Erythropoietin in Premature Infants to Prevent Encephalopathy

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

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

Conditions
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Premature Infant

Intervention / Treatment
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* Drug: Epo
* Drug: Normal saline


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Birthweight less or equal 1500 grams Less than 32 weeks gestation at birth Less than 48 hours of life at time of enrollment Written informed consent of parent or guardian Exclusion Criteria: Intrauterine Growth Retardation Severe Congenital Anomalies adversely affecting life expectancy or neurodevelopment Genetic Metabolic Diseases Seizures within first 24 hours of life Severe neutropenia (ANC < 500 cells/microL) within first 24 hours of life Polycythemia (Hct > 65%) within first 24 hours of life Thrombocytopenia (platelets < 50K cells/microL) within first 24 hours of life Hypertension (SBP > 100mmHg) without vasopressor support within first 24 hours of life Microcephaly Grade III-IV intracranial hemorrhage Termination Required by parent or guardian; Polycythemia through blood transfusion can not be relieved Oliguria（<0.5mL/kg/h for at least 24 hours） Progression of azotemia Pulmonary hypertension or Cardiac arrhythmia

Ages Eligible for Study
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Maximum Age: 48 Hours

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Erythropoietin<br>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<br>* 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.<br>* Other names: Epoietin Beta;|
| Placebo Comparator: Normal saline<br>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<br>* 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.<br>* Other names: N/S solution;|

What is the study measuring?
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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 |