Trial Review

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Trial registered on ANZCTR


Registration number
ACTRN12606000441516
Ethics application status
Approved
Date submitted
12/10/2006
Date registered
16/10/2006
Date last updated
4/03/2019
Date data sharing statement initially provided
4/03/2019
Date results information initially provided
4/03/2019
Type of registration
Prospectively registered

Titles & IDs
Public title
A multi-site randomised controlled trial comparing regional and general anaesthesia for effects on neurodevelopmental outcome and apnoea in infants
Scientific title
A multi-site randomised controlled trial comparing bupivacaine (regional) anaesthesia versus sevoflurane (general) anaesthesia for effects on neurodevelopmental outcome and apnoea in infants scheduled for unilateral or bilateral inguinal hernia repair
Secondary ID [1] 280471 0
NCT00756600
Universal Trial Number (UTN)
Trial acronym
GAS Study
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Infant scheduled for unilateral or bilateral inguinal hernia repair 1413 0
Condition category
Condition code
Anaesthesiology 1509 1509 0 0
Other anaesthesiology
Surgery 1510 1510 0 0
Other surgery
Neurological 2775 2775 0 0
Other neurological disorders

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
The general anaesthesia group received sevoflurane for induction and maintenance. The airway could be maintained with a face mask, laryngeal mask or endotracheal tube, with or without neuromuscular blocking agents. Analgesia can be supplied with a caudal and/or ilioinguinal nerve block with bupivacaine or levo-bupivacaine up to a maximum dose of 2.5 mg/kg.

The regional anaesthesia group received no sedative agents. The regional blockade may be with spinal block alone, spinal block with caudal block, spinal with ilioinguinal block or caudal alone. A maximum dose of 2.5 mg/kg of bupivacaine or levo-bupivacaine can be used.
Intervention code [1] 1167 0
Treatment: Drugs
Comparator / control treatment
Comparator treatment is regional anaesthesia (either: spinal block alone,
spinal and caudal block, spinal and ilioinguinal block, caudal block alone) with bupivacaine or levo-bupivacaine to be administered by caudal and/or subarachnoid routes at the beginning of the surgical procedure. Spinal dose: 0.2 ml/kg 0.5% bupivacaine or levo-bupivacaine.. Caudal dose: 2.5 mg/kg bupivacaine or levo-bupivacaine. The duration lasts for approximately 90 minutes. Patients are observed for up to 12 hours (if they are in hospital) and parents are telephoned a week after the procedure to see how their child is recovering.
Control group
Active

Outcomes
Primary outcome [1] 2086 0
The primary outcome will be the Wechsler Preschool and Primary Scale of Intelligence - Third Edition (WPPSI-III) full Scale IQ score. This scale will be used to determine whether different types of anaesthesia (Regional vs General) given to infants undergoing inguinal hernia repair results in equivalent neurodevelopmental outcomes.
Timepoint [1] 2086 0
At 5 years chronological age
Secondary outcome [1] 3602 0
Bayley neurodevelopmental scale. Investigators will also monitor and record heart rate, respiration and oxygen saturation post anaesthesia in order to measure the frequency and characteristics of apnoea in the post-operative period after both regional and general anaesthesia for inguinal hernia repair in infants for up to 12 hours post anaesthesia.
Timepoint [1] 3602 0
At 2 years corrected age.
Secondary outcome [2] 351026 0
Composite/domain scores of the WPPSI-III, specifically:
(a) Verbal IQ (VIQ; reflecting verbal intellectual skills)
(b) Performance IQ (PIQ; reflecting visuo-spatial intellectual skills)
(c) Processing Speed Quotient (PSQ; reflecting speed of cognitive processing)
Timepoint [2] 351026 0
At 5 years chronological age
Secondary outcome [3] 351027 0
Selected Developmental Neuropsychological Assessment, second edition (NEPSY-II) subtests to assess other cognitive skills consisting of:
(a) Attention/executive function – span – Sentence Repetition scaled score
(b) Attention/executive function – sustained – Auditory Attention combined scaled score
(c) Attention/executive function – inhibitory control– Inhibition combined scaled score
(d) Attention/executive function – inhibitory control – Statue scaled score
(e) Verbal/language skills – Word Generation scaled score
(f) Verbal/language skills – Speeded Naming combined scaled score
(g) Memory & learning - Memory for Names and Memory for Names Delay (combined) scaled score
(h) Social perception - Affect Recognition scaled score
(i) Social perception - Theory of Mind scaled score
(j) Sensorimotor skills - Fingertip Tapping consisting of
- Repetitions scaled score
- Sequences scaled score
(k) Visuomotor integration - Design Copy Process Total scaled score
Timepoint [3] 351027 0
At 5 years chronological age
Secondary outcome [4] 351028 0
The Wechsler Individual Achievement Test – Second Edition Abbreviated (WIAT- II Abbreviated) to assess the academic skills of the child specifically:
(a) Word Reading standard score
(b) Numerical Operations standard score
(c) Spelling standard score
Timepoint [4] 351028 0
At 5 years chronological age
Secondary outcome [5] 351029 0
The Children’s Memory Scale (CMS) to assess:
(a) Attention/executive function – working memory – Numbers Total scaled score
(b) Memory and learning – Word Lists I (learning) scaled score
(c) Memory and learning – Word Lists II (delayed) scaled score
Timepoint [5] 351029 0
At 5 years chronological age
Secondary outcome [6] 351030 0
Parent/caregiver rated scales to assess the behaviour of the children using:
The Global Executive Composite (GEC, T score) of the Behaviour Rating Inventory of Executive Function – Preschool Version Parent Form (BRIEF-P) to measure behavioural executive abilities
Timepoint [6] 351030 0
At 5 years chronological age
Secondary outcome [7] 351031 0
Parent/caregiver rated scales to assess the behaviour of the children using:
The Global Adaptive Composite (GAC, composite score) of the Adaptive Behavior Assessment System – Second Edition (ABAS-II) to measure the child’s adaptive behavior
Timepoint [7] 351031 0
At 5 years chronological age
Secondary outcome [8] 351032 0
Parent/caregiver rated scales to assess the behaviour of the children using
The Child Behaviour Checklist Caregiver Questionnaire (CBCL) to measure behavioural problems consisting of
- The Total Problems Score (T score)
- CBCL internalising problems T score
- CBCL externalising problems T score
Timepoint [8] 351032 0
At 5 years chronological age
Secondary outcome [9] 351033 0
Any developmental issue (speech language issues/interventions, psychomotor issues /interventions, global developmental delay) assessed by interview with parent/caregiver
Timepoint [9] 351033 0
At 5 years chronological age
Secondary outcome [10] 351034 0
Child has speech or language issues / interventions assessed by interview with parent/caregiver
Timepoint [10] 351034 0
At 5 years chronological age
Secondary outcome [11] 351035 0
Child has psychomotor issues / interventions assessed by interview by interview with parent/caregiver
Timepoint [11] 351035 0
At 5 years chronological age
Secondary outcome [12] 351036 0
Child has global developmental delay assessed by interview with parent/caregiver
Timepoint [12] 351036 0
At 5 years chronological age
Secondary outcome [13] 351037 0
Any behavioural disorders (Attention Deficit Hyperactivity Disorder, Autism Spectrum Disorder or Oppositional Defiant Disorder) assessed by interview with parent/caregiver
Timepoint [13] 351037 0
At 5 years chronological age
Secondary outcome [14] 351038 0
Child has been diagnosed with Attention Deficit Hyperactivity Disorder (ADHD) assessed by interview with parent/caregiver
Timepoint [14] 351038 0
At 5 years chronological age
Secondary outcome [15] 351039 0
Child has been diagnosed with Autism Spectrum Disorder (ASD) assessed by interview with parent/caregiver
Timepoint [15] 351039 0
At 5 years chronological age
Secondary outcome [16] 351040 0
Child has a hearing abnormality and or hearing aid assessed by interview with parent/caregiver
Timepoint [16] 351040 0
At 5 years chronological age
Secondary outcome [17] 351041 0
Child has a visual defect in either eye and or is legally blind assessed by interview with parent/caregiver
Timepoint [17] 351041 0
At 5 years chronological age
Secondary outcome [18] 351042 0
Child has cerebral palsy assessed by interview with parent/caregiver
Timepoint [18] 351042 0
At 5 years chronological age
Secondary outcome [19] 351043 0
Parents’ awareness of group allocation
Timepoint [19] 351043 0
At 5 years chronological age
Secondary outcome [20] 351044 0
Awareness of group allocation by Psychologist / Paediatrician
Timepoint [20] 351044 0
At 5 years chronological age

Eligibility
Key inclusion criteria
* Any infant scheduled for unilateral or bilateral inguinal hernia repair (with or without circumcision) * Any infant whose gestational age is 26 weeks or more (GA = 182 days)* Any infant whose post-menstrual age is up to 60 weeks (PMA = 426 days)
Minimum age
26 Weeks
Maximum age
60 Weeks
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
* Any child older than 60 weeks post menstrual age * Any child born at less than 26 weeks gestation * Any contraindication to general or spinal/caudal anaesthesia (for example: neuromuscular disorder or coagulopathy)* Pre-operative ventilation immediately prior to surgery* Congenital heart disease that has required surgery or will require surgery or which requires ongoing pharmacotherapy* Known chromosomal abnormality or any other known acquired or congenital abnormalities (apart from prematurity) which are likely to affect development* Children where follow-up would be difficult for geographic or social reasons* Families where English (or French for Paris and Montreal sites) is not the language spoken at home* Known neurological injury such as cystic periventricular leukomalacia (PVL), or grade 3 or 4 intra ventricular haemorrhage (IVH) (+/- post haemorrhage ventricular dilatation)* Previous exposure to volatile anaesthesia or benzodiazepines as a neonate or in the third trimester in utero.

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)
Access to randomisation codes will be via a password protected 24 hour web-based randomisation service.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Randomisation sequence is generated by computerised sequence generation. Randomisation to either group will be by block and stratified by site and gestational age at birth. Gestational age at birth strata will be: 26 weeks to 29 weeks and 6 days, 30 weeks to 36 weeks and 6 days, 37 weeks and more.
Masking / blinding
Blinded (masking used)
Who is / are masked / blinded?



Intervention assignment
Parallel
Other design features
The assessing psychologist will be blinded to treatment allocation. This study is a multisite trial and recruitment will take place in Australia, New Zealand, The Netherlands, Italy, Canada, US and The UK.
Phase
Phase 4
Type of endpoint/s
Bio-equivalence
Statistical methods / analysis

Recruitment
Recruitment status
Completed
Date of first participant enrolment
Anticipated
30/10/2006
Actual
9/02/2007
Date of last participant enrolment
Anticipated
20/12/2012
Actual
31/01/2013
Date of last data collection
Anticipated
31/01/2018
Actual
20/04/2018
Sample size
Target
720
Accrual to date
Final
722
Recruitment in Australia
Recruitment state(s)
SA,WA,VIC
Recruitment postcode(s) [1] 357 0
3052
Recruitment outside Australia
Country [1] 364 0
New Zealand
State/province [1] 364 0
Auckland
Country [2] 365 0
United Kingdom
State/province [2] 365 0
Scotland
Country [3] 366 0
United States of America
State/province [3] 366 0
Massachusetts
Country [4] 367 0
Canada
State/province [4] 367 0
Quebec
Country [5] 7468 0
Netherlands
State/province [5] 7468 0
Country [6] 7469 0
Italy
State/province [6] 7469 0

Funding & Sponsors
Funding source category [1] 1645 0
Government body
Name [1] 1645 0
Murdoch Childrens Research Institute
Country [1] 1645 0
Australia
Primary sponsor type
Individual
Name
Professor Andrew Davidson
Address
Royal Children's Hospital
Flemington Road
Parkville VIC 3052
Country
Australia
Secondary sponsor category [1] 1453 0
Individual
Name [1] 1453 0
Associate Professor Mary Ellen McCann
Address [1] 1453 0
Department of Anesthesiology
Perioperative and Pain Medicine
Children's Hospital Boston
300 Longwood Avenue
Boston MA 02115-5737
Country [1] 1453 0
United States of America
Secondary sponsor category [2] 1454 0
Individual
Name [2] 1454 0
Dr Neil Morton
Address [2] 1454 0
Department of Anaesthesia
Royal Hospital for Sick Children
Yorkhill
Glasgow G3 8SJ
Country [2] 1454 0
United Kingdom

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 3094 0
Royal Children's Hospital
Ethics committee address [1] 3094 0
Melbourne
Ethics committee country [1] 3094 0
Australia
Date submitted for ethics approval [1] 3094 0
Approval date [1] 3094 0
21/11/2006
Ethics approval number [1] 3094 0
26135
Ethics committee name [2] 4854 0
Clinical Investigation Office, Children's Hospital Boston
Ethics committee address [2] 4854 0
333 Longwood Avenue
4th floor
Boston MA 02115-5737
Ethics committee country [2] 4854 0
United States of America
Date submitted for ethics approval [2] 4854 0
Approval date [2] 4854 0
23/10/2006
Ethics approval number [2] 4854 0
06-07-0320
Ethics committee name [3] 4855 0
West Glasgow Ethics Committee
Ethics committee address [3] 4855 0
West Research Office
Administration Building
Ground Floor
Room 9
Western Infirmary
Glasgow G11 6NT
Ethics committee country [3] 4855 0
United Kingdom
Date submitted for ethics approval [3] 4855 0
Approval date [3] 4855 0
20/02/2007
Ethics approval number [3] 4855 0
07/S0709/20

Summary
Brief summary
The primary purpose of the GAS study is to determine whether different types of anaesthesia (Spinal Vs General) given to 660 infants undergoing inguinal hernia repair results in equivalent neurodevelopmental outcomes. The study also aims to describe the incidence of apnoea in the post-operative period after both spinal and general anaesthesia for inguinal hernia repair in infants. This study is important as it will provide the greatest evidence for safety or toxicity of general anaesthesia for human infants.
Trial website
Trial related presentations / publications
Davidson AJ, Morton NS, Arnup SJ, de Graaff JC, Disma N, Withington DE, Frawley G, Hunt RW, Hardy P, Khotcholava M, von Ungern Sternberg BS, Wilton N, Tuo P, Salvo I, Ormond G, Stargatt R, Locatelli BG, McCann ME; General Anesthesia compared to Spinal anesthesia (GAS) Consortium. Apnea after Awake Regional and General Anesthesia in Infants: The General Anesthesia Compared to Spinal Anesthesia Study-Comparing Apnea and Neurodevelopmental Outcomes, A Randomized Controlled Trial. Anesthesiology. 2015 Jul;123(1):38-54..

Frawley G, Bell G, Disma N, Withington DE, de Graaff JC, Morton NS, McCann ME, Arnup SJ, Bagshaw O, Wolfler A, Bellinger D, Davidson AJ; General Anesthesia compared to Spinal anesthesia (GAS) Consortium. Predictors of Failure of Awake Regional Anesthesia for Neonatal Hernia Repair: Data from the General Anesthesia Compared to Spinal Anesthesia Study-Comparing Apnea and Neurodevelopmental Outcomes. Anesthesiology. 2015 Jul;123(1):55-65.

Davidson AJ, Disma N, de Graaff JC, Withington DE, Dorris L, Bell G, Stargatt R, Bellinger DC, Schuster T, Arnup SJ, Hardy P, Hunt RW, Takagi MJ, Giribaldi G, Hartmann PL, Salvo I, Morton NS, von Ungern Sternberg BS, Locatelli BG, Wilton N, Lynn A, Thomas JJ, Polaner D, Bagshaw O, Szmuk P, Absalom AR, Frawley G, Berde C, Ormond GD, Marmor J, McCann ME; GAS consortium. Neurodevelopmental outcome at 2 years of age after general anaesthesia and awake-regional anaesthesia in infancy (GAS): an international multicentre, randomised controlled trial. Lancet. 2016 Jan 16;387(10015):239-50

Davidson AJ, Disma N, de Graaff JC, Withington DE, McCann ME. The GAS trial - Authors' reply. Lancet. 2016 Apr 16;387(10028):1615.

McCann ME, Withington DE, Arnup SJ, Davidson AJ, Disma N, Frawley G, Morton NS, Bell G, Hunt RW, Bellinger DC, Polaner DM, Leo A, Absalom AR, von Ungern-Sternberg BS, Izzo F, Szmuk P, Young V, Soriano SG, de Graaff JC; GAS Consortium. Differences in Blood Pressure in Infants After General Anesthesia Compared to Awake Regional Anesthesia (GAS Study-A Prospective Randomized Trial). Anesth Analg. 2017 Sep;125(3):837-845.

Disma N, Withington D, McCann ME, Hunt RW, Arnup SJ, Izzo F, de Graaff JC, Mattioli G, Morton N, Frawley G, Davidson A, Lynn A, Szmuk P, Thomas JJ, Ragg P, Pini Prato A; GAS Consortium. Surgical practice and outcome in 711 neonates and infants undergoing hernia repair in a large multicenter RCT: Secondary results from the GAS Study. J Pediatr Surg. 2018 Jan 31. pii: S0022-3468(18)30005-8. doi: 10.1016/j.jpedsurg.2018.01.003.
Public notes
Attachments [1] 3022 3022 0 0
/AnzctrAttachments/1422-GAS SAP 5 years.pdf (Other)

Contacts
Principal investigator
Name 35939 0
Prof Andrew Davidson
Address 35939 0
Department of Anaesthesia Royal Children's Hospital Flemington Road Parkville VIC 3052
Country 35939 0
Australia
Phone 35939 0
+61 3 93455233
Fax 35939 0
+61 3 93456003
Email 35939 0
[email protected]
Contact person for public queries
Name 10356 0
Prof Andrew Davidson
Address 10356 0
Department of Anaesthesia
Royal Children's Hospital
Flemington Road
Parkville VIC 3052
Country 10356 0
Australia
Phone 10356 0
+61 3 93455233
Fax 10356 0
+61 3 93456003
Email 10356 0
[email protected]
Contact person for scientific queries
Name 1284 0
Prof Andrew Davidson
Address 1284 0
Department of Anaesthesia
Royal Children's Hospital
Flemington Road
Parkville VIC 3052
Country 1284 0
Australia
Phone 1284 0
+61 3 93455233
Fax 1284 0
+61 3 93456003
Email 1284 0
[email protected]

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
No/undecided IPD sharing reason/comment


What supporting documents are/will be available?

No Supporting Document Provided



Results publications and other study-related documents

Documents added manually

Documents added automatically
SourceTitleYear of PublicationDOI
EmbaseChildhood neurodevelopmental outcome following extremely preterm birth.2018https://dx.doi.org/10.1016/S2352-4642%2818%2930308-0
EmbaseNeurodevelopmental outcome at 2 years of age after general anaesthesia and awake-regional anaesthesia in infancy (GAS): An international multicentre, randomised controlled trial.2016https://dx.doi.org/10.1016/S0140-6736%2815%2900608-X
EmbaseDifferences in Blood Pressure in Infants after General Anesthesia Compared to Awake Regional Anesthesia (GAS Study - A Prospective Randomized Trial).2017https://dx.doi.org/10.1213/ANE.0000000000001870
EmbaseNeurodevelopmental outcome at 5 years of age after general anaesthesia or awake-regional anaesthesia in infancy (GAS): an international, multicentre, randomised, controlled equivalence trial.2019https://dx.doi.org/10.1016/S0140-6736%2818%2932485-1
EmbaseApnea after Awake Regional and General Anesthesia in Infants: The General Anesthesia Compared to Spinal Anesthesia Study-Comparing Apnea and Neurodevelopmental Outcomes, a Randomized Controlled Trial.2015https://dx.doi.org/10.1097/ALN.0000000000000709
Dimensions AIQuestioning the outcome of the Building Blocks trial2016https://doi.org/10.1016/s0140-6736(16)30201-x
Dimensions AIPredictors of Failure of Awake Regional Anesthesia for Neonatal Hernia Repair2015https://doi.org/10.1097/aln.0000000000000708
N.B. These documents automatically identified may not have been verified by the study sponsor.