Preterm Erythropoietin Neuroprotection Trial (PENUT Trial)
Condition: Extreme Prematurity
MeSH terms: Premature Birth
Study type: Interventional
Phase: Phase 3

Summary: 
      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.
    

Detailed description: 
      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.

      Clinical information including co-morbidities of extreme prematurity, information about
      transfusions, and specific laboratory values were collected in the PENUT database.
    

Intervention name(s): Epo; Control
Intervention type(s): Drug; Other
Intervention description(s): Enrollment will occur within 24 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.; 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. Following high dose administration, sham subcutaneous injections will be given three times a week through to 32-6/7 weeks postmenstrual age.
Other intervention name(s): Epotin; Erythropoietin; Saline
Intervention MeSH terms: Epoetin Alfa
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary purpose: Treatment
Keywords: neuroprotection; erythropoietin; Epo; ELGANs; preterm; neonate