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Erythropoietin and Darbepoetin in Neonatal Encephalopathy Trial (EDEN)

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ClinicalTrials.gov Identifier: NCT04432662
Recruitment Status : Not yet recruiting
First Posted : June 16, 2020
Last Update Posted : June 17, 2020
Sponsor:
Information provided by (Responsible Party):
Thayyil, Sudhin

Tracking Information
First Submitted Date  ICMJE June 11, 2020
First Posted Date  ICMJE June 16, 2020
Last Update Posted Date June 17, 2020
Estimated Study Start Date  ICMJE September 1, 2020
Estimated Primary Completion Date September 1, 2022   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: June 15, 2020)
Primary outcome measure (Mean (SD) of thalamic NAA level) [ Time Frame: Expected average 1 to 2 weeks after birth ]
Mean (SD) of thalamic NAA level in babies treated with Epo and Darbe when compared with untreated infants.
Original Primary Outcome Measures  ICMJE Same as current
Change History No Changes Posted
Current Secondary Outcome Measures  ICMJE
 (submitted: June 15, 2020)
Secondary outcome measure (accurate quantification of NAA level) [ Time Frame: 24 months ]
Number of babies in whom thalamic NAA level could be accurately quantified in 3Telsa and 1.5Tesla MR scanners.
Original Secondary Outcome Measures  ICMJE Same as current
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Erythropoietin and Darbepoetin in Neonatal Encephalopathy Trial
Official Title  ICMJE Erythropoietin and Darbepoetin in Neonatal Encephalopathy (EDEN) Trial
Brief Summary

Hypoxic Ischemic Encephalopathy is also known as 'birth asphyxia related brain injury' and happens when the brain does not receive enough oxygen or blood flow around the time of birth. Birth asphyxia related brain injury is the most common cause of death and neurodisability in term babies.

Cooling therapy has substantially improved the outcomes of babies with HIE. However, unacceptably high rate of adverse outcomes are still seen in cooled babies with HIE.

The EDEN trial is a 3 arm randomised control trial and aims to examine the physiological effects of erythropoietin (Epo) and Darbepoetin alfa (Darbe) therapy on proton magnetic resonance spectroscopy thalamic N-acetylaspartate (NAA) level in babies with neonatal encephalopathy undergoing cooling therapy.

A total of 220 babies with neonatal encephalopathy will be recruited from the participating sites in UK over a 24 month period. The babies will be randomly allocated to erythropoietin, darbepoetin or usual care. MR imaging and spectroscopy will be performed at 1 to 2 weeks of age to examine the brain injury. Neurodevelopmental outcomes will be assessed at 18 months of age.

Detailed Description

Birth asphyxia related brain injury (hypoxic ischemic encephalopathy; HIE) occurs in 2.6 (95% CI 2.5 to 2.8) per 1000 live births in the UK, and is the most common cause of death and neurodisability in term babies. The economic burden to the treasury on support costs of neuro-disability from HIE is massive.

The only effective treatment for HIE is whole body cooling, with an estimated saving of £100 million per annum to the UK economy, since its introduction as a standard therapy in the NHS in 2007. Cooling therapy has substantially improved the outcomes of babies with HIE in the past decade. However, unacceptably high rate of adverse outcomes are still seen in cooled babies with moderate or severe HIE, and hence better treatments and further optimisation of cooling therapy is required.

A key roadblock in clinical translation of over 15 highly effective neuroprotective treatments in animal models is the long delay between the intervention and outcome assessments in HIE. i.e. the earliest age at which neurodevelopmental outcome can be accurately assessed is 18 months. Hence, despite having over 2 dozen highly effective treatments in animal models, no further neuroprotective drugs in HIE have been introduced into the NHS in the past 10 years.

Erythropoietin (Epo) is a widely used and FDA approved drug for treating anaemia in various age groups, including newborn infants. Over 34 randomised controlled trials recruiting over 3500 premature babies have reported the safety and efficacy of Epo therapy for anaemia of prematurity.

Several recent reviews have highlighted Erythropoietin as one of the most promising therapies to augment hypothermic neuroprotection. Epo has both acute effects (anti-inflammatory, anti-excitotoxic, anti-oxidant, and anti-apoptotic) and regenerative effects (neurogenesis, angiogenesis, and oligodendrogenesis) essential for the repair of injury and normal neurodevelopment in animal models5. Of the long list of highly effective drugs in animal models of HIE and early clinical studies, Epo is the most promising. It is the only drug with a long therapeutic window (at least 24 hours), is widely available, inexpensive, and can be easily administered on a once a day dosing schedule. It has been extensive evaluated in large randomised controlled trials for anaemia of prematurity and has a proven safety profile in newborn infants.

Darbepoetin, a long acting erythropoiesis stimulating agent, has dual erythropoietic and potential neuroprotective effects. It has been extensively evaluated in newborn infants for its erythropoietic effects.

The EDEN trial is a 3 arm randomised control trial and aims to examine the physiological effects of erythropoietin (Epo) and Darbepoetin alfa (Darbe) therapy on proton magnetic resonance spectroscopy thalamic N-acetylaspartate (NAA) level in babies with neonatal encephalopathy undergoing cooling therapy.

After informed parental consent, a total of 220 babies with HIE (aged <24 hours) 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 will have electroencephalography (EEG), MR imaging and spectroscopy will be performed at 1 to 2 weeks of age to examine the brain injury. The neurological outcomes will be assessed between 18 to 22 months of age. The trial duration will be 4 years, consisting of a 4 week start up period, 24 month recruitment period, a 18 month follow-up period, and 5 months for data analysis and write up.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 2
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double (Participant, Outcomes Assessor)
Primary Purpose: Treatment
Condition  ICMJE Neonatal Encephalopathy
Intervention  ICMJE
  • Drug: Erythropoietin
    Administration of Erythropoietin (1000 U/kg) IV once a day x 5 doses along with cooling therapy
  • Drug: Darbepoetin Alfa
    Administration of Darbepoetin Alpha (10 mcg/kg) IV single dose given less than 24 hours of age along with cooling therapy.
Study Arms  ICMJE
  • Active Comparator: Erythropoietin
    Administration of Erythropoietin (1000 U/kg) IV once a day x 5 doses along with cooling therapy
    Intervention: Drug: Erythropoietin
  • Active Comparator: Darbepoetin Alpha
    Administration of Darbepoetin Alpha (10 mcg/kg) IV single dose given less than 24 hours of age along with cooling therapy
    Intervention: Drug: Darbepoetin Alfa
  • No Intervention: Standard of care
    Standard of care: Cooling only
Publications * Lally PJ, Montaldo P, Oliveira V, Soe A, Swamy R, Bassett P, Mendoza J, Atreja G, Kariholu U, Pattnayak S, Sashikumar P, Harizaj H, Mitchell M, Ganesh V, Harigopal S, Dixon J, English P, Clarke P, Muthukumar P, Satodia P, Wayte S, Abernethy LJ, Yajamanyam K, Bainbridge A, Price D, Huertas A, Sharp DJ, Kalra V, Chawla S, Shankaran S, Thayyil S; MARBLE consortium. Magnetic resonance spectroscopy assessment of brain injury after moderate hypothermia in neonatal encephalopathy: a prospective multicentre cohort study. Lancet Neurol. 2019 Jan;18(1):35-45. doi: 10.1016/S1474-4422(18)30325-9. Epub 2018 Nov 15.

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Not yet recruiting
Estimated Enrollment  ICMJE
 (submitted: June 15, 2020)
220
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE September 2, 2023
Estimated Primary Completion Date September 1, 2022   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  1. Age < 24 hours
  2. Birth-weight >1.8 kg
  3. Gestation >=36 weeks
  4. Need for continued resuscitation at 10 minutes after birth and/or 10 minutes Apgar score <6
  5. Cooling therapy initiated for neonatal encephalopathy within 6 hours of age as a part of standard clinical care, with an intention of continuing for 72 hours.

Exclusion Criteria:

  1. Major life-threatening congenital malformation.
  2. Concomitant participation in other research projects
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE up to 24 Hours   (Child)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Contact: Sudhin Thayyil, PhD 02033132488 s.thayyil@imperial.ac.uk
Contact: Stuti Pant, MA 02033132488 s.pant@imperial.ac.uk
Listed Location Countries  ICMJE United Kingdom
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT04432662
Other Study ID Numbers  ICMJE 277361
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Product Manufactured in and Exported from the U.S.: No
IPD Sharing Statement  ICMJE
Plan to Share IPD: Yes
Plan Description: IPD data will be shared for meta-analysis
Supporting Materials: Study Protocol
Supporting Materials: Informed Consent Form (ICF)
Time Frame: 2 years after the trial is published
Access Criteria: Quality of the meta-analysis and the credibility of the team
Responsible Party Thayyil, Sudhin
Study Sponsor  ICMJE Thayyil, Sudhin
Collaborators  ICMJE Not Provided
Investigators  ICMJE Not Provided
PRS Account Thayyil, Sudhin
Verification Date June 2020

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP