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NCT Number: NCT02621944

Melatonin as a Neuroprotective Therapy in Neonates With HIE Undergoing Hypothermia

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.

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Key information

Conditions

Hypoxic Ischemic Encephalopathy Brain Diseases Brain Ischemia Cardiovascular Diseases Central Nervous System Diseases Cerebrovascular Disorders Hypoxia Hypoxia, Brain Hypoxia-Ischemia, Brain Nervous System Diseases Pathological Conditions, Signs and Symptoms Signs and Symptoms Signs and Symptoms, Respiratory Vascular Diseases

Age range

Up to 6 hour

Sex eligibility

All sexes

Study type

Interventional

Phase

Early Phase 1

Primary location

University of Florida, Gainesville, Florida, United States

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About this study

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.

Who can participate

Healthy volunteers accepted: No

Only the study team can determine whether someone qualifies for participation.

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.

Treatment and study plan

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.

Magnetic Resonance Imaging

Other

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

Other names: MRI

Pharmacokinetics

Other

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

Neurological Outcome Assessment

Behavioral

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

Primary outcomes

  1. To identify the maximum tolerated dose of Melatonin

    Time frame: Changes in Baseline to day 3

    The maximum tolerated dose (MTD) is defined as the highest dose level without adverse events in no more than 1 out of 6 patients

  2. Bayley-III Index Scores (Cognitive, Language, and Motor) will be used for neurological outcome assessment

    Time frame: Approximately 18 - 20 Months

    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".

  3. Peak Plasma Concentration (Cmax) of Melatonin 0.5 mg/kg.

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

    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.

  4. 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.

    Time frame: Baseline ongoing to Day 14

    Incidence/Grade of Treatment Emergent Adverse Events (TEAEs), Serious Adverse Events (SAEs), laboratory abnormalities Percentage and number of subjects who discontinued for adverse event

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

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

    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.

  6. Peak Plasma Concentration (Cmax) of Melatonin 5 mg/kg.

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

    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.

Secondary outcomes

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

    Time frame: Approximately 18 - 20 Months

    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".

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

    Time frame: Approximately 7 - 12 days

    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).

Study contacts

Contact information is provided by the study sponsor or research team.

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

CONTACT

[email protected]

3526275016

Kristine Boykin, BSN

CONTACT

[email protected]

3522738706

Sponsors and collaborators

Lead sponsor

University of Florida

Other

Collaborators

  • Thrasher Research Fund

Registry information

Important dates

Study start
2016
Primary completion
2027
Study completion
2027
First posted
Dec 4, 2015
Registry last updated
Jun 29, 2026

OpenTrials presents study information sourced from ClinicalTrials.gov. The official registry record should be consulted for the latest information.

View the official ClinicalTrials.gov record (opens in a new tab)

This listing is for discovery and informational purposes only. It is not medical advice, does not guarantee that a study is recruiting, and does not determine eligibility. Contact the study team and a qualified healthcare professional when considering participation.

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