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Trial registered on ANZCTR


Registration number
ACTRN12615000992505
Ethics application status
Approved
Date submitted
10/09/2015
Date registered
22/09/2015
Date last updated
12/06/2019
Date data sharing statement initially provided
12/06/2019
Type of registration
Prospectively registered

Titles & IDs
Public title
A randomized controlled trial of Theta Burst Stimulation for the treatment of mild to moderate Alzheimer’s disease
Scientific title
A randomized controlled trial of Theta Burst Stimulation for the treatment of mild to moderate Alzheimer’s disease
Secondary ID [1] 287444 0
Nil
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Alzheimer’s disease 296159 0
Condition category
Condition code
Neurological 296442 296442 0 0
Alzheimer's disease

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Transcranial Magnetic Stimulation involves the repeated application of a strong but highly localised magnetic field to a small cortical area, and when given at high frequency (i.e. greater than one pulse per second) can increase lasting changes in local cortical activity.
Theta Burst Stimulation (TBS) is a form of TMS where pulses are applied in patterned bursts (3 at a time) but at high frequency (usually 50 Hz).These short bursts are repeated at an inter-burst interval of 200ms (5 Hz). Intermittent TBS (iTBS) involves applying TBS in two second trains every 10 seconds and has been shown to result in significantly greater, and longer lasting, increases in cortical excitability than standard high frequency TMS. A typical rTMS protocol is likely to take between 40 and 45 minutes per day whereas iTBS stimulation is complete within 3 minutes. Therefore, TBS would allow for targeting of multiple brain regions in the one treatment sessions, as well as potentially producing greater and longer lasting effects compared with standard TMS.
Patients will undergo a total of 21 sessions over six weeks (daily sessions Mon-Fri for week one to week three, followed by 3 treatments in week four, 2 treatments in week five and 1 treatment in week six) of either active or sham iTBS to the left dorsolateral pre frontal cortex (lDLPFC), right dorsolateral pre frontal cortex (rDLPFC), left posterior parietal cortext (lPPC) and right posterior parietal cortex (rPPC).
All sites will be stimulated using 3 bursts of high frequency TBS (pulse 50-Hz) lasting a total of 2 seconds, repeated every 10 seconds for a total of 180 seconds per site. Therefore stimulation for all four sites will take 12 minutes per treatment session. iTBS will be applied at 100% of the participants resting motor threshold (RMT). Sham stimulation will be provided with a sham coil. All stimulation will be conducted by a fully qualified and TMS certified research nurse.

Participants will be seated in a comfortable chair with their neck supported whilst the TMS coil is held in position against the scalp. They will be monitored at all times. A record of treatment time and date will be logged on a participant's treatment sheet.
Intervention code [1] 292813 0
Treatment: Devices
Comparator / control treatment
The proposed study is a double-blind randomized placebo-controlled pilot trial of iTBS in patients with mild to moderate AD. Patients will be randomised to real or sham iTBS via the generation of a computer number sequence by an independent researcher.
Control group
Placebo

Outcomes
Primary outcome [1] 296060 0
We will use the Alzheimer’s Disease Assessment Scale – Cognition (ADAS-COG) as our primary outcome measure. This is the standard diagnostic and severity assessment tool for AD).
Timepoint [1] 296060 0
At baseline, week 3 and week 6 of treatment, as well as at 3 and 6 month follow up appointments.
Primary outcome [2] 296129 0
We will also utilize the CogState Alzheimer’s battery. The CogState Alzheimer’s battery is a series of computerized tasks designed to sensitively assess the cognitive domains affected in AD including attention, speed of processing, learning and memory, visuospatial ability and executive function. It has been specifically developed for repeat use in clinical trials of AD.
Timepoint [2] 296129 0
At baseline, week 3 and week 6 of treatment, as well as at 3 and 6 month follow up appointments.
Primary outcome [3] 296130 0
A quality of life assessment designed specifically for AD, i.e. the AD-QOL will also be used.
Timepoint [3] 296130 0
At baseline, week 3 and week 6 of treatment, as well as at 3 and 6 month follow up appointments.
Secondary outcome [1] 317402 0
Transcranial Magnetic Stimulation -Electroencephalography Assessment (TMS-EEG). 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 [1] 317402 0
We will conduct the TMS-EEG assessment at baseline and the week 6 assessment only.

Eligibility
Key inclusion criteria
100 individuals with AD will participate in the study. Participants will be included if they: (1) are competent to consent based on their ability to provide a spontaneous narrative description of the key elements of the study, as assessed by a clinical staff member independent of the research project; (2) have a diagnosis of AD based on general medical, neurological, and neuropsychological examinations according to the National Institute of Neurological and Communication Disorders–Alzheimer’s Disease and Related Disorders Association (NINCDS–ADRDA) criteria for probable Alzheimer’s disease and the DSM-IV clinical criteria for dementia of the Alzheimer’s type; (3)meet criteria for mild-to-moderate AD as indicated by a score of 12 or above on the Mini-Mental State Evaluation (MMSE); and (4) are either not on psychotropic medication or their dose of medication has been unchanged for a minimum of 4 weeks prior to entry into the study. Medication dose will not be able to be altered during participation: if this is clinically required the patient will be withdrawn from the study.
Minimum age
50 Years
Maximum age
95 Years
Gender
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
Patients will be excluded if they (1) have metal in the cranium, a pacemaker, cochlear implant, medication pump or other electronic device ;(2) have a DSM-IV history of substance abuse or dependence in the last 6 months; (3) have a concomitant major and unstable medical, psychiatric or neurological illness; (4) have a history of seizures (5) are pregnant or breast feeding; (6) have had brain stimulation in the past three months or (7) are professional drivers.

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)
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Masking / blinding
Who is / are masked / blinded?



Intervention assignment
Other design features
Phase
Not Applicable
Type of endpoint(s)
Statistical methods / analysis

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

Funding & Sponsors
Funding source category [1] 292867 0
University
Name [1] 292867 0
Monash University
Address [1] 292867 0
Wellington Road
Clayton
Victoria 3800
Australia
Country [1] 292867 0
Australia
Funding source category [2] 292868 0
Charities/Societies/Foundations
Name [2] 292868 0
Mason Foundation National Medical Program
Address [2] 292868 0
Equity Trustees
GPO Box 2307
Melbourne

VIC 3001
Country [2] 292868 0
Australia
Primary sponsor type
Individual
Name
Professor Paul Fitzgerald
Address
Epworth Centre for Innovation in Mental Health
888 Toorak Rd, Camberwell VIC 3124
Country
Australia
Secondary sponsor category [1] 290687 0
Individual
Name [1] 290687 0
Dr Kate Hoy
Address [1] 290687 0
Epworth Centre for Innovation in Mental Health
888 Toorak Rd, Camberwell VIC 3124
Country [1] 290687 0
Australia

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 293506 0
The Alfred Hospital Ethics Committee
Ethics committee address [1] 293506 0
Office of Ethics & Research Governance
Alfred Hospital
55 Commercial Rd, Melbourne VIC 3004
Ethics committee country [1] 293506 0
Australia
Date submitted for ethics approval [1] 293506 0
Approval date [1] 293506 0
08/09/2015
Ethics approval number [1] 293506 0
372/15
Ethics committee name [2] 294368 0
Monash University Human Research Ethics Committee (MUHREC)
Ethics committee address [2] 294368 0
Wellington Road
Clayton
Victoria 3800
Australia
Ethics committee country [2] 294368 0
Australia
Date submitted for ethics approval [2] 294368 0
30/11/2015
Approval date [2] 294368 0
30/11/2015
Ethics approval number [2] 294368 0
CF15/4504 - 2015001953

Summary
Brief summary
There is an urgent need for the development of novel approaches to the treatment of Alzheimer’s disease (AD). AD is characterised by progressive decline in cognitive functioning in most areas, including in memory, attention, visuospatial ability, language and executive function. Although there are medications that can slow the progression of symptoms somewhat, there are currently no effective treatments for these hallmark symptoms of AD. Recent research has indicated that the progressive cognitive decline seen in AD may be a result of decreased functional connectivity throughout what is known as the default mode network (DMN), a brain network whose anatomy closely mirrors the pattern of cortical atrophy seen in AD patients (i.e. prefrontal, posterior parietal, and medial temporal). An approach that is able to specifically target this network in order to enhance connectivity, and thus functioning, could result in a highly effective therapy for the cognitive impairments in AD.
Non-invasive brain stimulation (NIBS) techniques have considerable promise in this regard. NIBS has been shown to modulate activation throughout large scale cortical networks, such as the one implicated in cognitive impairment in AD, to enhance cognition in a number of disorders and to produce long lasting behavioural effects. In particular, Theta Burst Stimulation (TBS) is a highly effective form of NIBS and allows for multi-site stimulation within a single treatment session. The use of TBS for the treatment of cognitive impairment in AD is an area of significant potential, and one that has yet to be adequately explored. We propose to conduct a double-blind placebo-controlled randomised pilot study comparing a treatment course of active TBS to sham TBS (i.e. 21 daily treatment sessions over six weeks). In each treatment sessions 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).
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 60194 0
A/Prof Kate Hoy
Address 60194 0
Epworth Centre for Innovation in Mental Health
Faculty of Medicine, Nursing and Health Sciences
888 Toorak Rd
Camberwell VIC 3124
Country 60194 0
Australia
Phone 60194 0
+61398054363
Fax 60194 0
Email 60194 0
Kate.hoy@monash.edu
Contact person for public queries
Name 60195 0
A/Prof Kate Hoy
Address 60195 0
Epworth Centre for Innovation in Mental Health
Faculty of Medicine, Nursing and Health Sciences
888 Toorak Rd
Camberwell VIC 3124
Country 60195 0
Australia
Phone 60195 0
+61398054363
Fax 60195 0
Email 60195 0
Kate.hoy@monash.edu
Contact person for scientific queries
Name 60196 0
A/Prof Kate Hoy
Address 60196 0
Epworth Centre for Innovation in Mental Health
888 Toorak Rd, Camberwell VIC 3124
Country 60196 0
Australia
Phone 60196 0
+61398054363
Fax 60196 0
Email 60196 0
Kate.hoy@monash.edu

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
No
No/undecided IPD sharing reason/comment
Undecided - will require ethical approval.
What supporting documents are/will be available?
No other documents available
Summary results
No Results