Clinical trial NCT03806816: Use of Melatonin for Neuroprotection in Asphyxiated Newborns
Official title: Use of Melatonin for Neuroprotection in Term Infants With Hypoxic-ischaemic Encephalopathy
Study type: INTERVENTIONAL
Overall status: UNKNOWN
Phase: NA
Conditions: Hypoxic-Ischemic Encephalopathy
Cell Damage
Asphyxia Perinatal
Keywords: autophagy
neuroprotection
melatonin
Hypoxic-Ischemic Encephalopathy
hypothermia
newborn
neurological outcome
perinatal asphyxia
Lead sponsor: University Hospital of Ferrara
Sponsor class: OTHER
Collaborators: name: AUSL Romagna Rimini
First posted: 2019-01-16
Enrollment: 100
Sex: ALL
Minimum age (years): 1
Maximum age (years): 6
Standard ages: CHILD
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

Eligibility criteria: 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

Primary outcomes:
measure: Bayley III scale
timeFrame: 12 months
Secondary outcomes:
measure: brain MRI
timeFrame: between the 5th and 7th days of life
measure: continuous aEEG
timeFrame: Continuous monitoring for the first 72 hours and for the rewarmed
measure: Plasma Concentration of Melatonin
timeFrame: at birth, 24 hours, 48 hours, 72 hours, 5 days, 7 days of life
measure: ATG5 Plasma concentration
timeFrame: at birth, 24 hours, 48 hours, 72 hours, 5 days, 7 days of life
Other outcomes:
Locations:
city: Vatican City
country: Holy See (Vatican City State)
facility: Ospedale Pediatrico Bambin Gesù
city: Bolzano
country: Italy
facility: ospdale di Bolzano
city: Cesena
country: Italy
facility: Bufalini Hospital Cesena
city: Ferrara
country: Italy
facility: University Hospital "Sant'Anna" of Ferrara
city: L'Aquila
country: Italy
facility: ospedale San Salvatore
city: Rimini
country: Italy
facility: Infermi Hospital Rimini
Study officials:
affiliation: University Hospital of Ferrara
name: Anna Tarocco, MD
role: PRINCIPAL_INVESTIGATOR
References:
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