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.

Inclusion Criteria:

- Inborn and outborn preterm infants

- 23 0/7-28 6/7 weeks gestation

- ≤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