Does Erythropoietin Improve Outcome in Very Preterm Infants?

October 27, 2018 updated by: Bucher Hans Ulrich, Swiss Neonatal Network

Neuroprotective Effect of High Dose Erythropoietin in Very Preterm Infants

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.

Study Overview

Status

Completed

Conditions

Intervention / Treatment

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 Type

Interventional

Enrollment (Actual)

420

Phase

  • Phase 2

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • Switzerland
      • Aarau, Switzerland
        • Kantonsspital
      • Basel, Switzerland
        • Kantonsspital
      • Chur, Switzerland
        • Kantonsspital
      • Geneva, Switzerland
        • Hopital Universitaire
      • Zurich, Switzerland, CH-8091
        • University Hospital

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

No older than 3 years (Child)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

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

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Prevention
  • Allocation: Randomized
  • Interventional Model: Parallel Assignment
  • Masking: Quadruple

Arms and Interventions

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

What is the study measuring?

Primary Outcome Measures

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

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
MRI at term equivalent
Time Frame: 40 postmenstrual weeks
White matter injury score grey matter injury score brain maturation
40 postmenstrual weeks
cerebral palsy.
Time Frame: First 24 months of life (corrected for prematurity)
First 24 months of life (corrected for prematurity)
Cognitive development and cerebral palsy
Time Frame: 5 years

Kaufmann ABC II, standardized neurological, visual and hearing examination, questionnaire about health status and behavior.

Classification of impairments, disabilities and handicaps.
5 years

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Swiss Neonatal Network

Collaborators

Swiss National Science Foundation

Investigators

  • Principal Investigator: Hans U Bucher, Prof, University of Zurich

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Helpful Links

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start

January 1, 2006

Primary Completion (Actual)

December 1, 2012

Study Completion (Actual)

December 1, 2012

Study Registration Dates

First Submitted

December 18, 2006

First Submitted That Met QC Criteria

December 19, 2006

First Posted (Estimate)

December 20, 2006

Study Record Updates

Last Update Posted (Actual)

October 30, 2018

Last Update Submitted That Met QC Criteria

October 27, 2018

Last Verified

October 1, 2018

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • 3200B0-108176 (Other Grant/Funding Number: SNF 3200B0-108176)
  • RoFAR ID 2127989593 (Other Grant/Funding Number: 3200B0-108176)

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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