High-Dose Erythropoietin in Extremely Premature Infants to Prevent/Attenuate Brain Injury: A Phase II Study

High-Dose Erythropoietin in Very Low Birth Weight Infants for the Potential Treatment of Prematurity-Related Cerebral Hemorrhagic-Ischemic Injury: A Phase II Safety/Tolerability Study

The highest risk for perinatal brain injury occurs among extremely premature infants who weigh less than 1250 grams at birth. Such perinatal brain injury is currently irreversible, associated with neurodevelopmental disability, and without adequate treatment modalities. Research in recent years suggest in both animal and human studies that erythropoietin (Epo) may have significant neuroprotective effects. Given the historical safe medical profile of Epo when used for anemia of prematurity but the likely need for a greater dosage regimen for activation of neuroprotective pathways against neonatal brain injury, we therefore propose this phase II study of high-dose Epo in very low birth weight infants for the prevention and/or attenuation of prematurity-related cerebral hemorrhagic-ischemic injury.

Study Overview

• Status: Terminated
• Conditions: Brain Injury; Intraventricular Hemorrhage; Randomized Clinical Trial; Infant, Premature; Periventricular Leukomalacia; Neurodevelopmental Outcomes; Erythropoietin
• Intervention / Treatment: Drug: Saline placebo; Drug: Erythropoietin

Detailed Description

Eligible extremely premature infants will be enrolled in this double-blind, placebo-controlled randomized trial from the neonatal intensive care unit at Morristown Memorial Hospital (Morristown, New Jersey). Subjects will be enrolled within the first 24 hours of life and randomly assigned to receive Epo or saline vehicle placebo.

Standard NICU care will be provided to all subjects. Serial exams, CBC-d, reticulocyte counts, serum Epo levels, serial HUS, and head MRI will be collected at established time points during the study period. At 18 to 22 months corrected age, subjects will undergo a neurodevelopmental evaluation assessing for cerebral palsy, Bayley Scores of Infant Development-II (BSID-II) Mental Development Index (MDI), BSID-II Psychomotor Development Index (PDI), bilateral hearing aid use, and visual impairment.

• Study Type: Interventional
• Enrollment (Actual): 22
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • New Jersey
    • Morristown, New Jersey, United States, 07960
      • Morristown Medical Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: No older than 1 day (CHILD)
• Accepts Healthy Volunteers: Yes
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• 500 to 1250 grams at birth
• Less than 32 weeks gestation at birth
• Less than 24 hours of life at time of enrollment

Exclusion Criteria:

• Congenital anomalies (chromosomal, CNS, cardiac, GI, pulmonary)
• Seizures within first 24 hours of life
• Severe neutropenia (ANC < 500 cells/microL) within first 24 hours of life
• Polycythemia (Hct > 65%) within first 24 hours of life
• Thrombocytopenia (platelets < 50K cells/microL) within first 24 hours of life
• Hypertension (SBP > 100mmHg) without vasopressor support within first 24 hours of life

Study Plan

How is the study designed?

Design Details

• Primary Purpose: PREVENTION
• Allocation: RANDOMIZED
• Interventional Model: PARALLEL
• Masking: QUADRUPLE

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
PLACEBO_COMPARATOR: EPO###; All subjects will be identified as a such by the study identifier "EPO###" where EPO designates enrollment in this study and ### is a numeric identifier (e.g. 103).	Drug: Saline placebo; Saline vehicle at a volume of 1 mL given over 1 hour intravenously once a day for the first seven days of life.; Other Names: Confidential Randomization Number
EXPERIMENTAL: EPO ###; All subjects will be identified as a such by the study identifier "EPO###" where EPO designates enrollment in this study and ### is a numeric identifier (e.g. 103).	Drug: Erythropoietin; 5 of first 10 subjects (Group 1): 400 units/kg/dose once daily for 7 days 5 of next 10 subjects (Group 2): 800 units/kg/dose once daily for 7 days 20 of next 30 subjects (Group 3): 1000 units/kg/dose once daily for 7 days administered i.v. over 1 hour. The volume of the study drug will be 1 mL in a 1 mL Tuberculin syringe to be administered over 1 hour.; Other Names: Confidential Randomization Number

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Neurodevelopmental evaluations at 18 to 22 months corrected age (cerebral palsy, Bayley Scores of Infant Development Mental Development Index (MDI), Psychomotor Development Index (PDI), bilateral hearing aid use, and visual impairment)	18-22 months corrected age

Secondary Outcome Measures

Outcome Measure	Time Frame
Severe intraventricular hemorrhage	First ten days of life
Polycythemia, neutropenia, thrombocytopenia, hypertension, sepsis, hemorrhage, seizure	NICU hospitalization

Collaborators and Investigators

• Sponsor: Atlantic Health System

Publications and helpful links

General Publications

• Lin FK, Suggs S, Lin CH, Browne JK, Smalling R, Egrie JC, Chen KK, Fox GM, Martin F, Stabinsky Z, et al. Cloning and expression of the human erythropoietin gene. Proc Natl Acad Sci U S A. 1985 Nov;82(22):7580-4. doi: 10.1073/pnas.82.22.7580.
• Ascensao JL, Bilgrami S, Zanjani ED. Erythropoietin. Biology and clinical applications. Am J Pediatr Hematol Oncol. 1991 Winter;13(4):376-87. doi: 10.1097/00043426-199124000-00002.
• Buemi M, Aloisi C, Cavallaro E, Corica F, Floccari F, Grasso G, Lasco A, Pettinato G, Ruello A, Sturiale A, Frisina N. Recombinant human erythropoietin (rHuEPO): more than just the correction of uremic anemia. J Nephrol. 2002 Mar-Apr;15(2):97-103.
• Fisher JW. Erythropoietin: physiology and pharmacology update. Exp Biol Med (Maywood). 2003 Jan;228(1):1-14. doi: 10.1177/153537020322800101.
• Maier RF, Obladen M, Muller-Hansen I, Kattner E, Merz U, Arlettaz R, Groneck P, Hammer H, Kossel H, Verellen G, Stock GJ, Lacaze-Masmonteil T, Claris O, Wagner M, Matis J, Gilberg F; European Multicenter Erythropoietin Beta Study Group. Early treatment with erythropoietin beta ameliorates anemia and reduces transfusion requirements in infants with birth weights below 1000 g. J Pediatr. 2002 Jul;141(1):8-15. doi: 10.1067/mpd.2002.124309.
• Ohls RK, Harcum J, Schibler KR, Christensen RD. The effect of erythropoietin on the transfusion requirements of preterm infants weighing 750 grams or less: a randomized, double-blind, placebo-controlled study. J Pediatr. 1997 Nov;131(5):661-5. doi: 10.1016/s0022-3476(97)70089-1.
• Shannon KM, Keith JF 3rd, Mentzer WC, Ehrenkranz RA, Brown MS, Widness JA, Gleason CA, Bifano EM, Millard DD, Davis CB, et al. Recombinant human erythropoietin stimulates erythropoiesis and reduces erythrocyte transfusions in very low birth weight preterm infants. Pediatrics. 1995 Jan;95(1):1-8.
• Meyer MP, Meyer JH, Commerford A, Hann FM, Sive AA, Moller G, Jacobs P, Malan AF. Recombinant human erythropoietin in the treatment of the anemia of prematurity: results of a double-blind, placebo-controlled study. Pediatrics. 1994 Jun;93(6 Pt 1):918-23.
• Ohls RK, Ehrenkranz RA, Wright LL, Lemons JA, Korones SB, Stoll BJ, Stark AR, Shankaran S, Donovan EF, Close NC, Das A. Effects of early erythropoietin therapy on the transfusion requirements of preterm infants below 1250 grams birth weight: a multicenter, randomized, controlled trial. Pediatrics. 2001 Oct;108(4):934-42. doi: 10.1542/peds.108.4.934.
• Brown MS, Keith JF 3rd. Comparison between two and five doses a week of recombinant human erythropoietin for anemia of prematurity: a randomized trial. Pediatrics. 1999 Aug;104(2 Pt 1):210-5. doi: 10.1542/peds.104.2.210.
• Newton NR, Leonard CH, Piecuch RE, Phibbs RH. Neurodevelopmental outcome of prematurely born children treated with recombinant human erythropoietin in infancy. J Perinatol. 1999 Sep;19(6 Pt 1):403-6. doi: 10.1038/sj.jp.7200244.
• Maier RF, Obladen M, Kattner E, Natzschka J, Messer J, Regazzoni BM, Speer CP, Fellman V, Grauel EL, Groneck P, Wagner M, Moriette G, Salle BL, Verellen G, Scigalla P. High-versus low-dose erythropoietin in extremely low birth weight infants. The European Multicenter rhEPO Study Group. J Pediatr. 1998 May;132(5):866-70. doi: 10.1016/s0022-3476(98)70320-8.
• Shalak L, Perlman JM. Hemorrhagic-ischemic cerebral injury in the preterm infant: current concepts. Clin Perinatol. 2002 Dec;29(4):745-63. doi: 10.1016/s0095-5108(02)00048-9.
• Guzzetta F, Shackelford GD, Volpe S, Perlman JM, Volpe JJ. Periventricular intraparenchymal echodensities in the premature newborn: critical determinant of neurologic outcome. Pediatrics. 1986 Dec;78(6):995-1006.
• Bada HS, Green RS, Pourcyrous M, Leffler CW, Korones SB, Magill HL, Arheart K, Fitch CW, Anderson GD, Somes G, et al. Indomethacin reduces the risks of severe intraventricular hemorrhage. J Pediatr. 1989 Oct;115(4):631-7. doi: 10.1016/s0022-3476(89)80300-2.
• Schmidt B, Davis P, Moddemann D, Ohlsson A, Roberts RS, Saigal S, Solimano A, Vincer M, Wright LL; Trial of Indomethacin Prophylaxis in Preterms Investigators. Long-term effects of indomethacin prophylaxis in extremely-low-birth-weight infants. N Engl J Med. 2001 Jun 28;344(26):1966-72. doi: 10.1056/NEJM200106283442602.
• Juul S. Recombinant erythropoietin as a neuroprotective treatment: in vitro and in vivo models. Clin Perinatol. 2004 Mar;31(1):129-42. doi: 10.1016/j.clp.2004.03.004.
• Wen TC, Rogido M, Genetta T, Sola A. Permanent focal cerebral ischemia activates erythropoietin receptor in the neonatal rat brain. Neurosci Lett. 2004 Jan 30;355(3):165-8. doi: 10.1016/j.neulet.2003.10.078.
• Sola A, Rogido M, Lee BH, Genetta T, Wen TC. Erythropoietin after focal cerebral ischemia activates the Janus kinase-signal transducer and activator of transcription signaling pathway and improves brain injury in postnatal day 7 rats. Pediatr Res. 2005 Apr;57(4):481-7. doi: 10.1203/01.PDR.0000155760.88664.06. Epub 2005 Feb 17.
• Sola A, Wen TC, Hamrick SE, Ferriero DM. Potential for protection and repair following injury to the developing brain: a role for erythropoietin? Pediatr Res. 2005 May;57(5 Pt 2):110R-117R. doi: 10.1203/01.PDR.0000159571.50758.39. Epub 2005 Apr 6.
• Ehrenreich H, Hasselblatt M, Dembowski C, Cepek L, Lewczuk P, Stiefel M, Rustenbeck HH, Breiter N, Jacob S, Knerlich F, Bohn M, Poser W, Ruther E, Kochen M, Gefeller O, Gleiter C, Wessel TC, De Ryck M, Itri L, Prange H, Cerami A, Brines M, Siren AL. Erythropoietin therapy for acute stroke is both safe and beneficial. Mol Med. 2002 Aug;8(8):495-505.
• Juul SE, Harcum J, Li Y, Christensen RD. Erythropoietin is present in the cerebrospinal fluid of neonates. J Pediatr. 1997 Mar;130(3):428-30. doi: 10.1016/s0022-3476(97)70205-1.
• Brines ML, Ghezzi P, Keenan S, Agnello D, de Lanerolle NC, Cerami C, Itri LM, Cerami A. Erythropoietin crosses the blood-brain barrier to protect against experimental brain injury. Proc Natl Acad Sci U S A. 2000 Sep 12;97(19):10526-31. doi: 10.1073/pnas.97.19.10526.
• Widness JA, Veng-Pedersen P, Peters C, Pereira LM, Schmidt RL, Lowe LS. Erythropoietin pharmacokinetics in premature infants: developmental, nonlinearity, and treatment effects. J Appl Physiol (1985). 1996 Jan;80(1):140-8. doi: 10.1152/jappl.1996.80.1.140.
• Volpe JJ. Neurology of the newborn. 4th ed. Philadelphia: WB Saunders; 2001.

Study record dates

Study Major Dates

• Study Start: July 1, 2007
• Primary Completion (ACTUAL): September 1, 2010
• Study Completion (ACTUAL): September 1, 2010

Study Registration Dates

• First Submitted: December 27, 2007
• First Submitted That Met QC Criteria: December 27, 2007
• First Posted (ESTIMATE): January 10, 2008

Study Record Updates

• Last Update Posted (ESTIMATE): July 30, 2013
• Last Update Submitted That Met QC Criteria: July 29, 2013
• Last Verified: July 1, 2013

More Information

Terms related to this study

• Keywords: Erythropoietin; Randomized Clinical Trial; Intraventricular Hemorrhage; Periventricular Leukomalacia; Extreme Prematurity; Perinatal Brain Injury; Neurodevelopmental Outcomes
• Additional Relevant MeSH Terms: Pathologic Processes; Cardiovascular Diseases; Vascular Diseases; Cerebrovascular Disorders; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Infant, Newborn, Diseases; Craniocerebral Trauma; Trauma, Nervous System; Pregnancy Complications; Obstetric Labor Complications; Obstetric Labor, Premature; Infant, Premature, Diseases; Encephalomalacia; Brain Injuries; Wounds and Injuries; Hemorrhage; Premature Birth; Leukomalacia, Periventricular; Hematinics; Epoetin Alfa
• Other Study ID Numbers: R06-04-004; IND12537