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Effect of Erythropoietin in Premature Infants on White Matter Lesions and Neurodevelopmental Outcome

Primary Purpose

Premature Infants, Intracranial Hemorrhages, Periventricular Leukomalacia

Status
Unknown status
Phase
Phase 3
Locations
China
Study Type
Interventional
Intervention
Erythropoietin
Normal saline
Sponsored by
First Affiliated Hospital Xi'an Jiaotong University
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Premature Infants

Eligibility Criteria

undefined - 3 Days (Child)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

  • premature infants who admitted to the neonatal intensive care unit(NICU) Within 72 hours after birth, gestational ages younger than 32 weeks, birth weight less than 1500 gram, informed consent was obtained from the infants' parents or guardians

Exclusion Criteria:

  • born with anemia, polycythemia, hemolysis and other hematological diseases
  • hypertension,
  • convulsions,
  • a genetically defined syndrome
  • a severe congenital malformation adversely affecting life expectancy or neurodevelopment
  • severe intraventricular hemorrhage
  • thrombosis disease
  • other fatal diseases or which can seriously affect the prognosis

Sites / Locations

  • First Affiliated Hospital of Xian JiaotongUniversityRecruiting

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Placebo Comparator

Arm Label

Erythropoietin

Normal saline

Arm Description

Erythropoietin is administered 750U/kg intravenously every other day for 2 weeks (a cumulative dose of 5,250U/kg over the course of 7 separate intravenous injections regardless of gestational age), starting with the first dose within 72 hours after birth. A single dose consisted of 750U EPO per kg of birth weight dissolved in 3mL/kg normal saline was administered intravenously during a period of 5 minutes.

Normal saline is administered 3ml/kg intravenously every other day for 2 weeks, starting with the first dose within 72 hours after birth. Similarly, the placebo dose consisted of 3mL of normal saline per kilogram birth weight was administered intravenously during a period of 5 minutes.

Outcomes

Primary Outcome Measures

Neurodevelopmental outcome
To evaluate neurodevelopmental function via Bayley Scales of Infant Development, second edition (BSID-II) at 18 months corrected age and gain incidence of MDI<70(Severe) or MDI<85(Moderate).

Secondary Outcome Measures

TBSS(Tract-based spatial statistics)
White matter disease of the preterm infant, was semiquantitatively assessed from MRI at term-equivalent age based on an established scoring method.

Full Information

First Posted
March 15, 2017
Last Updated
September 28, 2017
Sponsor
First Affiliated Hospital Xi'an Jiaotong University
Collaborators
Xian Children's Hospital, Shaanxi Provincial People's Hospital, Second Affiliated Hospital of Xi'an Jiaotong University, Tang-Du Hospital, Xijing Hospital, Xi'an No.4 Hospital, Northwest Women's and Children's Hospital, Xi'an, Shaanxi
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1. Study Identification

Unique Protocol Identification Number
NCT03110341
Brief Title
Effect of Erythropoietin in Premature Infants on White Matter Lesions and Neurodevelopmental Outcome
Official Title
Effect of Early Application of Recombinant Human Erythropoietin in Premature Infants on White Matter Lesions and Neurodevelopmental Outcome
Study Type
Interventional

2. Study Status

Record Verification Date
September 2017
Overall Recruitment Status
Unknown status
Study Start Date
April 10, 2017 (Actual)
Primary Completion Date
December 2018 (Anticipated)
Study Completion Date
June 2019 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
First Affiliated Hospital Xi'an Jiaotong University
Collaborators
Xian Children's Hospital, Shaanxi Provincial People's Hospital, Second Affiliated Hospital of Xi'an Jiaotong University, Tang-Du Hospital, Xijing Hospital, Xi'an No.4 Hospital, Northwest Women's and Children's Hospital, Xi'an, Shaanxi

4. Oversight

Studies a U.S. FDA-regulated Drug Product
No
Studies a U.S. FDA-regulated Device Product
No
Product Manufactured in and Exported from the U.S.
No
Data Monitoring Committee
Yes

5. Study Description

Brief Summary
Preterm and very preterm infants are at risk of developing encephalopathy of prematurity and long-term neurodevelopmental delay. Magnetic resonance imaging (MRI) allows the characterization of specific features of encephalopathy of prematurity, including structural changes of brain white matter and gray matter. This study wants to investigate important evidence that early repeated high-dose rhEPO(5250 IU/kg) treatment improves long-term neurological outcomes in very preterm infants and without obvious adverse effects.
Detailed Description
HYPOTHESIS Early administration of human erythropoietin (EPO) in preterm infants reduces perinatal injury to the brain and improves neurodevelopmental outcome at 24 months corrected age. PRIMARY OBJECTIVE To determine whether cerebral outcome is improved if infants born between 28 0/7 and 34 6/7 gestational weeks at birth receive erythropoietin in high dose in the first two weeks after birth. Biomarkers of encephalopathy of prematurity assessed on magnetic resonance imaging (MRI) at term equivalent age. RATIONALE Erythropoietin (EPO) was first recognized for its hematopoietic properties; recombinant human EPO (rhEPO) has been used to treat a number of anemic states, including early and late anemia of prematurity, and it has been found to be safe and to reduce the need for blood transfusions. EPO produced in the central nervous system7 is upregulated after insult and plays a role in neuroprotection. Experimental studies have reported that rhEPO possesses neuroprotective properties in different neonatal brain injury animal models, and clinical studies have shown that rhEPO treatment reduces brain injury and the incidence of neurological disabilities in infants.8,14-17 In addition, improved neurodevelopmental outcomes have been observed in preterm infants with anemia after rhEPO treatment. The neuroprotective effect of rhEPO was suggested to be through acting against apoptosis, inflammation, and neurotoxicity and by acting as an antioxidant in protecting white matter from injury and in promoting neural regeneration, injury repair, and normal development. STUDY DESIGN Randomized, double-masked, placebo-controlled multicenter clinical trial. Research plan 400 infants will be randomized during the first three hours of life to receive EPO (5250 U/kg body weight) or placebo intravenously, the first dose(750U/kg) will be injected within 24h after birth, subsequent injection will be given each other day for 2 weeks. Standardized evaluation including cerebral sonography at day 1, 7 and 28 will determine the presence or absence of complications. Cerebral volume and white matter volume will be assessed at 40 postmenstrual weeks with MRI (only if available). Experienced examiners will assess developmental function at 6 and 12 months corrected age using the reliable and validly revised Bayley Scales III of Infant Development and determine the presence or absence of impairment of motor function (cerebral palsy) and neurosensory function (blindness or deafness). Primary outcome was cognitive development assessed with the Mental Development Index (MDI; norm, 100 [SD, 15]; higher values indicate better function) of the Bayley Scales of Infant Development, second edition (BSID-II) at 1 years corrected age. Second outcome assess the effect of early administration of rh Epo on white matter development in preterm infants using Tract-based spatial statistics (TBSS ). White matter disease of the preterm infant, was semiquantitatively assessed from MRI at term-equivalent age based on an established scoring method.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Premature Infants, Intracranial Hemorrhages, Periventricular Leukomalacia, Cerebral Palsy

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 3
Interventional Study Model
Parallel Assignment
Masking
ParticipantOutcomes Assessor
Allocation
Randomized
Enrollment
400 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title
Erythropoietin
Arm Type
Experimental
Arm Description
Erythropoietin is administered 750U/kg intravenously every other day for 2 weeks (a cumulative dose of 5,250U/kg over the course of 7 separate intravenous injections regardless of gestational age), starting with the first dose within 72 hours after birth. A single dose consisted of 750U EPO per kg of birth weight dissolved in 3mL/kg normal saline was administered intravenously during a period of 5 minutes.
Arm Title
Normal saline
Arm Type
Placebo Comparator
Arm Description
Normal saline is administered 3ml/kg intravenously every other day for 2 weeks, starting with the first dose within 72 hours after birth. Similarly, the placebo dose consisted of 3mL of normal saline per kilogram birth weight was administered intravenously during a period of 5 minutes.
Intervention Type
Drug
Intervention Name(s)
Erythropoietin
Other Intervention Name(s)
Epoetin Beta
Intervention Description
rhEPO 750U/kg was injected within 72h after birth, subsequent injection was given every other day for 2 weeks (a cumulative dose of 5,250U/kg over the course of 7 separate intravenous injections.
Intervention Type
Drug
Intervention Name(s)
Normal saline
Other Intervention Name(s)
NaCl 0.9%
Intervention Description
placebo (Normal saline 3 ml/kg birth weight) was injected within 72h after birth, subsequent injection was given every other day for 2 weeks.
Primary Outcome Measure Information:
Title
Neurodevelopmental outcome
Description
To evaluate neurodevelopmental function via Bayley Scales of Infant Development, second edition (BSID-II) at 18 months corrected age and gain incidence of MDI<70(Severe) or MDI<85(Moderate).
Time Frame
corrected age of 18 months
Secondary Outcome Measure Information:
Title
TBSS(Tract-based spatial statistics)
Description
White matter disease of the preterm infant, was semiquantitatively assessed from MRI at term-equivalent age based on an established scoring method.
Time Frame
corrected age of 40 weeks

10. Eligibility

Sex
All
Maximum Age & Unit of Time
3 Days
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: premature infants who admitted to the neonatal intensive care unit(NICU) Within 72 hours after birth, gestational ages younger than 32 weeks, birth weight less than 1500 gram, informed consent was obtained from the infants' parents or guardians Exclusion Criteria: born with anemia, polycythemia, hemolysis and other hematological diseases hypertension, convulsions, a genetically defined syndrome a severe congenital malformation adversely affecting life expectancy or neurodevelopment severe intraventricular hemorrhage thrombosis disease other fatal diseases or which can seriously affect the prognosis
Central Contact Person:
First Name & Middle Initial & Last Name or Official Title & Degree
Xihui Zhou, Doctor
Phone
+8618991232230
Email
zhouxih@xjtu.edu.cn
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Xihui Zhou, Doctor
Organizational Affiliation
First Affiliated Hospital of Xian JiaotongUniversity
Official's Role
Principal Investigator
Facility Information:
Facility Name
First Affiliated Hospital of Xian JiaotongUniversity
City
Xi'an
State/Province
Shaanxi
ZIP/Postal Code
710061
Country
China
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Xihui Zhou, Doctor
Phone
+8618991232230
Email
zhouxih@xjtu.edu.cn

12. IPD Sharing Statement

Plan to Share IPD
Yes
Citations:
PubMed Identifier
25534356
Citation
O'Gorman RL, Bucher HU, Held U, Koller BM, Huppi PS, Hagmann CF; Swiss EPO Neuroprotection Trial Group. Tract-based spatial statistics to assess the neuroprotective effect of early erythropoietin on white matter development in preterm infants. Brain. 2015 Feb;138(Pt 2):388-97. doi: 10.1093/brain/awu363. Epub 2014 Dec 22.
Results Reference
result
PubMed Identifier
27244862
Citation
Wu YW, Mathur AM, Chang T, McKinstry RC, Mulkey SB, Mayock DE, Van Meurs KP, Rogers EE, Gonzalez FF, Comstock BA, Juul SE, Msall ME, Bonifacio SL, Glass HC, Massaro AN, Dong L, Tan KW, Heagerty PJ, Ballard RA. High-Dose Erythropoietin and Hypothermia for Hypoxic-Ischemic Encephalopathy: A Phase II Trial. Pediatrics. 2016 Jun;137(6):e20160191. doi: 10.1542/peds.2016-0191. Epub 2016 May 2.
Results Reference
result
PubMed Identifier
27187300
Citation
Natalucci G, Latal B, Koller B, Ruegger C, Sick B, Held L, Bucher HU, Fauchere JC; Swiss EPO Neuroprotection Trial Group. Effect of Early Prophylactic High-Dose Recombinant Human Erythropoietin in Very Preterm Infants on Neurodevelopmental Outcome at 2 Years: A Randomized Clinical Trial. JAMA. 2016 May 17;315(19):2079-85. doi: 10.1001/jama.2016.5504.
Results Reference
result
PubMed Identifier
25157725
Citation
Leuchter RH, Gui L, Poncet A, Hagmann C, Lodygensky GA, Martin E, Koller B, Darque A, Bucher HU, Huppi PS. Association between early administration of high-dose erythropoietin in preterm infants and brain MRI abnormality at term-equivalent age. JAMA. 2014 Aug 27;312(8):817-24. doi: 10.1001/jama.2014.9645.
Results Reference
result
PubMed Identifier
27130143
Citation
Song J, Sun H, Xu F, Kang W, Gao L, Guo J, Zhang Y, Xia L, Wang X, Zhu C. Recombinant human erythropoietin improves neurological outcomes in very preterm infants. Ann Neurol. 2016 Jul;80(1):24-34. doi: 10.1002/ana.24677. Epub 2016 May 11.
Results Reference
result

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Effect of Erythropoietin in Premature Infants on White Matter Lesions and Neurodevelopmental Outcome

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