alan , Dodd Kenneth W. , Driver Brian , Ellender Timothy , Elmer Jonathan , Evans Dominique , Falcucci Octavio , Fowler Jennifer , Frazier Madison , Fuentes Megan , Gaieski David , Gentile Nina , Gilmore Emily , Ginde Adit , Goldstein Joshua , Grafton Gillian , Greer Matthew , Griffeth Valerie , Gupta Vedant , Hall Alex , Hall Grace , Harden Christopher , Harrison Robert , Haukoos Jason , Hemphill J. Claude , Hiller Terra , Hirsch Karen , Hunter Benton , Hypes Cameron , Idris Ahamed , James Nastasia , Jayaprakash Namita , Jones Elizabeth , Jones Christopher , Kapinos Gregory , Katsandres Sarah , Kessler Adam , Kim Joy , Kisken Kathryn , Klausner Howard , Klavens Jennifer , Knight William , Kurz Michael Christopher , Labinski Jacob , Le Nancy , Lewandowski Christopher , Limkakeng Alexander , Lyle Carol Lynn , Marks David , Maruggi Ellen , Mattrisch Linda , May Teresa , Mazzocco Thomas , McKaig Brenna , Melnychuk Eric , Merck Lisa H. , Mika Valerie , Miller Joseph , Miller Benjamin , Miner James , Mohamed Wazim , Molignoni Karli , Montero Cindy , Muschong Kayla , Na Sung Min , Nanchal Rahul , Neumar Robert , Nishijima Daniel , Nugent Katherine , O’Connor Robert E. , Obialisi Gloria , Ornato Joseph , Parker Alex , Parry Blair Alden , Patkar Nivedita , Paul Jonathan , Peberdy MaryAnn , Peterson Lars-Kristofer , Porter Tedra , Prekker Matthew , Pruitt Peter , Purim-Shem-Tov Yanina , Puskarich Michael , Randazzo Dominica , Remboski Lauren , Reynolds Joshua , Rittenberger Jon , Roberts Christopher , Rodriguez Robert , Sah Birendra , Sebat Christian , Sell Rebecca , Shaker Reza , Shelton Shelby , Sherma Arun , Silverman Michael , Siry Bonnie , Spurlock Bill , Srinivasan Vasisht , Stanley Nicholas , Starkman Sidney , Suh Edward , Thayer Timothy , Thomas Michael , Thompson Kathryn , Tolles Juliana , Toossi Shahed , Torbati Sam , Vollmer Abigail , Wang Henry , Wardi Gabriel , Wesner Nicholas , Wilson Kathleen , Wira Charles , Wood Nancy , Yadav Kabir , Yang Jenny , Zimmermann Lara , Zwank Michael D. 
Published: July 2024

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.