Neonatal anemia is the most commonly encountered hematologic problem among all neonates cared
for in the neonatal intensive care unit (NICU). This project seeks to better understand the
pathophysiology and treatment of this challenging and important condition, especially as it
affects premature, critically ill very low birth weight (VLBW) infants who require intensive
laboratory blood monitoring leading to the need for multiple red blood cell (RBC)
transfusions (RBCTX). In the research strategy proposed in Study 1, Aims 1, 2 and 3,
recombinant human erythropoietin (Epoetin Alpha, PROCRIT, provided by Janssen Scientific
Affairs) will first be administered to 1.0 to 1.5 kg VLBW infants; then comprehensive
pharmacokinetics (PK) and pharmacodynamics (PD) data will be systematically gathered and
analyzed to identify clinical and laboratory covariate parameters differentiating the infants
based on their level of Epoetin Alpha responsiveness. Finally the Epoetin Alpha
responsiveness predictors thus determined will be applied prospectively in the Aim 4 Study, a
2 x 2 design in which VLBW infants will be identified as good or poor Epoetin Alpha
responders, based on the predictors, and then randomly assigned to receive Epoetin Alpha
treatment or no treatment. This will test the central hypothesis: RBCTX can be eliminated in
the majority of good Epoetin Alpha responders by optimal administration of Epoetin Alpha, but
only marginal reductions in RBCTx will occur in the poor Epoetin Alpha responders. This
project challenges the prevailing thinking that the efficacy of Epoetin Alpha dosing in
stimulating erythropoiesis is insufficient to eliminate the need for RBC transfusions in VLBW
infants. Based on extensive preclinical and clinical PK/PD studies by our PPG team, we
contend that previous Erythropoietin treatment studies in VLBW infants were not able to
realize the full potential of Erythropoietin to eliminate RBCTX (in contrast to the very
successful use of Erythropoietin in adult renal failure patients) because previous VLBW
studies were conducted 1) without Epoetin Alpha dosing individualized for the complexities of
neonatal erythropoiesis and PK/PD of Epoetin Alpha and 2) without consistent criteria for RBC
transfusion, Epoetin Alpha dosing, and patient enrollment. Net Epoetin Alpha responsiveness
as reflected in Hb level depends on two components: Epoetin Alpha PD and RBC lifespan (Fig
15). By determining RBC lifespan, we will explain inter-subject variability of Epoetin Alpha
responsiveness resulting from one of these components. The fetal lifespan data will be
examined for its correlation with gestational age. If the correlation is statistically
significant, gestational age will be included in the final selection of covariates for the
population PK/PD model to be developed at the end of Infant Study 1. To fully understand the
correlation of RBC lifespan with gestational age infants ranging from 22-42 weeks gestational
age will be studied. The overall impact of Project 1 will be significant and potentially
transformative: the development of a personalized, mechanism-driven approach built on sound
principles will improve understanding of neonatal anemia and will be applicable to the care
of premature, anemic infants.
RELEVANCE Project 1 results confirming our hypothesis that PK/PD optimized Epo treatment is
effective in eliminating RBC transfusions administered to a select sub-group of NICU infants
will provide fundamental knowledge about neonatal anemia that will reduce the burden of
illness and disability caused by this condition. In addition, our results will stimulate
researchers to extend our findings to other sub-groups with neonatal anemia, ie, smaller and
sicker infants, and will stimulate novel treatments with similar, new biotechnology-produced
protein drugs.
Phase:
Phase 2
Details
Lead Sponsor:
John A Widness University of Iowa
Collaborators:
Department of Health and Human Services Janssen Scientific Affairs, LLC National Heart, Lung, and Blood Institute (NHLBI)