Preterm Erythropoietin Neuroprotection Trial (PENUT Trial) (PENUT)

April 27, 2026 updated by: Sandra E Juul, MD, PhD, University of Washington

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.

Study Overview

Status

Completed

Conditions

Intervention / Treatment

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.

Study Type

Interventional

Enrollment (Actual)

941

Phase

  • Phase 3

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • United States
    • Arkansas
      • Little Rock, Arkansas, United States, 72202
        • University of Arkansas
    • Florida
      • Gainesville, Florida, United States, 32610
        • University of Florida
      • Miami, Florida, United States, 33146
        • South Miami Hospital
      • Orlando, Florida, United States, 32804
        • Florida Hospital
      • St. Petersburg, Florida, United States, 33701
        • All Childrens Hospital
    • Illinois
      • Chicago, Illinois, United States, 60611
        • Prentice Women's Hospital
      • Chicago, Illinois, United States, 60612
        • Children's Hospital of the University of Illinois
    • Kentucky
      • Louisville, Kentucky, United States, 40202
        • University of Louisville
    • Maryland
      • Baltimore, Maryland, United States, 21224
        • Johns Hopkins
    • Massachusetts
      • Boston, Massachusetts, United States, 02215
        • Beth Israel Deaconess Hospital
    • Minnesota
      • Minneapolis, Minnesota, United States, 55455
        • University of Minnesota Amplatz Children's Hospital
      • Minneapolis, Minnesota, United States, 55404
        • Children's Hospital of Minnesota, MN
      • Saint Paul, Minnesota, United States, 55102
        • Children's Hospital of Minnesota, St. Paul
    • New Mexico
      • Albuquerque, New Mexico, United States, 87131
        • University of New Mexico Children's Hospital
    • New York
      • Valhalla, New York, United States, 10595
        • Maia Fareri Children's Hospital
    • North Carolina
      • Winston-Salem, North Carolina, United States, 27157
        • Wake Forest School of Medicine
    • Texas
      • San Antonio, Texas, United States, 78229
        • Methodist Children's Hospital
    • Utah
      • Salt Lake City, Utah, United States, 84108
        • University of Utah
    • Washington
      • Seattle, Washington, United States, 98195
        • University of Washington

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

5 months to 6 months (Child)

Accepts Healthy Volunteers

No

Description

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. Hematologic crises such as DIC, or hemolysis due to blood group incompatibilities
  3. Polycythemia (hematocrit > 65)
  4. Congenital infection

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

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

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
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. Following high dose administration, sham subcutaneous injections will be given three times a week through to 32-6/7 weeks postmenstrual age.
Other: 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. Following high dose administration, sham subcutaneous injections will be given three times a week through to 32-6/7 weeks postmenstrual age.
Other Names:
  • Saline
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. Following the high dose period, subjects will receive subcutaneous Epo 400 U/kg/dose three times a week until 32-6/7 weeks postmenstrual age.
Drug: Epo
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.
Other Names:
  • Erythropoietin
  • Epotin

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Number of Participants With Death or Severe Neurodevelopmental Impairment (NDI) at 22-26 Months Corrected Age
Time Frame: 22-26 months corrected age

Severe NDI was defined as Bayley Scales of infant Development, 3rd edition composite motor score or composite cognitive score <70. This instrument is normed at 100 with standard deviation of 15.

Cerebral palsy was classified as hemiplegia, diplegia, or quadriplegia, and severity was determined according to the Gross Motor Function Classification System (GMFCS) (levels range from 0 [no impairment] to 5 [most severe impairment]). Severe cerebral palsy was defined as a GMFCS level higher than 2.
22-26 months corrected age

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Number of Participants With a Serious Adverse Events (SAE)
Time Frame: From birth to hospital discharge (average 12-16 weeks depending on gestational age at birth)
Serious adverse events were prespecified. These included any symptomatic thrombosis involving a major vessel, unrelated to an infusion catheter requiring anticoagulation therapy, hematocrit level >65% or an increase of ≥15% in hematocrit in the absence of a preceding blood transfusion, hypertension (defined by receipt of antihypertensive therapy for more than 1 month, discharge with medication, or both), severe pulmonary hemorrhage, severe necrotizing enterocolitis (defined as Bell's stage 2b or 3), severe retinopathy of prematurity resulting in laser surgery or bevacizumab therapy, severe sepsis (defined as culture-proven bacterial or fungal sepsis resulting in blood-pressure support or substantive new respiratory support), grade 3 or 4 intracranial hemorrhage, cardiac arrest that did not result in death, and death.
From birth to hospital discharge (average 12-16 weeks depending on gestational age at birth)
Imaging
Time Frame: 36 weeks postmenstrual age
Brain MRI at 36 weeks PMA. Injury scoring was done using a modified scoring system of Kidokoro, with higher scores indicating greater brain injury. Scoring Range: 0-39
36 weeks postmenstrual age
Biomarkers
Time Frame: Baseline (first 24 hours after birth), days 7, 9 and 14 after birth
Plasma Epo concentrations were measured in both groups within the first 24 h after birth before study drug administration (baseline), 30 minutes after study drug administration on day 7 (peak Epo concentration) and 30 minutes before study drug on day 9 (trough Epo) and a random level on day 14 after transition to subcutaneous dosing.
Baseline (first 24 hours after birth), days 7, 9 and 14 after birth

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

University of Washington

Collaborators

National Institute of Neurological Disorders and Stroke (NINDS)

Investigators

  • Principal Investigator: Sandra E Juul, MD, PhD, University of Washington

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Helpful Links

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start

December 1, 2013

Primary Completion (Actual)

February 28, 2019

Study Completion (Actual)

February 28, 2020

Study Registration Dates

First Submitted

June 20, 2011

First Submitted That Met QC Criteria

June 21, 2011

First Posted (Estimated)

June 22, 2011

Study Record Updates

Last Update Posted (Actual)

May 19, 2026

Last Update Submitted That Met QC Criteria

April 27, 2026

Last Verified

April 1, 2026

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • STUDY00007464
  • U01NS077953 (U.S. NIH Grant/Contract)

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

YES

IPD Plan Description

The Archived Clinical Research Datasets at NINDS are currently being migrated to new repositories, and data requests will no longer be accepted. If you require access to these datasets, please contact the Principal Investigators (PIs) of the respective studies.

IPD Sharing Time Frame

December 2020

IPD Sharing Access Criteria

The data will be made available upon publication of all PENUT Trial related manuscripts to researchers who provide a methodologically sound proposal for use in achieving the goals of the approved proposal.

IPD Sharing Supporting Information Type

  • STUDY_PROTOCOL
  • SAP
  • ICF
  • ANALYTIC_CODE
  • CSR

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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