Recombinant Erythropoietin for Neuroprotection in Very Preterm Infants

May 28, 2009 updated by: China Medical University Hospital

Early Treatment With Recombinant Erythropoietin for Neuroprotection in Very Preterm Infants: Comparison of High and Low Dose

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.

Study Overview

Status

Unknown

Conditions

Intervention / Treatment

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.

Study Type

Interventional

Enrollment (Anticipated)

100

Phase

  • Phase 2
  • Phase 1

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • Taiwan
      • Taichung, Taiwan, 400
        • China Medical University Hospital

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

1 year to 1 year (Child)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

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.

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Prevention
  • Allocation: Randomized
  • Interventional Model: Parallel Assignment
  • Masking: Quadruple

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
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 3000 U/kg, iv at 3 to 6 hours after birth, and at 24 hours interval for another 2 doses.
Other Names:
  • Epoietin Beta
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 Names:
  • 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 Names:
  • Epoietin Beta
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 Names:
  • 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 Names:
  • N/S solution

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Time Frame
The primary short-term outcome measures are brain injury (intraventricular hemorrhage (IVH) and periventricular leukomalacia (PVL)) and ROP.
Time Frame: 2 months
2 months

Secondary Outcome Measures

Outcome Measure
Time Frame
The secondary outcomes are sepsis, necrotizing enterocolitis (NEC), persistent ductus arteriosus (PDA), apnea of prematurity, and chronic lung disease.
Time Frame: 2 months
2 months

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

China Medical University Hospital

Investigators

  • Study Chair: Bai-Horng Su, MD, PhD, China Medical University Hospital,Taiwan

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start

August 1, 2009

Primary Completion (Anticipated)

July 1, 2011

Study Completion (Anticipated)

July 1, 2011

Study Registration Dates

First Submitted

May 28, 2009

First Submitted That Met QC Criteria

May 28, 2009

First Posted (Estimate)

May 29, 2009

Study Record Updates

Last Update Posted (Estimate)

May 29, 2009

Last Update Submitted That Met QC Criteria

May 28, 2009

Last Verified

May 1, 2009

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • DMR-98 (Other Grant/Funding Number: China Medical University Hospital)

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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