Darbepoetin Administration to Preterm Infants
Condition: Infant, Newborn
Study type: Interventional
Phase: Phase 2

Summary: 
      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: 
      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:

        1. 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)

        2. Dosing will begin 1-2 days earlier on average than in any previously published study

        3. Transfusion guidelines are the most rigorous applied to date, and will be used at sites
           that are all at altitudes > 4,000 feet

        4. 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
    

Intervention name(s): Darbepoetin Alfa Injection; erythropoietin alfa injection; sham injection
Intervention type(s): Drug; Drug; Drug
Intervention description(s): darbepoetin alfa injection 10 mics/kg once a week SC for 10 weeks or until 35 completed weeks; Epo 400 units/kg 3 x weekly SC for 10 weeks or until 35 completed weeks gestation; sham injection other names: not applicable
Other intervention name(s): aranesp; Darbe; procrit, epoetin alfa; placebo
Intervention MeSH terms: Epoetin Alfa; Darbepoetin alfa
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary purpose: Treatment
Keywords: erythropoietin; darbepoetin; transfusions; neonates; outcomes; neurodevelopment