Erythropoietin in Premature Infants to Prevent Encephalopathy

Premature Infant Clinical Trial

Official title:

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

Clinical Trial Details — Status: Not yet recruiting

Administrative data

• NCT number: NCT02601872
• Other study ID #: PHDehong_NNICU4
• Status: Not yet recruiting
• Phase: Phase 2
• First received: November 9, 2015
• Last updated: November 9, 2015
• Start date: November 2015
• Est. completion date: December 2018

Study information

• Verified date: November 2015
• Source: The People's Hospital of Dehong Autonomous Prefecture
• Contact: Zhaoqing Yin, bachelor
• Email: zhaoqingyin99[@]sina.com
• Is FDA regulated: No
• Health authority: China: Health and Family planning commision Dehong Autonomous Prefecture of Dai and Jingpo Ethnic Groups,Yunnnan Province
• Study type: Interventional

Clinical Trial 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.

Description:

EPO has been safely used to 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.

Recruitment information / eligibility

• Status: Not yet recruiting
• Enrollment: 200
• Est. completion date: December 2018
• Est. primary completion date: December 2018
• Accepts healthy volunteers: No
• Gender: Both
• Age group: N/A to 48 Hours

Eligibility

Inclusion Criteria:

1. Birth weight 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 Design

Allocation: Randomized, Intervention Model: Parallel Assignment, Masking: Double Blind (Subject, Caregiver, Outcomes Assessor), Primary Purpose: Treatment

Related Conditions & MeSH terms

• Brain Diseases
• Premature Birth
• Premature Infant

Intervention

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.
• 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.

Locations

Country	Name	City	State
n/a

Sponsors (7)

Lead Sponsor	Collaborator
The People's Hospital of Dehong Autonomous Prefecture	Children's Hospital of Fudan University, Guangzhou Women and Children's Medical Center, Maternal and Child Health Hospital of Guangxi Zhuang Autonomous Region, Maternal and Child Health Hospital of Hubei Province, Second Affiliated Hospital of Wenzhou Medical University, Xiamen Children's Hospital, Fujian of China

References & Publications (4)

Dame C, Langer J, Koller BM, Fauchère 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. Epub 2012 Jul 4. — View 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. — View Citation

Leuchter RH, Gui L, Poncet A, Hagmann C, Lodygensky GA, Martin E, Koller B, Darqué A, Bucher HU, Hüppi 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. — View 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. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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	No
Primary	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	No
Secondary	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	No
Secondary	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	No
Secondary	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	No
Secondary	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	No
Secondary	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	No
Secondary	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	No
Secondary	Somatosensory Evoked Potential	To compare changes in brain electrophysiology by SSEP at 36 weeks.	At corrected age of 9 months	No
Secondary	Somatosensory Evoked Potential	To compare changes in brain electrophysiology by SSEP at 18 months.	At corrected age of 18 months	No
Secondary	Visual Evoked Potential	To compare changes in brain electrophysiology by VEP at 36 weeks.	At corrected age of 9 months	No
Secondary	Visual Evoked Potential	To compare changes in brain electrophysiology by VEP at 18 months.	At corrected age of 18 months	No
Secondary	Brain Stem Auditory Evoked Potential	To compare changes in brain electrophysiology by BAER at 36 weeks.	At corrected age of 9 months	No
Secondary	Brain Stem Auditory Evoked Potential	To compare changes in brain electrophysiology by BAER at 18 months.	At corrected age of 18 months	No
Secondary	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 treatment period (in 34 weeks)	No
Secondary	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	No
Secondary	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	No
Secondary	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	No