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

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.

Study Overview

• Status: Completed
• Conditions: Hypoxic Ischaemic Encephalopathy
• Intervention / Treatment: Other: Xenon gas

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.

• Study Type: Interventional
• Enrollment (Actual): 92
• Phase: Not Applicable

Contacts and Locations

Study Locations

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

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 1 hour to 12 hours (Child)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Single

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Combination of hypothermia and xenon; Combination of hypothermia and inhaled xenon	Other: Xenon gas; 30% Xenon gas inhaled for 24 hours; Other Names: LENOXe
No Intervention: Hypothermia and standard intensive care

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Lactate (Lac) / N Acetyl Aspartate (NAA) Ratio on Magnetic Resonance Spectroscopy	Cerebral Lac/NAA ratio measured by magnetic resonance spectroscopy in patents	10 days
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	10 days

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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.	At discharge from hospital

Collaborators and Investigators

• Sponsor: Imperial College London
• Collaborators: University College London Hospitals; Guy's and St Thomas' NHS Foundation Trust
• Investigators: Principal Investigator: Denis Azzopardi, MD, Imperial College London

Publications and helpful links

General Publications

• 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.
• 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.

Study record dates

Study Major Dates

• Study Start: February 1, 2012
• Primary Completion (Actual): September 1, 2014
• Study Completion (Actual): September 1, 2014

Study Registration Dates

• First Submitted: July 7, 2009
• First Submitted That Met QC Criteria: July 7, 2009
• First Posted (Estimate): July 8, 2009

Study Record Updates

• Last Update Posted (Actual): April 21, 2022
• Last Update Submitted That Met QC Criteria: April 20, 2022
• Last Verified: April 1, 2022

More Information

Terms related to this study

• Keywords: neuroprotection; encephalopathy; perinatal asphyxia
• Additional Relevant MeSH Terms: Pathologic Processes; Cardiovascular Diseases; Vascular Diseases; Cerebrovascular Disorders; Central Nervous System Diseases; Nervous System Diseases; Wounds and Injuries; Signs and Symptoms, Respiratory; Death; Body Temperature Changes; Hypoxia; Hypoxia, Brain; Brain Ischemia; Brain Diseases; Hypothermia; Hypoxia-Ischemia, Brain; Asphyxia; Physiological Effects of Drugs; Central Nervous System Depressants; Anesthetics, General; Anesthetics; Anesthetics, Inhalation; Xenon
• Other Study ID Numbers: prot-002-2009

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No