EPO-4-Rhesus Study

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

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

Conditions
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Erythroblastosis, Fetal, Erythroblastosis Fetalis, Rh Disease, Erythroblastosis Fetalis Due to RH Antibodies, Erythroblastosis Fetalis Due to Isoimmunization

Intervention / Treatment
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* Drug: Darbepoetin Alfa


Participation Criteria
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Eligibility Criteria
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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.

Ages Eligible for Study
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Maximum Age: 2 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: RCT with unblinded treatment allocation 1:1 ratio. Either treatment with darbepoetin alfa or standard care. No placebo.
Masking: None (Open Label)


Arms and Interventions

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

What is the study measuring?
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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) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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HDFN, Hemolytic disease of the fetus and newborn, Red blood cell alloimmunization