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Trial registered on ANZCTR


Registration number
ACTRN12623000757617
Ethics application status
Approved
Date submitted
27/06/2023
Date registered
11/07/2023
Date last updated
25/07/2024
Date data sharing statement initially provided
11/07/2023
Type of registration
Prospectively registered

Titles & IDs
Public title
Evaluating a new treatment for sleep difficulties in children with autism spectrum disorder.
Scientific title
A Randomised Waitlist Controlled Trial to Evaluate the Efficacy of Individual Alpha Frequency-guided Repetitive Transcranial Magnetic Stimulation for Sleep Difficulties in Children with Autism Spectrum Disorder.
Secondary ID [1] 309637 0
None
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Sleep difficulties 330483 0
Autism spectrum disorder 330484 0
Condition category
Condition code
Mental Health 327332 327332 0 0
Autistic spectrum disorders
Neurological 327333 327333 0 0
Other neurological disorders

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
The intervention is a planned, personalised treatment that uses individual alpha frequency (IAF) to guide repetitive transcranial magnetic stimulation (rTMS) protocol towards optimising outcomes due to the heterogeneous nature of sleep difficulties and an autism spectrum disorder.

Electroencephalogram/electrocardiogram (EEG/ECG) conducted by a trained technician (with over two years experience) on the TruScan acquisition software (Deymed diagnostic, s.r.o, Czech Republic) will be used to determine the participant's IAF, stimulation frequency and location. Briefly, EEG/ECG will be conducted under eyes closed conditions, and the recorded time series will be converted to the frequency domain using Fast Fourier Transform (FFT). The stimulating frequency will be determined by identifying the dominant peak frequency with the highest power in the 8-13Hz range and multiplying it by the higher harmonic frequency (5th to 10th) of the ECG nearest to the dominant peak frequency. The stimulation location will be the brain region with the highest aberrant cortical processes compared to a normative database with equal parameters and measured using the 10-20 system. The EEG/ECG will be conducted at baseline, posttreatment (post-completion of a two-week treatment program) and follow-up (one and four months posttreatment) periods of both treatment and control groups.

Data from the IAF, stimulation frequency, and location will be used by the trained technician in personalising the rTMS protocol for each participant. The rTMS is a 5-second stimulation train with pulses to be delivered at the determined stimulation frequency with 28-second intervals between 32 trains per-determined cortical location using an MCF-B65 butterfly coil and Magpro R30 TMS stimulator. The rTMS will be used to determine the resting motor threshold (RMT) by placing the centre of the coil on the motor cortex of the participant and gradually increasing the output of the TMS machine by 5% until a visible twitch in the muscle of the contralateral fingers is observed in two out of three trials. The output intensity of IAF-guided rTMS (if found) will be administered at 80% (RMT) to minimise potential side effects. If the RMT is not found, rTMS will be delivered at 50% and 40% output intensity at the frontal and posterior brain regions, respectively. A session of IAF-guided rTMS will be administered to both active and control groups each weekday for two weeks (I.e., ten sessions in total). Each daily session last approximately 40mins. The intervention is to be delivered within an outpatient clinic.

Participants' adherence to the intervention will be documented by the treatment technician during each clinic visit using a self-designed treatment log. The treatment log will report the number of sessions delivered, the output intensity, frequency and location of treatment, sleep onset and awake times, and other feedback from primary caregivers on any distinct observed behavioural changes, side effects from previous sessions.



Intervention code [1] 326406 0
Treatment: Devices
Comparator / control treatment
This research uses a waitlist control group (WLC). The WLC is an active control that will receive the same sessions of IAF-guided rTMS as the treatment group (TG).

Before the WLC receives the intervention, they will have to wait (carrying on with their routine activities during the period) until the TG has completed the intervention.

Given the waiting period is not prolonged, this mimics the operational factor experienced within a clinical setting.
Control group
Active

Outcomes
Primary outcome [1] 335202 0
The primary outcome will be the difference in sleep quality and quantity following IAF-guided rTMS. This will be assessed as a composite outcome using actigraphy, polysomnography and the children's sleep habit questionnaire.
Timepoint [1] 335202 0
At baseline, during the intervention (all day of the intervention), after intervention (the day following completion of the treatment program), and follow-up (one and four months posttreatment),
Secondary outcome [1] 423436 0
The secondary outcome will be the differences in ASD symptoms following IAF-guided rTMS. This will be assessed using the primary caregiver-rated Social Responsive Scale.
Timepoint [1] 423436 0
At baseline, after intervention (the day following completion of the treatment program), and follow-up (one and four months posttreatment),
Secondary outcome [2] 423437 0
The secondary outcome will be the differences in the quality of life parameters of the participant following IAF-guided rTMS. This will be assessed using the primary caregiver-rated Paediatric Quality of Life Inventory 4.0 (PQoL).
Timepoint [2] 423437 0
At baseline, after intervention (the day following completion of the treatment program), and follow-up (one and four months posttreatment),
Secondary outcome [3] 423738 0
The secondary outcomes will be the differences in the quality of life parameters of the primary caregiver following IAF-guided rTMS. This will be assessed using the self-reported Short Form 12 item (version 2) Health Survey,
Timepoint [3] 423738 0
At baseline, after intervention (the day following completion of the treatment program), and follow-up (one and four months posttreatment),
Secondary outcome [4] 423739 0
The secondary outcomes will be the documented reports on safety parameters to the participant following IAF-guided rTMS. This will be assessed based on the daily primary caregiver's report on any observed side effects.
Timepoint [4] 423739 0
Daily primary caregiver's report on any observed side effects during the treatment period.
Secondary outcome [5] 423996 0
The secondary outcome will be the differences in ASD symptoms following IAF-guided rTMS. This will be assessed using the primary caregiver-rated Social Responsive Survey version 2
Timepoint [5] 423996 0
At baseline, after intervention (the day following completion of the treatment program), and follow-up (one and four months posttreatment),

Eligibility
Key inclusion criteria
i. Children aged 6-12 years with a valid diagnosis of ASD (level 2) and SD, and their primary caregivers,
ii. Meet the definition of sleep difficulties based on the clinical cut-off of >41 on the Children's Sleep Habits Questionnaire (CSHQ).
iii. Children who can complete pre-assessment EEG and polysomnography (level 2 home sleep study).
Minimum age
6 Years
Maximum age
12 Years
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
Co-diagnosis of congenital conditions such as Down syndrome.
ii. Child with a reported history of rTMS use.
iii. Child with diagnosed nocturnal seizures, blindness, and moderate-severe obstructive sleep apnoea (OSA).
iv. Child with body implants such as pacemaker, Defibrillator, Vagal Nerve Stimulator, VP Shunt/ Magnetic intracranial shunts, Deep Brain Stimulator, Epidural Cortical stimulator, Steel shunts/stents, Cranial metal fragments (i.e. shrapnel, excluding titanium), Cochlear implant, aneurysm clips, coils, pipelines flow diversion, magnetic dental implants, Implanted cardioverter defibrillators (ICD), and Ocular implants
v. Child that is still breast feeding.
vi. Child with primary brain cancer / metastatic legions in the brain (unless palliative care)


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)
Simple randomisation using a randomisation table created by computer software (i.e. computerised sequence generation)
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Other
Other design features
This research is designed as a randomised, waitlist-controlled, open-label pilot trial. Participants in the waitlist controlled group receive IAF-guided rTMS only after the completion of the same intervention by the treatment group.
Phase
Not Applicable
Type of endpoint/s
Safety/efficacy
Statistical methods / analysis
A sample size of twenty is deemed sufficient to detect a medium to large effect size within a pilot trial. Data will be aggregated and analysed to compare primary outcomes between the TG and WLC groups at the end of each post-randomisation stage. Analysis of the primary and secondary outcomes will be carried out using linear mixed effects regression with results presented as mean differences (and 95% confidence intervals).
A single mixed-effect model incorporating the different stages of the study will be conducted to further analyse individual differences following the repeated measures. For group differences at the different stages of the study, post-intervention, scores at baseline are added as a covariate. The differences in the group outcomes will be assessed using linear mixed models.

Recruitment
Recruitment status
Active, not recruiting
Date of first participant enrolment
Anticipated
1/09/2023
Actual
1/09/2023
Date of last participant enrolment
Anticipated
30/09/2023
Actual
30/04/2024
Date of last data collection
Anticipated
31/10/2024
Actual
Sample size
Target
20
Accrual to date
Final
20
Recruitment in Australia
Recruitment state(s)
QLD
Recruitment postcode(s) [1] 40646 0
4506 - Morayfield

Funding & Sponsors
Funding source category [1] 313824 0
University
Name [1] 313824 0
University of the Sunshine Coast Australia
Country [1] 313824 0
Australia
Funding source category [2] 314166 0
Commercial sector/Industry
Name [2] 314166 0
Brain Treatment Centre Australia
Country [2] 314166 0
Australia
Primary sponsor type
Individual
Name
Uchenna Ezedinma
Address
University of the Sunshine Coast Australia, 90 Sippy Downs Dr, Sippy Downs QLD 4556
Country
Australia
Secondary sponsor category [1] 316082 0
Individual
Name [1] 316082 0
Evan Jones
Address [1] 316082 0
Brain Treatment Centre Australia Ground Floor, 19/31 Dickson Rd, Morayfield QLD 4105
Country [1] 316082 0
Australia
Secondary sponsor category [2] 316149 0
Individual
Name [2] 316149 0
Florin Oprescu
Address [2] 316149 0
University of the Sunshine Coast Australia, 90 Sippy Downs Dr, Sippy Downs QLD 4556
Country [2] 316149 0
Australia

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 312980 0
Human Research Ethics Committee of the University of the Sunshine Coast
Ethics committee address [1] 312980 0
90 Sippy Down dr Sippy Downs QLD 4556
Ethics committee country [1] 312980 0
Australia
Date submitted for ethics approval [1] 312980 0
20/12/2022
Approval date [1] 312980 0
10/01/2023
Ethics approval number [1] 312980 0
S221766

Summary
Brief summary
The increasing prevalence of neurodevelopmental disorders is a global concern. Autism spectrum disorder (ASD) affects approximately 1/100 children worldwide. More so, sleep disorders (SD) co-occurring with autistic traits have been more frequently reported in 40-80% of children diagnosed with ASD. These symptom constellations are strongly associated with concomitant parental stress, reduced quality of life and an economic burden to family and society. Consequently, the National Sleep Foundation identifies children with ASD as one of the highest-priority populations for sleep research.
Several risk factors have been identified in the aetiologies of ASD and SD. For instance, abnormal organisation and maturation of grey matter have been linked to a negative correlation to sleep architecture. Other studies indicate that an imbalance in GABAergic and glutamatergic systems disrupts neural signalling and development with corresponding presentations of ASD behaviours linked to SD. A study suggested a correlation between more severe core ASD symptoms in children and disruption in sleep architecture.
Interventions that target these shared pathologies could hold clinical benefits for ASD and SD outcomes. Repetitive Transcranial magnetic stimulation (rTMS) is an intervention of interest due to its effect on abnormal brain functions implicated in ASD. rTMS is a non-pharmacological and non-invasive brain stimulation that uses the magnetic field generated from an electromagnetic coil placed on the scalp to alter neural structures and functions. Its clinical potential has been demonstrated in several neurological conditions, with FDA approval for use in depression.
A recent study demonstrated rTMS to be effective and safe in children with ASD and SD. The study showed improved sleep outcomes based on the children's sleep habit questionnaire (CSHQ) following the use of the same rTMS protocol across participants. Such one-shoe-size-fits-all (standard) treatment approaches are thought to limit the optimisation of rTMS potential, especially within a heterogeneous population. The heterogeneous characteristics such as individual alpha frequency (IAF), stimulation frequency, and age are known determinants of the intervention outcome.
A chart study of IAF-guided rTMS documented improvement in ASD symptoms and sleep outcomes. Consequently, there is a sparse study on the efficacy and safety of IAF-guided rTMS in children with ASD and SD. This study aims to evaluate the efficacy and safety of IAF-guided rTMS on ASD symptoms and comorbid SD and quality of life in children and their primary caregivers based on pre-post objective and subjective measures. For the primary outcome, the study hypothesis is that IAF-guided rTMS improve sleep quality and quantity and other SD parameters.
The study design is a randomised, waitlist-controlled, open-label pilot trial.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 126570 0
Mr UCHENNA EZEDINMA
Address 126570 0
The University of the Sunshine Coast,
90 Sippy Downs Drive
Sippy Downs
Queensland 4556
Country 126570 0
Australia
Phone 126570 0
+61 1300 428 228
Fax 126570 0
Email 126570 0
[email protected]
Contact person for public queries
Name 126571 0
UCHENNA EZEDINMA
Address 126571 0
The University of the Sunshine Coast,
90 Sippy Downs Drive
Sippy Downs
Queensland 4556
Country 126571 0
Australia
Phone 126571 0
+61 1300 428 228
Fax 126571 0
Email 126571 0
[email protected]
Contact person for scientific queries
Name 126572 0
UCHENNA EZEDINMA
Address 126572 0
The University of the Sunshine Coast,
90 Sippy Downs Drive
Sippy Downs
Queensland 4556
Country 126572 0
Australia
Phone 126572 0
+61 1300 428 228
Fax 126572 0
Email 126572 0
[email protected]

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
Yes
What data in particular will be shared?
All of the de-identified individual participant data collected during the trial
When will data be available (start and end dates)?
Immediately following publication of main results, no end date determined yet.
Available to whom?
Only researchers who provide a methodologically sound proposal or on a case-by-case basis at the discretion of Primary Sponsors.
Available for what types of analyses?
Any purpose, only to achieve the aims in the approved proposal.
How or where can data be obtained?
Access is subject to approvals by Principal Investigator ([email protected])


What supporting documents are/will be available?

Doc. No.TypeCitationLinkEmailOther DetailsAttachment
19544Ethical approval    385878-(Uploaded-27-06-2023-09-52-21)-Study-related document.pdf



Results publications and other study-related documents

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