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The study was concluded as planned upon reaching its predetermined endpoint, which included the completion of data collection and achievement of the necessary sample size for statistical significance.
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| Name | Class |
|---|---|
| Xiamen Children's Hospital, Fujian of China | OTHER |
| Maternal and Child Health Hospital of Guangxi Zhuang Autonomous Region | OTHER |
| Guangzhou Women and Children's Medical Center | OTHER |
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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.
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.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Erythropoietin | Experimental | 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. |
|
| Normal saline | Placebo Comparator | 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. |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Epo | Drug | 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. |
| 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 |
| 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) |
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Inclusion Criteria:
Exclusion Criteria:
Termination
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| Name | Affiliation | Role |
|---|---|---|
| Wenhao Zhou, Doctor | Children's Hospital of Fudan University | Study Chair |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Children Hospital of Fudan University | Shanghai | Shanghai Municipality | 201102 | China |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 25157725 | Background | 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. | |
| 22776958 | Background |
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| ID | Term |
|---|---|
| D047928 | Premature Birth |
| ID | Term |
|---|---|
| D007752 | Obstetric Labor, Premature |
| D007744 | Obstetric Labor Complications |
| D011248 | Pregnancy Complications |
| D005261 | Female Urogenital Diseases and Pregnancy Complications |
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| ID | Term |
|---|---|
| D047209 | Eosinophil Peroxidase |
| D000077330 | Saline Solution |
| ID | Term |
|---|---|
| D010544 | Peroxidases |
| D010088 | Oxidoreductases |
| D004798 | Enzymes |
| D045762 | Enzymes and Coenzymes |
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| Second Affiliated Hospital of Wenzhou Medical University | OTHER |
| Maternal and Child Health Hospital of Hubei Province | OTHER |
| The Maternal & Children Health Hospital of Dehong, Yunnan of China | OTHER |
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|
| Normal saline | Drug | 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. |
|
|
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 |
| 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. |
| 25803909 | Background | 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. |
| 24192275 | Background | 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. |
| D000091642 | Urogenital Diseases |
| D047091 |
| Eosinophil Granule Proteins |
| D007162 | Immunoproteins |
| D001798 | Blood Proteins |
| D011506 | Proteins |
| D000602 | Amino Acids, Peptides, and Proteins |
| D000077324 | Crystalloid Solutions |
| D007552 | Isotonic Solutions |
| D012996 | Solutions |
| D004364 | Pharmaceutical Preparations |