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Recombinant Erythropoietin for Neuroprotection in Very Preterm Infants

The recruitment status of this study is unknown because the information has not been verified recently.
Verified May 2009 by China Medical University Hospital.
Recruitment status was  Not yet recruiting
Sponsor:
Information provided by:
China Medical University Hospital
ClinicalTrials.gov Identifier:
NCT00910234
First received: May 28, 2009
Last updated: NA
Last verified: May 2009
History: No changes posted
  Purpose

Periventricular leukomalacia (PVL) is one of the most common brain injuries that occur in preterm infants. Inflammation, hypoxia-ischemia, free oxygen radical formation and excitotoxicity are all known pathogenic mechanisms that mediate this injury. Erythropoietin (EPO) has been shown to be protective against hypoxic-ischemic and inflammatory injuries. During the past decade, recombinant human Epo (rhEpo) has been widely used in preterm infants to prevent or treat the anemia of prematurity, in general, rhEpo has been considered to be safe and well tolerated in preterm infants. EPO was considered not capable of passing through blood-brain-barrier at low dose. Evidence from animal experiments reveals that rhEpo must be given in high doses at the beginning or within a short (up to 6 hours), critical time period after the onset of brain injury to achieve a significant neuroprotective effect. A recent study using high-dose rhEpo (3000 U rhEpo/kg body weight at birth) for neuroprotection in very preterm infants revealed that no signs of adverse effects of early high-dose rhEpo treatment in very preterm infants were identified. Contrary to this, a recent study in PVL of a rat model revealed that using a low dose rhEpo (50-100 U/kg) was effective in the treatment of brain damage induced by hypoxia-ischemia and did not affect normal oligodendrocyte maturity. On this basis, the researchers intent to investigate (1) whether low-dose rhEpo (100 U/kg) or high-dose rhEpo (3,000 U/kg) given to very preterm infants (gestation age < 32 weeks) immediately after birth and subsequently during the first 2 days is safe and possesses neuroprotective properties;(2) whether there are gender differences in response to the hypoxia-ischemic insult and EPO treatment; (3)the pharmacokinetics of low dose and high dose rhEPO. Very preterm infants with gestational age of < 32 weeks and admitted to the NICU are eligible for enrollment.


Condition Intervention Phase
Infant, Premature
Leukomalacia, Periventricular
Intraventricular Hemorrhage
Retinopathy of Prematurity
Drug: recombinant human erythropoietin (rhEpo)
Drug: Normal saline
Phase 1
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: Prevention
Official Title: Early Treatment With Recombinant Erythropoietin for Neuroprotection in Very Preterm Infants: Comparison of High and Low Dose

Resource links provided by NLM:


Further study details as provided by China Medical University Hospital:

Primary Outcome Measures:
  • The primary short-term outcome measures are brain injury (intraventricular hemorrhage (IVH) and periventricular leukomalacia (PVL)) and ROP. [ Time Frame: 2 months ] [ Designated as safety issue: Yes ]

Secondary Outcome Measures:
  • The secondary outcomes are sepsis, necrotizing enterocolitis (NEC), persistent ductus arteriosus (PDA), apnea of prematurity, and chronic lung disease. [ Time Frame: 2 months ] [ Designated as safety issue: Yes ]

Estimated Enrollment: 100
Study Start Date: August 2009
Estimated Study Completion Date: July 2011
Estimated Primary Completion Date: July 2011 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Active Comparator: Drug: rhEpo, low dose
rhEpo is administered 100 U/kg, iv at 3 to 6 hours after birth, and at 24 hours interval for another 2 doses.
Drug: recombinant human erythropoietin (rhEpo)
rhEpo is administered 100 U/kg, iv at 3 to 6 hours after birth, and at 24 hours interval for another 2 doses.
Other Name: Epoietin Beta
Active Comparator: Drug: rhEpo, high dose
rhEpo is administered 3000 U/kg, iv at 3 to 6 hours after birth, and at 24 hours interval for another 2 doses.
Drug: recombinant human erythropoietin (rhEpo)
rhEpo is administered 3000 U/kg, iv at 3 to 6 hours after birth, and at 24 hours interval for another 2 doses.
Other Name: Epoietin Beta
Placebo Comparator: Control Normal saline
normal saline is administered 0.5/kg, iv at 3 to 6 hours after birth, and at 24 hours interval for another 2 doses.
Drug: Normal saline
normal saline is administered 0.5/kg, iv at 3 to 6 hours after birth, and at 24 hours interval for another 2 doses.
Other Name: N/S solution

Detailed Description:

Periventricular leukomalacia (PVL) is one of the most common brain injuries that occur in preterm infants. Inflammation, hypoxia-ischemia, free oxygen radical formation and excitotoxicity are all known pathogenic mechanisms that mediate this injury. Although several treatment strategies have been devised, few therapies effectively mitigate the harmful effects of hypoxia-ischemia in preterm newborns and the ensuing neurodevelopment sequelae. Erythropoietin (EPO) has been shown to be protective against hypoxic-ischemic and inflammatory injuries in neuronal cell culture, animal models of brain injury, and clinical trials of adult humans. During the past decade, recombinant human Epo (rhEpo) has been widely used in preterm infants to prevent or treat the anemia of prematurity, in general, rhEpo has been considered to be safe and well tolerated in preterm infants. EPO was considered not capable of passing through blood-brain-barrier at low dose. Evidence from animal experiments reveals that rhEpo must be given in high doses at the beginning or within a short (up to 6 hours), critical time period after the onset of brain injury to achieve a significant neuroprotective effect. A recent study using high-dose rhEpo (3000 U rhEpo/kg body weight at birth) for neuroprotection in very preterm infants revealed that no signs of adverse effects of early high-dose rhEpo treatment in very preterm infants were identified. Contrary to this, a recent study in PVL of a rat model revealed that using a low dose rhEpo (50-100 U/kg) was effective in the treatment of brain damage induced by hypoxia-ischemia and did not affect normal oligodendrocyte maturity. Clinical studies suggest that gender influences the response to brain injury. Ment and coworkers have reported that the cyclooxygenase inhibitor indomethacin ameliorated intraventricular hemorrhage and improved cognition in very low birth weight boys, but not girls. On this basis, the researchers intent to investigate (i) whether low-dose rhEpo (100 U/kg) or high-dose rhEpo (3,000 U/kg) given to very preterm infants (gestation age < 32 weeks) immediately after birth and subsequently during the first 2 days is safe and possesses neuroprotective properties; (ii) whether there are gender differences in response to the hypoxia-ischemic insult and EPO treatment; (iii)the pharmacokinetics of low dose and high dose rhEPO. Very preterm infants with gestational age of < 32 weeks and admit to our NICU are eligible for enrollment. After informed consent is obtained, infants will be randomly assigned to three groups based on a double-blind design. The study medication (rhEpo or NaCl 0.9%) is dispensed to each patient number that is blinded to the clinical investigators. Epoietin Beta or an equivalent volume of normal saline placebo is given intravenously during a period of 10 minutes at 3 to 6 hours after birth, and at 24 hours interval for another 2 doses.The primary short-term outcome measures are brain injury (intraventricular hemorrhage (IVH) and periventricular leukomalacia (PVL)) and ROP. The secondary outcomes are sepsis, necrotizing enterocolitis (NEC), persistent ductus arteriosus (PDA), apnea of prematurity, and chronic lung disease. The long term outcomes are whether early low-dose or high-dose treatment of rhEpo in very preterm infants finally improves neurodevelopmental outcome at 24 months' and 5 years' corrected age.

  Eligibility

Ages Eligible for Study:   up to 6 Hours
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • After informed consent is obtained, very preterm infants with gestational age of < 32 weeks and admit to our NICU are eligible for enrollment.

Exclusion Criteria:

  • Genetically defined syndromes,
  • Congenital malformations that adversely affect neurodevelopment.
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT00910234

Contacts
Contact: Bai-Horng Su, MD, PhD 886-4-22052121 ext 2061 bais@ms49.hinet.net

Locations
Taiwan
China Medical University Hospital Not yet recruiting
Taichung, Taiwan, 400
Contact: Hsiang-Yu Lin, MD    886-4-22052121 ext 2531    hsyulin@gmail.com   
Principal Investigator: Bai-Horng Su, MD, PhD         
Sub-Investigator: Hsiang-Yu Lin, MD         
Sponsors and Collaborators
China Medical University Hospital
Investigators
Study Chair: Bai-Horng Su, MD, PhD China Medical University Hospital, Taiwan
  More Information

No publications provided

Responsible Party: Bai-Horng Su, MD, PhD., Chairman of Department of Pediatrics, China Medical University
ClinicalTrials.gov Identifier: NCT00910234     History of Changes
Other Study ID Numbers: DMR-98
Study First Received: May 28, 2009
Last Updated: May 28, 2009
Health Authority: Taiwan: Department of Health

Keywords provided by China Medical University Hospital:
Periventricular leukomalacia (PVL)
Erythropoietin (EPO)
Retinopathy of prematurity (ROP)
Hypoxia-ischemia

Additional relevant MeSH terms:
Cerebral Hemorrhage
Hemorrhage
Leukomalacia, Periventricular
Retinal Diseases
Retinopathy of Prematurity
Brain Diseases
Cardiovascular Diseases
Central Nervous System Diseases
Cerebrovascular Disorders
Encephalomalacia
Eye Diseases
Infant, Newborn, Diseases
Infant, Premature, Diseases
Intracranial Hemorrhages
Nervous System Diseases
Pathologic Processes
Vascular Diseases
Epoetin alfa
Hematinics
Hematologic Agents
Pharmacologic Actions
Therapeutic Uses

ClinicalTrials.gov processed this record on November 25, 2014