Erythropoietin in Infants With Hypoxic Ischemic Encephalopathy (HIE)

September 24, 2009 updated by: Tanta University

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.

Study Overview

Status

Completed

Conditions

Intervention / Treatment

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.

Study Type

Interventional

Enrollment (Actual)

45

Phase

  • Phase 2
  • Phase 1

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • Egypt
      • Tanta, Egypt
        • Tanta University Faculty of medicine

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

No older than 1 day (CHILD)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

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

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: TREATMENT
  • Allocation: NON_RANDOMIZED
  • Interventional Model: PARALLEL
  • Masking: TRIPLE

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
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.
OTHER: 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.

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Time Frame
Neurodevelopmental outcomes
Time Frame: 6 months
6 months
EEG changes
Time Frame: 2-3 weeks
2-3 weeks
MRI of the brain
Time Frame: 3 weeks
3 weeks

Secondary Outcome Measures

Outcome Measure
Time Frame
Nitric oxide concentrations in the plasma
Time Frame: 2 weeks
2 weeks

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Tanta University

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start

October 1, 2007

Primary Completion (ACTUAL)

December 1, 2008

Study Completion (ACTUAL)

June 1, 2009

Study Registration Dates

First Submitted

July 23, 2009

First Submitted That Met QC Criteria

July 23, 2009

First Posted (ESTIMATE)

July 24, 2009

Study Record Updates

Last Update Posted (ESTIMATE)

September 28, 2009

Last Update Submitted That Met QC Criteria

September 24, 2009

Last Verified

September 1, 2009

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • 1102007

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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