Oral Melatonin as Neuroprotectant in Preterm Infants

Oral Melatonin as Neuroprotectant in Preterm Infants .A Prospective, Double Blind vs Placebo, Parallel Arms Study

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.

Study Overview

• Status: Completed
• Conditions: Malondialdehyde; Melatonin
• Intervention / Treatment: Dietary supplement: melatonin; Drug: placebo

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.

• Study Type: Interventional
• Enrollment (Actual): 60
• Phase: Not Applicable

Contacts and Locations

Study Locations

• Italy
  • BS
    • Brescia, BS, Italy, 25123
      • Child and Adolescence Neuropsychiatry Unit, Children's Hospital "Spedali Civili" of Brescia, 25123 Brescia, Italy.
    • Brescia, BS, Italy, 25123
      • Neonatal Intensive Care Unit, Children's Hospital, University Hospital "Spedali Civili" Brescia, 25123 Brescia, Italy.
  • PV
    • Pavia, PV, Italy, 27100
      • Fondazione IRCCS Mondino
    • Pavia, PV, Italy, 27100
      • Neonatal Unit and NICU, Radiology, Clinical Chemistry Lab., Fondazione IRCCS Policlinico S. Matteo.

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 5 months to 6 months (CHILD)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: SUPPORTIVE_CARE
• Allocation: RANDOMIZED
• Interventional Model: PARALLEL
• Masking: DOUBLE

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
EXPERIMENTAL: melatonin; melatonin oral drops; 3 mg/kg/day for 15 days	Dietary supplement: melatonin; orally administered drops; Other Names: not reported
PLACEBO_COMPARATOR: placebo; oral drops manufactured to mimic melatonin	Drug: placebo; orally administered drops; Other Names: not reported

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Malondialdehyde	plasmatic concentration pg/ml	15 days
Melatonin	plasmatic concentration pg/ml	15 days

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Cranial ultrasound (cUS) Assessment	to identify and score White Matter injuries	up to 40 weeks
Brain Magnetic Resonance Immaging (cMRI) Assessment	Identify and score White Matter injuries	up to 40 weeks
Auditory brain stem evoked response (ABR) Assessments	Identify and score auditory diseases	up to 40 weeks

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Fagan Test of Infant Intelligence (FTII)	Measure the time ( minutes) to recognize unfamiliar versus familiar human faces to gauge visual-spatial encoding, attention, and working memory in infants.	up to 24 months
Griffiths Mental Developmental Scales'Revised (GMDS-R)	The scales rate infant development across 5 main areas (locomotor, personal and social skills, hearing and language, eye and hand co-ordination, and performance), providing a general developmental quotient (DQ) of infants' abilities and 5 subscale quotients (SQ).	up to 24 months
Child Behavior Checklist (CBCL) scales.	A self-rating scale to evaluate emotional, social, and behavioral problems in infants, according to the parents' evaluation.	up to 24 months

Collaborators and Investigators

• Sponsor: Francesca Garofoli
• Collaborators: Azienda Socio Sanitaria Territoriale degli Spedali Civili di Brescia; IRCCS National Neurological Institute "C. Mondino" Foundation
• Investigators: Principal Investigator: Chryssoula Tzialla, MD, IRCCS Policlinico S. Matteo

Publications and helpful links

General Publications

• 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.

Study record dates

Study Major Dates

• Study Start (ACTUAL): May 25, 2020
• Primary Completion (ACTUAL): October 1, 2022
• Study Completion (ACTUAL): October 11, 2022

Study Registration Dates

• First Submitted: May 23, 2019
• First Submitted That Met QC Criteria: January 16, 2020
• First Posted (ACTUAL): January 22, 2020

Study Record Updates

• Last Update Posted (ACTUAL): October 12, 2022
• Last Update Submitted That Met QC Criteria: October 11, 2022
• Last Verified: October 1, 2022

More Information

Terms related to this study

• Keywords: Melatonin; Malondialdehyde; Neuroprotection; Preterm neonate
• Additional Relevant MeSH Terms: Pregnancy Complications; Obstetric Labor Complications; Obstetric Labor, Premature; Premature Birth; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Central Nervous System Depressants; Protective Agents; Antioxidants; Melatonin
• Other Study ID Numbers: 20180004210 17/01/2018

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No