Use of Melatonin for Neuroprotection in Asphyxiated Newborns

Hypoxic-Ischemic Encephalopathy Clinical Trial

— MELPRO  

Official title:

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

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT03806816
• Other study ID #: 23/2018/SPER/AOUFE
• Status: Recruiting
• Phase: N/A
• Start date: December 13, 2018
• Est. completion date: December 31, 2022

Study information

• Verified date: October 2019
• Source: University Hospital of Ferrara
• Contact: Anna Tarocco, MD
• Phone: +390532236014
• Email: anna.tarocco[@]unife.it
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 100
• Est. completion date: December 31, 2022
• Est. primary completion date: December 31, 2021
• Accepts healthy volunteers: No
• Gender: All
• Age group: N/A to 6 Hours

Eligibility

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

Related Conditions & MeSH terms

• Asphyxia
• Asphyxia Perinatal
• Brain Diseases
• Brain Ischemia
• Cell Damage
• Hypoxia
• Hypoxia-Ischemia, Brain
• Hypoxic-Ischemic Encephalopathy
• Ischemia

Intervention

Dietary Supplement:
• Melatonin
5 daily enteral doses of melatonin 10 mg/kg. (=2 ml/kg)

Other:
• PLACEBO group
5 daily enteral doses of placebo 2 ml/kg

Locations

Country	Name	City	State
Holy See (Vatican City State)	Ospedale Pediatrico Bambin Gesù	Vatican City
Italy	ospdale di Bolzano	Bolzano
Italy	Bufalini Hospital Cesena	Cesena
Italy	University Hospital "Sant'Anna" of Ferrara	Ferrara
Italy	ospedale San Salvatore	L'Aquila
Italy	Infermi Hospital Rimini	Rimini

Sponsors (2)

Lead Sponsor	Collaborator
University Hospital of Ferrara	AUSL Romagna Rimini

Countries where clinical trial is conducted

Holy See (Vatican City State),  Italy, 

References & Publications (15)

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. — View Citation

Alonso-Alconada D, Alvarez A, Arteaga O, Martínez-Ibargüen 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. Review. — View Citation

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 — View Citation

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: 10.3109/1 — View Citation

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. Review. — View Citation

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. Review. — View Citation

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. — View Citation

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 20 — View Citation

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. — View Citation

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. Review. — View Citation

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. — View Citation

Ramos E, Patiño P, Reiter RJ, Gil-Martín 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.2017.0 — View Citation

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. Review. — View Citation

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. Review. — View Citation

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 201 — View Citation

* Note: There are 15 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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	brain MRI	to evaluate the presence of deep grey matter, PLIC, white matter, brainstem and hippocampus lesions	between the 5th and 7th days of life
Secondary	continuous aEEG	Al Naqueeb classification for aEEG will be used.Background voltage pattern will be scored in NORMAL (Lower margin >5µV,Upper margin >10µV The activity is continuous), MODERATELY ABORMAL (Lower margin <5µV, upper margin >10µV,The activity is moderately discontinuous)SEVERELY ABNORMAL/ SUPPRESSED (Lower margin <5µV, upper margin <10µV)	Continuous monitoring for the first 72 hours and for the rewarmed
Secondary	Plasma Concentration of Melatonin	UPLC-Massa Acquity-Xevo TQD (Waters) will be used to measure melatonin concentrations in the plasma	at birth, 24 hours, 48 hours, 72 hours, 5 days, 7 days of life
Secondary	ATG5 Plasma concentration	ELISA test will be used to measure plasma levels of ATG5	at birth, 24 hours, 48 hours, 72 hours, 5 days, 7 days of life