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A Study to Compare the Long-term Outcomes After Two Different Anaesthetics (TREX)

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ClinicalTrials.gov Identifier: NCT03089905
Recruitment Status : Recruiting
First Posted : March 24, 2017
Last Update Posted : February 4, 2019
Sponsor:
Collaborators:
Sydney Children's Hospitals Network
University Medical Center Groningen
Texas Medical Center
Boston Children’s Hospital
Oregon Health and Science University
Erasmus Medical Center
Great Ormond Street Hospital for Children NHS Foundation Trust
Uppsala University Hospital
University of Toronto
The Cleveland Clinic
University of Texas, Southwestern Medical Center at Dallas
Princess Margaret Hospital for Children
University Hospital, Geneva
Royal Children's Hospital, Melbourne
Children's Hospital of Philadelphia
Queensland Children's Hospital
Information provided by (Responsible Party):
Murdoch Childrens Research Institute

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.


Condition or disease Intervention/treatment Phase
Anesthesia Neurotoxicity Child Development Drug: Sevoflurane Drug: Remifentanil Drug: Dexmedetomidine Phase 3

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 450 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Intervention Model Description: Participants will be randomised to receive either low-dose sevoflurane/dexmedetomidine/remifentanil OR standard dose sevoflurane anaesthesia.
Masking: Single (Outcomes Assessor)
Masking Description: Randomisation 1:1 will be stratified by site and age at exposure (less than 12 months and greater than or equal to 12 months). Randomisation will be in blocks of variable size. The treating anaesthetist will not be blinded to treatment arm. The assessing neuropsychologist and parents will be blinded to treatment arm.
Primary Purpose: Treatment
Official Title: Neurodevelopmental Outcome After Standard Dose Sevoflurane Versus Low-dose Sevoflurane/Dexmedetomidine/Remifentanil Anaesthesia in Young Children- The TREX Trial
Actual Study Start Date : August 10, 2017
Estimated Primary Completion Date : April 2022
Estimated Study Completion Date : April 2022


Arm Intervention/treatment
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.

Drug: 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.
Other Name: Sevorane

Drug: Remifentanil
Experimental arm: loading dose: 1 mcg/kg, infusion starting at 0.1 mcg/kg/min or greater.
Other Name: Ultiva

Drug: Dexmedetomidine
Experimental arm: loading dose:1mcg/kg, infusion: 1 mcg/kg/hr.
Other Name: Precedex

Active Comparator: Sevoflurane
End tidal concentration of 2.5-3.0% or greater.
Drug: 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.
Other Name: Sevorane




Primary Outcome Measures :
  1. 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.


Secondary Outcome Measures :
  1. incidence of intra-operative hypotension [ Time Frame: 150 minutes- duration of surgery (baseline) ]
    Blood pressure measurements will be recorded during surgery

  2. incidence of intra-operative bradycardia [ Time Frame: 150 minutes- duration of surgery (baseline) ]
    Heart rate will be recorded during surgery

  3. Post-operative pain [ Time Frame: 60 minutes- after surgery ]
    Pain scores will be recorded after surgery

  4. Time to recovery [ Time Frame: 60 minutes- after surgery ]
    Time of removal of airway, eye-opening and discharge from PACU will be recorded.

  5. Language outcomes [ Time Frame: 3 years of age ]
    Clinical Evaluation of Language Fundamentals- Preschool, Version 2 (CELF-P2)

  6. Attention/Executive Function/impulse control [ Time Frame: 3 years of age ]
    A Developmental NEuroPSYchological Assessment- Second Edition (NEPSY-2): Statue Subtest

  7. Memory [ Time Frame: 3 years of age ]
    A Developmental NEuroPSYchological Assessment- Second Edition (NEPSY-2): Narrative memory

  8. Adaptive behaviour [ Time Frame: 3 years of age ]
    Adaptive Behavior Assessment System - Third Edition (ABAS-III)

  9. Clinical Behavior [ Time Frame: 3 years of age ]
    Child Behavior Checklist (CBCL)

  10. Executive Function [ Time Frame: 3 years of age ]
    Behavior Rating of Executive Function- Preschool (BRIEF-P)

  11. Social Skills [ Time Frame: 3 years of age ]
    Social Skills Improvement System (SSIS)



Information from the National Library of Medicine

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Ages Eligible for Study:   up to 2 Years   (Child)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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.

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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03089905


Contacts
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Contact: Andrew J Davidson, MD +61393455233 andrew.davidson@rch.org.au
Contact: Suzette J Sheppard, Bsc (Hons) +61393454901 suzette.sheppard@mcri.edu.au

Locations
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United States, Massachusetts
Boston Children's Hospital Recruiting
Boston, Massachusetts, United States, 02115
Contact: Mary Ellen McCann       Mary.McCann@childrens.harvard.edu   
Contact: Charles Berde       Charles.Berde@childrens.harvard.edu   
Principal Investigator: Mary Ellen McCann         
Sub-Investigator: Charles Berde         
United States, Ohio
Cincinnati Children's Hospital Medical Center Not yet recruiting
Cincinnati, Ohio, United States, 45229
Contact: Andreas W Loepke, MD    513-636-4408    Andreas.Loepke@cchmc.org   
Contact: Chris S Lee, MD    513-636-4408    Christopher.Lee@cchmc.org   
United States, Oregon
Oregon Health and Science University Not yet recruiting
Portland, Oregon, United States, 97239
Contact: Heike Gries, MD       griesh@ohsu.edu   
United States, Pennsylvania
The Children's Hospital of Philadelphia Not yet recruiting
Philadelphia, Pennsylvania, United States, 19104
Contact: Francis X McGowan       McGowanF@email.chop.edu   
Principal Investigator: Francis X McGowan         
United States, Texas
The University of Texas Southwestern Medical Center Recruiting
Dallas, Texas, United States, 75390
Contact: Peter Szmuk, MD    214-456-8559    Peter.Szmuk@UTSouthwestern.edu   
Texas Children's Hospital Recruiting
Houston, Texas, United States, 77030
Contact: Dean B Andropoulos, MD    832-826-5831    dra@bcm.edu   
United States, Washington
Seattle Children's Hospital Not yet recruiting
Seattle, Washington, United States, 98105
Contact: Katherine Gentry, MD       Katherine.Gentry@seattlechildrens.org   
Australia, New South Wales
Sydney Children's Hospital Recruiting
Randwick, New South Wales, Australia, 2031
Contact: Shona Chung       Shona.Chung@health.nsw.gov.au   
Principal Investigator: Shona Chung         
Children's Hospital at Westmead Recruiting
Westmead, New South Wales, Australia, 2145
Contact: Justin J Skowno       justin.skowno@health.nsw.gov.au   
Principal Investigator: Justin J Skowno         
Australia, Queensland
Queensland Children's Hospital Recruiting
Brisbane, Queensland, Australia, 4101
Contact: Paul Lee-Archer       pleearcher@hotmail.com   
Australia, Victoria
Royal Children's Hospital Recruiting
Parkville, Victoria, Australia, 3052
Contact: Andrew J Davidson, MD    +61393455233    andrew.davidson@rch.org.au   
Contact: Suzette J Sheppard    +61393454901    suzette.sheppard@mcri.edu.au   
Principal Investigator: Andrew J Davidson, MD         
Australia, Western Australia
Princess Margaret Hospital Recruiting
Perth, Western Australia, Australia, 6008
Contact: Britta von ungern Sternberg       britta.regli-vonungern@health.wa.gov.au   
Principal Investigator: Britta von ungern Sternberg         
Netherlands
University Medical Center Groningen Not yet recruiting
Groningen, Netherlands
Contact: Anthony Absalom       a.r.absalom@umcg.nl   
Principal Investigator: Anthony Absalom         
Sophia Children's Hospital Not yet recruiting
Rotterdam, Netherlands
Contact: Jurgen deGraaff       j.degraaff@erasmusmc.nl   
Principal Investigator: Jurgen deGraaff         
Sweden
Uppsala University Hospital Not yet recruiting
Uppsala, Sweden
Contact: Peter Frykholm       peter.frykholm@akademiska.se   
Principal Investigator: Peter Frykolm         
Switzerland
University Hospital Not yet recruiting
Geneva, Switzerland
Contact: Laszlo Vutskits       Laszlo.Vutskits@unige.ch   
Principal Investigator: Laszlo Vutskits         
United Kingdom
Great Ormond Street Hospital Not yet recruiting
London, United Kingdom
Contact: Nicola Disma       nicoladisma@gmail.com   
Principal Investigator: Nicola Disma         
Sub-Investigator: Suellen Walker         
Sponsors and Collaborators
Murdoch Childrens Research Institute
Sydney Children's Hospitals Network
University Medical Center Groningen
Texas Medical Center
Boston Children’s Hospital
Oregon Health and Science University
Erasmus Medical Center
Great Ormond Street Hospital for Children NHS Foundation Trust
Uppsala University Hospital
University of Toronto
The Cleveland Clinic
University of Texas, Southwestern Medical Center at Dallas
Princess Margaret Hospital for Children
University Hospital, Geneva
Royal Children's Hospital, Melbourne
Children's Hospital of Philadelphia
Queensland Children's Hospital
Investigators
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Study Chair: Andrew J Davidson, MD Royal Children's Hospital, Melbourne

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Responsible Party: Murdoch Childrens Research Institute
ClinicalTrials.gov Identifier: NCT03089905     History of Changes
Other Study ID Numbers: TREX TRIAL
First Posted: March 24, 2017    Key Record Dates
Last Update Posted: February 4, 2019
Last Verified: January 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Yes
Plan Description:

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.

Supporting Materials: Study Protocol
Statistical Analysis Plan (SAP)
Informed Consent Form (ICF)
Clinical Study Report (CSR)
Analytic Code
Time Frame: 6 months after publication of primary outcome
Access Criteria: Prior to releasing any data the following are required: a data access agreement must be signed between relevant parties, the TREX Trial Steering Committee must see and approve the analysis plan describing how the data will be analysed, there must be an agreement around appropriate acknowledgement and any additional costs involved must be covered. Data will only be shared with a recognised research institution which has approved the proposed analysis plan.

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Product Manufactured in and Exported from the U.S.: No
Additional relevant MeSH terms:
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Neurotoxicity Syndromes
Nervous System Diseases
Poisoning
Chemically-Induced Disorders
Dexmedetomidine
Remifentanil
Sevoflurane
Hypnotics and Sedatives
Central Nervous System Depressants
Physiological Effects of Drugs
Analgesics, Non-Narcotic
Analgesics
Sensory System Agents
Peripheral Nervous System Agents
Adrenergic alpha-2 Receptor Agonists
Adrenergic alpha-Agonists
Adrenergic Agonists
Adrenergic Agents
Neurotransmitter Agents
Molecular Mechanisms of Pharmacological Action
Analgesics, Opioid
Narcotics
Platelet Aggregation Inhibitors
Anesthetics, Inhalation
Anesthetics, General
Anesthetics