Does Erythropoietin Improve Outcome in Very Preterm Infants?

Phase 2

Completed

• Conditions: Periventricular Leukomalacia; Cerebral Palsy; Developmental Psychomotor Disorders; Intracranial Hemorrhage
• Interventions: Drug: Recombinant human Erythropoietin; Drug: saline

• Registration Number: NCT00413946
• Lead Sponsor: Swiss Neonatal Network

Brief Summary

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

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.

Study Timeline

• Study Start: 2006-01
• Study First Submitted: 2006-12-18
• Study First Submitted QC: 2006-12-19
• Study First Posted: 2006-12-20
• Primary Completion: 2012-12
• Study Completion: 2012-12
• Status Verified: 2018-10
• Last Update Submitted: 2018-10-27
• Last Update Posted: 2018-10-30

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 420

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)

Read More

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

Read More

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Erythropoietin	Recombinant human Erythropoietin	Three doses of rErythropoietin (3000 U/kg body weight) intravenously at 3, 12-18 and 36-42 hours after birth.
saline	saline	Three doses of placebo (0.9% saline 1 ml/kg body weight) intravenously at 3, 12-18 and 36-42 hours after birth

Primary Outcome Measures

Name	Time	Method
Mental developmental index (Bayley II) and motor, visual and hearing impairment	at age of 24 months corrected for prematurity.

Secondary Outcome Measures

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

Trial Locations

Locations (3)

Kantonsspital; 🇨🇭 Chur, Switzerland

University Hospital; 🇨🇭 Zurich, Switzerland

Hopital universitaire; 🇨🇭 Geneva, Switzerland