Erythropoietin for the Repair of Cerebral Injury in Very Preterm Infants (EpoRepair)

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

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.

Study Overview

• Status: Active, not recruiting
• Conditions: Intraventricular Hemorrhage of Prematurity
• Intervention / Treatment: Drug: recombinant human Erythropoietin; Drug: Placebo

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Actual): 120
• Phase: Phase 3

Contacts and Locations

Study Locations

• Austria
  • Vienna, Austria
    • Medical University of Vienna
• Switzerland
  • Aarau, Switzerland, 5001
    • Kantonsspital Aarau
  • Basel, Switzerland, 4031
    • University Children's Hospital Basel (UKBB)
  • Bern, Switzerland, 3010
    • University Hospital Bern
  • Chur, Switzerland, 7000
    • Kantonsspital Graubünden
  • Lausanne, Switzerland, 1011
    • Centre Hospitalier Universitaire Vaudois (Chuv)
  • St. Gallen, Switzerland, 9006
    • Ostschweizer Kinderspital
  • Zurich, Switzerland, 8091
    • University Hospital Zurich

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 5 months to 7 months (Child)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

1. Infants with less than 32 weeks of gestation and/or less than 1500 g weight at birth
2. Intraventricular hemorrhage and/or hemorrhagic parenchymal infarction
3. Less than 8 days of life
4. Informed written parental consent

Exclusion Criteria:

1. Genetically defined syndrome
2. Severe congenital malformation adversely affecting life expectancy and/or neurodevelopment
3. A priory palliative care
4. Unlikely to participate at 5-year follow-up examination

Study Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: recombinant human Erythropoietin (Epo); 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; i.v. administration; Other Names: Epoetin beta
Placebo Comparator: Control; 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; i.v. administration; Other Names: normal saline

What is the study measuring?

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

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Course of intracerebral bleeding	Course of intracerebral bleeding from onset until term equivalent age with additional visits at 28 days of life and 36 weeks postmenstrual age.; No remaining lesions as recorded by cranial ultrasound; Persisting posthemorrhagic hydrocephalus without any drainage; Persisting posthemorrhagic hydrocephalus with repetitive but transient csf-drainage; Posthemorrhagic hydrocephalus with permanent csf-drainage; Convulsions and other abnormalities or medications related to intracerebral bleeding	Infants will be followed for the duration of hospital stay, an expected average of 14 weeks

Collaborators and Investigators

• Sponsor: University of Zurich
• Collaborators: Swiss National Science Foundation
• Investigators: Principal Investigator: Sven Wellmann, MD, University of Zurich; Study Chair: Hans Ulrich Bucher, MD, PhD, University of Zurich

Publications and helpful links

General Publications

• Ruegger CM, Hagmann CF, Buhrer C, Held L, Bucher HU, Wellmann S; EpoRepair Investigators. Erythropoietin for the Repair of Cerebral Injury in Very Preterm Infants (EpoRepair). Neonatology. 2015;108(3):198-204. doi: 10.1159/000437248. Epub 2015 Aug 8.

Helpful Links

• EpoRepair trial homepage

Study record dates

Study Major Dates

• Study Start: March 1, 2014
• Primary Completion (Anticipated): December 1, 2023
• Study Completion (Anticipated): March 1, 2024

Study Registration Dates

• First Submitted: February 25, 2014
• First Submitted That Met QC Criteria: February 27, 2014
• First Posted (Estimate): March 3, 2014

Study Record Updates

• Last Update Posted (Actual): November 23, 2018
• Last Update Submitted That Met QC Criteria: November 21, 2018
• Last Verified: November 1, 2018

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Pathologic Processes; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Wounds and Injuries; Craniocerebral Trauma; Trauma, Nervous System; Brain Injuries; Hemorrhage; Hematinics; Epoetin Alfa
• Other Study ID Numbers: EpoRepair; 2013DR3204 (Other Identifier: Swissmedic)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED