Melatonin as a Neuroprotective Therapy in Neonates With HIE Undergoing Hypothermia

NCT02621944 | Recruiting Early Phase 1 DMC FDA Drug

• 1 other identifier: IRB201500886
• Study Type: interventional
• Target: 70
• Locations: 1 country
• Sites: 2

Brief Summary

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.

Conditions

Hypoxic Ischemic Encephalopathy

Outcome Measures

Primary Outcomes (6)

• 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

  Changes in Baseline to day 3

• 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".

  Approximately 18 - 20 Months

• 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.

  0 (baseline), 3, 5, 6, 12, 24, 48, 96 hours and day 14 (one sample)

• 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

  Baseline ongoing to Day 14

• Peak Plasma Concentration (Cmax) of Melatonin 3 mg/kg.

  HPLC-ESI/MS/MS will be used to measure melatonin concentrations in the serum. 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.

  0 (baseline), 3, 5, 6, 12, 24, 48, 96 hours and day 14 (one sample)

• Peak Plasma Concentration (Cmax) of Melatonin 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.

  0 (baseline), 3, 5, 6, 12, 24, 48, 96 hours and day 14 (one sample)

Secondary Outcomes (2)

• Bayley-III Index Scores Subscales (Receptive and Expressive Language, Fine and Gross Motor) will be used for neurological outcome assessment

  Approximately 18 - 20 Months

• Evaluation of The Impact of Melatonin using Magnetic Resonance Image (MRI)

  Approximately 7 - 12 days

Study Arms (3)

Participants 1-10

EXPERIMENTAL

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.

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

Participants 11-20

EXPERIMENTAL

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.

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

Participants 21-30

EXPERIMENTAL

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.

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

Interventions

Melatonin DRUG

Participants 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.

Participants 1-10; Participants 11-20; Participants 21-30

Magnetic Resonance Imaging OTHER

All participants will receive an MRI between 7-12 days of age.

Also known as: MRI

Participants 1-10; Participants 11-20; Participants 21-30

Pharmacokinetics OTHER

All participants will receive pharmacokinetics to test the amount of melatonin in the blood.

Participants 1-10; Participants 11-20; Participants 21-30

Neurological Outcome Assessment BEHAVIORAL

All participants will receive the Bayley-III Scores and Subsets for neurological outcome assessments.

Participants 1-10; Participants 11-20; Participants 21-30

Eligibility Criteria

• Age: Up to 6 Hours
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17)

You may qualify if:

• 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.

You may not qualify if:

• 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.

Sponsors & Collaborators

• University of Florida: lead
• Thrasher Research Fund: collaborator

Study Sites (2)

University of Florida

Gainesville, Florida, 32610, United States

RECRUITING

Florida Hospital for Children

Orlando, Florida, 32803, United States

RECRUITING

MeSH Terms

Conditions

Hypoxia-Ischemia, Brain

Interventions

Melatonin; Magnetic Resonance Spectroscopy; Pharmacokinetics

Condition Hierarchy (Ancestors)

Brain Ischemia; Cerebrovascular Disorders; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Hypoxia, Brain; Vascular Diseases; Cardiovascular Diseases; Hypoxia; Signs and Symptoms, Respiratory; Signs and Symptoms; Pathological Conditions, Signs and Symptoms

Intervention Hierarchy (Ancestors)

Tryptamines; Indoles; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Spectrum Analysis; Chemistry Techniques, Analytical; Investigative Techniques; Metabolism; Pharmacological and Toxicological Phenomena; Physiological Phenomena

Study Officials

• Michael D Weiss, MD

  University of Florida

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Alison A McMurray, M.A.M.C.

CONTACT

3526275016; amcmurra@ufl.edu

Kristine Boykin, BSN

CONTACT

3522738706; kristineboykin@ufl.edu

Study Design

• Study Type: interventional
• Phase: early phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: October 19, 2015
• First Posted: December 4, 2015
• Study Start: November 1, 2016
• Primary Completion: March 1, 2026
• Study Completion: March 1, 2026
• Last Updated: October 2, 2025

Record last verified: 2025-09

Locations

US (2)