California Transport Cooling Trial

Hypoxic Ischemic Encephalopathy Clinical Trial

— CTCT  

Official title:

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT01683383
• Other study ID #: 22993
• Status: Completed
• Phase: N/A
• First received: September 6, 2012
• Last updated: December 1, 2014
• Start date: September 2012
• Est. completion date: October 2013

Study information

• Verified date: December 2014
• Source: Stanford University
• Contact: n/a
• Is FDA regulated: No
• Health authority: United States: Food and Drug Administration
• Study type: Interventional

Clinical Trial Summary

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.

Description:

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 101
• Est. completion date: October 2013
• Est. primary completion date: October 2013
• Accepts healthy volunteers: No
• Gender: Both
• Age group: N/A to 6 Hours

Eligibility

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

Study Design

Allocation: Randomized, Endpoint Classification: Efficacy Study, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Treatment

Related Conditions & MeSH terms

• Brain Diseases
• Brain Ischemia
• Hypoxia-Ischemia, Brain
• Hypoxic Ischemic Encephalopathy
• Ischemia

Intervention

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.

Other:
• Control (standard practice)
Subjects in Arm 1 will receive passive or active cooling as per center practice with rectal temperatures being recorded every 15 minutes.

Locations

Country	Name	City	State
United States	Loma Linda University Children's Hospital	Loma Linda	California
United States	Children's Hospital Central California	Madera	California
United States	Children's Hospital & Research Center	Oakland	California
United States	Kaiser Permanente Oakland/Walnut Creek	Oakland	California
United States	Stanford University	Palo Alto	California
United States	Sutter Medical Center	Sacramento	California
United States	Rady Childrens Hospital	San Diego	California
United States	University of California San Francisco Medical Center	San Francisco	California
United States	Santa Clara Valley Medical Center	San Jose	California

Sponsors (2)

Lead Sponsor	Collaborator
Stanford University	Inspiration Healthcare LTD UK

Country where clinical trial is conducted

United States, 

References & Publications (15)

Akula VP, Davis AS, Gould JB, Van Meurs K. Therapeutic hypothermia during neonatal transport: current practices in California. Am J Perinatol. 2012 May;29(5):319-26. doi: 10.1055/s-0031-1295661. Epub 2011 Dec 5. — View Citation

Azzopardi DV, Strohm B, Edwards AD, Dyet L, Halliday HL, Juszczak E, Kapellou O, Levene M, Marlow N, Porter E, Thoresen M, Whitelaw A, Brocklehurst P; TOBY Study Group. Moderate hypothermia to treat perinatal asphyxial encephalopathy. N Engl J Med. 2009 Oct 1;361(14):1349-58. doi: 10.1056/NEJMoa0900854. Erratum in: N Engl J Med. 2010 Mar 18;362(11):1056. — View Citation

Eicher DJ, Wagner CL, Katikaneni LP, Hulsey TC, Bass WT, Kaufman DA, Horgan MJ, Languani S, Bhatia JJ, Givelichian LM, Sankaran K, Yager JY. Moderate hypothermia in neonatal encephalopathy: efficacy outcomes. Pediatr Neurol. 2005 Jan;32(1):11-7. — View Citation

Fairchild K, Sokora D, Scott J, Zanelli S. Therapeutic hypothermia on neonatal transport: 4-year experience in a single NICU. J Perinatol. 2010 May;30(5):324-9. doi: 10.1038/jp.2009.168. Epub 2009 Oct 22. — View Citation

Gluckman PD, Williams CE. When and why do brain cells die? Dev Med Child Neurol. 1992 Nov;34(11):1010-4. Review. — View Citation

Gluckman PD, Wyatt JS, Azzopardi D, Ballard R, Edwards AD, Ferriero DM, Polin RA, Robertson CM, Thoresen M, Whitelaw A, Gunn AJ. Selective head cooling with mild systemic hypothermia after neonatal encephalopathy: multicentre randomised trial. Lancet. 2005 Feb 19-25;365(9460):663-70. — View Citation

Gunn AJ, Gunn TR, de Haan HH, Williams CE, Gluckman PD. Dramatic neuronal rescue with prolonged selective head cooling after ischemia in fetal lambs. J Clin Invest. 1997 Jan 15;99(2):248-56. — View Citation

Hallberg B, Olson L, Bartocci M, Edqvist I, Blennow M. Passive induction of hypothermia during transport of asphyxiated infants: a risk of excessive cooling. Acta Paediatr. 2009 Jun;98(6):942-6. — View Citation

Iwata O, Iwata S, Thornton JS, De Vita E, Bainbridge A, Herbert L, Scaravilli F, Peebles D, Wyatt JS, Cady EB, Robertson NJ. "Therapeutic time window" duration decreases with increasing severity of cerebral hypoxia-ischaemia under normothermia and delayed hypothermia in newborn piglets. Brain Res. 2007 Jun 18;1154:173-80. Epub 2007 Apr 1. — View Citation

Jacobs SE, Morley CJ, Inder TE, Stewart MJ, Smith KR, McNamara PJ, Wright IM, Kirpalani HM, Darlow BA, Doyle LW; Infant Cooling Evaluation Collaboration. Whole-body hypothermia for term and near-term newborns with hypoxic-ischemic encephalopathy: a randomized controlled trial. Arch Pediatr Adolesc Med. 2011 Aug;165(8):692-700. doi: 10.1001/archpediatrics.2011.43. Epub 2011 Apr 4. — View Citation

Kendall GS, Kapetanakis A, Ratnavel N, Azzopardi D, Robertson NJ; Cooling on Retrieval Study Group. Passive cooling for initiation of therapeutic hypothermia in neonatal encephalopathy. Arch Dis Child Fetal Neonatal Ed. 2010 Nov;95(6):F408-12. doi: 10.1136/adc.2010.187211. Epub 2010 Sep 24. — View Citation

Shankaran S, Laptook AR, Ehrenkranz RA, Tyson JE, McDonald SA, Donovan EF, Fanaroff AA, Poole WK, Wright LL, Higgins RD, Finer NN, Carlo WA, Duara S, Oh W, Cotten CM, Stevenson DK, Stoll BJ, Lemons JA, Guillet R, Jobe AH; National Institute of Child Health and Human Development Neonatal Research Network. Whole-body hypothermia for neonates with hypoxic-ischemic encephalopathy. N Engl J Med. 2005 Oct 13;353(15):1574-84. — View Citation

Simbruner G, Mittal RA, Rohlmann F, Muche R; neo.nEURO.network Trial Participants. Systemic hypothermia after neonatal encephalopathy: outcomes of neo.nEURO.network RCT. Pediatrics. 2010 Oct;126(4):e771-8. doi: 10.1542/peds.2009-2441. Epub 2010 Sep 20. — View Citation

Van Meurs K, Akula VP, Davis AS, Gould J. Therapeutic hypothermia during neonatal transport in 2010: Data from the California Perinatal Quality Care Collaborative (CPQCC) and the California Perinatal Transport System (CPeTS). International Perinatal Collegium XXII Biennial Meeting, Amalfi, Italy, June 25-29, 2011.

Vannucci RC, Perlman JM. Interventions for perinatal hypoxic-ischemic encephalopathy. Pediatrics. 1997 Dec;100(6):1004-14. Review. — View Citation

* Note: There are 15 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	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.	Participants will be followed for the duration of neonatal transport from the birth hospital to the cooling center, an expected average of 4 hours	Yes
Primary	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	No
Secondary	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	No
Secondary	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	No
Secondary	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	No