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Erythropoietin in Infants With Hypoxic Ischemic Encephalopathy (HIE)

This study has been completed.
Sponsor:
Information provided by:
Tanta University
ClinicalTrials.gov Identifier:
NCT00945789
First received: July 23, 2009
Last updated: September 24, 2009
Last verified: September 2009

July 23, 2009
September 24, 2009
October 2007
December 2008   (final data collection date for primary outcome measure)
  • Neurodevelopmental outcomes [ Time Frame: 6 months ] [ Designated as safety issue: Yes ]
  • EEG changes [ Time Frame: 2-3 weeks ] [ Designated as safety issue: Yes ]
  • MRI of the brain [ Time Frame: 3 weeks ] [ Designated as safety issue: Yes ]
Same as current
Complete list of historical versions of study NCT00945789 on ClinicalTrials.gov Archive Site
Nitric oxide concentrations in the plasma [ Time Frame: 2 weeks ] [ Designated as safety issue: No ]
Same as current
Not Provided
Not Provided
 
Erythropoietin in Infants With Hypoxic Ischemic Encephalopathy (HIE)
Human Recombinant Erythropoietin (HrEPO) in Asphyxia Neonatorum: A Pilot Trial

In this prospective trial the investigators plan to study the efficacy of erythropoietin as a therapeutic agent in neonates who suffer from brain injury following perinatal asphyxia.

During HIE free radicals are generated within mitochondria and also as byproducts in the synthesis of prostaglandins.These free radicals ignite a secondary phase of subsequent damage to the brain by attacking membranal fatty acids. Nitric oxide (NO) is involved in the cascade of metabolic events that contributes to HIE. It mediates, in part, the cytotoxic activity of macrophages, induces relaxation of blood vessels, and also acts as a neurotransmitter in the central and peripheral nervous system. Therefore, the therapeutic value of NO synthase inhibitors, among many other agents used to ameliorate the course of HIE, is currently under investigation in experimental animals.

Erythropoietin (EPO) is a cytokine originally identified for its role in erythropoiesis and more recently shown to be produced in the central nervous system.Relative insufficiency of endogenous EPO during periods of ischemic stress may trigger neuronal apoptosis, whereas the provision of exogenous EPO has been shown to inhibit this process. The potential immediate protective effects of EPO include decreased NO production, activation of antioxidant enzymes, reduction of glutamate toxicity, inhibition of lipid peroxidation, and reduction of inflammation. Long-term protective effects of EPO include the generation of neuronal anti-apoptotic mechanisms, stimulation of angiogenesis, and modulation of neurogenesis.

Preliminary data supports a protective role of exogenous EPO to neuronal cells. The presence of EPO rescues in vitro cultured neurons from NO-induced death. It specifically protects cultured neurons from N-methyl-D-aspartate (NMDA) receptor-mediated glutamate toxicity. Intercerebroventricular injection of EPO offered significant protection of neuronal tissue in animals with focal cerebral ischemia. EPO is able to cross the blood brain barrier, and its concentration in the cerebrospinal fluid in normal rats significantly increases within 30 minutes following intravenous administration. EPO also offered neuronal protection when it was administered systemically to animals suffering from global and focal cerebral ischemia. In adult patients with stroke, the administration of EPO ameliorates the course of the disease. Therefore, EPO has recently received much attention and is speculated to have a role in the protection of HIE infants. However, despite the biological plausibility and the encouraging preliminary data from animals and adult humans, surprisingly EPO has never been tried in newborns with HIE even though it has already been used in neonates for other indications and is known to be safe.

Interventional
Phase 1
Phase 2
Allocation: Non-Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Parallel Assignment
Masking: Double Blind (Subject, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Hypoxic Ischemic Encephalopathy
  • Drug: Human recombinant erythropoietin
    Epo dse is 2500 IU/kg subcutaneous daily for 5 days.
  • Procedure: EEG and Brain MRI
    EEG to be done twice in hte first 48 hours and at 2-3 weeks. MRI to be done at 3 weeks of age.
  • Biological: Nitric oxide measurement in the blood
    Concentration of nitric oxide is measured in the blood at enrollment. For the 2 groups with asphyxia, measurement to be repeated in 2 weeks.
  • Experimental: EPO HIE Group
    Infants with hypoxic ischemic encephalopathy receive human recombinant erythropoietin
    Interventions:
    • Drug: Human recombinant erythropoietin
    • Procedure: EEG and Brain MRI
    • Biological: Nitric oxide measurement in the blood
  • No Intervention: Control HIE
    Infants with hypoxic ischemic encephalopathy who do not receive treatment drug (EPO)
    Interventions:
    • Procedure: EEG and Brain MRI
    • Biological: Nitric oxide measurement in the blood
  • Healthy Controls
    Healthy newborn without hypoxic ischemic encephalopathy
    Intervention: Biological: Nitric oxide measurement in the blood
Elmahdy H, El-Mashad AR, El-Bahrawy H, El-Gohary T, El-Barbary A, Aly H. Human recombinant erythropoietin in asphyxia neonatorum: pilot trial. Pediatrics. 2010 May;125(5):e1135-42. doi: 10.1542/peds.2009-2268. Epub 2010 Apr 12.

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Completed
45
June 2009
December 2008   (final data collection date for primary outcome measure)

Inclusion Criteria:

  • Inborn infants at term gestation (38-42 weeks)
  • Apgar score ≤ 3 at 5 minutes and/or delayed first breath beyond five minutes after birth
  • Profound metabolic or mixed acidosis with serum bicarbonate <12 mMol/L in initial arterial blood gas
  • Evidence of encephalopathy such as stupor, coma, seizures, or hypotonia in the immediate neonatal period

Exclusion Criteria:

  • Twin gestation
  • Maternal diabetes
  • Congenital malformations of the central nervous system
  • Chromosomal abnormalities
  • Chorioamnionitis and congenital infections
  • Intrauterine growth restriction
Both
up to 24 Hours
No
Contact information is only displayed when the study is recruiting subjects
Egypt
 
NCT00945789
1102007
Yes
Abdul rahman Al Mashad, MD Associate Professor of Pediatrics, Tanta University Faculty of Medicine
Tanta University
Not Provided
Not Provided
Tanta University
September 2009

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP