Late Hypothermia for Hypoxic-Ischemic Encephalopathy

Study Overview
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Brief Summary
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This study is a randomized, placebo-controlled, clinical trial to evaluate whether induced whole-body hypothermia initiated between 6-24 hours of age and continued for 96 hours in infants ≥ 36 weeks gestational age with hypoxic-ischemic encephalopathy will reduce the incidence of death or disability at 18-22 months of age. The study will enroll 168 infants with signs of hypoxic-ischemic encephalopathy at 16 NICHD Neonatal Research Network sites, and randomly assign them to either receive hypothermia or participate in a non-cooled control group.

Detailed Description
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Hypoxic-ischemic encephalopathy (HIE) is a rare, but life-threatening condition characterized by acute or subacute brain injury due to asphyxia. In most cases the underlying cause and timing of injury are unknown, but many cases are 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. The incidence of long-term complications depends on the severity of HIE. Up to 80 percent of infants who survive stage 3 HIE develop significant long-term neurological disabilities - mental retardation, epilepsy, and cerebral palsy with hemiplegia, paraplegia, or quadriplegia; 10-20 percent develop moderately serious disabilities; and up to 10 percent are normal. Because animal data suggests that brain injury from HIE evolves over several hours to days after the initial asphyxic insult, induced hypothermia holds promise as a neuroprotective therapy. Additional trials are needed to help define the most effective cooling strategies. With this in mind, and knowing that many babies with HIE arrive at neonatal intensive care units several hours after birth, this study will evaluate the safety and efficacy of initiating hypothermia 6-24 hours after birth. Study subjects: Infants born at 36 0/7ths weeks or greater gestational age that have been diagnosed with neonatal depression, perinatal asphyxia, or encephalopathy. The goal is to enroll 168 subjects. Stratification: After informed consent is obtained, infants will be randomized to either a hypothermia arm (with a target esophageal temperature of 33.5°C) or a control arm (37.0°C) for 96 hours. Enrolled infants will be stratified by age of enrollment (≤ 12 and > 12 hours) and stage of encephalopathy (moderate or severe). Informed Consent: Parents of eligible infants will be approached for consent to enroll in the study if the infant has a high probability of acute hemodynamic compromise, as defined above. Subsequent screening will determine whether the infant meets all inclusion criteria. Randomization: eligible and consented infants will be randomly assigned to either a hypothermia intervention group, or a non-cooled (control) group. Study Intervention: Induced whole-body hypothermia (with a target esophageal temperature of 33.5°C) or a control group (37.0°C) for 96 hours. Interim Study Interruptions: None to date. Secondary Study includes determining an association between MRI detectable injury and neurodevelopment at 18-22 months.

Official Title
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Evaluation of Systemic Hypothermia Initiated After 6 Hours of Age in Infants ≥36 Weeks Gestation With Hypoxic-Ischemic Encephalopathy: A Bayesian Evaluation. A Protocol for the NICHD Neonatal Research Network

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

Intervention / Treatment
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* Procedure: Hypothermia
* Procedure: Normothermic Control


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Infants born at 36 0/7ths weeks gestational age or greater (by best obstetrical estimate) Postnatal age between 6 and 24 hours following birth Infants with a high probability of acute hemodynamic compromise, such as those with: An acute perinatal event (abruptio placenta, cord prolapse, severe FHR abnormality) An Apgar score ≤ 5 at 10 minutes Continued need for ventilation initiated at birth for at least 10 minutes Cord pH or first postnatal blood gas pH at ≤ 1 hour of ≤ 7.0 Base deficit on cord gas or first postnatal blood gas at ≤ 1 hour of ≥ 16 mEq/L Infants matching the above criteria who also have an abnormal neurological exam showing the presence of moderate or severe encephalopathy Infants whose parents/legal guardians have provided consent for enrollment. NOTE: These inclusion criteria are identical to the NICHD Neonatal Research Network's 2005 Hypothermia study (see links below), except for the time of entry (6-24 hours vs. < 6 hours of age). Exclusion Criteria: Any infant with a core body temperature (axilla, rectal) less than 34.0°C for greater than 1 hour Presence of a known anomaly or chromosomal aberration Birth weight < 1,800 grams Infant in extremis Infants whose parents/legal guardians or attending physician refuse consent

Ages Eligible for Study
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Minimum Age: 6 Hours
Maximum Age: 24 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 |
| --- | --- |
| Experimental: Whole-body Hypothermia<br>Induced Whole-body hypothermia (with a target esophageal temperature of 33.5°C) for 96 hours | Procedure: Hypothermia<br>* Induced Whole-body hypothermia (with a target esophageal temperature of 33.5°C) for 96 hours<br>|
| Active Comparator: Normothermia<br>Normothermic Control group (with esophageal temperature at or near 37.0°C) for 96 hours | Procedure: Normothermic Control<br>* Normothermic Control group (with esophageal temperature at or near 37.0°C) for 96 hours<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Death or Moderate or Severe Disability | Severe disability was defined by any of the following: a Bayley III cognitive score < 70 or Gross Motor Functional (GMF) Level of 3-5 blindness or profound hearing loss requiring amplification but still unable to follow commands/communicate. Moderate disability was defined as a Bayley III cognitive score between 70-84 and either a GMF level of 2 or a seizure disorder or a hearing deficit. | Birth to 18-22 months corrected gestational age | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Deaths in the NICU and Following Discharge |  | Birth to 18-22 months corrected gestational age | 
| Number of Infants With Moderate and Severe Disability | Moderate disability will be defined as a Bayley III cognitive score between 70-84 and either a GMF level of 2 or a seizure disorder or a hearing deficit. Severe disability will be defined by any of the following: a Bayley III cognitive score < 70 or Gross Motor Functional (GMF) Level of 3-5 or blindness or profound hearing loss requiring amplification but still unable to follow commands/communicate. | Birth to 18-22 months corrected gestational age | 
| Number of Infants With Mild, Moderate and Severe Disability | Mild disability will be defined by either a Bayley III cognitive score of 70-84 alone or a Bayley III cognitive score >= 85 and any of the following: presence of a GMF level 1 or 2 OR seizure disorder or hearing loss. Moderate disability was defined as a Bayley III cognitive score between 70-84 and either a GMF level of 2 or a seizure disorder or a hearing deficit. Severe disability will be defined by any of the following: a Bayley III cognitive score < 70 OR Gross Motor Functional (GMF) Level of 3-5 OR blindness or profound hearing loss requiring amplification but still unable to follow commands/communicate. | Birth to 18-22 months corrected gestational age | 
| Number of Infants With Any Disability Based on Level of Encephalopathy at Randomization | Mild disability will be defined by either a Bayley III cognitive score of 70-84 alone or a Bayley III cognitive score >= 85 and any of the following: presence of a GMF level 1 or 2OR seizure disorder or hearing loss. Moderate disability was defined as a Bayley III cognitive score between 70-84 and either a GMF level of 2 or a seizure disorder or a hearing deficit. Severe disability will be defined by any of the following: a Bayley III cognitive score < 70 OR Gross Motor Functional (GMF) Level of 3-5 OR blindness or profound hearing loss requiring amplification but still unable to follow commands/communicate. | Birth to 18-22 months corrected gestational age | 
| Number of Infants With Non-CNS Organ System Dysfunction | Based on observing presence of organ dysfunction on at least one of the following: Pulmonary (Meconium aspiration syndrome, PPHN, Pulmonary hemorrhage, Pneumonia, Chronic lung disease, ECMO, INO), Cardiovascular (Cardiomegaly, Cardiac failure, Cardiac dysfunction (by echo), Cardiac ischemia (by EKG and/or increased enzymes), Hypotension, Arrhythmia), Renal (Oliguria, Anuria, Dialysis), Gastrointestinal (NEC, Hepatic dysfunction), Hematologic (DIC) and Metabolic (Hypoglycemia, Hypocalcemia, Hypomagnesemia) | Birth to 18-22 months corrected gestational age | 
| Number of Infants With a DNR Order |  | Birth to 18-22 months corrected gestational age | 
| Number of Infants With a DNR Order and Support is Withdrawn |  | Birth to 18-22 months corrected gestational age | 
| Number of Infants With a DNR Order That Died |  | Birth to 18-22 months corrected gestational age | 
| Number of Infants With Neonatal Seizures, With and Without EEG Abnormalities |  | Birth to 18-22 months corrected gestational age | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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NICHD Neonatal Research Network, Hypoxic-ischemic encephalopathy (HIE), Hypothermia, Neonatal depression, Perinatal asphyxia