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

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

Tracking Information
First Submitted Date  ICMJE February 25, 2014
First Posted Date  ICMJE March 3, 2014
Last Update Posted Date November 23, 2018
Study Start Date  ICMJE March 2014
Estimated Primary Completion Date December 2023   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (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  ICMJE
 (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
Change History
Current Secondary Outcome Measures  ICMJE
 (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  ICMJE
 (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  ICMJE Erythropoietin for the Repair of Cerebral Injury in Very Preterm Infants
Official Title  ICMJE 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  ICMJE Interventional
Study Phase  ICMJE Phase 3
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Condition  ICMJE Intraventricular Hemorrhage of Prematurity
Intervention  ICMJE
  • Drug: recombinant human Erythropoietin
    i.v. administration
    Other Name: Epoetin beta
  • Drug: Placebo
    i.v. administration
    Other Name: normal saline
Study Arms  ICMJE
  • 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.

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Active, not recruiting
Actual Enrollment  ICMJE
 (submitted: February 27, 2014)
120
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE March 2024
Estimated Primary Completion Date December 2023   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 23 Weeks to 31 Weeks   (Child)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE Austria,   Switzerland
Removed Location Countries Germany
 
Administrative Information
NCT Number  ICMJE NCT02076373
Other Study ID Numbers  ICMJE EpoRepair
2013DR3204 ( Other Identifier: Swissmedic )
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE
Plan to Share IPD: Undecided
Responsible Party University of Zurich
Study Sponsor  ICMJE University of Zurich
Collaborators  ICMJE Swiss National Science Foundation
Investigators  ICMJE
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

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP