Erythropoietin and darbepoetin treatment to reduce brain injury after birth asphyxia
| ISRCTN | ISRCTN13423963 |
|---|---|
| DOI | https://doi.org/10.1186/ISRCTN13423963 |
| EudraCT/CTIS number | 2020-002831-31 |
| IRAS number | 277361 |
| ClinicalTrials.gov number | NCT04432662 |
| Secondary identifying numbers | CPMS 45286, IRAS 277361 |
- Submission date
- 09/07/2020
- Registration date
- 20/08/2020
- Last edited
- 02/10/2023
- Recruitment status
- No longer recruiting
- Overall study status
- Completed
- Condition category
- Neonatal Diseases
Plain English Summary
Background and study aims
Hypoxic Ischemic Encephalopathy (HIE) is also known as birth asphyxia related brain injury and happens when the brain does not receive enough oxygen or blood flow during the time of birth. Birth asphyxia related brain injury is the most common cause of death and neurodisability in term babies.
Previous studies have shown that brain cooling (hypothermic neuroprotection) can reduce brain injury in some of the affected infants. However, despite cooling a proportion of these babies may still have disability, varying from minor to more severe. This injury is often a result of ongoing damage to the brain cells and is more common if there is an associated infection.
Cooling therapy has substantially improved the outcomes of babies with HIE in the past decade. However, an unacceptably high rate of adverse outcomes is still seen in cooled babies with moderate or severe HIE, hence better treatments and further optimisation of cooling therapy are required.
Erythropoietin (Epo) and Darbepoetin alfa (Darbe) are FDA-approved drugs for treating anemia, with a proven safety profile in newborn infants and have potential neuroprotective benefits in neonatal encephalopathy. Darbe has similar effects to Epo and requires less frequent administration. Several recent reviews have highlighted Epo as one of the most promising treatments to augment hypothermic neuroprotection. Epo has acute effects and restores brain cells, this is essential for the repair of injury and normal neurodevelopment in animal models. It is possible that these drugs may reduce brain injury further when used alongside cooling therapy in babies with HIE.
The aim of this study is to examine the effects of Epo and Darbe on proton magnetic resonance spectroscopy thalamic N-acetylaspartate (NAA) level in babies with neonatal encephalopathy undergoing cooling therapy.
Who can participate?
Babies born with over 36 weeks gestational age with HIE and undergoing cooling therapy
What does the study involve?
The babies will be randomly allocated to erythropoietin, darbepoetin or usual care within the first 24 hours of life. As part of their routine clinical care, the babies will have an MRI scan between 1 and 2 weeks of age to see if they have any visible brain injury, so that the researchers can make a prediction of the long-term implications on their health. A blood sample will be collected on admission and when they are around 80 hours old for research purposes. The researchers will examine subtle genetic variations that can influence how babies respond to this type of brain injury. Data from the babies’ clinical records will be collected, and the results of other tests they may receive as a part of their routine care. This may include an aEEG/EEG (brain activity recording), a brain ultrasound scan, and blood tests. Babies will also have a detailed neurological assessment at 2 years of age to see how they are developing.
What are the possible benefits and risks of participating?
Epo and Darbe may reduce brain injury in babies with HIE. Also, the study may help to improve the treatment of babies with HIE in the future. There are no reported adverse effects of Epo and Darbe in newborn infants. Occasional side effects like joint pains, clotting problems, headache, hypertension, influenza-like illness and skin reactions are reported with prolonged use over several months in adults. None of these have been reported in newborn infants, although the researchers will closely watch for the haemoglobin levels of the baby during Epo treatment. Cooling is remarkably safe and is used as standard therapy for birth asphyxia-related brain injury. It may lower the platelet (blood clotting) levels in the baby’s blood. The researchers will monitor the platelet levels as usual and will administer platelet transfusions if required.
Where is the study run from?
Imperial College London (UK)
When is the study starting and how long is it expected to run for?
August 2019 to December 2024
Who is funding the study?
National Institute for Health Research (NIHR) (UK)
Who is the main contact?
1. Prof. Sudhin Thayyil, s.thayyil@imperial.ac.uk
2. Ms Stuti Pant
Contact information
Scientific
Centre for Perinatal Neuroscience
Department of Paediatrics
Imperial College London and Imperial Neonatal Service
Du Cane Road
London
W12 0HS
United Kingdom
| Phone | +44 (0)203 313 8515 |
|---|---|
| s.thayyil@imperial.ac.uk |
Study information
| Study design | Randomized; Both; Design type: Treatment, Drug, Imaging, Cohort study |
|---|---|
| Primary study design | Interventional |
| Secondary study design | Randomised controlled trial |
| Study setting(s) | Hospital |
| Study type | Treatment |
| Participant information sheet | ISRCTN13423963_PIS_v3_07May20.pdf |
| Scientific title | Erythropoietin and Darbepoetin in Neonatal Encephalopathy (EDEN) study |
| Study acronym | EDEN |
| Study hypothesis | Erythropoietin and darbepoetin therapy will reduce brain injury on magnetic resonance imaging and increase in thalamic NAA at 1 to 2 weeks of age. |
| Ethics approval(s) | Approved 27/05/2020, West of Scotland REC5 (West of Scotland Research Ethics Service, Ward 11, Dykebar Hospital. Grahamston Road, Paisley, PA2 7DE, UK; +44 (0)141 314 0213; WoSREC5@ggc.scot.nhs.uk), REC ref: 20/WS/0057 |
| Condition | Neonatal encephalopathy |
| Intervention | The EDEN study is a three-arm open-label pilot randomised controlled trial. This study will be conducted in 15 tertiary neonatal units in the UK; seven with 3 Tesla MR scanners and eight with 1.5 Telsa MR scanner, using the optimised MR spectroscopy sequences. 20 healthy adult volunteers will be recruited at Imperial NHS Trust and Imperial College London over a 2-month period. All volunteers will be scanned at 1.5 Telsa and 3 Tesla MR scanners, and the sequences will be optimised to obtained comparable thalamic NAA levels. This will allow the researchers to develop comparable 1.5 Tesla and 3 Tesla MR spectroscopy sequences for obtaining similar thalamic N-acetyl aspartate levels. The researchers will recruit 220 term or near term (>36 weeks) babies with neonatal encephalopathy over a 2-year period. Parents will be informed about the study at the earliest appropriate opportunity (after being explained about their baby’s clinical status and when they feel ready) and be given a parent information leaflet (PIL). Parents wishing to participate in the study will be asked to sign an informed consent form, once ready, and be given a copy for their records (with the PIL). After parental consent, the encephalopathic infants at <24 hours of age undergoing therapeutic hypothermia will be randomised to one of the following groups: Arm 1: Erythropoietin (1000 U/kg) IV once a day x 5 doses along with cooling therapy Arm 2: Darbepoetin Alpha (10 mcg/kg) IV single dose given less than 24 hours of age along with cooling therapy Arm 3: Cooling only (usual care) Babies recruited from Imperial NHS trust will have a 16-channel video electroencephalography (EEG), and those recruited from other centres will have amplitude-integrated EEG (aEEG) measurements for the first 80 hours. The researchers will collect 0.5 ml of blood at the time of randomisation and again at 80 hours of age from all recruited babies for gene expression studies. The blood (venous or arterial) will be collected in a PAXGENE bottle, at the time of routine clinical sampling, whenever possible. Details of antenatal and post-natal events, and other routine clinical and imaging data will be collected. The researchers will also obtain relevant clinical data from the participants’ medical records or from GP/local hospital if needed (GPs will be informed of study participation unless otherwise requested by parents). They will also collect the MR imaging data that is acquired as a part of routine clinical care. Parents will be contacted regularly via their preferred method of contact. Study newsletters will be sent to parents, unless they opt out. All babies will have detailed neurodevelopmental evaluation including Bayley scales of infant development (BSID-III or IV if available), gross motor function system classification (GMFCS), and hearing and vision assessment between 18 to 24 months of age, as a part of routine clinical care. Severe disability will be defined as any one of the following: both cognitive and language composite BSID-III scores <70, GMFCS level 3–5, hearing impairment requiring hearing aids or blindness. Moderate disability will be defined as both cognitive and language composite scores BSID-III between 70 and 84 and one or more of the following: GMFCS level 2, hearing impairment with no amplification or a persistent seizure disorder. The outcomes will also be assessed by categorisation of these scores and by including mortality as an outcome. Adverse outcome will be defined as death or, in survivors, moderate or severe disability. |
| Intervention type | Mixed |
| Primary outcome measure | Mean (SD) of thalamic NAA level in babies treated with Epo and Darbe when compared with untreated infants, measured using magnetic resonance spectroscopy between 1 and 2 weeks after birth |
| Secondary outcome measures | Number of babies in whom thalamic NAA level could be accurately quantified in magnetic resonance spectroscopy in 3 Tesla and 1.5 Tesla MR scanners, measured between 1 and 2 weeks after birth |
| Overall study start date | 01/08/2019 |
| Overall study end date | 30/12/2024 |
Eligibility
| Participant type(s) | Mixed |
|---|---|
| Age group | Mixed |
| Sex | Both |
| Target number of participants | Planned Sample Size: 240; UK Sample Size: 240 |
| Participant inclusion criteria | Study 1: Healthy adult volunteers Study 2: Babies (> 36-week gestation and birthweight > 1.8 kg) requiring resuscitation at birth with evidence of acute perinatal asphyxia (metabolic acidosis in cord and/or blood gas (pH< 7.15; BE > -12) within 1h of birth; acute obstetric event) AND the need for continued resuscitation or ventilation at 10 minutes and a 10 min Apgar score < 6 AND evidence of moderate or severe HIE on an NICHD neurological examination performed between 1 and 6h of birth AND cooling was initiated before 6 h of age. |
| Participant exclusion criteria | Study 1: 1. Adults with disease 2. Adults with metal implant fitted, such as a pacemaker or artificial joint 3. Pregnant adults Study 2: 1. Babies with lethal congenital malformations 2. Concomitant participation in other research projects 3. Lack of parental consent |
| Recruitment start date | 01/09/2020 |
| Recruitment end date | 30/09/2024 |
Locations
Countries of recruitment
- England
- United Kingdom
Study participating centres
Praed Street
London
W2 1NY
United Kingdom
Windmill Road
Gillingham
ME7 5NY
United Kingdom
Liverpool
L8 7SS
United Kingdom
London
E9 6SR
United Kingdom
Freeman Road
High Heaton
Newcastle-upon-Tyne
NE7 7DN
United Kingdom
Trust HQ, PO Box 9551
Edgbaston
Birmingham
B15 2TH
United Kingdom
Hills Road
Cambridge
CB2 0QQ
United Kingdom
Duckworth Lane
Bradford
BD9 6RJ
United Kingdom
Sponsor information
University/education
c/o Mr Keith Boland
Clinical Trials Manager
Joint Research Compliance Office
Imperial College London and Imperial College Healthcare NHS Trust
Room 221, Level 2
Medical School Building
Norfolk Place
London
W2 1PG
England
United Kingdom
| Phone | +44 (0)20 7594 9480 |
|---|---|
| k.boland@imperial.ac.uk | |
| Website | http://www3.imperial.ac.uk/ |
"ROR" |
https://ror.org/041kmwe10 |
Funders
Funder type
Government
Government organisation / National government
- Alternative name(s)
- National Institute for Health Research, NIHR Research, NIHRresearch, NIHR - National Institute for Health Research, NIHR (The National Institute for Health and Care Research), NIHR
- Location
- United Kingdom
Results and Publications
| Intention to publish date | 30/03/2025 |
|---|---|
| Individual participant data (IPD) Intention to share | No |
| IPD sharing plan summary | Stored in repository |
| Publication and dissemination plan | Planned publication in a high-impact peer-reviewed journal |
| IPD sharing plan | The datasets generated during and/or analysed during the current study will be stored in a non-publically available repository. Personal identification data including telephone numbers and all contact details will be stored as: 1. Hardcopies in a research folder in locked cupboards in site principal investigators office, or Imperial College London research office 2. NHS computers at the recruiting sites (only for babies recruited from that site) 3. Secure and encrypted server at Imperial College London for storage of personal data. All data will be linked anonymized using a study code, which will be stored as 1. hardcopies in a research folder in locked cupboards in site principal investigators office, or Imperial College London research office 2. NHS computers at the recruiting sites (only for babies recruited from that site) 3. Secure and encrypted server at Imperial College London for storage of personal data. Linked anonymized data will be stored in all other places, as described below. 1. Electronic transfer by magnetic or optical media, email or computer networks The case reports forms will be electronic so that this can be filled in by the recruiting centres directly into the research database (Redcap). Redcap is a GCP compliant database with audit trails and widely used for CTIMPs by many major research universities in the UK and USA (https://www.project-redcap.org). No patient identifiable data will be held in the research database, and the cases will be anonymized (linked) as described above. The database will be hosted in a secure and encrypted Imperial College or private cloud server. MRI scans will be again anonymized using the study number and encrypted with a password prior to transfer by electronic media. Imperial College file transfer protocol will be used for data transfers. Patient identifiable data need to be transferred only through NHS emails or NHS.net emails which have enhanced facilities for transfer of personal data. 2. Use of personal addresses, postcodes, faxes, emails or telephone numbers These data are essential for maintaining regular contact with parents of the recruited babies. As the study involves long term follow-up, the researchers have seen that without regular contact from the research team at Imperial, follow-up rates are low. Furthermore, some babies may come to imperial for 24-month assessment or Imperial team may go to the local hospital to undertake this assessment. These will be stored as: 1. Hardcopies in a research folder in locked cupboards in site principal investigators office, or Imperial College London research office 2. NHS computers at the recruiting sites (only for babies recruited from that site) 3. Secure and encrypted server at Imperial College London for storage of personal data. Storage of personal data on any of the following: 1. Manual files including consent forms, and personal data – Research folder in locked cupboards in site principal investigators office, or Imperial College London research office 2. NHS computers – Personal data will be stored in a dedicated password-protected folder. All NHS computers have facilities for storage of personal data. 3. University computers – personal data will be stored only in a secure and encrypted server at Imperial College London which has got enhanced features for storage of personal data 4. Laptop computers – NO personal data will be stored on laptop computers. However, linked anonymized and password-protected data will be stored in laptops belonging to Imperial College London, which has enhanced security features. All personal data will be stored for a period of 10 years and will be destroyed using standard Imperial College London protocols (including removal by specialist software’s for electronic data), unless parental consent for further research is obtained at that time. The researchers are hoping to undertake long-term follow-up of the recruited babies (subject to further funding), hence it is essential to store identifiable data at Imperial College London. |
Study outputs
| Output type | Details | Date created | Date added | Peer reviewed? | Patient-facing? |
|---|---|---|---|---|---|
| Participant information sheet | version v3 | 07/05/2020 | 20/08/2020 | No | Yes |
| Protocol file | version V3 | 07/05/2020 | 20/08/2020 | No | No |
| HRA research summary | 20/09/2023 | No | No |
Additional files
- ISRCTN13423963_PROTOCOL_V3_07May20.pdf
- uploaded 20/08/2020
- ISRCTN13423963_PIS_v3_07May20.pdf
- uploaded 20/08/2020
Editorial Notes
02/10/2023: The following changes have been made:
1. The recruitment end date has been changed from 31/10/2023 to 30/09/2024.
2. The overall study end date has been changed from 31/03/2024 to 30/12/2024 and the plain English summary updated accordingly.
3. The intention to publish date has been changed from 31/03/2025 to 30/03/2025.
20/09/2023: A link to the HRA research summary was added.
05/05/2023: The study has been reviewed and confirmed as up to date by Imperial College London (UK).
20/09/2021: Internal review.
20/08/2020: The participant information sheet was uploaded as an additional file. Uploaded protocol (not peer reviewed) Version 3.0 07 May 2020.
09/07/2020: Trial's existence confirmed by the NIHR.
