Clinical trial NCT02621944: Melatonin as a Neuroprotective Therapy in Neonates With HIE Undergoing Hypothermia
Official title: Melatonin as a Neuroprotective Therapy in Neonates With HIE Undergoing Hypothermia
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: EARLY_PHASE1
Conditions: Hypoxic Ischemic Encephalopathy
Lead sponsor: University of Florida
Sponsor class: OTHER
Collaborators: name: Thrasher Research Fund
First posted: 2015-12-04
Enrollment: 70
Sex: ALL
Maximum age (years): 6
Standard ages: CHILD
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

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.

Detailed 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.

Eligibility criteria: 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.

Primary outcomes:
measure: To identify the maximum tolerated dose of Melatonin
timeFrame: Changes in Baseline to day 3
measure: Bayley-III Index Scores (Cognitive, Language, and Motor) will be used for neurological outcome assessment
timeFrame: Approximately 18 - 20 Months
measure: Peak Plasma Concentration (Cmax) of Melatonin 0.5 mg/kg.
timeFrame: 0 (baseline), 3, 5, 6, 12, 24, 48, 96 hours and day 14 (one sample)
measure: 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.
timeFrame: Baseline ongoing to Day 14
measure: Peak Plasma Concentration (Cmax) of Melatonin 3 mg/kg.
timeFrame: 0 (baseline), 3, 5, 6, 12, 24, 48, 96 hours and day 14 (one sample)
measure: Peak Plasma Concentration (Cmax) of Melatonin 5 mg/kg.
timeFrame: 0 (baseline), 3, 5, 6, 12, 24, 48, 96 hours and day 14 (one sample)
Secondary outcomes:
measure: Bayley-III Index Scores Subscales (Receptive and Expressive Language, Fine and Gross Motor) will be used for neurological outcome assessment
timeFrame: Approximately 18 - 20 Months
measure: Evaluation of The Impact of Melatonin using Magnetic Resonance Image (MRI)
timeFrame: Approximately 7 - 12 days
Other outcomes:
Locations:
city: Gainesville
country: United States
facility: University of Florida
state: Florida
city: Orlando
country: United States
facility: Florida Hospital for Children
state: Florida
Study officials:
affiliation: University of Florida
name: Michael D Weiss, MD
role: PRINCIPAL_INVESTIGATOR
References: