Recombinant Human Erythropoietin Improve Neurodevelopmental Outcomes in Extremely Preterm Infants

Study Overview
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Brief Summary
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In the ELGAN (Extremely Low Gestational Age Newborn) study, abnormal brain structure and function were associated with intermittent or sustained systemic inflammation (ISSI). Since EPO has anti-inflammatory properties in the kidney and in muscle as well as growth/trophic properties. Based on its potential for neuroprotection, the prospective randomized and masked study was designed to determine whether rhEPO （500u/kg) was also effective in improving developmental outcomes for extremely low gestational age newborns.

Detailed Description
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Exogenous erythropoietin (EPO) is currently used to reduce or prevent the need for red blood cell transfusions in preterm infants. Just two decades ago, erythropoietin (EPO) receptors were first identified in the brain, and astrocytes were found to be capable of synthesizing EPO . Subsequently, it was found that cultured hippocampal and cerebral cortical neurons exposed to EPO were spared some of the glutamate-induced cell death seen in neurons not exposed to EPO. Thus began the concept that EPO protects the brain against adversity. Several follow-up studies of children who had participated in trials of recombinant EPO for the prevention or treatment of anemia, term newborn encephalopathy,or retinopathy of prematurity have also provided evidence of neuroprotective effects. In the ELGAN (Extremely Low Gestational Age Newborn) study, abnormal brain structure and function were associated with intermittent or sustained systemic inflammation (ISSI) . Since EPO has anti-inflammatory properties in the kidney and in muscle as well as growth/trophic properties, we reasoned that elevated circulating levels might convey information about reduced risk of brain damage in ELGANs. Although major neurodevelopmental disabilities such as cerebral palsy (CP), mental disabilities, and learning and attention deficits during school age figure prominently in the outcomes of ELBW infants, successful neuroprotective interventions have yet to be developed. Investagators designed a prospective, randomized, masked study to evaluate rhEPO during initial hospitalization and follow up, and hypothesized that rhEPO recipients would receive fewer transfusions during initial hospitalization in extremely preterm infants. Based on its potential for neuroprotection, our study was designed to determine whether rhEPO (500 u/kg) was also effective in improving developmental outcomes for extremely low gestational age newborns. The neurodevelopmental outcomes of rhEPO in treating extremely preterm infants are not clear. Investigators propose an early-childhood neurodevelopmental follow-up study to compare long-term effects of the rhEPO as measured by, Bayley Scales of Infant Development III. We plan to follow extremely low gestational age children around 24 months' corrected age (CA) who are enrolled in this study.

Conditions
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Developmental Disabilities

Intervention / Treatment
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* Drug: Recombinant human erythropoietin
* Drug: Normal saline


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Preterm infants admitted to NICU wuth gestational age less than 28 weeks Age less than 3 days; parental informed consent. Exclusion Criteria: Major life-threatening anomalies (brain, cardiac, chromosomal anomalies) Hematologic crises such as DIC, or hemolysis due to blood group incompatibilities Polycythemia (hematocrit > 65); Hypertension Seizures Congenital infection

Ages Eligible for Study
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Minimum Age: 1 Day
Maximum Age: 3 Days

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Prevention
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: EPO group<br>In EPO group, The recombinant human erythropoietin (rhEPO) will be given by 500 U/kg/dose intravenously within 72h after birth, and every other day up to 32 weeks of corrected age. | Drug: Recombinant human erythropoietin<br>* rhEPO is administered 500IU/kg, intravenously within 72h after birth, and every other day up to 32 weeks of corrected age.<br>* Other names: Epoietin Beta;|
| Placebo Comparator: Normal saline<br>Normal saline is administered the same volume with EPO, intravenously within 72h after birth, and every other day up to 32 weeks of corrected age. | Drug: Normal saline<br>* Normal salin is administered the same volume with rhEPO intravenously within 72h after birth, and every other day up to 32 weeks of corrected age..<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Mortality | To compare the death rate of EPO and control groups at 2 years old | 2 years | 
| Incidence of neurological disability | To assess the incidence of neurological disability of EPO and control groups at 2 years old | 2 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of MDI<70 | To compare the incidence of MDI<70 via Bayley Scales of Infant Development between the two groups at 2 years old | 2 years | 
| Incidence of cerebral palsy | To compare the incidence of cerebral palsy between the two groups at 2 years old | 2 years | 
| Short-term complicatioins | Retinopathy of prematurity, periventricular leukomalacia,Intraventricular hemorrhage, necrotising enterocolitis and sepsis | 3 months | 
| Incidence of blindness | To compare the incidence of blindness via visual acuity between the two groups at 2 years old | 2 years | 
| Incidence of deafness | To compare the incidence of blindness via auditory brainstem response measurements between the two groups at 2 years old | 2 years | 
| Early blood biomarkers for poor neurological outcomes | To investigate early blood biomarkers via multi-omics to predict poor neurological outcomes | 4 weeks | 
| Brain imaging biomarkers for poor neurological outcomes | To investigate Brain imaging biomarkers via MRI to predict poor neurological outcomes | Up to 40 weeks of corrected age | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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erythropoietin, preterm, brain injury, cerebral palsy, PVL