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Xenon and Cooling Therapy in Babies at High Risk of Brain Injury Following Poor Condition at Birth (CoolXenon3)

This study is currently recruiting participants.
Verified August 2017 by University Hospitals Bristol NHS Foundation Trust
Sponsor:
ClinicalTrials.gov Identifier:
NCT02071394
First Posted: February 25, 2014
Last Update Posted: August 25, 2017
The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
Collaborator:
University of Bristol
Information provided by (Responsible Party):
University Hospitals Bristol NHS Foundation Trust
  Purpose
This study examines the effect of inhaled xenon gas in the treatment of newborn infants with hypoxic-ischemic encephalopathy (HIE) in combination with cooling, which is the standard treatment for this condition. The hypothesis is that the xenon + cooling combination will produce better neuroprotection than the standard treatment of cooling alone.

Condition Intervention Phase
Hypoxic Ischaemic Encephalopathy Drug: Xenon gas Other: Whole body cooling Phase 2

Study Type: Interventional
Study Design: Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Xenon and Cooling Therapy in Babies at High Risk of Brain Injury Following Poor Condition at Birth: A Randomised Pilot Outcomes Study (COOLXENON3 Study)

Further study details as provided by University Hospitals Bristol NHS Foundation Trust:

Primary Outcome Measures:
  • Death and moderate or severe disability - Bayley III neurodevelopmental outcome score [ Time Frame: 18 months of age ]
    Cognition, language and motor scores, hearing and vision


Secondary Outcome Measures:
  • Brain MRI [ Time Frame: Before hospital discharge, within 2 weeks of birth ]
    Magnetic Resonance Imaging findings at less than 2 weeks of age

  • Amplitude Integrated Electroencephalogram (aEEG) grading [ Time Frame: Before hospital discharge, usually within 1 week of birth ]
    Number of hours after birth when aEEG voltage has reached a normal or discontinuous normal pattern


Other Outcome Measures:
  • Dubovitz [ Time Frame: Seven days ]
    Developmental assessment

  • Number of normal infants [ Time Frame: 18-24 months ]
    Bayley III composite score ≥ 85 and no neurosensory disability as described above


Estimated Enrollment: 52
Study Start Date: March 2014
Estimated Study Completion Date: August 31, 2019
Estimated Primary Completion Date: August 31, 2019 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: 72h cooling + 18h xenon inhalation
Babies in poor condition at birth and referred to our neonatal unit for standard therapy of cooling to 33.5 degree C body temperature will be randomised to receive xenon gas at 50% concentration for 18 hours
Drug: Xenon gas
Inhalation via endotracheal tube of 50% xenon for 18 hours, including during transport for outborn babies, starting within 5 hours after birth.
Other Name: LENOXe
Other: Whole body cooling
Cooling of baby to reduce rectal temperature to 33.5 degree Centigrade(standard treatment), including during transport for outborn babies, starting within 3 hours after birth.
Other Name: Therapeutic hypothermia
Active Comparator: Standard 72 h whole body cooling therapy
Whole body cooling therapy to rectal temperature of 33.5 degree Centigrade (standard therapy)
Other: Whole body cooling
Cooling of baby to reduce rectal temperature to 33.5 degree Centigrade(standard treatment), including during transport for outborn babies, starting within 3 hours after birth.
Other Name: Therapeutic hypothermia

  Eligibility

Information from the National Library of Medicine

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Ages Eligible for Study:   Child, Adult, Senior
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Infants will be eligible for for the trial if the St Michael's hospital standard inclusion criteria for cooling and additional inclusion criteria for xenon administration are met.

St Michael's hospital standard inclusion criteria for standard hypothermia treatment of 72 hrs:

A: Neonates born at greater than 36 weeks gestation (estimated or clinical assessment) with at least ONE of the following:

  1. Apgar score of ≤5 at ten minutes after birth
  2. Continued need for resuscitation, including tracheal or mask ventilation, at ten minutes after birth
  3. Acidosis, defined as either umbilical cord pH or any arterial, venous or capillary pH within 60 minutes of birth less < 7.00
  4. Base deficit ≥16 mmol/L in umbilical cord blood sample or any blood sample within 60 minutes of birth (arterial or venous blood).

If the infant meets criterion A then assess for neurological abnormality using criterion B and C (by trained personnel):

B: Moderate or Severe encephalopathy as evidenced by any of the following:

  1. Altered state of consciousness (reduced or absent responses or pathological irritability and hyper responsive and at least ONE or more of the following:
  2. Hypotonia
  3. Abnormal reflexes including oculomotor or pupillary abnormalities
  4. Absent or weak suck
  5. Clinical seizures, as recorded by trained personnel

And

C: At least 30 minutes duration of amplitude-integrated electroencephalography (aEEG) recording that shows abnormal background aEEG activity. The decision to cool is based on the worst 30 min section of the aEEG, not the best [35] or seizures (clinical or electrical) thus meeting ONE of the following:

  1. Normal background with some (> 5 min) electrical seizure activity
  2. Moderately abnormal activity (upper margin of trace >10μV and lower margin <5μV)
  3. Suppressed activity (upper margin of trace <10μV and lower margin of trace <5μV)
  4. Definite seizure activity

Additional inclusion criteria for xenon:

Before being considered for additional inhaled xenon therapy via the breathing gas mixture, the infant would need to meet further additional entry criteria (all must be met):

  1. Intubated, ventilated, sedated, being cooled
  2. ≤ 5 hours old
  3. Any seizures under control
  4. Weight > 2nd centile for gestational age
  5. Stable cardiovascular parameters; Mean arterial pressure >40mmHg.
  6. Oxygen requirement via mechanical ventilator ≤ 40%.
  7. Positive End Expiratory Pressure (PEEP) requirement ≤ 8cm H2O
  8. Arterial (preferable)/capillary/venous pCO2 within acceptable range (<7kPa)
  9. Postnatal age ≤ 5 hours
  10. Absence of major congenital abnormalities, imperforate anus and in particular any bowel obstruction, congenital abnormalities suggestive of chromosomal anomaly or other syndromes that include brain dysgenesis. Congenital syndromes affecting the brain should be excluded when diagnosed.

Exclusion criteria for cooling in the CoolXenon3 study:

  1. Infants expected to be greater than 3 hours of age at the time of starting cooling treatment.
  2. Futility. Where prognosis is considered to be hopeless e.g. no cardiac output for 20 minutes.
  Contacts and Locations
Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02071394


Contacts
Contact: Marianne Thoresen, Professor +44117 342 5226 carol.s.bond@bristol.ac.uk
Contact: Carol Bond +44117 342 5226 carol.s.bond@bristol.ac.uk

Locations
United Kingdom
St Michael's Hospital Recruiting
Bristol, United Kingdom, BS2 8EG
Principal Investigator: Ela Chakkarapani, MD         
Imperial College / Hammersmith Hospital Recruiting
London, United Kingdom, W12 0HS
Contact: Vania Oliveira, BSc, MSc    (44) 203 313 2473    v.oliveira@imperial.ac.uk   
Principal Investigator: Sudhin Thayyil, MD, PhD         
Sponsors and Collaborators
University Hospitals Bristol NHS Foundation Trust
University of Bristol
Investigators
Principal Investigator: Marianne Thoresen, Professor University of Bristol
  More Information

Publications:
Chakkarapani E, Thoresen M, Hobbs CE, Aquilina K, Liu X, Dingley J. A closed-circuit neonatal xenon delivery system: a technical and practical neuroprotection feasibility study in newborn pigs. Anesth Analg. 2009 Aug;109(2):451-60. doi: 10.1213/ane.0b013e3181aa9550.
Hobbs C, Thoresen M, Tucker A, Aquilina K, Chakkarapani E, Dingley J. Xenon and hypothermia combine additively, offering long-term functional and histopathologic neuroprotection after neonatal hypoxia/ischemia. Stroke. 2008 Apr;39(4):1307-13. doi: 10.1161/STROKEAHA.107.499822. Epub 2008 Feb 28.
Thoresen M, Hobbs CE, Wood T, Chakkarapani E, Dingley J. Cooling combined with immediate or delayed xenon inhalation provides equivalent long-term neuroprotection after neonatal hypoxia-ischemia. J Cereb Blood Flow Metab. 2009 Apr;29(4):707-14. doi: 10.1038/jcbfm.2008.163. Epub 2009 Jan 14.
Chakkarapani E, Dingley J, Liu X, Hoque N, Aquilina K, Porter H, Thoresen M. Xenon enhances hypothermic neuroprotection in asphyxiated newborn pigs. Ann Neurol. 2010 Sep;68(3):330-41. doi: 10.1002/ana.22016.
Chakkarapani E, Thoresen M, Liu X, Walloe L, Dingley J. Xenon offers stable haemodynamics independent of induced hypothermia after hypoxia-ischaemia in newborn pigs. Intensive Care Med. 2012 Feb;38(2):316-23. doi: 10.1007/s00134-011-2442-7. Epub 2011 Dec 13.
Dingley J, Tooley J, Liu X, Scull-Brown E, Elstad M, Chakkarapani E, Sabir H, Thoresen M. Xenon ventilation during therapeutic hypothermia in neonatal encephalopathy: a feasibility study. Pediatrics. 2014 May;133(5):809-18. doi: 10.1542/peds.2013-0787.
Dingley J, Liu X, Gill H, Smit E, Sabir H, Tooley J, Chakkarapani E, Windsor D, Thoresen M. The feasibility of using a portable xenon delivery device to permit earlier xenon ventilation with therapeutic cooling of neonates during ambulance retrieval. Anesth Analg. 2015 Jun;120(6):1331-6. doi: 10.1213/ANE.0000000000000693.

Responsible Party: University Hospitals Bristol NHS Foundation Trust
ClinicalTrials.gov Identifier: NCT02071394     History of Changes
Other Study ID Numbers: CH/2013/4414
2013-004478-80 ( EudraCT Number )
13/SW/0300 ( Other Identifier: NRES Committee South West )
CI/2013/0050 ( Other Identifier: MHRA Devices )
12893/0235/001-0001 ( Other Identifier: MHRA Medicines )
First Submitted: February 21, 2014
First Posted: February 25, 2014
Last Update Posted: August 25, 2017
Last Verified: August 2017
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Undecided

Keywords provided by University Hospitals Bristol NHS Foundation Trust:
Xenon
Hypothermia
Hypoxic Ischemic Encephalopathy
Newborn
Neonate
Term
Neuroprotection
Cooling
HIE

Additional relevant MeSH terms:
Brain Injuries
Brain Diseases
Brain Ischemia
Hypoxia-Ischemia, Brain
Central Nervous System Diseases
Nervous System Diseases
Craniocerebral Trauma
Trauma, Nervous System
Wounds and Injuries
Cerebrovascular Disorders
Vascular Diseases
Cardiovascular Diseases
Hypoxia, Brain
Xenon
Anesthetics, Inhalation
Anesthetics, General
Anesthetics
Central Nervous System Depressants
Physiological Effects of Drugs


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