Recombinant Human Erythropoietin Improve Neurodevelopmental Outcomes in Extremely Preterm Infants

Developmental Disabilities Clinical Trial

— EPO  

Clinical Trial Details — Status: Enrolling by invitation

Administrative data

• NCT number: NCT02745990
• Other study ID #: CZS-EPO
• Status: Enrolling by invitation
• Phase: N/A
• Start date: May 2016
• Est. completion date: December 2022

Study information

• Verified date: August 2021
• Source: Zhengzhou Children's Hospital, China
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

In the ELGAN (Extremely Low Gestational Age Newborn) study, abnormal brain structure and function were associated with intermittent or sustained systemic inflammation (ISSI). Since EPO has anti-inflammatory properties in the kidney and in muscle as well as growth/trophic properties. Based on its potential for neuroprotection, the prospective randomized and masked study was designed to determine whether rhEPO （500u/kg) was also effective in improving developmental outcomes for extremely low gestational age newborns.

Description:

Exogenous erythropoietin (EPO) is currently used to reduce or prevent the need for red blood cell transfusions in preterm infants. Just two decades ago, erythropoietin (EPO) receptors were first identified in the brain, and astrocytes were found to be capable of synthesizing EPO . Subsequently, it was found that cultured hippocampal and cerebral cortical neurons exposed to EPO were spared some of the glutamate-induced cell death seen in neurons not exposed to EPO. Thus began the concept that EPO protects the brain against adversity. Several follow-up studies of children who had participated in trials of recombinant EPO for the prevention or treatment of anemia, term newborn encephalopathy,or retinopathy of prematurity have also provided evidence of neuroprotective effects.

In the ELGAN (Extremely Low Gestational Age Newborn) study, abnormal brain structure and function were associated with intermittent or sustained systemic inflammation (ISSI) . Since EPO has anti-inflammatory properties in the kidney and in muscle as well as growth/trophic properties, we reasoned that elevated circulating levels might convey information about reduced risk of brain damage in ELGANs.

Although major neurodevelopmental disabilities such as cerebral palsy (CP), mental disabilities, and learning and attention deficits during school age figure prominently in the outcomes of ELBW infants, successful neuroprotective interventions have yet to be developed. Investagators designed a prospective, randomized, masked study to evaluate rhEPO during initial hospitalization and follow up, and hypothesized that rhEPO recipients would receive fewer transfusions during initial hospitalization in extremely preterm infants. Based on its potential for neuroprotection, our study was designed to determine whether rhEPO (500 u/kg) was also effective in improving developmental outcomes for extremely low gestational age newborns.

The neurodevelopmental outcomes of rhEPO in treating extremely preterm infants are not clear. Investigators propose an early-childhood neurodevelopmental follow-up study to compare long-term effects of the rhEPO as measured by, Bayley Scales of Infant Development III. We plan to follow extremely low gestational age children around 24 months' corrected age (CA) who are enrolled in this study.

Recruitment information / eligibility

• Status: Enrolling by invitation
• Enrollment: 440
• Est. completion date: December 2022
• Est. primary completion date: December 2022
• Accepts healthy volunteers: No
• Gender: All
• Age group: N/A to 3 Days

Eligibility

Inclusion Criteria:

• Preterm infants admitted to NICU wuth gestational age less than 28 weeks

• Age less than 3 days;

• parental informed consent.

Exclusion Criteria:

• Major life-threatening anomalies (brain, cardiac, chromosomal anomalies)

• Hematologic crises such as DIC, or hemolysis due to blood group incompatibilities

• Polycythemia (hematocrit > 65);

• Hypertension

• Seizures

• Congenital infection

Related Conditions & MeSH terms

• Developmental Disabilities

Intervention

Drug:
• Recombinant human erythropoietin
rhEPO is administered 500IU/kg, intravenously within 72h after birth, and every other day up to 32 weeks of corrected age.
• Normal saline
Normal salin is administered the same volume with rhEPO intravenously within 72h after birth, and every other day up to 32 weeks of corrected age..

Locations

Country	Name	City	State
n/a

Sponsors (3)

Lead Sponsor	Collaborator
Huiqing Sun	Göteborg University, Zhengzhou University

References & Publications (11)

Brown MS, Eichorst D, Lala-Black B, Gonzalez R. Higher cumulative doses of erythropoietin and developmental outcomes in preterm infants. Pediatrics. 2009 Oct;124(4):e681-7. doi: 10.1542/peds.2008-2701. Epub 2009 Sep 28. — View Citation

Contaldo C, Lindenblatt N, Elsherbiny A, Högger DC, Borozadi MK, Vetter ST, Lang KS, Handschin AE, Giovanoli P. Erythropoietin requires endothelial nitric oxide synthase to counteract TNF-[alpha]-induced microcirculatory dysfunction in murine striated mus — View Citation

Korzeniewski SJ, Allred E, Logan JW, Fichorova RN, Engelke S, Kuban KC, O'Shea TM, Paneth N, Holm M, Dammann O, Leviton A; ELGAN study investigators. Elevated endogenous erythropoietin concentrations are associated with increased risk of brain damage in e — View Citation

Lee SH, Li C, Lim SW, Ahn KO, Choi BS, Kim YS, Moon IS, Kim J, Bang BK, Yang CW. Attenuation of interstitial inflammation and fibrosis by recombinant human erythropoietin in chronic cyclosporine nephropathy. Am J Nephrol. 2005 Jan-Feb;25(1):64-76. Epub 20 — View Citation

Leviton A, Kuban KC, Allred EN, Fichorova RN, O'Shea TM, Paneth N; ELGAN Study Investigators. Early postnatal blood concentrations of inflammation-related proteins and microcephaly two years later in infants born before the 28th post-menstrual week. Early — View Citation

Milne S, McDonald J, Comino EJ. The use of the Bayley Scales of Infant and Toddler Development III with clinical populations: a preliminary exploration. Phys Occup Ther Pediatr. 2012 Feb;32(1):24-33. doi: 10.3109/01942638.2011.592572. Epub 2011 Aug 4. — View Citation

Moore EM, Bellomo R, Nichol AD. Erythropoietin as a novel brain and kidney protective agent. Anaesth Intensive Care. 2011 May;39(3):356-72. Review. — View Citation

O'Shea TM, Shah B, Allred EN, Fichorova RN, Kuban KCK, Dammann O, Leviton A; ELGAN Study Investigators. Inflammation-initiating illnesses, inflammation-related proteins, and cognitive impairment in extremely preterm infants. Brain Behav Immun. 2013 Mar;29 — View Citation

Ohls RK, Kamath-Rayne BD, Christensen RD, Wiedmeier SE, Rosenberg A, Fuller J, Lacy CB, Roohi M, Lambert DK, Burnett JJ, Pruckler B, Peceny H, Cannon DC, Lowe JR. Cognitive outcomes of preterm infants randomized to darbepoetin, erythropoietin, or placebo. — View Citation

Rees S, Harding R, Walker D. The biological basis of injury and neuroprotection in the fetal and neonatal brain. Int J Dev Neurosci. 2011 Oct;29(6):551-63. doi: 10.1016/j.ijdevneu.2011.04.004. Epub 2011 Apr 15. Review. — View Citation

Zhu C, Kang W, Xu F, Cheng X, Zhang Z, Jia L, Ji L, Guo X, Xiong H, Simbruner G, Blomgren K, Wang X. Erythropoietin improved neurologic outcomes in newborns with hypoxic-ischemic encephalopathy. Pediatrics. 2009 Aug;124(2):e218-26. doi: 10.1542/peds.2008- — View Citation

* Note: There are 11 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Mortality	To compare the death rate of EPO and control groups at 2 years old	2 years
Primary	Incidence of neurological disability	To assess the incidence of neurological disability of EPO and control groups at 2 years old	2 years
Secondary	Incidence of MDI<70	To compare the incidence of MDI<70 via Bayley Scales of Infant Development between the two groups at 2 years old	2 years
Secondary	Incidence of cerebral palsy	To compare the incidence of cerebral palsy between the two groups at 2 years old	2 years
Secondary	Short-term complicatioins	Retinopathy of prematurity, periventricular leukomalacia,Intraventricular hemorrhage, necrotising enterocolitis and sepsis	3 months
Secondary	Incidence of blindness	To compare the incidence of blindness via visual acuity between the two groups at 2 years old	2 years
Secondary	Incidence of deafness	To compare the incidence of blindness via auditory brainstem response measurements between the two groups at 2 years old	2 years
Secondary	Early blood biomarkers for poor neurological outcomes	To investigate early blood biomarkers via multi-omics to predict poor neurological outcomes	4 weeks
Secondary	Brain imaging biomarkers for poor neurological outcomes	To investigate Brain imaging biomarkers via MRI to predict poor neurological outcomes	Up to 40 weeks of corrected age