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

Study Hypothesis: Preterm infants administered weekly Darbe during the neonatal period will have improved neurocognitive outcome at 22-26 months compared to placebo

Study Overview

• Status: Completed
• Conditions: Neonatal; Neurodevelopmental Impairment; Neurocognitive; Neuroprotective
• Intervention / Treatment: Drug: Darbepoetin; Drug: Placebo

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Actual): 650
• Phase: Phase 3

Contacts and Locations

Study Locations

• United States
  • Alabama
    • Birmingham, Alabama, United States, 35233
      • University of Alabama at Birmingham
  • California
    • Palo Alto, California, United States, 94304
      • Stanford University
  • Georgia
    • Atlanta, Georgia, United States, 30303
      • Emory University
  • Iowa
    • Iowa City, Iowa, United States, 52242
      • University of Iowa
  • New Mexico
    • Albuquerque, New Mexico, United States, 87131
      • University of New Mexico
  • New York
    • Rochester, New York, United States, 14642
      • University of Rochester
  • North Carolina
    • Durham, North Carolina, United States, 27710
      • Duke University
    • Durham, North Carolina, United States, 27705
      • RTI International
  • Ohio
    • Cincinnati, Ohio, United States, 45267
      • Cincinnati Children's Medical Center
    • Cleveland, Ohio, United States, 44106
      • Case Western Reserve University, Rainbow Babies and Children's Hospital
    • Columbus, Ohio, United States, 43205
      • Research Institute at Nationwide Children's Hospital
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19104
      • Univeristy of Pennsylvania
  • Rhode Island
    • Providence, Rhode Island, United States, 02905
      • Brown University - Women and Infants Hospital of Rhode Island
  • Texas
    • Dallas, Texas, United States, 75235
      • University of Texas Southwestern Medical Center at Dallas
    • Houston, Texas, United States, 77030
      • University of Texas Health Science Center at Houston
  • Utah
    • Salt Lake City, Utah, United States, 84108
      • University of Utah

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 5 months to 6 months (Child)
• Accepts Healthy Volunteers: No

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Darbepoetin; Darbepoetin 10 micrograms/kg/once every week (IV or SC)	Drug: Darbepoetin; 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.; Other Names: Darbe
Placebo Comparator: Placebo; Equal volume normal saline for IV administration, or sham dosing	Drug: Placebo; normal saline for IV administration, or sham dosing. Infants will be treated until 35 completed weeks gestation, discharge, or transfer to another hospital.; Other Names: normal saline for IV administration, or sham dosing

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Bayley III Composite Cognitive Score	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.	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

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Transfusions Per Infant	The number of transfusions recorded during the study, up to 35 completed weeks gestational age	Birth, up to the earliest of: death, hospital discharge, or 35 completed weeks gestational age (a median of 9 weeks)
Total Volume of Transfusions Per Infant	The total volume of transfusions for the infant if ever transfused	Birth, up to the earliest of: death, hospital discharge, or 35 completed weeks gestational age (a median of 9 weeks)
Number of Donor Exposures Per Infant	The number of donor exposures recorded during the study, up to 35 completed weeks gestational age	Birth, up to the earliest of: death, hospital discharge, or 35 completed weeks gestational age (a median of 9 weeks)
Hematocrit	Hematocrit adjusted for center, gestational age group, and familial clustering	at 2 and at 7 weeks in the study
Red Cell Mass	Red Cell Mass (Circulating Erythrocyte Volume), adjusted for center, gestational age group, and familial clustering	at 2 and at 7 weeks in the study
Necrotizing Enterocolitis, Bells Stage >=2 With Surgery	This is measured as Yes if experienced necrotizing enterocolitis, Bells stage >=2 with surgery; Otherwise, No.	Birth to initial hospital discharge or to death if it occurs earlier (a median of 94 days)
Bronchopulmonary Dysplasia Grades 2 or 3	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.	At 36 weeks postmenstrual age
Retinopathy of Prematurity Stage >=3 or Treatment for That Condition Received	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.	Birth to initial hospital discharge or to death if it occurs earlier (a median of 94 days)
Intraventricular Hemorrhage Grade I+	This is measured as Yes if experienced Grade I+ Intraventricular Hemorrhage; Otherwise, No.	Birth to initial hospital discharge or to death if it occurs earlier (a median of 94 days)
Length of Hospital Stay	This is measured as the length of stay up to hospital discharge or death, whichever occurred first.	At initial hospital discharge or at death if it occurs earlier (a median of 94 days), assessed up to one year of life.
Death	This is measured as Yes if an infant died between birth and 22-26 months corrected age; Otherwise, No.	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
Neurodevelopmental Impairment	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.	At 22-26 months corrected age (a median of 25 months corrected age)
Any Cerebral Palsy	This is measured as Yes if the child has been deemed by the medical examiner as having Cerebral Palsy; Otherwise, No.	At 22-26 months corrected age (a median of 25 months corrected age)

Collaborators and Investigators

• Sponsor: NICHD Neonatal Research Network
• Collaborators: National Heart, Lung, and Blood Institute (NHLBI)
• Investigators: Principal Investigator: Robin Ohls, MD, University of Utah

Publications and helpful links

General Publications

• 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.
• 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.
• 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.

Study record dates

Study Major Dates

• Study Start (Actual): September 20, 2017
• Primary Completion (Actual): December 23, 2022
• Study Completion (Actual): May 12, 2025

Study Registration Dates

• First Submitted: May 24, 2017
• First Submitted That Met QC Criteria: May 25, 2017
• First Posted (Actual): May 30, 2017

Study Record Updates

• Last Update Posted (Estimated): November 17, 2025
• Last Update Submitted That Met QC Criteria: November 10, 2025
• Last Verified: November 1, 2025

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Health Services Administration; Amino Acids, Peptides, and Proteins; Proteins; Pharmaceutical Preparations; Carbohydrates; Crystalloid Solutions; Isotonic Solutions; Solutions; Glycoproteins; Glycoconjugates; Colony-Stimulating Factors; Erythropoietin; Darbepoetin alfa; Saline Solution; Organization and Administration
• Other Study ID Numbers: NICHD-NRN-0058

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: NIH has had a long-standing policy to share and make available to the public the results and accomplishments of the activities that it funds. The NRN plans to share de-identified data after final publication in an NIH supported data repository such as the NICHD Data and Specimen Hub (https://dash.nichd.nih.gov) or NHLBI BIOLINCC (https://biolincc.nhlbi.nih.gov/home/).

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No