Use of Melatonin for Neuroprotection in Asphyxiated Newborns

NCT03806816 | Unknown DMC

• 1 other identifier: 23/2018/SPER/AOUFE
• Study Type: interventional
• Target: 100
• Locations: 2 countries
• Sites: 6

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.

Conditions

Hypoxic-Ischemic Encephalopathy; Cell Damage; Asphyxia Perinatal

Keywords

autophagy; neuroprotection; melatonin; Hypoxic-Ischemic Encephalopathy; hypothermia; newborn; neurological outcome; perinatal asphyxia

Outcome Measures

Primary Outcomes (1)

• Bayley III scale

  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.

  12 months

Secondary Outcomes (4)

• 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

Study Arms (2)

HYPOTHERMIA / MELATONIN group

EXPERIMENTAL

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

Dietary Supplement: Melatonin

HYPOTHERMIA / PLACEBO group

EXPERIMENTAL

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

Other: PLACEBO group

Interventions

Melatonin DIETARY_SUPPLEMENT

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

Also known as: Buona Circadiem

HYPOTHERMIA / MELATONIN group

PLACEBO group OTHER

5 daily enteral doses of placebo 2 ml/kg

Also known as: placebo

HYPOTHERMIA / PLACEBO group

Eligibility Criteria

• Age: 1 Hour - 6 Hours
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17)

You may qualify if:

• 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

You may not qualify if:

• suspected inborn errors of metabolism
• major chromosomal congenital defects

Sponsors & Collaborators

• University Hospital of Ferrara: lead
• AUSL Romagna Rimini: collaborator

Study Sites (6)

Ospedale Pediatrico Bambin Gesù

Vatican City, Holy See

RECRUITING

ospdale di Bolzano

Bolzano, Italy

RECRUITING

Bufalini Hospital Cesena

Cesena, Italy

RECRUITING

University Hospital "Sant'Anna" of Ferrara

Ferrara, 44124, Italy

RECRUITING

ospedale San Salvatore

L’Aquila, Italy

RECRUITING

Infermi Hospital Rimini

Rimini, 47923, Italy

RECRUITING

Related Publications (15)

• Wang Q, Lv H, Lu L, Ren P, Li L. Neonatal hypoxic-ischemic encephalopathy: emerging therapeutic strategies based on pathophysiologic phases of the injury. J Matern Fetal Neonatal Med. 2019 Nov;32(21):3685-3692. doi: 10.1080/14767058.2018.1468881. Epub 2018 May 2.

  PMID: 29681183 RESULT

• Hassell KJ, Ezzati M, Alonso-Alconada D, Hausenloy DJ, Robertson NJ. New horizons for newborn brain protection: enhancing endogenous neuroprotection. Arch Dis Child Fetal Neonatal Ed. 2015 Nov;100(6):F541-52. doi: 10.1136/archdischild-2014-306284. Epub 2015 Jun 10.

  PMID: 26063194 RESULT

• McAdams RM, Juul SE. Neonatal Encephalopathy: Update on Therapeutic Hypothermia and Other Novel Therapeutics. Clin Perinatol. 2016 Sep;43(3):485-500. doi: 10.1016/j.clp.2016.04.007. Epub 2016 Jun 22.

  PMID: 27524449 RESULT

• Ramos E, Patino P, Reiter RJ, Gil-Martin E, Marco-Contelles J, Parada E, de Los Rios C, Romero A, Egea J. Ischemic brain injury: New insights on the protective role of melatonin. Free Radic Biol Med. 2017 Mar;104:32-53. doi: 10.1016/j.freeradbiomed.2017.01.005. Epub 2017 Jan 6.

  PMID: 28065781 RESULT

• Balduini W, Carloni S, Perrone S, Bertrando S, Tataranno ML, Negro S, Proietti F, Longini M, Buonocore G. The use of melatonin in hypoxic-ischemic brain damage: an experimental study. J Matern Fetal Neonatal Med. 2012 Apr;25 Suppl 1:119-24. doi: 10.3109/14767058.2012.663232. Epub 2012 Mar 5.

  PMID: 22348528 RESULT

• Parikh P, Juul SE. Neuroprotective Strategies in Neonatal Brain Injury. J Pediatr. 2018 Jan;192:22-32. doi: 10.1016/j.jpeds.2017.08.031. Epub 2017 Oct 12. No abstract available.

  PMID: 29031859 RESULT

• Martinello K, Hart AR, Yap S, Mitra S, Robertson NJ. Management and investigation of neonatal encephalopathy: 2017 update. Arch Dis Child Fetal Neonatal Ed. 2017 Jul;102(4):F346-F358. doi: 10.1136/archdischild-2015-309639. Epub 2017 Apr 6.

  PMID: 28389438 RESULT

• Shea KL, Palanisamy A. What can you do to protect the newborn brain? Curr Opin Anaesthesiol. 2015 Jun;28(3):261-6. doi: 10.1097/ACO.0000000000000184.

  PMID: 25827279 RESULT

• Alonso-Alconada D, Alvarez A, Arteaga O, Martinez-Ibarguen A, Hilario E. Neuroprotective effect of melatonin: a novel therapy against perinatal hypoxia-ischemia. Int J Mol Sci. 2013 Apr 29;14(5):9379-95. doi: 10.3390/ijms14059379.

  PMID: 23629670 RESULT

• Fan X, van Bel F. Pharmacological neuroprotection after perinatal asphyxia. J Matern Fetal Neonatal Med. 2010 Oct;23 Suppl 3:17-9. doi: 10.3109/14767058.2010.505052.

  PMID: 20695757 RESULT

• Cilio MR, Ferriero DM. Synergistic neuroprotective therapies with hypothermia. Semin Fetal Neonatal Med. 2010 Oct;15(5):293-8. doi: 10.1016/j.siny.2010.02.002. Epub 2010 Mar 7.

  PMID: 20207600 RESULT

• Aly H, Elmahdy H, El-Dib M, Rowisha M, Awny M, El-Gohary T, Elbatch M, Hamisa M, El-Mashad AR. Melatonin use for neuroprotection in perinatal asphyxia: a randomized controlled pilot study. J Perinatol. 2015 Mar;35(3):186-91. doi: 10.1038/jp.2014.186. Epub 2014 Nov 13.

  PMID: 25393080 RESULT

• Fulia F, Gitto E, Cuzzocrea S, Reiter RJ, Dugo L, Gitto P, Barberi S, Cordaro S, Barberi I. Increased levels of malondialdehyde and nitrite/nitrate in the blood of asphyxiated newborns: reduction by melatonin. J Pineal Res. 2001 Nov;31(4):343-9. doi: 10.1034/j.1600-079x.2001.310409.x.

  PMID: 11703564 RESULT

• Ahmad QM, Chishti AL, Waseem N. Role of melatonin in management of hypoxic ischaemic encephalopathy in newborns: A randomized control trial. J Pak Med Assoc. 2018 Aug;68(8):1233-1237.

  PMID: 30108392 RESULT

• Roohbakhsh A, Shamsizadeh A, Hayes AW, Reiter RJ, Karimi G. Melatonin as an endogenous regulator of diseases: The role of autophagy. Pharmacol Res. 2018 Jul;133:265-276. doi: 10.1016/j.phrs.2018.01.022. Epub 2018 Feb 3.

  PMID: 29408249 RESULT

MeSH Terms

Conditions

Hypoxia-Ischemia, Brain; Hypothermia

Interventions

Melatonin

Condition Hierarchy (Ancestors)

Brain Ischemia; Cerebrovascular Disorders; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Hypoxia, Brain; Vascular Diseases; Cardiovascular Diseases; Hypoxia; Signs and Symptoms, Respiratory; Signs and Symptoms; Pathological Conditions, Signs and Symptoms; Body Temperature Changes

Intervention Hierarchy (Ancestors)

Tryptamines; Indoles; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists

Study Officials

• Anna Tarocco, MD

  University Hospital of Ferrara

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Anna Tarocco, MD

CONTACT

+390532236014; anna.tarocco@unife.it

Paolo Pinton, Professor

CONTACT

+390532455802; paolo.pinton@unife.it

Study Design

• Study Type: interventional
• Phase: not applicable
• Allocation: RANDOMIZED
• Masking: SINGLE
• Who Masked: OUTCOMES ASSESSOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Medical Doctor, Principal Investigator

Study Record Dates

• First Submitted: January 14, 2019
• First Posted: January 16, 2019
• Study Start: December 13, 2018
• Primary Completion: December 31, 2021
• Study Completion: December 31, 2022
• Last Updated: October 11, 2019

Record last verified: 2019-10

Data Sharing

• IPD Sharing: Will not share

Locations

HO (1); IT (5)