Melatonin as a Neuroprotective Therapy in Neonates With HIE Undergoing Hypothermia

Обзор

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.

Подробное описание

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.

Вмешательства

• Препарат Melatonin
  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.
• Другое Magnetic Resonance Imaging
  All participants will receive an MRI between 7-12 days of age.
• Другое Pharmacokinetics
  All participants will receive pharmacokinetics to test the amount of melatonin in the blood.
• Поведенческое Neurological Outcome Assessment
  All participants will receive the Bayley-III Scores and Subsets for neurological outcome assessments.

Первичные конечные точки

• To identify the maximum tolerated dose of Melatonin [Срок оценки: Changes in Baseline to day 3]
• Bayley-III Index Scores (Cognitive, Language, and Motor) will be used for neurological outcome assessment [Срок оценки: Approximately 18 - 20 Months]
• Peak Plasma Concentration (Cmax) of Melatonin 0.5 mg/kg. [Срок оценки: 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. [Срок оценки: Baseline ongoing to Day 14]
• Peak Plasma Concentration (Cmax) of Melatonin 3 mg/kg. [Срок оценки: 0 (baseline), 3, 5, 6, 12, 24, 48, 96 hours and day 14 (one sample)]
• Peak Plasma Concentration (Cmax) of Melatonin 5 mg/kg. [Срок оценки: 0 (baseline), 3, 5, 6, 12, 24, 48, 96 hours and day 14 (one sample)]

Вторичные конечные точки (2)

• Bayley-III Index Scores Subscales (Receptive and Expressive Language, Fine and Gross Motor) will be used for neurological outcome assessment [Срок оценки: Approximately 18 - 20 Months]
• Evaluation of The Impact of Melatonin using Magnetic Resonance Image (MRI) [Срок оценки: Approximately 7 - 12 days]

Критерии участия

Критерии включения

• 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.

Критерии исключения

• 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.

Критерии приведены из реестра в оригинале (на английском). Окончательную оценку соответствия проводит исследовательский центр.

Здоровые добровольцы: Нет

Дизайн исследования

Распределение

Нерандомизированное

Модель

Одна группа

Маскирование

Открытое

Основная цель

Лечение

Центры проведения

США · 2 центра

• University of Florida — Gainesville
• Florida Hospital for Children — Orlando

Идентификаторы

NCT: NCT02621944 · IRB201500886

Первоисточники (государственные реестры)

• ClinicalTrials.gov (NIH, США)

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