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.
Eligible infants are >36 0/7th weeks gestation,
pH (cord or neonatal) <7.0,
base deficit >16 mEq/L,
no available blood gas,
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.
Single group
Melatonin
DrugParticipants 1-10 will receive a 0.5 mg/kg enteral dose of Melatonin. Participants 11-20 will receive Melatonin dose of 3 mg/kg enteral. Participants 21-30 will receive Melatonin dose of 5 mg/kg enterally.
Magnetic Resonance Imaging
Other interventionAll participants will receive an MRI between 7-12 days of age.
Pharmacokinetics
Other interventionAll participants will receive pharmacokinetics to test the amount of melatonin in the blood.
Neurological Outcome Assessment
BehavioralAll participants will receive the Bayley-III Scores and Subsets for neurological outcome assessments.
To identify the maximum tolerated dose of Melatonin
The maximum tolerated dose (MTD) is defined as the highest dose level without adverse events in no more than 1 out of 6 patients
Bayley-III Index Scores (Cognitive, Language, and Motor) will be used for neurological outcome assessment
All raw scores will be transformed into norm-referenced standard scores (scale mean = 100 with s.d. = 15) using the Bayley-III scoring software published with the test. To dichotomize "good" and "poor" outcomes for statistical analysis, standardized scores that are at or greater than one standard deviation below the normative sample mean published with the test (i.e., standard scores \< 85) will be classified as "poor outcome" while higher scores will be classified as "good outcome".
Peak Plasma Concentration (Cmax) of Melatonin 0.5 mg/kg.
HPLC-ESI/MS/MS will be used to measure melatonin concentrations in the serum samples. The two-way ANOVA (treatments are dose level and timepoint) framework for testing. Testing will be done using a likelihood ratio test, either using large-sample theory approximation or using bootstrap.
Number of participants with treatment-related adverse events as assessed by MedDRA ??? This is something the PI/Team needs to agree on which one to use.
Incidence/Grade of Treatment Emergent Adverse Events (TEAEs), Serious Adverse Events (SAEs), laboratory abnormalities Percentage and number of subjects who discontinued for adverse event
Bayley-III Index Scores Subscales (Receptive and Expressive Language, Fine and Gross Motor) will be used for neurological outcome assessment
The four performance-based subscales of the Bayley-III Index Scores (Receptive and Expressive Language, Fine and Gross Motor) and two parent-reported scales (Social-Emotional and Adaptive Behavior) will be collected. All raw scores will be transformed into norm-referenced standard scores (scale mean = 100 with s.d. = 15) using the Bayley-III scoring software published with the test. To dichotomize "good" and "poor" outcomes for statistical analysis, standardized scores that are at or greater than one standard deviation below the normative sample mean published with the test (i.e., standard scores \< 85) will be classified as "poor outcome" while higher scores will be classified as "good outcome".
Evaluation of The Impact of Melatonin using Magnetic Resonance Image (MRI)
The MRI study scores of neonates treated with hypothermia plus melatonin will be compared with historical controls that have matched Sarnat exams (exam of HIE severity at the time of admission).
Click on the lead sponsor to view all of their trials.
University of Florida
Lead sponsor
Thrasher Research Fund
Collaborator
