Does Erythropoietin Improve Outcome in Very Preterm Infants?

Swiss Neonatal Network

Status and phase

Completed

Phase 2

Conditions

Developmental Psychomotor Disorders

Intracranial Hemorrhage

Cerebral Palsy

Periventricular Leukomalacia

Treatments

Drug: Recombinant human Erythropoietin

Drug: saline

Study type

Interventional

Funder types

Other

NETWORK

Identifiers

NCT00413946

3200B0-108176 (Other Grant/Funding Number)

RoFAR ID 2127989593 (Other Grant/Funding Number)

Details and patient eligibility

About

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.

Full 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.

Enrollment

420 patients

Sex

All

Ages

Under 3 hours old

Volunteers

No Healthy Volunteers

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