Clinical trial NCT02550054: Erythropoietin in Premature Infants to Prevent Encephalopathy
Official title: Erythropoietin in Premature Infants to Prevent Encephalopathy: A Multi-Centre Randomized Blinded Controlled Study of the Efficacy of Erythropoietin in China
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE2
Conditions: Premature Infant
Lead sponsor: Children's Hospital of Fudan University
Sponsor class: OTHER
Collaborators: name: Xiamen Children's Hospital, Fujian of China
name: Maternal and Child Health Hospital of Guangxi Zhuang Autonomous Region
name: Guangzhou Women and Children's Medical Center
name: Second Affiliated Hospital of Wenzhou Medical University
name: Maternal and Child Health Hospital of Hubei Province
name: The Maternal & Children Health Hospital of Dehong, Yunnan of China
First posted: 2015-09-15
Enrollment: 58
Sex: ALL
Maximum age (years): 48
Standard ages: CHILD
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

Eligibility criteria: 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

Primary outcomes:
measure: Neurodevelopment(Bayley Scores)
timeFrame: At corrected age of 18 months
measure: Neurological Evaluation(GMFM-88 Scores)
timeFrame: At corrected age of 18 months
Secondary outcomes:
measure: Brain Structural Alterations(MRI)
timeFrame: At corrected age of 9 months
measure: Brain Structural Alterations(MRI)
timeFrame: At corrected age of 18 months
measure: Intracranial Hemorrhage(MRI)
timeFrame: At corrected age of 9 months
measure: Intracranial Hemorrhage(MRI)
timeFrame: At corrected age of 18 months
measure: Brain Parenchyma Alterations(MRI)
timeFrame: At corrected age of 9 months
measure: Brain Parenchyma Alterations(MRI)
timeFrame: At corrected age of 18 months
measure: Somatosensory Evoked Potential
timeFrame: At corrected age of 9 months
measure: Somatosensory Evoked Potential
timeFrame: At corrected age of 18 months
measure: Visual Evoked Potential
timeFrame: At corrected age of 9 months
measure: Visual Evoked Potential
timeFrame: At corrected age of 18 months
measure: Brain Stem Auditory Evoked Potential
timeFrame: At corrected age of 9 months
measure: Brain Stem Auditory Evoked Potential
timeFrame: At corrected age of 18 months
measure: Incidence of complication
timeFrame: During treament period (in 34 weeks)
measure: SDF-1 in Serum
timeFrame: At 34 weeks
measure: TNF-alpha in Serum
timeFrame: At 34 weeks
measure: IL-1 in Serum
timeFrame: At 34 weeks
Other outcomes:
Locations:
city: Shanghai
country: China
facility: Children Hospital of Fudan University
state: Shanghai
Study officials:
affiliation: Children's Hospital of Fudan University
name: Wenhao Zhou, Doctor
role: STUDY_CHAIR
References:
citation: 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.
citation: 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.
citation: 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.
citation: 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.