AnesthesiaPhase 3TREXNCT03089905
A Study to Compare the Long-term Outcomes After Two Different Anaesthetics
A Phase 3 study testing Sevoflurane, Remifentanil and Dexmedetomidine in people with Anesthesia and Neurotoxicity, run by Murdoch Childrens Research Institute at 21 sites in 4 countries.
Trial 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. Read more about this study
- Who is it for?
- Ages Up to 2 years
- Conditions the study is for
- Anesthesia, Neurotoxicity, Child Development
- What is being tested?
- Sevoflurane, Remifentanil and Dexmedetomidine
- Type of treatment
- Injection or infusion
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 450 participants
- Where
- 21 sitesin 4 countries
- Study dates
- 10 Aug 2017to Oct 2026
- Phase
- Phase 3
- Are there results?
- Not yet: the study is under way
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages Up to 2 years
- All sexes
- No healthy volunteers
- Child
Who may be able to join
- 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.
Who cannot join
- 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)
Show all 13Show fewer
- 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
Trial locations and contacts
21 sites in 4 countries.
21 sites in 4 countries
Italy8 sites
Presidio Ospedale Infantile C.Arrigo Azienda Ospedaliera
Alessandria
Azienda ospedaliero-universitaria di Bologna
Bologna
Azienda Ospedaliero-Universitaria Meyer
Florence
Istituto Giannina Gaslini
Genova
Fondazione IRCCS Cà Granda Ospedale Maggiore Policlinico - Clinica Mangiagalli
Milan
Vittore Buzzi Children's Hospital
Milan
Azienda Ospedaliero Universitaria Pisana
Pisa
Ospedale Bambino Gesù
Roma
Australia7 sites
Women's and Children's Hospital
Adelaide, South Australia, 5006
Flinders Medical Centre
Bedford Park, South Australia, 5042
Queensland Children's Hospital
Brisbane, Queensland, 4101
Royal Children's Hospital
Parkville, Victoria, 3052
Perth Children's Hospital
Perth, Western Australia, 6008
Sydney Children's Hospital
Randwick, New South Wales, 2031
Children's Hospital at Westmead
Westmead, New South Wales, 2145
United States5 sites
Boston Children's Hospital
Boston, Massachusetts, 02115
Cleveland Clinic
Cleveland, Ohio, 44195
The University of Texas Southwestern Medical Center
Dallas, Texas, 75390
Texas Children's Hospital
Houston, Texas, 77030
The Children's Hospital of Philadelphia
Philadelphia, Pennsylvania, 19104
About this study
Official title: Neurodevelopmental Outcome After Standard Dose Sevoflurane Versus Low-dose Sevoflurane/Dexmedetomidine/Remifentanil Anaesthesia in Young Children- The TREX Trial
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).
Read more
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.
- Conditions
- Anesthesia, Neurotoxicity, Child Development
- Being tested
- Sevoflurane, Remifentanil, Dexmedetomidine
- Medical subject headings
- Neurotoxicity Syndromes
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
SevofluraneDrug
Also called Sevorane
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.
RemifentanilDrug
Also called Ultiva
Experimental arm: loading dose: 1 mcg/kg, infusion starting at 0.1 mcg/kg/min or greater.
DexmedetomidineDrug
Also called Precedex, Dexmedetomidine Ever Pharma
Experimental arm: loading dose:1mcg/kg, infusion: 1 mcg/kg/hr.
| Study group | Role | What they receive |
|---|---|---|
| Sevoflurane/dexmedetomidine/remifentanil | Experimental | 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. Receives: Drug: Sevoflurane; Drug: Remifentanil; Drug: Dexmedetomidine |
| Sevoflurane | Active comparator | End tidal concentration of 2.5-3.0% or greater. Receives: Drug: Sevoflurane |
What is being measured
The primary outcome is the main question the study is designed to answer.
Full Scale IQ
Global cognitive function as assessed by the full scale IQ score of the Wechsler Preschool and Primary School Intelligence Scale.
Measured: 3 years of age
Secondary outcomes (11)
incidence of intra-operative hypotension
Blood pressure measurements will be recorded during surgery
Measured: 150 minutes- duration of surgery (baseline)
incidence of intra-operative bradycardia
Heart rate will be recorded during surgery
Measured: 150 minutes- duration of surgery (baseline)
Post-operative pain
Pain scores will be recorded after surgery
Measured: 60 minutes- after surgery
Time to recovery
Time of removal of airway, eye-opening and discharge from PACU will be recorded.
Measured: 60 minutes- after surgery
Language outcomes
Clinical Evaluation of Language Fundamentals- Preschool, Version 2 (CELF-P2)
Measured: 3 years of age
Attention/Executive Function/impulse control
A Developmental NEuroPSYchological Assessment- Second Edition (NEPSY-2): Statue Subtest
Measured: 3 years of age
Memory
A Developmental NEuroPSYchological Assessment- Second Edition (NEPSY-2): Narrative memory
Measured: 3 years of age
Adaptive behaviour
Adaptive Behavior Assessment System - Third Edition (ABAS-III)
Measured: 3 years of age
Clinical Behavior
Child Behavior Checklist (CBCL)
Measured: 3 years of age
Executive Function
Behavior Rating of Executive Function- Preschool (BRIEF-P)
Measured: 3 years of age
Social Skills
Social Skills Improvement System (SSIS)
Measured: 3 years of age
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted24 Mar 2017
- Study start10 Aug 2017
- Primary completionOct 2026 (estimated)
- Study completionOct 2026 (estimated)
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (3)Papers the sponsor has linked to this study.
- Other trials for AnesthesiaStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 3
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Model description
- Participants will be randomised to receive either low-dose sevoflurane/dexmedetomidine/remifentanil OR standard dose sevoflurane anaesthesia.
- Masking
- Single blind
- Who is masked
- Outcomes assessor
- Enrolment
- 450 participants (actual)
Sponsor and investigators
- Lead sponsor
- Murdoch Childrens Research Institute
- Sponsor type
- University, hospital or other
- Collaborators
- Sydney Children's Hospitals Network, Baylor College of Medicine, Boston Children's Hospital, The Cleveland Clinic, University of Texas, Southwestern Medical Center at Dallas, Royal Children's Hospital, Children's Hospital of Philadelphia, Queensland Children's Hospital, Perth Children's Hospital, Women and Children's Hospital, Istituto Giannina Gaslini, Flinders Medical Centre
- Responsible party
- Sponsor
- Investigators
- Andrew J Davidson, MD, Study chair, Royal Children's Hospital
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT03089905
- Sponsor's protocol ID
- TREX TRIAL
- Other IDs
- 2024-512385-34-00
- Acronym
- TREX
- Status last verified
- Sep 2026
- First submitted
- 8 Mar 2017
- Last updated
- 10 Sep 2026
- Results posted
- No
- Data monitoring committee
- Yes
- FDA-regulated drug
- Yes
- FDA-regulated device
- No
- Individual data sharing
- Yes: The de-identified data set collected for this analysis of the TREX trial will be available six months after publication of the primary outcome. The study protocol, analysis plan and consent forms will also be available. The data may be obtained from the Murdoch Children's Research Institute by emailing andrew.davidson@rch.org.au.
Publications
Saynhalath R, Disma N, Taverner FJ, von Ungern-Sternberg BS, Andropoulos D, Ng AS, Shields BB, Izzo F, Lee-Archer P, McCann ME, Montagnini L, Kuppers B, Lenares E, Sheppard S, de Graaff JC, Lee KJ, Wang X, Szmuk P, Davidson AJ, Skowno JJ; TREX (Trial Remifentanil DEXmedetomidine) Consortium. Short-term Outcomes in Infants after General Anesthesia with Low-dose Sevoflurane/Dexmedetomidine/Remifentanil versus Standard-dose Sevoflurane (the TREX Trial). Anesthesiology. 2024 Dec 1;141(6):1075-1085. doi: 10.1097/ALN.0000000000005232.
PubMed 39283983Oltean T, Ostlund S, Rinehart J, Vandenabeele P, Kain ZN, Coeckelenbergh S. Neuronal Cell Death Modalities and Protective Mechanisms Induced By Sevoflurane: A Narrative Review. Anesth Analg. 2026 Oct 1;143(4):807-821. doi: 10.1213/ANE.0000000000008035. Epub 2026 May 6.
PubMed 42090240Chen DX, Tan ZM, Lin XM. General Anesthesia Exposure in Infancy and Childhood: A 10-year Bibliometric Analysis. J Perianesth Nurs. 2024 Oct;39(5):772-781. doi: 10.1016/j.jopan.2023.12.006. Epub 2024 Mar 21.
PubMed 38520467
Study at a glance
From the registry record, last updated by the sponsor on 10 Sep 2026. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Neurodevelopmental Outcome After Standard Dose Sevoflurane Versus Low-dose Sevoflurane/Dexmedetomidine/Remifentanil Anaesthesia in Young Children- The TREX Trial
- ClinicalTrials.gov ID
- NCT03089905
- Acronym / sponsor ID
- TREX / TREX TRIAL
- Conditions
- Anesthesia, Neurotoxicity, Child Development
- Phase
- Phase 3
- Study type
- Interventional
- Recruitment status
- Active, not recruiting
- Enrolment
- 450 participants (actual)
- Lead sponsor
- Murdoch Childrens Research InstituteUniversity, hospital or other
- Collaborators
- Sydney Children's Hospitals Network, Baylor College of Medicine, Boston Children's Hospital, The Cleveland Clinic, University of Texas, Southwestern Medical Center at Dallas, Royal Children's Hospital, Children's Hospital of Philadelphia, Queensland Children's Hospital, Perth Children's Hospital, Women and Children's Hospital, Istituto Giannina Gaslini, Flinders Medical Centre
- Study start
- 10 Aug 2017 (actual)
- Primary completion
- Oct 2026 (estimated)
- Study completion
- Oct 2026 (estimated)
- First posted
- 24 Mar 2017 (actual)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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.
Study design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Single blind (outcomes assessor)
- Number of arms
- 2
- Model description
- Participants will be randomised to receive either low-dose sevoflurane/dexmedetomidine/remifentanil OR standard dose sevoflurane anaesthesia.
| Arm | Type | Receives |
|---|---|---|
| Sevoflurane/dexmedetomidine/remifentanil | Experimental | Drug: Sevoflurane, Drug: Remifentanil, Drug: DexmedetomidineDexmedetomidine: 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. |
| Sevoflurane | Active comparator | Drug: SevofluraneEnd tidal concentration of 2.5-3.0% or greater. |
Who may qualify
- Ages
- Up to 2 years
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Child
Key inclusion criteria (3 listed)
- 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.
Key exclusion criteria (13 listed)
- 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
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| SevofluraneAlso: SevoraneExperimental arm: end tidal concentration of 0.6 -0.8% or less. Active comparator arm: end tidal concentration of 2.5-3.0% or greater. | Drug | Sevoflurane, Sevoflurane/dexmedetomidine/remifentanil |
| RemifentanilAlso: UltivaExperimental arm: loading dose: 1 mcg/kg, infusion starting at 0.1 mcg/kg/min or greater. | Drug | Sevoflurane/dexmedetomidine/remifentanil |
| DexmedetomidineAlso: Precedex, Dexmedetomidine Ever PharmaExperimental arm: loading dose:1mcg/kg, infusion: 1 mcg/kg/hr. | Drug | Sevoflurane/dexmedetomidine/remifentanil |
Primary outcome
Full Scale IQ
Time frame: 3 years of age
Global cognitive function as assessed by the full scale IQ score of the Wechsler Preschool and Primary School Intelligence Scale.
11 secondary outcomes
incidence of intra-operative hypotension
Time frame: 150 minutes- duration of surgery (baseline)
incidence of intra-operative bradycardia
Time frame: 150 minutes- duration of surgery (baseline)
Post-operative pain
Time frame: 60 minutes- after surgery
Time to recovery
Time frame: 60 minutes- after surgery
Language outcomes
Time frame: 3 years of age
Attention/Executive Function/impulse control
Time frame: 3 years of age
Memory
Time frame: 3 years of age
Adaptive behaviour
Time frame: 3 years of age
Clinical Behavior
Time frame: 3 years of age
Executive Function
Time frame: 3 years of age
Social Skills
Time frame: 3 years of age
Results and safety
This study is still under way. Results are not available in the source record yet.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 10 Sep 2026.
- Results publication: PubMed 39283983Saynhalath R, Disma N, Taverner FJ, von Ungern-Sternberg BS, Andropoulos D, Ng AS, Shields BB, Izzo F, Lee-Archer P, McCann ME, Montagnini L, Kuppers B, Lenares E, Sheppard S, de Graaff JC, Lee KJ, Wang X, Szmuk P, Davidson AJ, Skowno JJ; TREX (Trial Remifentanil DEXmedetomidine) Consortium. Short-term Outcomes in Infants after General Anesthesia with Low-dose Sevoflurane/Dexmedetomidine/Remifentanil versus Standard-dose Sevoflurane (the TREX Trial). Anesthesiology. 2024 Dec 1;141(6):1075-1085. doi: 10.1097/ALN.0000000000005232.
- Derived from this study: PubMed 42090240Oltean T, Ostlund S, Rinehart J, Vandenabeele P, Kain ZN, Coeckelenbergh S. Neuronal Cell Death Modalities and Protective Mechanisms Induced By Sevoflurane: A Narrative Review. Anesth Analg. 2026 Oct 1;143(4):807-821. doi: 10.1213/ANE.0000000000008035. Epub 2026 May 6.
- Derived from this study: PubMed 38520467Chen DX, Tan ZM, Lin XM. General Anesthesia Exposure in Infancy and Childhood: A 10-year Bibliometric Analysis. J Perianesth Nurs. 2024 Oct;39(5):772-781. doi: 10.1016/j.jopan.2023.12.006. Epub 2024 Mar 21.
- Individual participant dataSharing planned: Yes. The de-identified data set collected for this analysis of the TREX trial will be available six months after publication of the primary outcome. The study protocol, analysis plan and consent forms will also be available. The data may be obtained from the Murdoch Children's Research Institute by emailing andrew.davidson@rch.org.au.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Andrew J Davidson, MD study chair
Royal Children's Hospital
21 sites in 4 countries: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 3 study testing Sevoflurane, Remifentanil and Dexmedetomidine in people with Anesthesia and Neurotoxicity, run by Murdoch Childrens Research Institute at 21 sites in 4 countries.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 3 inclusion and 13 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: under way, not looking for participants, as of the sponsor's last update on 10 Sep 2026. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 21 sites in Italy, Australia, United States, Spain. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 3 studies compare the treatment with the current standard treatment or a placebo in a large group, to confirm how well it works and watch for side effects.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
This study is still under way. Results are not available in the source record yet.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Full Scale IQ (time frame: 3 years of age). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT03089905, which also lists 3 linked publications.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 10 Sep 2026.