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

NICHD Neonatal Research Network

Status and phase: Completed; Phase 3

Conditions: Neurodevelopmental Impairment; Neurocognitive; Neuroprotective; Neonatal

Treatments: Drug: Placebo; Drug: Darbepoetin

Study type: Interventional

Funder types: NETWORK; NIH

Identifiers

NCT03169881

NICHD-NRN-0058

Details and patient eligibility

About

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

Full 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.

Enrollment: 650 patients

Sex: All

Ages: 1 to 24 hours old

Volunteers: No Healthy Volunteers

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

Trial design

Primary purpose: Treatment

Allocation: Randomized

Interventional model: Parallel Assignment

Masking: Quadruple Blind

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650 participants in 2 patient groups, including a placebo group

Darbepoetin

Experimental group

Description:

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

Treatment:

Drug: Darbepoetin

Placebo

Placebo Comparator group

Description:

Equal volume normal saline for IV administration, or sham dosing

Treatment:

Drug: Placebo