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

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ClinicalTrials.gov Identifier: NCT03110341
Recruitment Status : Recruiting
First Posted : April 12, 2017
Last Update Posted : October 2, 2017
Sponsor:
Collaborators:
Xian Children's Hospital
Shaanxi Provincial People's Hospital
Second Affiliated Hospital of Xi'an Medical University
Tang-Du Hospital
Xijing Hospital
Xi'an No.4 Hospital
Northwest Women and Children's Hospital
Information provided by (Responsible Party):
First Affiliated Hospital Xi'an Jiaotong University

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.

Condition or disease Intervention/treatment Phase
Premature Infants Intracranial Hemorrhages Periventricular Leukomalacia Cerebral Palsy Drug: Erythropoietin Drug: Normal saline Phase 3

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.


Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 400 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double (Participant, Outcomes Assessor)
Primary Purpose: Treatment
Official Title: Effect of Early Application of Recombinant Human Erythropoietin in Premature Infants on White Matter Lesions and Neurodevelopmental Outcome
Actual Study Start Date : April 10, 2017
Estimated Primary Completion Date : December 2018
Estimated Study Completion Date : June 2019

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Experimental: Erythropoietin
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.
Drug: Normal saline
placebo (Normal saline 3 ml/kg birth weight) was injected within 72h after birth, subsequent injection was given every other day for 2 weeks.
Other Name: NaCl 0.9%

Placebo Comparator: Normal saline
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.
Drug: Erythropoietin
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.
Other Name: Epoetin Beta




Primary Outcome Measures :
  1. Neurodevelopmental outcome [ Time Frame: corrected age of 18 months ]
    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 :
  1. TBSS(Tract-based spatial statistics) [ Time Frame: corrected age of 40 weeks ]
    White matter disease of the preterm infant, was semiquantitatively assessed from MRI at term-equivalent age based on an established scoring method.



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Ages Eligible for Study:   up to 3 Days   (Child)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03110341


Contacts
Contact: Xihui Zhou, Doctor +8618991232230 zhouxih@xjtu.edu.cn

Locations
China, Shaanxi
First Affiliated Hospital of Xian JiaotongUniversity Recruiting
Xi'an, Shaanxi, China, 710061
Contact: Xihui Zhou, Doctor    +8618991232230    zhouxih@xjtu.edu.cn   
Sponsors and Collaborators
First Affiliated Hospital Xi'an Jiaotong University
Xian Children's Hospital
Shaanxi Provincial People's Hospital
Second Affiliated Hospital of Xi'an Medical University
Tang-Du Hospital
Xijing Hospital
Xi'an No.4 Hospital
Northwest Women and Children's Hospital
Investigators
Principal Investigator: Xihui Zhou, Doctor First Affiliated Hospital of Xian JiaotongUniversity

Publications of Results:

Responsible Party: First Affiliated Hospital Xi'an Jiaotong University
ClinicalTrials.gov Identifier: NCT03110341     History of Changes
Other Study ID Numbers: XJTU1AF-CRF-2016-023
First Posted: April 12, 2017    Key Record Dates
Last Update Posted: October 2, 2017
Last Verified: September 2017
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Yes

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

Additional relevant MeSH terms:
Encephalomalacia
Hemorrhage
Premature Birth
Cerebral Palsy
Intracranial Hemorrhages
Leukomalacia, Periventricular
Pathologic Processes
Obstetric Labor, Premature
Obstetric Labor Complications
Pregnancy Complications
Brain Damage, Chronic
Brain Diseases
Central Nervous System Diseases
Nervous System Diseases
Cerebrovascular Disorders
Vascular Diseases
Cardiovascular Diseases
Infant, Premature, Diseases
Infant, Newborn, Diseases
Epoetin Alfa
Hematinics