<clinical_study>
  <!-- This xml conforms to an XML Schema at:
    https://clinicaltrials.gov/ct2/html/images/info/public.xsd -->
  <required_header>
    <download_date>ClinicalTrials.gov processed this data on September 20, 2023</download_date>
    <link_text>Link to the current ClinicalTrials.gov record.</link_text>
    <url>https://clinicaltrials.gov/ct2/show/NCT04432662</url>
  </required_header>
  <id_info>
    <org_study_id>277361</org_study_id>
    <nct_id>NCT04432662</nct_id>
  </id_info>
  <brief_title>Darbepoetin in Neonatal Encephalopathy Trial</brief_title>
  <acronym>EDEN</acronym>
  <official_title>Darbepoetin in Neonatal Encephalopathy (EDEN) Trial</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Thayyil, Sudhin</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>Thayyil, Sudhin</source>
  <oversight_info>
    <has_dmc>Yes</has_dmc>
    <is_fda_regulated_drug>No</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
    <is_us_export>No</is_us_export>
  </oversight_info>
  <brief_summary>
    <textblock>
      Hypoxic Ischemic Encephalopathy is also known as 'birth asphyxia related brain injury' and&#xD;
      happens when the brain does not receive enough oxygen or blood flow around the time of birth.&#xD;
      Birth asphyxia related brain injury is the most common cause of death and neurodisability in&#xD;
      term babies.&#xD;
&#xD;
      Cooling therapy has substantially improved the outcomes of babies with HIE. However,&#xD;
      unacceptably high rate of adverse outcomes are still seen in cooled babies with HIE.&#xD;
&#xD;
      The EDEN trial is a 2 arm randomised control trial and aims to examine the physiological&#xD;
      effects of Darbepoetin alfa (Darbe) therapy on proton magnetic resonance spectroscopy&#xD;
      thalamic N-acetylaspartate (NAA) level in babies with neonatal encephalopathy undergoing&#xD;
      cooling therapy.&#xD;
&#xD;
      A total of 150 babies with neonatal encephalopathy will be recruited from the participating&#xD;
      sites in UK over a 24 month period. The babies will be randomly allocated to darbepoetin or&#xD;
      usual care. MR imaging and spectroscopy will be performed at 1 to 2 weeks of age to examine&#xD;
      the brain injury. Neurodevelopmental outcomes will be assessed at 18 months of age.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Birth asphyxia related brain injury occurs in 2.6 (95% CI 2.5 to 2.8) per 1000 live births in&#xD;
      the UK and is the most common cause of death and neurodisability in term babies. The economic&#xD;
      burden to the treasury on support costs of neurodisability from neonatal encephalopathy is&#xD;
      massive (£4 billion per year). In addition, birth asphyxia related (obstetric) claims&#xD;
      accounted for almost half of the NHS litigation expenses in 2016/17 (approx. £2 billion),&#xD;
      increasing by 15% from the previous year. It has been reported that the NHS cost to meet the&#xD;
      complex life-long care needs of babies born with brain damage could be soon over £20m per&#xD;
      child, and this situation is unsustainable to the NHS.The UK Government has recently (October&#xD;
      2016) announced that reducing birth asphyxia related costs is a priority area for the&#xD;
      Government.&#xD;
&#xD;
      The only effective treatment for neonatal encephalopathy is whole-body cooling, with an&#xD;
      estimated saving of £100 million per annum to the UK economy, since its introduction as&#xD;
      standard therapy in the NHS in 2007. Cooling therapy has substantially improved the outcomes&#xD;
      of babies with neonatal encephalopathy in the past decade. However, unacceptably high rate of&#xD;
      adverse outcomes are still seen in cooled babies with moderate or severe neonatal&#xD;
      encephalopathy : death 28% (range 24-38); cognitive impairment 24% (range 21-25); cerebral&#xD;
      palsy 22% (range 13-28); epilepsy 19% (range 15-24); cortical visual impairment 6% (range&#xD;
      1-10), with combined death or moderate/severe disability 48% (range 44- 53), and hence better&#xD;
      treatments and further optimisation of cooling therapy is required. Additionally, cooling&#xD;
      provides a window of opportunity for therapeutic interventions that may arrest or reduce&#xD;
      secondary brain injury and it is unclear whether it provides protection from a sub-acute&#xD;
      chronic injury that may have occurred during the antenatal period.&#xD;
&#xD;
      A key roadblock in clinical translation of over fifteen highly effective neuroprotective&#xD;
      treatments in animal models is the long delay between the intervention and outcome&#xD;
      assessments in neonatal encephalopathy . i.e., the earliest age at which neurodevelopmental&#xD;
      outcome can be accurately assessed is 18 months. Hence, despite having several highly&#xD;
      effective treatments in animal models, no further neuroprotective drugs in neonatal&#xD;
      encephalopathy have been introduced into the NHS in the past ten years.&#xD;
&#xD;
      Erythropoietin (Epo) is a widely used drug for treating anaemia in various age groups,&#xD;
      including newborn infants. Several recent reviews have highlighted Epo as one of the most&#xD;
      promising therapies to augment hypothermic neuroprotection. Epo has both acute effects&#xD;
      (anti-inflammatory, anti-excitotoxic, anti-oxidant, and anti-apoptotic) and regenerative&#xD;
      effects (neurogenesis, angiogenesis, and oligodendrogenesis) essential for the repair of&#xD;
      injury and normal neurodevelopment in animal models. Of the long list of highly effective&#xD;
      drugs in animal models of neonatal encephalopathy and early clinical studies, Epo is the most&#xD;
      promising. It is the only drug with a long therapeutic window, is widely available,&#xD;
      inexpensive, and can be easily administered on a once-a-day dosing schedule. It has been&#xD;
      extensively evaluated in large randomised controlled trials for anaemia of prematurity and&#xD;
      has a proven safety profile in newborn infants. Due to the regenerative effects and the&#xD;
      longer therapeutic window provided by Epo, there is potential to impact the chronic injury&#xD;
      caused to an antenatally compromised foetus.&#xD;
&#xD;
      Although earlier studies have shown benefit with Epo, the time of initiation and duration of&#xD;
      treatment remains uncertain. Moreover, recently published High-Dose Erythropoietin for&#xD;
      Asphyxia and Encephalopathy (HEAL) trial which administered high dose Epo (1000u/kg/day)&#xD;
      within 24 hours of birth and continued until 7 days of age failed to demonstrate the&#xD;
      neuroprotective effect of erythropoietin in moderate and severe encephalopathy as an adjuvant&#xD;
      to therapeutic hypothermia. This result suggest the exposure of the drug during the&#xD;
      therapeutic hypothermia may not be beneficial due to an overlap in the neuroprotective&#xD;
      mechanism. Perhaps a prolonged exposure of Epo following therapeutic hypothermia might be&#xD;
      beneficial.&#xD;
&#xD;
      Another erythropoiesis stimulating agent is Darbepoetin (Darbe) with dual erythropoietic and&#xD;
      potential neuroprotective effects. Darbe is an ideal candidate to augment hypothermic&#xD;
      neuroprotection as it is a long-acting erythropoiesis stimulating agent, allowing prolonged&#xD;
      exposure with less dosing. In preclinical study in rats, darbepoetin alfa crossed the blood&#xD;
      brain barrier and remained stable up to 24 hours. Neuroprotective effects of darbepoetin were&#xD;
      demonstrated following the contusion injury and hemorrhage in rats. The DANCE study&#xD;
      (Darbepoetin Administered to Neonates undergoing Cooling for Encephalopathy) randomised 30&#xD;
      term infants with moderate to severe neonatal encephalopathy to placebo (n=10), 2 μg/kg Darbe&#xD;
      (n=10) or 10 μg/kg Darbe (n=10). At 2 and 10 μg/kg Darbe, t1/2 was 24 and 32 hours. A dose of&#xD;
      10 μg/kg dose achieved an AUC in the neuroprotective range and a terminal t1/2 of 53.4 hours&#xD;
      when compared to the 2 μg/kg dose. No side effects attributable to Darbe were reported. In&#xD;
      another feasibility and safety trial, infants with mild encephalopathy were randomised to&#xD;
      receive Darbepoetin 10 μg/kg single dose within 24 hours and found the drug to be safe with&#xD;
      no reported adverse events.&#xD;
&#xD;
      The EDEN trial is a 2 arm randomised control trial and aims to examine the physiological&#xD;
      effects of Darbepoetin alfa (Darbe) therapy on proton magnetic resonance spectroscopy&#xD;
      thalamic N-acetylaspartate (NAA) level in babies with neonatal encephalopathy undergoing&#xD;
      cooling therapy.&#xD;
&#xD;
      After informed parental consent, a total of 150 babies with HIE (aged &lt;24 hours) undergoing&#xD;
      therapeutic hypothermia will be randomised to one of the following groups&#xD;
&#xD;
        -  Arm 1:Darbepoetin Alpha (10 mcg/kg) IV x2 doses following cooling therapy.&#xD;
&#xD;
        -  Arm 2: Cooling only (usual care)&#xD;
&#xD;
      Babies recruited will have electroencephalography (EEG), MR imaging and spectroscopy will be&#xD;
      performed at 1 to 2 weeks of age to examine the brain injury. The neurological outcomes will&#xD;
      be assessed between 18 to 22 months of age. The trial duration will be 4 years, consisting of&#xD;
      a 4 week start up period, 24 month recruitment period, a 18 month follow-up period, and 5&#xD;
      months for data analysis and write up.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Recruiting</overall_status>
  <start_date type="Actual">May 28, 2021</start_date>
  <completion_date type="Anticipated">April 1, 2024</completion_date>
  <primary_completion_date type="Anticipated">February 1, 2024</primary_completion_date>
  <phase>Phase 2</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>Randomized</allocation>
    <intervention_model>Parallel Assignment</intervention_model>
    <primary_purpose>Treatment</primary_purpose>
    <masking>Single (Outcomes Assessor)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Primary outcome measure (Mean (SD) of thalamic NAA level)</measure>
    <time_frame>Expected average 1 to 2 weeks after birth</time_frame>
    <description>Mean (SD) of thalamic NAA level in babies treated with Darbe when compared with untreated infants.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Secondary outcome measure (accurate quantification of NAA level)</measure>
    <time_frame>24 months</time_frame>
    <description>Number of babies in whom thalamic NAA level could be accurately quantified in 3Telsa and 1.5Tesla MR scanners.</description>
  </secondary_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Anticipated">150</enrollment>
  <condition>Neonatal Encephalopathy</condition>
  <arm_group>
    <arm_group_label>Darbepoetin Alpha</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>Administration of Darbepoetin Alpha (10 mcg/kg) IV x2 doses following cooling therapy.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Standard of care</arm_group_label>
    <arm_group_type>No Intervention</arm_group_type>
    <description>Standard of care: Cooling only</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Darbepoetin Alfa</intervention_name>
    <description>Administration of Darbepoetin Alpha (10 mcg/kg) IV x2 doses following cooling therapy.</description>
    <arm_group_label>Darbepoetin Alpha</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
        All the following criteria should be met&#xD;
&#xD;
          1. Babies aged &lt; 24 hours, gestation age &gt;36 weeks with a birthweight &gt;1.8kg.&#xD;
&#xD;
          2. Acute perinatal asphyxia (metabolic acidosis in cord and/or blood gas (pH&lt;7.0; base&#xD;
             deficit &gt; 16 mmol/L) within first 1 hour of birth). If pH between 7.01 and 7.15, a&#xD;
             base deficit between 10 and 15.9 mmol/L, additionally acute obstetric event and either&#xD;
             need for continued resuscitation or ventilation at 10 minutes after birth and/or 10&#xD;
             minutes Apgar score &lt;5 is required.&#xD;
&#xD;
          3. Evidence of mild, moderate, or severe encephalopathy on an NICHD neurological&#xD;
             examination performed between 1 and 6 hours of birth. The worst recorded&#xD;
             encephalopathy stage between 1 and 6 hours of birth should be used.&#xD;
&#xD;
          4. Cooling therapy initiated for neonatal encephalopathy within 6 hours of age as a part&#xD;
             of standard clinical care, with an intention of continuing for 72 hours.&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          1. Major life-threatening congenital malformation.&#xD;
&#xD;
          2. Concomitant participation in other research projects&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>1 Hour</minimum_age>
    <maximum_age>24 Hours</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_contact>
    <last_name>Sudhin Thayyil, PhD</last_name>
    <phone>02033132488</phone>
    <email>s.thayyil@imperial.ac.uk</email>
  </overall_contact>
  <overall_contact_backup>
    <last_name>Ismita Chhetri, PhD</last_name>
    <phone>02033132488</phone>
    <email>i.chhetri@imperial.ac.uk</email>
  </overall_contact_backup>
  <location>
    <facility>
      <name>Birmingham Womens Hospital</name>
      <address>
        <city>Birmingham</city>
        <country>United Kingdom</country>
      </address>
    </facility>
    <status>Not yet recruiting</status>
    <contact>
      <last_name>Manobi Boorah, FRCPCH</last_name>
    </contact>
  </location>
  <location>
    <facility>
      <name>Bradford Teaching Hospitals NHS Foundation Trust</name>
      <address>
        <city>Bradford</city>
        <country>United Kingdom</country>
      </address>
    </facility>
    <status>Not yet recruiting</status>
    <contact>
      <last_name>Sam Oddie</last_name>
      <email>sam.oddie@bthft.nhs.uk</email>
    </contact>
  </location>
  <location>
    <facility>
      <name>Cambridge University Hospitals NHS Foundation Trust</name>
      <address>
        <city>Cambridge</city>
        <country>United Kingdom</country>
      </address>
    </facility>
    <status>Not yet recruiting</status>
    <contact>
      <last_name>Topun Austin, MD</last_name>
    </contact>
  </location>
  <location>
    <facility>
      <name>Medway NHS Foundation Trust</name>
      <address>
        <city>Gillingham</city>
        <country>United Kingdom</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Dr Aung Soe, FRCPCH</last_name>
      <email>aung.soe@medway.nhs.uk</email>
    </contact>
    <contact_backup>
      <last_name>Russel Pryce, PhD</last_name>
    </contact_backup>
  </location>
  <location>
    <facility>
      <name>Liverpool Womens NHS Foundation Trust</name>
      <address>
        <city>Liverpool</city>
        <country>United Kingdom</country>
      </address>
    </facility>
    <status>Not yet recruiting</status>
    <contact>
      <last_name>Balamurugan Palanisami, MBBS</last_name>
      <email>Balamurugan.Palanisami@lwh.nhs.uk</email>
    </contact>
  </location>
  <location>
    <facility>
      <name>Homerton University Hospital</name>
      <address>
        <city>London</city>
        <country>United Kingdom</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Narendra Aldangady</last_name>
    </contact>
  </location>
  <location>
    <facility>
      <name>Imperial College Healthcare Trust</name>
      <address>
        <city>London</city>
        <country>United Kingdom</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Gaurav Atreja, MD</last_name>
      <phone>02033131134</phone>
      <email>gatreja@nhs.net</email>
    </contact>
    <contact_backup>
      <last_name>Maria Moreno Morales, BsC</last_name>
      <phone>02033132473</phone>
      <email>m.moreno-morales@imperial.ac.uk</email>
    </contact_backup>
  </location>
  <location>
    <facility>
      <name>Bedfordshire Hospitals NHS Foundation Trust</name>
      <address>
        <city>Luton</city>
        <country>United Kingdom</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Bharat Vakharia, MD</last_name>
    </contact>
  </location>
  <location>
    <facility>
      <name>The Newcastle Upon Tyne NHS Foundation Trust</name>
      <address>
        <city>Newcastle</city>
        <country>United Kingdom</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Dr Sundeep Harigopal</last_name>
      <email>sundeep.harigopal@nuth.nhs.uk</email>
    </contact>
  </location>
  <location_countries>
    <country>United Kingdom</country>
  </location_countries>
  <reference>
    <citation>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.</citation>
    <PMID>30447969</PMID>
  </reference>
  <verification_date>June 2022</verification_date>
  <study_first_submitted>June 11, 2020</study_first_submitted>
  <study_first_submitted_qc>June 15, 2020</study_first_submitted_qc>
  <study_first_posted type="Actual">June 16, 2020</study_first_posted>
  <last_update_submitted>July 27, 2022</last_update_submitted>
  <last_update_submitted_qc>July 27, 2022</last_update_submitted_qc>
  <last_update_posted type="Actual">July 29, 2022</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Brain Diseases</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Darbepoetin alfa</mesh_term>
  </intervention_browse>
  <patient_data>
    <sharing_ipd>Yes</sharing_ipd>
    <ipd_description>IPD data will be shared for meta-analysis</ipd_description>
    <ipd_info_type>Study Protocol</ipd_info_type>
    <ipd_info_type>Informed Consent Form (ICF)</ipd_info_type>
    <ipd_time_frame>2 years after the trial is published</ipd_time_frame>
    <ipd_access_criteria>Quality of the meta-analysis and the credibility of the team</ipd_access_criteria>
  </patient_data>
  <!-- Results have not yet been posted for this study                                          -->
</clinical_study>


download date: ClinicalTrials.gov processed this data on September 20, 2023
link text: Link to the current ClinicalTrials.gov record.
url: https://clinicaltrials.gov/ct2/show/NCT04432662
org study id: 277361
nct id: NCT04432662
lead sponsor: 
has dmc: Yes
is fda regulated drug: No
is fda regulated device: No
is us export: No
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 2 arm randomised control trial and aims to examine the physiological
      effects of 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 150 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 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.
Birth asphyxia related brain injury 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 neurodisability from neonatal encephalopathy is
      massive (£4 billion per year). In addition, birth asphyxia related (obstetric) claims
      accounted for almost half of the NHS litigation expenses in 2016/17 (approx. £2 billion),
      increasing by 15% from the previous year. It has been reported that the NHS cost to meet the
      complex life-long care needs of babies born with brain damage could be soon over £20m per
      child, and this situation is unsustainable to the NHS.The UK Government has recently (October
      2016) announced that reducing birth asphyxia related costs is a priority area for the
      Government.

      The only effective treatment for neonatal encephalopathy is whole-body cooling, with an
      estimated saving of £100 million per annum to the UK economy, since its introduction as
      standard therapy in the NHS in 2007. Cooling therapy has substantially improved the outcomes
      of babies with neonatal encephalopathy in the past decade. However, unacceptably high rate of
      adverse outcomes are still seen in cooled babies with moderate or severe neonatal
      encephalopathy : death 28% (range 24-38); cognitive impairment 24% (range 21-25); cerebral
      palsy 22% (range 13-28); epilepsy 19% (range 15-24); cortical visual impairment 6% (range
      1-10), with combined death or moderate/severe disability 48% (range 44- 53), and hence better
      treatments and further optimisation of cooling therapy is required. Additionally, cooling
      provides a window of opportunity for therapeutic interventions that may arrest or reduce
      secondary brain injury and it is unclear whether it provides protection from a sub-acute
      chronic injury that may have occurred during the antenatal period.

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

      Erythropoietin (Epo) is a widely used drug for treating anaemia in various age groups,
      including newborn infants. Several recent reviews have highlighted Epo 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 models. Of the long list of highly effective
      drugs in animal models of neonatal encephalopathy and early clinical studies, Epo is the most
      promising. It is the only drug with a long therapeutic window, is widely available,
      inexpensive, and can be easily administered on a once-a-day dosing schedule. It has been
      extensively evaluated in large randomised controlled trials for anaemia of prematurity and
      has a proven safety profile in newborn infants. Due to the regenerative effects and the
      longer therapeutic window provided by Epo, there is potential to impact the chronic injury
      caused to an antenatally compromised foetus.

      Although earlier studies have shown benefit with Epo, the time of initiation and duration of
      treatment remains uncertain. Moreover, recently published High-Dose Erythropoietin for
      Asphyxia and Encephalopathy (HEAL) trial which administered high dose Epo (1000u/kg/day)
      within 24 hours of birth and continued until 7 days of age failed to demonstrate the
      neuroprotective effect of erythropoietin in moderate and severe encephalopathy as an adjuvant
      to therapeutic hypothermia. This result suggest the exposure of the drug during the
      therapeutic hypothermia may not be beneficial due to an overlap in the neuroprotective
      mechanism. Perhaps a prolonged exposure of Epo following therapeutic hypothermia might be
      beneficial.

      Another erythropoiesis stimulating agent is Darbepoetin (Darbe) with dual erythropoietic and
      potential neuroprotective effects. Darbe is an ideal candidate to augment hypothermic
      neuroprotection as it is a long-acting erythropoiesis stimulating agent, allowing prolonged
      exposure with less dosing. In preclinical study in rats, darbepoetin alfa crossed the blood
      brain barrier and remained stable up to 24 hours. Neuroprotective effects of darbepoetin were
      demonstrated following the contusion injury and hemorrhage in rats. The DANCE study
      (Darbepoetin Administered to Neonates undergoing Cooling for Encephalopathy) randomised 30
      term infants with moderate to severe neonatal encephalopathy to placebo (n=10), 2 μg/kg Darbe
      (n=10) or 10 μg/kg Darbe (n=10). At 2 and 10 μg/kg Darbe, t1/2 was 24 and 32 hours. A dose of
      10 μg/kg dose achieved an AUC in the neuroprotective range and a terminal t1/2 of 53.4 hours
      when compared to the 2 μg/kg dose. No side effects attributable to Darbe were reported. In
      another feasibility and safety trial, infants with mild encephalopathy were randomised to
      receive Darbepoetin 10 μg/kg single dose within 24 hours and found the drug to be safe with
      no reported adverse events.

      The EDEN trial is a 2 arm randomised control trial and aims to examine the physiological
      effects of 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 150 babies with HIE (aged <24 hours) undergoing
      therapeutic hypothermia will be randomised to one of the following groups

        -  Arm 1:Darbepoetin Alpha (10 mcg/kg) IV x2 doses following cooling therapy.

        -  Arm 2: 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.
allocation: Randomized
intervention model: Parallel Assignment
primary purpose: Treatment
masking: Single (Outcomes Assessor)
measure: Primary outcome measure (Mean (SD) of thalamic NAA level)
time frame: Expected average 1 to 2 weeks after birth
description: Mean (SD) of thalamic NAA level in babies treated with Darbe when compared with untreated infants.
measure: Secondary outcome measure (accurate quantification of NAA level)
time frame: 24 months
description: Number of babies in whom thalamic NAA level could be accurately quantified in 3Telsa and 1.5Tesla MR scanners.
arm group label: Darbepoetin Alpha
arm group type: Active Comparator
description: Administration of Darbepoetin Alpha (10 mcg/kg) IV x2 doses following cooling therapy.
arm group label: Standard of care
arm group type: No Intervention
description: Standard of care: Cooling only
intervention type: Drug
intervention name: Darbepoetin Alfa
description: Administration of Darbepoetin Alpha (10 mcg/kg) IV x2 doses following cooling therapy.
arm group label: Darbepoetin Alpha
criteria: 
gender: All
minimum age: 1 Hour
maximum age: 24 Hours
healthy volunteers: No
last name: Sudhin Thayyil, PhD
phone: 02033132488
email: s.thayyil@imperial.ac.uk
last name: Ismita Chhetri, PhD
phone: 02033132488
email: i.chhetri@imperial.ac.uk
facility: 
status: Not yet recruiting
contact: 
facility: 
status: Not yet recruiting
contact: 
facility: 
status: Not yet recruiting
contact: 
facility: 
status: Recruiting
contact: 
contact backup: 
facility: 
status: Not yet recruiting
contact: 
facility: 
status: Recruiting
contact: 
facility: 
status: Recruiting
contact: 
contact backup: 
facility: 
status: Recruiting
contact: 
facility: 
status: Recruiting
contact: 
country: United Kingdom
citation: 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.
PMID: 30447969
responsible party type: Sponsor
mesh term: Brain Diseases
mesh term: Darbepoetin alfa
sharing ipd: Yes
ipd description: IPD data will be shared for meta-analysis
ipd info type: Study Protocol
ipd info type: Informed Consent Form (ICF)
ipd time frame: 2 years after the trial is published
ipd access criteria: Quality of the meta-analysis and the credibility of the team