Clinical trial NCT04235673: Oral Melatonin as Neuroprotectant in Preterm Infants
Official title: Oral Melatonin as Neuroprotectant in Preterm Infants .A Prospective, Double Blind vs Placebo, Parallel Arms Study
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: NA
Conditions: Malondialdehyde
Melatonin
Keywords: Preterm neonate
Neuroprotection
Malondialdehyde
Melatonin
Lead sponsor: Fondazione IRCCS Policlinico San Matteo di Pavia
Sponsor class: OTHER
Collaborators: name: IRCCS National Neurological Institute "C. Mondino" Foundation
name: Azienda Socio Sanitaria Territoriale degli Spedali Civili di Brescia
First posted: 2020-01-22
Enrollment: 60
Sex: ALL
Minimum age (years): 25
Maximum age (years): 30
Standard ages: CHILD
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: SUPPORTIVE_CARE

Brief summary: Preterm newborns survival rates are improved, but long-term disabilities are still common. Major destructive focal lesions became less common, the most predominant lesion at present is diffuse white matter (WM damage). Melatonin (ME) serves as a neuroprotectant cerebral ischemia through its potent anti-oxidant/-inflammatory effect. Preclinical studies demonstrated that protects the developing brain by preventing abnormal myelination and inflammatory glial reaction. Clinical studies demonstrated ME ability in reducing brain damage after neonatal Hypoxic Ischemic Encephalopathy (HIE) or preventing neonatal impairments due to antenatal/ post-natal injuries: preeclampsia, IntraUterineGrowthRestriction (IUGR), ventilation, Bronchopulmonary Dysplasia (BPD). ME has a good safety profile with no known adverse effects. This study aims to highlight that ME can prevent brain impairment due to premature birth. ME will be administered orally (3 mg/kg/die for 15 days to neonates born before 29+6 week gestation, in a prospective double blind, randomized vs placebo study, 2 parallel arms. ME and malondialdehyde (MDA), a lipid peroxidation product) levels before and at the end of treatment will be measured . Other outcomes: Cerebral ultrasounds (cUS); cerebral magnetic resonance imaging (cMRI), " Fagan test " eye tracking, ophthalmological, auditory, neurological/cognitive child assessments. Monitoring parental distress, which can influence the neurodevelopmental outcome in preterms.

Detailed description: About 552.000 infants are born in Italy each year, 1% of them with gestational age under 30 weeks. Survival rates are improved, but long-term disabilities are still common. Major destructive focal lesions became less common, the most predominant lesion at present is diffuse white matter (WM damage). The prevention of neurodevelopmental impairment is a major public health challenge and efforts are needed to test neuroprotective strategies. Melatonin (ME) serves as a neuroprotectant cerebral ischemia through its potent anti-oxidant/-inflammatory effect. Preclinical studies demonstrated that protects the developing brain by preventing abnormal myelination and inflammatory glial reaction. Clinical studies demonstrated ME ability in reducing brain damage after neonatal Hypoxic Ischemic Encephalopathy (HIE) or preventing neonatal impairments due to antenatal/ post-natal injuries: preeclampsia, IntraUterineGrowthRestriction (IUGR), ventilation, Bronchopulmonary Dysplasia (BPD). Ongoing studies are testing in premature neonates and pregnant women its neuroprotective properties. ME has a good safety profile with no known adverse effects.

This study aims to highlight that ME can prevent brain impairment due to premature birth. ME will be administered orally (3 mg/kg/die for 15 days within 96 hours from birth) to neonates born before 29+6 week gestation age (GA), in a prospective double blind, randomized vs placebo study, 2 parallel arms (30 preterm infants each). ME and malondialdehyde (MDA, a lipid peroxidation product) levels will be measured before and at the end of treatment. At birth, within 40 weeks of neonatal age, at 4-6 and at 24 months of age the following examinations are performed: Cerebral ultrasounds (cUS); cerebral magnetic resonance imaging (cMRI), during natural sleep (i.e. adopting sleep deprivation and/or feeding protocols); "Fagan test"eye tracking, ophthalmological, auditory brain stem evoked response (ABR), neurological/cognitive child assessments. Monitoring parental distress, which can influence the neurodevelopmental outcome in preterms.

Eligibility criteria: Inclusion Criteria

* preterm newborns gestational age GA \< 29+6 weeks + day
* able to receive min 20ml/kg/day enteral nutrition, within 96 hours from birth
* written informed consent by both the parents.

Exclusion Criteria:

* preterm newborns GA \> 29+6 weeks + days
* not able to receive enteral nutrition (min 20 ml/kg/die) within 96 hours of life
* infants with genetic and/or congenital metabolic or chronic diseases
* intraventricular hemorrhage (IVH) ≥ III,
* parents refusing to sign a written informed consent

Primary outcomes:
measure: Malondialdehyde
timeFrame: 15 days
measure: Melatonin
timeFrame: 15 days
Secondary outcomes:
measure: Cranial ultrasound (cUS) Assessment
timeFrame: up to 40 weeks
measure: Brain Magnetic Resonance Immaging (cMRI) Assessment
timeFrame: up to 40 weeks
measure: Auditory brain stem evoked response (ABR) Assessments
timeFrame: up to 40 weeks
Other outcomes:
measure: Fagan Test of Infant Intelligence (FTII)
timeFrame: up to 24 months
measure: Griffiths Mental Developmental Scales'Revised (GMDS-R)
timeFrame: up to 24 months
measure: Child Behavior Checklist (CBCL) scales.
timeFrame: up to 24 months
Locations:
city: Brescia
country: Italy
facility: Child and Adolescence Neuropsychiatry Unit, Children's Hospital "Spedali Civili" of Brescia, 25123 Brescia, Italy.
state: BS
city: Brescia
country: Italy
facility: Neonatal Intensive Care Unit, Children's Hospital, University Hospital "Spedali Civili" Brescia, 25123 Brescia, Italy.
state: BS
city: Pavia
country: Italy
facility: Fondazione IRCCS Mondino
state: PV
city: Pavia
country: Italy
facility: Neonatal Unit and NICU, Radiology, Clinical Chemistry Lab., Fondazione IRCCS Policlinico S. Matteo.
state: PV
Study officials:
affiliation: Fondazione IRCCS Policlinico San Matteo di Pavia
name: Chryssoula Tzialla, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Garofoli F, Longo S, Pisoni C, Accorsi P, Angelini M, Aversa S, Caporali C, Cociglio S, De Silvestri A, Fazzi E, Rizzo V, Tzialla C, Zecca M, Orcesi S. Oral melatonin as a new tool for neuroprotection in preterm newborns: study protocol for a randomized controlled trial. Trials. 2021 Jan 22;22(1):82. doi: 10.1186/s13063-021-05034-w.