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Trial registered on ANZCTR

Registration number

ACTRN12624000600549

Ethics application status

Approved

Date submitted

9/11/2023

Date registered

9/05/2024

Date last updated

1/09/2024

Date data sharing statement initially provided

9/05/2024

Type of registration

Prospectively registered

Titles & IDs

Public title

Low-Intensity Transcranial Focused Ultrasound for the Treatment of Obsessive-Compulsive Disorder

Scientific title

Modulation of Brain Network Activity in Obsessive-Compulsive Disorder Using Low-Intensity Transcranial Focused Ultrasound

Secondary ID [1]

QIMR Berghofer Medical Research Institute Protocol P3857

Universal Trial Number (UTN)

U1111-1299-0008

Trial acronym

Linked study record

Health condition

Health condition(s) or problem(s) studied:

Obsessive-Compulsive Disorder

Condition category

Condition code

Mental Health

Other mental health disorders

Intervention/exposure

Study type

Interventional

Description of intervention(s) / exposure

The investigational product is the NeuroFUS PRO V2.0 with a DPX-500-4CH transducer and TPO-203 Transducer Power Output. NeuroFUS PRO is a computer system (hardware and software, including in addition to the above: the Brainsight Neuronavigation system manufactured by Rogue Research Inc. Montreal, Canada, and the k-Plan software developed by University College London, United Kingdom). This system delivers low-intensity (nonthermal) focused ultrasound (FUS) for transcranial brain modulation. It is provided and supported by Brainbox Ltd (Cardiff, UK). The TPO-203 (manufactured by Sonic Concepts Inc, Bothell WA, US) is the ultrasound transducer component which converts electrical energy into the sonic energy used in the intervention. The TPO-203 features four channels (to allow for convergent targeted sonication from multiple sources) with a total of 80 watts of power (20w per channel) calibrated to a 50 O load. The device can generate frequencies between 10-kHz and 10MHz in 10Hz increments, with burst lengths of 1µs to 9µs in 1µs steps, and 10µs – 120µs in 10µs steps.

The intervention will be delivered to the Nucleus Accumbens (NAcc) and the Basolateral Amygdala via application of the transducer to the participant’s scalp. Trial participants in each group will receive stimulation to both brain regions (crossover design). The sonication will be delivered as theta-burst transcranial ultrasound stimulation (tbTUS). tbTUS will consist of an 80-second train of 20-millisecond ultrasound bursts (0.5MHz) repeated every 200 milliseconds (pulse repetition frequency of 5Hz, duty cycle of 10%, 400 bursts) with an amplifier intensity of 20W.
In the first 3 TUS sessions, Group 1 will receive stimulation to the NAcc and Group 2 to the Basolateral Amygdala only. In the second 3 TUS sessions the groups will be reversed and receive stimulation to the other region only.
TUS sessions are likely to last approximately 45 minutes each in total, including setting up neuronavigation, administering TUS and completion of the task.
The intervention will be administered by the TUS Laboratory Technician at QIMR Berghofer, under the direct supervision of Dr Mosley.
The CRF includes questions and checklists to be completed in each session to ensure compliance with the required steps. In addition, all sessions will be completed by the same TUS Technician, supervised by Dr Mosley, both of whom will be extensively trained in the protocol.

Each participant will receive one such 80-second train per session, across six sessions. Three task-based sessions will be delivered in one week (Monday, Wednesday, Friday) targeted to the basolateral amygdala in a task state (see below). Three further sessions will be delivered in a subsequent week (following four weeks washout) on Monday, Wednesday and Friday, targeted to the nucleus accumbens in a state of rest. The order of stimulation sites will be counterbalanced amongst the cohort.

Stimulation in the task state will be delivered while participants are presented with a set of images drawn from the International Affective Picture System, a database of stimuli designed to elicit attention and emotion. Alongside, positive and neutral pictures, each set of images will contain a number of pictures chosen to provoke discomfort in each participant according to their symptoms (e.g., a person with harm-oriented OCD will be shown images of a knife or blood). Participants will be debriefed by Dr Mosley to ensure that distress returns to baseline levels.

Total participation time is expected to be around ten weeks per participant plus 4 weeks follow-up. This includes an initial screening, a targeting session followed by two rounds of clinical assessments, baseline imaging, two five-day TUS interventions, post-intervention imaging and clinical assessments separated by a washout period of four weeks.

This is a randomised, single-blind, crossover clinical trial. There will be two active treatment groups who will complete both of two treatment conditions. Fifty percent of participants will be assigned to Group 1, while 50% will be assigned to Group 2. Participant IDs will be assigned by a member of the research team who is not involved in baseline assessments or delivering the TUS intervention. Participants will be randomly assigned. The numbers 1-6 will be generated in a random order using the random number generator function in the software package R. Participants will be allocated these numbers in the order of their participant ID numbers. Those allocated the random numbers 1-3 will be placed in group one, with those allocated 4-6 placed in group two.
Each treatment will consist of three sessions of TUS delivered across a period of five days to one of two target brain regions, and there will be a one-month washout period between the treatment conditions. Follow-up clinical and brain imaging assessments will occur for all participants within a week of the completion of their treatment. Follow-up of adverse event diaries will occur at four weeks post-treatment. In total, participants are expected to participate in the trial for a period of approximately ten weeks, plus follow-up.
The intervention will be delivered at a single academic centre, QIMR Berghofer Medical Research Institute. Participants will undergo brain imaging at the Herston Imaging Research Facility.

Intervention code [1]

Treatment: Devices

Comparator / control treatment

The two groups in this study will not be directly compared. The comparison used will be between changes induced by stimulation to the NAcc and stimulation to the Amygdala. Both groups will undergo stimulations to both targets in a crossover design.

Control group

Active

Outcomes

Primary outcome [1]

Safety

Timepoint [1]

At the beginning of each treatment session and during each clinical assessment, the clinical investigator will also make an objective assessment of changes in the participants’ physical and psychological condition. A question eliciting information regarding any adverse events will also be asked by the clinical investigator preceding each treatment session and answers recorded in the clinical file.
The clinical assessments are at the commencement of participation (within 14 days following consent processes), then within 5 working days of the final intervention session of the first intervention, then between 30 and 40 days after that assessment, then within 5 working days of the final intervention session of the second intervention. Adverse events will also be enquired about and recorded for inclusion in this analysis during every participant visit after and including the first neuroimaging session.

Primary outcome [2]

Feasibility

Timepoint [2]

Results on this outcome will be assessed at Time Point 1, Study Visit 1 - Screening (up to 14 days prior to first clinical assessment; proportion who participate) and time point 13, Study Visit 16 - Post 2 Clinical Assessment (within 5 working days of the final intervention session; proportion who complete the treatment and assessment).

Secondary outcome [1]

Obsessive-Compulsive Disorder (OCD) Symptoms

Timepoint [1]

Secondary outcome [2]

Depressive Symptoms

Timepoint [2]

The assessment of this scale will take place pre and post each phase of the TUS intervention. Timepoint 2 (baseline assessment), Timepoint 7 (post-completion of phase 1), Timepoint 10 (pre-commencement of phase 2), Timepoint 13 (post-completion of phase 2). Please note there are two pre and post time points per phase – a brain imaging one (ie, 6) and a clinical one (ie 7) which are not the same occasion.

Secondary outcome [3]

Fronto-Striatal System Activity

Timepoint [3]

The Fronto-Striatal System Activity will be measured at Pre and post intervention time points for each condition. Timepoint 4 (pre-commencement of phase 1), Timepoint 6 (post-completion of phase 1), Timepoint 9 (pre-commencement of phase 2), Timepoint 12 (post-completion of phase 2).

Secondary outcome [4]

Extended Amygdala System Activity

Timepoint [4]

Extended Amygdala System Activity will be measured at pre and post intervention time points for each condition (time points 4, 6, 9 and 12).

Secondary outcome [5]

Anxiety Symptoms

Timepoint [5]

Eligibility

Key inclusion criteria

1) Have the capacity to give informed consent to participate in the clinical trial and provide a signed and dated informed consent form.
2) Willing to comply with all study procedures and be available to attend QIMRB and HIRF for the required imaging, clinical assessments and treatment sessions during the study.
3) Aged between 18-50 years.
4) Have a primary diagnosis of Obsessive-Compulsive Disorder (OCD) according to the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition Text Revision (DSM-5-TR; APA, 2022) criteria.
5) Have a diagnosis of OCD for a period greater than 12 months.
In addition, participants must also pass an MRI Safety Screening, a TUS Safety Screening, an Alcohol Screening, and undergo a clinical interview with the chief investigator Dr Mosley to be considered eligible.

Minimum age

18 Years

Maximum age

50 Years

Sex

Both males and females

Can healthy volunteers participate?

Key exclusion criteria

1) Participant’s pharmaceutical treatment changed in the past month.
2) Participant is pregnant or trying to fall pregnant.
3) Participant has ever attempted suicide.
4) Participant has ever been diagnosed with a psychotic disorder.
5) Participant has ever experienced a manic episode.
6) Participant has ever experienced a spontaneous seizure.
7) Participant has a neurological disorder.
8) Participant has ever experienced a traumatic brain injury.
9) Participant has a current substance abuse disorder or alcohol/drug misuse (except tobacco).
10) Participant has any contraindications for MRI scanning.

With regards to criterion 6, seizures elicited via electro-convulsive therapy (ECT) are not considered spontaneous in nature and are not considered part of the exclusion criteria.

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 is not concealed

Methods used to generate the sequence in which subjects will be randomised (sequence generation)

Fifty percent of participants will be assigned to Group 1, while 50% will be assigned to Group 2. Participant IDs will be assigned by a member of the research team (the Project Manager) who is not involved in baseline assessments or delivering the TUS intervention. Participants will be randomly assigned. The numbers 1-6 will be generated in a random order using a random number generator function in the software package R. Participants will be allocated these numbers in the order of their participant ID numbers. Those allocated the random numbers 1-3 will be placed in group one, with those allocated 4-6 placed in group two. As this study is a cross-over single-blinded trial, maintenance and breaking of randomisation codes will not be necessary.

Masking / blinding

Blinded (masking used)

Who is / are masked / blinded?

The people receiving the treatment/s

Intervention assignment

Crossover

Other design features

Phase

Not Applicable

Type of endpoint/s

Safety/efficacy

Statistical methods / analysis

Recruitment

Recruitment status

Recruiting

Date of first participant enrolment

Anticipated

13/05/2024

Actual

1/07/2024

Date of last participant enrolment

Anticipated

1/09/2024

Actual

Date of last data collection

Anticipated

1/12/2024

Actual

Sample size

Target

Accrual to date

Final

Recruitment in Australia

Recruitment state(s)

NSW,QLD

Recruitment hospital [1]

St Andrew's War Memorial Hospital - Brisbane

Recruitment postcode(s) [1]

4000 - Brisbane

Funding & Sponsors

Funding source category [1]

Government body

Name [1]

Australian Government Department of Health and Aged Care Medical Research Future Fund Early Career Fellowship, and NHMRC

Address [1]

Country [1]

Australia

Primary sponsor type

Other Collaborative groups

Name

QIMR Berghofer Medical Research Institute

Address

300 Herston Road, Herston QLD 4066

Country

Australia

Secondary sponsor category [1]

None

Name [1]

Address [1]

Country [1]

Ethics approval

Ethics application status

Approved

Ethics committee name [1]

QIMR Berghofer HREC (EC00278)

Ethics committee address [1]

300 Herston Road, Herston, QLD 4006, Australia

Ethics committee country [1]

Australia

Date submitted for ethics approval [1]

16/10/2023

Approval date [1]

14/11/2023

Ethics approval number [1]

Summary

Brief summary

This study aims to assess the safety and potential effectiveness of low-intensity transcranial focused ultrasound for the treatment of obsessive-compulsive disorder.

You may be eligible for this study if you are aged between 18 and 50 years and you have been diagnosed with moderate to severe Obsessive-Compulsive Disorder (OCD) for more than 12 months.

Transcranial ultrasound stimulation (TUS) will be delivered via the NeuroFUS system. This uses focused ultrasound sonication, delivered to the scalp, to stimulate neural activity in cortical and subcortical regions of the brain. In total, participants will receive six sessions of stimulation [80 second stimulation sessions of theta burst patterned TUS], delivered to two brain regions for three sessions each in the resting state, and during a symptom-inducing task. The duration of the participant participation is 10 week plus 4 weeks follow-up.

Trial website

Trial related presentations / publications

Public notes

Contacts

Principal investigator

Name

Dr Luca Cocchi

Address

QIMR Berghofer, 300 Herston Rd, Herston QLD 4006

Country

Australia

Phone

+61 7 3845 3008

Fax

[email protected]

Contact person for public queries

Name

Philip Mosley

Address

QIMR Berghofer, 300 Herston Rd, Herston QLD 4006

Country

Australia

Phone

+61 7 3845 3008

Fax

[email protected]

Contact person for scientific queries

Name

Philip Mosley

Address

QIMR Berghofer, 300 Herston Rd, Herston QLD 4006

Country

Australia

Phone

+61 7 3845 3008

Fax

[email protected]

Data sharing statement

Will individual participant data (IPD) for this trial be available (including data dictionaries)?

Yes

What data in particular will be shared?

All individual participant data collected during the trial, after de-identification.

When will data be available (start and end dates)?

Immediately following publication, no end date

Available to whom?

Researchers who provide a methodologically-sound proposal and supply evidence of HREC approval.

Available for what types of analyses?

Any purpose

How or where can data be obtained?

Subject to approval by principal investigators Dr Luca Cocchi ([email protected]) or Dr Philip Mosley ([email protected])

What supporting documents are/will be available?

Doc. No.	Type	Other Details
20865	Study protocol	Available with published paper
20866	Informed consent form	Available with published paper
20867	Analytic code	Available with published paper

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.

Trial Review

Documents added manually

Documents added automatically