An interventional study of Device (servo-regulated cooling) and Control (standard practice) in Hypoxic Ischemic Encephalopathy, sponsored by Stanford University. Completed at 9 sites in United States. Open to participants aged Up to 6 Hours. Per ClinicalTrials.gov, last updated 2014-12-08.
Sponsored by Stanford University · Not applicable, Interventional, and Treatment
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.
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.
240 studies on the registry are indexed under Hypoxia-Ischemia, Brain; 85 are open to participants now.
This study's enrollment of 101 is above the median of 50 across 140 interventional studies indexed under Hypoxia-Ischemia, Brain.
Browse Hypoxia-Ischemia, Brain studies →Stanford University is the lead sponsor of 2,162 studies on the registry; 429 are open to participants now.
Of its 267 completed or terminated interventional studies of FDA-regulated products, 207 (78%) have results posted.
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Exclusion Criteria:
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)
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)
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.
Also known as: Tecotherm Neo
Subjects in Arm 1 will receive passive or active cooling as per center practice with rectal temperatures being recorded every 15 minutes.
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.
Time frame: Participants will be followed for the duration of neonatal transport from the birth hospital to the cooling center, an expected average of 4 hours
Time to Target Temperature
Time to the target temperature range (33°-34°C) from initiation of cooling by the transport team
Time frame: 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
Time frame: 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
Time frame: Participants will be followed for the duration of neonatal transport from the birth hospital to the cooling center, an expected average of 4 hours
Safety Outcomes
The incidence, intervention and outcome of cardiac arrhythmia, major bleeding, altered skin integrity, pulmonary hypertension, device-related events, death, and other serious adverse events from the time of initiation of transport cooling to the time of completion will be monitored.
Time frame: Participants will be followed for the duration of neonatal transport from the birth hospital to the cooling center, an expected average of 4 hours
131 infants were screened for eligibility at nine participating NICUs between October 1, 2012 and September 27th, 2013. Eligible infants had a gestational age of at least 35 weeks, met institutional criteria for use of therapeutic hypothermia, and a decision had been made to initiate cooling in transport.
| Milestone | Control (Standard Cooling) | Device (Servo-regulated Cooling) |
|---|---|---|
| Started | 50 | 51 |
| Transported and treated | 49 | 51 |
| Completed | 49 | 51 |
| Not completed | 1 | 0 |
| Withdrew: Infant was not transported | 1 | 0 |
The percentage of temperatures in the target range (33°-34°C) during transport after cooling initiation by the transport team.
| Percentage of temperatures | Control (Standard Cooling) | Device (Servo-regulated Cooling) |
|---|---|---|
| Percentage of Temperatures in Target Range During Transport | 0 (0 to 52) | 73 (17 to 88) |
Time to the target temperature range (33°-34°C) from initiation of cooling by the transport team
| Minutes | Control (Standard Cooling) | Device (Servo-regulated Cooling) |
|---|---|---|
| Time to Target Temperature | 63 ± 37 | 44 ± 31 |
Percentage of participants in target range (33°-34°C) one hour after cooling initiation by the transport team
| Percentage of participants | Control (Standard Cooling) | Device (Servo-regulated Cooling) |
|---|---|---|
| Percentage of Participants in the Target Range at 1 Hour | 8 | 28 |
Participants in target temperature range (33-34 C) anytime during transport
| Participants | Control (Standard Cooling) | Device (Servo-regulated Cooling) |
|---|---|---|
| Participants in Target Temperature Range Anytime During Transport | 24 | 41 |
The incidence, intervention and outcome of cardiac arrhythmia, major bleeding, altered skin integrity, pulmonary hypertension, device-related events, death, and other serious adverse events from the time of initiation of transport cooling to the time of completion will be monitored.
| Participants | Control (Standard Cooling) | Device (Servo-regulated Cooling) |
|---|---|---|
| Cardiac arrhythmia | 0 | 0 |
| Major bleeding (pulmonary hemorrhage) | 0 | 1 |
| Altered skin integrity | 0 | 0 |
| Pulmonary hypertension | 0 | 0 |
| Device-related events | 0 | 2 |
| Death | 6 | 9 |
Collected over Data were collected from the time of initiation of cooling (Arm 1 or Arm 2) to admission at the cooling center. Non-serious events are listed at a 0% frequency threshold.
| Group | Deaths | Serious | Other |
|---|---|---|---|
| Control (Standard Cooling) | — | 6/49 (12.2%) | 0/49 (0%) |
| Device (Servo-regulated Cooling) | — | 10/51 (19.6%) | 2/51 (3.9%) |
| Event | Control (Standard Cooling) | Device (Servo-regulated Cooling) |
|---|---|---|
| DeathGeneral disorders | 6/49 | 9/51 |
| Pulmonary hemorrhageVascular disorders | 0/49 | 1/51 |
| Event | Control (Standard Cooling) | Device (Servo-regulated Cooling) |
|---|---|---|
| Equipment alarmsGeneral disorders | 0/49 | 2/51 |
Eligible newborns
| Age, Customized(Hours) | Control (Standard Cooling) | Device (Servo-regulated Cooling) | Total |
|---|---|---|---|
| Chron. age at cooling initiation at birth hospital | 26 ± 6 | 28 ± 6 | 27 ± 6 |
| Sex: Female, Male(Participants) | Control (Standard Cooling) | Device (Servo-regulated Cooling) | Total |
|---|---|---|---|
| Female | 25 | 22 | 47 |
| Male | 24 | 29 | 53 |
| Birth weight(Grams) | Control (Standard Cooling) | Device (Servo-regulated Cooling) | Total |
|---|---|---|---|
| Mean | 3397 ± 627 | 3321 ± 523 | 3358 ± 610 |
| Gestational age(Weeks) | Control (Standard Cooling) | Device (Servo-regulated Cooling) | Total |
|---|---|---|---|
| Mean | 39.1 ± 1.7 | 39.1 ± 1.7 | 39.1 ± 1.7 |
| Apgar scores @ 1 minute(Participants) | Control (Standard Cooling) | Device (Servo-regulated Cooling) | Total |
|---|---|---|---|
| Apgar @ 1 min ≤ 5 | 47 | 42 | 89 |
| Apgar @ 1 min > 5 | 2 | 9 | 11 |
| Apgar scores @ 5 minutes(Participants) | Control (Standard Cooling) | Device (Servo-regulated Cooling) | Total |
|---|---|---|---|
| Apgar @ 5 min ≤ 5 | 42 | 38 | 80 |
| Apgar @ 5 min > 5 | 7 | 13 | 20 |
| Apgar scores @ 10 minutes(Participants) | Control (Standard Cooling) | Device (Servo-regulated Cooling) | Total |
|---|---|---|---|
| Apgar @ 10 min ≤ 5 | 27 | 24 | 51 |
| Apgar @ 10 min > 5 | 22 | 27 | 49 |
| Delivery room resuscitation: Oxygen(Participants) | Control (Standard Cooling) | Device (Servo-regulated Cooling) | Total |
|---|---|---|---|
| Oxygen | 46 | 47 | 93 |
| No oxygen | 3 | 4 | 7 |
14 further baseline measures are reported on the registry.
The record gives a start of Sep 2012, a primary completion of Oct 2013 and a completion of Oct 2013. It does not say whether these dates are actual or estimated.
Results were first posted in Dec 2014, 1 year 2 months after primary completion.
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