Optimized Erythropoietin (EPO) Treatment

NCT02075970 | Completed Phase 2 DMC FDA Drug

• 2 other identifiers: 2013067293P01HL046925
• Study Type: interventional
• Target: 62
• Locations: 1 country
• Sites: 1

Brief 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.

Conditions

Neonatal Anemia

Keywords

Neonatal; Anemia; Transfusion; Erythropoetin; Epoetin Alpha; Red Blood Cell; Survival; Pharmacodynamics; Model

Outcome Measures

Primary Outcomes (1)

• Number of red blood cell transfusions

  The count of the number of packed red blood cell transfusions an infant receives during the entire course of their initial hospital stay.

  From date of randomization through day of life 28 or death, whichever comes first

Secondary Outcomes (1)

• Survival of Fetal Red Blood Cells in number of days

  From date of transfusion of biotinylated red blood cells until biotinylated red blood cells are no longer detectable in leftover blood samples, or death, whichever comes first. An expected average of 80-120 days. Assessed up to 5 months.

Other Outcomes (1)

• Derivation of an individualized, optimal Epoetin Alpha dosing algorithm and prediction model for each subject

  From birth through discharge or death, whichever comes first. An average of 4 weeks to 6 months. Assessed up to 12 months.

Study Arms (3)

Epoetin Alpha study 1

EXPERIMENTAL

Epoetin Alpha Tthe number of separate doses (per kg) to be given over 4 weeks by day of age will not exceed 10. These will be administered as follows: day of life (DOL) 2 (1200 U), DOL 4 (600 U), DOL 5 (600 U), DOL 6 (600U), DOL 7 (600 U), DOL 9 (600 U), DOL 14 (600 U), DOL 15 (600 U), DOL 16 (1200 U), and DOL 28 (600 U). The greatest dose in any 1 wk period is 3600 U. Infant study 1 Drug Intervention: all infants will be treated with Epoetin Alpha during the first four weeks of life to provide data for determining: 1) the PK/PD model determined optimized Epoetin Alpha dosing schedule; and 2) clinical and laboratory covariates predictive of which infants are good and poor Epoetin Alpha responder.

Drug: Epoetin Alpha

Epoetin Alpha study 2

PLACEBO COMPARATOR

Epoetin Alpha dosing schedule will be determined based on the results of Infant Study 1. Infant Study 2 is a randomized, masked study to test the hypothesis that optimized Epoetin Alpha treatment of VLBW infants predicted to be good responders will result in the elimination of RBCTx relative to poor responders. Infant Study 2 in Years 4 and 5 will make use of the knowledge acquired in Infant Study 1 to test the central hypothesis that 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.

Drug: Epoetin Alpha

Biotinylated red blood cells

EXPERIMENTAL

Individual fetal RBC lifespans will be determined by administering biotinylated red blood cells, both autologous and allogeneic, simultaneously. Left over red blood cells are examined to determine red cell survival.

Drug: Biotinylated Red Blood Cells

Interventions

Epoetin Alpha DRUG

Infant study 1: VLBW infant study subjects (weighing 1.0 to 1.5 kg at birth) who are otherwise receiving standard clinical care will be treated with Epoetin Alpha according to a dosing algorithm. Infant study 2: Dosing algorithm will be determined by results of Infant Study 1.

Also known as: Procrit

Epoetin Alpha study 1; Epoetin Alpha study 2

Biotinylated Red Blood Cells DRUG

Biotinylated red blood cells will be transfused to infants to determine red blood cell lifespan.

Also known as: BioRBC

Biotinylated red blood cells

Eligibility Criteria

• Age: Up to 2 Days
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17)

You may qualify if:

• Post-menstrual age at birth less than 37 wk;
• birth weight of 1,001 to 1,500 g;
• postnatal age \<48 h;
• respiratory distress requiring ventilation;
• signed consent by parent or guardian.

You may not qualify if:

• Anticipated survival \<72 h;
• Hemolytic anemia due to alloimmune disease (including due to ABO), and other hemolytic disease processes;
• Major anomalies that are life-threatening during the neonatal and infant periods (central nervous system, cardiac, metabolic chromosomal including, but not limited to, trisomies, deletions, and trinucleotide repeats);
• Clinical seizures;
• Congenital thrombotic or hemorrhagic conditions including disseminated intravascular coagulation;
• Positive blood or spinal fluid bacterial or fungal culture, or other laboratory and/or clinical data indicative of sepsis, including TORCH infections, prior to 48 h of age;
• Hematocrit \>50%;
• Platelet count \>400,000 per µL in first 48 h of life;
• Hypertension with systolic blood pressure \>100 mm Hg.
• Any condition, in the opinion of the investigators, that would compromise the well being of the subject or the study, or prevent the subject from meeting or performing study requirements.

Sponsors & Collaborators

• John A Widness: lead
• Department of Health and Human Services: collaborator
• National Heart, Lung, and Blood Institute (NHLBI): collaborator
• Janssen Scientific Affairs, LLC: collaborator

Study Sites (1)

University of Iowa Hospitals and Clinics

Iowa City, Iowa, 52242, United States

Location

MeSH Terms

Conditions

Anemia, Neonatal; Anemia

Interventions

Epoetin Alfa

Condition Hierarchy (Ancestors)

Hematologic Diseases; Hemic and Lymphatic Diseases; Infant, Newborn, Diseases; Congenital, Hereditary, and Neonatal Diseases and Abnormalities

Intervention Hierarchy (Ancestors)

Erythropoietin; Colony-Stimulating Factors; Glycoproteins; Glycoconjugates; Carbohydrates; Hematopoietic Cell Growth Factors; Cytokines; Intercellular Signaling Peptides and Proteins; Peptides; Amino Acids, Peptides, and Proteins; Proteins; Biological Factors

Study Officials

• John A Widness, MD

  University of Iowa

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: TRIPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR
• Purpose: PREVENTION
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR INVESTIGATOR
• PI Title: Professor, Department of Pediatrics

Study Record Dates

• First Submitted: May 30, 2013
• First Posted: March 3, 2014
• Study Start: June 1, 2014
• Primary Completion: June 1, 2019
• Study Completion: December 1, 2019
• Last Updated: April 29, 2021

Record last verified: 2021-04

Data Sharing

• IPD Sharing: Will not share

Locations

US (1)