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Trial registered on ANZCTR


Registration number
ACTRN12619000010190
Ethics application status
Approved
Date submitted
19/12/2018
Date registered
8/01/2019
Date last updated
10/07/2019
Date data sharing statement initially provided
8/01/2019
Type of registration
Prospectively registered

Titles & IDs
Public title
Investigating a Novel Brain Stimulation Treatment for Mild Alzheimer's Disease
Scientific title
Investigating the effect of a novel brain stimulation treatment on episodic memory and gamma activity in Mild Alzheimer's Disease
Secondary ID [1] 296807 0
None
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Mild Alzheimer's Disease 310695 0
Condition category
Condition code
Neurological 309396 309396 0 0
Alzheimer's disease

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Transcranial Alternating Current (tACS) is a form of non-invasive brain stimulation that delivers a weak electrical current that alternates at a specified frequency back and forth between electrodes. The tACS device in this trial consists of a purpose-built handheld battery driven unit that delivers a current controlled voltage across an active and reference electrode. The active and reference electrodes are placed within commercially supplied saline soaked sponges, held in place using a custom designed headset such that the active electrode will be positioned over the left DLPFC and the reference electrode will be positioned over the right supraorbital space. Configuration of the headset to ensure correct electrode placement will be conducted by researchers at the beginning of the participant’s first tACS session. Electrode placement on the headset will then be clearly marked to ensure accurate and replicable positioning for future sessions.

tACS treatment course: The tACS treatment course is a 4 week program where participants will undergo 20 sessions (daily weekday sessions Mon-Fri for four weeks) of 40 Hz gamma tACS stimulation applied at 0.057mA/cm2 peak to peak for 20 minutes per session.

First, participants will attend the research centre with their nominated caregiver/support person for their baseline assessment, tACS training and their first stimulation session. This will allow researchers to observe and confirm correct self-administration of tACS.

Following this, for the remainder of the treatment course participants will self-administer tACS in their own homes with remote monitoring by researchers (this will include videoconferencing where required, to be determined on a case by case basis by the PI) and assistance from their nominated caregiver/support person if required. Researchers will contact participants by phone at the end of their stimulation session each day to confirm adherence (this will also be checked via the stimulator software at the end of the treatment course) and to discuss any adverse events. If at any time participants required additional instruction for the self-administration of tACS, researchers will arrange for them to come back into the research centre for additional training and treatment observation until the researchers are satisfied they are able to self-administer (determined via the use of a published training checklist).
Intervention code [1] 313097 0
Treatment: Devices
Comparator / control treatment
Participants in the sham condition will undergo 20 sessions (daily sessions Mon-Fri for four weeks) of sham gamma (40Hz) tACS at a current density of 0.057mA/cm2.

Sham stimulation is achieved by switching off stimulation after approximately 30 seconds, which occurs within the software of the device, allowing for administrator and participant blinding. There is no evidence that 30 seconds of tACS induces any changes in the brain. The provision of stimulation for 30 seconds allows participants to experience the initial physical sensations of tACS, which typically fade after 30 seconds, thus providing a robust sham. This is a standard method of blinding for tACS.
Control group
Placebo

Outcomes
Primary outcome [1] 308354 0
Changes in verbal episodic memory, as measured by change in Rey Auditory Verbal Learning Test (RAVLT) total score.
Timepoint [1] 308354 0
Assessed at baseline, end of treatment (primary endpoint), and at the 6-week and 3-month follow-up appointments.
Primary outcome [2] 308370 0
Gamma power, as measured using resting EEG.
Timepoint [2] 308370 0
Assessed at baseline and at the end of the treatment course.
Primary outcome [3] 318512 0
Connectivity, as measured using resting EEG.
Timepoint [3] 318512 0
Assessed at baseline and at the end of the treatment course.
Secondary outcome [1] 354706 0
Changes in overall cognitive ability, assessed using the Alzheimer's Disease Assessment Scale-Cog (ADAS-Cog), a global measure of cognitive decline.
Timepoint [1] 354706 0
Assessed at baseline, end of treatment, and at the 6-week and 3-month follow-up appointments.
Secondary outcome [2] 354776 0
Changes in attention, measured by change in Digit Span scores.
Timepoint [2] 354776 0
Assessed at baseline, end of treatment, and at the 6-week and 3-month follow-up appointments.
Secondary outcome [3] 365235 0
Changes in information processing speed, measured by change in Digit Symbol Coding scores
Timepoint [3] 365235 0
Assessed at baseline, end of treatment, and at the 6-week and 3-month follow-up appointments.
Secondary outcome [4] 365236 0
Changes in visual episodic memory, measured by change in Brief Visuospatial Memory Test (BVMT) scores.
Timepoint [4] 365236 0
Assessed at baseline, end of treatment, and at the 6-week and 3-month follow-up appointments.
Secondary outcome [5] 365237 0
Changes in visual recall, measured by change in Rey Complex Figure Test (Recall) scores.
Timepoint [5] 365237 0
Assessed at baseline, end of treatment, and at the 6-week and 3-month follow-up appointments.
Secondary outcome [6] 365238 0
Changes in language, measured by change in Verbal Fluency (FAS) scores.
Timepoint [6] 365238 0
Assessed at baseline. end of treatment. and at the 6-week and 3-month follow-up appointments.
Secondary outcome [7] 365239 0
Changes in visuospatial/visuoconstructional ability, measured by change in Rey Complex Figure Test (Copy) scores.
Timepoint [7] 365239 0
Assessed at baseline, end of treatment, and at the 6-week and 3-month follow-up appointments.
Secondary outcome [8] 365240 0
Changes in executive function, measured by change in Stroop scores.
Timepoint [8] 365240 0
Assessed at baseline, end of treatment, and at the 6-week and 3-month follow-up appointments.
Secondary outcome [9] 365241 0
Changes in global cognition and function, as measured by change in Clinical Dementia Rating Scale (CDR-SB) scores.
Timepoint [9] 365241 0
Assessed at baseline, end of treatment, and at the 6-week and 3-month follow-up appointments.
Secondary outcome [10] 365242 0
Changes in function and daily living, as measured by change in Alzheimer's Disease Cooperative Study ADL Scale (ADCS-ADL) scores.
Timepoint [10] 365242 0
Assessed at baseline, end of treatment, and at the 6-week and 3-month follow-up appointments.
Secondary outcome [11] 365243 0
Changes in quality of life, as measured by change in Quality of Life-Alzheimer's Disease (QOL-AD) scores.
Timepoint [11] 365243 0
Assessed at baseline, end of treatment. and at the 6-week and 3-month follow-up appointments.
Secondary outcome [12] 365244 0
The tolerability of active compared with sham stimulation, as measured by scores on the usability questionnaire and side-effects questionnaire, designed specifically for this study. This is a composite secondary outcome.
Timepoint [12] 365244 0
Assessed at end of treatment course.
Secondary outcome [13] 365245 0
Participant experience of the tACS treatment, its translation into daily life, possible personal implications of undertaking a course of tACS, and any potential areas for further improvement will be assessed in tACS user experience interviews. Interviews will be in-depth, face-to-face semi-structured interviews with open-ended questions, and are expected to take approximately 30-45 minutes. All responses will be voice-recorded and transcribed verbatim, and will undergo thematic analysis (please refer to Step 6: Study Design, Statistical methods/Analysis).
Timepoint [13] 365245 0
Assessed at end of treatment, and at the 3-month follow-up appointment.

Eligibility
Key inclusion criteria
-Aged between 50-85 years
-Demonstrated ability to give informed consent
-Diagnosis of probable AD according to the National Institute of Neurological and Communication Disorders–Alzheimer’s Disease and Related Disorders Association (NINCDS–ADRDA) criteria
-Meet criteria for mild AD as indicated by a score of greater than 19 on the Mini-Mental State Evaluation (MMSE)
-Not on a cholinesterase inhibitor or memantine or have been on a stable dose for at least two months prior to screening
-Not on psychotropic medication or their dose of psychotropic medication has been unchanged for a minimum of 4 weeks prior to entry into the study
-Frequent contact with a caregiver who can provide information on the participant’s cognitive and functional abilities at study visits and assist with at home stimulation procedures where required
-Able to participate in cognitive testing in English
Minimum age
50 Years
Maximum age
85 Years
Gender
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
-Concomitant major and unstable medical, psychiatric or neurological illness
-Pregnancy

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)
This is a double-blind study. Neither the participant nor the researcher conducting the assessments will know what type of stimulation the participant is receiving during each session. An external researcher, who will be unblinded, will randomise participants and assign either an 'active' programmed or a 'sham' programmed device.
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 administering 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)
Efficacy
Statistical methods / analysis
The study is primarily powered to detect a significant improvement in cognitive function, namely in episodic memory, following tACS. Single sessions of transcranial electrical stimulation have been shown to have a moderate effect size on cognition (Cohen’s d = 0.50) in older adults. Therefore, in the proposed study we are predicting that repeated sessions of tACS will result in at least a moderate to large effect size (d = 0.60); using this effect size a sample of 50 will provide 80% power to show a five point difference in change in the primary outcome measure assuming a SD of 5 at the 5% level of significance.

To assess the primary hypothesis, cognitive data will be analysed using linear mixed-effects modelling (participant as random effect) of the group x time interaction. If a significant interaction between stimulation type and time is observed, post-hoc between-group comparisons of the change will occur. The primary dependent variable will be the total score on the RAVLT . Neurobiological data analysis will again be conducted using linear mixed-effects modelling as described above. Dependent variables will be gamma power and connectivity at rest. The same analysis will be conducted for the following secondary outcome measures: cognitive scores across the remaining tasks conducted, ADAS-Cog, CDR-SB, ADCS-ADL, QOL-AD, and tolerability/side effects. In all cases, p-values <0.05 will be considered significant.

To assess the qualitative secondary hypothesis, after completion of the assessments, all interviews will be transcribed verbatim and thematic analysis will be performed following Braun & Clarke’s20 guidelines for Thematic Analysis. Upon this procedure, responses will be read through repeatedly. This exercise helps the researcher to cluster similar quotes and identify relevant codes. These codes will then be organised into patterns, which later will lead to identifying a hierarchy of themes. Codes from across multiple questionnaire items that relate to a shared theme or sub-theme will be also clustered. These themes will reflect important factors as gleaned from the data, with the relevance in addressing specific content of this research determined. Subsequently, themes will be reviewed, refined and named. As a guard against potential coding bias, the interviewer collecting responses from participants will not participate in, or contribute to, the conduct of the intervention. To guarantee consistency in the coding process, a second independent reviewer will be invited to cross-check the coding structure.

Recruitment
Recruitment status
Recruiting
Date of first participant enrolment
Anticipated
Actual
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
VIC
Recruitment hospital [1] 12668 0
Epworth Rehabilitation Camberwell - Camberwell
Recruitment postcode(s) [1] 25090 0
3124 - Camberwell

Funding & Sponsors
Funding source category [1] 301380 0
Hospital
Name [1] 301380 0
Epworth HealthCare - Epworth Research Institute Grant
Address [1] 301380 0
Epworth Camberwell
888 Toorak Road
Camberwell
VICTORIA 3124
Country [1] 301380 0
Australia
Primary sponsor type
University
Name
Monash University
Address
Wellington Rd, Clayton VIC 3800
Country
Australia
Secondary sponsor category [1] 301062 0
None
Name [1] 301062 0
Address [1] 301062 0
Country [1] 301062 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 302118 0
Monash Health Human Research Ethics Committee
Ethics committee address [1] 302118 0
246 Clayton Road
Clayton
VIC 3168
Ethics committee country [1] 302118 0
Australia
Date submitted for ethics approval [1] 302118 0
17/10/2018
Approval date [1] 302118 0
11/12/2018
Ethics approval number [1] 302118 0
RES-18-0000646A

Summary
Brief summary
This study is a randomised controlled trial involving 50 patients with mild Alzheimer’s disease (aged 50-85), that aims to investigate the efficacy of Transcranial Alternating Current Stimulation (tACS), a gentle non-invasive brain stimulation technique, in reducing symptoms of Alzheimer’s. Patient and carer experience with the tACS treatment will also be examined. Participants will be randomised to either active or placebo tACS, and will receive 20 treatment sessions over four-weeks. Clinical symptoms, cognition and quality of life will be assessed pre-treatment, at the end of the treatment course, and at 6 week and 3 month follow-ups. At the conclusion of the study, participants who initially received placebo tACS will be given the option of receiving active treatment.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 89174 0
A/Prof Kate Hoy
Address 89174 0
Monash Alfred Psychiatry Research Centre, Level 4 607 St Kilda Road
Melbourne VIC 3004
Country 89174 0
Australia
Phone 89174 0
+61 3 9076 5034
Fax 89174 0
Email 89174 0
kate.hoy@monash.edu
Contact person for public queries
Name 89175 0
Miss Bridget Kennedy
Address 89175 0
Epworth Centre for Innovation in Mental Health
Ground Floor
888 Toorak Rd
Camberwell
VIC 3124
Country 89175 0
Australia
Phone 89175 0
+61 3 9805 4389
Fax 89175 0
Email 89175 0
bridget.kennedy@epworth.org.au
Contact person for scientific queries
Name 89176 0
A/Prof Kate Hoy
Address 89176 0
Monash Alfred Psychiatry Research Centre, Level 4 607 St Kilda Road
Melbourne VIC 3004
Country 89176 0
Australia
Phone 89176 0
+61 3 9076 5034
Fax 89176 0
Email 89176 0
kate.hoy@monash.edu

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
Yes
What data in particular will be shared?
The data set will be shared, in de-identified form only.
When will data be available (start and end dates)?
Available following publication, and no end date determined.
Available to whom?
Available on a case-by-case basis at the discretion of the Principal Investigator, dependent on the proposal and methods of those wishing to access.
Available for what types of analyses?
Dependent on the proposal and methods of those wishing to access.
How or where can data be obtained?
As yet undecided.
What supporting documents are/will be available?
No other documents available
Summary results
No Results