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 - ICECAP trial investigators
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 - Idris, Ahamed
N1 - Publisher Copyright:
© The Author(s) 2024.
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
UR - http://www.scopus.com/inward/record.url?scp=85199368409&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85199368409&partnerID=8YFLogxK
U2 - 10.1186/s13063-024-08280-w
DO - 10.1186/s13063-024-08280-w
M3 - Article
C2 - 39044295
AN - SCOPUS:85199368409
SN - 1745-6215
VL - 25
JO - Trials
JF - Trials
IS - 1
M1 - 502
ER -