Darbepoetin Administration to Preterm Infants

Study Overview
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Brief Summary
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Infants born prematurely do not increase production of the primary red cell growth factor, erythropoietin (Epo), and often develop an anemia called the anemia of prematurity. The anemia of prematurity is the most common anemia seen in neonates, and is due to a failure of Epo production. Human recombinant Epo (rHuEpo), given three to five times a week, is successful in treating the anemia of prematurity. A slightly modified, long-acting version of rHuEpo, called darbepoetin alfa (darbepoetin), is now available and has proven effective in increasing hematocrit (red blood cell levels) in adults. In addition to its red cell stimulating properties, recent evidence has shown that rHuEpo is protective in the developing or injured brain. We have designed a randomized, masked, placebo-controlled study to determine the safety and short and long term efficacy of darbepoetin. At this time, darbepoetin has been studied primarily in adults and pediatric patients, but there is evidence from pilot studies that darbepoetin would be useful in the neonatal setting as well. It also may well improve neurodevelopmental outcomes in preterm neonates. We hypothesize that: 1. The administration of darbepoetin to preterm infants 500 to 1,250 grams birth weight will result in increased reticulocyte counts and decreased transfusions compared to placebo; and 2. The administration of darbepoetin will be associated with an increased mental developmental index at 18-22 months compared to placebo.

Detailed Description
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A novel erythropoiesis stimulating protein, Darbepoetin alfa (Darbepoetin) has been developed by Amgen Inc. and has been shown to be effective in increasing hematocrit using once weekly or once every other week dosing in adults with anemia due to end stage renal disease or cancer. However, it is presently being evaluated for use in children with hyporegenerative anemias, and has not yet been evaluated for use in infants with anemia of prematurity. Preterm infants respond to human recombinant erythropoietin (Epo) by increasing reticulocytes, yet the multiple subcutaneous doses diminish its routine use in the NICU. With the possibility of once a week or once every other week dosing, the use of Darbepoetin in this population appears promising. While it is likely that the use of red cell growth factors such as rHuEpo or darbepoetin will not eliminate the need for all erythrocyte transfusions in all infants, it is reasonable to postulate that the use of darbepoetin will eliminate the need for transfusion in some preterm infants, and reduce the need in others. European studies evaluating rHuEpo in preterm infants have successfully decreased donor exposure to 1 per patient. Our goal is to achieve similar success, which we define as a donor exposure of ≤1 donor per infant in clinical practice. This can be achieved through the use of red cell growth factors, judicious use of blood work for monitoring, and stringent transfusion guidelines. By decreasing total transfusions to <4 per infant, we can achieve this goal of ≤1 donor exposure per infant. There will remain a population of extremely small, extremely ill infants in whom phlebotomy losses exceed the capacity to increase red cell mass through the use of Epo. Some investigators believe a combination of single donor erythrocyte transfusions and recombinant erythropoietin can serve to maintain an adequate circulating erythrocyte volume. A reasonable algorithm can be developed to assist in these determinations only through continued research. Continued critical evaluation of transfusion criteria, outcomes, new technologies limiting phlebotomy loss, and novel biologic and pharmacologic treatments can only serve to improve the care of ELBW infants who are highest risk for repeated transfusions. Our research aim is to study the safety and efficacy of darbepoetin in preterm infants in order to improve the outcomes of preterm infants by significantly decreasing the number of transfusions. Moreover, improving neurodevelopmental outcomes for preterm infants continues to be a goal for neonatal care providers that might begin to be approached through darbepoetin therapy. This study differs from previous erythropoietin studies in the following ways: Darbepoetin will be compared to placebo and to rHuEpo, allowing two thirds of the patients to receive some form of red cell growth factor, and allowing SC dosing to occur once a week in the darbepoetin recipients compared with the usual three times a week SC dosing in the rHuEpo recipients (those in the placebo group will not receive sham injections) Dosing will begin 1-2 days earlier on average than in any previously published study Transfusion guidelines are the most rigorous applied to date, and will be used at sites that are all at altitudes > 4,000 feet A target Epo concentration of >500 mU/mL in the treatment group is proposed in order to evaluate neurodevelopmental differences between groups, and the study is powered to determine a difference between treatment groups and placebo

Official Title
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A Randomized, Masked, Placebo Controlled Study to Assess the Safety and Efficacy of Darbepoetin Alfa Administered to Preterm Infants

Conditions
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Infant, Newborn

Intervention / Treatment
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* Drug: Darbepoetin Alfa Injection
* Drug: erythropoietin alfa injection
* Drug: sham injection


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: 500-1250 grams birth weight less than or equal to 32 weeks gestation less than 2 days of age Exclusion Criteria: severe hemorrhagic disease severe hemolytic disease DIC seizures hypertension thromboses receiving erythropoietin

Ages Eligible for Study
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Minimum Age: 1 Hour
Maximum Age: 49 Hours

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
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Darbepoetin alfa injection<br>Darbepoetin alfa 10 mics/kg/week subcutaneous injection x 10 weeks or until 35 completed weeks Drug: Darbepoetin alfa Other names: Aranesp Darbe SC injection | Drug: Darbepoetin Alfa Injection<br>* darbepoetin alfa injection 10 mics/kg once a week SC for 10 weeks or until 35 completed weeks<br>* Other names: Darbe;|
| Active Comparator: erythropoietin alfa injection<br>Epo 400 units/kg three times a week SC x 10 weeks or until 35 completed weeks Drug: erythropoietin other names: epogen Epo SC injection | Drug: erythropoietin alfa injection<br>* Epo 400 units/kg 3 x weekly SC for 10 weeks or until 35 completed weeks gestation<br>* Other names: procrit, epoetin alfa;|
| Placebo Comparator: placebo/control<br>Sham injection | Drug: sham injection<br>* sham injection other names: not applicable<br>* Other names: placebo;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Transfusions During Hospitalization |  | From birth to 36 weeks gestational age | 
| Composite Cognitive Score at 18-22 Months Corrected Age | Bayley Scale of Infant Development Composite Cognitive Score. The total composite score is reported, ranging from the lowest score of 55 to the highest score of 145. Lower values specify worse outcome. | 18-22 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Hematocrit |  | From birth to 36 weeks gestational age | 
| Reticulocyte Count | absolute retic count measured at the end of study | at day 60 of study | 
| Volume of Transfusions |  | From birth to 36 weeks gestational age | 
| Epo Concentrations |  | peak from birth to 36 weeks gestational age | 
| Object Permanence Scores at 18-22 Months | Scores are 0-3, with 3 being the best score. | 18-22 months | 
| Overall Neurodevelopmental Impairment at 18-22 Months (Visual Impairment, Hearing Impariment, Cerebral Palsy, or Cognitive Score <85/<70 (NDI/Moderate NDI) |  | 18-22 months | 
| Incidence of Retinopathy of Prematurity Stage 3 or Greater |  | From birth to 36 weeks gestational age | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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erythropoietin, darbepoetin, transfusions, neonates, outcomes, neurodevelopment