A Randomized, Masked, Placebo-Controlled Study of Darbepoetin Alfa in Preterm Infants

Abstract

BACKGROUND: A novel erythropoiesis stimulating agent (ESA), darbepoetin alfa (Darbe), increases hematocrit in anemic adults when administered every 1 to 3 weeks. Weekly Darbe dosing has not been evaluated in preterm infants. We hypothesized that infants would respond to Darbe by decreasing transfusion needs compared with placebo, with less-frequent dosing than erythropoietin (Epo). METHODS: Preterm infants 500 to 1250 g birth weight and ≤48 hours of age were randomized to Darbe (10 μg/kg, 1 time per week subcutaneously), Epo (400 U/kg, 3 times per week subcutaneously) or placebo (sham dosing) through 35 weeks’ gestation. All received supplemental iron, folate, and vitamin E, and were transfused according to protocol. Transfusions (primary outcome), complete blood counts, absolute reticulocyte counts (ARCs), phlebotomy losses, and adverse events were recorded. RESULTS: A total of 102 infants (946 ± 196 g, 27.7 ± 1.8 weeks’ gestation, 51 ± 25 hours of age at first dose) were enrolled. Infants in the Darbe and Epo groups received significantly fewer transfusions (P = .015) and were exposed to fewer donors (P = .044) than the placebo group (Darbe: 1.2 ± 2.4 transfusions and 0.7 ± 1.2 donors per infant; Epo: 1.2 ± 1.6 transfusions and 0.8 ± 1.0 donors per infant; placebo: 2.4 ± 2.9 transfusions and 1.2 ± 1.3 donors per infant). Hematocrit and ARC were higher in the Darbe and Epo groups compared with placebo (P = .001, Darbe and Epo versus placebo for both hematocrit and ARCs). Morbidities were similar among groups, including the incidence of retinopathy of prematurity. CONCLUSIONS: Infants receiving Darbe or Epo received fewer transfusions and fewer donor exposures, and fewer injections were given to Darbe recipients. Darbepoetin and Epo successfully serve as adjuncts to transfusions in maintaining red cell mass in preterm infants.

Cognitive Outcomes of Preterm Infants Randomized to Darbepoetin, Erythropoietin, or Placebo

“…We previously reported that preterm infants randomized to Epo and Darbe received half the number of transfusions and were exposed to half the donors compared with the placebo group. 12 Based on its potential for neuroprotection, our study was designed to determine whether Darbe was also effective in improving developmental outcomes. …”

Stimulating erythropoiesis in neonates

“…Since the early 1990s, a number of studies have explored whether erythropoietin (Epo) administration could help to reduce the number of or need for packed red cell transfusions in neonates with the anemia of prematurity [10]. Epo stimulates a crucial signaling pathway that promotes erythroid progenitor and precursor survival, proliferation, and differentiation ( Fig.…”

“…In a recent study from Ohls et al, a randomized, placebo-controlled trial was performed to test whether either Epo or the longer-acting Epo analog darbepoetin alfa (Darbe) can reduce the need for transfusions, while also measuring the incidence of morbidities of concern in these groups, such as the ROP [10]. The authors provided preterm infants with birth weights between 500 and 1250 g who were less than 48 hr at the time of enrollment, with either weekly Darbe treatment at 10 mg/kg subcutaneously or Epo at 400 U/kg three times per week subcutaneously.…”

“…A sham-dosing scheme was used as the placebo for blinding purposes. All patients in the study received supplementation with iron, folate, and vitamin E. In addition, all enrolled patients were transfused according to a strict protocol that depended upon the need for respiratory support and symptoms [10]. This protocol is consistent with restrictive transfusion regimens that are used in a variety of major NICUs.…”

“…Ohls et al have additionally measured the incidence of a variety of morbidities of concern in the treatment and placebo groups [10]. There was no significant difference in the incidence of ROP, ICH, NEC, or other complications seen frequently in the NICU.…”