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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
  Purpose

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.


Condition Intervention Phase
Hypoxic Ischemic Encephalopathy
Drug: Human recombinant erythropoietin
Procedure: EEG and Brain MRI
Biological: Nitric oxide measurement in the blood
Phase 1
Phase 2

Study Type: Interventional
Study Design: Allocation: Non-Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Parallel Assignment
Masking: Double Blind (Subject, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Official Title: Human Recombinant Erythropoietin (HrEPO) in Asphyxia Neonatorum: A Pilot Trial

Resource links provided by NLM:


Further study details as provided by Tanta University:

Primary Outcome Measures:
  • 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 ]

Secondary Outcome Measures:
  • Nitric oxide concentrations in the plasma [ Time Frame: 2 weeks ] [ Designated as safety issue: No ]

Enrollment: 45
Study Start Date: October 2007
Study Completion Date: June 2009
Primary Completion Date: December 2008 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: EPO HIE Group
Infants with hypoxic ischemic encephalopathy receive human recombinant erythropoietin
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.
No Intervention: Control HIE
Infants with hypoxic ischemic encephalopathy who do not receive treatment drug (EPO)
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.
Healthy Controls
Healthy newborn without hypoxic ischemic encephalopathy
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.

Detailed Description:

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.

  Eligibility

Ages Eligible for Study:   up to 24 Hours
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

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
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT00945789

Locations
Egypt
Tanta University Faculty of Medicine
Tanta, Egypt
Sponsors and Collaborators
Tanta University
  More Information

No publications provided by Tanta University

Additional publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
Responsible Party: Abdul rahman Al Mashad, MD Associate Professor of Pediatrics, Tanta University Faculty of Medicine
ClinicalTrials.gov Identifier: NCT00945789     History of Changes
Other Study ID Numbers: 1102007
Study First Received: July 23, 2009
Last Updated: September 24, 2009
Health Authority: Egypt: Institutional Review Board

Keywords provided by Tanta University:
Asphyxia neonatorum
Infants
EEG
Brain MRI
Nitric oxide

Additional relevant MeSH terms:
Asphyxia Neonatorum
Brain Diseases
Brain Ischemia
Hypoxia-Ischemia, Brain
Ischemia
Cardiovascular Diseases
Central Nervous System Diseases
Cerebrovascular Disorders
Hypoxia, Brain
Infant, Newborn, Diseases
Nervous System Diseases
Pathologic Processes
Vascular Diseases
Epoetin alfa
Nitric Oxide
Anti-Asthmatic Agents
Antioxidants
Autonomic Agents
Bronchodilator Agents
Cardiovascular Agents
Endothelium-Dependent Relaxing Factors
Free Radical Scavengers
Gasotransmitters
Hematinics
Hematologic Agents
Molecular Mechanisms of Pharmacological Action
Neurotransmitter Agents
Peripheral Nervous System Agents
Pharmacologic Actions
Physiological Effects of Drugs

ClinicalTrials.gov processed this record on November 20, 2014