Trial Review

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Trial registered on ANZCTR


Registration number
ACTRN12621000620820
Ethics application status
Approved
Date submitted
26/02/2021
Date registered
24/05/2021
Date last updated
13/04/2022
Date data sharing statement initially provided
24/05/2021
Type of registration
Prospectively registered

Titles & IDs
Public title
A randomised controlled trial of acute and maintenance Theta Burst Stimulation for mild to moderate Alzheimer's
Scientific title
A randomized controlled trial of acute and maintenance Theta Burst Stimulation for the cognitive symptoms of mild to moderate Alzheimer’s: The MAINTAIN study.
Secondary ID [1] 303441 0
Nil known
Universal Trial Number (UTN)
Trial acronym
MAINTAIN
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Alzheimer’s disease 320745 0
Condition category
Condition code
Neurological 318584 318584 0 0
Alzheimer's disease

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
A triple-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. 92 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 followed by a 12-week maintenance phase and a 3 and 6-month follow up. 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 posterior parietal cortex (lPPC, rPPC).

Stimulation Parameters: All sites will be stimulated using 3-pulse 50-Hz bursts applied at 5 Hz with a 2-second train of TBS repeated every 10 seconds for a total of 180 seconds per site (i.e. 600 pulses). Therefore, stimulation for all four sites will take 12 minutes. iTBS will be applied at 100% of the RMT. TBS will be provided by a trained nurse. There will be a total of 48 TBS treatments provided.
Intervention code [1] 319741 0
Treatment: Devices
Comparator / control treatment
TBS Treatment will be administered with the Neurosoft MS/D. The Neurosoft MS/D system allows the provision of both active and sham stimulation using the same TMS coil. Sham TBS will be provided in the exact same ‘manner’ as active TBS. The sham setting on the coil mimics the sound and tactile sensation without the provision of magnetic stimulation and is considered the current gold standard for TMS blinding.
Control group
Placebo

Outcomes
Primary outcome [1] 326544 0
Episodic verbal memory, using a word list learning task.

Timepoint [1] 326544 0
- at the end of the acute treatment phase (i.e. week 6) (primary endpoint).

- at the end of the maintenance treatment phase (i.e. week 18).

- at 3 and 6-month post treatment follow up.
Secondary outcome [1] 391809 0
The ADASCog-Plus, a global measure of cognition (standard diagnostic and severity assessment tool expanded to maximise sensitivity in early illnesses stages)
Timepoint [1] 391809 0
- at the end of the acute treatment phase (i.e. week 6).

- at the end of the maintenance treatment phase (i.e. week 18).

- at 3 and 6-month post treatment follow up.
Secondary outcome [2] 391810 0
Quality of life using the Alz specific scales: ADCS-ADL, caregiver version and the AD-QOL patient and carer version
Timepoint [2] 391810 0
- at the end of the acute treatment phase (i.e. week 6).

- at the end of the maintenance treatment phase (i.e. week 18).

- at 3 and 6-month post treatment follow up.
Secondary outcome [3] 391817 0
EEG and TMS-EEG assessments to assess changes in functional connectivity and cortical excitation/inhibition.

Three minutes of resting eyes open and three minutes of resting eyes closed EEG will be recorded. We will also collect TMS-EEG data. TMS-EEG is performed by stimulating the scalp over the DLPFC while simultaneously recording brain activity via surrounding EEG electrodes. The TMS pulse produces a neurophysiological response in the underlying cortex, referred to as a TMS evoked potential (TEP), which is recorded on EEG and the TEP amplitude gives an index of cortical excitability
Timepoint [3] 391817 0
- at the end of the acute treatment phase (i.e. week 6).

- at the end of the maintenance treatment phase (i.e. week 18).

Eligibility
Key inclusion criteria
Participants will be included if they:
(1) are between 50 and 85 years;
(2) are competent to consent based on their ability to provide a spontaneous narrative description of the key elements of the study, as assessed by an independent clinical staff member. Participants will complete an advanced care directive to allow for the possibility they may lose capacity during the trial;
(3) have a diagnosis of probable Alz according to the National Institute on Aging /Alzheimer's Association diagnostic guidelines for Alzheimer's disease (NIA-AA)
(4) meet criteria for mild or moderate Alz as indicated by >12 on the Mini-Mental State Evaluation; (5) are either not on a cholinesterase inhibitor or memantine or have been on a stable dose for at least 2 months prior to screening;
(6) are either not on psychotropic medication or their dose of psychotropic medication has been unchanged for at least 4 weeks prior to study entry. Psychotropic medication 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;
(8) are able to participate in cognitive testing in English.

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;
(2) are pregnant;
(3) have medically implanted material that could interact with the magnetic field.

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 PIs who determine if a subject is eligible for inclusion in the trial will be unaware at the time of this decision, to which group the subject will be allocated.
Methods used to generate the sequence in which subjects will be randomised (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
Intervention assignment
Other design features
Phase
Not Applicable
Type of endpoint/s
Efficacy
Statistical methods / analysis
Data will be pre-processed, cleaned and validated using programmed edit checks, and stored in a secure database until the time of statistical analysis. We will use an intention to treat approach for all analyses. For the primary hypotheses, the cognitive data will be analysed using an ANCOVA to compare the groups (active, sham) at weeks 6, 18, 30, 42 allowing for baseline within a linear mixed-effects modelling framework. We will primarily analyse performance on the word list task. For secondary hypotheses, we will utilise the ANCOVA approach for the dependent variables ADAS-Cog, ADCS-ADL and AD-QOL. We will use the same statistical approach for the neurobiological outcomes comparing the groups at 6-weeks, controlling for baseline. Exploratory graphic and linear mixed model analyses, including testing for possible curvilinear effects across time, will be carried out on all timepoints by group. Disease severity (mild, moderate) will be included as a potential confounder for all analyses. Alpha will be set at p < 0.05, 2-tailed. 95% confidence intervals will be reported throughout.

Recruitment
Recruitment status
Withdrawn
Reason for early stopping/withdrawal
Lack of funding/staff/facilities
Date of first participant enrolment
Anticipated
1/01/2022
Actual
Date of last participant enrolment
Anticipated
1/04/2026
Actual
Date of last data collection
Anticipated
30/06/2027
Actual
Sample size
Target
92
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
ACT,NSW,NT,QLD,SA,TAS,WA,VIC

Funding & Sponsors
Funding source category [1] 307862 0
University
Name [1] 307862 0
Monash University
Country [1] 307862 0
Australia
Primary sponsor type
University
Name
Monash University
Address
Wellington Rd
Clayton VIC 3800
Country
Australia
Secondary sponsor category [1] 308572 0
None
Name [1] 308572 0
None
Address [1] 308572 0
None
Country [1] 308572 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 307865 0
Monash Health
Ethics committee address [1] 307865 0
246 Clayton Rd,
Clayton VIC 3168
Ethics committee country [1] 307865 0
Australia
Date submitted for ethics approval [1] 307865 0
16/01/2021
Approval date [1] 307865 0
17/02/2021
Ethics approval number [1] 307865 0
RES-21-0000-022A
Ethics committee name [2] 307866 0
Monash University
Ethics committee address [2] 307866 0
Wellington Rd,
Clayton VIC 3800
Ethics committee country [2] 307866 0
Australia
Date submitted for ethics approval [2] 307866 0
01/03/2021
Approval date [2] 307866 0
Ethics approval number [2] 307866 0

Summary
Brief summary
Although the underlying causes of Alzheimer’s disease (Alz) remain unknown, there is clear evidence the disease process disrupts connections in brain networks underpinning cognition. Research, including our own, indicates this dysfunctional connectivity is proximate to the cognitive symptoms of Alz. Treatment approaches which have aimed to reduce disease protein burden in Alz have consistently failed to improve cognition; perhaps understandably, as none of these approaches attempt to restore dysfunctional connectivity. In contrast, we propose a therapeutic approach, using non-invasive brain stimulation, which directly targets activity in relevant neural networks in order to restore optimal connectivity and improve cognition.

Theta Burst Stimulation (TBS) is an efficient and potent form of transcranial magnetic stimulation (TMS). It has been shown to modulate activity throughout large-scale cortical networks, enhance cognition and produce lasting behavioural improvements. We have conducted a proof-of-concept study demonstrating that 6-weeks of TBS applied to key regions of affected networks can alter connectivity and produce significant memory improvement in patients with mild to moderate Alz. We are now proposing to conduct a 30-week randomised controlled trial, with both acute and maintenance treatment phases and a 3 and 6-month follow up. We aim to confirm our proof-of-concept and to extend these findings by demonstrating whether standalone TBS can produce sustained gains in cognition and associated improvements in function and quality of life.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 108746 0
Prof Kate Hoy
Address 108746 0
Faculty of Medicine, Nursing and Health Sciences
Monash University
888 Toorak Road
Camberwell VIC 3124
Melbourne, Australia
Country 108746 0
Australia
Phone 108746 0
+61398054186
Fax 108746 0
Email 108746 0
kate.hoy@monash.edu
Contact person for public queries
Name 108747 0
Prof Kate Hoy
Address 108747 0
Faculty of Medicine, Nursing and Health Sciences
Monash University
888 Toorak Road
Camberwell VIC 3124
Melbourne, Australia
Country 108747 0
Australia
Phone 108747 0
+61398054186
Fax 108747 0
Email 108747 0
kate.hoy@monash.edu
Contact person for scientific queries
Name 108748 0
Prof Kate Hoy
Address 108748 0
Faculty of Medicine, Nursing and Health Sciences
Monash University
888 Toorak Road
Camberwell VIC 3124
Melbourne, Australia
Country 108748 0
Australia
Phone 108748 0
+61398054186
Fax 108748 0
Email 108748 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?
1. Clinical and Cognitive data (i.e. assessment scores)
2. Biological data (i.e. TMS-EEG and EEG recordings)
When will data be available (start and end dates)?
01/01/2028 - ongoing
Available to whom?
Will be open access
Available for what types of analyses?
As this data will be open access, any analyses will be permitted
How or where can data be obtained?
data will be available via an open access data repository that will be determined by the publishing journal,


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.