Preterm Erythropoietin Neuroprotection Trial (PENUT Trial)

NCT01378273 | Completed Phase 3 Results DMC

• 2 other identifiers: STUDY00007464U01NS077953
• Study Type: interventional
• Target: 941
• Locations: 1 country
• Sites: 19

Brief 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. 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. 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. 3.To test whether Epo treatment decreases serial measures of circulating inflammatory mediators, and biomarkers of brain injury.
4. 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.

Conditions

Extreme Prematurity

Keywords

neuroprotection; erythropoietin; Epo; ELGANs; preterm; neonate

Outcome Measures

Primary Outcomes (1)

• Number of Participants With Death or Severe Neurodevelopmental Impairment (NDI) at 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 Outcomes (3)

• Number of Participants With a Serious Adverse Events (SAE)

  From birth to hospital discharge (average 12-16 weeks depending on gestational age at birth)

• Imaging

  36 weeks postmenstrual age

• Biomarkers

  Baseline (first 24 hours after birth), days 7, 9 and 14 after birth

Study Arms (2)

Control

PLACEBO COMPARATOR

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

Epo 1000 U/kg followed by 400 U/kg

EXPERIMENTAL

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

Interventions

Epo DRUG

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.

Also known as: Epotin, Erythropoietin

Epo 1000 U/kg followed by 400 U/kg

Control OTHER

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.

Also known as: Saline

Control

Eligibility Criteria

• Age: 24 Weeks - 27 Weeks
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17)

You may qualify if:

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

You may not qualify if:

• Major life-threatening anomalies (brain, cardiac, chromosomal anomalies)
• Hematologic crises such as DIC, or hemolysis due to blood group incompatibilities
• Polycythemia (hematocrit \> 65)
• Congenital infection

Sponsors & Collaborators

• University of Washington: lead
• National Institute of Neurological Disorders and Stroke (NINDS): collaborator

Study Sites (19)

University of Arkansas

Little Rock, Arkansas, 72202, United States

Location

University of Florida

Gainesville, Florida, 32610, United States

Location

South Miami Hospital

Miami, Florida, 33146, United States

Location

Florida Hospital

Orlando, Florida, 32804, United States

Location

All Childrens Hospital

St. Petersburg, Florida, 33701, United States

Location

Prentice Women's Hospital

Chicago, Illinois, 60611, United States

Location

Children's Hospital of the University of Illinois

Chicago, Illinois, 60612, United States

Location

University of Louisville

Louisville, Kentucky, 40202, United States

Location

Johns Hopkins

Baltimore, Maryland, 21224, United States

Location

Beth Israel Deaconess Hospital

Boston, Massachusetts, 02215, United States

Location

Children's Hospital of Minnesota, MN

Minneapolis, Minnesota, 55404, United States

Location

University of Minnesota Amplatz Children's Hospital

Minneapolis, Minnesota, 55455, United States

Location

Children's Hospital of Minnesota, St. Paul

Saint Paul, Minnesota, 55102, United States

Location

University of New Mexico Children's Hospital

Albuquerque, New Mexico, 87131, United States

Location

Maia Fareri Children's Hospital

Valhalla, New York, 10595, United States

Location

Wake Forest School of Medicine

Winston-Salem, North Carolina, 27157, United States

Location

Methodist Children's Hospital

San Antonio, Texas, 78229, United States

Location

University of Utah

Salt Lake City, Utah, 84108, United States

Location

University of Washington

Seattle, Washington, 98195, United States

Location

Related Publications (20)

• Juul SE, Mayock DE, Comstock BA, Heagerty PJ. Neuroprotective potential of erythropoietin in neonates; design of a randomized trial. Matern Health Neonatol Perinatol. 2015 Dec 2;1:27. doi: 10.1186/s40748-015-0028-z. eCollection 2015.

  PMID: 27057344 RESULT

• Starr MC, Askenazi DJ, Goldstein SL, MacDonald JW, Bammler TK, Afsharinejad Z, D Brophy P, Juul SE, Mayock DE, Hingorani SR. Impact of processing methods on urinary biomarkers analysis in neonates. Pediatr Nephrol. 2018 Jan;33(1):181-186. doi: 10.1007/s00467-017-3779-0. Epub 2017 Aug 19.

  PMID: 28821985 RESULT

• Juul SE, Comstock BA, Wadhawan R, Mayock DE, Courtney SE, Robinson T, Ahmad KA, Bendel-Stenzel E, Baserga M, LaGamma EF, Downey LC, Rao R, Fahim N, Lampland A, Frantz ID III, Khan JY, Weiss M, Gilmore MM, Ohls RK, Srinivasan N, Perez JE, McKay V, Vu PT, Lowe J, Kuban K, O'Shea TM, Hartman AL, Heagerty PJ; PENUT Trial Consortium. A Randomized Trial of Erythropoietin for Neuroprotection in Preterm Infants. N Engl J Med. 2020 Jan 16;382(3):233-243. doi: 10.1056/NEJMoa1907423.

  PMID: 31940698 RESULT

• Hanna M, Chock VY, Kamath N, Raj A, Swanson JR, Griffin R, Askenazi DJ, Nesargi S. Acute Kidney Injury and Neurodevelopmental Outcomes in Extremely Premature Neonates: A Secondary Analysis of a Randomized Clinical Trial. JAMA Netw Open. 2025 Nov 3;8(11):e2543270. doi: 10.1001/jamanetworkopen.2025.43270.

  PMID: 41222934 DERIVED

• Valentine GC, Brandon OC, Perez KM, Strobel KM, Mayock DE, Law JB, Neches S, German K, Kolnik S, Heagerty PJ, Wood TR, Juul SE. Time to regain birthweight and in-hospital outcomes among United States-born extremely preterm newborns. Pediatr Res. 2025 Nov 10. doi: 10.1038/s41390-025-04563-3. Online ahead of print.

  PMID: 41214292 DERIVED

• Valentine GC, Perez KM, Wood TR, Mayock DE, Law JB, Kolnik S, Strobel KM, Brandon OC, Comstock BA, Heagerty PJ, Juul SE. Time to regain birthweight and association with neurodevelopmental outcomes among extremely preterm newborns. J Perinatol. 2024 Apr;44(4):554-560. doi: 10.1038/s41372-024-01869-8. Epub 2024 Jan 9.

  PMID: 38195922 DERIVED

• Strobel KM, Wood TR, Valentine GC, German KR, Gogcu S, Hendrixson DT, Kolnik SE, Law JB, Mayock DE, Comstock BA, Heagerty PJ, Juul SE. Contemporary definitions of infant growth failure and neurodevelopmental and behavioral outcomes in extremely premature infants at two years of age. J Perinatol. 2024 Jun;44(6):811-818. doi: 10.1038/s41372-023-01852-9. Epub 2024 Jan 9.

  PMID: 38195921 DERIVED

• Hingorani SR, Schmicker RH, Halloran B, Brophy P, Heagerty PJ, Juul S, Goldstein SL, Askenazi D; PENUT Investigators. Association Between Urinary Biomarkers and CKD in Extremely Low Gestational Age Neonates. Am J Kidney Dis. 2024 Apr;83(4):497-507. doi: 10.1053/j.ajkd.2023.09.008. Epub 2023 Nov 4.

  PMID: 37926336 DERIVED

• Valentine G, Perez K, Wood T, Mayock D, Law J, Kolnik S, Strobel K, Brandon O, Comstock B, Heagerty P, Juul S. Time to Regain Birthweight and Association with Neurodevelopmental Outcomes among Extremely Preterm Newborns. Res Sq [Preprint]. 2023 Sep 14:rs.3.rs-3249598. doi: 10.21203/rs.3.rs-3249598/v1.

  PMID: 37790304 DERIVED

• Starr MC, Griffin RL, Harer MW, Soranno DE, Gist KM, Segar JL, Menon S, Gordon L, Askenazi DJ, Selewski DT. Acute Kidney Injury Defined by Fluid-Corrected Creatinine in Premature Neonates: A Secondary Analysis of the PENUT Randomized Clinical Trial. JAMA Netw Open. 2023 Aug 1;6(8):e2328182. doi: 10.1001/jamanetworkopen.2023.28182.

  PMID: 37561461 DERIVED

• Starr MC, Griffin R, Gist KM, Segar JL, Raina R, Guillet R, Nesargi S, Menon S, Anderson N, Askenazi DJ, Selewski DT; Neonatal Kidney Collaborative Research Committee. Association of Fluid Balance With Short- and Long-term Respiratory Outcomes in Extremely Premature Neonates: A Secondary Analysis of a Randomized Clinical Trial. JAMA Netw Open. 2022 Dec 1;5(12):e2248826. doi: 10.1001/jamanetworkopen.2022.48826.

  PMID: 36580332 DERIVED

• Hingorani S, Schmicker R, Ahmad KA, Frantz ID, Mayock DE, La Gamma EF, Baserga M, Khan JY, Gilmore MM, Robinson T, Brophy P, Heagerty PJ, Juul SE, Goldstein S, Askenazi D; PENUT Trial Consortium; PENUT Primary Investigators and coauthors. Prevalence and Risk Factors for Kidney Disease and Elevated BP in 2-Year-Old Children Born Extremely Premature. Clin J Am Soc Nephrol. 2022 Aug;17(8):1129-1138. doi: 10.2215/CJN.15011121. Epub 2022 Jul 19.

  PMID: 35853728 DERIVED

• Garcia MR, Comstock BA, Patel RM, Tolia VN, Josephson CD, Georgieff MK, Rao R, Monsell SE, Juul SE, Ahmad KA; PENUT Trial Consortium. Iron supplementation and the risk of bronchopulmonary dysplasia in extremely low gestational age newborns. Pediatr Res. 2023 Feb;93(3):701-707. doi: 10.1038/s41390-022-02160-2. Epub 2022 Jun 20.

  PMID: 35725917 DERIVED

• Valentine GC, Perez KM, Wood TR, Mayock DE, Comstock BA, Puia-Dumitrescu M, Heagerty PJ, Juul SE. Postnatal maximal weight loss, fluid administration, and outcomes in extremely preterm newborns. J Perinatol. 2022 Aug;42(8):1008-1016. doi: 10.1038/s41372-022-01369-7. Epub 2022 Mar 25.

  PMID: 35338252 DERIVED

• Askenazi DJ, Halloran BA, Heagerty PJ, Schmicker RH, Brophy P, Juul SE, Hingorani S, Goldstein SL; PENUT Trial Consortium. Gestational age, sex, and time affect urine biomarker concentrations in extremely low gestational age neonates. Pediatr Res. 2022 Jul;92(1):151-167. doi: 10.1038/s41390-021-01814-x. Epub 2021 Nov 30.

  PMID: 34845352 DERIVED

• German KR, Vu PT, Comstock BA, Ohls RK, Heagerty PJ, Mayock DE, Georgieff M, Rao R, Juul SE; PENUT Consortium. Enteral Iron Supplementation in Infants Born Extremely Preterm and its Positive Correlation with Neurodevelopment; Post Hoc Analysis of the Preterm Erythropoietin Neuroprotection Trial Randomized Controlled Trial. J Pediatr. 2021 Nov;238:102-109.e8. doi: 10.1016/j.jpeds.2021.07.019. Epub 2021 Jul 27.

  PMID: 34324880 DERIVED

• Hingorani S, Schmicker RH, Brophy PD, Heagerty PJ, Juul SE, Goldstein SL, Askenazi D; PENUT Investigators. Severe Acute Kidney Injury and Mortality in Extremely Low Gestational Age Neonates. Clin J Am Soc Nephrol. 2021 Jun;16(6):862-869. doi: 10.2215/CJN.18841220. Epub 2021 Jun 11.

  PMID: 34117080 DERIVED

• Mayock DE, Xie Z, Comstock BA, Heagerty PJ, Juul SE; Preterm Epo Neuroprotection (PENUT) Trial Consortium. High-Dose Erythropoietin in Extremely Low Gestational Age Neonates Does Not Alter Risk of Retinopathy of Prematurity. Neonatology. 2020;117(5):650-657. doi: 10.1159/000511262. Epub 2020 Oct 28.

  PMID: 33113526 DERIVED

• Juul SE, Vu PT, Comstock BA, Wadhawan R, Mayock DE, Courtney SE, Robinson T, Ahmad KA, Bendel-Stenzel E, Baserga M, LaGamma EF, Downey LC, O'Shea M, Rao R, Fahim N, Lampland A, Frantz ID 3rd, Khan J, Weiss M, Gilmore MM, Ohls R, Srinivasan N, Perez JE, McKay V, Heagerty PJ; Preterm Erythropoietin Neuroprotection Trial Consortium. Effect of High-Dose Erythropoietin on Blood Transfusions in Extremely Low Gestational Age Neonates: Post Hoc Analysis of a Randomized Clinical Trial. JAMA Pediatr. 2020 Oct 1;174(10):933-943. doi: 10.1001/jamapediatrics.2020.2271.

  PMID: 32804205 DERIVED

• Askenazi DJ, Heagerty PJ, Schmicker RH, Griffin R, Brophy P, Juul SE, Mayock DE, Goldstein SL, Hingorani S; PENUT Trial Consortium. Prevalence of acute kidney injury (AKI) in extremely low gestational age neonates (ELGAN). Pediatr Nephrol. 2020 Sep;35(9):1737-1748. doi: 10.1007/s00467-020-04563-x. Epub 2020 Jun 2.

  PMID: 32488672 DERIVED

Related Links

• website for the PENUT Trial

MeSH Terms

Conditions

Premature Birth

Interventions

Eosinophil Peroxidase; Erythropoietin; Sodium Chloride

Condition Hierarchy (Ancestors)

Obstetric Labor, Premature; Obstetric Labor Complications; Pregnancy Complications; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases

Intervention Hierarchy (Ancestors)

Peroxidases; Oxidoreductases; Enzymes; Enzymes and Coenzymes; Eosinophil Granule Proteins; Immunoproteins; Blood Proteins; Proteins; Amino Acids, Peptides, and Proteins; Colony-Stimulating Factors; Glycoproteins; Glycoconjugates; Carbohydrates; Hematopoietic Cell Growth Factors; Cytokines; Intercellular Signaling Peptides and Proteins; Peptides; Biological Factors; Chlorides; Hydrochloric Acid; Chlorine Compounds; Inorganic Chemicals; Sodium Compounds

Results Point of Contact

• Title: Sandra Juul MD, PhD
• Organization: University of Washington

sjuul@uw.edu

2062216814

Study Officials

• Sandra E Juul, MD, PhD

  University of Washington

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Professor of Pediatrics

Study Record Dates

• First Submitted: June 20, 2011
• First Posted: June 22, 2011
• Study Start: December 1, 2013
• Primary Completion: February 28, 2019
• Study Completion: February 28, 2020
• Last Updated: August 26, 2020
• Results First Posted: August 17, 2020

Record last verified: 2020-08

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL, SAP, ICF, CSR, ANALYTIC CODE
• Time Frame: December 2020
• 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.

Locations

US (19)