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Optimizing (Longer, Deeper) Cooling for Neonatal Hypoxic-Ischemic Encephalopathy(HIE)

N

NICHD Neonatal Research Network

Status

Terminated

Conditions

Infant, Newborn
Ischemic-Hypoxic Encephalopathy
Hypoxia-Ischemia, Brain
Hypoxic-Ischemic Encephalopathy
Encephalopathy, Hypoxic-Ischemic
Hypoxia, Brain

Treatments

Procedure: Whole-body Cooling

Study type

Interventional

Funder types

NETWORK
NIH

Identifiers

NCT01192776
U10HD053109 (U.S. NIH Grant/Contract)
UL1RR025761 (U.S. NIH Grant/Contract)
UL1RR024979 (U.S. NIH Grant/Contract)
U10HD068270 (U.S. NIH Grant/Contract)
U10HD021364 (U.S. NIH Grant/Contract)
NICHD-NRN-0043
UL1RR025764 (U.S. NIH Grant/Contract)
U10HD027880 (U.S. NIH Grant/Contract)
U10HD036790 (U.S. NIH Grant/Contract)
U10HD027856 (U.S. NIH Grant/Contract)
U10HD053089 (U.S. NIH Grant/Contract)
U10HD027851 (U.S. NIH Grant/Contract)
U10HD068244 (U.S. NIH Grant/Contract)
UL1RR025747 (U.S. NIH Grant/Contract)
U10HD040689 (U.S. NIH Grant/Contract)
UL1RR025008 (U.S. NIH Grant/Contract)
U10HD068278 (U.S. NIH Grant/Contract)
U10HD027871 (U.S. NIH Grant/Contract)
UL1RR024139 (U.S. NIH Grant/Contract)
U10HD021373 (U.S. NIH Grant/Contract)
U10HD027853 (U.S. NIH Grant/Contract)
U10HD053119 (U.S. NIH Grant/Contract)
UL1RR025744 (U.S. NIH Grant/Contract)
U10HD040492 (U.S. NIH Grant/Contract)
U10HD053124 (U.S. NIH Grant/Contract)
U10HD068284 (U.S. NIH Grant/Contract)
U10HD068263 (U.S. NIH Grant/Contract)
U10HD034216 (U.S. NIH Grant/Contract)
U10HD021385 (U.S. NIH Grant/Contract)
U10HD027904 (U.S. NIH Grant/Contract)

Details and patient eligibility

About

The Optimizing Cooling trial will compare four whole-body cooling treatments for infants born at 36 weeks gestational age or later with hypoxic-ischemic encephalopathy: (1) cooling for 72 hours to 33.5°C; (2) cooling for 120 hours to 33.5°C; (3) cooling for 72 hours to 32.0°C; and (4) cooling for 120 hours to 32.0°C. The objective of this study is to evaluate whether whole-body cooling initiated at less than 6 hours of age and continued for 120 hours and/or a depth at 32.0°C in will reduce death and disability at 18-22 months corrected age.

Full description

Hypoxic-ischemic encephalopathy (HIE) is a rare, but life-threatening condition characterized by brain injury due to asphyxia diagnosed at or shortly after birth. According to the World Health Organization, more than 722,000 children died from birth asphyxia and birth trauma worldwide in 2004. An estimated 50-75 percent of infants with severe (stage 3) HIE will die, with 55 percent of these deaths occurring in the first month. Up to 80 percent of infants who survive stage 3 HIE develop significant long-term disabilities, including intellectual disabilities, epilepsy, and cerebral palsy with hemiplegia, paraplegia, or quadriplegia; 10-20 percent develop moderately serious disabilities; and up to 10 percent are normal.

Previous studies have shown treatment with hypothermia to be an effective therapy for HIE. Currently, infants diagnosed with HIE at less than six hours of age are given whole-body cooling, decreasing their core body temperature to 33.5°C (93.2° Fahrenheit) for a period 72 hours using a cooling blanket. This treatment appears to protect the brain, decreasing the rate of death and disability and improving the chances of survival and neurodevelopmental outcomes at 18 months correct age. But additional trials are needed to help define the most effective cooling strategies.

The Optimizing Cooling trial will examine whether cooling for a longer time period and/or to a lower temperature will improve the chance of survival and neurodevelopmental outcomes at 18-22 months corrected age. Eligible infants with HIE will be placed in one of four cooling groups: (1) cooling for 72 hours to 33.5°C; (2) cooling for 120 hours to 33.5°C; (3) cooling for 72 hours to 32.0°C; and (4) cooling for 120 hours to 32.0°C. Infants will be monitored closely and receive the care of the Neonatal Intensive Care Unit (NICU).

Infants enrolled in the study will be placed on a cooling blanket - the same type of blanket children's hospitals use in the NICU, in operating rooms during surgeries, and to cool children with high fevers. Each infant will be cooled according to the study group he or she is assigned to. During cooling, the infant's temperature will be very closely monitored by continuous esophageal (core)temperature readings. This will be done by placing a soft, narrow, flexible plastic tube into the infant's nose and down to just above the stomach. Skin temperatures will also be monitored closely. At the end of the assigned period of cooling, the infant will be slowly re-warmed until a normal core temperature of 36.5 to 37.0°C (97.7 to 98.6°C) is reached.

Infants will be examined at 18-22 months corrected age to assess their neurodevelopmental outcomes.

Secondary Studies include:

A. Using aEEG to 1)predict mortality or moderate to severe disability at 18-22 months in term infants with HIE treated with systemic hypothermia and 2) to record electrical seizure activity to compare rewarming initiated at 72 hours and later rewarming that is initiated at 120 hours.

B. Secondary Study includes determining an association between MRI detectable injury and neurodevelopment at 18-22 months.

Enrollment

364 patients

Sex

All

Ages

Under 6 hours old

Volunteers

No Healthy Volunteers

Inclusion criteria

Eligibility will be determined in a stepped process:

  1. All infants with a gestational age ≥ 36 weeks will be screened for study entry if they are admitted to the NICU with a diagnosis of fetal acidosis, perinatal asphyxia, neonatal depression or encephalopathy.

  2. Infants will be eligible if:

    • They have a pH ≤ 7.0 or a base deficit ≥ 16m mEq/ L on umbilical cord or any postnatal sample within 1 hour of age.
    • If, during this interval, they have a pH between 7.01 and 7.15, a base deficit is between 10 and 15.9 mEq/L, or a blood gas is not available, AND they have an acute perinatal event AND either a 10-minute Apgar score ≤ 5 or assisted ventilation initiated at birth and continued for at least 10 minutes.
  3. Once these criteria are met, eligible infants will have a standardized neurological examination performed by a certified physician examiner. Infants will be candidates for the study when encephalopathy or seizures are present. For this study, encephalopathy is defined as the presence of 1 or more signs in 3 of the following 6 categories:

    • Level of consciousness: lethargy, stupor or coma;
    • Spontaneous activity: decreased, absent;
    • Posture: distal flexion, decerebrate;
    • tone: hypotonia, flaccid or hypertonia, rigid;
    • Primitive reflexes: a) suck, weak, absent; b) Moro, incomplete, flaccid;
    • Autonomic nervous system: a) pupils: constricted, unequal, skew deviation or non reactive to light; b) heart rate: bradycardia, variable heart rate or c) respiration: periodic breathing, apnea.

Eligible infants from multiple births will be enrolled in the same arm of the study.

Exclusion criteria

  • Inability to randomize by 6 hours of age
  • Major congenital abnormality
  • Major chromosomal abnormality (including Trisomy 21),
  • Severe growth restriction (≤ 1800gm birth weight),
  • Infant is moribund and will not receive any further aggressive treatment,
  • Refusal of consent by parent
  • Refusal of consent by attending neonatologist
  • Infants with a core temperature < 33.5°C for > 1 hour at the time of screening by the research team would not be eligible for the study.

Trial design

Primary purpose

Treatment

Allocation

Randomized

Interventional model

Factorial Assignment

Masking

None (Open label)

364 participants in 4 patient groups

33.5°C for 72 hours
Active Comparator group
Description:
Target Temp: 33.5°C Duration: 72 hrs
Treatment:
Procedure: Whole-body Cooling
33.5°C for 120 hours
Experimental group
Description:
Target Temp: 33.5°C Duration: 120 hrs
Treatment:
Procedure: Whole-body Cooling
32.0°C for 72 hours
Experimental group
Description:
Target Temp: 32.0°C Duration: 72 hrs
Treatment:
Procedure: Whole-body Cooling
32.0°C for 120 hours
Experimental group
Description:
Target Temp: 32.0°C Duration:120 hrs
Treatment:
Procedure: Whole-body Cooling

Trial contacts and locations

19

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Data sourced from clinicaltrials.gov

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