Erythropoietin in Infants With Hypoxic Ischemic Encephalopathy (HIE)

Study Results

Results pending

The study team has not published outcome measurements, participant flow, or safety data for this trial yet. Check back later for updates.

Basic Information

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Recruitment Status

COMPLETED

Clinical Phase

PHASE1/PHASE2

Total Enrollment

45 participants

Study Classification

INTERVENTIONAL

Study Start Date

2007-10-31

Study Completion Date

2009-06-30

Brief Summary

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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.

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Detailed Description

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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.

Conditions

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Hypoxic Ischemic Encephalopathy

Study Design

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Allocation Method

NON_RANDOMIZED

Intervention Model

PARALLEL

Primary Study Purpose

TREATMENT

Blinding Strategy

TRIPLE

Participants Investigators Outcome Assessors

Study Groups

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EPO HIE Group

Infants with hypoxic ischemic encephalopathy receive human recombinant erythropoietin

Group Type EXPERIMENTAL

Human recombinant erythropoietin

Intervention Type DRUG

Epo dse is 2500 IU/kg subcutaneous daily for 5 days.

EEG and Brain MRI

Intervention Type PROCEDURE

EEG to be done twice in hte first 48 hours and at 2-3 weeks. MRI to be done at 3 weeks of age.

Nitric oxide measurement in the blood

Intervention Type BIOLOGICAL

Concentration of nitric oxide is measured in the blood at enrollment. For the 2 groups with asphyxia, measurement to be repeated in 2 weeks.

Control HIE

Infants with hypoxic ischemic encephalopathy who do not receive treatment drug (EPO)

Group Type NO_INTERVENTION

EEG and Brain MRI

Intervention Type PROCEDURE

EEG to be done twice in hte first 48 hours and at 2-3 weeks. MRI to be done at 3 weeks of age.

Nitric oxide measurement in the blood

Intervention Type BIOLOGICAL

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

Group Type OTHER

Nitric oxide measurement in the blood

Intervention Type BIOLOGICAL

Concentration of nitric oxide is measured in the blood at enrollment. For the 2 groups with asphyxia, measurement to be repeated in 2 weeks.

Interventions

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Human recombinant erythropoietin

Epo dse is 2500 IU/kg subcutaneous daily for 5 days.

Intervention Type DRUG

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.

Intervention Type PROCEDURE

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.

Intervention Type BIOLOGICAL

Eligibility Criteria

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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

Maximum Eligible Age

24 Hours

Eligible Sex

ALL

Accepts Healthy Volunteers

No