Trial Review

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Trial registered on ANZCTR


Registration number
ACTRN12621000498897
Ethics application status
Approved
Date submitted
25/02/2021
Date registered
29/04/2021
Date last updated
15/11/2021
Date data sharing statement initially provided
29/04/2021
Type of registration
Prospectively registered

Titles & IDs
Public title
Novel transcranial electrical modulation for Major Depressive Disorder
Scientific title
Novel high-definition transcranial grey noise stimulation (HD-tGNS) for the treatment of Major Depressive Disorder: A proof of concept study
Secondary ID [1] 303547 0
Nil
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Major Depressive Disorder
 320893 0
Condition category
Condition code
Mental Health 318709 318709 0 0
Depression

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Intervention name: High Density Grey Noise Stimulation (HD-tGNS).

High-definition transcranial grey noise stimulation (HD-tGNS) will be used to disrupt pathological connectivity and restore normal function. Key structures of the Salience Network (SN) (Right Insular Cortex (RIC) and dorsal Anterior Cingulate cortex (dACC)) and Default Mode Network (DMN) (pregenual Anterior Cingulate Cortex (pgACC), and Posterior Cingulate Cortex (PCC)) will be targeted. The program required will be designed by Neuroelectrics® with the goal of restoring healthy functional communication between these brain regions.

HD-tGNS will be administered three times a week (30 minutes/session) for a total of six weeks (i.e. 18 sessions in total) by a researcher experienced in administering neuromodulation techniques. 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 multiple small electrode (size: 1 cm radius) that can focally target deeper brain regions. Thirty-two circular Ag/AgCl stimulation electrodes will be placed on a neoprene head cap. A 10-20 international placement EEG system will target the pgACC, PCC, dACC, and RIC and simultaneously to collect EEG data regarding functional connectivity. The optimal montages to target the network activity of the pgACC, PCC, dACC, and RIC will be created using the Stimweaver optimization software by the Neuroelectrics company. The placement of the electrodes will be identical for both the intervention groups.

The stimulation will be delivered continuously at a current strength of maximum of 2mA for 30min, with 60s ramp up and ramp down at the beginning and end of each stimulation session. The intervention dosage is chosen based on the safety guidelines of previous TES studies.

The intervention will be administered in person at the Otago Brai3n Laboratory of the Dunedin School of Medicine.

To assess adherence to the intervention, session attendance, drop-out rates, and participant satisfaction levels will be recorded. Adherence to the intervention will be measured as the number of treatment sessions attended by each participant and will be expressed as a percentage of the total number of sessions. Once the treatment phase is completed, adherence rates will be calculated. Conversely, drop-out rates will be measured as the number of participants who drop out in each group, expressed as a percentage of the total number of participants enrolled in the study. Drop-out rates will calculated on the follow-up phase is completed. Finally, participant satisfaction levels and acceptability for HD-tGNS as a treatment will be recorded on an 11-point numeric rating scale (0-Not at all satisfied/acceptable to 10-very satisfied/acceptable).
Intervention code [1] 319831 0
Treatment: Devices
Comparator / control treatment
For the sham stimulation, to create an identical skin sensation to the active stimulation, the current will be applied for a 60s ramp up (0-2mA) and 60s ramp down (2-0mA) at the beginning and the end of each stimulation session, without any current for the remainder of the stimulation period. Thus, the sham session will last as long as the real HD-tGNS session to blind the procedure appropriately. This sham procedure has been used by the previous TES studies and is shown to effectively blind participants to the stimulation condition. With the Starstim device, previous study has demonstrated that the participants do not feel any skin sensation during the active noise stimulation phase, which further ensures the blinding of participants to the intervention group.
Control group
Placebo

Outcomes
Primary outcome [1] 326642 0
Feasibility:

Feasibility for the study will be assessed as a composite of:
• Recruitment rate (i.e. the number of participants recruited per month, until the proposed sample size is reached). The coordinating investigator will record the recruitment rate every week, from 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.
• 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.
• 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.
• 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 [1] 326642 0
Every week from start of recruitment to end of the study.
Primary outcome [2] 326643 0
Safety:

Although transcranial electrical stimulation is a safe technique, any adverse effects (e.g., headache, pain flare-ups) that may have causal relationship with the intervention will be recorded by the treating researcher. A study-specific questionnaire will be used. This will help evaluate both the previous session’s (delayed) effects and the same session’s (immediate) effects. Safety will be assessed as a composite of:
• Qualitative description of each symptom
• 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.
• The number of drop-outs due to adverse effects.
Timepoint [2] 326643 0
At each session before the intervention, during the intervention (at intervals of 5 mins), and after completion of that day’s intervention session.
Primary outcome [3] 326644 0
Efficacy will be assessed using a composite of interview and self-rated questionnaires. Efficacy measures will include:

• Quick Inventory of Depressive Symptomatology- Self Report (QIDS-SR) consists of 16 self-rated questions relating to cognitive, emotional, and behavioural changes often seen in depression. It is renowned as one of the most specific scales for depression and for its sensitivity in detecting changes pre-and post-intervention.
• Montgomery-Asberg Depression Rating Scale (MADRS) is a clinician delivered interview. It not only involves questions within the key domains described for the QIDS-SR, but also accounts for clinician observations of the patient regarding apparent sadness and other variables.
• Rumination Response Scale (RRS) is the most validated scale for rating changes in cognition related to negative attention and rumination. It is a 22 question, self-rated measure.
• World Health Organisation- Five Well-Being Index (WHO-5) consists of self-reported 5 items that measure the participant’s current mental wellbeing. It is widely used for measuring well-being and has good psychometric properties.
Timepoint [3] 326644 0
Baseline (pre-intervention), at three weeks (at the intervention mid-point), and at six weeks (at the end of intervention).
Secondary outcome [1] 392265 0
A composite of changes in cortical activity and functional connectivity assessed using 64-electrode EEG will also be assessed as a primary outcome.

Resting-state EEG and source localization will be performed simultaneously in a quiet room while the participant is sitting upright in a comfortable chair by an independent researcher blinded to the treatment group. EEG data will be collected using the SynAmps RT Amplifier (Compudemics Neuroscan). The scalp will be cleaned with alcohol wipes before the baseline EEG recording. The EEG will be sampled with 64 electrodes placed in the standard 10–20 International placement and impedances will be checked to remain below 5 kO. Data will be collected for ~10 minutes with the participant’s eyes closed.

Participants will be instructed not to drink alcohol for 24 hours prior to or consume caffeine or nicotine products one hour before EEG recording to avoid substance-induced changes in the EEG stream. The alertness of participants will be checked by monitoring the alpha rhythm for slowing and appearance of spindles in the EEG stream to prevent possible enhancement of the theta power due to drowsiness during recording.

The EEG data will then be resampled to 128 Hz, band-pass filtered (through a fast Fourier transform filter) to 0.01–44 Hz, and re-referenced to the average reference using the EEGLAB function in Matlab. The data will then be plotted in EEGLAB for a careful inspection of artifacts. All episodic artifacts suggestive of eye blinks, eye movements, jaw tension, teeth clenching, or body movement will be manually removed from the EEG stream.
Timepoint [1] 392265 0
Recordings will be obtained at baseline (pre-intervention), at three weeks (at the intervention mid-point), and at six weeks (at the end of intervention).
Secondary outcome [2] 393330 0
Heart Rate Variability (HRV) will be assessed using an electrocardiograph.
Timepoint [2] 393330 0
Recordings will be obtained at baseline (pre-intervention), at three weeks (at the intervention mid-point), and at six weeks (at the end of intervention).

Eligibility
Key inclusion criteria
Participants with a diagnosis of MDD 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.
• A score lower than three on the Maudsley Staging Method for treatment resistant depression.
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:
• Other mental illness
• History of neurological diseases
• History of epilepsy or seizures
• History of substance abuse,
• Previous treatment with neuromodulation (e.g. Transcranial magnetic stimulation, electroconvulsive therapy, Neurofeedback, etc.)
• Dyslipidaemia
• Cognitive impairments (dementia, post-traumatic stress disorders, Alzheimer’s disease): 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 for the duration of the trial, with the type and dosage of medication being recorded throughout the duration of the trial. However, participants with the intention of taking new medications 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)
The randomisation schedule will be concealed in numbered, sealed, and opaque envelopes and effected after baseline measurements.
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
Sample size estimation has not been conducted as this is a pilot study. We aim to recruit a modest sample (12 per group). Effect sizes will be calculated based on outcomes, which will be used to calculate sample size for the future fully powered trial.

The Evaluable Participant Population (EPP) will be defined as all participants who successfully complete the intervention phase. The primary population for the evaluation of study objectives in this trial will be the EPP.

Feasibility, safety, and clinical variables: SPSS version 22.0 will be used for all statistical analyses. Descriptive statistics will be used to analyse feasibility and safety measures. Linear mixed model regression analysis will be used to estimate the treatment effects on efficacy measures.

Resting-state EEG data: The sLORETA programme will be used to explore the effect of HD-tGNS on the activity and functional connectivity between the targeted brain regions. Average Fourier cross-spectral matrices will be computed for bands infraslow (0.01-0.1 Hz), slow (0.2-1.5), delta (2–3.5 Hz), theta (4–7.5 Hz), alpha1 (8–10 Hz), alpha2 (10.5–12 Hz), beta1 (12.5–18 Hz), beta2 (18.5–21 Hz), beta3 (21.5–30 Hz), and gamma (30.5–44 Hz).

Recruitment
Recruitment status
Recruiting
Date of first participant enrolment
Anticipated
19/05/2021
Actual
14/06/2021
Date of last participant enrolment
Anticipated
19/11/2021
Actual
Date of last data collection
Anticipated
31/12/2021
Actual
Sample size
Target
24
Accrual to date
12
Final
Recruitment outside Australia
Country [1] 23488 0
New Zealand
State/province [1] 23488 0
Otago

Funding & Sponsors
Funding source category [1] 307970 0
University
Name [1] 307970 0
The University of Otago
Country [1] 307970 0
New Zealand
Primary sponsor type
Individual
Name
Dirk De Ridder
Address
Department of Surgical Sciences
University of Otago
201 Great King Street
Dunedin
9016
Country
New Zealand
Secondary sponsor category [1] 308689 0
Individual
Name [1] 308689 0
Divya Adhia
Address [1] 308689 0
Department of Surgical Sciences
University of Otago
201 Great King Street
Dunedin
9016
Country [1] 308689 0
New Zealand
Secondary sponsor category [2] 308690 0
Individual
Name [2] 308690 0
Paul Glue
Address [2] 308690 0
Department of Psychological Medicine.
University of Otago
201 Great King Street
Dunedin
9016
Country [2] 308690 0
New Zealand
Other collaborator category [1] 281668 0
Individual
Name [1] 281668 0
Paul Glue
Address [1] 281668 0
362 Leith Street, North Dunedin, Dunedin 9016, Otago

Department of Psychological Medicine,
Chair, Psychiatry; Division of Health Sciences Associate Dean
Country [1] 281668 0
New Zealand
Other collaborator category [2] 281700 0
Individual
Name [2] 281700 0
Nathaniel Hutchinson-Wong
Address [2] 281700 0
Department of Surgical Sciences
University of Otago
201 Great King Street
Dunedin
9016
Country [2] 281700 0
New Zealand
Other collaborator category [3] 281702 0
Individual
Name [3] 281702 0
Nathaniel Hutchinson-Wong
Address [3] 281702 0
Department of Surgical Sciences
University of Otago
201 Great King Street
Dunedin
9016
Country [3] 281702 0
New Zealand

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 307964 0
Health and Disability Committee (HDEC) New Zealand
Ethics committee address [1] 307964 0
Ministry of Health
133 Molesworth Street
PO Box 5013
Wellington 6011
Ethics committee country [1] 307964 0
New Zealand
Date submitted for ethics approval [1] 307964 0
02/12/2020
Approval date [1] 307964 0
29/04/2021
Ethics approval number [1] 307964 0

Summary
Brief summary
The purpose of this study is to evaluate the safety and to explore the effect of a new brain stimulation technique on brain signals related to suffering and symptoms of depression in people diagnosed with Major Depressive Disorder.

This study will involve stimulating the activity of the brain regions that have been associated with attention and self-identity. Altered communication between these brain areas has been associated with depression and its associated suffering.

The results obtained from this study will help us to develop new treatments for improving health outcomes (feelings of suffering and symptoms of depression) in individuals diagnosed with depression.

It is our hypotheses that:

• The HD-tGNS technique targeting key structures of the brain associated with attention and self-identity will improve unhealthy signals related to repetitive, negative, self-image/thoughts and depression in patients with Major Depressive Disorder.
• Compared to the placebo (sham) stimulation technique, the HD-tGNS technique will change activity and functional connectivity in the resting-state brain networks, particularly in/of the areas of interest.
• These changes in activity and functional connectivity between the resting-state brain networks will show improvement alongside improvement in clinical outcomes.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 109066 0
Prof Dirk De Ridder
Address 109066 0
362 Leith Street, North Dunedin, Dunedin 9016, Otago

The Dunedin School of Medicine, The University of Otago,
Chair, Neurosurgery
Country 109066 0
New Zealand
Phone 109066 0
+64 03 470 9337
Fax 109066 0
Email 109066 0
[email protected]
Contact person for public queries
Name 109067 0
Dr Divya Adhia
Address 109067 0
Department of Surgical Sciences
University of Otago
201 Great King Street
Dunedin
9016
Country 109067 0
New Zealand
Phone 109067 0
+64 03 470 9337
Fax 109067 0
Email 109067 0
[email protected]
Contact person for scientific queries
Name 109068 0
Dr Divya Adhia
Address 109068 0
Department of Surgical Sciences
University of Otago
201 Great King Street
Dunedin
9016
Country 109068 0
New Zealand
Phone 109068 0
+64 03 470 9337
Fax 109068 0
Email 109068 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.