Hypoxic-Ischemic Encephalopathy Clinical Trial
— MELPROOfficial title:
Use of Melatonin for Neuroprotection in Term Infants With Hypoxic-ischaemic Encephalopathy
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.
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 |
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 |
Lead Sponsor | Collaborator |
---|---|
University Hospital of Ferrara | AUSL Romagna Rimini |
Holy See (Vatican City State), Italy,
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
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 |
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