Darbepoetin Administration to Preterm Infants

NCT ID: NCT00334737

Last Updated: 2019-02-04

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE2
• Total Enrollment: 102 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2006-06-30
• Study Completion Date: 2014-06-30

Brief 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

Conditions

Infant, Newborn

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: QUADRUPLE

Study Groups

Darbepoetin alfa injection

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

Group Type: EXPERIMENTAL

Darbepoetin Alfa Injection

Intervention Type: DRUG

darbepoetin alfa injection 10 mics/kg once a week SC for 10 weeks or until 35 completed weeks

erythropoietin alfa injection

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

Group Type: ACTIVE_COMPARATOR

erythropoietin alfa injection

Intervention Type: DRUG

Epo 400 units/kg 3 x weekly SC for 10 weeks or until 35 completed weeks gestation

placebo/control

Sham injection

Group Type: PLACEBO_COMPARATOR

sham injection

Intervention Type: DRUG

sham injection other names: not applicable

Interventions

Darbepoetin Alfa Injection

darbepoetin alfa injection 10 mics/kg once a week SC for 10 weeks or until 35 completed weeks

Intervention Type: DRUG

erythropoietin alfa injection

Epo 400 units/kg 3 x weekly SC for 10 weeks or until 35 completed weeks gestation

Intervention Type: DRUG

sham injection

sham injection other names: not applicable

Intervention Type: DRUG

Other Intervention Names

aranesp; Darbe; procrit, epoetin alfa; placebo

Eligibility Criteria

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

• Minimum Eligible Age: 1 Hour
• Maximum Eligible Age: 49 Hours
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Thrasher Research Fund

OTHER

Sponsor Role: collaborator

University of Colorado, Denver

OTHER

Sponsor Role: collaborator

Intermountain Health Care, Inc.

OTHER

Sponsor Role: collaborator

University of New Mexico

OTHER

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Robin K Ohls, MD

Role: PRINCIPAL_INVESTIGATOR

University of New Mexico

Robert D Christensen, MD

Role: PRINCIPAL_INVESTIGATOR

McKay-Dee Hospital, Ogden, Utah

Susan Wiedmeier, MD

Role: PRINCIPAL_INVESTIGATOR

LDS Hospital, Salt Lake City, Utah

Adam Rosenberg, MD

Role: PRINCIPAL_INVESTIGATOR

University of Colorado, Denver

Locations

University of Colorado

Denver, Colorado, United States

McKay-Dee Hospital

Ogden, Utah, United States

LDS Hospital

Salt Lake City, Utah, United States

Countries

United States

References

Warwood TL, Ohls RK, Wiedmeier SE, Lambert DK, Jones C, Scoffield SH, Neeraj G, Veng-Pedersen P, Christensen RD. Single-dose darbepoetin administration to anemic preterm neonates. J Perinatol. 2005 Nov;25(11):725-30. doi: 10.1038/sj.jp.7211387.

Reference Type: BACKGROUND

PMID: 16151471 (View on PubMed)

Ohls RK, Dai A. Long-acting erythropoietin: clinical studies and potential uses in neonates. Clin Perinatol. 2004 Mar;31(1):77-89. doi: 10.1016/j.clp.2004.03.006.

Reference Type: BACKGROUND

PMID: 15183658 (View on PubMed)

Warwood TL, Ohls RK, Lambert DK, Jones C, Scoffield SH, Gupta N, Veng-Pedersen P, Christensen RD. Intravenous administration of darbepoetin to NICU patients. J Perinatol. 2006 May;26(5):296-300. doi: 10.1038/sj.jp.7211498.

Reference Type: BACKGROUND

PMID: 16554846 (View on PubMed)

Ohls RK, Ehrenkranz RA, Das A, Dusick AM, Yolton K, Romano E, Delaney-Black V, Papile LA, Simon NP, Steichen JJ, Lee KG; National Institute of Child Health and Human Development Neonatal Research Network. Neurodevelopmental outcome and growth at 18 to 22 months' corrected age in extremely low birth weight infants treated with early erythropoietin and iron. Pediatrics. 2004 Nov;114(5):1287-91. doi: 10.1542/peds.2003-1129-L.

Reference Type: BACKGROUND

PMID: 15520109 (View on PubMed)

Lowe JR, Rieger RE, Moss NC, Yeo RA, Winter S, Patel S, Phillips J, Campbell R, Baker S, Gonzales S, Ohls RK. Impact of Erythropoiesis-Stimulating Agents on Behavioral Measures in Children Born Preterm. J Pediatr. 2017 May;184:75-80.e1. doi: 10.1016/j.jpeds.2017.01.020. Epub 2017 Feb 6.

Reference Type: DERIVED

PMID: 28185625 (View on PubMed)

Ohls RK, Cannon DC, Phillips J, Caprihan A, Patel S, Winter S, Steffen M, Yeo RA, Campbell R, Wiedmeier S, Baker S, Gonzales S, Lowe J. Preschool Assessment of Preterm Infants Treated With Darbepoetin and Erythropoietin. Pediatrics. 2016 Mar;137(3):e20153859. doi: 10.1542/peds.2015-3859. Epub 2016 Feb 15.

Reference Type: DERIVED

PMID: 26908704 (View on PubMed)

Other Identifiers

06-139

Identifier Type: -

Identifier Source: org_study_id