Darbepoetin Administration to Preterm Infants
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Purpose
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.
| Condition | Intervention | Phase |
|---|---|---|
|
Infant, Newborn |
Drug: darbepoetin alfa Drug: erythropoietin Drug: sham injection |
Phase 2 |
| Study Type: | Interventional |
| Study Design: | Allocation: Randomized Endpoint Classification: Safety/Efficacy Study Intervention Model: Parallel Assignment Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor) Primary Purpose: Treatment |
| Official Title: | A Randomized, Masked, Placebo Controlled Study to Assess the Safety and Efficacy of Darbepoetin Alfa Administered to Preterm Infants |
- Number of transfusions during hospitalization [ Time Frame: at discharge ] [ Designated as safety issue: No ]
- MDI at 18-22 months corrected age [ Time Frame: 18-22 months ] [ Designated as safety issue: No ]
- hematocrit [ Time Frame: at discharge ] [ Designated as safety issue: No ]
- reticulocyte count [ Time Frame: at discharge ] [ Designated as safety issue: No ]
- volume of transfusions [ Time Frame: at discharge ] [ Designated as safety issue: No ]
- Epo concentrations [ Time Frame: at discharge ] [ Designated as safety issue: No ]
- PDI at 18-22 months [ Time Frame: 18-22 months ] [ Designated as safety issue: No ]
- overall neurodevelopmental impairment at 18-22 months [ Time Frame: 18-22 months ] [ Designated as safety issue: No ]
- incidence of retinopathy of prematurity stage 3 or greater [ Time Frame: during hospitalization ] [ Designated as safety issue: Yes ]
| Estimated Enrollment: | 102 |
| Study Start Date: | June 2006 |
| Estimated Study Completion Date: | December 2012 |
| Estimated Primary Completion Date: | December 2012 (Final data collection date for primary outcome measure) |
| Arms | Assigned Interventions |
|---|---|
|
Experimental: Darbe
Darbepoetin 10 mics/kg/week x 10 weeks or until 35 completed weeks
|
Drug: darbepoetin alfa
darbepoetin 10 mics/kg once a week SC for 10 weeks or until 35 completed weeks
Other Name: aranesp
|
|
Active Comparator: Epo
Epo 400 units/kg three times a week SC x 10 weeks or until 35 completed weeks
|
Drug: erythropoietin
Epo 400 units/kg 3 x weekly SC for 10 weeks or until 35 completed weeks gestation
Other Name: procrit, epoetin alfa
|
|
Placebo Comparator: placebo/control
Sham injection
|
Drug: sham injection
sham injection
|
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:
- 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
Eligibility| Ages Eligible for Study: | up to 49 Hours |
| Genders Eligible for Study: | Both |
| Accepts Healthy Volunteers: | No |
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
Contacts and Locations| United States, Colorado | |
| University of Colorado | |
| Denver, Colorado, United States, 80218 | |
| United States, Utah | |
| McKay-Dee Hospital | |
| Ogden, Utah, United States, 84403 | |
| LDS Hospital | |
| Salt Lake City, Utah, United States, 84103 | |
| Principal Investigator: | Robin K Ohls, MD | University of New Mexico |
| Principal Investigator: | Robert D Christensen, MD | McKay-Dee Hospital, Ogden, Utah |
| Principal Investigator: | Susan Wiedmeier, MD | LDS Hospital, Salt Lake City, Utah |
| Principal Investigator: | Adam Rosenberg, MD | University of Colorado, Denver |
More Information
Additional Information:
Publications:
| Responsible Party: | Robin Ohls, Professor of Pediatrics, University of New Mexico |
| ClinicalTrials.gov Identifier: | NCT00334737 History of Changes |
| Other Study ID Numbers: | 06-139 |
| Study First Received: | June 7, 2006 |
| Last Updated: | June 12, 2012 |
| Health Authority: | United States: Food and Drug Administration |
Keywords provided by University of New Mexico:
|
erythropoietin darbepoetin transfusions |
neonates outcomes neurodevelopment |
Additional relevant MeSH terms:
|
Darbepoetin alfa Epoetin Alfa Hematinics |
Hematologic Agents Therapeutic Uses Pharmacologic Actions |
ClinicalTrials.gov processed this record on October 16, 2012
