Effect of Erythropoietin on Neurodevelopmental Outcomes in Very Preterm Infants With Intraventricular Hemorrhage

Erythropoietin (EPO) has been shown to be neurotrophic and neuroprotective in several animal models and some clinical studies. Our hypothesis is that EPO could improve long-term neurological outcomes in very preterm infants with intraventricular hemorrhage (IVH). The aim of this study is to evaluate the long-term neuroprotective effect of repeated low-dose EPO (500 U/kg) in very preterm infants with IVH.

Study Overview

• Status: Completed
• Conditions: Premature Infants
• Intervention / Treatment: Drug: Erythropoietin; Drug: Normal saline

Detailed Description

IVH is one of the most common complications in preterm infants. Nearly 60% of preterm infants with grade III-IV IVH develop severe neurodevelopmental outcomes. There are currently no effective treatments to prevent preterm infants with IVH from developing ventricular dilation or serious neurological disabilities. Recent studies have shown that EPO could improve neurodevelopmental outcomes in preterm infants with grade III-IV IVH. However, the dose and course of EPO in preterm infants is still uncertain. The purpose of the study was whether repeated low-dose EPO (500 U/kg, every other day, for 2 weeks) given to very preterm right after the diagnosis of IVH could improve long-term neurological outcomes. Very preterm infants with gestational age of ≤ 32 weeks who are diagnosed with IVH within 72 hours after birth in NICU are eligible for enrolment. After informed consent is obtained, infants will be randomly assigned to EPO group or vehicle group. The primary outcome is whether EPO improves mortality and neurological disabilities in very preterm infants with IVH at 18 months of corrected age, and the secondary outcome was whether EPO decrease the incidence of cerebral palsy, MDI<70, blindness, and deafness.

• Study Type: Interventional
• Enrollment (Actual): 316
• Phase: Phase 2

Contacts and Locations

Study Locations

• China
  • Henan
    • Zhengzhou, Henan, China, 450052
      • Third Affiliated Hospital of Zhengzhou University

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: No older than 3 days (Child)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Preterm infants admitted to NICU ≤ 32 weeks gestation at birth
• Birth weight less than 1500 g
• Less than 72 hours of life at time of enrolment
• Diagnosed as IVH by head ultrasound
• Written informed consent of parent or guardian

Exclusion Criteria:

• Genetic metabolic diseases
• Congenital abnormalities
• Polycythaemia (Hct > 65%) within first 24 hours of life
• Thrombocytopenia (platelets < 50K cells/microL) within first 24 hours of life
• Unstable vital signs (such as respiration and circulation failure)

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Double

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Erythropoietin; EPO is administered 500IU/kg, intravenously after diagnosis of IVH within 72h after birth, and every other day for 2 weeks. Recombinant human erythropoietin was configured by the hospital pharmacy intravenous Centre Configuration, melted configured with saline to 1ml/kg solution.	Drug: Erythropoietin; EPO is administered 500IU/kg, intravenously after diagnosis of IVH within 72h after birth, and every other day for 2 weeks.; Other Names: Epoietin Beta
Placebo Comparator: Normal saline; Normal saline is administered the same volume with EPO, intravenously after diagnosis of IVH within 72h after birth, and every other day for 2 weeks.	Drug: Normal saline; Normal saline is administered the same volume with EPO, intravenously after diagnosis of IVH within 72h after birth, and every other day for 2 weeks.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Mortality	To compare the death rate in EPO treatment and control groups at 18 months of corrected age.	At corrected age of 18 months
Incidence of neurological disability	To evaluate neurodevelopmental function via Bayley Infant Development scale (2nd Edition), visual acuity and auditory brainstem response measurements at 18 months of corrected age.	At corrected age of 18 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Incidence of cerebral palsy	To compare the incidence of cerebral palsy in EPO treatment and control groups at 18 months of corrected age.	At corrected age of 18 months
Incidence of MDI<70	To compare the incidence of MDI<70 via Bayley Infant Development scale (2nd Edition) in EPO treatment and control groups at 18 months of corrected age.	At corrected age of 18 months
Incidence of blindness	To compare the incidence of blindness via visual acuity and sight radius examinations in EPO treatment and control groups at 18 months of corrected age.	At corrected age of 18 months
Incidence of deafness	To compare the incidence of deafness via auditory brainstem response measurements in EPO treatment and control groups at 18 months of corrected age.	At corrected age of 18 months
The effect of EPO treatment on blood mRNA expression	To investigate different mRNA expression between EPO and control group, peripheral venous blood of preterm infants after EPO treatment will be collected in both EPO group and control group, and the transcriptome of the premature infant blood will be assayed by RNA sequencing.	At 3 weeks after birth

Collaborators and Investigators

• Sponsor: Zhengzhou University
• Collaborators: Göteborg University; Zhengzhou Children's Hospital, China
• Investigators: Study Chair: Changlian Zhu, PhD, Third Affiliated Hospital of Zhengzhou University

Publications and helpful links

General Publications

• Song J, Wang Y, Xu F, Sun H, Zhang X, Xia L, Zhang S, Li K, Peng X, Li B, Zhang Y, Kang W, Wang X, Zhu C. Erythropoietin Improves Poor Outcomes in Preterm Infants with Intraventricular Hemorrhage. CNS Drugs. 2021 Jun;35(6):681-690. doi: 10.1007/s40263-021-00817-w. Epub 2021 May 6.

Study record dates

Study Major Dates

• Study Start (Actual): July 1, 2014
• Primary Completion (Actual): July 1, 2019
• Study Completion (Actual): July 1, 2019

Study Registration Dates

• First Submitted: April 11, 2019
• First Submitted That Met QC Criteria: April 11, 2019
• First Posted (Actual): April 16, 2019

Study Record Updates

• Last Update Posted (Actual): February 26, 2021
• Last Update Submitted That Met QC Criteria: February 25, 2021
• Last Verified: February 1, 2021

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Pathologic Processes; Hemorrhage; Hematinics; Epoetin Alfa
• Other Study ID Numbers: EPO2014

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• 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