Trial Review

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Trial registered on ANZCTR


Registration number
ACTRN12613000057785
Ethics application status
Approved
Date submitted
11/01/2013
Date registered
16/01/2013
Date last updated
4/10/2017
Type of registration
Prospectively registered

Titles & IDs
Public title
A randomised controlled trial of effects of early life exposure to general anaesthesia on neurobehavioural outcomes in children with cystic fibrosis (CF)
Scientific title
A randomised controlled trial of effects of early life exposure to general anaesthesia on neurobehavioural outcomes in children with cystic fibrosis (CF)
Secondary ID [1] 281735 0
Nil
Universal Trial Number (UTN)
U1111-1138-3181
Trial acronym
CF GAIN Study
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Early life exposure to general anaesthesia 288038 0
Neurobehavioural outcomes 288039 0
Cystic Fibrosis 288040 0
Condition category
Condition code
Anaesthesiology 288415 288415 0 0
Anaesthetics
Human Genetics and Inherited Disorders 288461 288461 0 0
Cystic fibrosis

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Children with cystic fibrosis with exposure to general anaesthesia (GA) in the first 2 years of life.
Children who were randomised to the bronchoalveolar lavage (BAL) treatment arm of the ACFBAL Study (ACTRN12605000665639) had baseline BAL under GA at a median age of 144 days. Following the baseline BAL, further bronchoscopies were performed in children in the BAL arm with hospitalisation for intravenous antibiotics if Pseudomonas aeruginosa was cultured from oropharyngeal specimens, and following completion of Pseudomonas aeruginosa eradication therapy. Thus, the total number of GA exposures for the BAL arm was different for each participant depending on clinical presentation.

The protocol for GA included no premedication. 100% oxygen with sevoflurane up to 8% was used for induction of anaesthesia. Atropine was administered 5mcg/kg and lignocaine 1% sprayed onto the vocal cords to a max of 3mg/kg. A laryngeal mask was placed when adequate depth of anaesthesia was achieved. 100% oxygen with sevoflurane up to 8% was given and adjusted to allow spontaneous breathing. Propofol use was accepted at the discretion of the anaesthetist and if required 0.5mg/kg was given in incremental boluses or run by continuous infusion. If coughing was a significant problem, muscle relaxants could be administered with full reversal at the end of the procedure.
Intervention code [1] 286271 0
Treatment: Drugs
Comparator / control treatment
Children with cystic fibrosis not exposed to general anaesthesia in the first 2 years of life.
Control group
Active

Outcomes
Primary outcome [1] 288583 0
Conners Continuous Performance Test (CPT-II ), Inattention Composite (IAC) which measures aspects of attention and EF including sustained attention (Omissions variability), response inhibition (Commissions) and processing speed (RT). The primary outcome measure will be a composite (average of T-scores, M=50, SD=10) of the Conners CPT-II indices associated with inattention (Omissions, Commissions, Hit RT, Hit RT Standard Error, Variability, Detectability (d’), Hit RT ISI Change, and Hit SE ISI Change).
Timepoint [1] 288583 0
In 2013, children who took part in the ACFBAL Study will be between 9 and 14 years of age. This outcome is assessed once only in each child.
Secondary outcome [1] 300514 0
Memory and New learning skills will be tested using a range of tests:
1.. Wechsler Abbreviated Scale of Intelligence (WASI-II), Record Form, NCS Pearson Inc, 2nd Edition 2011
2. Description of Connors Continuous Performance Test Performance (only available as a computer test)
3. NEPSY-II, NCS Pearson Inc, 2007 Record Form, 2nd Edition
4. Wechsler Intelligence Scale for Children (WISC-IV) Response Booklet 1, NCS Pearson INC, 2003
5. Clinical Evaluation of Language Fundamentals (CELF-4), NCS Pearson Inc, 2004 Record Form
6. Delis Kaplan Executive Function System (DKEFS) Trail Making Test, NCS Pearson Inc, 2001
7. Test of Everyday Attention for Children (TEA-Ch), Thames Valley Test Company, 1999 Procedural Guide and Scoring Sheet
8. Behaviour Assessment System for Children, 2nd Ed., (BASC-2) – Self Report Child Ages 8 – 11, and Adolescent Ages 12 - 21
Timepoint [1] 300514 0
In 2013, children who took part in the ACFBAL study will be between 9 and 14 years of age. This outcome is assessed once only in each child.
Secondary outcome [2] 300536 0
Executive Function: Key components of executive function in verbal and spatial modalities using Delis-Kaplan Executive Function System (D-KEFS) and executive function in the home and school environment using the Behaviour Rating Inventory of Executive Function (BRIEF).
Timepoint [2] 300536 0
In 2013, children who took part in the ACFBAL study will be between 9 and 14 years of age. This outcome is assessed once only in each child.
Secondary outcome [3] 300645 0
Neurocognitive Measures of language and cognition: Wechsler Abbreviated Scale of Intelligence-Second Ed (WASI-II) and Clinical Evaluation of Language Fundamentals (CELF-4).
Timepoint [3] 300645 0
In 2013, children who took part in the ACFBAL study will be between 9 and 14 years of age. This outcome is assessed once only in each child.
Secondary outcome [4] 300647 0
HRQOL, Behavioural Adjustment and Family Stress: Behaviour Assessment System for Children, 2nd Ed. (BASC-II), HRQOL using the Cystic Fibrosis Questionnaire-Revised will be completed by both parent and child (CFQ-R), the Conners Parent Questionnaire (long version) and the Family Stress Scale (FSS).
Timepoint [4] 300647 0
In 2013, children who took part in the ACFBAL study will be between 9 and 14 years of age. This outcome is assessed once only in each child.
Secondary outcome [5] 300648 0
MRI
Brain morphometry analysis: The T1w and T2w scans will be non-rigidly registered to a common template and segmented into white matter, gray matter (GM) and cerebro-spinal fluid using standard methods. Two approaches will then be used to analyse the resulting GM segmentation. i) From the atlas parcellation, region of interest (ROI) of the brain cortex and sub-cortical structures will be defined. Inside each ROI, GM volume (and thickness for the cortex) will be averaged. ROI will be merged into lobes, such as the frontal lobe or larger areas associated with executive functions. We will test if atrophy is associated with GA exposure and if correlations exist with clinical variables found to be different in the other aims of our study. ii) An exploratory study will be done using a volumetric voxel based morphometry by estimating locally difference in GM content between the two groups of our study.
Brain connectivity analysis: Diffusion weighted imaging (DWI) data will be analysed with a multi-fibre model using spherical harmonic deconvolution. Several metrics will be computed such as fractional anisotropy, mean diffusivity and apparent fibre diffusivity. Two approaches will also be used for the analysis: i) ROI will be defined from our hypotheses (e.g. corpus callosum, hippocampus), average of metrics will be computed for ROI (in the case of the CC). Tractography from those ROIs will define tracts used as new ROI to investigate metrics along tracts. ii) voxel based morphometry will be used as an exploratory experiment to detect those pixels where metrics are different between the two groups of our study.
Timepoint [5] 300648 0
In 2013, children who took part in the ACFBAL study will be between 9 and 14 years of age. This outcome is assessed once only in each child.

Eligibility
Key inclusion criteria
Children will be eligible for this study if they received no general anaesthesia prior to randomisation for the ACFBAL study.
ACTRN12605000665639
Wainwright CE, Vidmar S, Armstrong DS, et al. Effect of bronchoalveolar lavage-directed therapy on Pseudomonas aeruginosa infection and structural lung injury in children with cystic fibrosis: a randomized trial. Jama 2011;306:163-71.
Minimum age
9 Years
Maximum age
15 Years
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
Children will not be eligible for this study if they received general anaesthesia prior to randomisation for the ACFBAL study or if they were diagnosed with a condition that affects neurobehavioural testing prior to randomisation for the ACFBAL Study.

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)
The ACFBAL study was a RCT designed to examine the effects of bronchoalveolar lavage (BAL) directed therapy in reducing chronic Pseudomonas aeruginosa infection and improving structural lung disease over the first 5 years of life in children diagnosed with CF through newborn screening. Children were randomised at 3.6 months to receive either standard care (based on clinical assessment and oropharyngeal cultures) or flexible bronchoscopy and BAL culture directed therapy. In those randomised to the BAL group, BAL was performed under general anaesthetic (GA) (with a standardised anaesthetic protocol) initially at <6 months of age and subsequently with significant respiratory exacerbations. This new randomised controlled trial will examine neurobehavioural outcomes and structural changes identified on brain magnetic resonance imaging (MRI) in this cohort of children, comparing those who were randomised to early exposure to anaesthesia with those who were not exposed.
The neurobehavioural testing and MRI outcomes will be measured blinded to the randomisation group.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Randomisation was by a centralised computer-generated schedule with allocation revealed by telephone after confirmed recruitment.
Masking / blinding
Blinded (masking used)
Who is / are masked / blinded?


The people assessing the outcomes
Intervention assignment
Parallel
Other design features
The Primary Aim of this study: To evaluate the neurobehavioural function of children with CF who were exposed in the first 2 years of life to GA and to compare their performance across cognitive and behavioural domains to children with CF who were not exposed to anaesthesia.
Secondary Aim: To determine whether neurobehavioural function and health- related quality of life (HRQOL) for children with CF is related to cumulative exposure to GA over the first 5 years of life.
Exploratory Aim: To compare brain morphometry measured by MRI in children with CF who were or were not exposed in the first 2 years of life to GA, and to examine any potential associations between structural and functional outcomes.

Phase
Not Applicable
Type of endpoint/s
Safety/efficacy
Statistical methods / analysis
Statistical Analysis
Primary Aim: The primary comparison will be by intention-to-treat, with the outcome (CPT-II IAC) presented as a mean difference between the two groups (GA vs. No GA) with a 2-sided 95% CI and corresponding t-test. In secondary analyses we will explore the potentially confounding or mediating role of other risk factors such as gender, nutritional status as determined by body-mass index percentile, lung function as percent predicted adjusted for age, and family measures such as Conners Parent questionnaire, Family Stress Scale and SES). Further analysis will be conducted to attempt to better define the causal effect of GA, e.g. by excluding those children in the Standard arm (n=12) who had exposure to GA in the first 2 years of life.
Secondary outcomes (D-KEFS, BRIEF, WASI-II, and CFQ-R) will be compared between groups in a similar fashion.
Secondary Aim: Multivariable regression analysis will be undertaken to examine the relationship between the cumulative exposure to GA and each outcome of CPT IAC score, and the CFQ-R Emotional and Social Functioning Scales, adjusting for covariates (BASC2, WASI, pulmonary function, number of GA exposures, Family Stress Scale, and SES). This analysis will also examine the age of GA exposure, since early exposure to GA is expected potentially to have a greater effect on neurodevelopment than later exposure.
Exploratory Aim: Similar statistical analysis will be performed for the imaging results. Analysis will be performed for brain lobes, regions of interest, and for each voxel with appropriate multiple comparison correction techniques (e.g. false discovery rate). Results will be displayed on the brain template surface with colour map for p-values and regression coefficients. Maximum intensity projection will also be used to display voxel-based morphometry over the whole brain volume.

Recruitment
Recruitment status
Completed
Date of first participant enrolment
Anticipated
4/02/2013
Actual
5/12/2014
Date of last participant enrolment
Anticipated
31/12/2016
Actual
31/03/2017
Date of last data collection
Anticipated
31/12/2016
Actual
30/06/2017
Sample size
Target
132
Accrual to date
Final
98
Recruitment in Australia
Recruitment state(s)
NSW,QLD,SA,VIC
Recruitment hospital [1] 392 0
Royal Children's Hospital - Herston
Recruitment hospital [2] 393 0
The Royal Childrens Hospital - Parkville
Recruitment hospital [3] 394 0
The Children's Hospital at Westmead - Westmead
Recruitment hospital [4] 396 0
Womens and Childrens Hospital - North Adelaide
Recruitment hospital [5] 397 0
John Hunter Hospital Royal Newcastle Centre - New Lambton
Recruitment hospital [6] 4693 0
Lady Cilento Children's Hospital - South Brisbane
Recruitment outside Australia
Country [1] 4781 0
New Zealand
State/province [1] 4781 0

Funding & Sponsors
Funding source category [1] 286523 0
Government body
Name [1] 286523 0
National Health and Medical Research Council Project Grant Funding
Country [1] 286523 0
Australia
Primary sponsor type
Government body
Name
Department of Health and Ageing
Address
GPO Box 9848
Canberra ACT 2601
Country
Australia
Secondary sponsor category [1] 285309 0
None
Name [1] 285309 0
Address [1] 285309 0
Country [1] 285309 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 288594 0
Children's Health Services Queensland Human Research Ethics Committee
Ethics committee address [1] 288594 0
Respiratory & Sleep Medicine
Lady Cilento Children's Hospital
501 Stanley St
South Brisbane QLD 4101
Ethics committee country [1] 288594 0
Australia
Date submitted for ethics approval [1] 288594 0
Approval date [1] 288594 0
17/12/2012
Ethics approval number [1] 288594 0
HREC/09/QRCH/60/AM04

Summary
Brief summary
The use of general anaesthesia (GA) in infants and young children has generally been considered safe. Recent research from laboratory animal studies has raised concerns that exposure to anaesthetic medicines in early life could potentially be related to impaired memory, learning and behaviour.
Cystic Fibrosis (CF) is an inherited condition that is usually diagnosed in the first few weeks of life through the newborn screening program. CF leads to serious chest infections and lung damage. To try and identify chest infections and treat them early before they have a chance to cause lung damage, children with CF may undergo many tests and treatments.
The ACFBAL study was initiated to examine the use of BAL to direct therapy in young children with CF who are unable to expectorate sputum. This current study takes advantage of the previous randomisation to bronchoscopy directed therapy where children received bronchoscopy and BAL at baseline initially in the first six months of life, and subsequently with exacerbations requiring hospital admission or with Pseudomonas aeruginosa identified from oropharyngeal sampling.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 36858 0
Prof Claire Wainwright
Address 36858 0
5a Dept. of Respiratory & Sleep Medicine
Lady Cilento Children's Hospital
501 Stanley Street
South Brisbane QLD 4101
Country 36858 0
Australia
Phone 36858 0
+617 3068 1111
Fax 36858 0
+61 7 3068 2309
Email 36858 0
Claire.Wainwright@health.qld.gov.au
Contact person for public queries
Name 36859 0
Ms Joyce Cheney
Address 36859 0
5a Dept. of Respiratory & Sleep Medicine
Lady Cilento Children's Hospital
501 Stanley Street
South Brisbane QLD 4101
Country 36859 0
Australia
Phone 36859 0
+617 3069 7195
Fax 36859 0
+617 3069 7159
Email 36859 0
Joyce.Cheney@health.qld.gov.au
Contact person for scientific queries
Name 36860 0
Prof Claire Wainwright
Address 36860 0
5a Dept. of Respiratory & Sleep Medicine
Lady Cilento Children's Hospital
501 Stanley Street
South Brisbane QLD 4101
Country 36860 0
Australia
Phone 36860 0
+617 3068 1111
Fax 36860 0
+617 3068 2309
Email 36860 0
Claire.Wainwright@health.qld.gov.au

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