Trial Review

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Trial registered on ANZCTR


Registration number
ACTRN12624000889550p
Ethics application status
Submitted, not yet approved
Date submitted
3/07/2024
Date registered
22/07/2024
Date last updated
22/07/2024
Date data sharing statement initially provided
22/07/2024
Type of registration
Prospectively registered

Titles & IDs
Public title
Personalised transcranial alternating current stimulation as a novel therapeutic treatment for post-traumatic stress disorder
Scientific title
Evaluating the effects of personalised alpha-tACS on alpha power in participants with post-traumatic stress disorder (PTSD)
Secondary ID [1] 312444 0
None
Universal Trial Number (UTN)
NA
Trial acronym
tACS for PTSD
Linked study record
NA

Health condition
Health condition(s) or problem(s) studied:
PTSD 334271 0
Condition category
Condition code
Mental Health 330934 330934 0 0
Other mental health disorders

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Transcranial alternating current stimulation (tACS) is a form of non-invasive brain stimulation that externally applies weak oscillatory electrical currents (typically 1-2mA) at a specified frequency to the brain. tACS can modulate cortical excitability through entrainment and spike-timing dependent plasticity. Entrainment is a primary mechanism proposed to drive the modulatory effects of tACS on cortical excitability and refers to the synchronisation of endogenous brain oscillations to another (external) driving frequency. Entrainment effects can be optimised by matching the tACS frequency to the individual’s dominant endogenous frequency for a particular band of oscillation, in this instance the individual’s endogenous alpha frequency. Electroencephalography (EEG) recordings will be used to determine a subject’s dominant endogenous oscillatory frequency within the alpha band, which will then be used to personalise stimulation frequency for tACS therapy.

Administration of tACS will be provided using the Rio transceiver device (eemagine Medical Imaging Solutions GmbH), a mobile device for recording EEG signals combined with transcranial alternating current stimulation (tACS). Controlled electrical current stimulation can be triggered from a software application, via external triggers, or via an internal feature extraction pipeline with minimum latency and jitter. The device has been produced and appropriately tested in the ISO accredited facilities ANT Neuro in Germany. The device delivers a voltage controlled current across stimulation electrodes made of conductive rubber encased in commercially supplied saline soaked sponges and are held in place with a fitted cap.

The study will use a cross-over, double blind design. Potential participants will complete an initial pre-screen phone call with a research team member. If deemed eligible, participants will complete a consent and baseline session. Participants will provide demographic information, medical history and complete clinician rated assessments and self-report assessments throughout the study period; including MINI-DSM5, CAPS-5, MINI, PCL-5, AQoL and PHQ.

Resting-state electroencephalography (EEG; 64-channels) will be completed prior to the start of each treatment block and at the end of each treatment block (conducted at the ANU). Participants will complete two treatment blocks where they will receive 15 sessions, daily (Monday - Friday) for 3 weeks of personalised alpha-tACS and 15 sessions, daily (Monday - Friday) for 3 weeks of sham-tACS. The EEG data recorded will be used to determine participant's individual alpha frequency (IAF), during active treatment block (alpha-tACS condition) the stimulation frequency will be uploaded onto the device.
There will be a 4-week break (minimum 4, maximum 8) between blocks and the order of completion counterbalanced across the participant pool. Resting-state EEG (10 channels) will be recorded for 3 minutes prior to, and following, each treatment session (i.e., daily) to track changes in alpha power and posterior-frontal connectivity across treatment periods.

On site: Treatment will be administered by a study researcher. The study researcher will provide clear instructions on where the participant is to be seated and demonstrate how to prepare the tACS-EEG cap and fit it to the participant's head. Administration of tACS and recording with EEG will be automatically triggered while participants complete a series of working memory tasks. Following the completion of the working memory tasks, the study researcher will remove the cap and demonstrate how to clean and care for the equipment, Sessions on site are not limited, participants will be able to attend all sessions on site until competency to carry out at home session is clearly demonstrated.

At home: All procedures outlined above will be presented to participants in a way that will teach them how to self-administer treatment at home. The treatment itself is pre-programmed into the device and triggered by participants as they complete a highly guided series of working memory tasks. We will use a checklist to assess competency before participants start treatment at home. The checklist requires researchers to assess and sign off on participants' use of the device on several items pertaining to head and cap preparation, machine preparation and stimulation, steps involved during and post stimulation. The participants will only take home the device for self-administration when they have passed this assessment and feel confident with using the device. When participants are competent and feel comfortable to conduct treatments at home, we can monitor use for several sessions over zoom and be available for troubleshooting, if required.

For all active tACS treatment session, a peak-to-peak intensity of 2 mA will be administered for 20 minutes, with a 10 s ramp-up and a 10 s ramp-down every time the stimulation starts and stops. The frequency of the tACS will be matched to the participants dominant alpha frequency measured with EEG at baseline and end of the break period.
Intervention code [1] 328950 0
Treatment: Devices
Comparator / control treatment
Sham-tACS
In the sham condition, the current will be delivered at an intensity of 2 mA in the first and last 30 seconds (including a 10 s ramp-up/down) at the IAF, to emulate sensations associated with tACS administration without producing any enduring physiological effects.
Control group
Active

Outcomes
Primary outcome [1] 338696 0
Changes in Alpha power between active treatment and sham
Timepoint [1] 338696 0
Pre-treatment block and post-treatment block for personalised alpha-tACS and sham-tACS
Secondary outcome [1] 437061 0
Changes in post-traumatic stress disorder (PTSD) severity
Timepoint [1] 437061 0
Baseline, post-treatment block 1, pre- and post-treatment block 2 and at 4-week follow-up
Secondary outcome [2] 437062 0
Changes in PTSD severity
Timepoint [2] 437062 0
Baseline, post-treatment block 1, pre- and post-treatment block 2 and at 4-week follow-up
Secondary outcome [3] 437063 0
Changes in clinical severity of depression
Timepoint [3] 437063 0
Baseline, post-treatment block 1, pre- and post-treatment bloc 2 and at 4-week follow-up
Secondary outcome [4] 437064 0
Changes in participants' quality of life
Timepoint [4] 437064 0
Baseline, post-treatment block 1, pre- and post-treatment bloc 2 and at 4-week follow-up

Eligibility
Key inclusion criteria
Aged between 18-80 years of age
Clinician-Administered PTSD Scale (CAPS-5) total score of moderate-severe (greater than or equal to 20)
No change or initiation of new medication (antidepressant or other psychoactive) in the four weeks prior to screening
Demonstrated capacity to give informed consent
Minimum age
18 Years
Maximum age
80 Years
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
Inability to provide informed consent
Medically unstable
Concomitant active neurological disorder
Individuals who are pregnant or breastfeeding
Active suicidal intent
Any psychotic disorder or current active psychotic symptoms
Meets criteria for current DSM 5 alcohol or substance dependence
Borderline personality disorder judged by an investigator to prevent appropriate engagement in the study
Individuals who have intracranial implants
Another AXIS I or II disorder judged to impact on the likelihood of response to treatment

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)
Allocation to treatment group is concealed; by the research staff contacting the study investigators, after the participant is deemed eligible and has consented for the study.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Participants will be randomly allocated to study group using simple randomisation techniques i.e. using a computerised sequence generation
Masking / blinding
Blinded (masking used)
Who is / are masked / blinded?
The people receiving the treatment/s

The people assessing the outcomes
Intervention assignment
Crossover
Other design features
Phase
Not Applicable
Type of endpoint/s
Efficacy
Statistical methods / analysis
Sample Size
A within-subjects repeated measures ANOVA with 80% power and a medium effect size (f = .25) will require a minimum of 24 subjects to detect a difference in EEG outcomes (4 measurements with 64 channels), 21 subjects for clinical CAPS-5 outcomes (5 measurements), and 15 subjects for clinical PCL-5 outcomes (9 measurements). Therefore, we will include 26 subjects in this study.

EEG Variables
Following processing of the EEG data, the Randomised Graphical User Interface (RAGU) will be used to determine if differences between groups in overall alpha power or the distribution of alpha activity are present at occipitoparietal and frontal regions. RAGU uses powerful randomization statistics to make comparisons between groups including activity from all electrodes and time points simultaneously, while still using robust multiple comparison controls. Differences detected at the scalp level using this approach indicate differences in the underlying sources generating the neural activity.

Behavioural Variables
We will use mixed model analyses to study the change in PTSD severity across time. The repeated measurements of outcome variables (e.g., CAPS-5 and PCL-5) will be analysed by fitting linear mixed models using restricted maximum likelihood (REML) – this will allow all available data to be used without the need for imputation of missing values, the selection of the most suitable variance-covariance model for the repeated measures, using Akaike’s Information Criterion, and the investigation of commonality of any nonlinear trends over time via smoothing splines. The F-test will be used to test for a treatment by time interaction and comparisons between treatment conditions at each time point will be based on t-tests that utilize the predicted means and standard errors of difference that are recovered from the fitted mixed model. Diagnostic plots of residuals will be assessed and if deemed necessary, variance-stabilizing transformations will be applied to the outcome variables and inferences will be based on the analyses conducted on the transformed scale. In a series of exploratory analyses, mixed models with covariates for gender, age and time since diagnosis, order of treatment (sham v active), and their interactions with treatment condition and time, will be fitted to identify possible moderating effects. ¬

Recruitment
Recruitment status
Not yet recruiting
Date of first participant enrolment
Anticipated
2/09/2024
Actual
Date of last participant enrolment
Anticipated
26/06/2026
Actual
Date of last data collection
Anticipated
23/10/2026
Actual
Sample size
Target
26
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
ACT

Funding & Sponsors
Funding source category [1] 316861 0
University
Name [1] 316861 0
Australian National University SMP Fast Grants Seed Funding Scheme 2024
Country [1] 316861 0
Australia
Primary sponsor type
University
Name
Australian National University
Address
Country
Australia
Secondary sponsor category [1] 319100 0
None
Name [1] 319100 0
Address [1] 319100 0
Country [1] 319100 0

Ethics approval
Ethics application status
Submitted, not yet approved
Ethics committee name [1] 315620 0
ACT Health Human Research Ethics Committee
Ethics committee address [1] 315620 0
Ethics committee country [1] 315620 0
Australia
Date submitted for ethics approval [1] 315620 0
03/07/2024
Approval date [1] 315620 0
Ethics approval number [1] 315620 0

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

Contacts
Principal investigator
Name 135282 0
Dr Stephanie Gotsis
Address 135282 0
Rm 1.46, Florey Building, 54 Mills Road, Australian National University ACT 2601
Country 135282 0
Australia
Phone 135282 0
+61 2 6125 4153
Fax 135282 0
Email 135282 0
[email protected]
Contact person for public queries
Name 135283 0
Jeydhurga Raveendran
Address 135283 0
Rm 1.46, Florey Building, 54 Mills Road, The Australian National University, Canberra ACT, 2601
Country 135283 0
Australia
Phone 135283 0
+61 2 6125 4153
Fax 135283 0
Email 135283 0
[email protected]
Contact person for scientific queries
Name 135284 0
Stephanie Gotsis
Address 135284 0
Rm 1.46, Florey Building, 54 Mills Road, Australian National University ACT 2601
Country 135284 0
Australia
Phone 135284 0
+61 2 6125 4153
Fax 135284 0
Email 135284 0
[email protected]

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
No
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
No documents have been uploaded by study researchers.

Documents added automatically
No additional documents have been identified.