Trial Review

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Trial registered on ANZCTR


Registration number
ACTRN12623000668606
Ethics application status
Approved
Date submitted
6/06/2023
Date registered
21/06/2023
Date last updated
21/06/2023
Date data sharing statement initially provided
21/06/2023
Type of registration
Prospectively registered

Titles & IDs
Public title
Theta Burst Stimulation for Mild to Moderate Alzheimer's disease.
Scientific title
A Randomised Controlled Trial of individualised Theta Burst Stimulation on Functional Connectivity and Symptom Severity for Mild to Moderate Alzheimer's disease.
Secondary ID [1] 309852 0
None
Universal Trial Number (UTN)
Trial acronym
TBS-AD
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Alzheimer's Disease 330294 0
Condition category
Condition code
Neurological 327151 327151 0 0
Alzheimer's disease

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
A double-blind placebo-controlled clinical trial comparing a course of active theta burst stimulation (TBS) (an efficient and potent form of transcranial magnetic stimulation (TMS)) to sham TBS. Participants with mild to moderate Alz will be randomised to 1 of 2 conditions (active TBS vs sham TBS) in a 1 to 1 allocation ratio. The treatment course will involve a 6-week acute phase (daily treatments Mon-Fri) followed by a 6-week maintenance phase (once weekly treatment) and 3, 6 and 12-month follow ups. In each treatment session TBS will be sequentially provided to four brain regions, the left and right dorsolateral prefrontal cortex (lDLPFC, rDLPFC) and the left and right inferior parietal lobule (lIPL, rIPL).

Stimulation Parameters: Stimulation will be provided using a MagVenture Magpro30 (MagVenture, Lucerne, Denmark) magnetic stimulator with a butterfly figure-of-8 coil (MagVenture Cool-B65 coil). All four brain sites will be stimulated using an individualised intermittent TBS protocol. Specifically, all sites will be stimulated using 3-pulse individualised gamma-Hz bursts applied at individualised theta-Hz with a 2-second train of TBS repeated every 10 seconds for a total of 180 seconds per site (i.e., approximately 600 pulses). Stimulation of all four sites will take 12 minutes per treatment session. Treatment sessions, including setup and coil repositioning, will be no longer than 30 minutes in total. iTBS will be applied at 100% of the Resting Motor Threshold and all treatments will be provided by a trained TMS clinician. There will be a total of 36 iTBS treatments provided over a 12 week period. Treatment adherence will be recorded by TMS clinicians via the use of session attendance checklists.

Individualised stimulation parameters will be obtained via EEG and fMRI which will be collected during the baseline assessments, which will occur within a two week window prior to treatment commencement.
Intervention code [1] 326287 0
Treatment: Devices
Comparator / control treatment
Sham (placebo) iTBS will be provided in the exact same ‘manner’ as active iTBS (described above) but will utilise a sham coil (MagVenture MCF-P-B65 Coil) which can mimic the sound and tactile sensation stimulation and is considered the current gold standard for blinding.
Control group
Placebo

Outcomes
Primary outcome [1] 335028 0
Functional Connectivity as measured using resting state functional Magnetic Resonance Imaging (rs-fMRI).
Timepoint [1] 335028 0
This outcome will be measured at baseline and at the end of treatment (i.e. week 12 post baseline, primary timepoint)
Primary outcome [2] 335029 0
The Alzheimer’s Disease Assessment Scale–Cognitive Subscale (ADAS-Cog).
Timepoint [2] 335029 0
This outcome will be measured at baseline, end of treatment (Week 12 post-baseline, primary timepoint), 3, 6 and 12 month follow-ups post-completion of treatment.
Primary outcome [3] 335030 0
Clinical Dementia Rating Sum of Boxes (CDR-SB, composite scale for cognition and function)
Timepoint [3] 335030 0
This outcome will be measured at baseline, end of treatment (Week 12 post-baseline, primary timepoint), 3, 6 and 12 month follow-ups post-completion of treatment.
Secondary outcome [1] 422763 0
Ability to perform activities of daily living (ADLs) assessed using the Alzheimer's Disease Cooperative ADL Scale (ADCS-ADL)
Timepoint [1] 422763 0
Baseline, End of treatment (Week 12 post-baseline), 3, 6 and 12 month follow-ups post-completion of treatment.
Secondary outcome [2] 422766 0
Quality of Life in Alzheimer's disease ( QoL-AD)
Timepoint [2] 422766 0
Baseline, End of treatment (Week 12 post-baseline), 3, 6 and 12 month follow-ups post-completion of treatment.
Secondary outcome [3] 422769 0
Tailored Cognitive Battery: This cognitive battery will use reliable and well validated pen and paper neuropsychological assessments including: Digit Span (forward and backward); Digit Symbol Coding; Hopkins Verbal Learning Test (HVLT); Brief Visuospatial Memory Test (BVMT), and Verbal Fluency. This will be assessed as a composite outcome
Timepoint [3] 422769 0
Baseline, week 6 mid treatment, End of treatment (Week 12 post-baseline), 3, 6 and 12 month follow-ups post-completion of treatment.
Secondary outcome [4] 422772 0
Functional connectivity measured using functional Near Infrared Spectroscopy (fNIRS)
Timepoint [4] 422772 0
This outcome will be measure at baseline and at the end of treatment (i.e. week 12 post baseline)
Secondary outcome [5] 422774 0
Blood plasma biomarkers (i.e., p-tau 181, Nfl, AB-42)
Timepoint [5] 422774 0
This outcome will be measure at baseline and at the end of treatment (i.e. week 12 post baseline)
Secondary outcome [6] 422775 0
TMS Side effect and Tolerability Questionnaires, This will be assessed as a composite measure
Timepoint [6] 422775 0
Weekly during the 12 week treatment course
Secondary outcome [7] 422776 0
Clinical Progression using the Alzheimer's Disease Composite Score (ADCOMS)
Timepoint [7] 422776 0
Baseline, End of treatment (Week 12 post-baseline), 3, 6 and 12 month follow-ups post-completion of treatment.
Secondary outcome [8] 423004 0
Note: this is a primary outcome.
Functional Connectivity as measured using Electroencephalography (EEG)
Timepoint [8] 423004 0
Baseline, week 6 mid treatment, End of treatment (Week 12 post-baseline, primary timepoint), 3 month follow-ups post-completion of treatment.

Eligibility
Key inclusion criteria
Participants will be included if they:
(1) are between 50 and 85 years of age;
(2) have a diagnosis of 'probable Alzheimer's disease (AD) dementia' according to the National Institute on Aging/Alzheimer's Association diagnostic guidelines of AD (NIA-AA)
(3) meet criteria for mild or moderate AD as indicated by a score >12 on the Mini-Mental State Evaluation;
(4) are competent to consent based on their ability to provide a spontaneous narrative description of the key elements of the study, or, if they are unable to consent, consent may be provided on their behalf by a legally authorized representative, who may be a family member, legal guardian, or other designated representative as consistent with the relevant state and federal legislation applicable for each study site. Where participants can consent an advance care directive will be taken, whereby if they lose capacity to consent during the trial they can choose to either withdraw or for consent to be sought from their legally authorized representative. In all instances where consent is provided by the participant's legally authorized representative, the participant's willingness to participate (i.e., assent) will be required and documented.
(5) are either not on a cholinesterase inhibitor and/or memantine or have been on a stable dose for at least 3 months prior to screening;
(6) are either not on a psychotropic medication or their dose of psychotropic medication has been unchanged for at least 4 weeks prior to study entry. Psychotropic dose will not be able to be altered during the trial: if this is clinically required the participant will be withdrawn;
(7) have frequent contact with a close other who can provide information on the participant's cognitive and functional abilities.
Minimum age
50 Years
Maximum age
85 Years
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
Participants will be excluded if they:
(1) have a concomitant major and unstable medical, psychiatric, or neurological illness or seizure disorder history;
(3) are pregnant;
(3) have medically implanted material that could interact with the magnetic field (relevant for Magnetic Resonance Imaging and Transcranial Magnetic Stimulation).

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)
Permuted block randomisation
Masking / blinding
Blinded (masking used)
Who is / are masked / blinded?
The people receiving 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

Recruitment
Recruitment status
Not yet recruiting
Date of first participant enrolment
Anticipated
26/06/2023
Actual
Date of last participant enrolment
Anticipated
29/05/2028
Actual
Date of last data collection
Anticipated
25/06/2029
Actual
Sample size
Target
168
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
VIC

Funding & Sponsors
Funding source category [1] 314037 0
Other Collaborative groups
Name [1] 314037 0
Bionics Institute of Australia
Country [1] 314037 0
Australia
Primary sponsor type
Other Collaborative groups
Name
Bionics Institute of Australia
Address
384-388 Albert St, East Melbourne VIC 3002
Country
Australia
Secondary sponsor category [1] 315933 0
None
Name [1] 315933 0
Address [1] 315933 0
Country [1] 315933 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 313172 0
The St Vincent's Hospital Melbourne Human Research Ethics Committee
Ethics committee address [1] 313172 0
Research Governance Unit

Level 1

93-103 Victoria Parade

Fitzroy VIC 3065
Ethics committee country [1] 313172 0
Australia
Date submitted for ethics approval [1] 313172 0
Approval date [1] 313172 0
11/01/2023
Ethics approval number [1] 313172 0
2022/PID06554

Summary
Brief summary
Memory problems in Alzheimer's disease (AD) are linked to disruptions in the connections between brain regions. In a recent study we demonstrated that Theta Burst Stimulation (TBS), a type of brain stimulation, can alter the connections between brain regions and improve memory in patients with AD. We now propose a randomised controlled trial to examine whether TBS can lead to lasting improvements in 168 individuals with mild to moderate AD. We plan to compare active vs sham (placebo) TBS. Treatment will involve a 6-weeks of daily treatment (Monday – Friday) followed by a 6-weeks of once-weekly treatment. Treatment will be individualised for each participant. This means that stimulation will be based on the individual participant’s brain activity, recorded using electroencephalography (EEG). Additionally, the treatment will be delivered to four areas of the brain, the locations of which will be identified for each participant using a brain scan: a functional magnetic resonance imaging (fMRI) scan. We will examine changes in brain activity, memory and other symptoms of AD before and after treatment, as well as at 3, 6, and 12 month follow ups. If effective, individualised TBS could be used as a new therapy for AD.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 127242 0
Prof Kate Hoy
Address 127242 0
Bionics Institute
384-388 Albert St, East Melbourne VIC 3002
Country 127242 0
Australia
Phone 127242 0
+61 3 8622 7104
Fax 127242 0
Email 127242 0
khoy@bionicsinstitute.org
Contact person for public queries
Name 127243 0
Dr Oscar Murphy
Address 127243 0
Bionics Institute
384-388 Albert St, East Melbourne VIC 3002
Country 127243 0
Australia
Phone 127243 0
+61 3 9667 7500
Fax 127243 0
Email 127243 0
dementia@bionicsinstitute.org
Contact person for scientific queries
Name 127244 0
Prof Kate Hoy
Address 127244 0
Bionics Institute
384-388 Albert St, East Melbourne VIC 3002
Country 127244 0
Australia
Phone 127244 0
+61 3 8622 7104
Fax 127244 0
Email 127244 0
khoy@bionicsinstitute.org

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
Yes
What data in particular will be shared?
1. Clinical and Cognitive data (i.e. assessment scores)
2. Biological data (i.e.fMRI, fNIRS and EEG recordings)
When will data be available (start and end dates)?
Immediately following publication, no end date.
Available to whom?
Data will be made available for use by future researchers from a recognised research institution whose proposed use of the data has been ethically reviewed and approved by an independent ethics committee and who accept Bionics Institute's conditions for access.
Available for what types of analyses?
Analyses that have been ethically reviewed and approved by an independent ethics committee
How or where can data be obtained?
Scientific data will be hosted on the Bionics Institute (BI) secure servers. Access to data can be requested via emailing the Principal Investigator (khoy@bionicsinstitute.org). In line with BIs Data Management Policy, access to research data is considered in the context of ethical, privacy, confidentiality, cultural, contractual, and intellectual property requirements.


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.