California Transport Cooling Trial

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.

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