Trial of Erythropoietin Neuroprotection in Extremely Preterm Infants (PENUT)

This study is currently recruiting participants.
Verified December 2013 by University of Washington
Sponsor:
Collaborator:
Information provided by (Responsible Party):
Sandra Juul, University of Washington
ClinicalTrials.gov Identifier:
NCT01378273
First received: June 20, 2011
Last updated: December 19, 2013
Last verified: December 2013

June 20, 2011
December 19, 2013
December 2013
December 2018   (final data collection date for primary outcome measure)
neurodevelopmental outcome [ Time Frame: 24-26 months corrected age ] [ Designated as safety issue: No ]
neurodevelopmental exam Bayley III: MDI and PDI
neurodevelopmental outcome [ Time Frame: 24-26 months ] [ Designated as safety issue: No ]
neurodevelopmental exam Bayley III: MDI and PDI
Complete list of historical versions of study NCT01378273 on ClinicalTrials.gov Archive Site
  • safety [ Time Frame: term PMA ] [ Designated as safety issue: Yes ]
    The safety of Epo treatment will be assessed by comparing adverse events and co-morbidities between groups
  • biomarkers [ Time Frame: 24-26 months ] [ Designated as safety issue: No ]
    MRI at 36 weeks PMA will be used as a biomarker of long-term outcomes
Same as current
Not Provided
Not Provided
 
Trial of Erythropoietin Neuroprotection in Extremely Preterm Infants
Preterm Erythropoietin Neuroprotection Trial (PENUT Trial)

Approximately 50,000 infants per year (961 per week) are born at less than 28 weeks of gestation in the US. Cerebral palsy, deafness, blindness, and/or mental retardation are present in up to 50% of surviving extremely preterm infants at school age. Perinatal care costs for these infants exceed US$18 billion every year. The burden of extreme prematurity to each patient and to society is further magnified by the years of productive life lost. New therapies are needed to improve these outcomes.

Recombinant human erythropoietin (Epo) is a promising novel neuroprotective agent. Epo decreases neuronal programmed cell death resulting from brain injury; it has anti-inflammatory effects, increases neurogenesis, and protects oligodendrocytes from injury.

We hypothesize that neonatal Epo treatment of ELGANs will decrease the combined outcome of death or severe NDI from 40% to 30% (primary outcome), or the combined outcome of death plus moderate or severe NDI from 60% to 40% (secondary outcome) measured at 24-26 months corrected age.

  1. To determine whether Epo decreases the combined outcome of death or NDI at 24-26 months corrected age. NDI is defined as the presence of any one of the following: CP, Bayley Scales of Infant and Toddler Development, 3rd Edition (Bayley-III) Cognitive Scale < 70 (severe, 2 SD below mean) or 85 (moderate, 1 SD below mean). CP will be diagnosed and classified by standardized neurologic exam, with severity classified by Gross Motor Function Classification System (GMFCS).
  2. To determine whether there are risks to Epo administration in ELGANs by examining, in a blinded manner, Epo-related safety measures comparing infants receiving Epo with those given placebo.
  3. To test whether Epo treatment decreases serial measures of circulating inflammatory mediators, and biomarkers of brain injury.
  4. To compare brain structure (as measured by MRI) in Epo treatment and control groups at 36 weeks PMA. MRI assessments will include documentation of intraventricular hemorrhage (IVH), white matter injury (WMI) and hydrocephalus (HC), volume of total and deep gray matter, white matter and cerebellum, brain gyrification, and tract-based spatial statistics (TBSS based on diffusion tensor imaging). As an exploratory aim, we will determine which of the above MRI measurements best predict neurodevelopment (CP, cognitive and motor scales) at 24-26 months corrected age.

Anticipated outcomes: Early Epo treatment of ELGANs will decrease biochemical and MRI markers of brain injury, will be safe, and will confer improved neurodevelopmental outcome at 24-26 months corrected age compared to placebo, and will provide a much-needed therapy for this group of vulnerable infants.

This is a randomized, placebo-controlled, study of Epo treatment of preterm infants 24-0/7 to 27-6/7 weeks of gestation, beginning in the first 24 hours after birth. Randomization will be stratified by site and gestational age at birth (<26 week or 26-27-6/7). Study size sample is 940 patients. We expect to evaluate 752 subjects at 24-26 months corrected age, our primary endpoint. There is no enrollment restriction based on gender, ethnicity or race. Enrollment is expected to take 24-26 months, with each subject participating through 24-26 months corrected age when neurodevelopmental outcomes are assessed. The combined outcome of death or severe NDI will be compared between Epo-treated and control subjects. All outcomes will be collected in a blinded manner. Subjects will be randomized by the data-coordinating center (DCC) to Epo treatment or placebo, and Epo treatment will continue until 32-6/7 weeks post menstrual age. Serial measurements of circulating inflammatory mediators and biomarkers of brain injury will be made. A brain MRI will be done at 36 weeks post menstrual age in the same subset of infants. Phone contact will occur at 4, 8, 12, and 18 months. Face to face follow up will occur at 24-26 months corrected age. The primary outcome is death or severe NDI at 24-26 months corrected age, with a secondary outcome of death or moderate NDI. Our primary sample size calculation is based on the conservative assumptions that Epo treatment will result in a 40% reduction in the severe NDI rate (the range in animal studies is 49-70%) and minimal impact on death. This would yield a control group rate for the primary outcome of 40.4% and an expected treated rate of 31.5% thus yielding an 8.9% lower rate of Death + NDI.

Interventional
Phase 3
Allocation: Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Parallel Assignment
Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Extreme Prematurity
Drug: Epo
Enrollment will occur within 48 hours of birth. Study drug will be administered intravenously for the first 6 doses. Subjects in the Epo arm will then receive 400 U/kg/dose three times a week until they reach 32-6/7 weeks postmenstrual age. Control infants will receive sham injections.
Other Names:
  • Epotin
  • Erythropoietin
  • Placebo Comparator: Control
    Subjects will receive 6 doses of vehicle intravenously during the first 2 weeks of life. Doses will be administered at 48 hour intervals from the time of enrollment. Sham subcutaneous injections will be given three times a week from day 14 of life to 32-6/7 weeks postmenstrual age.
  • Experimental: Epo 1000 U/kg followed by 400 U/kg
    Subjects will receive 6 doses of intravenous Epo 1000 U/kg/dose at 48 hour intervals from the time of enrollment. Beginning on day 14 of life, subjects will receive subcutaneous Epo 400 U/kg/dose three times a week until 32-6/7 weeks postmenstrual age.
    Intervention: Drug: Epo
Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruiting
940
December 2018
December 2018   (final data collection date for primary outcome measure)

Inclusion Criteria:

  1. NICU inpatients between 24-0/7 and 27-6/7 weeks of gestation
  2. Less than twenty four hours of age
  3. Parental informed consent

Exclusion Criteria:

  1. Major life-threatening anomalies (brain, cardiac, chromosomal anomalies)
  2. Hematopoietic crises such as DIC, or hemolysis due to blood group incompatibilities
  3. Polycythemia (hematocrit > 65)
  4. Congenital infection
Both
24 Weeks to 27 Weeks
No
Contact: Sandra E Juul 206 221-6814 sjuul@uw.edu
United States
 
NCT01378273
U01NS077953-01
Yes
Sandra Juul, University of Washington
University of Washington
National Institute of Neurological Disorders and Stroke (NINDS)
Principal Investigator: Sandra E Juul, MD, PhD University of Washington
University of Washington
December 2013

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