Clinical Trial Details
— Status: Completed
Administrative data
NCT number |
NCT02075970 |
Other study ID # |
201306729 |
Secondary ID |
3P01HL046925 |
Status |
Completed |
Phase |
Phase 2
|
First received |
|
Last updated |
|
Start date |
June 2014 |
Est. completion date |
December 2019 |
Study information
Verified date |
April 2021 |
Source |
University of Iowa |
Contact |
n/a |
Is FDA regulated |
No |
Health authority |
|
Study type |
Interventional
|
Clinical Trial Summary
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.
Description:
SPECIFIC AIMS Erythropoietin (Epo) stimulates red blood cell (RBC) production. Erythropoietin
treatment of anemic, very low birth weight (VLBW) preterm infants has not been as effective
as originally anticipated in eliminating multiple RBC transfusions (RBCTX). This conclusion
is based on Epoetin Alpha dosing studies employing inconsistent RBCTX criteria, and study
designs that did not fully consider Epoetin Alpha's complex pharmacokinetics (PK) and
pharmacodynamics (PD). The hypothesis of this project challenges the conclusion that Epoetin
Alpha therapy cannot reduce RBCTX in VLBW infants to a clinically important extent. This
challenge is based on our novel comprehensive determinations of the PD of endogenous Epo in
VLBW infants, and on our recent computer Epo simulation modeling results predicting that
RBCTX can be eliminated in a select group of VLBW infants.
Study Objective To develop a pharmacodynamically-based, individualized medicine approach
capable of completely eliminating RBCTX in an identifiable group of VLBW infants by optimally
administering Epoetin Alpha.
Central Hypotheses Infants with good Epoetin Alpha responsiveness can be identified by a
mechanism-driven, individualized prediction model. Optimized Epoetin Alpha treatment of the
predicted good responders that is based on sound, evidence based PK/PD principles will
eliminate the need for RBCTX.
Epoetin Alpha responsiveness is determined by two key components: 1) RBC production, which
depends on Epoetin Alpha PD. 2) RBC lifespan. Individualized covariate-based (ie, patient
specific characteristics) prediction of these two components is critical for the development
of an individualized prediction model of Epoetin Alpha responsiveness that will be used for
testing the Central Hypothesis. These important predictors of Epoetin Alpha responsiveness
will be investigated in the following Specific Aims (SA) and Hypotheses (HY):
INFANT STUDY 1 (Years 1-3) performed in VLBW infants with birth weights from 1.0 to 1.5 kg SA
1 Determine clinical and laboratory covariates (ie, patient-specific characteristics)
controlling the large inter-subject variability in Epoetin Alpha's PD using data from Epoetin
Alpha dosing of VLBW infants HY 1 The inter-subject variability in Epoetin Alpha's PD is
predictable by several covariates that are identifiable by our PK/PD modeling approach.
SA 2 Determine the lifespan of fetal RBC in the gestational age spectrum of the study
infants.
HY 2 There exists a significant inter-subject variability in the lifespan of fetal RBCs in
VLBW infants that is predictable based on gestational age.
SA 3 Derive an individualized, optimal Epoetin Alpha dosing algorithm and an individualized
prediction model for the Epoetin Alpha responsiveness in VLBW infants from the results in
Specific Aims 1 and 2.
HY 3 Crossvalidation-type computer simulations based on individualized and optimized Epoetin
Alpha dosing in a subgroup of VLBW infants with good Epoetin Alpha responsiveness, identified
by the prediction model, will indicate that RBCTX can be avoided in a select group of VLBW
infants.
INFANT STUDY 2 (Years 3-4, to be addressed as a modification after completion of study 1)
also performed in VLBW infant with birth weights from 1.0 to 1.5 kg SA 4 Apply the optimal
Epoetin Alpha dosing algorithm and Epoetin Alpha responsiveness prediction model developed in
Infant Study 1 to an Epoetin Alpha dosing study to test the Central Hypothesis.
HY 4 The subgroup of VLBW infants with good Epoetin Alpha responsiveness will have a higher
proportion of infants that will not have any RBCTX compared to those with poor Epoetin Alpha
responsiveness.
Expected Outcomes SA 1 Among the covariates considered in Specific Aims 1 (e.g. clinical
neonatal/maternal factors, blood cell parameters, cytokines linked to erythropoiesis,
inflammation biomarkers, oxidative stress, iron status, and genetic factors), we will
identify several with statistically significant correlations to Epoetin Alpha's PD.
SA2 The lifespan of fetal RBCs will show similar relationship to gestational age as that
which was observed by us in the ovine fetus.
SA3 The model will accurately predict individual Epoetin Alpha responsiveness to optimized
Epo dosing and will provide strong support for our hypothesis that RBCTX can be completely
eliminated in a select group of VLBW infants.
SA4 Infant Study 2 will show that the select group of VLBW infants that are predicted to be
good Epoetin Alpha responders by the combined use of an individualized Epoetin Alpha
responsiveness prediction model and an optimal, individualized Epo dosing algorithm will have
a greater proportion of infants who do not require any RBCTX compared to those predicted to
have poor Epoetin Alpha responsiveness.
A successful completion of the proposed research is potentially transformative and is likely
to be applied to the care of VLBW infants, resulting in a significant overall impact.
Moreover, a successful demonstration of the utility and power of these principles will lead
to improvements in the complex pharmacotherapy of VLBW infants, who are among the most
difficult to study of any patient group.