EPO-4-Rhesus Study (EPO-4-Rhesus)

Randomized Controlled Trial on the Use of EPO to Reduce Top-up Transfusions in Neonates With Red Blood Cell Alloimmunization Treated With Intrauterine Transfusions

Up to 80% of infants with hemolytic disease due to maternal alloimmunization, treated with IUT, require at least one top-up transfusion for late anemia during the first 3 months of life. Erythropoietin deficiency is also considered as a possible contributing factor to late anemia and therefore we will assess the role of EPO (darbepoetin alfa) in the treatment of these infants.

Study Overview

• Status: Unknown
• Conditions: Erythroblastosis, Fetal; Erythroblastosis Fetalis, Rh Disease; Erythroblastosis Fetalis Due to RH Antibodies; Erythroblastosis Fetalis Due to Isoimmunization
• Intervention / Treatment: Drug: Darbepoetin Alfa

Detailed Description

The mainstay of antenatal treatment of fetal anemia due to red cell alloimmunization is (serial) IUT. The mainstay of postnatal treatment in HDN is (1) intensive phototherapy and exchange transfusion to treat hyperbilirubinemia and prevent kernicterus, and (2) top-up transfusions to treat anemia. Up to 80% of infants with HDN treated with IUT require at least one top-up transfusion for late anemia during the first 3 months of life.

Several risk factors for late anemia have been reported, including serial IUT (due to bone marrow suppression), severity of HDN, reduced use of exchange transfusions during the neonatal period and reduced survival of transfused red blood cells. Finally, erythropoietin deficiency is also considered as a possible contributing factor to late anemia.

EPO has been increasingly used in neonates to prevent or reduce neonatal anemia without short or long-term adverse effects. Several small studies and casuistic reports suggest that neonates with HDN may benefit from treatment with EPO to reduce the risk of delayed anemia and subsequent top-up transfusions. However, other authors found that EPO may be less effective than expected. Due to the lack of evidence, routine use of EPO is currently not recommended. To determine a role for EPO in this group of patients, a well-designed randomized controlled clinical trial of sufficient sample size is required. Potentially, EPO stabilizes the hemoglobin levels of these infants and thus prevents top-up transfusions and extra admissions, creating a more stable and natural postnatal course for patients with HDN.

• Study Type: Interventional
• Enrollment (Anticipated): 42
• Phase: Phase 2; Phase 3

Contacts and Locations

• Study Contact: Name: Isabelle MC Ree, MD; Phone Number: +31715262814; Email: i.m.c.ree@lumc.nl
• Study Contact Backup: Name: Enrico Lopriore, MD PhD; Phone Number: +31715262965; Email: e.lopriore@lumc.nl

Study Locations

• Netherlands
  • Leiden, Netherlands, 2300RC
    • Recruiting
    • Leiden University Medical Center
    • Contact: Enrico Lopriore, MD Phd; Email: E.Lopriore@lumc.nl

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: No older than 2 years (Child)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• all (near)-term neonates (gestational age ≥ 35 weeks) admitted to the Leiden University Medical Center (LUMC) with HDFN, treated with IUT.

Exclusion Criteria:

• none.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Darbepoetin alfa group; Group treated with darbepoetin alfa (Aranesp) 10microg/kg once a week for a period of 8 weeks.	Drug: Darbepoetin Alfa; Darbepoetin alfa dosage 10microg/kg once a week for 8 weeks; Other Names: Aranesp
No Intervention: Control group; "Standard care" which involves close monitoring of hemoglobin levels and if necessary, top-up red cell transfusion.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of top-up transfusions required per infant	Number of top-up transfusions required per infant	First 3 months of life

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
The percentage of infants requiring a top-up transfusion	The percentage of infants requiring a top-up transfusion	First 3 months of life
Number of days of admission for top-up transfusions	Number of days of admission for top-up transfusions	First 3 months of life
Occurrence of hypertension	The percentage of infants with a systolic blood pressure ≥ 2 SD above age adjusted mean systolic blood pressure during treatment	8 weeks (treatment course)
Occurrence of high ferritin levels	The percentage of infants with ferritin levels >200 μg/L during treatment	8 weeks (treatment course)

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Long-term neurodevelopmental outcome	Exploratory outcome; Long-term neurodevelopmental outcome at 2 years of age using the BSID-III test	2 years of age

Collaborators and Investigators

• Sponsor: Sanquin-LUMC J.J van Rood Center for Clinical Transfusion Research
• Collaborators: Leiden University Medical Center
• Investigators: Principal Investigator: Masja de Haas, MD PhD, Sanquin Research

Study record dates

Study Major Dates

• Study Start (Actual): October 31, 2017
• Primary Completion (Anticipated): August 1, 2020
• Study Completion (Anticipated): August 1, 2020

Study Registration Dates

• First Submitted: April 3, 2017
• First Submitted That Met QC Criteria: April 3, 2017
• First Posted (Actual): April 7, 2017

Study Record Updates

• Last Update Posted (Actual): October 2, 2019
• Last Update Submitted That Met QC Criteria: September 30, 2019
• Last Verified: September 1, 2019

More Information

Terms related to this study

• Keywords: Hemolytic disease of the fetus and newborn; HDFN; Red blood cell alloimmunization
• Additional Relevant MeSH Terms: Immune System Diseases; Hematologic Diseases; Infant, Newborn, Diseases; Fetal Diseases; Pregnancy Complications; Erythroblastosis, Fetal; Hematinics; Darbepoetin alfa
• Other Study ID Numbers: P17.102

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No