Use of Melatonin for Neuroprotection in Asphyxiated Newborns

Use of Melatonin for Neuroprotection in Term Infants With Hypoxic-ischaemic Encephalopathy


Lead Sponsor: University Hospital of Ferrara

Collaborator: AUSL Romagna Rimini

Source 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.

Overall Status Recruiting
Start Date December 13, 2018
Completion Date December 31, 2022
Primary Completion Date December 31, 2021
Phase N/A
Study Type Interventional
Primary Outcome
Measure Time Frame
Bayley III scale 12 months
Secondary Outcome
Measure Time Frame
brain MRI between the 5th and 7th days of life
continuous aEEG Continuous monitoring for the first 72 hours and for the rewarmed
Plasma Concentration of Melatonin at birth, 24 hours, 48 hours, 72 hours, 5 days, 7 days of life
ATG5 Plasma concentration at birth, 24 hours, 48 hours, 72 hours, 5 days, 7 days of life
Enrollment 100

Intervention Type: Dietary Supplement

Intervention Name: Melatonin

Description: 5 daily enteral doses of melatonin 10 mg/kg. (=2 ml/kg)

Arm Group Label: HYPOTHERMIA / MELATONIN group

Other Name: Buona Circadiem

Intervention Type: Other

Intervention Name: PLACEBO group

Description: 5 daily enteral doses of placebo 2 ml/kg

Arm Group Label: HYPOTHERMIA / PLACEBO group

Other Name: placebo



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

Gender: All

Minimum Age: N/A

Maximum Age: 6 Hours

Healthy Volunteers: No

Overall Official
Last Name Role Affiliation
Anna Tarocco, MD Principal Investigator University Hospital of Ferrara
Overall Contact

Last Name: Anna Tarocco, MD

Phone: +390532236014

Email: [email protected]

Facility: Status: Contact: Contact Backup:
Ospedale Pediatrico Bambin Gesù | Vatican City, Holy See (Vatican City State) Recruiting Immacolata Savarese, MD
ospdale di Bolzano | Bolzano, Italy Recruiting Elisabetta Chiodin, MD
Bufalini Hospital Cesena | Cesena, Italy Recruiting MARCELLO Stella [email protected]
University Hospital "Sant'Anna" of Ferrara | Ferrara, 44124, Italy Recruiting Anna Tarocco, MD +390532236014 [email protected]
ospedale San Salvatore | L'Aquila, Italy Recruiting Eugenia Maranella, MD
Infermi Hospital Rimini | Rimini, 47923, Italy Recruiting Gina Ancora, MD PhD +390541705445 [email protected]
Location Countries

Holy See (Vatican City State)


Verification Date

October 2019

Responsible Party

Type: Principal Investigator

Investigator Affiliation: University Hospital of Ferrara

Investigator Full Name: Anna Tarocco

Investigator Title: Medical Doctor, Principal Investigator

Has Expanded Access No
Condition Browse
Number Of Arms 2
Arm Group


Type: Experimental

Description: HIE infants who will receive melatonin in addition to the routine cooling treatment


Type: Experimental

Description: HIE infants who will not receive melatonin in addition to the routine cooling treatment

Acronym MELPRO
Patient Data No
Study Design Info

Allocation: Randomized

Intervention Model: Parallel Assignment

Primary Purpose: Treatment

Masking: Single (Outcomes Assessor)