Use of Melatonin for Neuroprotection in Asphyxiated Newborns

NCT ID: NCT03806816

Last Updated: 2019-10-11

Study Results

Results pending

The study team has not published outcome measurements, participant flow, or safety data for this trial yet. Check back later for updates.

Basic Information

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Recruitment Status

UNKNOWN

Clinical Phase

NA

Total Enrollment

100 participants

Study Classification

INTERVENTIONAL

Study Start Date

2018-12-13

Study Completion Date

2022-12-31

Brief Summary

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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

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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.

Conditions

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Hypoxic-Ischemic Encephalopathy Cell Damage Asphyxia Perinatal

Study Design

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Allocation Method

RANDOMIZED

Intervention Model

PARALLEL

Primary Study Purpose

TREATMENT

Blinding Strategy

SINGLE

Outcome Assessors

Study Groups

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HYPOTHERMIA / MELATONIN group

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

Group Type EXPERIMENTAL

Melatonin

Intervention Type DIETARY_SUPPLEMENT

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

HYPOTHERMIA / PLACEBO group

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

Group Type EXPERIMENTAL

PLACEBO group

Intervention Type OTHER

5 daily enteral doses of placebo 2 ml/kg

Interventions

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Melatonin

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

Intervention Type DIETARY_SUPPLEMENT

PLACEBO group

5 daily enteral doses of placebo 2 ml/kg

Intervention Type OTHER

Other Intervention Names

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Buona Circadiem placebo

Eligibility Criteria

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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
Minimum Eligible Age

1 Hour

Maximum Eligible Age

6 Hours

Eligible Sex

ALL

Accepts Healthy Volunteers

No

Sponsors

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AUSL Romagna Rimini

OTHER

Sponsor Role collaborator

University Hospital of Ferrara

OTHER

Sponsor Role lead

Responsible Party

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Anna Tarocco

Medical Doctor, Principal Investigator

Responsibility Role PRINCIPAL_INVESTIGATOR

Principal Investigators

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Anna Tarocco, MD

Role: PRINCIPAL_INVESTIGATOR

University Hospital of Ferrara

Locations

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Ospedale Pediatrico Bambin Gesù

Vatican City, , Holy See

Site Status RECRUITING

ospdale di Bolzano

Bolzano, , Italy

Site Status RECRUITING

Bufalini Hospital Cesena

Cesena, , Italy

Site Status RECRUITING

University Hospital "Sant'Anna" of Ferrara

Ferrara, , Italy

Site Status RECRUITING

ospedale San Salvatore

L’Aquila, , Italy

Site Status RECRUITING

Infermi Hospital Rimini

Rimini, , Italy

Site Status RECRUITING

Countries

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Holy See Italy

Central Contacts

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Anna Tarocco, MD

Role: CONTACT

+390532236014

Paolo Pinton, Professor

Role: CONTACT

+390532455802

Facility Contacts

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Immacolata Savarese, MD

Role: primary

Andrea Dotta, MD

Role: backup

Elisabetta Chiodin, MD

Role: primary

Alex Staffler, MD

Role: backup

MARCELLO Stella

Role: primary

Elisa Mariani

Role: backup

Anna Tarocco, MD

Role: primary

+390532236014

Paolo Pinton, Prof

Role: backup

+390532455802

Eugenia Maranella, MD

Role: primary

Sandra Di Fabio, MD

Role: backup

Gina Ancora, MD PhD

Role: primary

+390541705445

Miria Natile, MD

Role: backup

+390541705445

References

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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.

Reference Type RESULT
PMID: 29681183 (View on PubMed)

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.

Reference Type RESULT
PMID: 26063194 (View on PubMed)

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.

Reference Type RESULT
PMID: 27524449 (View on PubMed)

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.

Reference Type RESULT
PMID: 28065781 (View on PubMed)

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.

Reference Type RESULT
PMID: 22348528 (View on PubMed)

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.

Reference Type RESULT
PMID: 29031859 (View on PubMed)

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.

Reference Type RESULT
PMID: 28389438 (View on PubMed)

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.

Reference Type RESULT
PMID: 25827279 (View on PubMed)

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.

Reference Type RESULT
PMID: 23629670 (View on PubMed)

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.

Reference Type RESULT
PMID: 20695757 (View on PubMed)

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.

Reference Type RESULT
PMID: 20207600 (View on PubMed)

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.

Reference Type RESULT
PMID: 25393080 (View on PubMed)

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.

Reference Type RESULT
PMID: 11703564 (View on PubMed)

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.

Reference Type RESULT
PMID: 30108392 (View on PubMed)

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.

Reference Type RESULT
PMID: 29408249 (View on PubMed)

Other Identifiers

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23/2018/SPER/AOUFE

Identifier Type: -

Identifier Source: org_study_id

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