Clinical trial NCT01378273: Preterm Erythropoietin Neuroprotection Trial (PENUT Trial)
Official title: Preterm Erythropoietin Neuroprotection Trial (PENUT Trial)
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Extreme Prematurity
Keywords: neuroprotection
erythropoietin
Epo
ELGANs
preterm
neonate
Lead sponsor: University of Washington
Sponsor class: OTHER
Collaborators: name: National Institute of Neurological Disorders and Stroke (NINDS)
First posted: 2011-06-22
Enrollment: 941
Sex: ALL
Minimum age (years): 24
Maximum age (years): 27
Standard ages: CHILD
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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. 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.

Eligibility criteria: 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

Primary outcomes:
measure: Number of Participants With Death or Severe Neurodevelopmental Impairment (NDI) at 22-26 Months Corrected Age
timeFrame: 22-26 months corrected age
Secondary outcomes:
measure: Number of Participants With a Serious Adverse Events (SAE)
timeFrame: From birth to hospital discharge (average 12-16 weeks depending on gestational age at birth)
measure: Imaging
timeFrame: 36 weeks postmenstrual age
measure: Biomarkers
timeFrame: Baseline (first 24 hours after birth), days 7, 9 and 14 after birth
Other outcomes:
Locations:
city: Little Rock
country: United States
facility: University of Arkansas
state: Arkansas
city: Gainesville
country: United States
facility: University of Florida
state: Florida
city: Miami
country: United States
facility: South Miami Hospital
state: Florida
city: Orlando
country: United States
facility: Florida Hospital
state: Florida
city: Saint Petersburg
country: United States
facility: All Childrens Hospital
state: Florida
city: Chicago
country: United States
facility: Prentice Women's Hospital
state: Illinois
city: Chicago
country: United States
facility: Children's Hospital of the University of Illinois
state: Illinois
city: Louisville
country: United States
facility: University of Louisville
state: Kentucky
city: Baltimore
country: United States
facility: Johns Hopkins
state: Maryland
city: Boston
country: United States
facility: Beth Israel Deaconess Hospital
state: Massachusetts
city: Minneapolis
country: United States
facility: Children's Hospital of Minnesota, MN
state: Minnesota
city: Minneapolis
country: United States
facility: University of Minnesota Amplatz Children's Hospital
state: Minnesota
city: Saint Paul
country: United States
facility: Children's Hospital of Minnesota, St. Paul
state: Minnesota
city: Albuquerque
country: United States
facility: University of New Mexico Children's Hospital
state: New Mexico
city: Valhalla
country: United States
facility: Maia Fareri Children's Hospital
state: New York
city: Winston-Salem
country: United States
facility: Wake Forest School of Medicine
state: North Carolina
city: San Antonio
country: United States
facility: Methodist Children's Hospital
state: Texas
city: Salt Lake City
country: United States
facility: University of Utah
state: Utah
city: Seattle
country: United States
facility: University of Washington
state: Washington
Study officials:
affiliation: University of Washington
name: Sandra E Juul, MD, PhD
role: PRINCIPAL_INVESTIGATOR
References:
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.