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Trial registered on ANZCTR


Registration number
ACTRN12623000250639
Ethics application status
Approved
Date submitted
22/02/2023
Date registered
8/03/2023
Date last updated
8/03/2023
Date data sharing statement initially provided
8/03/2023
Type of registration
Prospectively registered

Titles & IDs
Public title
High-definition transcranial grey noise stimulation (HD-tGNS) as an intervention for generalised anxiety disorder (GAD): A proof of concept study
Scientific title
High-definition transcranial grey noise stimulation (HD-tGNS) for the treatment of generalised anxiety disorder (GAD) in adults: A proof of concept study
Secondary ID [1] 309010 0
None
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Generalised Anxiety Disorder 329054 0
Condition category
Condition code
Mental Health 326034 326034 0 0
Anxiety

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
High definition transcranial grey noise stimulation (HD-tGNS) will be applied to key structures of the anxiety/fear network [main regions: amygdala, anterior cingulate cortex (ACC), orbitofrontal cortex (OFC), insula, and parahippocampus]. The intervention will be administered three times a week (30 minutes per session) for a total of 6 weeks (i.e. 18 sessions in total) using a 32-channel transcranial current stimulator (Starstim32 TES®, Neuroelectrics, Spain). Participants in the delayed-start group will receive Sham stimulation for the first three weeks followed by HD-tGNS for three weeks; whereas participants in the early-start group will receive HD-tGNS throughout the intervention phase (i.e. for a total of 6 weeks).
The intervention will be undertaken by a researcher experienced in administering neuromodulation techniques. Each participant will undergo the intervention individually at the department of surgical sciences at Dunedin Hospital.

A battery-driven wireless 32 channel transcranial current stimulator (Starstim32 TES®, Neuroelectrics, Spain, http://www.neuroelectrics.com) will be used to deliver stimulation while the participants are comfortably and quietly seated. The Starstim32 is a high definition system with small electrode size that can focally target deeper brain regions. The Ag/AgCl stimulation electrodes will be placed on a neoprene head cap following the International 10-20 EEG system.

For the HD-tGNS, the stimulation will be delivered at a current strength of maximum of 2mA for 30min, with 60s ramp up and ramp down at the beginning and the end of each stimulation session, with continuous stimulation in between.

Adherence of the intervention will be monitored using session attendance checklist.
Intervention code [1] 325452 0
Treatment: Devices
Comparator / control treatment
For sham stimulation phase, to create an identical skin sensation to the active stimulation, the actisham protocol created by the neuroelectrics will be used. The current will be applied for a 60s ramp up and 60s ramp down at the beginning of each stimulation session, without any current for the remainder of the stimulation period. This sham procedure has been previously shown to effectively blind participants to the stimulation condition, as it can induce the same scalp sensations perceived during active stimulation, both in terms of intensity and localization, while preventing currents from reaching the cortex and causing changes in brain excitability.

The sham intervention will be administered three times a week (30 minutes per session) for a total of 3 weeks (i.e. 9 sessions in total) using a 32-channel transcranial current stimulator (Starstim32 TES®, Neuroelectrics, Spain).

Only participants in the delayed-start group will receive Sham stimulation for the first three weeks, following which they will receive the HD-tGNS for a further three weeks.
Control group
Placebo

Outcomes
Primary outcome [1] 333893 0
Hospital Anxiety and Depression Scale (HADS)
Timepoint [1] 333893 0
Baseline, midway through the experiment (i.e., at three weeks post-commencement of intervention), and immediately post-intervention period (i.e., at six weeks post-commencement of intervention)
Primary outcome [2] 333894 0
Generalised Anxiety Disorder Scale- 7 (GAD-7)
Timepoint [2] 333894 0
Baseline, midway through the experiment (i.e., at three weeks post-commencement of intervention), and immediately post-intervention period (i.e., at six weeks post-commencement of intervention)
Primary outcome [3] 333895 0
Resting state brain activity and functional connectivity measured by Electroencephalography (EEG)
Timepoint [3] 333895 0
Baseline, midway through the experiment (i.e., at three weeks post-commencement of intervention), and immediately post-intervention period (i.e., at six weeks post-commencement of intervention)
Secondary outcome [1] 418638 0
Safety Measures - Any adverse events or side effects (e.g. tingling or burning under stimulation electrodes). [Primary outcome measure]

Although transcranial electrical stimulation is a safe technique, any adverse effects (e.g., headache, pain flare-ups) that likely have a causal relationship with the intervention will be recorded by the treating researcher at each session before the intervention, during the intervention (at intervals of 5 mins), and after completion of that day’s intervention session.

The following variables will be recorded:
· Qualitative description of each symptom assessed by study-specific questionnaire
· The intensity of each symptom will be measured using a Likert scale ranging from 0 (none) to 10 (extreme)
· Relation of the symptom to the treatment, measured on a scale ranging from 1 (unrelated) to 5 (strongly related).
· Duration of each symptom and the time taken for resolution of each symptom, expressed in minutes.
· Any drop-outs due to adverse effects will also be recorded and assessed via audit of study enrolment logs.
Timepoint [1] 418638 0
Throughout the intervention process and post-intervention (i.e., at each assessment and treatment session)
Secondary outcome [2] 418639 0
Feasibility measures [Primary outcome measure]

The following feasibility outcomes will be measured:
· Recruitment rate (i.e. the number of participants recruited per month, until the proposed sample size is reached) assessed by audit of study recruitment logs. The recruitment rate will be recorded by the co-ordinating investigator (CI) every week, since the release of the advertisements, and the number of advertisements will also be recorded.
· Proportion of participants recruited from the total number screened (with reasons for exclusion), expressed as a percentage, assessed by audit of study recruitment logs.
· Adherence to intervention measured as number of treatment sessions attended by each participant and expressed as a percentage of the total number of sessions. Adherence rates will be calculated once the treatment phase is completed. This will be assessed by audit of study logs.
· Drop-out rates, measured as the number of participants who dropped-out in each group, and expressed as a percentage of the total number of participants enrolled in the study. Drop-outs rates will be calculated once the follow-up phase is completed, by audit of study logs.
· Participant satisfaction levels regarding treatment and the acceptability of the HD-tGNS will also be recorded on an 11-point numeric rating scale (0-Not at all satisfied/acceptable to 10-Very satisfied/acceptable).
Timepoint [2] 418639 0
Throughout the intervention process and post-intervention.

Recruitment rate and drop-outs rates will be calculated once the follow-up phase is completed,

Adherence to intervention will be calculated midway through the experiment (i.e., at three weeks post-commencement of intervention), and immediately post-intervention period (i.e., at six weeks post-commencement of intervention).

Participant satisfaction levels and acceptability will be recorded immediately post-intervention period (i.e., at six weeks post-commencement of intervention).
Secondary outcome [3] 418640 0
State Trait Anxiety Inventory (STAI) [Primary outcome measure]
Timepoint [3] 418640 0
Baseline, midway through the experiment (i.e., at three weeks post-commencement of intervention), and immediately post-intervention period (i.e., at six weeks post-commencement of intervention)
Secondary outcome [4] 418641 0
World Health Organisation- Five Well-Being Index (WHO-5)
Timepoint [4] 418641 0
Baseline, midway through the experiment (i.e., at three weeks post-commencement of intervention), and immediately post-intervention period (i.e., at six weeks post-commencement of intervention)

Eligibility
Key inclusion criteria
Participants with a diagnosis of GAD will be eligible to participate. To be included in the study, participants must meet all of the following inclusion criteria:

· Capable of understanding the study information and able to sign the informed consent form.
· Age between 18 to 60 years on the day of the consent.
Minimum age
18 Years
Maximum age
60 Years
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
Participants who meet any of the following conditions will be excluded:
· History of neurological disorders
· History of epilepsy or seizures
· History of substance abuse (i.e., consuming more than 3 drinks on any day or more than 7 drinks per week for women, and more than 4 drinks on any day or more than 14 drinks per week for men).
· Previous treatment with neuromodulation (e.g. Transcranial magnetic stimulation, electroconvulsive therapy, Neurofeedback, etc.)
· Dyslipidaemia
· Cognitive impairments (Dementia, Alzheimer’s disease, personality disorders, substance use disorders, certain medical conditions): A total score of 24 or below on Mini-Mental State Examination
· History of uncontrolled/untreated hypertension
· Presence of any pacemaker or defibrillator
· Presence of any electronic implants or metal implant in the body (particularly head and neck)
· Recent or current pregnancy

Note ~ Participants will be permitted to continue their medications or ongoing psychotherapy for the duration of the trial, with the type and dosage of medication/therapy being recorded throughout the duration of the trial. However, participants with the intention of taking new medications/therapies in the next 2 months, will be excluded.

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)
A research administrator, not involved in the treatment or assessment procedures, will randomize eligible volunteers using an open-access randomization software program, to start with either a) delayed start group, or b) early start group.

The randomization schedule will be concealed in a number sealed and opaque envelopes and will be opened at the individual testing session.
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
Blinded (masking used)
Who is / are masked / blinded?
The people receiving the treatment/s

The people assessing the outcomes
Intervention assignment
Parallel
Other design features
Phase
Not Applicable
Type of endpoint/s
Safety/efficacy
Statistical methods / analysis
SPSS version 28.0 and R version 4.1.0 will be used for all statistical analyses.

Descriptive statistics will be used to analyse feasibility and safety measures. Percentage change to baseline will be calculated for the primary and secondary measures. Simple statistical analysis (e.g., t-test) will be used to obtain estimates of the intervention effects on primary and secondary outcome measures.

The sLORETA programme will be used to explore the effect of HD-tGNS on the activity and functional connectivity between the targeted brain regions comparing pre and post-treatment measurements.

Recruitment
Recruitment status
Not yet recruiting
Date of first participant enrolment
Anticipated
10/03/2023
Actual
Date of last participant enrolment
Anticipated
31/08/2023
Actual
Date of last data collection
Anticipated
31/10/2023
Actual
Sample size
Target
24
Accrual to date
Final
Recruitment outside Australia
Country [1] 25272 0
New Zealand
State/province [1] 25272 0
Otago

Funding & Sponsors
Funding source category [1] 313223 0
University
Name [1] 313223 0
University of Otago
Country [1] 313223 0
New Zealand
Primary sponsor type
University
Name
Otago University
Address
362 Leith Street, North Dunedin, Dunedin 9016, New Zealand
Country
New Zealand
Secondary sponsor category [1] 314944 0
None
Name [1] 314944 0
NA
Address [1] 314944 0
NA
Country [1] 314944 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 312453 0
Northern B Health and disability ethics committees
Ethics committee address [1] 312453 0
Ministry of Health
133 Molesworth Street
PO Box 5013
Wellington
6011
Ethics committee country [1] 312453 0
New Zealand
Date submitted for ethics approval [1] 312453 0
16/11/2022
Approval date [1] 312453 0
13/02/2023
Ethics approval number [1] 312453 0
2023 FULL 13910

Summary
Brief summary
This study is a pilot study with delayed-start double-blinded (participant and outcome assessor) randomised sham-controlled trial with outcome measures collected at baseline, mid, and immediately post-intervention.

This study aims to 1) evaluate the feasibility of high-definition transcranial grey noise stimulation (HD-tGNS) in individuals with generalised anxiety disorder (GAD), 2) evaluate the effect of HD-tGNS on the functional connectivity between key hubs of the anxiety/fear network, and 3) investigate the effect of HD-tGNS on clinical outcomes in individuals with GAD (as trends in anxiety, suffering, and wellbeing). Up to 24 participants will be targeted.

HD-tGNS will be applied to key structures of the anxiety/fear network (main regions: amygdala, ACC, OFC, insula, parahippocampus). The intervention will be administered three times a week (30 minutes per session) for a total of 6 weeks (i.e. 18 sessions in total) using a 32-channel transcranial current stimulator (Starstim32 TES®, Neuroelectrics, Spain). Participants in the delayed-start group will receive Sham stimulation for the first three weeks followed by HD-tGNS for three weeks; whereas participants in the early-start group will receive HD-tGNS throughout the intervention phase (i.e. for a total of 6 weeks).

Outcome measures include: Safety and Feasibility, the Generalised Anxiety Disorder Scale (GAD-7), Hospital Anxiety and Depression Scale (HADS), and the State-Trait Anxiety Inventory (STAI) for measures of anxiety, the WHO-5 wellbeing index as a measure of wellbeing, and Resting state electroencephalography (EEG). The outcomes of this study will help us to develop new brain stimulation treatments for people with GAD.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 124722 0
Dr Divya Adhia
Address 124722 0
201 Great King Street, Dunedin hospital, 6th floor, Room 607,
Department of Surgical Sciences, Otago Medical School, University of Otago.
Dunedin
9013
Country 124722 0
New Zealand
Phone 124722 0
+64 211167594
Fax 124722 0
Email 124722 0
divya.adhia@otago.ac.nz
Contact person for public queries
Name 124723 0
Ms Cindy van Sleeuwen
Address 124723 0
201 Great King Street, Dunedin hospital, 6th floor, Room 607,
Department of Surgical Sciences, Otago Medical School, University of Otago.
Dunedin
9013
Country 124723 0
New Zealand
Phone 124723 0
+64 2102954664
Fax 124723 0
Email 124723 0
vanci236@student.otago.ac.nz
Contact person for scientific queries
Name 124724 0
Dr Divya Adhia
Address 124724 0
201 Great King Street, Dunedin hospital, 6th floor, Room 607,
Department of Surgical Sciences, Otago Medical School, University of Otago.
Dunedin
9013
Country 124724 0
New Zealand
Phone 124724 0
+64 211167594
Fax 124724 0
Email 124724 0
divya.adhia@otago.ac.nz

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
No
No/undecided IPD sharing reason/comment
None.


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.