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.

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 United States. 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 hours of therapeutic 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 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, 2019-12-30).
Competing Interests: Competing interests {28} B Abella: Funding: NIH, DOD, Neuroptics, Becton Dickinson; equity: VOC Health, Neuroptics, MDAlly, volunteer: AHA T Aufderheide: Unrestricted research grant from ZOLL Medical, Inc. S Berry: Part owner of Berry Consultants K Broglio: Owns stock in AstraZeneca NIH (K23HL157610) and Hyper ne (SAFE MRI study) S Cho: NIH (K23HL157610) and Hyper ne (SAFE MRI study) R Lewis: I am the Senior Medical Scientist at Berry Consultants, LLC, a statistical consulting firm that specializes in the design, conduct, and analysis of Bayesian adaptive clinical trials. Berry Consultants contributed to the statistical design of the trial reported here. All other authors declare that they have no competing interests.