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CompletedNCT00934700TOBYXeUpdated Apr 21, 2022Results posted

Neuroprotective Effects of Hypothermia Combined With Inhaled Xenon Following Perinatal Asphyxia

An interventional study of Xenon gas in Hypoxic Ischaemic Encephalopathy, sponsored by Imperial College London. Completed at 1 site in United Kingdom. Open to participants aged 1 Hour to 12 Hours. Per ClinicalTrials.gov, last updated 2022-04-21.

Sponsored by Imperial College London · Not applicable, Interventional, and Treatment

Phase
Not applicable
Study type
Interventional
Enrollment
92
Allocation
Randomized
Ages
1 Hour to 12 Hours
Sex
All
01

Study summary

This is a randomised controlled trial in newborn infants with perinatal asphyxial encephalopathy assessing whether a combination of hypothermia and inhaled xenon preserve cerebral metabolism and structure.

Read the detailed description

The study hypothesis is that: Following perinatal asphyxia treatment with a combination of hypothermia and inhaled xenon preserves cerebral metabolism and structure. Following informed parental consent, infants that continue to require endotracheal tube ventilation following resuscitation will be randomised to treatment with hypothermia only or hypothermia and xenon. All infants in both groups will be treated with hypothermia for 72 hours started within 6 hours of delivery and infants allocated to hypothermia and xenon will also receive 30% xenon (balanced with oxygen and air) for 24 hours through a purpose designed delivery system. Structured neurological examination will be done daily during the 1st week after birth and at discharge. MRS and MRI will be performed once between 4-10 days of age. MRS/MRI data analysis will be by investigators blinded to the allocated intervention.

02

Conditions studied

  • Hypoxic Ischaemic Encephalopathy

Keywords

  • perinatal asphyxia
  • encephalopathy
  • neuroprotection
03

Who can participate

Ages eligible
1 Hour to 12 Hours
Sexes eligible
All
Accepts healthy volunteers
No

Inclusion criteria

Infants will be eligible for enrolment into the trial if each of the following criteria is fulfilled:

  • Infants 36 to 43 weeks gestation with at least one of the following:

    • Apgar score of \<5 at 10 minutes after birth;
    • Continued need for resuscitation, including endotracheal or mask ventilation, at 10 minutes after birth;
    • Acidosis defined as pH \<7.00 and/or base deficit >15 mmol/L in umbilical cord blood sample or any blood sample within 60 minutes of birth (arterial or venous blood).
  • Moderate to severe encephalopathy consisting of altered state of consciousness (reduced or absent response to stimulation) and hypotonia, and abnormal primitive reflexes (weak or absent suck or Moro response). Clinical severity of HIE will be assessed by Thompson encephalopathy score, and modified Sarnat score.
  • At least 30 minutes duration of amplitude integrated EEG (aEEG) recording that shows moderately abnormal or suppressed background aEEG activity or seizures

Exclusion criteria

Exclusion Criteria:

  • If treatment with hypothermia is delayed beyond 6 hours, or infants are expected to be >12 hours of age at the time of randomisation; Infants with ventilatory oxygen requirement > 70%; Attending clinician considers infant not suitable to participate because of other serious congenital abnormalities, or the infant's condition appears terminal.
04

Study design

Phase
Not applicable
Primary purpose
Treatment
Allocation
Randomized
Intervention model
Parallel assignment
Masking
Single (Outcomes assessor)
Enrollment
92 participants (actual)

Study arms

  • Experimental
    Combination of hypothermia and xenon

    Combination of hypothermia and inhaled xenon

    Other: Xenon gas

  • No intervention
    Hypothermia and standard intensive care

    Hypothermia and standard intensive care

Interventions

  • OtherXenon gas

    30% Xenon gas inhaled for 24 hours

    Also known as: LENOXe

05

What researchers measure

Primary outcomes

  1. Lactate (Lac) / N Acetyl Aspartate (NAA) Ratio on Magnetic Resonance Spectroscopy

    Cerebral Lac/NAA ratio measured by magnetic resonance spectroscopy in patents

    Time frame: 10 days

  2. Cerebral Fractional Anisotropy Measured by Diffusion Weighted Magnetic Resonance Imaging

    Fractional anisotropy (FA) is a measure of tissue integrity in white matter tracts measured by diffusion tensor MRI, and it has been used in work in animals to assess potential neuroprotectants and can be used to predict subsequent neurological outcomes after birth asphyxia, including in infants treated with moderate hypothermia. It is a scalar value between 0-1 that describe anisotropy of a diffusion process. A value of zero means that diffusion is unrestricted (or equally restricted) in all directions. A value of one means that diffusion occurs only along one axis and is fully restricted along all other directions" or similar. Fractional anisotropy data were extracted froma mask of the posterior limb of the internal capsule via tract-based spatial statistics. \*Coefficient of variation=√(exp(var)-1), where var is the variance on the log scale

    Time frame: 10 days

Secondary outcomes

  1. Amiel Tison Evaluation at Hospital Discharge

    Amiel Tison neurological assessment at discharge from hospital. Amiel Tison evaluation was developed to detect transient and permanent abnormalities in an infant's neuromotor development. Its main focus is to examine active and passive muscle tone.

    Time frame: At discharge from hospital

06

Results

Posted Apr 21, 2022

Participant flow

Participant flow — Overall Study
MilestoneCombination of Hypothermia and XenonHypothermia and Standard Intensive Care
Started4646
Completed3334
Not completed1312
Withdrew: Missing scan59
Withdrew: Death83

Outcome measures

PrimaryLactate (Lac) / N Acetyl Aspartate (NAA) Ratio on Magnetic Resonance Spectroscopy

Cerebral Lac/NAA ratio measured by magnetic resonance spectroscopy in patents

Time frame:
10 days
Reported as:
Geometric mean · ratio
Lactate (Lac) / N Acetyl Aspartate (NAA) Ratio on Magnetic Resonance Spectroscopy
ratioCombination of Hypothermia and XenonHypothermia and Standard Intensive Care
Lactate (Lac) / N Acetyl Aspartate (NAA) Ratio on Magnetic Resonance Spectroscopy0.25 ± 1.300.28 ± 1.45
PrimaryCerebral Fractional Anisotropy Measured by Diffusion Weighted Magnetic Resonance Imaging

Fractional anisotropy (FA) is a measure of tissue integrity in white matter tracts measured by diffusion tensor MRI, and it has been used in work in animals to assess potential neuroprotectants and can be used to predict subsequent neurological outcomes after birth asphyxia, including in infants treated with moderate hypothermia. It is a scalar value between 0-1 that describe anisotropy of a diffusion process. A value of zero means that diffusion is unrestricted (or equally restricted) in all directions. A value of one means that diffusion occurs only along one axis and is fully restricted along all other directions" or similar. Fractional anisotropy data were extracted froma mask of the posterior limb of the internal capsule via tract-based spatial statistics. \*Coefficient of variation=√(exp(var)-1), where var is the variance on the log scale

Time frame:
10 days
Reported as:
Mean · units on a scale
Cerebral Fractional Anisotropy Measured by Diffusion Weighted Magnetic Resonance Imaging
units on a scaleCombination of Hypothermia and XenonHypothermia and Standard Intensive Care
Cerebral Fractional Anisotropy Measured by Diffusion Weighted Magnetic Resonance Imaging0.40 ± 0.050.40 ± 0.05
SecondaryAmiel Tison Evaluation at Hospital Discharge

Amiel Tison neurological assessment at discharge from hospital. Amiel Tison evaluation was developed to detect transient and permanent abnormalities in an infant's neuromotor development. Its main focus is to examine active and passive muscle tone.

Time frame:
At discharge from hospital
Reported as:
Count of participants · Participants
Amiel Tison Evaluation at Hospital Discharge
ParticipantsCombination of Hypothermia and XenonHypothermia and Standard Intensive Care
Normal or mildly abnormal3029
Moderately abnormal37
Very abnormal21

Adverse events

Collected over 10days. Non-serious events are listed at a 0% frequency threshold.

Adverse event summary by group
GroupDeathsSeriousOther
Combination of Hypothermia and Xenon11/46 (23.9%)0/46 (0%)2/46 (4.3%)
Hypothermia and Standard Intensive Care9/46 (19.6%)0/46 (0%)0/46 (0%)
Most frequent other events
Most frequent other events
EventCombination of Hypothermia and XenonHypothermia and Standard Intensive Care
Subcutaneous fat necrosisSkin and subcutaneous tissue disorders1/460/46
Transient desaturation during MRI scanGeneral disorders1/460/46

Baseline characteristics

Age, Continuous
Age, Continuous(weeks, gestation)Combination of Hypothermia and XenonHypothermia and Standard Intensive CareTotal
Mean39.8 ± 1.739.8 ± 1.339.8 ± 1.5
Sex: Female, Male
Sex: Female, Male(Participants)Combination of Hypothermia and XenonHypothermia and Standard Intensive CareTotal
Female202545
Male262147
Race and Ethnicity Not Collected
Race and Ethnicity Not Collected(Participants)Combination of Hypothermia and XenonHypothermia and Standard Intensive CareTotal
Count of participants——0
Region of Enrollment
Region of Enrollment(participants)Combination of Hypothermia and XenonHypothermia and Standard Intensive CareTotal
United Kingdom464692
07

Study locations

1 site
  • Imperial College Academic Healthcare Trust
    London, W12 0HS, United Kingdom
08

References and documents

Publications

  • Azzopardi D, Robertson NJ, Bainbridge A, Cady E, Charles-Edwards G, Deierl A, Fagiolo G, Franks NP, Griffiths J, Hajnal J, Juszczak E, Kapetanakis B, Linsell L, Maze M, Omar O, Strohm B, Tusor N, Edwards AD. Moderate hypothermia within 6 h of birth plus inhaled xenon versus moderate hypothermia alone after birth asphyxia (TOBY-Xe): a proof-of-concept, open-label, randomised controlled trial. Lancet Neurol. 2016 Feb;15(2):145-153. doi: 10.1016/S1474-4422(15)00347-6. Epub 2015 Dec 19. PubMed 26708675 ↗
  • Shankaran S. Outcomes of hypoxic-ischemic encephalopathy in neonates treated with hypothermia. Clin Perinatol. 2014 Mar;41(1):149-59. doi: 10.1016/j.clp.2013.10.008. PubMed 24524452 ↗

Individual participant data

Plan to share: No

09

Registry details

Key details

Study ID
NCT00934700
Lead sponsor
Imperial College London
Collaborators
University College London Hospitals, Guy's and St Thomas' NHS Foundation Trust
Responsible party
Sponsor
First posted
Jul 8, 2009
Start date
Feb 2012
Primary completion
Sep 2014
Completion
Sep 2014
Results posted
Apr 21, 2022
Last update
Apr 21, 2022

Study contacts

Denis Azzopardi, MD
principal investigator · Imperial College London

Oversight

Data monitoring committee
Yes
FDA-regulated drug
No
View the source record on ClinicalTrials.gov ↗

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