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Trial registered on ANZCTR


Registration number
ACTRN12620000890932
Ethics application status
Approved
Date submitted
11/08/2020
Date registered
10/09/2020
Date last updated
7/03/2023
Date data sharing statement initially provided
10/09/2020
Type of registration
Prospectively registered

Titles & IDs
Public title
A multisite clinical trial of repetitive transcranial magnetic stimulation (rTMS) for social communication in autism spectrum disorder (ASD).
Scientific title
Does repetitive transcranial magnetic stimulation (rTMS), compared to sham rTMS, improve social communication in adolescents and young adults with autism spectrum disorder (ASD)?
Secondary ID [1] 301961 0
None
Universal Trial Number (UTN)
U1111-1256-5457
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Autism spectrum disorder 318519 0
Condition category
Condition code
Mental Health 316522 316522 0 0
Autistic spectrum disorders

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Intermittent theta burst stimulation (iTBS) to right temporoparietal junction (rTPJ). iTBS is a form of repetitive transcranial magnetic stimulation (rTMS), which is a non-invasive brain stimulation technique. It involves the introduction of weak electrical current in the brain, which is achieved by delivering powerful but brief magnetic pulses to the scalp with a plastic-coated metallic coil.

rTMS will be administered each consecutive weekday for a four-week period (e.g., 20 treatments in total).

The site of stimulation (i.e., where the coil will be positioned) will be determined by co-registering the participant’s head to their structural magnetic resonance imaging (MRI) brain scan, and determining the scalp position that sits over the target brain region (rTPJ).

Each iTBS treatment will last for 3 minutes and 20 seconds. Including setup time, each iTBS treatment is expected to take approximately 10 minutes.

TBS will be delivered at an intensity equivalent to 70% of the participant’s “resting motor threshold” (RMT), which is the minimum stimulator intensity required to produce a discernable hand-muscle response following a single TMS pulse delivered to the primary motor cortex.

In terms of stimulation frequency, iTBS involves the administration of 3 TMS pulses at 50Hz, repeated 5 times per second, for 2 seconds, followed by an 8 second rest. This is repeated until a total of 600 pulses have been delivered.

Treating staff will use a standardised treatment form to monitor adherence (e.g., number of sessions attended, percentage of protocol delivered).
Intervention code [1] 318252 0
Treatment: Devices
Comparator / control treatment
The comparator treatment will be sham/placebo iTBS to rTPJ. This is identical to the active treatment except that no electromagnetic stimulation is delivered by the coil. This is achieved by the use of a "sham" rTMS coil, which mimics the look, sound, and sensation (via vibration of the coil against the scalp) of active rTMS.
Control group
Placebo

Outcomes
Primary outcome [1] 324708 0
Change in social relating as measured by the Social Responsiveness Scale - 2nd Edition (SRS-2).
Timepoint [1] 324708 0
1-month post-treatment completion (compared with baseline).
Secondary outcome [1] 385439 0
Change in social relating as measured by Social Responsiveness Scale - 2nd Edition (SRS-2) (self-report and parent/informant report).
Timepoint [1] 385439 0
Baseline; Immediately post-treatment completion; 1-month post-treatment completion; 3-months post-treatment completion; 6-months post-treatment completion.
Secondary outcome [2] 385440 0
Change in ADHD symptomatology as measured by the Conners 3 (parent/guardian report)/Conners Adult ADHD Rating Scales (CAARS) (informant-report and adult self-report).
Timepoint [2] 385440 0
Baseline; Immediately post-treatment completion; 1-month post-treatment completion; 3-months post-treatment completion; 6-months post-treatment completion.
Secondary outcome [3] 385441 0
Change in behavioural disturbances as measured by the Aberrant Behaviour Checklist – Second Edition (ABC-2) (parent/guardian/informant report).
Timepoint [3] 385441 0
Baseline; Immediately post-treatment completion; 1-month post-treatment completion; 3-months post-treatment completion; 6-months post-treatment completion.
Secondary outcome [4] 385442 0
Change in executive function as measured by the Behaviour Rating Scale of Executive Function (BRIEF)/ Behaviour Rating Scale of Executive Function - Adult Version (BRIEF-A) (parent/guardian/informant report and adult self-report).
Timepoint [4] 385442 0
Baseline; Immediately post-treatment completion; 1-month post-treatment completion; 3-months post-treatment completion; 6-months post-treatment completion.
Secondary outcome [5] 385443 0
Change in adaptive behaviour as measured by the World Health Organization Disability Assessment Schedule 2.0 (WHODAS 2.0) (parent/guardian/informant report).
Timepoint [5] 385443 0
Baseline; Immediately post-treatment completion; 1-month post-treatment completion; 3-months post-treatment completion; 6-months post-treatment completion.
Secondary outcome [6] 385444 0
Change in mental health as measured by Depression, Anxiety and Stress Scale (DASS) (self-report).
Timepoint [6] 385444 0
Baseline; Immediately post-treatment completion; 1-month post-treatment completion; 3-months post-treatment completion; 6-months post-treatment completion.
Secondary outcome [7] 385445 0
Change in personal wellbeing as measured by Personal Wellbeing Index (PWI) (self-report).
Timepoint [7] 385445 0
Baseline; Immediately post-treatment completion; 1-month post-treatment completion; 3-months post-treatment completion; 6-months post-treatment completion.
Secondary outcome [8] 385446 0
Change in neuropsychological performance as measured by the NIH Cognition Toolbox (administered to participant).
Timepoint [8] 385446 0
Baseline; Immediately post-treatment completion; 1-month post-treatment completion; 6-months post-treatment completion.
Secondary outcome [9] 385447 0
Change in social cognition as measured by the Reading the Mind in the Eyes Test (RMET) (administered to participant).
Timepoint [9] 385447 0
Baseline; Immediately post-treatment completion; 1-month post-treatment completion; 3-months post-treatment completion; 6-months post-treatment completion.
Secondary outcome [10] 385448 0
Change in neurophysiological activity as measured by Resting-state Electroencephalography (rsEEG) (administered to participant).
Timepoint [10] 385448 0
Baseline; Immediately post-treatment completion.
Secondary outcome [11] 385449 0
Non-invasive brain stimulation Post-stimulation Survey, version 4 (formal safety/side-effect measure; possible side-effects include mild headache and transient discomfort at the site of stimulation during stimulation).
Timepoint [11] 385449 0
End of each iTBS treatment week.
Secondary outcome [12] 386674 0
Change in neurophysiological activity as measured by Facial Processing Event-related Potentials (FP-ERP) (administered to participant).
Timepoint [12] 386674 0
Baseline; Immediately post-treatment completion.
Secondary outcome [13] 386694 0
Change in facial identity recognition as measured by the Benton Facial Recognition Test (BFRT).
Timepoint [13] 386694 0
Baseline; Immediately post-treatment completion; 1-month post-treatment completion; 3-months post-treatment completion; 6-months post-treatment completion.
Secondary outcome [14] 386695 0
Change in memory for faces as measured by the Cambridge Face Memory Test (CFMT).
Timepoint [14] 386695 0
Baseline; Immediately post-treatment completion; 1-month post-treatment completion; 3-months post-treatment completion; 6-months post-treatment completion.

Eligibility
Key inclusion criteria
• Aged between14-40 years
• Diagnosed with autism spectrum disorder (ASD) based on DSM-5 criteria, and confirmed via Autism Diagnostic Observation Schedule – Second Edition (ADOS-2)
Minimum age
14 Years
Maximum age
40 Years
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
• History of seizure/s or epilepsy
• History of serious head injury
• Contraindication to magnetic resonance imaging (MRI)
• Formal verbal intelligence quotient VIQ assessment <55, as determined by Wechsler Abbreviated Scale of Intelligence (WASI-2) or another standardised cognitive assessment
• Comorbid neurological or psychiatric diagnosis not commonly associated with ASD (e.g., psychosis)
• Unstable medical condition
• Unstable medication regime, or medication contraindicated for TMS
• Substance use/abuse disorder
• Concurrent treatment targeting social communication
• Evidence of significant epileptiform activity on EEG (e.g., seizures on EEG, runs of epileptiform discharges)

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)
Central randomisation by computer.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
A computerised adaptive randomisation procedure (minimisation method) will be performed, adjusting for baseline characteristics (age, sex, SRS T0 score), which ensures a balance of conditions across trial sites.
Masking / blinding
Blinded (masking used)
Who is / are masked / blinded?
The people receiving the treatment/s

The people assessing the outcomes
The people analysing the results/data
Intervention assignment
Parallel
Other design features
Phase
Not Applicable
Type of endpoint/s
Safety/efficacy
Statistical methods / analysis
Allowing for 10% attrition of our 150 participants, and based on the estimated effect size from our published RCT (which revealed a moderate effect of rTMS), a sample size of n = 135 in a mixed-model (2 groups, 5 time- points) will yield power of 0.99 (f = .20, a = 0.01). While this sample size is larger than the minimum suggested by a priori power analysis (n = 64, based on f = .20, a = 0.01, Power = 0.95), this will enable exploratory analysis to determine demographic, clinical, neuroimaging, and genetic predictors of treatment response.

A random effects linear mixed model will be used to ensure the inclusion of participants who have missing data, including those that withdraw from the study. Specifically, this will involve a between-subjects factor (rTMS condition: active vs. placebo) and a within-subjects factor (time of assessment: pre vs. post vs. one-month vs. three-months vs. six-months), with participant and site entered as random effects. We will examine rTMS safety by exploring descriptive statistics arising from the structured measure related to the development of possible side-effects.

Exploratory analyses will be undertaken to investigate factors that influence treatment response, and to investigate epigenetic changes following rTMS. We will use linear mixed models to determine the effect of rTMS on SRS-2 score, but with additional independent variables (e.g., age, sex, cognitive ability, ADOS-2 symptom severity, rTPJ structural and functional connectivity within social brain networks, polygenic risk score [PRS] for ASD).

Epigenetic variation refers to variation in chromatin structure, which is associated with variation in gene expression. In contrast to DNA, epigenetic variation can change over time, for example following treatment. Accordingly, we will compare epigenetic variation for DNA samples collected before and after treatment and investigate any associations with treatment response.

Recruitment
Recruitment status
Recruiting
Date of first participant enrolment
Anticipated
1/06/2021
Actual
17/01/2022
Date of last participant enrolment
Anticipated
30/06/2024
Actual
Date of last data collection
Anticipated
28/02/2025
Actual
Sample size
Target
150
Accrual to date
20
Final
Recruitment in Australia
Recruitment state(s)
NSW,QLD,SA,WA,VIC

Funding & Sponsors
Funding source category [1] 306385 0
Government body
Name [1] 306385 0
National Health and Medical Research Council
Country [1] 306385 0
Australia
Primary sponsor type
University
Name
Deakin University
Address
75 Pigdons Rd, Waurn Ponds VIC 3216
Country
Australia
Secondary sponsor category [1] 306938 0
None
Name [1] 306938 0
Address [1] 306938 0
Country [1] 306938 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 306582 0
Monash Health
Ethics committee address [1] 306582 0
Ethics committee country [1] 306582 0
Australia
Date submitted for ethics approval [1] 306582 0
19/08/2020
Approval date [1] 306582 0
05/10/2020
Ethics approval number [1] 306582 0
Ethics committee name [2] 306625 0
Deakin University Human Research Ethics Committee
Ethics committee address [2] 306625 0
Ethics committee country [2] 306625 0
Australia
Date submitted for ethics approval [2] 306625 0
01/10/2020
Approval date [2] 306625 0
Ethics approval number [2] 306625 0
Ethics committee name [3] 306626 0
Monash University Human Research Ethics Committee
Ethics committee address [3] 306626 0
Ethics committee country [3] 306626 0
Australia
Date submitted for ethics approval [3] 306626 0
01/10/2020
Approval date [3] 306626 0
Ethics approval number [3] 306626 0
Ethics committee name [4] 306628 0
CHQ Hospital and Health Service Human Research Ethics Committee
Ethics committee address [4] 306628 0
Ethics committee country [4] 306628 0
Australia
Date submitted for ethics approval [4] 306628 0
01/10/2020
Approval date [4] 306628 0
Ethics approval number [4] 306628 0
Ethics committee name [5] 306629 0
University of Queensland Human Research Ethics Committee
Ethics committee address [5] 306629 0
Ethics committee country [5] 306629 0
Australia
Date submitted for ethics approval [5] 306629 0
01/10/2020
Approval date [5] 306629 0
Ethics approval number [5] 306629 0
Ethics committee name [6] 306630 0
Metro North Office of Research Human Research and Ethics Committee
Ethics committee address [6] 306630 0
Ethics committee country [6] 306630 0
Australia
Date submitted for ethics approval [6] 306630 0
01/10/2020
Approval date [6] 306630 0
Ethics approval number [6] 306630 0
Ethics committee name [7] 306631 0
University of Sydney Human Research Ethics Committee
Ethics committee address [7] 306631 0
Ethics committee country [7] 306631 0
Australia
Date submitted for ethics approval [7] 306631 0
01/10/2020
Approval date [7] 306631 0
Ethics approval number [7] 306631 0
Ethics committee name [8] 306632 0
Epworth HealthCare Research Development and Governance Unit
Ethics committee address [8] 306632 0
Ethics committee country [8] 306632 0
Australia
Date submitted for ethics approval [8] 306632 0
01/10/2020
Approval date [8] 306632 0
Ethics approval number [8] 306632 0
Ethics committee name [9] 306633 0
Central Adelaide Local Health Network Human Research Ethics Committee (CALHN HREC)
Ethics committee address [9] 306633 0
Ethics committee country [9] 306633 0
Australia
Date submitted for ethics approval [9] 306633 0
01/10/2020
Approval date [9] 306633 0
Ethics approval number [9] 306633 0
Ethics committee name [10] 306634 0
University of Adelaide Human Research Ethics Committee
Ethics committee address [10] 306634 0
Ethics committee country [10] 306634 0
Australia
Date submitted for ethics approval [10] 306634 0
01/10/2020
Approval date [10] 306634 0
Ethics approval number [10] 306634 0
Ethics committee name [11] 306635 0
University of Western Australia Human Research Ethics Committee
Ethics committee address [11] 306635 0
Ethics committee country [11] 306635 0
Australia
Date submitted for ethics approval [11] 306635 0
01/10/2020
Approval date [11] 306635 0
Ethics approval number [11] 306635 0
Ethics committee name [12] 306636 0
Murdoch University Human Research Ethics Committee
Ethics committee address [12] 306636 0
Ethics committee country [12] 306636 0
Australia
Date submitted for ethics approval [12] 306636 0
01/10/2020
Approval date [12] 306636 0
Ethics approval number [12] 306636 0

Summary
Brief summary
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 104366 0
Prof Peter Enticott
Address 104366 0
School of Psychology, Deakin University, 221 Burwood Hwy. Burwood, VIC 3125
Country 104366 0
Australia
Phone 104366 0
+61 3 9244 5504
Fax 104366 0
Email 104366 0
peter.enticott@deakin.edu.au
Contact person for public queries
Name 104367 0
Peter Enticott
Address 104367 0
School of Psychology, Deakin University, 221 Burwood Hwy. Burwood, VIC 3125
Country 104367 0
Australia
Phone 104367 0
+61 3 9244 5504
Fax 104367 0
Email 104367 0
peter.enticott@deakin.edu.au
Contact person for scientific queries
Name 104368 0
Peter Enticott
Address 104368 0
School of Psychology, Deakin University, 221 Burwood Hwy. Burwood, VIC 3125
Country 104368 0
Australia
Phone 104368 0
+61 3 9244 5504
Fax 104368 0
Email 104368 0
peter.enticott@deakin.edu.au

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
Yes
What data in particular will be shared?
Individual participant data underlying published results only.
When will data be available (start and end dates)?
From publication of the trial findings (expected 2025), with no end date imposed.
Available to whom?
Anyone who wishes to access it.
Available for what types of analyses?
Any purpose.
How or where can data be obtained?
Open Science Framework (www.osf.io). This link will become available in 2025, and can be accessed by contact the Principal Investigator (peter.enticott@deakin.edu.au).


What supporting documents are/will be available?

No Supporting Document Provided



Results publications and other study-related documents

Documents added manually
No documents have been uploaded by study researchers.

Documents added automatically
No additional documents have been identified.