Darbepoetin Trial to Improve Red Cell Mass and Neuroprotection in Preterm Infants

Advances in neonatal care have led to significant improvements in the survival of the nearly 60,000 very low birth weight (VLBW) infants born each year in the U.S. Improving neurodevelopmental outcomes for these preterm infants continues to be a major goal for neonatal care providers. A subset of these infants sustain a grade 3 or 4 intraventricular hemorrhage (IVH) resulting in an increase in the incidence of developmental delay. Moreover, almost one third of preterm infants with normal head ultrasounds also develop cognitive delay. Although a variety of neuroprotective treatment strategies have been evaluated, no specific treatment has been identified to reduce or prevent brain injury in these most vulnerable preterm infants.

A potential neuroprotective therapy involves administering erythropoiesis stimulating agents (ESAs) such as erythropoietin (Epo) and Darbepoetin (Darbe, a longer acting ESA). In addition to stimulating erythropoiesis, ESAs have been shown to be protective in the developing brain in animal models, making it possibly beneficial for very premature infants who are at risk for intraventricular hemorrhage, hypoxic-ischemic injury, and developmental delay. The neuroprotective mechanisms of ESAs include increased neurogenesis, decreased neuronal susceptibility to glutamate toxicity, decreased neuronal apoptosis, decreased inflammation, decreased nitric oxide-mediated injury, increased antioxidant response, decreased axonal degeneration, and increased protective effects on glia. This is a randomized, masked, placebo controlled clinical study in which enrolled infants will receive weekly Darbe or placebo (sham) dosing.

Extended follow-up: Subjects will be seen for follow-up at 4-5 years (i.e., 4 years - 4 years 11 months) corrected age and 6-7 years (i.e., 6 years - 6 years 11 months) corrected age to characterize the functional, behavioral and neurological outcomes of the extremely low birth weight (ELBW) population at school age based on treatment with darbepoetin versus placebo in the neonatal period.

• Darbepoetin (Drug), also known as Darbe: Darbepoetin 10 micrograms/kg/once every week (IV or SC). Infants will be treated until 35 completed weeks gestation, discharge, or transfer to another hospital.
• Placebo (Drug), also known as normal saline for IV administration, or sham dosing: normal saline for IV administration, or sham dosing. Infants will be treated until 35 completed weeks gestation, discharge, or transfer to another hospital.

Primary outcomes

• Bayley III Composite Cognitive Score [22-26 months corrected age (a median of 25 months corrected age, which corresponds to a median of 29 months calendar age in the analysis population), unless the subject died earlier]: Bayley Scale of Infant and Toddler Development (BSID)-III composite cognitive score, where subjects who died prior to the follow-up assessment are assigned the lowest possible score of 54. This is a standardized scale where a score that is more than 1 normative standard deviation from the normative mean of 100 signifies mild developmental delay (score < 85); 2 standard deviations below the mean, moderate delay (score < 70); and 3 standard deviations below the mean, severe delay (score < 55). This self-standing scale comprises the primary outcome for the Darbe study.

Secondary outcomes

• Number of Transfusions Per Infant [Birth, up to the earliest of: death, hospital discharge, or 35 completed weeks gestational age (a median of 9 weeks)]: The number of transfusions recorded during the study, up to 35 completed weeks gestational age
• Total Volume of Transfusions Per Infant [Birth, up to the earliest of: death, hospital discharge, or 35 completed weeks gestational age (a median of 9 weeks)]: The total volume of transfusions for the infant if ever transfused
• Number of Donor Exposures Per Infant [Birth, up to the earliest of: death, hospital discharge, or 35 completed weeks gestational age (a median of 9 weeks)]: The number of donor exposures recorded during the study, up to 35 completed weeks gestational age
• Hematocrit [at 2 and at 7 weeks in the study]: Hematocrit adjusted for center, gestational age group, and familial clustering
• Red Cell Mass [at 2 and at 7 weeks in the study]: Red Cell Mass (Circulating Erythrocyte Volume), adjusted for center, gestational age group, and familial clustering
• Necrotizing Enterocolitis, Bells Stage >=2 With Surgery [Birth to initial hospital discharge or to death if it occurs earlier (a median of 94 days)]: This is measured as Yes if experienced necrotizing enterocolitis, Bells stage >=2 with surgery; Otherwise, No.
• Bronchopulmonary Dysplasia Grades 2 or 3 [At 36 weeks postmenstrual age]: This is measured as Yes if infant is on invasive mechanical ventilation, nasal cannula >2 L/min or noninvasive positive airway pressure at 36 weeks of postmenstrual age; Otherwise, No.
• Retinopathy of Prematurity Stage >=3 or Treatment for That Condition Received [Birth to initial hospital discharge or to death if it occurs earlier (a median of 94 days)]: This is measured as Yes if experienced Retinopathy of prematurity stage >=3 or treatment for that condition received; Otherwise, No. Higher stages of ROP indicate a worse outcome; the stages range from 1 for "mild" disease, to 5 for "severe" disease.
• Intraventricular Hemorrhage Grade I+ [Birth to initial hospital discharge or to death if it occurs earlier (a median of 94 days)]: This is measured as Yes if experienced Grade I+ Intraventricular Hemorrhage; Otherwise, No.
• Length of Hospital Stay [At initial hospital discharge or at death if it occurs earlier (a median of 94 days), assessed up to one year of life.]: This is measured as the length of stay up to hospital discharge or death, whichever occurred first.
• Death [Birth, through the 22-26 months corrected age follow-up window, which corresponds to a median of 29 months calendar age in the analysis population]: This is measured as Yes if an infant died between birth and 22-26 months corrected age; Otherwise, No.
• Neurodevelopmental Impairment [At 22-26 months corrected age (a median of 25 months corrected age)]: This is a 4-level outcome, where Severe NDI denotes a BSID III cognitive score less than 70, a Gross Motor Functional (GMF) level of 3-5 (where higher scores indicate worse outcomes), blindness (less than 20/200 vision), and/or profound hearing loss, Moderate NDI denotes a BSID III cognitive score from 70-84 and either a GMF level of 2 or limited blindness / moderate hearing loss, Mild NDI denotes a BSID III cognitive score from 70-84, or a cognitive score >=85 with a GMF level of 1 and/or mild hearing loss, and No NDI denotes a cognitive score >= 85 and an absence of neurosensory deficits.
• Any Cerebral Palsy [At 22-26 months corrected age (a median of 25 months corrected age)]: This is measured as Yes if the child has been deemed by the medical examiner as having Cerebral Palsy; Otherwise, No.

Sex: All, ages: 1 Hour to 24 Hours

Inclusion Criteria:

* Inborn and outborn preterm infants
* 23 0/7-28 6/7 weeks gestational age
* ≤24 hours postnatal age

Exclusion Criteria:

* Hematocrit > 60%
* Infants with known congenital or chromosomal anomalies, including congenital heart disease and known brain anomalies
* Hemorrhagic or hemolytic disease
* EEG- confirmed seizures
* Congenital thrombotic disease
* Systolic blood pressures >100 mm Hg while not on pressor support
* Receiving Epo or Darbe clinically, or planning to receive Epo or Darbe during hospitalization
* Infants in whom no aggressive therapy is planned
* Family will NOT be available for follow-up at 22-26 months

Participant flow

Outcome results

• Bayley III Composite Cognitive Score (Primary), Mean, score on a scale: Darbepoetin 80.7 +/- 19.5; Placebo 80.1 +/- 18.7 (p 0.88)
• Number of Transfusions Per Infant (Secondary), Mean, Transfusions: Darbepoetin 2.3 +/- 3.1; Placebo 3.3 +/- 3.5
• Total Volume of Transfusions Per Infant (Secondary), Mean, mL: Darbepoetin 54.5 +/- 51.9; Placebo 69.0 +/- 51.0
• Number of Donor Exposures Per Infant (Secondary), Mean, Donors: Darbepoetin 1.6 +/- 2.3; Placebo 2.2 +/- 2.3
• Hematocrit (Secondary), Least squares mean, Percent of blood volume made up of RBCs: Darbepoetin 36.84 (36.35 to 37.33); Placebo 33.88 (33.4 to 34.36)
• Red Cell Mass (Secondary), Least squares mean, mL: Darbepoetin 28.35 (27.26 to 29.43); Placebo 24.74 (23.67 to 25.82)
• Necrotizing Enterocolitis, Bells Stage >=2 With Surgery (Secondary), Count of participants, Participants: Darbepoetin 14; Placebo 13
• Bronchopulmonary Dysplasia Grades 2 or 3 (Secondary), Count of participants, Participants: Darbepoetin 91; Placebo 128
• Retinopathy of Prematurity Stage >=3 or Treatment for That Condition Received (Secondary), Count of participants, Participants: Darbepoetin 238; Placebo 234
• Intraventricular Hemorrhage Grade I+ (Secondary), Count of participants, Participants: Darbepoetin 108; Placebo 98
• Length of Hospital Stay (Secondary), Mean, Days: Darbepoetin 96.2 +/- 58.5; Placebo 104.8 +/- 67.3
• Death (Secondary), Count of participants, Participants: Darbepoetin 52; Placebo 53
• Neurodevelopmental Impairment (Secondary), Count of participants, Participants: Darbepoetin 72; Placebo 68
• Any Cerebral Palsy (Secondary), Count of participants, Participants: Darbepoetin 40; Placebo 38

Adverse events

Time frame: SAEs and Other AEs were monitored from the first dose of study drug through 36 completed weeks PMA (7 days after administration of the last dose of study drug). All-cause mortality was monitored through 22-26 months corrected age.

Serious adverse events by term

4 more terms not shown.

Other adverse events by term

• Results publication: Maxwell JR, Ohls RK, An G, Winter D, Beauman S, Buhrman J, Jantzie LL. Development of an electrochemiluminescence assay to measure serum darbepoetin concentration in extremely preterm infants. Bioanalysis. 2025 Dec;17(23):1553-1559. doi: 10.1080/17576180.2025.2600914. Epub 2025 Dec 14. PMID 41392547
• Results publication: Ohls RK, Das A, Tan S, Lowe JR, Schibler K, Beauman SS, Bell EF, Laptook AR, Baserga M, Patel RM, Carlton DP, Flibotte J, Grisby C, Higgins RD, Shankaran S, Watterberg K, Hibbs AM, Carlo WA, Colaizy TT, Van Meurs KP, Kicklighter SD, Moore R, Sollinger C, Chalak LF, Ghavam S, Poindexter BB, Tyson JE, Cotten CM, Baack ML, Fathi O, DeMauro SB, Laughon MM, Reynolds AM, Duncan AF, Winter S, Wilson-Costello DE, Peralta-Carcelen M, Vohr BR, Harmon HM, Hintz SR, Cavanaugh B, Heyne RJ, Merhar S, Mosquera R, Sewell E, Malcolm WF, Richards LA, Benninger KL, Trembath A; Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network. Darbepoetin, Red Cell Mass, and Neuroprotection in Preterm Infants: A Randomized Clinical Trial. JAMA Pediatr. 2025 Aug 1;179(8):836-845. doi: 10.1001/jamapediatrics.2025.0807. PMID 40354084
• Results publication: Bahr TM, Tan S, Smith E, Beauman SS, Schibler KR, Grisby CA, Lowe JR, Bell EF, Laptook AR, Shankaran S, Carlton DP, Rau C, Baserga MC, Flibotte J, Zaterka-Baxter K, Walsh MC, Das A, Christensen RD, Ohls RK; Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network. Serum ferritin values in neonates <29 weeks' gestation are highly variable and do not correlate with reticulocyte hemoglobin content. J Perinatol. 2023 Nov;43(11):1368-1373. doi: 10.1038/s41372-023-01751-z. Epub 2023 Aug 18. PMID 37596391
• Results publication: Vu PT, Ohls RK, Mayock DE, German KR, Comstock BA, Heagerty PJ, Juul SE; PENUT Consortium. Transfusions and neurodevelopmental outcomes in extremely low gestation neonates enrolled in the PENUT Trial: a randomized clinical trial. Pediatr Res. 2021 Jul;90(1):109-116. doi: 10.1038/s41390-020-01273-w. Epub 2021 Jan 11. PMID 33432157

• Study Protocol (PDF, 2019-02-25)
• Statistical Analysis Plan (PDF, 2023-01-20)
• Informed Consent Form (PDF, 2019-02-25)

• Robin Ohls, MD, Principal investigator, University of Utah