Premature Infant
Conditions
Brief summary
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
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.
Interventions
DRUGEpo
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.
DRUGNormal 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.
Sponsors
Xiamen Children's Hospital, Fujian of China
Maternal and Child Health Hospital of Guangxi Zhuang Autonomous Region
Guangzhou Women and Children's Medical Center
Second Affiliated Hospital of Wenzhou Medical University
Maternal and Child Health Hospital of Hubei Province
The Maternal & Children Health Hospital of Dehong, Yunnan of China
Children's Hospital of Fudan University
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Caregiver, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
No minimum to 48 Hours
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Neurodevelopment(Bayley Scores) | At corrected age of 18 months | 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). |
| Neurological Evaluation(GMFM-88 Scores) | At corrected age of 18 months | 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). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Brain Parenchyma Alterations(MRI) | At corrected age of 9 months | To compare changes in brain as measured by MRI in Epo treatment and control groups at 9 months. |
| Somatosensory Evoked Potential | At corrected age of 9 months | To compare changes in brain electrophysiology by SSEP at 36 weeks. |
| Visual Evoked Potential | At corrected age of 9 months | To compare changes in brain electrophysiology by VEP at 36 weeks. |
| Brain Stem Auditory Evoked Potential | At corrected age of 9 months | To compare changes in brain electrophysiology by BAER at 36 weeks. |
| Brain Structural Alterations(MRI) | At corrected age of 9 months | To compare changes in brain as measured by MRI in Epo treatment and control groups at 9 months. |
| SDF-1 in Serum | At 34 weeks | Biomarkers for Oxidative Stress, Inflammation and immune response as a measure of efficacy of erythropoietin for hypoxic ischemic encephalopathy. |
| TNF-alpha in Serum | At 34 weeks | Biomarkers for Oxidative Stress, Inflammation and immune response as a measure of efficacy of erythropoietin for hypoxic ischemic encephalopathy. |
| IL-1 in Serum | At 34 weeks | Biomarkers for Oxidative Stress, Inflammation and immune response as a measure of efficacy of erythropoietin for hypoxic ischemic encephalopathy. |
| Incidence of complication | During treament period (in 34 weeks) | 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. |
| Intracranial Hemorrhage(MRI) | At corrected age of 9 months | To compare changes in brain as measured by MRI in Epo treatment and control groups at 9 months. |
Countries
China
Outcome results
None listed