Preemie Hypothermia for Neonatal Encephalopathy

Study Overview
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Brief Summary
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This study is a randomized, controlled trial to assess safety and effectiveness of whole body hypothermia for 72 hours in preterm infants 33-35 weeks gestational age (GA) who present at <6 hours postnatal age with moderate to severe neonatal encephalopathy (NE). The study will enroll infants with signs of NE at 18 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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Most clinical studies of neonatal encephalopathy (NE) and potential interventions have focused on infants ≥36 weeks GA. Although many interventions have been suggested and assessed for prevention or palliation of NE, the only one currently supported by rigorous clinical evidence to improve outcome in human newborns has been hypothermia implemented at <6 hours of postnatal age and maintained for 72 hrs. Data about diagnosis, frequency, severity, and outcome of NE in infants 33-35 weeks GA are sparse. This trial will assess safety and effectiveness of whole body hypothermia for 72 hours in preterm infants 33-35 weeks gestational age (GA) who present at <6 hrs postnatal age with moderate to severe neonatal encephalopathy. Infants 33 0/7 to 35 6/7 weeks GA (best obstetrical estimate) and greater than or equal to 1500 grams birth weight (selected to minimize potential difficulties placing esophageal probe) who meet clinical, biochemical and neurologic criteria for moderate to severe NE will be randomized to either whole body hypothermia or participate in a non-cooled control group. The primary outcome will be death or moderate to severe disability at 18-22 months corrected age. The presence or absence of disability will be determined by the standard NRN interdisciplinary follow-up exam. Secondary Study includes determining an association between MRI detectable injury and neurodevelopment at 18-22 months.

Official Title
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A Randomized Trial of Targeted Temperature Management With Whole Body Hypothermia For Moderate And Severe Hypoxic-Ischemic Encephalopathy In Premature Infants 33-35 Weeks Gestational Age.

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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* Device: Hypothermia
* Procedure: Normothermic Control


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Infants 33 0/7 to 35 6/7 weeks GA (best obstetrical estimate) Infants weight greater than or equal to 1500 grams at birth Postnatal age less than 6 hours Infants who meet clinical, biochemical and neurologic criteria for moderate to severe NE: Biochemical: Cord gas or blood gas within first hour of life with pH ≤7.00 or base deficit (BD) ≥16 mEq/L OR Acute perinatal event (e.g., abruptio placenta, cord prolapse, uterine rupture, severe FHR abnormality such as variable or late decelerations) AND Requirement for positive pressure ventilation for apnea or poor respiratory effort since birth for at least 10 minutes OR 10 minute Apgar score ≤5 AND Neurologic: Seizures OR modified Sarnat score with abnormalities in at least 3 of the 6 categories; at least one must be altered level of consciousness (lethargy or stupor/coma) as determined by a certified examiner (All infants who meet criteria for potential inclusion will undergo standard neurologic exam as for infants ≥36 wks GA being considered for hypothermia, with findings recorded) Exclusion Criteria: Receipt of sedative, analgesic or paralytic agent that may confound the qualifying neurologic exam Etiology of NE not likely to be hypoxic-ischemic in origin Major congenital anomaly that may confound outcome Considered to be moribund and will not be receiving full intensive care Equipment and/or appropriate staff not available Core temperature < 33.5oC for more than one hour at time of screening Unable to randomize by 6 hours of age Infant needs ECMO All blood gases (cord and postnatal at < 1hr of age) have a pH > 7.15 AND a base deficit < 10mEq/L

Ages Eligible for Study
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Minimum Age: 33 Weeks
Maximum Age: 35 Weeks

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 72 hours | Device: Hypothermia<br>* Induced Whole-body hypothermia (with a target esophageal temperature of 33.5°C) for 72 hours<br>|
| Placebo Comparator: Normothermia<br>Control group (with esophageal temperature at or near 37.0°C) for 72 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 |  | Birth to 18-22 months corrected 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 age | 
| Differences in MRI findings after cessation of cooling/control obtained |  | Birth to 40 weeks corrected age | 
| Number of infants with moderate and severe disability |  | Birth to 18-22 months corrrected age | 
| Causes of Death | withdrawal of support and reasons for such will be tracked; attempts will be made to obtain autopsy whenever possible | Birth to 18-22 months corrrected age | 
| Neurological injury by cranial ultrasound within 24 hours of enrollment |  | Birth to 2 days of life | 

 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