Recombinant Erythropoietin for Neuroprotection in Very Preterm Infants

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Brief Title

Recombinant Erythropoietin for Neuroprotection in Very Preterm Infants

Official Title

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

Brief Summary

      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.
    

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 Phase

Phase 1/Phase 2

Study Type

Interventional


Primary Outcome

The primary short-term outcome measures are brain injury (intraventricular hemorrhage (IVH) and periventricular leukomalacia (PVL)) and ROP.

Secondary Outcome

 The secondary outcomes are sepsis, necrotizing enterocolitis (NEC), persistent ductus arteriosus (PDA), apnea of prematurity, and chronic lung disease.

Condition

Infant, Premature

Intervention

recombinant human erythropoietin (rhEpo)

Study Arms / Comparison Groups

 Drug: rhEpo, low dose
Description:  rhEpo is administered 100 U/kg, iv at 3 to 6 hours after birth, and at 24 hours interval for another 2 doses.

Publications

* Includes publications given by the data provider as well as publications identified by National Clinical Trials Identifier (NCT ID) in Medline.

Recruitment Information


Recruitment Status

Drug

Estimated Enrollment

100

Start Date

August 2009

Completion Date

July 2011

Primary Completion Date

July 2011

Eligibility 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.
      

Gender

All

Ages

N/A - 6 Hours

Accepts Healthy Volunteers

No

Contacts

Bai-Horng Su, MD, PhD, 886-4-22052121, [email protected]

Location Countries

Taiwan

Location Countries

Taiwan

Administrative Informations


NCT ID

NCT00910234

Organization ID

DMR-98



Study Sponsor

China Medical University Hospital


Study Sponsor

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


Verification Date

May 2009