Erythropoietin in Infants With Hypoxic Ischemic Encephalopathy (HIE)

Hypoxic Ischemic Encephalopathy Clinical Trial

Official title:

Human Recombinant Erythropoietin (HrEPO) in Asphyxia Neonatorum: A Pilot Trial

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00945789
• Other study ID #: 1102007
• Status: Completed
• Phase: Phase 1/Phase 2
• First received: July 23, 2009
• Last updated: September 24, 2009
• Start date: October 2007
• Est. completion date: June 2009

Study information

• Verified date: September 2009
• Source: Tanta University
• Contact: n/a
• Is FDA regulated: No
• Health authority: Egypt: Institutional Review Board
• Study type: Interventional

Clinical Trial Summary

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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 45
• Est. completion date: June 2009
• Est. primary completion date: December 2008
• Accepts healthy volunteers: No
• Gender: Both
• Age group: N/A to 24 Hours

Eligibility

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 Design

Allocation: Non-Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Double Blind (Subject, Investigator, Outcomes Assessor), Primary Purpose: Treatment

Related Conditions & MeSH terms

• Asphyxia Neonatorum
• Brain Diseases
• Brain Ischemia
• Hypoxia-Ischemia, Brain
• Hypoxic Ischemic Encephalopathy

Intervention

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.

Locations

Country	Name	City	State
Egypt	Tanta University Faculty of Medicine	Tanta

Sponsors (1)

Lead Sponsor	Collaborator
Tanta University

Country where clinical trial is conducted

Egypt, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Neurodevelopmental outcomes		6 months	Yes
Primary	EEG changes		2-3 weeks	Yes
Primary	MRI of the brain		3 weeks	Yes
Secondary	Nitric oxide concentrations in the plasma		2 weeks	No