Erythropoietin in Premature Infants to Prevent Encephalopathy

Erythropoietin in Premature Infants to Prevent Encephalopathy: A Multi-Centre Randomized Blinded Controlled Study of the Efficacy of Erythropoietin in China

The main goal of this trial is to investigate whether early administration of human erythropoietin (EPO) in preterm infants improves neurodevelopmental outcome at 18 months corrected age. This study is designed as randomized, double-masked, placebo controlled multicenter study involving at least 312 patients.

Study Overview

• Status: Terminated
• Conditions: Premature Infant
• Intervention / Treatment: Drug: Epo; Drug: Normal saline

Detailed Description

EPO has been safely used for prevent preterm anemia and recent studies have shown the neuro-protective effect. Our hypothesis is that EPO could prevent preterm brain injury and reduce the rate of premature death and disability from encephalopathy. The aims of this study include: to investigate the safety and efficacy of EPO by using 1000u/kg higher than the dose of anemia treatment (250u/kg); to evaluate the effect of EPO on neurodevelopment in preterm infants; to detect biological and imaging indicators of EPO. Eligible premature infants will be enrolled in this double-blind, placebo-controlled randomized trial from the neonatal neurological intensive care unit (NNICU) at 7 Children's Hospital in 6 provinces of China. Subjects will be enrolled within the first 24 hours of life and randomly assigned to receive Epo or saline vehicle placebo. Standard NICU care will be provided to all subjects. Pharmacokinetic data, serial brain electrophysiologic and imaging exams, circulating inflammatory mediators, biomarkers and complications like polycythemia, neutropenia, thrombocytopenia, hypertension, sepsis, hemorrhage, seizure, necrotizing enterocolitis (NEC), persistent ductus arterious (PDA), apnea of prematurity, pulmonary haemorrhage, pulmonary hypertension, Prolonged blood coagulation time, retinopathy of prematurity (ROP), cardiac arrhythmia, major venous thrombosis, Renal failure treated with dialysis, pneumonia, pulmonary airleak and chronic lung disease will be collected at established time points during the study period. At 18 months corrected age, subjects will undergo a neurodevelopmental evaluation assessing for cerebral palsy, Bayley Scores of Mental Development Index (MDI) use.

• Study Type: Interventional
• Enrollment (Actual): 58
• Phase: Phase 2

Contacts and Locations

Study Locations

• China
  • Shanghai
    • Shanghai, Shanghai, China, 201102
      • Children Hospital of Fudan University

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: No older than 2 days (Child)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. Birthweight less or equal 1500 grams
2. Less than 32 weeks gestation at birth
3. Less than 48 hours of life at time of enrollment
4. Written informed consent of parent or guardian

Exclusion Criteria:

1. Intrauterine Growth Retardation
2. Severe Congenital Anomalies adversely affecting life expectancy or neurodevelopment
3. Genetic Metabolic Diseases
4. Seizures within first 24 hours of life
5. Severe neutropenia (ANC < 500 cells/microL) within first 24 hours of life
6. Polycythemia (Hct > 65%) within first 24 hours of life
7. Thrombocytopenia (platelets < 50K cells/microL) within first 24 hours of life
8. Hypertension (SBP > 100mmHg) without vasopressor support within first 24 hours of life
9. Microcephaly
10. Grade III-IV intracranial hemorrhage

Termination

1. Required by parent or guardian;
2. Polycythemia through blood transfusion can not be relieved
3. Oliguria（<0.5mL/kg/h for at least 24 hours）
4. Progression of azotemia
5. Pulmonary hypertension or Cardiac arrhythmia

Study Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Erythropoietin; Epo is administered 1000 U/kg, iv in 48 hours after premature birth, and at 48 hours interval for 3 doses per week. After 6 doses, Subcutaneously 3 doses per week until at corrected age of 34 weeks.	Drug: Epo; Epo is administered 1000 U/kg, iv in 48 hours after premature birth, and at 48 hours interval for 3 doses per week. After 6 doses, subcutaneously 400 U/Kg per injection and 3 doses per week until at corrected age of 34 weeks.; Other Names: Epoietin Beta
Placebo Comparator: Normal saline; Normal saline is administered 5ml, iv at 3 to 6 hours after premature birth, and at 48 hours interval for 3 doses per week. After 6 doses, Subcutaneously 3 doses per week until at corrected age of 34 weeks.	Drug: Normal saline; Normal saline is administered 5ml, iv at 3 to 6 hours after premature birth, and at 48 hours interval for 3 doses per week. After 6 doses, Subcutaneously 3 doses per week until at corrected age of 34 weeks.; Other Names: N/S solution

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Neurodevelopment(Bayley Scores)	To evaluate neurodevelopmental function via Bayley Scores of Infant Development Mental Development Index (BSID) and gain incidence of MDI<70(Severe) or MDI<85(Moderate).	At corrected age of 18 months
Neurological Evaluation(GMFM-88 Scores)	To gain changes in standardized gross motor function using GMFM (Gross Motor Function Measure) as a standardized measurement tool for assessing Gross Motor Function consisting of sub-scales, lying & rolling, sitting, crawling & kneeling, standing, walking, running & jumping (range: 0~100 , Higher value means better gross motor function).	At corrected age of 18 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Brain Structural Alterations(MRI)	To compare changes in brain as measured by MRI in Epo treatment and control groups at 9 months.	At corrected age of 9 months
Brain Structural Alterations(MRI)	To compare changes in brain as measured by MRI in Epo treatment and control groups at 18 months.	At corrected age of 18 months
Intracranial Hemorrhage(MRI)	To compare changes in brain as measured by MRI in Epo treatment and control groups at 9 months.	At corrected age of 9 months
Intracranial Hemorrhage(MRI)	To compare changes in brain as measured by MRI in Epo treatment and control groups at 18 months.	At corrected age of 18 months
Brain Parenchyma Alterations(MRI)	To compare changes in brain as measured by MRI in Epo treatment and control groups at 9 months.	At corrected age of 9 months
Brain Parenchyma Alterations(MRI)	To compare changes in brain as measured by MRI in Epo treatment and control groups at 18 months.	At corrected age of 18 months
Somatosensory Evoked Potential	To compare changes in brain electrophysiology by SSEP at 36 weeks.	At corrected age of 9 months
Somatosensory Evoked Potential	To compare changes in brain electrophysiology by SSEP at 18 months.	At corrected age of 18 months
Visual Evoked Potential	To compare changes in brain electrophysiology by VEP at 36 weeks.	At corrected age of 9 months
Visual Evoked Potential	To compare changes in brain electrophysiology by VEP at 18 months.	At corrected age of 18 months
Brain Stem Auditory Evoked Potential	To compare changes in brain electrophysiology by BAER at 36 weeks.	At corrected age of 9 months
Brain Stem Auditory Evoked Potential	To compare changes in brain electrophysiology by BAER at 18 months.	At corrected age of 18 months
Incidence of complication	To gain the incidence of Polycythemia, neutropenia, thrombocytopenia, hypertension, sepsis, intraventricular hemorrhage(IVH), periventricular leukomalacia(PVL), seizure, necrotizing enterocolitis (NEC), persistent ductus arterious (PDA), apnea of prematurity, pulmonary haemorrhage, pulmonary hypertension, Prolonged blood coagulation time, retinopathy of prematurity(ROP), cardiac arrhythmia, major venous thrombosis, Renal failure treated with dialysis, pneumonia, pulmonary airleak and chronic lung disease.	During treament period (in 34 weeks)
SDF-1 in Serum	Biomarkers for Oxidative Stress, Inflammation and immune response as a measure of efficacy of erythropoietin for hypoxic ischemic encephalopathy.	At 34 weeks
TNF-alpha in Serum	Biomarkers for Oxidative Stress, Inflammation and immune response as a measure of efficacy of erythropoietin for hypoxic ischemic encephalopathy.	At 34 weeks
IL-1 in Serum	Biomarkers for Oxidative Stress, Inflammation and immune response as a measure of efficacy of erythropoietin for hypoxic ischemic encephalopathy.	At 34 weeks

Collaborators and Investigators

• Sponsor: Children's Hospital of Fudan University
• Collaborators: Second Affiliated Hospital of Wenzhou Medical University; Guangzhou Women and Children's Medical Center; Maternal and Child Health Hospital of Hubei Province; Maternal and Child Health Hospital of Guangxi Zhuang Autonomous Region; Xiamen Children's Hospital, Fujian of China; The Maternal & Children Health Hospital of Dehong, Yunnan of China
• Investigators: Study Chair: Wenhao Zhou, Doctor, Children's Hospital of Fudan University

Publications and helpful links

General Publications

• 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.
• Dame C, Langer J, Koller BM, Fauchere JC, Bucher HU. Urinary erythropoietin concentrations after early short-term infusion of high-dose recombinant epo for neuroprotection in preterm neonates. Neonatology. 2012;102(3):172-7. doi: 10.1159/000339283. Epub 2012 Jul 4.
• Kuki I, Kawawaki H, Horino A, Inoue T, Nukui M, Okazaki S, Tomiwa K, Amo K, Togawa M, Shiomi M. [A clinical study on high-dose erythropoietin therapy for acute encephalopathy or encephalitis]. No To Hattatsu. 2015 Jan;47(1):32-6. Japanese.
• Traudt CM, McPherson RJ, Bauer LA, Richards TL, Burbacher TM, McAdams RM, Juul SE. Concurrent erythropoietin and hypothermia treatment improve outcomes in a term nonhuman primate model of perinatal asphyxia. Dev Neurosci. 2013;35(6):491-503. doi: 10.1159/000355460. Epub 2013 Nov 1.

Study record dates

Study Major Dates

• Study Start (Actual): September 8, 2015
• Primary Completion (Actual): December 30, 2016
• Study Completion (Actual): December 30, 2016

Study Registration Dates

• First Submitted: September 4, 2015
• First Submitted That Met QC Criteria: September 14, 2015
• First Posted (Estimated): September 15, 2015

Study Record Updates

• Last Update Posted (Actual): December 29, 2023
• Last Update Submitted That Met QC Criteria: December 27, 2023
• Last Verified: December 1, 2023

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Central Nervous System Diseases; Nervous System Diseases; Pregnancy Complications; Obstetric Labor Complications; Obstetric Labor, Premature; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Premature Birth; Brain Diseases
• Other Study ID Numbers: CHFudanU_NNICU4