Recombinant Erythropoietin for Neuroprotection in Very Preterm Infants

Retinopathy of Prematurity Clinical Trial

Official title:

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

Clinical Trial Details — Status: Not yet recruiting

Administrative data

• NCT number: NCT00910234
• Other study ID #: DMR-98
• Status: Not yet recruiting
• Phase: Phase 1/Phase 2
• First received: May 28, 2009
• Last updated: May 28, 2009
• Start date: August 2009
• Est. completion date: July 2011

Study information

• Verified date: May 2009
• Source: China Medical University Hospital
• Contact: Bai-Horng Su, MD, PhD
• Phone: 886-4-22052121
• Email: bais[@]ms49.hinet.net
• Is FDA regulated: No
• Health authority: Taiwan: Department of Health
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Not yet recruiting
• Enrollment: 100
• Est. completion date: July 2011
• Est. primary completion date: July 2011
• Accepts healthy volunteers: No
• Gender: Both
• Age group: N/A to 6 Hours

Eligibility

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 Design

Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor), Primary Purpose: Prevention

Related Conditions & MeSH terms

• Cerebral Hemorrhage
• Infant, Premature
• Intraventricular Hemorrhage
• Leukomalacia, Periventricular
• Premature Birth
• Retinal Diseases
• Retinopathy of Prematurity

Intervention

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.
• 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.
• 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.

Locations

Country	Name	City	State
Taiwan	China Medical University Hospital	Taichung

Sponsors (1)

Lead Sponsor	Collaborator
China Medical University Hospital

Country where clinical trial is conducted

Taiwan, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	The primary short-term outcome measures are brain injury (intraventricular hemorrhage (IVH) and periventricular leukomalacia (PVL)) and ROP.		2 months	Yes
Secondary	The secondary outcomes are sepsis, necrotizing enterocolitis (NEC), persistent ductus arteriosus (PDA), apnea of prematurity, and chronic lung disease.		2 months	Yes