Erythropoietin for the Repair of Cerebral Injury in Very Preterm Infants

Study Overview
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Brief Summary
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The purpose of this randomized and placebo-controlled EpoRepair trial is to evaluate the effect of intravenously administered recombinant human erythropoietin (Epo) as compared to placebo in preterm infants with brain damage on neurological development until five years od age.

Detailed Description
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Worldwide, 1% of all infants are born very preterm with less than 32 weeks of gestation, which is more than 2 months before expected date of delivery. If these smallest infants suffer in addition to prematurity a second hit, such as intraventricular hemorrhage or parenchymal infarction, they are at high risk for learning disabilities, mental retardation, and cerebral palsy in later life. Intraventricular hemorrhage and parenchymal infarction occur in about 12% of very preterm infants, mostly in the very smallest and within the first few days after birth, and can be recorded by cranial ultrasound. Except for shunt insertion to divert cerebrospinal fluid in infants with posthemorrhagic hydrocephalus and possibly the removal of blood clots, there is no treatment for established intracerebral bleeding, and no medical therapies exist to ameliorate the neurodevelopmental sequelae. Apart from stimulating production of red blood cells in the bone marrow, recombinant human erythropoietin (Epo) has been shown to exert neuroprotective action in a variety of animal models and in clinical studies. Epo administration has been found to be beneficial and safe in randomized controlled trials (RCT) involving adult and infant patients. Observational data suggest that Epo administered to very preterm infants in order to prevent from anemia improves long-term cognitive outcomes until school-age especially in those infants who had suffered intracerebral bleeding. These data, however, are observational and therefore do not allow for any firm conclusions or recommendations. The hypothesis generated by these data calls for confirmation or refutation by an RCT designed to address this question.

Official Title
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Erythropoietin for the Repair of Cerebral Injury in Very Preterm Infants - a Randomized, Double-blind, Placebo-controlled, Prospective, and Multicenter Clinical Study

Conditions
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Intraventricular Hemorrhage of Prematurity

Intervention / Treatment
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* Drug: recombinant human Erythropoietin
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Infants with less than 32 weeks of gestation and/or less than 1500 g weight at birth Intraventricular hemorrhage and/or hemorrhagic parenchymal infarction Less than 8 days of life Informed written parental consent Exclusion Criteria: Genetically defined syndrome Severe congenital malformation adversely affecting life expectancy and/or neurodevelopment A priory palliative care Unlikely to participate at 5-year follow-up examination

Ages Eligible for Study
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Minimum Age: 23 Weeks
Maximum Age: 31 Weeks

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: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: recombinant human Erythropoietin (Epo)<br>Epo 2000 U in normal saline per ml/kg of body weight 5 times intravenously, total dosage 10000 U per 5ml/kg. In detail: For loading 3 times beginning at day 5 of life (± 2 days), followed at 24 hours and 48 hours later. For maintenance 2 times, at day 10 and day 17 after the first study medication. | Drug: recombinant human Erythropoietin<br>* i.v. administration<br>* Other names: Epoetin beta;|
| Placebo Comparator: Control<br>Placebo 1 ml normal saline/kg of body weight 5 times intravenously, total dosage 5 ml/kg. In detail: For loading 3 times beginning at day 5 of life (± 2 days), followed at 24 hours and 48 hours later. For maintenance 2 times, at day 10 and day 17 after the first study medication. | Drug: Placebo<br>* i.v. administration<br>* Other names: normal saline;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Neurodevelopmental outcome | With 5 years of age, composite intelligence quotient to be assessed by standardized IQ tests. | 5 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Biomarker cranial MRI | Brain injury score assessed on cranial MRI, including brain maturation score and white matter and gray matter injury scores, as biomarker for long-term neurodevelopmental outcome. | 40 weeks postmenstrual age | 
| Safety | Analysis will be performed to get insight about the distributions of adverse events and other safety relevant outcomes between groups. | Infants will be followed for the duration of hospital stay, an expected average of 14 weeks | 
| Neurodevelopmental outcome | Bayley Scales of Infant Development (BSID-III) and the presence or absence of impairment of motor function (cerebral palsy) and neurosensory function (blindness or deafness) will be assessed with 18 to 24 months. | 2 years | 
| Biomarker serial cranial ultrasound | Cranial ultrasound is a useful point of care method to detect, confirm and monitor brain damage including intracerebral bleeding. It is part of clinical routine for the duration of hospital stay. | Infants will be followed for the duration of hospital stay, an expected average of 14 weeks | 
| Overall developmental outcome | Neurological and formal psychological examination. Normal Overall developmental outcome is classified as normal if IQ >84 and without one or more of the following: motor impairment, cognitive impairment, behavior problems, poor general health, severe hearing loss, or bilateral blindness. | 5 years |