Erythropoietin in Infants With Hypoxic Ischemic Encephalopathy (HIE)

Tracking Information
First Submitted Date ICMJE	July 23, 2009
First Posted Date ICMJE	July 24, 2009
Last Update Posted Date	September 28, 2009
Study Start Date ICMJE	October 2007
Actual Primary Completion Date	December 2008 (Final data collection date for primary outcome measure)
Current Primary Outcome Measures ICMJE; (submitted: July 23, 2009)	Neurodevelopmental outcomes [ Time Frame: 6 months ]; EEG changes [ Time Frame: 2-3 weeks ]; MRI of the brain [ Time Frame: 3 weeks ]
Original Primary Outcome Measures ICMJE	Same as current
Change History	Complete list of historical versions of study NCT00945789 on ClinicalTrials.gov Archive Site
Current Secondary Outcome Measures ICMJE; (submitted: July 23, 2009)	Nitric oxide concentrations in the plasma [ Time Frame: 2 weeks ]
Original Secondary Outcome Measures ICMJE	Same as current
Current Other Outcome Measures ICMJE	Not Provided
Original Other Outcome Measures ICMJE	Not Provided
Descriptive Information
Brief Title ICMJE	Erythropoietin in Infants With Hypoxic Ischemic Encephalopathy (HIE)
Official Title ICMJE	Human Recombinant Erythropoietin (HrEPO) in Asphyxia Neonatorum: A Pilot Trial
Brief 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.
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 ICMJE	Interventional
Study Phase	Phase 1; Phase 2
Study Design ICMJE	Allocation: Non-Randomized; Intervention Model: Parallel Assignment; Masking: Triple (Participant, Investigator, Outcomes Assessor); Primary Purpose: Treatment
Condition ICMJE	Hypoxic Ischemic Encephalopathy
Intervention ICMJE	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.
Study Arms	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
Publications *	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.
Recruitment Information
Recruitment Status ICMJE	Completed
Actual Enrollment ICMJE; (submitted: July 23, 2009)	45
Original Actual Enrollment ICMJE	Same as current
Actual Study Completion Date	June 2009
Actual Primary Completion Date	December 2008 (Final data collection date for primary outcome measure)
Eligibility Criteria ICMJE	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
Sex/Gender	Sexes Eligible for Study: All
Ages	up to 24 Hours (Child)
Accepts Healthy Volunteers	No
Contacts ICMJE	Contact information is only displayed when the study is recruiting subjects
Listed Location Countries ICMJE	Egypt
Removed Location Countries
Administrative Information
NCT Number ICMJE	NCT00945789
Other Study ID Numbers ICMJE	1102007
Has Data Monitoring Committee	Yes
U.S. FDA-regulated Product	Not Provided
IPD Sharing Statement	Not Provided
Responsible Party	Abdul rahman Al Mashad, MD Associate Professor of Pediatrics, Tanta University Faculty of Medicine
Study Sponsor ICMJE	Tanta University
Collaborators ICMJE	Not Provided
Investigators ICMJE	Not Provided
PRS Account	Tanta University
Verification Date	September 2009
ICMJE Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP