California Transport Cooling Trial

Study Overview
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Brief Summary
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Hypoxic ischemic encephalopathy (HIE) remains a major cause of death and severe disability despite advances in neonatal and perinatal medicine. Therapeutic hypothermia is the single most promising intervention for HIE. Reduction of brain temperature by 2° to 5°C has shown to be neuroprotective in newborn and adult animal models of brain ischemia. Therapeutic hypothermia instituted within 6 hours of birth has been shown to significantly improve survival and neurodevelopmental outcome in term newborns with HIE. Hypothermia is most effective if begun during the latent period, before the secondary energy failure. It is not known whether cooling initiated after 6 hours of age is effective. The goal of this proposal is to test the efficacy of the cooling device in achieving the target temperatures in patients with moderate to severe HIE during transport when compared with current practices.

Detailed Description
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Statement of the Problem: Hypoxic ischemic encephalopathy (HIE) remains a major cause of death and severe disability despite advances in neonatal and perinatal medicine. Therapeutic hypothermia is the single most promising intervention for HIE. Reduction of brain temperature by 2° to 5°C has shown to be neuroprotective in newborn and adult animal models of brain ischemia. Therapeutic hypothermia instituted within 6 hours of birth has been shown to significantly improve survival and neurodevelopmental outcome in term newborns with HIE. Hypothermia is most effective if begun during the latent period, before secondary energy failure. It is not known whether cooling initiated after 6 hours of age is effective. Animal studies have shown that the sooner the initiation of cooling, the better the outcome. They have also suggested that the latent period may be shorter with a more severe insult. Cooling should be initiated as soon as possible, preferably within 2 hours and not later than 6 hours. There have been six large randomized clinical trials supporting the efficacy of therapeutic hypothermia for HIE and it is now the standard of care in the U.S. and internationally. Once a patient qualifies for cooling, whole body cooling or selective head cooling is initiated. However, most birth hospitals do not have the ability to provide therapeutic hypothermia; thus, patients must be transported to Level 3 NICUs specially equipped to provide this therapy. As there is a limited therapeutic window for induction of hypothermia, it would be ideal to initiate therapeutic hypothermia as soon as the patient qualifies for cooling therapy. If cooling is initiated at the birth hospital, neuroprotective temperatures can be achieved several hours prior to arrival in the cooling center. At this time patients cooled in transport receive passive cooling (turning off the active warming devices such as the transport isolette) or active cooling (ice packs placed around the baby). These practices have been shown to present a significant risk for over-cooling and under-cooling. The risks associated with excessive cooling include bradycardia, cardiac arrest, and coagulation disturbances. Undercooling likely results in reduced efficacy of the neuroprotective effects provided by therapeutic hypothermia. Primary and secondary endpoints Primary end point: The percentage of temperatures in the target range (33°-34°C) both within and between enrolled infants after cooling initiation by the transport team. Secondary end point: Time to the target temperature range (33°-34°C), percentage of newborns in target temperature range one hour after cooling initiation by transport team, and temperature ranges. Study Design The proposed California Transport Cooling Trial (CTCT) is a prospective randomized multi-center clinical trial to be conducted by nine transport teams based at level III NICUs in California who perform therapeutic hypothermia for HIE. The on-call neonatologist at the participating cooling center will determine if the infant qualifies for cooling. Infants greater than or equal to 35 weeks and less than six hours of age who are being transported to a cooling center will be eligible. The transport team will randomize the infant to either cooling as per center practice (Arm 1) or device-regulated cooling (Arm 2). Subjects in Arm 1 will receive passive or active cooling as per center practice with rectal temperatures being recorded every 15 minutes. Subjects in Arm 2 will be placed on cooling blanket connected to the Tecotherm Neo. Temperature will be monitored continuously and servo-regulated using a rectal temperature probe. Pertinent clinical data will be collected using CPQCC/CPeTS data forms and CTCT data forms. Temperatures from initiation of cooling until admission to the cooling center will be analyzed for percentage of temperatures in the target range after cooling initiation by the transport team, time to target temperature range, percentage of newborns in the target temperature range 1 hour after cooling initiation by the transport team, and temperature ranges. ANOVA method will be used to compare the temperature ranges across arms. Cox proportional hazard model will be used to compare time to target temperature. Safety outcomes will be compared using standard logistic regression. Study Methods Subjects assigned to Arm 1 will be cooled as per the usual center practice with recording of rectal temperatures every 15 minutes. Arm 2 subjects will be cooled using a portable servo-regulated cooling device using a rectal probe. Temperatures will be stored on the memory card every minute. No PHI will be stored in the cooling device. Data will be downloaded from the device at the conclusion of the transport. Sample Size and Estimated Study Duration Power calculations for this study were based on anticipated 140 patients requiring initiation of therapeutic hypothermia by nine transport teams over a period of one year. A 70% consent rate and 50 patients per arm will provide 90% power to detect 30% absolute difference in the percentage of temperatures in the target range assuming a standard deviation for percentage of temperature in the target range of 45% based on the Kendall study, published in Archives of Diseases of Childhood in 2010. All analyses will adjust for center and will be two-sided and conducted at the 0.05 level of significance. We estimate that patient enrollment will take approximately one year. Data analysis, manuscript preparation, and submission will be completed within 6 months of completion of enrollment.

Official Title
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A Randomized Clinical Trial of Therapeutic Hypothermia During Transport for Hypoxic Ischemic Encephalopathy (HIE): Device-regulated Cooling Versus Standard Practice.

Conditions
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Hypoxic Ischemic Encephalopathy

Intervention / Treatment
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* Device: Device (servo-regulated cooling)
* Other: Control (standard practice)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Term or near-term infants with gestational age ≥35 weeks who meet institutional criteria for use of therapeutic hypothermia and in whom the decision has been made to perform cooling during transport. Exclusion Criteria: Presence of a congenital or lethal chromosomal anomaly Decision to not provide full intensive care Refusal to consent

Ages Eligible for Study
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Maximum Age: 6 Hours

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Control (standard practice)<br>Subjects in Arm 1 will receive passive or active cooling as per center practice with rectal temperatures being recorded every 15 minutes. | Other: Control (standard practice)<br>* Subjects in Arm 1 will receive passive or active cooling as per center practice with rectal temperatures being recorded every 15 minutes.<br>|
| Experimental: Device (servo-regulated cooling)<br>Subjects in Arm 2 will be placed on cooling blanket connected to the Tecotherm Neo (Inspiration Healthcare LTD UK). Temperature will be monitored continuously and servo-regulated using a rectal temperature probe. | Device: Device (servo-regulated cooling)<br>* Subjects in Arm 2 will be placed on cooling blanket connected to the Tecotherm Neo (Inspiration Healthcare LTD UK). Temperature will be monitored continuously and servo-regulated using a rectal temperature probe.<br>* Other names: Tecotherm Neo;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Temperatures in Target Range During Transport | The percentage of temperatures in the target range (33°-34°C) during transport after cooling initiation by the transport team. | Participants will be followed for the duration of neonatal transport from the birth hospital to the cooling center, an expected average of 4 hours | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time to Target Temperature | Time to the target temperature range (33°-34°C) from initiation of cooling by the transport team | Participants will be followed for the duration of neonatal transport from the birth hospital to the cooling center, an expected average of 4 hours | 
| Percentage of Participants in the Target Range at 1 Hour | Percentage of participants in target range (33°-34°C) one hour after cooling initiation by the transport team | Participants will be followed for the duration of neonatal transport from the birth hospital to the cooling center, an expected average of 4 hours | 
| Participants in Target Temperature Range Anytime During Transport | Participants in target temperature range (33-34 C) anytime during transport | Participants will be followed for the duration of neonatal transport from the birth hospital to the cooling center, an expected average of 4 hours | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Hypoxic ischemic encephalopathy, Therapeutic hypothermia, Whole body cooling, Transport cooling