Does Erythropoietin Improve Outcome in Very Preterm Infants?

Study Overview
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Brief Summary
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The main goal of this trial is to investigate whether early administration of human erythropoietin (EPO) in very preterm infants improves neurodevelopmental outcome at 24 months corrected age. This study is designed as randomized, double-masked, placebo controlled multicenter study involving at least 420 patients.

Detailed Description
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HYPOTHESIS Early administration of human erythropoietin (EPO) in very preterm infants reduces perinatal injury to the brain (retina), lung and gut and improves neurodevelopmental outcome at 24 months corrected age. PRIMARY OBJECTIVE To determine whether cerebral outcome is improved if infants born between 26 0/7 and 31 6/7 gestational weeks at birth receive erythropoietin in high dose in the first three days after birth. SECONDARY OBJECTIVES To determine whether early administration of EPO alters the incidence of complications typically associated with preterm birth, i.e. mortality, septicaemia, necrotising enterocolitis, bronchopulmonary dysplasia (oxygen dependency at 36 weeks postmenstrual age), retinopathy, intracranial haemorrhage, white matter disease (periventricular leucomalacia), growth failure, cerebral palsy and handicap at 5 years. Biomarkers of encephalopathy of prematurity assessed on magnetic resonance imaging (MRI) at term equivalent age. RATIONALE EPO has been shown to be protective against hypoxic-ischaemic and inflammatory injuries in a broad range of tissues and organs besides promoting red cell formation. It has been shown to have neuroprotective and neurotrophic activity in animals after acute brain damage as well as in adult stroke patients. Several mechanisms explaining this activity have been recognized: EPO inhibits glutamate release in the brain, modulates intracellular calcium metabolism, induces the generation of anti-apoptotic factors, reduces inflammation, decreases nitric oxide-mediated injury, and has direct antioxidant effects. Very preterm infants have significant delay in mental and physical development assessed at 24 months corrected age. The most critical period are the first days after preterm birth where the oxygenation of the brain may be impaired by respiratory, circulatory and nutritional insufficiency. Although there are probably several mechanisms involved in permanent brain damage, it is most likely that EPO with its multiple action may reduce this damage. EPO has been studied in several trials in preterm infants to prevent anaemia and is now widely used for this indication. STUDY DESIGN Randomized, double-masked, placebo-controlled multicenter clinical trial. Research plan 420 infants will be randomized during the first three hours of life to receive EPO (3000 U/kg body weight) or placebo intravenously at 3, 12-18 and 36-42 hours after birth. Standardized evaluation including cerebral sonography at day 1 and 7 and at 36 0/7 gestational weeks (or at discharge home if discharged before) will determine the presence or absence of complications. Cerebral volume and white matter volume will be assessed at 40 postmenstrual weeks with MRI (only if available). Experienced examiners will assess developmental function at 24 months corrected age using the reliable and validly revised Bayley Scales II of Infant Development and determine the presence or absence of impairment of motor function (cerebral palsy) and neurosensory function (blindness or deafness). CLINICAL SIGNIFICANCE At least 1 of every 100 live born infants is born very preterm. 90% of these infants survive but >50% have a delay in mental and physical development assessed at 24 months corrected age. More subtle problems affecting cognition, vision and hearing are common at the age of five years and have an impact on school performance and quality of life of the infants and their families. The aim of this trial is to examine whether a short, easily applicable and well tolerated pharmacological intervention can improve neurodevelopmental outcome.

Official Title
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Neuroprotective Effect of High Dose Erythropoietin in Very Preterm Infants

Conditions
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Intracranial Hemorrhage, Periventricular Leukomalacia, Cerebral Palsy, Developmental Psychomotor Disorders

Intervention / Treatment
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* Drug: Recombinant human Erythropoietin
* Drug: saline


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Infants born between 26 0/7 and 31 6/7 gestational weeks Postnatal age less than 3 hours Informed parental consent (preferably obtained before birth) Exclusion Criteria: Genetically defined syndrome Severe congenital malformation adversely affecting life expectancy Severe congenital malformation adversely affecting neurodevelopment A priory palliative care Intracranial haemorrhage grade 3 or more detected before dose 3 of Erythropoietin

Ages Eligible for Study
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Maximum Age: 3 Hours

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: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Erythropoietin<br>Three doses of rErythropoietin (3000 U/kg body weight) intravenously at 3, 12-18 and 36-42 hours after birth. | Drug: Recombinant human Erythropoietin<br>* 3 doses 3000 units (1 ml) of recombinant human erythropoietin per kg body weight<br>|
| Placebo Comparator: saline<br>Three doses of placebo (0.9% saline 1 ml/kg body weight) intravenously at 3, 12-18 and 36-42 hours after birth | Drug: saline<br>* three doses of 1.0 ml saline per body weight<br>* Other names: NaCl 0.9%;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Mental developmental index (Bayley II) and motor, visual and hearing impairment |  | at age of 24 months corrected for prematurity. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| MRI at term equivalent | White matter injury score grey matter injury score brain maturation | 40 postmenstrual weeks | 
| cerebral palsy. |  | First 24 months of life (corrected for prematurity) | 
| Cognitive development and cerebral palsy | Kaufmann ABC II, standardized neurological, visual and hearing examination, questionnaire about health status and behavior. Classification of impairments, disabilities and handicaps. | 5 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Premature infant, developmental outcome