Use of Melatonin for Neuroprotection in Asphyxiated Newborns

Not Applicable

• Conditions: Hypoxic-Ischemic Encephalopathy; Cell Damage; Asphyxia Perinatal
• Interventions: Dietary Supplement: Melatonin; Other: PLACEBO group

• Registration Number: NCT03806816
• Lead Sponsor: University Hospital of Ferrara

Brief Summary

Protection of brain development is a major aim in the Neonatal Intensive Care Unit. Hypoxic-Ischemic Encephalopathy (HIE) occurs in 3-5 per 1000 births. Only 47% of neonates have normal outcomes. The neurodevelopmental consequences of brain injury for asphyxiated term infants include cerebral palsy, severe intellectual disabilities and also a number of minor behavioural and cognitive deficits. However, there are very few therapeutic strategies for the prevention or treatment of brain damage. The gold standard is hypothermic treatment but, according to the literature, melatonin potentially acts in synergy with hypothermia for neuroprotection and to improve neurologic outcomes. Melatonin appears to be a good candidate because of its different protective effects including reactive oxygen species scavenging, excitotoxic cascade blockade, modulation of neuroinflammatory pathways.

The research study will evaluate the neuroprotective properties and the effects of Melatonin in association with therapeutic hypothermia for hypoxic ischemic encephalopathy.

Detailed Description

It is a randomized double blind, placebo controlled trial on 100 neonates with moderate to moderately to severe hypoxic ischemic encephalopathy (HIE) . HIE infants are randomized into two groups: Whole body cooling group (N = 50 receive 72 hours of whole body hypothermia) and melatonin/ hypothermia group (N = 50; receive hypothermia and 5 daily enteral doses of melatonin 10 mg/kg). Serum melatonin and autophagy levels are measured at enrollment, daily during the hypothermic treatment, at day 5 and 7 for the two HIE groups.

aEEG will be performed for 72 hrs during the hypothermic treatment and the re-warming. MRI and Spectroscopy analysis will be performed between day 5 and 7 of. After hospital discharge the infants will enter a follow-up program consisting in periodic clinical and developmental assessments until 2 years of age corrected for prematurity. An expert psychologist and a neonatologist will assess neurodevelopmental outcome using the Bayley Scales III at 6-12-24 months of corrected age.

Study Timeline

• Study Start: 2018-12-13
• Study First Submitted: 2019-01-14
• Study First Submitted QC: 2019-01-14
• Study First Posted: 2019-01-16
• Status Verified: 2019-10
• Last Update Submitted: 2019-10-10
• Last Update Posted: 2019-10-11
• Primary Completion: 2021-12-31
• Study Completion: 2022-12-31

Recruitment & Eligibility

• Status: UNKNOWN
• Sex: All
• Target Recruitment: 100

Inclusion Criteria

• gestational age > 35 weeks and weight > 1800 gr
• Apgar score < 5 at 10 minutes o need for cardiopulmonary resuscitation at 10 minutes or evidence of base excess > 12 mmol/L or pH < 7,0 at initial blood gas analyses
• evidence of moderate or severa encephalopathy graded according to Sarnat&Sarnat neurological evaluation
• abnormal amplitude integrated electroencephalography

Exclusion Criteria

• suspected inborn errors of metabolism
• major chromosomal congenital defects

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
HYPOTHERMIA / MELATONIN group	Melatonin	HIE infants who will receive melatonin in addition to the routine cooling treatment
HYPOTHERMIA / PLACEBO group	PLACEBO group	HIE infants who will not receive melatonin in addition to the routine cooling treatment

Primary Outcome Measures

Name	Time	Method
Bayley III scale	12 months	Bayley scale of infant and toddler development. It measures developmental skills reached by infant and young children between 1 month and 42 months The scale is subdivided into 5 subscales Cognitive,Receptive communication,Expressive communication,Fine motor ,Gross motor.Receptive and expressive communication have a composite in language score So as fine and gross motor in motor score For all subtests raw scores correspond to scaled scores ranging from 1 to 19 with a mean of 10 and SD of 3 The composite scores are given by the sum of the corresponding subtests scaled scores.; Two parent-reported scales (Social-Emotional and Adaptive Behavior) will be collected.

Secondary Outcome Measures

Name	Time	Method
brain MRI	between the 5th and 7th days of life	to evaluate the presence of deep grey matter, PLIC, white matter, brainstem and hippocampus lesions
continuous aEEG	Continuous monitoring for the first 72 hours and for the rewarmed	Al Naqueeb classification for aEEG will be used.Background voltage pattern will be scored in NORMAL (Lower margin \>5μV,Upper margin \>10μV The activity is continuous), MODERATELY ABORMAL (Lower margin \<5μV, upper margin \>10μV,The activity is moderately discontinuous)SEVERELY ABNORMAL/ SUPPRESSED (Lower margin \<5μV, upper margin \<10μV)
Plasma Concentration of Melatonin	at birth, 24 hours, 48 hours, 72 hours, 5 days, 7 days of life	UPLC-Massa Acquity-Xevo TQD (Waters) will be used to measure melatonin concentrations in the plasma
ATG5 Plasma concentration	at birth, 24 hours, 48 hours, 72 hours, 5 days, 7 days of life	ELISA test will be used to measure plasma levels of ATG5

Trial Locations

Locations (6)

Ospedale Pediatrico Bambin Gesù; 🇻🇦 Vatican City, Holy See (Vatican City State)

ospdale di Bolzano; 🇮🇹 Bolzano, Italy

Bufalini Hospital Cesena; 🇮🇹 Cesena, Italy

University Hospital "Sant'Anna" of Ferrara; 🇮🇹 Ferrara, Italy

ospedale San Salvatore; 🇮🇹 L'Aquila, Italy

Infermi Hospital Rimini; 🇮🇹 Rimini, Italy