Premature InfantsPhase 3NCT03110341
Effect of Erythropoietin in Premature Infants on White Matter Lesions and Neurodevelopmental Outcome
A Phase 3 study testing Erythropoietin and Normal saline in people with Premature Infants and Intracranial Hemorrhages, run by First Affiliated Hospital Xi'an Jiaotong University at 1 site in China.
Trial summary
Preterm and very preterm infants are at risk of developing encephalopathy of prematurity and long-term neurodevelopmental delay. Magnetic resonance imaging (MRI) allows the characterization of specific features of encephalopathy of prematurity, including structural changes of brain white matter and gray matter. Read more about this study
- Who is it for?
- Ages Up to 3 days
- Conditions the study is for
- Premature Infants, Intracranial Hemorrhages, Periventricular Leukomalacia
- What is being tested?
- Erythropoietin and Normal saline
- Type of treatment
- Injection or infusion
- Could I receive a placebo?
- Yes, some participants may receive a placebo
- How many people
- 400 participants
- Where
- 1 siteChina
- Study dates
- 10 Apr 2017to Jun 2019
- Phase
- Phase 3
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages Up to 3 days
- All sexes
- No healthy volunteers
- Child
Who may be able to join
- premature infants who admitted to the neonatal intensive care unit(NICU) Within 72 hours after birth, gestational ages younger than 32 weeks, birth weight less than 1500 gram, informed consent was obtained from the infants' parents or guardians
Who cannot join
- born with anemia, polycythemia, hemolysis and other hematological diseases
- hypertension,
- convulsions,
- a genetically defined syndrome
- a severe congenital malformation adversely affecting life expectancy or neurodevelopment
- severe intraventricular hemorrhage
- thrombosis disease
- other fatal diseases or which can seriously affect the prognosis
Trial locations and contacts
1 site in 1 country.
China1 site, 1 recruiting
- Recruiting
First Affiliated Hospital of Xian JiaotongUniversity
Xi'an, Shaanxi, 710061
Xihui Zhou, Doctor, +8618991232230, zhouxih@xjtu.edu.cn
About this study
Official title: Effect of Early Application of Recombinant Human Erythropoietin in Premature Infants on White Matter Lesions and Neurodevelopmental Outcome
Preterm and very preterm infants are at risk of developing encephalopathy of prematurity and long-term neurodevelopmental delay. Magnetic resonance imaging (MRI) allows the characterization of specific features of encephalopathy of prematurity, including structural changes of brain white matter and gray matter. This study wants to investigate important evidence that early repeated high-dose rhEPO(5250 IU/kg) treatment improves long-term neurological outcomes in very preterm infants and without obvious adverse effects.
Read the detailed description
HYPOTHESIS Early administration of human erythropoietin (EPO) in preterm infants reduces perinatal injury to the brain and improves neurodevelopmental outcome at 24 months corrected age.
PRIMARY OBJECTIVE To determine whether cerebral outcome is improved if infants born between 28 0/7 and 34 6/7 gestational weeks at birth receive erythropoietin in high dose in the first two weeks after birth.
Biomarkers of encephalopathy of prematurity assessed on magnetic resonance imaging (MRI) at term equivalent age.
RATIONALE Erythropoietin (EPO) was first recognized for its hematopoietic properties; recombinant human EPO (rhEPO) has been used to treat a number of anemic states, including early and late anemia of prematurity, and it has been found to be safe and to reduce the need for blood transfusions. EPO produced in the central nervous system7 is upregulated after insult and plays a role in neuroprotection. Experimental studies have reported that rhEPO possesses neuroprotective properties in different neonatal brain injury animal models, and clinical studies have shown that rhEPO treatment reduces brain injury and the incidence of neurological disabilities in infants.8,14-17 In addition, improved neurodevelopmental outcomes have been observed in preterm infants with anemia after rhEPO treatment. The neuroprotective effect of rhEPO was suggested to be through acting against apoptosis, inflammation, and neurotoxicity and by acting as an antioxidant in protecting white matter from injury and in promoting neural regeneration, injury repair, and normal development.
STUDY DESIGN Randomized, double-masked, placebo-controlled multicenter clinical trial. Research plan 400 infants will be randomized during the first three hours of life to receive EPO (5250 U/kg body weight) or placebo intravenously, the first dose(750U/kg) will be injected within 24h after birth, subsequent injection will be given each other day for 2 weeks. Standardized evaluation including cerebral sonography at day 1, 7 and 28 will determine the presence or absence of complications. Cerebral volume and white matter volume will be assessed at 40 postmenstrual weeks with MRI (only if available).
Experienced examiners will assess developmental function at 6 and 12 months corrected age using the reliable and validly revised Bayley Scales III of Infant Development and determine the presence or absence of impairment of motor function (cerebral palsy) and neurosensory function (blindness or deafness).
Primary outcome was cognitive development assessed with the Mental Development Index (MDI; norm, 100 [SD, 15]; higher values indicate better function) of the Bayley Scales of Infant Development, second edition (BSID-II) at 1 years corrected age.
Second outcome assess the effect of early administration of rh Epo on white matter development in preterm infants using Tract-based spatial statistics (TBSS ). White matter disease of the preterm infant, was semiquantitatively assessed from MRI at term-equivalent age based on an established scoring method.
- Being tested
- Erythropoietin, Normal saline
- Medical subject headings
- Premature Birth, Intracranial Hemorrhages, Leukomalacia, Periventricular, Cerebral Palsy
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
ErythropoietinDrug
Also called Epoetin Beta
rhEPO 750U/kg was injected within 72h after birth, subsequent injection was given every other day for 2 weeks (a cumulative dose of 5,250U/kg over the course of 7 separate intravenous injections.
Normal salineDrug
Also called NaCl 0.9%
placebo (Normal saline 3 ml/kg birth weight) was injected within 72h after birth, subsequent injection was given every other day for 2 weeks.
| Study group | Role | What they receive |
|---|---|---|
| Erythropoietin | Experimental | Erythropoietin is administered 750U/kg intravenously every other day for 2 weeks (a cumulative dose of 5,250U/kg over the course of 7 separate intravenous injections regardless of gestational age), starting with the first dose within 72 hours after birth. A single dose consisted of 750U EPO per kg of birth weight dissolved in 3mL/kg normal saline was administered intravenously during a period of 5 minutes. Receives: Drug: Normal saline |
| Normal saline | Placebo comparator | Normal saline is administered 3ml/kg intravenously every other day for 2 weeks, starting with the first dose within 72 hours after birth. Similarly, the placebo dose consisted of 3mL of normal saline per kilogram birth weight was administered intravenously during a period of 5 minutes. Receives: Drug: Erythropoietin |
What is being measured
The primary outcome is the main question the study is designed to answer.
Neurodevelopmental outcome
To evaluate neurodevelopmental function via Bayley Scales of Infant Development, second edition (BSID-II) at 18 months corrected age and gain incidence of MDI<70(Severe) or MDI<85(Moderate).
Measured: corrected age of 18 months
Secondary outcomes (1)
TBSS（Tract-based spatial statistics）
White matter disease of the preterm infant, was semiquantitatively assessed from MRI at term-equivalent age based on an established scoring method.
Measured: corrected age of 40 weeks
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted12 Apr 2017
- Study start10 Apr 2017
- Primary completionDec 2018 (estimated)
- Study completionJun 2019 (estimated)
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (5)Papers the sponsor has linked to this study.
- Other trials for Premature InfantsStudies of the same condition, open and under way.
- More trials run by First Affiliated Hospital Xi'an Jiaotong UniversityThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 3
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Double blind
- Who is masked
- Participant, Outcomes assessor
- Enrolment
- 400 participants (estimated)
Sponsor and investigators
- Sponsor type
- University, hospital or other
- Collaborators
- Xian Children's Hospital, Shaanxi Provincial People's Hospital, Second Affiliated Hospital of Xi'an Jiaotong University, Tang-Du Hospital, Xijing Hospital, Xi'an No.4 Hospital, Northwest Women's and Children's Hospital, Xi'an, Shaanxi
- Responsible party
- Sponsor
- Investigators
- Xihui Zhou, Doctor, Principal investigator, First Affiliated Hospital of Xian JiaotongUniversity
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT03110341
- Sponsor's protocol ID
- XJTU1AF-CRF-2016-023
- Status last verified
- Sep 2017
- First submitted
- 15 Mar 2017
- Last updated
- 2 Oct 2017
- Results posted
- No
- Data monitoring committee
- Yes
- FDA-regulated drug
- No
- FDA-regulated device
- No
- Individual data sharing
- Yes
Publications
O'Gorman RL, Bucher HU, Held U, Koller BM, Huppi PS, Hagmann CF; Swiss EPO Neuroprotection Trial Group. Tract-based spatial statistics to assess the neuroprotective effect of early erythropoietin on white matter development in preterm infants. Brain. 2015 Feb;138(Pt 2):388-97. doi: 10.1093/brain/awu363. Epub 2014 Dec 22.
PubMed 25534356Wu YW, Mathur AM, Chang T, McKinstry RC, Mulkey SB, Mayock DE, Van Meurs KP, Rogers EE, Gonzalez FF, Comstock BA, Juul SE, Msall ME, Bonifacio SL, Glass HC, Massaro AN, Dong L, Tan KW, Heagerty PJ, Ballard RA. High-Dose Erythropoietin and Hypothermia for Hypoxic-Ischemic Encephalopathy: A Phase II Trial. Pediatrics. 2016 Jun;137(6):e20160191. doi: 10.1542/peds.2016-0191. Epub 2016 May 2.
PubMed 27244862Natalucci G, Latal B, Koller B, Ruegger C, Sick B, Held L, Bucher HU, Fauchere JC; Swiss EPO Neuroprotection Trial Group. Effect of Early Prophylactic High-Dose Recombinant Human Erythropoietin in Very Preterm Infants on Neurodevelopmental Outcome at 2 Years: A Randomized Clinical Trial. JAMA. 2016 May 17;315(19):2079-85. doi: 10.1001/jama.2016.5504.
PubMed 27187300Leuchter 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.
PubMed 25157725Song J, Sun H, Xu F, Kang W, Gao L, Guo J, Zhang Y, Xia L, Wang X, Zhu C. Recombinant human erythropoietin improves neurological outcomes in very preterm infants. Ann Neurol. 2016 Jul;80(1):24-34. doi: 10.1002/ana.24677. Epub 2016 May 11.
PubMed 27130143
Study at a glance
From the registry record, last updated by the sponsor on 2 Oct 2017. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Effect of Early Application of Recombinant Human Erythropoietin in Premature Infants on White Matter Lesions and Neurodevelopmental Outcome
- ClinicalTrials.gov ID
- NCT03110341
- Acronym / sponsor ID
- XJTU1AF-CRF-2016-023
- Phase
- Phase 3
- Study type
- Interventional
- Recruitment status
- Unknown status
- Enrolment
- 400 participants (estimated)
- Lead sponsor
- First Affiliated Hospital Xi'an Jiaotong UniversityUniversity, hospital or other
- Collaborators
- Xian Children's Hospital, Shaanxi Provincial People's Hospital, Second Affiliated Hospital of Xi'an Jiaotong University, Tang-Du Hospital, Xijing Hospital, Xi'an No.4 Hospital, Northwest Women's and Children's Hospital, Xi'an, Shaanxi
- Study start
- 10 Apr 2017 (actual)
- Primary completion
- Dec 2018 (estimated)
- Study completion
- Jun 2019 (estimated)
- First posted
- 12 Apr 2017 (actual)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
Preterm and very preterm infants are at risk of developing encephalopathy of prematurity and long-term neurodevelopmental delay. Magnetic resonance imaging (MRI) allows the characterization of specific features of encephalopathy of prematurity, including structural changes of brain white matter and gray matter. This study wants to investigate important evidence that early repeated high-dose rhEPO(5250 IU/kg) treatment improves long-term neurological outcomes in very preterm infants and without obvious adverse effects.
Detailed description
HYPOTHESIS Early administration of human erythropoietin (EPO) in preterm infants reduces perinatal injury to the brain and improves neurodevelopmental outcome at 24 months corrected age.
PRIMARY OBJECTIVE To determine whether cerebral outcome is improved if infants born between 28 0/7 and 34 6/7 gestational weeks at birth receive erythropoietin in high dose in the first two weeks after birth.
Biomarkers of encephalopathy of prematurity assessed on magnetic resonance imaging (MRI) at term equivalent age.
RATIONALE Erythropoietin (EPO) was first recognized for its hematopoietic properties; recombinant human EPO (rhEPO) has been used to treat a number of anemic states, including early and late anemia of prematurity, and it has been found to be safe and to reduce the need for blood transfusions. EPO produced in the central nervous system7 is upregulated after insult and plays a role in neuroprotection. Experimental studies have reported that rhEPO possesses neuroprotective properties in different neonatal brain injury animal models, and clinical studies have shown that rhEPO treatment reduces brain injury and the incidence of neurological disabilities in infants.8,14-17 In addition, improved neurodevelopmental outcomes have been observed in preterm infants with anemia after rhEPO treatment. The neuroprotective effect of rhEPO was suggested to be through acting against apoptosis, inflammation, and neurotoxicity and by acting as an antioxidant in protecting white matter from injury and in promoting neural regeneration, injury repair, and normal development.
STUDY DESIGN Randomized, double-masked, placebo-controlled multicenter clinical trial. Research plan 400 infants will be randomized during the first three hours of life to receive EPO (5250 U/kg body weight) or placebo intravenously, the first dose(750U/kg) will be injected within 24h after birth, subsequent injection will be given each other day for 2 weeks. Standardized evaluation including cerebral sonography at day 1, 7 and 28 will determine the presence or absence of complications. Cerebral volume and white matter volume will be assessed at 40 postmenstrual weeks with MRI (only if available).
Experienced examiners will assess developmental function at 6 and 12 months corrected age using the reliable and validly revised Bayley Scales III of Infant Development and determine the presence or absence of impairment of motor function (cerebral palsy) and neurosensory function (blindness or deafness).
Primary outcome was cognitive development assessed with the Mental Development Index (MDI; norm, 100 [SD, 15]; higher values indicate better function) of the Bayley Scales of Infant Development, second edition (BSID-II) at 1 years corrected age.
Second outcome assess the effect of early administration of rh Epo on white matter development in preterm infants using Tract-based spatial statistics (TBSS ). White matter disease of the preterm infant, was semiquantitatively assessed from MRI at term-equivalent age based on an established scoring method.
Study design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Double blind (participant, outcomes assessor)
- Number of arms
- 2
| Arm | Type | Receives |
|---|---|---|
| Erythropoietin | Experimental | Drug: Normal salineErythropoietin is administered 750U/kg intravenously every other day for 2 weeks (a cumulative dose of 5,250U/kg over the course of 7 separate intravenous injections regardless of gestational age), starting with the first dose within 72 hours after birth. A single dose consisted of 750U EPO per kg of birth weight dissolved in 3mL/kg normal saline was administered intravenously during a period of 5 minutes. |
| Normal saline | Placebo comparator | Drug: ErythropoietinNormal saline is administered 3ml/kg intravenously every other day for 2 weeks, starting with the first dose within 72 hours after birth. Similarly, the placebo dose consisted of 3mL of normal saline per kilogram birth weight was administered intravenously during a period of 5 minutes. |
Who may qualify
- Ages
- Up to 3 days
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Child
Key inclusion criteria (1 listed)
- premature infants who admitted to the neonatal intensive care unit(NICU) Within 72 hours after birth, gestational ages younger than 32 weeks, birth weight less than 1500 gram, informed consent was obtained from the infants' parents or guardians
Key exclusion criteria (8 listed)
- born with anemia, polycythemia, hemolysis and other hematological diseases
- hypertension,
- convulsions,
- a genetically defined syndrome
- a severe congenital malformation adversely affecting life expectancy or neurodevelopment
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| ErythropoietinAlso: Epoetin BetarhEPO 750U/kg was injected within 72h after birth, subsequent injection was given every other day for 2 weeks (a cumulative dose of 5,250U/kg over the course of 7 separate intravenous injections. | Drug | Normal saline |
| Normal salineAlso: NaCl 0.9%placebo (Normal saline 3 ml/kg birth weight) was injected within 72h after birth, subsequent injection was given every other day for 2 weeks. | Drug | Erythropoietin |
Primary outcome
Neurodevelopmental outcome
Time frame: corrected age of 18 months
To evaluate neurodevelopmental function via Bayley Scales of Infant Development, second edition (BSID-II) at 18 months corrected age and gain incidence of MDI<70(Severe) or MDI<85(Moderate).
1 secondary outcome
TBSS（Tract-based spatial statistics）
Time frame: corrected age of 40 weeks
Results and safety
Results are not available in the source record.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 2 Oct 2017.
- Results publication: PubMed 25534356O'Gorman RL, Bucher HU, Held U, Koller BM, Huppi PS, Hagmann CF; Swiss EPO Neuroprotection Trial Group. Tract-based spatial statistics to assess the neuroprotective effect of early erythropoietin on white matter development in preterm infants. Brain. 2015 Feb;138(Pt 2):388-97. doi: 10.1093/brain/awu363. Epub 2014 Dec 22.
- Results publication: PubMed 27244862Wu YW, Mathur AM, Chang T, McKinstry RC, Mulkey SB, Mayock DE, Van Meurs KP, Rogers EE, Gonzalez FF, Comstock BA, Juul SE, Msall ME, Bonifacio SL, Glass HC, Massaro AN, Dong L, Tan KW, Heagerty PJ, Ballard RA. High-Dose Erythropoietin and Hypothermia for Hypoxic-Ischemic Encephalopathy: A Phase II Trial. Pediatrics. 2016 Jun;137(6):e20160191. doi: 10.1542/peds.2016-0191. Epub 2016 May 2.
- Results publication: PubMed 27187300Natalucci G, Latal B, Koller B, Ruegger C, Sick B, Held L, Bucher HU, Fauchere JC; Swiss EPO Neuroprotection Trial Group. Effect of Early Prophylactic High-Dose Recombinant Human Erythropoietin in Very Preterm Infants on Neurodevelopmental Outcome at 2 Years: A Randomized Clinical Trial. JAMA. 2016 May 17;315(19):2079-85. doi: 10.1001/jama.2016.5504.
- Results publication: PubMed 25157725Leuchter 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.
- Results publication: PubMed 27130143Song J, Sun H, Xu F, Kang W, Gao L, Guo J, Zhang Y, Xia L, Wang X, Zhu C. Recombinant human erythropoietin improves neurological outcomes in very preterm infants. Ann Neurol. 2016 Jul;80(1):24-34. doi: 10.1002/ana.24677. Epub 2016 May 11.
- Individual participant dataSharing planned: Yes
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Xihui Zhou, Doctor principal investigator
First Affiliated Hospital of Xian JiaotongUniversity
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 3 study testing Erythropoietin and Normal saline in people with Premature Infants and Intracranial Hemorrhages, run by First Affiliated Hospital Xi'an Jiaotong University at 1 site in China.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 1 inclusion and 8 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: status not confirmed, as of the sponsor's last update on 2 Oct 2017. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in China. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. Some participants in this study may receive a placebo. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 3 studies compare the treatment with the current standard treatment or a placebo in a large group, to confirm how well it works and watch for side effects.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
Results are not available in the source record.
How can a doctor refer a patient or contact the research team?
Contact Xihui Zhou, Doctor (+8618991232230, zhouxih@xjtu.edu.cn), or a site near the patient. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Neurodevelopmental outcome (time frame: corrected age of 18 months). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT03110341, which also lists 5 linked publications.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 2 Oct 2017.