Melatonin as a Neuroprotective Therapy in Neonates With HIE Undergoing Hypothermia

University of Florida

Status and phase: Enrolling; Early Phase 1

Conditions: Hypoxic Ischemic Encephalopathy

Treatments: Other: Pharmacokinetics; Other: Magnetic Resonance Imaging; Drug: Melatonin; Behavioral: Neurological Outcome Assessment

Study type: Interventional

Funder types: Other

Identifiers

NCT02621944

IRB201500886

Details and patient eligibility

About

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.

Full description

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.

Enrollment: 70 estimated patients

Sex: All

Ages: Under 6 hours old

Volunteers: No Healthy Volunteers

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.

Trial design

Primary purpose: Treatment

Allocation: Non-Randomized

Interventional model: Single Group Assignment

Masking: None (Open label)

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70 participants in 3 patient groups

Participants 1-10

Experimental group

Description:

This group will receive a 0.5 mg/kg enteral dose of Melatonin. The first dose will be administered via enteral route within 12 hours of life with a target of 6 hours of life. The melatonin will be administered as a single dose for the first 5 participants in allowing the investigators to determine if the dosing frequency has the potential to decrease in the elimination with hypothermia. The next 5 subjects who will receive multiple doses if there are not any safety concerns. Additionally, the participants will have the following test performed: Magnetic Resonance Imaging (MRI), Neurological Outcome Assessment, Pharmacokinetics, and safety monitoring.

Treatment:

Behavioral: Neurological Outcome Assessment

Drug: Melatonin

Other: Magnetic Resonance Imaging

Other: Pharmacokinetics

Participants 11-20

Experimental group

Description:

This group will the Melatonin dose of 3 mg/kg enteral, only if the group Participants 1-10 has meet the safety goals. The first dose will be administered via enteral route within 12 hours of life with a target of 6 hours of life. The melatonin will be administered as a single dose for the first 5 participants in allowing the investigators to determine if the dosing frequency has the potential to decrease in the elimination with hypothermia. The next 5 subjects who will receive multiple doses if there are not any safety concerns. Additionally, the participants will have the following test performed: Magnetic Resonance Imaging (MRI), Neurological Outcome Assessment, Pharmacokinetics, and safety monitoring.

Treatment:

Behavioral: Neurological Outcome Assessment

Drug: Melatonin

Other: Magnetic Resonance Imaging

Other: Pharmacokinetics

Participants 21-30

Experimental group

Description:

This group will receive Melatonin dose of 5 mg/kg enterally, only if the group Participants 11-20 has meet the safety goals. The first dose will be administered via enteral route within 12 hours of life with a target of 6 hours of life. The melatonin will be administered as a single dose for the first 5 participants in allowing the investigators to determine if the dosing frequency has the potential to decrease in the elimination with hypothermia. The next 5 subjects who will receive multiple doses if there are not any safety concerns. Additionally, the participants will have the following test performed: Magnetic Resonance Imaging (MRI), Neurological Outcome Assessment, Pharmacokinetics, and safety monitoring.

Treatment:

Behavioral: Neurological Outcome Assessment

Drug: Melatonin

Other: Magnetic Resonance Imaging

Other: Pharmacokinetics