Melatonin as a Neuroprotective Therapy in Neonates With HIE Undergoing Hypothermia

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  • sponsor
    University of Florida
Updated on 2 June 2022
free radical
base deficit


Hypoxic-Ischemic Encephalopathy (HIE) occurs in 20 per 1000 births. Only 47% of neonates treated with the state of the art therapy (induced systemic hypothermia) have normal outcomes. Therefore, other promising therapies that potentially work in synergy with hypothermia to improve neurologic outcomes need to be tested. One potential agent is melatonin. Melatonin is a naturally occurring substance produced mainly from the pineal gland. Melatonin is widely known for its role in regulating the circadian rhythm, but it has many other effects that may benefit infants with HI injury. Melatonin serves as a free radical scavenger, decreases inflammatory cytokines, and stimulates anti-oxidant enzymes. Therefore, melatonin may interrupt several key components in the pathophysiology of HIE, in turn minimizing cell death and improving outcomes. The research study will evaluate the neuroprotective properties and appropriate dose of Melatonin to give to infants undergoing therapeutic hypothermia for hypoxic ischemic encephalopathy.


Thirty subjects will be enrolled in a dose escalation study. Subjects 1-10 will receive melatonin (0.5 mg/kg). If that dose proves to be safe, subjects 11-20 will receive an increased dose of melatonin (3 mg/kg). Subjects 21-30 will receive a dose increased to the targeted projected therapeutic dose (5 mg/kg).

The serum concentration of melatonin and capture adverse event reports during this dose escalation study in neonates undergoing hypothermia and the long-term safety and potential efficacy via developmental follow-up performed at 18-22 months of age. In addition, this study will determine the effect of melatonin on the inflammatory cascade, oxidative stress, free radical production, and serum biomarkers of brain injury in neonates undergoing hypothermia.

Condition Hypoxic Ischemic Encephalopathy
Treatment magnetic resonance imaging, Pharmacokinetics, Melatonin, Neurological Outcome Assessment, Generalized Motor Assessment
Clinical Study IdentifierNCT02621944
SponsorUniversity of Florida
Last Modified on2 June 2022


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Inclusion Criteria

Eligible infants are >36 0/7th weeks gestation
pH (cord or neonatal) <7.0
base deficit >16 mEq/L
no available blood gas
a cord blood/first hour of life blood gas with pH > 7.0 and < 7.15
base deficit between 10 and 15.9 mEq/L
infants must have a history of an acute perinatal event
either a 10-minute Apgar < 5 or a continued need for ventilation
All infants must have signs of encephalopathy within 6 hours of age using the modified Sarnat scoring system
neonates cooled within 6 hours of birth will be included in the study

Exclusion Criteria

suspected inborn errors of metabolism (elevated ammonia) and hypoglycemia
clinical signs and symptoms consistent with meningitis detected upon sepsis evaluation
a diagnosis of congenital abdominal surgical problems along with multiple congenital anomalies and/or chromosomal abnormalities
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