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Trial details imported from ClinicalTrials.gov

For full trial details, please see the original record at https://clinicaltrials.gov/show/NCT03089905




Registration number
NCT03089905
Ethics application status
Date submitted
8/03/2017
Date registered
24/03/2017
Date last updated
5/04/2021

Titles & IDs
Public title
A Study to Compare the Long-term Outcomes After Two Different Anaesthetics
Scientific title
Neurodevelopmental Outcome After Standard Dose Sevoflurane Versus Low-dose Sevoflurane/Dexmedetomidine/Remifentanil Anaesthesia in Young Children- The TREX Trial
Secondary ID [1] 0 0
TREX TRIAL
Universal Trial Number (UTN)
Trial acronym
TREX
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Anesthesia 0 0
Neurotoxicity 0 0
Child Development 0 0
Condition category
Condition code
Neurological 0 0 0 0
Other neurological disorders
Injuries and Accidents 0 0 0 0
Poisoning

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Treatment: Drugs - Sevoflurane
Treatment: Drugs - Remifentanil
Treatment: Drugs - Dexmedetomidine

Experimental: Sevoflurane/dexmedetomidine/remifentanil - Dexmedetomidine: loading dose of 1mcg/kg over 10 minutes followed by an infusion of at 1 mcg/kg/hr.
Remifentanil: loading dose 1 mcg/kg over 2 minutes followed by an infusion starting at 0.1 mcg/kg/min or greater.
Sevoflurane: end tidal concentration of 0.6 -0.8% or less.

Active Comparator: Sevoflurane - End tidal concentration of 2.5-3.0% or greater.


Treatment: Drugs: Sevoflurane
Experimental arm: end tidal concentration of 0.6 -0.8% or less. Active comparator arm: end tidal concentration of 2.5-3.0% or greater.

Treatment: Drugs: Remifentanil
Experimental arm: loading dose: 1 mcg/kg, infusion starting at 0.1 mcg/kg/min or greater.

Treatment: Drugs: Dexmedetomidine
Experimental arm: loading dose:1mcg/kg, infusion: 1 mcg/kg/hr.

Intervention code [1] 0 0
Treatment: Drugs
Comparator / control treatment
Control group

Outcomes
Primary outcome [1] 0 0
Full Scale IQ - Global cognitive function as assessed by the full scale IQ score of the Wechsler Preschool and Primary School Intelligence Scale.
Timepoint [1] 0 0
3 years of age
Secondary outcome [1] 0 0
incidence of intra-operative hypotension - Blood pressure measurements will be recorded during surgery
Timepoint [1] 0 0
150 minutes- duration of surgery (baseline)
Secondary outcome [2] 0 0
incidence of intra-operative bradycardia - Heart rate will be recorded during surgery
Timepoint [2] 0 0
150 minutes- duration of surgery (baseline)
Secondary outcome [3] 0 0
Post-operative pain - Pain scores will be recorded after surgery
Timepoint [3] 0 0
60 minutes- after surgery
Secondary outcome [4] 0 0
Time to recovery - Time of removal of airway, eye-opening and discharge from PACU will be recorded.
Timepoint [4] 0 0
60 minutes- after surgery
Secondary outcome [5] 0 0
Language outcomes - Clinical Evaluation of Language Fundamentals- Preschool, Version 2 (CELF-P2)
Timepoint [5] 0 0
3 years of age
Secondary outcome [6] 0 0
Attention/Executive Function/impulse control - A Developmental NEuroPSYchological Assessment- Second Edition (NEPSY-2): Statue Subtest
Timepoint [6] 0 0
3 years of age
Secondary outcome [7] 0 0
Memory - A Developmental NEuroPSYchological Assessment- Second Edition (NEPSY-2): Narrative memory
Timepoint [7] 0 0
3 years of age
Secondary outcome [8] 0 0
Adaptive behaviour - Adaptive Behavior Assessment System - Third Edition (ABAS-III)
Timepoint [8] 0 0
3 years of age
Secondary outcome [9] 0 0
Clinical Behavior - Child Behavior Checklist (CBCL)
Timepoint [9] 0 0
3 years of age
Secondary outcome [10] 0 0
Executive Function - Behavior Rating of Executive Function- Preschool (BRIEF-P)
Timepoint [10] 0 0
3 years of age
Secondary outcome [11] 0 0
Social Skills - Social Skills Improvement System (SSIS)
Timepoint [11] 0 0
3 years of age

Eligibility
Key inclusion criteria
- Younger than 2 years (chronological age)

- Scheduled for anaesthesia that is expected to last at least 2 hours (and/or total
operating room time is scheduled to be at least 2.5 hours)

- Has a legally acceptable representative capable of understanding the informed consent
document and providing consent on the participant's behalf.
Minimum age
No limit
Maximum age
2 Years
Gender
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
- Known neurologic, chromosomal or congenital anomaly which is likely to be associated
with poor neurobehavioural outcome

- Existing diagnosis of behavioural or neurodevelopmental disability

- Prematurity (defined as < 36 weeks gestational age at birth)

- Birth weight less than 2 kg.

- Congenital cardiac disease requiring surgery

- Intracranial neurosurgery and intracranial craniofacial surgery (isolated cleft lip is
not an exclusion)

- Previous cumulative exposure to general anaesthesia exceeding 2 hours

- Planned future cumulative exposure to anaesthesia exceeding 2 hours before the age of
3 years.

- Any specific contra-indication to any aspect of the protocol

- Previous adverse reaction to any anaesthetic

- Circumstances likely to make long term follow-up impossible

- Living in a household where the primary language spoken at home is not a language in
which we can administer the Wechsler Preschool and Primary School Intelligence Scale

- Planned postoperative sedation with any agent except opioids (e.g. benzodiazepines,
dexmedetomidine, ketamine, barbiturates, propofol, clonidine, chloral hydrate, and
other non-opioid sedatives). For example if such sedation is planned for
post-operative ventilation

Study design
Purpose of the study
Treatment
Allocation to intervention
Randomised controlled trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Masking / blinding
Blinded (masking used)
Who is / are masked / blinded?


The people assessing the outcomes
Intervention assignment
Parallel
Other design features
Phase
Phase 3
Type of endpoint(s)
Statistical methods / analysis

Recruitment
Recruitment status
Recruiting
Data analysis
Reason for early stopping/withdrawal
Other reasons
Date of first participant enrolment
Anticipated
Actual
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
NSW,QLD,SA,VIC,WA
Recruitment hospital [1] 0 0
Sydney Children's Hospital - Randwick
Recruitment hospital [2] 0 0
Children's Hospital at Westmead - Westmead
Recruitment hospital [3] 0 0
Queensland Children's Hospital - Brisbane
Recruitment hospital [4] 0 0
Women's and Children's Hospital - Adelaide
Recruitment hospital [5] 0 0
Flinders Medical Centre - Bedford Park
Recruitment hospital [6] 0 0
Royal Children's Hospital - Parkville
Recruitment hospital [7] 0 0
Perth Children's Hospital - Perth
Recruitment postcode(s) [1] 0 0
2031 - Randwick
Recruitment postcode(s) [2] 0 0
2145 - Westmead
Recruitment postcode(s) [3] 0 0
4101 - Brisbane
Recruitment postcode(s) [4] 0 0
5006 - Adelaide
Recruitment postcode(s) [5] 0 0
5042 - Bedford Park
Recruitment postcode(s) [6] 0 0
3052 - Parkville
Recruitment postcode(s) [7] 0 0
6008 - Perth
Recruitment outside Australia
Country [1] 0 0
United States of America
State/province [1] 0 0
Massachusetts
Country [2] 0 0
United States of America
State/province [2] 0 0
Pennsylvania
Country [3] 0 0
United States of America
State/province [3] 0 0
Texas
Country [4] 0 0
Italy
State/province [4] 0 0
Bologna
Country [5] 0 0
Italy
State/province [5] 0 0
Genova
Country [6] 0 0
Italy
State/province [6] 0 0
Pisa
Country [7] 0 0
Italy
State/province [7] 0 0
Roma

Funding & Sponsors
Primary sponsor type
Other
Name
Murdoch Childrens Research Institute
Address
Country
Other collaborator category [1] 0 0
Other
Name [1] 0 0
Sydney Children's Hospitals Network
Address [1] 0 0
Country [1] 0 0
Other collaborator category [2] 0 0
Other
Name [2] 0 0
Baylor College of Medicine
Address [2] 0 0
Country [2] 0 0
Other collaborator category [3] 0 0
Other
Name [3] 0 0
Boston Children's Hospital
Address [3] 0 0
Country [3] 0 0
Other collaborator category [4] 0 0
Other
Name [4] 0 0
The Cleveland Clinic
Address [4] 0 0
Country [4] 0 0
Other collaborator category [5] 0 0
Other
Name [5] 0 0
University of Texas, Southwestern Medical Center at Dallas
Address [5] 0 0
Country [5] 0 0
Other collaborator category [6] 0 0
Other
Name [6] 0 0
Royal Children's Hospital, Melbourne
Address [6] 0 0
Country [6] 0 0
Other collaborator category [7] 0 0
Other
Name [7] 0 0
Children's Hospital of Philadelphia
Address [7] 0 0
Country [7] 0 0
Other collaborator category [8] 0 0
Other
Name [8] 0 0
Queensland Children's Hospital
Address [8] 0 0
Country [8] 0 0
Other collaborator category [9] 0 0
Other
Name [9] 0 0
Perth Children's Hospital
Address [9] 0 0
Country [9] 0 0
Other collaborator category [10] 0 0
Other
Name [10] 0 0
Women's and Children's Hospital, Adelaide
Address [10] 0 0
Country [10] 0 0
Other collaborator category [11] 0 0
Other
Name [11] 0 0
Istituto Giannina Gaslini, Genoa, Italy
Address [11] 0 0
Country [11] 0 0
Other collaborator category [12] 0 0
Other
Name [12] 0 0
Flinders Medical Centre
Address [12] 0 0
Country [12] 0 0

Ethics approval
Ethics application status

Summary
Brief summary
There is considerable evidence that most general anaesthetics modulate brain development in
animal studies. The impact is greater with longer durations of exposure and in younger
animals. There is great controversy over whether or not these animal data are relevant to
human clinical scenarios.

The changes seen in preclinical studies are greatest with GABA agonists and NMDA antagonists
such as volatile anaesthetics (eg sevoflurane), propofol, midazolam, ketamine, and nitrous
oxide. There is less evidence for an effect with opioid (such as remifentanil) or with alpha
2 agonists (such as dexmedetomidine).

Some, but not all, human cohort studies show an association between exposure to anaesthesia
in infancy or early childhood and later changes in cognitive tests, school performance or
risk of developing neurodevelopmental disorders. The evidence is weak due to possible
confounding.

A recent well designed cohort study (the PANDA study) comparing young children that had
hernia repair to their siblings found no evidence for a difference in a range of detailed
neuropsychological tests. In that study most children were exposed to up to two hours of
anaesthesia. The only trial (the GAS trial) has compared children having hernia repair under
regional or general anesthesia and has found no evidence for a difference in neurodevelopment
when tested at two years of age. The GAS and PANDA studies confirm the animal data that short
exposure is unlikely to cause any neurodevelopmental impact.

The impact of longer exposures is still unknown. In humans the strongest evidence for an
association between surgery and poor neurodevelopmental outcome is in infants having major
surgery. However, this is also the group where confounding is most likely.

The aim of our study is to see if a new combination of anaesthetic drugs results in a better
long-term developmental outcome than the current standard of care for children having
anaesthesia expected to last 2 hours or longer.

Children will be randomised to receive either a low dose
sevoflurane/remifentanil/dexmedetomidine or standard dose sevoflurane anaesthetic.

They will receive a neurodevelopmental assessment at 3 years of age to assess global
cognitive function.
Trial website
https://clinicaltrials.gov/show/NCT03089905
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 0 0
Andrew J Davidson, MD
Address 0 0
Royal Children's Hospital, Melbourne
Country 0 0
Phone 0 0
Fax 0 0
Email 0 0
Contact person for public queries
Name 0 0
Andrew J Davidson, MD
Address 0 0
Country 0 0
Phone 0 0
+61393455233
Fax 0 0
Email 0 0
andrew.davidson@rch.org.au
Contact person for scientific queries

Summary results
For IPD and results data, please see https://clinicaltrials.gov/show/NCT03089905