Trial Review

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Trial registered on ANZCTR


Registration number
ACTRN12625000792426
Ethics application status
Approved
Date submitted
2/07/2025
Date registered
25/07/2025
Date last updated
25/07/2025
Date data sharing statement initially provided
25/07/2025
Type of registration
Prospectively registered

Titles & IDs
Public title
Brain-Informed Tailored Interventions for Alcohol Use Disorder
Scientific title
Evaluating the effect of neural network modelling informed personalized brain stimulation on alcohol consumption in individuals with moderate to severe alcohol use disorder
Secondary ID [1] 314640 0
Therapeutic Goods Association (TGA) CTN:06697-1
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Alcohol Use Disorder (AUD) 337795 0
Condition category
Condition code
Mental Health 334139 334139 0 0
Addiction

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Background:
Interventions comprise different non-invasive brain stimulation approaches. The specific intervention each participant receives will be determined by brain imaging analyses. Participants will undergo a functional magnetic resonance imaging (MRI) scan prior to intervention allocation, in which brain network function will be assessed using resting-state fMRI. The fMRI time series will be analyzed using spectral dynamic causal modeling (spDCM) to estimate individual-level features of effective connectivity in a predefined network of interest comprising Dorsolateral Prefrontal Cortex (DLPFC), Ventromedial Prefrontal Cortex (VMPFC), Insula, and Striatum.

The resulting parameters will be incorporated into a generative embedding framework to classify participants with AUD into biotypes based on the following subnetworks:
1. ‘Ventromedial stream’: Altered connectivity in the VMPFC subnetwork.
2. ‘Dorsolateral stream’: Altered connectivity in the DLPFC subnetwork.

A machine learning derived classification method will then determine the participant's subtype and appropriate biotype-matched intervention. Participants will be biotyped as
‘Ventromedial stream’ or ‘Dorsolateral stream’, and allocated to personalized VMPFC (Arm 1) or DLPFC (Arm 2) brain stimulation interventions, respectively.

Duration:
Participants will complete 5 consecutive stimulation days. Four intervention doses are provided on each day, with a 50-minute break between each administration. Therefore an intervention day will be 3-4 hours long. Baseline and outcome data will be collected during neurocognitive sessions conducted at three timepoints: baseline, immediately post-intervention, and Day 90. These sessions will run for approximately 6-8 hours, including a lunch break, with total duration dependent on task completion speed and participant preference for additional breaks. The primary alcohol consumption outcome will be assessed separately at Day 30 in a dedicated 1-hour session.

The duration for each iTBS dose is approximately 7 minutes, the duration for each cTBS dose is approximately 3 minutes, and the duration for the sham dose is 5 minutes.

Mode of delivery:
Face-to-face administration, provided individually to each participant.

Materials:
The interventions will be delivered using Deep Transcranial Magnetic
Stimulation (dTMS). As a result, the administration structure in both arms is identical, except for differences in stimulation parameters and resting motor threshold protocol.

Arm 1: To modify altered connectivity in the 'Ventromedial stream', continuous theta-burst stimulation (cTBS) over the VMPFC will be applied. cTBS will be administered using the H7 Brainsway coil targeting the vmPFC positioned 4 cm anterior to the motor hotspot using standardized localization procedures (Isserles et al., 2021).

Arm 2: To modify altered connectivity in the 'Dorsolateral stream', intermittent theta-burst stimulation (iTBS) over the dlPFC will be applied. iTBS will be administered using the H1 Brainsway coil targeting the dlPFC, positioned 6 cm anterior to the motor hotspot, using standardized localization procedures (Feifel et al., 2016; Pell et al., 2022).

Intervention administrators:
The administration of these interventions will be conducted exclusively by a dTMS clinician. Here, a dTMS clinician is defined as an individual holding a PhD or possessing equivalent expertise in neuromodulation, demonstrated by a minimum of three years of relevant experience, or an individual who has undergone specific training and is operating under the direct supervision of the neurostimulation leads, who each have ten years of experience in the field.

Intervention dosage:
In both arms, before the administration of dTMS, resting motor threshold (RMT) for each participant will be determined. The RMT is the minimum stimulation intensity required to elicit visible motor responses from 3 out of 6 pulses. The site of motor response (foot in Arm 1, hand in Arm 2) is determined by the coil used in each arm per standard Brainsway protocol. The dose of dTMS will be set based on a percentage of each individual's RMT, following standardised procedures. RMT is followed by a short adaptation procedure, to ensure participants are comfortable with the stimulation intensity. The adaptation procedure will involve exposing the participant to a short train (~2 s for iTBS, 4 s for cTBS) of the dTMS protocol at a reduced intensity to acclimate the participant.

Arm 1: dTMS will be administered at 80% of foot RMT. The cTBS protocol will consist of two trains of a standard cTBS sequence (per Huang et al., 2005), with a 30-second intertrain interval. Each train will consist of 600 pulses, comprising three-pulse bursts at 50Hz repeated every 200ms (5Hz) for 40 seconds.

Arm 2: dTMS will be administered at 100% of hand RMT. The iTBS protocol will consist of three-pulse bursts at 50Hz repeated every 200ms (5Hz) for 2 seconds, with an 8-second intertrain interval, for 40 trains (1200 pulses).

Intervention adherence/fidelity and tolerance:
Adherence to the interventions will be measured by tracking participants’ attendance across the 20 stimulation doses. We will use standard pre and post stimulation interviews to monitor tolerability, track session attendance, and assess barriers to adherence, such as participant discomfort, through feedback gathered during and after the sessions. Adherance will be monitored via a REDCap tool that is completed for each dose to track dose completion and intensity.

Participants must complete a minimum of 4 days of the intervention (this involves 16 sessions), with no more than 3 consecutive days between any two sessions. Participants must receive at least 16 total stimulation doses across all sessions.

Treatment intensity must meet the following thresholds:
- In Session 1, the average intensity across all doses must be within 30% of the target intensity.
- In all subsequent Sessions, the average intensity across doses must be within 10% of the target intensity.
- All sessions must be completed within a maximum treatment window of 9 calendar days.
- These treatment intensity thresholds were informed by a pilot study, where iTBS (with a target intensity of 100%) was delivered at an average of 95%, and cTBS (with a target intensity of 80%) was delivered at an average of 70%. Therefore, the target of within 10% across sessions should be feasible for both intervention arms, especially considering the capacity to titrate intensity up across doses.
Intervention code [1] 331269 0
Treatment: Devices
Comparator / control treatment
Placebo (Common sham; sham dTMS stimulation).

Sham stimulation administration will be identical to active. However, it will be delivered via a sham coil (Brainsway H4S) at 90% RMT, to replicate the acoustic and scalp sensations of active stimulation without generating effective field penetration into the brain, per the manufacturer's standard protocol. The duration for sham stimulation is approximately 5 minutes.
Control group
Placebo

Outcomes
Primary outcome [1] 341795 0
Number of standard drinks total consumed (1 standard drink equal to 10g of pure alcohol) over the past 30 days
Timepoint [1] 341795 0
30 days following the baseline session (Day 30; primary); 90 days post-baseline (Day 90).
Secondary outcome [1] 448708 0
Number of heavy drinking days over the past 30 days
Timepoint [1] 448708 0
30 days following the baseline session (Day 30); 90 days post-baseline (Day 90).
Secondary outcome [2] 448709 0
Daily drinking
Timepoint [2] 448709 0
Daily drinking will be assessed longitudinally 7 days prior to baseline and will continue one time daily until Day 90 post-baseline
Secondary outcome [3] 448710 0
Neural effective connectivity between the dorsolateral prefrontal cortex and the insula.
Timepoint [3] 448710 0
Baseline, post-intervention (within 24 hours of last intervention dose), Day 90 post-Baseline
Secondary outcome [4] 448711 0
Impulsive responding: Attentional control
Timepoint [4] 448711 0
Baseline, Day 90 post-baseline
Secondary outcome [5] 448712 0
Interoceptive awareness (Heartbeat Detection task)
Timepoint [5] 448712 0
Baseline, Day 90 post-baseline
Secondary outcome [6] 448713 0
Reward-based decision-making (Two Stage task)
Timepoint [6] 448713 0
Baseline, Day 90 post-baseline
Secondary outcome [7] 448714 0
Treatment fidelity (attrition rates)
Timepoint [7] 448714 0
Administered after each intervention dose
Secondary outcome [8] 448715 0
Metabolomic indicators (Short-chain fatty acids; SCFAs)
Timepoint [8] 448715 0
Baseline, post-intervention (within 24 hours of last intervention dose), Day 90 post-Baseline
Secondary outcome [9] 448718 0
Background and clinical characterisation (Psychological distress)
Timepoint [9] 448718 0
Baseline, Day 90 post-Baseline
Secondary outcome [10] 449639 0
Number of drinking days over the past 30 days
Timepoint [10] 449639 0
30 days following the baseline session (Day 30); 90 days post-baseline (Day 90).
Secondary outcome [11] 449640 0
Mood trajectories
Timepoint [11] 449640 0
Mood will be assessed longitudinally 7 days prior to baseline and will continue 3 times daily until Day 90 post-baseline
Secondary outcome [12] 449641 0
Sleep trajectories
Timepoint [12] 449641 0
Sleep quality will be assessed longitudinally 7 days prior to baseline and will continue one time daily until Day 90 post-baseline
Secondary outcome [13] 449642 0
Craving trajectories
Timepoint [13] 449642 0
Craving will be assessed longitudinally 7 days prior to baseline and will continue 3 times daily until Day 90 post-baseline
Secondary outcome [14] 449643 0
Passive Data of phone app usage
Timepoint [14] 449643 0
Passive data will be assessed longitudinally 7 days prior to baseline and will be captured continuously each day until Day 90 post-baseline
Secondary outcome [15] 449644 0
Interoceptive awareness of basic emotions (EmBODY)
Timepoint [15] 449644 0
Baseline, Day 90 post-baseline
Secondary outcome [16] 449645 0
Reward-based decision-making (Horizons)
Timepoint [16] 449645 0
Baseline, Day 90 post-baseline
Secondary outcome [17] 449646 0
Treatment fidelity (Standardised post-stimulation interview)
Timepoint [17] 449646 0
Administered after each intervention dose
Secondary outcome [18] 449647 0
Metabolomic indicators (Kynurenine pathway metabolites)
Timepoint [18] 449647 0
Baseline, post-intervention (within 24 hours of last intervention dose), Day 90 post-Baseline
Secondary outcome [19] 449648 0
Metabolomic indicators (Dopamine metabolites)
Timepoint [19] 449648 0
Baseline, post-intervention (within 24 hours of last intervention dose), Day 90 post-Baseline
Secondary outcome [20] 449649 0
Background and clinical characterisation (Alcohol craving)
Timepoint [20] 449649 0
Baseline, Day 30 post-Baseline, Day 90 post-Baseline
Secondary outcome [21] 449650 0
Background and clinical characterisation (Nicotine dependence)
Timepoint [21] 449650 0
Baseline, Day 90 post-Baseline
Secondary outcome [22] 449651 0
Background and clinical characterisation (Impulsivity traits)
Timepoint [22] 449651 0
Baseline, Day 90 post-Baseline
Secondary outcome [23] 449652 0
Background and clinical characterisation (Compulsive alcohol-related thoughts and behaviors)
Timepoint [23] 449652 0
Baseline, Day 90 post-Baseline
Secondary outcome [24] 449653 0
Background and clinical characterisation (Quality of life)
Timepoint [24] 449653 0
Baseline, Day 90 post-Baseline
Secondary outcome [25] 449977 0
Neural effective connectivity between the dorsolateral prefrontal cortex and the ventral striatum.
Timepoint [25] 449977 0
Baseline, post-intervention (within 24 hours of last intervention dose), Day 90 post-Baseline
Secondary outcome [26] 449978 0
Neural effective connectivity between the dorsolateral prefrontal cortex and the dorsal striatum.
Timepoint [26] 449978 0
Baseline, post-intervention (within 24 hours of last intervention dose), Day 90 post-Baseline
Secondary outcome [27] 449979 0
Neural effective connectivity between the ventromedial prefrontal cortex and the insula.
Timepoint [27] 449979 0
Baseline, post-intervention (within 24 hours of last intervention dose), Day 90 post-Baseline
Secondary outcome [28] 449980 0
Neural effective connectivity between the ventromedial prefrontal cortex and the ventral striatum.
Timepoint [28] 449980 0
Baseline, post-intervention (within 24 hours of last intervention dose), Day 90 post-Baseline
Secondary outcome [29] 449981 0
Neural effective connectivity between the ventromedial prefrontal cortex and the dorsal striatum.
Timepoint [29] 449981 0
Baseline, post-intervention (within 24 hours of last intervention dose), Day 90 post-Baseline
Secondary outcome [30] 449982 0
Impulsive responding: Information gathering
Timepoint [30] 449982 0
Baseline, Day 90 post-baseline
Secondary outcome [31] 449983 0
Impulsive responding: Feedback monitoring
Timepoint [31] 449983 0
Baseline, Day 90 post-baseline
Secondary outcome [32] 449984 0
Interoceptive awareness of craving-related emotions (EmBODY-Craving)
Timepoint [32] 449984 0
Baseline, Day 90 post-baseline
Secondary outcome [33] 449987 0
Metabolomic indicators (Epinephrine metabolites)
Timepoint [33] 449987 0
Baseline, post-intervention (within 24 hours of last intervention dose), Day 90 post-Baseline
Secondary outcome [34] 449988 0
Metabolomic indicators (Norepinephrine metabolites)
Timepoint [34] 449988 0
Baseline, post-intervention (within 24 hours of last intervention dose), Day 90 post-Baseline
Secondary outcome [35] 449989 0
Metabolomic indicators (Serotonin metabolites)
Timepoint [35] 449989 0
Baseline, post-intervention (within 24 hours of last intervention dose), Day 90 post-Baseline

Eligibility
Key inclusion criteria
Meet DSM-5 criteria for moderate-severe AUD in past 12 months
Aged 18-49 years
Can attend five non-invasive brain stimulation sessions and three assessment sessions in Clayton, Victoria.
Willing to abstain from alcohol 36 hours before each neurocognitive and intervention session.
Willing to abstain from recreational drugs 7 days prior to each neurocognitive and intervention session.
Consent to nominate a GP to receive details of any incidental findings
Willing to nominate an emergency contact for intervention sessions.
Have consumed alcoholic beverages in the past 90 days
Minimum age
18 Years
Maximum age
49 Years
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
Any MRI contraindication such as ferromagnetic metal in the head, brain surgery or implanted medical devices
Body weight of >250 kg (upper limit of MRI scanner)
Co-occurrence of serious or unstable mental disorders that can substantially interfere with the study protocols and therapeutic goals, such as psychosis, schizophrenia, and bipolar disorders (ascertained with the Structured Clinical Interview for DSM Disorders (SCID)/ Quick Structured Clinical Interview for DSM-5 (QuickSCID-5).

Self-reported history of brain trauma with loss-of-consciousness >30 minutes or any loss of consciousness in the past 6 months, seizures/epilepsy, neurodegenerative illnesses or any other neurological condition associated with severe cognitive impairment as indicated by the Montreal Cognitive Assessment test (MOCA) as these conditions can impact the safety and/or reduce the efficacy of the study.
Currently taking anti-craving medications (e.g., bupropion) that can mask or amplify the effects of the study.
Currently taking any dosage of medication that may interfere with safety of the intervention (i.e., high-dose diazepam, clozapine).
Not accessing formal treatment for alcohol use disorder currently, or within the past 28 days, and not planning to commence formal treatment for alcohol use disorder in the next 28 days.

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)
Allocation will be concealed using a central randomisation by computer created in advance by an independent statistician. The randomisation schedule will be held online on a secure university REDCap server, and only accessible by the designated dTMS clinicians after participant eligibility has been confirmed and baseline assessments completed. The researchers responsible for assessing eligibility and enrolling participants will not have access to the allocation schedule at any stage.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Participants will be allocated to treatment arms or control using permuted block randomisation. Initially, 40% of participants will be allocated to the control group; however, this proportion may be adjusted based on interim analyses. Randomisation will be stratified by biotype.
Masking / blinding
Blinded (masking used)
Who is / are masked / blinded?
The people receiving the treatment/s

The people assessing the outcomes
Intervention assignment
Other
Other design features
Biotype informed assignment to treatment arm; control arm common to both biotypes.
Phase
Not Applicable
Type of endpoint/s
Efficacy
Statistical methods / analysis
Power analysis was conducted using a between-within ANOVA design, comprising three treatment arms (between-subjects) and two assessment timepoints (within-subjects). This design was informed by Harel et al. (2022), who reported that targeted rTMS produced significant reductions in alcohol consumption relative to sham (Cohen’s d = 0.47). To ensure a conservative estimate, we powered our study to detect a smaller effect size (d = 0.35) in each active treatment arm. With a two-tailed alpha of 0.05, power (1-ß) of 0.80, and a moderate Pearson correlation coefficient (r = 0.07) between timepoints, a total sample of n = 132 was required. Simulations (n = 10,000) confirmed power of 80.86% and 80.98% for the two active treatment arms when each was compared separately with placebo. We inflated this sample size to account for 20% projected attrition to arrive at a target sample of 165 participants.

Descriptive statistics of key demographic and clinical characteristics will be reported at baseline.

The primary analysis model will utilise a Bayesian Mixed Model for Repeated Measures (bMMRM) approach with fixed effects for treatment arm, time and interaction effect for treatment arm * time. A random intercept will be modelled to account for variation anticipated between participants. A negative binomial distribution will be assumed to inform the self-reported number of standard drinks consumed (Primary aim).

Secondary and Exploratory outcomes will be analysed using multilevel mixed effects models (Bayesian models, where appropriate and depending on the structure of each dataset). Treatment fidelity will be assessed through session attendance (analysed via logistic regression) and tolerability ratings from post-session interviews (analysed using ordinal mixed models).

Recruitment
Recruitment status
Not yet recruiting
Date of first participant enrolment
Anticipated
30/07/2025
Actual
Date of last participant enrolment
Anticipated
30/04/2027
Actual
Date of last data collection
Anticipated
29/07/2027
Actual
Sample size
Target
165
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
VIC

Funding & Sponsors
Funding source category [1] 319203 0
Charities/Societies/Foundations
Name [1] 319203 0
Wellcome Leap
Country [1] 319203 0
United States of America
Primary sponsor type
University
Name
Monash University
Address
Country
Australia
Secondary sponsor category [1] 321670 0
None
Name [1] 321670 0
Address [1] 321670 0
Country [1] 321670 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 317783 0
Monash University Human Research Ethics Committee
Ethics committee address [1] 317783 0
Ethics committee country [1] 317783 0
Australia
Date submitted for ethics approval [1] 317783 0
16/04/2024
Approval date [1] 317783 0
25/06/2024
Ethics approval number [1] 317783 0
42604

Summary
Brief summary
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 142138 0
Prof Antonio Verdejo-García
Address 142138 0
18 Innovation Walk, Monash University, Clayton, VIC, Australia, 3168
Country 142138 0
Australia
Phone 142138 0
+61 3 9905 5374
Fax 142138 0
Email 142138 0
[email protected]
Contact person for public queries
Name 142139 0
Antonio Verdejo-García
Address 142139 0
18 Innovation Walk, Monash University, Clayton, VIC, Australia, 3168
Country 142139 0
Australia
Phone 142139 0
+61 3 9905 5374
Fax 142139 0
Email 142139 0
[email protected]
Contact person for scientific queries
Name 142140 0
Antonio Verdejo-García
Address 142140 0
18 Innovation Walk, Monash University, Clayton, VIC, Australia, 3168
Country 142140 0
Australia
Phone 142140 0
+61 3 9905 5374
Fax 142140 0
Email 142140 0
[email protected]

Data sharing statement
Will the study consider sharing individual participant data?
Yes
Will there be any conditions when requesting access to individual participant data?
Persons/groups eligible to request access:
• Researchers
Conditions for requesting access:
• Case-by-case basis at the discretion of Primary Sponsor. Wherever possible, deidentified data will be published on an open source data repository.


What individual participant data might be shared?
• De-identified individual participant data:
• All outcomes data
What types of analyses could be done with individual participant data?
• Any type of analysis (i.e. no restrictions on data re-use)
When can requests for individual participant data be made (start and end dates)?
From:
After publication of main results
To:
No end date
Where can requests to access individual participant data be made, or data be obtained directly?
• Data repository: Monash University Bridges open source data repository

• TBC

Are there extra considerations when requesting access to individual participant data?
No


What supporting documents are/will be available?

TypeCitationLinkEmailOther DetailsAttachment
Statistical analysis plan    V1 SAP Neural network informed personalised brain stim for AUD_Final.pdf


Results publications and other study-related documents

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No documents have been uploaded by study researchers.

Documents added automatically
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