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Neuroprotective Effects of Hypothermia Combined With Inhaled Xenon Following Perinatal Asphyxia (TOBYXe)

Primary Purpose

Hypoxic Ischaemic Encephalopathy

Status

Completed

Phase

Not Applicable

Locations

United Kingdom

Study Type

Interventional

Intervention

Xenon gas

About this trial

This is an interventional treatment trial for Hypoxic Ischaemic Encephalopathy focused on measuring perinatal asphyxia, encephalopathy, neuroprotection

Eligibility Criteria

1 Hour - 12 Hours (Child)All SexesDoes not accept healthy volunteers

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:

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.

Sites / Locations

Imperial College Academic Healthcare Trust

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

No Intervention

Arm Label

Combination of hypothermia and xenon

Hypothermia and standard intensive care

Arm Description

Combination of hypothermia and inhaled xenon

Hypothermia and standard intensive care

Outcomes

Primary Outcome Measures

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

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

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

Secondary Outcome Measures

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.

Full Information

NCT ID

NCT00934700

First Posted

July 7, 2009

Last Updated

April 20, 2022

Sponsor

Imperial College London

Collaborators

University College London Hospitals, Guy's and St Thomas' NHS Foundation Trust

1. Study Identification

Unique Protocol Identification Number

NCT00934700

Brief Title

Neuroprotective Effects of Hypothermia Combined With Inhaled Xenon Following Perinatal Asphyxia

Acronym

TOBYXe

Official Title

Neuroprotective Effects of Hypothermia Combined With Inhaled Xenon Following Perinatal Asphyxia

Study Type

Interventional

2. Study Status

Record Verification Date

April 2022

Overall Recruitment Status

Completed

Study Start Date

February 2012 (undefined)

Primary Completion Date

September 2014 (Actual)

Study Completion Date

September 2014 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Sponsor

Name of the Sponsor

Imperial College London

Collaborators

University College London Hospitals, Guy's and St Thomas' NHS Foundation Trust

4. Oversight

Studies a U.S. FDA-regulated Drug Product

Data Monitoring Committee

Yes

5. Study Description

Brief 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.

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Hypoxic Ischaemic Encephalopathy

Keywords

perinatal asphyxia, encephalopathy, neuroprotection

7. Study Design

Primary Purpose

Treatment

Study Phase

Not Applicable

Interventional Study Model

Parallel Assignment

Masking

Outcomes Assessor

Allocation

Randomized

Enrollment

92 (Actual)

8. Arms, Groups, and Interventions

Arm Title

Combination of hypothermia and xenon

Arm Type

Experimental

Arm Description

Combination of hypothermia and inhaled xenon

Arm Title

Hypothermia and standard intensive care

Arm Type

No Intervention

Arm Description

Hypothermia and standard intensive care

Intervention Type

Other

Intervention Name(s)

Xenon gas

Other Intervention Name(s)

LENOXe

Intervention Description

30% Xenon gas inhaled for 24 hours

Primary Outcome Measure Information:

Title

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

Description

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

Time Frame

10 days

Title

Cerebral Fractional Anisotropy Measured by Diffusion Weighted Magnetic Resonance Imaging

Description

Time Frame

10 days

Secondary Outcome Measure Information:

Title

Amiel Tison Evaluation at Hospital Discharge

Description

Time Frame

At discharge from hospital

10. Eligibility

Sex

All

Minimum Age & Unit of Time

1 Hour

Maximum Age & Unit of Time

12 Hours

Accepts Healthy Volunteers

Eligibility Criteria

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: 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.

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

Denis Azzopardi, MD

Organizational Affiliation

Imperial College London

Official's Role

Principal Investigator

Facility Information:

Facility Name

Imperial College Academic Healthcare Trust

City

London

ZIP/Postal Code

W12 0HS

Country

United Kingdom

12. IPD Sharing Statement

Plan to Share IPD

Citations:

PubMed Identifier

26708675

Citation

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.

Results Reference

result

PubMed Identifier

24524452

Citation

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.

Results Reference

derived

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Neuroprotective Effects of Hypothermia Combined With Inhaled Xenon Following Perinatal Asphyxia

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