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

• ClinicalTrials.gov Identifier: NCT02076373
• Recruitment Status: Active, not recruiting
• First Posted: March 3, 2014
• Last Update Posted: November 23, 2018
• Sponsor: University of Zurich
• Collaborator: Swiss National Science Foundation
• Information provided by (Responsible Party): University of Zurich

Tracking Information

• First Submitted Date: February 25, 2014
• First Posted Date: March 3, 2014
• Last Update Posted Date: November 23, 2018
• Study Start Date: March 2014
• Estimated Primary Completion Date: December 2023 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: May 9, 2016)

Neurodevelopmental outcome [ Time Frame: 5 years ]

With 5 years of age, composite intelligence quotient to be assessed by standardized IQ tests.

Original Primary Outcome Measures (submitted: February 27, 2014)

Neurodevelopmental outcome [ Time Frame: 5 years ]

With 5 years of age, composite intelligence quotient to be assessed by standardized IQ tests. In addition, children will be classified as either being normal or having minor or major impairment according to the overall results of the tests. Children with intelligence incapable of measurement because of impairment severity will be assigned IQ scores below the lowest standard score. Normal development: All of the following: 1) Normal neurological evaluation, IQ > 84; 2) No neurodevelopmental deficits. Minor impairment: One or more of the following problems: 1) Subnormal cognitive abilities (IQ, 70-84); 2) Gross and fine motor activity deficits; 3) Disorders of language development; 4) Visual and auditory deficiencies; 5) Attention disorders; 6) Abnormal socioemotional development. Major impairment: One or more of the following problems: 1) Cerebral palsy; 2) Mental retardation with IQ < 70; 3) Blindness, deafness; 4)Intractable epilepsy

Current Secondary Outcome Measures (submitted: May 9, 2016)

• Biomarker cranial MRI [ Time Frame: 40 weeks postmenstrual age ]
  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.
• Safety [ Time Frame: Infants will be followed for the duration of hospital stay, an expected average of 14 weeks ]
  Analysis will be performed to get insight about the distributions of adverse events and other safety relevant outcomes between groups.
• Neurodevelopmental outcome [ Time Frame: 2 years ]
  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.
• Biomarker serial cranial ultrasound [ Time Frame: Infants will be followed for the duration of hospital stay, an expected average of 14 weeks ]
  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.
• Overall developmental outcome [ Time Frame: 5 years ]
  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.

Original Secondary Outcome Measures (submitted: February 27, 2014)

• Biomarker cranial MRI [ Time Frame: 40 weeks postmenstrual age ]
  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.
• Safety [ Time Frame: Infants will be followed for the duration of hospital stay, an expected average of 14 weeks ]
  Analysis will be performed to get insight about the distributions of adverse events and other safety relevant outcomes between groups.
• Neurodevelopmental outcome [ Time Frame: 2 years ]
  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.
• Biomarker serial cranial ultrasound [ Time Frame: Infants will be followed for the duration of hospital stay, an expected average of 14 weeks ]
  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.

Current Other Pre-specified Outcome Measures (submitted: February 27, 2014)

Course of intracerebral bleeding [ Time Frame: Infants will be followed for the duration of hospital stay, an expected average of 14 weeks ]

Course of intracerebral bleeding from onset until term equivalent age with additional visits at 28 days of life and 36 weeks postmenstrual age.

1. No remaining lesions as recorded by cranial ultrasound
2. Persisting posthemorrhagic hydrocephalus without any drainage
3. Persisting posthemorrhagic hydrocephalus with repetitive but transient csf-drainage
4. Posthemorrhagic hydrocephalus with permanent csf-drainage
5. Convulsions and other abnormalities or medications related to intracerebral bleeding

• Original Other Pre-specified Outcome Measures: Same as current

Descriptive Information

• Brief Title: Erythropoietin for the Repair of Cerebral Injury in Very Preterm Infants
• Official Title: Erythropoietin for the Repair of Cerebral Injury in Very Preterm Infants - a Randomized, Double-blind, Placebo-controlled, Prospective, and Multicenter Clinical Study
• Brief Summary: 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.

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
• Study Phase: Phase 3
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor); Primary Purpose: Treatment
• Condition: Intraventricular Hemorrhage of Prematurity

Intervention

• Drug: recombinant human Erythropoietin
  i.v. administration
  Other Name: Epoetin beta
• Drug: Placebo
  i.v. administration
  Other Name: normal saline

Study Arms

• 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.

  Intervention: Drug: recombinant human Erythropoietin
• 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.

  Intervention: Drug: Placebo

• Publications *: Rüegger CM, Hagmann CF, Bührer 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.

Recruitment Information

• Recruitment Status: Active, not recruiting
• Actual Enrollment (submitted: February 27, 2014): 120
• Original Estimated Enrollment: Same as current
• Estimated Study Completion Date: March 2024
• Estimated Primary Completion Date: December 2023 (Final data collection date for primary outcome measure)

Eligibility Criteria

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

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 23 Weeks to 31 Weeks (Child)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: Austria, Switzerland
• Removed Location Countries: Germany

Administrative Information

• NCT Number: NCT02076373
• Other Study ID Numbers: EpoRepair; 2013DR3204 ( Other Identifier: Swissmedic )
• Has Data Monitoring Committee: Yes
• U.S. FDA-regulated Product: Not Provided

IPD Sharing Statement

• Plan to Share IPD: Undecided

• Current Responsible Party: University of Zurich
• Original Responsible Party: Same as current
• Current Study Sponsor: University of Zurich
• Original Study Sponsor: Same as current
• Collaborators: Swiss National Science Foundation

Investigators

• Principal Investigator: Sven Wellmann, MD; University of Zurich
• Study Chair: Hans Ulrich Bucher, MD, PhD; University of Zurich

• PRS Account: University of Zurich
• Verification Date: November 2018