Preterm Erythropoietin Neuroprotection Trial (PENUT Trial)
NCT ID: NCT01378273
Last Updated: 2020-08-26
Study Results
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View full resultsBasic Information
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COMPLETED
PHASE3
941 participants
INTERVENTIONAL
2013-12-31
2020-02-28
Brief Summary
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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.
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Detailed Description
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Clinical information including co-morbidities of extreme prematurity, information about transfusions, and specific laboratory values were collected in the PENUT database.
Conditions
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Study Design
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RANDOMIZED
PARALLEL
TREATMENT
QUADRUPLE
Study Groups
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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.
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.
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.
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.
Interventions
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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.
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 Intervention Names
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Eligibility Criteria
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Inclusion Criteria
2. Less than twenty four hours of age
3. Parental informed consent
Exclusion Criteria
2. Hematologic crises such as DIC, or hemolysis due to blood group incompatibilities
3. Polycythemia (hematocrit \> 65)
4. Congenital infection
24 Weeks
27 Weeks
ALL
No
Sponsors
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National Institute of Neurological Disorders and Stroke (NINDS)
NIH
University of Washington
OTHER
Responsible Party
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Sandra Juul
Professor of Pediatrics
Principal Investigators
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Sandra E Juul, MD, PhD
Role: PRINCIPAL_INVESTIGATOR
University of Washington
Locations
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University of Arkansas
Little Rock, Arkansas, United States
University of Florida
Gainesville, Florida, United States
South Miami Hospital
Miami, Florida, United States
Florida Hospital
Orlando, Florida, United States
All Childrens Hospital
St. Petersburg, Florida, United States
Prentice Women's Hospital
Chicago, Illinois, United States
Children's Hospital of the University of Illinois
Chicago, Illinois, United States
University of Louisville
Louisville, Kentucky, United States
Johns Hopkins
Baltimore, Maryland, United States
Beth Israel Deaconess Hospital
Boston, Massachusetts, United States
Children's Hospital of Minnesota, MN
Minneapolis, Minnesota, United States
University of Minnesota Amplatz Children's Hospital
Minneapolis, Minnesota, United States
Children's Hospital of Minnesota, St. Paul
Saint Paul, Minnesota, United States
University of New Mexico Children's Hospital
Albuquerque, New Mexico, United States
Maia Fareri Children's Hospital
Valhalla, New York, United States
Wake Forest School of Medicine
Winston-Salem, North Carolina, United States
Methodist Children's Hospital
San Antonio, Texas, United States
University of Utah
Salt Lake City, Utah, United States
University of Washington
Seattle, Washington, United States
Countries
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References
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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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
Provided Documents
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Document Type: Study Protocol and Statistical Analysis Plan
Related Links
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website for the PENUT Trial
Other Identifiers
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STUDY00007464
Identifier Type: -
Identifier Source: org_study_id
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