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Trial registered on ANZCTR


Registration number
ACTRN12625000030471
Ethics application status
Approved
Date submitted
25/11/2024
Date registered
16/01/2025
Date last updated
16/01/2025
Date data sharing statement initially provided
16/01/2025
Type of registration
Prospectively registered

Titles & IDs
Public title
Underlying Mechanisms of Non-Invasive Brain Stimulation on the Cognitive and Mood Symptoms of Menopause: A Randomised, Sham-Controlled, Double-Blinded, Pilot Clinical Trial (MenoStim Trial)
Scientific title
Underlying Mechanisms of Non-Invasive Brain Stimulation on the Cognitive and Mood Symptoms of Menopause: A Randomised, Sham-Controlled, Double-Blinded, Pilot Clinical Trial
Secondary ID [1] 313447 0
None
Universal Trial Number (UTN)
Trial acronym
MenoStim
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Menopause 335842 0
Condition category
Condition code
Reproductive Health and Childbirth 332420 332420 0 0
Menstruation and menopause

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Participants will receive five sessions of intermittent theta burst stimulation (iTBS), a form of transcranial magnetic stimulation (TMS). iTBS is a clinically proven, non-invasive brain stimulation technique that uses electromagnetic fields to activate neural networks in the brain to improve memory, thinking, and mood.

Participants will receive five sessions of iTBS over the left dorsolateral prefrontal cortex (DLPFC), delivered by a qualified and trained PhD candidate. iTBS will be delivered using a MagVenture Transcranial Magnetic Stimulator (MagVenture A/S DK-3520, Denmark).

The coil will be held tangential to the scalp with the handle pointed posterolaterally away from the midline at 45 degrees to induce a second phase current in the posterolateral to anteromedial direction. Resting motor threshold (rMT) will be determined as the lowest stimulation intensity at which 5 out of 10 TMS pulses produce a visible response in the first dorsal interossei muscle of the right hand. Stimulation intensity will be delivered at 90 % of the rMT, which will be assessed at the start of each rTMS session. The TMS coil will be positioned through a Brainsight neuro-navigation system (Rogue Research Inc., Canada) based on anatomical landmarks in Montreal Neurological Institute (MNI) space. The coil will be positioned over the left DLPFC in accordance with the BeamF3 algorithm. The left DLPFC was chosen as a core region involved in executive functions, and the U.S. Food and Drug Administration (FDA) has approved rTMS for the treatment of affective disorders targeting the region.

Following randomisation, participants will be allocated to one of the two trial arms (sham or active treatment). Active treatment will consist of five sessions of iTBS over five consecutive days. Participants will receive five blocks of iTBS, and each block will be separated by ten minutes. Bursts of three pulses will be delivered at 50 Hz, repeated at 200 millisecond intervals in trains of two seconds. Two-second trains of iTBS will be repeated every ten seconds for a total of 600 pulses per block, and 3000 pulses per session.

The intervention will be delivered on Western Sydney University's Westmead Campus. The laboratory is equipped with a Technical Laboratory Officer who will assist the PhD Candidate to monitor tolerability and adherence to the intervention via direct observation.

Additionally, the PhD candidate has been receiving training and piloting the use of the TMS device since December 2023, as supervised by a physiotherapist with TMS expertise. All training will be overseen by the supervisory panel and complete by January 2025 (prior to commencing recruitment for the MenoStim Trial).
Intervention code [1] 330022 0
Treatment: Devices
Comparator / control treatment
The sham condition will involve the use of a coil that reproduces the audible click of the active iTBS without applying any stimulus. The sham condition will follow the same protocol as the active treatment. Briefly, the sham condition will consist of five blocks of iTBS each day over five consecutive days, and each block will be separated by ten minutes. Two-second trains of iTBS will be repeated every ten seconds for a total of 600 pulses per block, and 3000 pulses per session. Importantly, no stimulus will be applied to the scalp.
Control group
Placebo

Outcomes
Primary outcome [1] 340130 0
Resting State Electroencephalograph (EEG)
Timepoint [1] 340130 0
Baseline (Day 1), Endpoint (Day 5), Follow Up (4 Weeks Post-Endpoint)
Secondary outcome [1] 442893 0
Aperiodic Pink Noise
Timepoint [1] 442893 0
Baseline (Day 1), Endpoint (Day 5), Follow Up (4 Weeks Post-Endpoint)
Secondary outcome [2] 442894 0
Short-Interval Intracortical Inhibition (SICI)
Timepoint [2] 442894 0
Baseline (Day 1), Endpoint (Day 5), Follow Up (4 Weeks Post-Endpoint)
Secondary outcome [3] 442895 0
Long-Interval Intracortical Inhibition (LICI)
Timepoint [3] 442895 0
Baseline (Day 1), Endpoint (Day 5), Follow Up (4 Weeks Post-Endpoint)
Secondary outcome [4] 442896 0
Short Interval Intracortical Facilitation (SICF)
Timepoint [4] 442896 0
Baseline (Day 1), Endpoint (Day 5), Follow Up (4 Weeks Post-Endpoint)
Secondary outcome [5] 442897 0
Short Latency Afferent Inhibition (SAI)
Timepoint [5] 442897 0
Baseline (Day 1), Endpoint (Day 5), Follow Up (4 Weeks Post-Endpoint)
Secondary outcome [6] 442898 0
Skin Conductance
Timepoint [6] 442898 0
Baseline (Day 1), Endpoint (Day 5), Follow Up (4 Weeks Post-Endpoint)
Secondary outcome [7] 442899 0
Heart Rate Variability
Timepoint [7] 442899 0
Baseline (Day 1), Endpoint (Day 5), Follow Up (4 Weeks Post-Endpoint)
Secondary outcome [8] 442900 0
C Reactive Protein (CRP)
Timepoint [8] 442900 0
Baseline (Day 1), Endpoint (Day 5), Follow Up (4 Weeks Post-Endpoint)
Secondary outcome [9] 442901 0
Interleukin-2 (IL-2)
Timepoint [9] 442901 0
Baseline (Day 1), Endpoint (Day 5), Follow Up (4 Weeks Post-Endpoint)
Secondary outcome [10] 442904 0
Adenosine Triphosphate (ATP)
Timepoint [10] 442904 0
Baseline (Day 1), Endpoint (Day 5), Follow Up (4 Weeks Post-Endpoint)
Secondary outcome [11] 442905 0
Nicotinamide Adenine Dinucleotide (NAD/NADH)
Timepoint [11] 442905 0
Baseline (Day 1), Endpoint (Day 5), Follow Up (4 Weeks Post-Endpoint)
Secondary outcome [12] 442906 0
Kynurenine Pathway (KP)
Timepoint [12] 442906 0
Baseline (Day 1), Endpoint (Day 5), Follow Up (4 Weeks Post-Endpoint)
Secondary outcome [13] 442907 0
Cognitive Confidence
Timepoint [13] 442907 0
Baseline (Day 1), Endpoint (Day 5), Follow Up (4 Weeks Post-Endpoint)
Secondary outcome [14] 442908 0
Verbal Learning and Memory
Timepoint [14] 442908 0
Baseline (Day 1), Endpoint (Day 5), Follow Up (4 Weeks Post-Endpoint)
Secondary outcome [15] 442910 0
Verbal Fluency
Timepoint [15] 442910 0
Baseline (Day 1), Endpoint (Day 5), Follow Up (4 Weeks Post-Endpoint)
Secondary outcome [16] 442911 0
Psychomotor Processing Speed
Timepoint [16] 442911 0
Baseline (Day 1), Endpoint (Day 5), Follow Up (4 Weeks Post-Endpoint)
Secondary outcome [17] 442912 0
Working Memory
Timepoint [17] 442912 0
Baseline (Day 1), Endpoint (Day 5), Follow Up (4 Weeks Post-Endpoint)
Secondary outcome [18] 442913 0
Sustained Attention and Vigilance
Timepoint [18] 442913 0
Baseline (Day 1), Endpoint (Day 5), Follow Up (4 Weeks Post-Endpoint)
Secondary outcome [19] 442914 0
State Fatigue
Timepoint [19] 442914 0
Baseline (Day 1), Endpoint (Day 5), Follow Up (4 Weeks Post-Endpoint)
Secondary outcome [20] 442915 0
Depression
Timepoint [20] 442915 0
Baseline (Day 1), Endpoint (Day 5), Follow Up (4 Weeks Post-Endpoint)
Secondary outcome [21] 442916 0
Anxiety
Timepoint [21] 442916 0
Baseline (Day 1), Endpoint (Day 5), Follow Up (4 Weeks Post-Endpoint)
Secondary outcome [22] 442917 0
Sleep Quality
Timepoint [22] 442917 0
Baseline (Day 1), Endpoint (Day 5), Follow Up (4 Weeks Post-Endpoint)
Secondary outcome [23] 442918 0
Quality of Life
Timepoint [23] 442918 0
Baseline (Day 1), Endpoint (Day 5), Follow Up (4 Weeks Post-Endpoint)

Eligibility
Key inclusion criteria
• Females undergoing the late menopausal transition stage according to the STRAW criteria as defined by: (a) amenorrhea of 60 days or longer; (b) FSH levels greater than 25 IU/L in a random blood draw; and (c) self-reported vasomotor symptoms, including hot flushes, sleep disturbances, and night sweats.
• Females experiencing self-reported subjective cognitive complaints relative to previously normal cognitive status; and self-reported depressive symptoms or anxiety.
• Willing to complete all study-related activities for the complete trial including in person assessments and remote follow-ups.
Minimum age
45 Years
Maximum age
55 Years
Sex
Females
Can healthy volunteers participate?
No
Key exclusion criteria
• Individuals who have contraindications to TMS identified using the Transcranial Magnetic Stimulation Adult Safety Screen questionnaire, including:
a. History of adverse reactions to rTMS or other forms of non-invasive brain stimulation such as transcranial direct current stimulation (tDCS).
b. History of seizures, a medical diagnosis of epilepsy, or family history of epilepsy.
c. History of strokes, head injuries with loss of consciousness > 30 min, severe dizzy spells, or frequent or severe headaches and/or migraines.
d. Individuals with metal inside the head (outside of the mouth), including shrapnel, surgical clips, or fragments from welding or metal works.
e. Individuals with any implanted devices such as cardiac pacemakers, medical pumps, intra-cardiac lines, or Cochlear implants; or with a fine-wire electrode inserted anywhere in their body.
• Reproductive age females; females in the late reproductive stage or the early menopausal transition; and postmenopausal females.
• Females who have been receiving MHT treatment for less than three months at the time of recruitment or plan to commence MHT treatment during the study duration.
• Individuals using neuroactive medications, including anticonvulsants, antidepressants, and anxiolytics.
• A diagnosis of neurodegenerative, psychiatric affective, non-affective, or neurological illness.
• Significant cognitive impairment as deemed by scoring 17 or less on the Telephone Montreal Cognitive Assessment (T-MoCA).
• Current episode of major depression as deemed by scoring 15 or greater according to the Patient Health Questionnaire-9 (PHQ-9).
• High dependence on medical care (including medications, particularly drugs with a narrow therapeutic index) due to past or current medical conditions (e.g., cancer) as deemed by the study physician.
• Study physician discretion regarding medical status, appropriateness of participation, or concern about intervention adherence.
• Individuals who are not willing to follow the study protocol e.g., are not able to attend face-to-face visits or those who plan to move out of the area or travel interstate or overseas within the treatment period.
• Individuals who are actively participating in another clinical trial(s).
• Individuals who are not proficient in reading and writing in English.

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)
Randomisation will be facilitated using REDCap, allowing for both concealment and randomisation. Participants will be randomly allocated to receive rTMS or sham at a 2:1 ratio using randomly permutated blocks of 6. The trial will be double-blinded, meaning that all participants, members of the research team, and statisticians will be blinded to group allocation.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Randomisation will be facilitated using REDCap, allowing for both concealment and randomisation. Participants will be randomly allocated to receive rTMS or sham at a 2:1 ratio using randomly permutated blocks of 6. The trial will be double-blinded, meaning that all participants, members of the research team, and statisticians will be blinded to group allocation.
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
A data-driven approach will be applied to de-identified data in StataTM (StataCorp, Texas, USA). Normality checks will be performed for all variables via visual inspection of histograms prior to statistical analyses to determine whether parametric or non-parametric approaches should be used. To compare participant baseline characteristics, two-tailed independent group t-tests with equal variances assumed will be used for all continuous variables, and chi-squared tests will be conducted for categorical variables. Dependent variables (e.g., cognitive and psychological test scores) taken at baseline and all following timepoints (endpoint and follow-up) will be analysed for within-subject and between-subject (active vs. sham) comparisons using generalised linear modes with planned simple contrasts for the within-subjects factor of time. To determine the relationship between biomarkers and changes in cognition and mood, a logistic regression analysis will be performed.

A possible signal of efficacy will be explored via effect-size estimates of changes tertiary outcomes (cognition and mood). Effect sizes, means, SDs, and CIs will be reported. Normality checks will be performed, and data will be transformed if necessary. Where appropriate, parametric tests will be applied. A generalised linear model with fixed and random effects will be applied for the tertiary outcomes. Variables will include the between-subjects factor of group (active vs. sham) and within-subjects factor of time (baseline, endpoint, follow-up). Pearson correlation coefficients (or their non-parametric counterpart) or multivariate regression involving tertiary outcomes will be conducted. All tests will be carried out one-tailed and using an alpha level of 0.05.

Recruitment
Recruitment status
Not yet recruiting
Date of first participant enrolment
Anticipated
3/02/2025
Actual
Date of last participant enrolment
Anticipated
29/06/2026
Actual
Date of last data collection
Anticipated
27/07/2026
Actual
Sample size
Target
60
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
NSW
Recruitment postcode(s) [1] 43450 0
2145 - Westmead

Funding & Sponsors
Funding source category [1] 317887 0
Government body
Name [1] 317887 0
National Health and Medical Research Council
Country [1] 317887 0
Australia
Primary sponsor type
University
Name
Western Sydney University
Address
Country
Australia
Secondary sponsor category [1] 320225 0
None
Name [1] 320225 0
Address [1] 320225 0
Country [1] 320225 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 316571 0
University of Western Sydney Human Research Ethics Committee
Ethics committee address [1] 316571 0
https://www.westernsydney.edu.au/research/research_ethics_and_integrity/human_ethics/apply_for_human_research_ethics_review
Ethics committee country [1] 316571 0
Australia
Date submitted for ethics approval [1] 316571 0
29/07/2024
Approval date [1] 316571 0
08/11/2024
Ethics approval number [1] 316571 0
H16200

Summary
Brief summary
The aim of this research is to investigate how a potential treatment works for the cognitive and mood symptoms experienced during menopause through a form of non-invasive brain stimulation.

Transcranial magnetic stimulation (TMS) is a technique that can alter activation in certain areas of the brain by using magnetic stimulation. This stimulation is non-invasive, which means it is applied to the top of your scalp. The stimulation then travels through the scalp and into the brain. Specific forms of TMS, like intermittent theta-burst stimulation (iTBS) are promising treatments for depression, memory, and thinking.

We hypothesise that this may be a promising treatment option that can improve cognition and mood in females going through the late menopause transition. This research will address this evidence-practice gap by testing whether the treatment works.
Trial website
https://nicmtrials.westernsydney.edu.au/surveys/?s=EKY38N33TNPXJWFX
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 138286 0
A/Prof Genevieve Steiner-Lim
Address 138286 0
NICM Health Research Institute, Western Sydney University, Locked Bag 1797, Penrith NSW 2751
Country 138286 0
Australia
Phone 138286 0
+61 410342397
Fax 138286 0
Email 138286 0
[email protected]
Contact person for public queries
Name 138287 0
Najwa-Joelle Metri
Address 138287 0
NICM Health Research Institute, Western Sydney University, Locked Bag 1797, Penrith NSW 2751
Country 138287 0
Australia
Phone 138287 0
+61 411622021
Fax 138287 0
Email 138287 0
[email protected]
Contact person for scientific queries
Name 138288 0
Najwa-Joelle Metri
Address 138288 0
NICM Health Research Institute, Western Sydney University, Locked Bag 1797, Penrith NSW 2751
Country 138288 0
Australia
Phone 138288 0
+61 411622021
Fax 138288 0
Email 138288 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?




Results publications and other study-related documents

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