A Phase 3 interventional study of Epo and Control in Extreme Prematurity, sponsored by University of Washington. Completed at 19 sites in United States. Open to participants aged 24 Weeks to 27 Weeks. Per ClinicalTrials.gov, last updated 2026-05-19.
Sponsored by University of Washington · Phase 3, Interventional, and Treatment
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.
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.
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.
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Exclusion Criteria:
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 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.
Also known as: Epotin, Erythropoietin
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
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.
Time frame: 22-26 months corrected age
Number of Participants With a Serious Adverse Events (SAE)
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.
Time frame: From birth to hospital discharge (average 12-16 weeks depending on gestational age at birth)
Imaging
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
Time frame: 36 weeks postmenstrual age
Biomarkers
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.
Time frame: Baseline (first 24 hours after birth), days 7, 9 and 14 after birth
| Milestone | Control | Epo 1000 U/kg Followed by 400 U/kg |
|---|---|---|
| Started | 464 | 477 |
| Completed | 460 | 476 |
| Not completed | 4 | 1 |
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.
| Participants | Control | Epo 1000 U/kg Followed by 400 U/kg |
|---|---|---|
| Number of Participants With Death or Severe Neurodevelopmental Impairment (NDI) at 22-26 Months Corrected Age | 94 | 97 |
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.
| Participants | Control | Epo 1000 U/kg Followed by 400 U/kg |
|---|---|---|
| Number of Participants With a Serious Adverse Events (SAE) | 284 | 282 |
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
| score on a scale | Control | Epo 1000 U/kg Followed by 400 U/kg |
|---|---|---|
| Imaging | 4.1 ± 2.6 | 3.8 ± 2.1 |
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.
| mU/mL | Control | Epo 1000 U/kg Followed by 400 U/kg |
|---|---|---|
| Baseline | 7.6 (3.4 to 20.5) | 7 (3.9 to 21.4) |
| Peak Epo | 2.2 (1.1 to 4.8) | 2,907 (1,731 to 6998) |
| Trough Epo | 5.1 (1.7 to 8.9) | 15.3 (7.4 to 28.9) |
| Random (day 14) | 4.6 (2.1 to 8.6) | 25 (9.6 to 66.5) |
Collected over Birth to hospital discharge (generally 12 to 16 weeks, depending on gestational age at birth). Non-serious events are listed at a 0% frequency threshold.
| Group | Deaths | Serious | Other |
|---|---|---|---|
| Control | 45/460 (9.8%) | 284/460 (61.7%) | 460/460 (100%) |
| Epo 1000 U/kg Followed by 400 U/kg | 53/476 (11.1%) | 282/476 (59.2%) | 476/476 (100%) |
| Event | Control | Epo 1000 U/kg Followed by 400 U/kg |
|---|---|---|
| Severe intracranial hemorrhageNervous system disorders | 64/460 | 57/476 |
| DeathGeneral disorders | 45/460 | 53/476 |
| Severe sepsisInfections and infestations | 38/460 | 35/476 |
| Necrotizing enterocolitisGastrointestinal disorders | 36/460 | 28/476 |
| Other unexpected life-threatening eventsGeneral disorders | 31/460 | 27/476 |
| Severe retinopathy of prematurityEye disorders | 30/460 | 30/476 |
| Severe pulmonary hemorrhageRespiratory, thoracic and mediastinal disorders | 19/460 | 30/476 |
| HypertensionCardiac disorders | 10/460 | 6/476 |
| Nonfatal cardiac arrestGeneral disorders | 8/460 | 9/476 |
| Major ThrombosisBlood and lymphatic system disorders | 2/460 | 5/476 |
| Event | Control | Epo 1000 U/kg Followed by 400 U/kg |
|---|---|---|
| Blood transfusionBlood and lymphatic system disorders | 401/460 | 341/476 |
| Retinopathy of Prematurity (all grades)Eye disorders | 258/460 | 244/476 |
| Intracranial hemorrhage (all grades)Nervous system disorders | 181/460 | 168/476 |
| Treated patent ductus arteriosusCardiac disorders | 172/460 | 178/476 |
| Bronchopulmonary dysplasiaRespiratory, thoracic and mediastinal disorders | 161/460 | 172/476 |
| Necrotizing enterocolitisGastrointestinal disorders | 53/460 | 46/476 |
| Periventricular leukomalasiaNervous system disorders | 43/460 | 41/476 |
| Cerebellar hemorrhageNervous system disorders | 10/460 | 8/476 |
| Age, Customized(Participants) | Control | Epo 1000 U/kg Followed by 400 U/kg | Total |
|---|---|---|---|
| 24 weeks of gestation | 119 | 113 | 232 |
| 25 weeks of gestation | 124 | 121 | 245 |
| 26 weeks of gestation | 118 | 103 | 221 |
| 27 weeks of gestation | 99 | 139 | 238 |
| Sex: Female, Male(Participants) | Control | Epo 1000 U/kg Followed by 400 U/kg | Total |
|---|---|---|---|
| Female | 218 | 232 | 450 |
| Male | 242 | 244 | 486 |
| Ethnicity (NIH/OMB)(Participants) | Control | Epo 1000 U/kg Followed by 400 U/kg | Total |
|---|---|---|---|
| Hispanic or Latino | 85 | 115 | 200 |
| Not Hispanic or Latino | 370 | 354 | 724 |
| Unknown or Not Reported | 5 | 7 | 12 |
| Race (NIH/OMB)(Participants) | Control | Epo 1000 U/kg Followed by 400 U/kg | Total |
|---|---|---|---|
| American Indian or Alaska Native | 7 | 9 | 16 |
| Asian | 18 | 10 | 28 |
| Native Hawaiian or Other Pacific Islander | 6 | 2 | 8 |
| Black or African American | 120 | 120 | 240 |
| White | 293 | 317 | 610 |
| More than one race | 2 | 2 | 4 |
| Unknown or Not Reported | 14 | 16 | 30 |
| Region of Enrollment(participants) | Control | Epo 1000 U/kg Followed by 400 U/kg | Total |
|---|---|---|---|
| United States | 460 | 476 | 936 |
| Consented and received first study drug dose(Participants) | Control | Epo 1000 U/kg Followed by 400 U/kg | Total |
|---|---|---|---|
| Count of participants | 460 | 476 | 936 |
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Supporting information: Study protocol, Sap, Icf, Csr, Analytic code
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