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

NCT ID: NCT03169881

Last Updated: 2025-11-17

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE3
• Total Enrollment: 650 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2017-09-20
• Study Completion Date: 2025-05-12

Brief Summary

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

Conditions

Neurocognitive; Neuroprotective; Neonatal; Neurodevelopmental Impairment

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: QUADRUPLE

Study Groups

Darbepoetin

Darbepoetin 10 micrograms/kg/once every week (IV or SC)

Group Type: EXPERIMENTAL

Darbepoetin

Intervention Type: DRUG

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

Equal volume normal saline for IV administration, or sham dosing

Group Type: PLACEBO_COMPARATOR

Placebo

Intervention Type: DRUG

normal saline for IV administration, or sham dosing. Infants will be treated until 35 completed weeks gestation, discharge, or transfer to another hospital.

Interventions

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.

Intervention Type: 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.

Intervention Type: DRUG

Other Intervention Names

Darbe; normal saline for IV administration, or sham dosing

Eligibility Criteria

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

• Minimum Eligible Age: 1 Hour
• Maximum Eligible Age: 24 Hours
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

NICHD Neonatal Research Network

NETWORK

Sponsor Role: lead

National Heart, Lung, and Blood Institute (NHLBI)

NIH

Sponsor Role: collaborator

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Robin Ohls, MD

Role: PRINCIPAL_INVESTIGATOR

University of Utah

Locations

University of Alabama at Birmingham

Birmingham, Alabama, United States

Stanford University

Palo Alto, California, United States

Emory University

Atlanta, Georgia, United States

University of Iowa

Iowa City, Iowa, United States

University of New Mexico

Albuquerque, New Mexico, United States

University of Rochester

Rochester, New York, United States

RTI International

Durham, North Carolina, United States

Duke University

Durham, North Carolina, United States

Cincinnati Children's Medical Center

Cincinnati, Ohio, United States

Case Western Reserve University, Rainbow Babies and Children's Hospital

Cleveland, Ohio, United States

Research Institute at Nationwide Children's Hospital

Columbus, Ohio, United States

Univeristy of Pennsylvania

Philadelphia, Pennsylvania, United States

Brown University - Women and Infants Hospital of Rhode Island

Providence, Rhode Island, United States

University of Texas Southwestern Medical Center at Dallas

Dallas, Texas, United States

University of Texas Health Science Center at Houston

Houston, Texas, United States

University of Utah

Salt Lake City, Utah, United States

Countries

United States

References

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.

Reference Type: DERIVED

PMID: 33432157 (View on PubMed)

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.

Reference Type: DERIVED

PMID: 40354084 (View on PubMed)

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.

Reference Type: DERIVED

PMID: 37596391 (View on PubMed)

Provided Documents

Document Type: Study Protocol

View Document

Document Type: Statistical Analysis Plan

View Document

Other Identifiers

NICHD-NRN-0058

Identifier Type: -

Identifier Source: org_study_id