Trial Review

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Trial registered on ANZCTR


Registration number
ACTRN12623000500651
Ethics application status
Approved
Date submitted
24/04/2023
Date registered
16/05/2023
Date last updated
1/09/2024
Date data sharing statement initially provided
16/05/2023
Type of registration
Prospectively registered

Titles & IDs
Public title
Deep Brain Stimulation for Treatment-Refractory Obsessive-Compulsive Disorder: Understanding the Mechanism of Action.
Scientific title
Deep Brain Stimulation for Treatment-Refractory Obsessive-Compulsive Disorder: Understanding the Mechanism of Action.
Secondary ID [1] 309514 0
QIMR Berghofer Medical Research Institute Protocol P3859
Universal Trial Number (UTN)
U1111-1288-3343
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Obsessive-Compulsive Disorder 329797 0
Condition category
Condition code
Mental Health 326692 326692 0 0
Anxiety

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Participants with severe, treatment-refractory obsessive-compulsive disorder (OCD) will be implanted with Medtronic electrodes bilaterally in the bed nucleus of the stria terminalis (BNST). The Medtronic Model B35200 Percept PC Neurostimulator is part of an active implantable device system for deep brain stimulation and brain sensing. The DBS system delivers electrical stimulation to targeted regions of the brain to suppress symptoms associated with a neurological or psychiatric disorder. The neurostimulator generates electrical current that is conducted through DBS extensions and leads to the implanted electrodes. The electrical current leaves the electrodes and interacts with the targeted brain tissue to achieve the desired effect. The Medtronic Percept PC Neurostimulator is approved by the Australian Therapeutic Goods Association for the treatment of obsessive-compulsive disorder.

Electrodes will be placed in the BNST in a neurosurgical procedure, led by a specialist neurosurgeon and neurologist, and connected to an implantable pulse generator. Over the following six months, electrical stimulation will be titrated in the BNST by a neuropsychiatrist with 10 years of experience in deep brain stimulation. Stimulation will be titrated in an identical manner for all participants. In each hemisphere, the active contact will be selected based upon postoperative imaging, which will identify the contact closest to the bed nucleus of the stria terminalis. Stimulation will be commenced at 1.5 Volts bilaterally in a monopolar configuration, with a pulse width of 90 microseconds and a frequency of 130 Hertz. Stimulation amplitude will initially be increased by 0.5 Volts weekly to a maximum of 5 Volts, with the final stimulation amplitude determined by clinical response and the emergence of adverse effects. If negligible clinical benefit is observed at this maximum amplitude, a second adjacent contact will be activated and following a further assessment interval the pulse width will be increased to a maximum of 120 microseconds. If intolerable side effects during the initial titration of stimulation limit further increases in the stimulation amplitude and clinical benefit is not forthcoming, then the pulse width will be reduced to 60 microseconds and titration will be re-attempted.
Postoperative neuroimaging of the electrodes will be used to inform the choice of the optimal contact on each electrode. The primary target guiding stimulation adjustment will be reduction of OCD symptoms as assessed by the Yale-Brown Obsessive-Compulsive Scale (Y-BOCS), a validated semi-structured interview rating OCD symptom severity.
Once participants have accrued a stable response to stimulation (reduced Y-BOCS score of at least 30% from baseline), they will receive a manualised course (10-12 weekly sessions) of exposure-oriented psychotherapy with a clinical psychologist trained in this modality of therapy. The manual is designed specifically for this study.

Twelve months after stimulation commencement, participants will enter a counterbalanced, randomised, double-blind, sham-controlled crossover phase during which time each participant will receive a month ‘on’ and a month ‘off’ stimulation in random order before resuming open-label therapy. The primary outcome will be the difference in Y-BOCS between treatment periods. Participants and those clinicians completing rating scales will be blinded to treatment allocation. The purpose of this crossover phase is to directly compare clinical (Y-BOCS) and electrophysiological data with and without effective treatment. All participants will have their DBS device turned back on at the end of the crossover trial to continue open-label treatment.

At baseline, prior to DBS device implantation, participants will undertake a functional brain scan during which brain activity will be measured at rest and during a symptom provocation task. In this task, participants will be 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). In the scanner, participants will rate the emotional valence of the picture from negative to positive on a Likert scale. Postoperatively, functional brain imaging will be repeated at three-monthly intervals: during DBS titration, before and after psychotherapy and finally monthly during each phase of the crossover trial. The purpose of the functional imaging is to understand how regional and network-wise brain activity changes in parallel with context (rest and symptom-induced) and with progressive symptom alleviation in severe OCD.
Participants will attend weekly for a 60-minute one-on-one session of psychotherapy. Sessions will focus on the establishment of an exposure hierarchy (i.e. a list of anxiety-provoking situations from least to most distressing) tailored to the participant's OCD. Participants will be gradually guided through deliberate exposure to these anxiety-provoking situations under the expectation that their anxiety will gradually reduce with repeated exposure.

Recordings of electrophysiological signals from the implanted DBS lead will also be obtained in parallel with functional neuroimaging acquisition during symptom provocation in the MRI scanner: during DBS titration, before and after psychotherapy and then during each phase of the crossover trial. Recordings will occur whilst the participant ‘behaves’ in their natural environment, particularly during exposure to anxiety-provoking situations (e.g. a person with contamination-oriented OCD will be asked to touch a dirty surface and refrain from handwashing). The purpose of acquiring electrophysiological data is to understand how local neural activity changes in parallel with OCD symptom severity.

Adherence to the protocol will be assessed through monitoring of the Case Report Forms (CRFs), which will be undertaken by the study sponsor QIMR Berghofer Medical Research Institute. A CRF will be completed at each attendance by the participant.
Intervention code [1] 325945 0
Treatment: Devices
Comparator / control treatment
Sham treatment with DBS will be performed on the "month off" stimulation, following the titration period.
Control group
Placebo

Outcomes
Primary outcome [1] 334554 0
The mean difference in OCD symptoms rated with the Y-BOCS between active and sham phases of deep brain stimulation
Timepoint [1] 334554 0
Timepoint: At the end of each 1-month treatment phase during the crossover phase of the trial
Secondary outcome [1] 421170 0
The mean difference in depressive symptoms rated with the Montgomery-Åsberg Depression Rating Scale (MADRS) between active and sham phases of deep brain stimulation
Timepoint [1] 421170 0
At the end of each 1-month treatment period during the crossover phase of the trial
Secondary outcome [2] 421171 0
The mean difference in anxiety symptoms rated with the Hamilton Anxiety Rating Scale (HAM-A) between active and sham phases of deep brain stimulation
Timepoint [2] 421171 0
At the end of each 1-month treatment period during the crossover phase of the trial
Secondary outcome [3] 421172 0
The difference between local field potential power spectral density (measured from the implanted electrodes) between active and sham phases of deep brain stimulation
Timepoint [3] 421172 0
At the end of each 1-month treatment period during the crossover phase of the trial
Secondary outcome [4] 421173 0
The difference between fMRI BOLD signal (in a network comprising the amygdala and orbitofrontal cortex) between active and sham phases of deep brain stimulation
Timepoint [4] 421173 0
At the end of each 1-month treatment period during the crossover phase of the trial
Secondary outcome [5] 421174 0
The mean change in OCD symptoms rated with the Y-BOCS at the end of the open phase of the trial.
Timepoint [5] 421174 0
12-months after DBS device implantation compared to baseline.
Secondary outcome [6] 421175 0
The mean change in depressive symptoms rated with the MADRS at the end of the open phase of the trial.
Timepoint [6] 421175 0
12-months after DBS device implantation compared to baseline.
Secondary outcome [7] 421179 0
The mean change in anxiety symptoms rated with the HAM-A at the end of the open phase of the trial.
Timepoint [7] 421179 0
12-months after DBS device implantation compared to baseline.
Secondary outcome [8] 421180 0
The mean change in local field potential power spectral density (measured from the implanted electrodes) at the end of the open phase of the trial
Timepoint [8] 421180 0
12-months after DBS device implantation compared to baseline.
Secondary outcome [9] 421181 0
The mean change in fMRI BOLD signal (in a network comprising the amygdala and orbitofrontal cortex) at the end of the open phase of the trial.
Timepoint [9] 421181 0
12-months after DBS device implantation compared to baseline.

Eligibility
Key inclusion criteria
To be eligible for participation in the study, participants must meet all of the following criteria:

1) Diagnosis – Participant is diagnosed with Obsessive Compulsive Disorder (OCD) according to DSM-5 Diagnostic Criteria.
2) Severity – Participant has a Yale Brown Obsessive Compulsive Scale (Y-BOCS) score of more than or equal to 24, measured twice at least 2 weeks apart.
3) Chronicity – Duration of illness greater than 5 years.
4) Treatment Refractoriness – No or insufficient response following at least
• 2 treatment trials with a Selective Serotonin Reuptake Inhibitor (SSRI), at maximum tolerated dosage for at least 12 weeks, plus
• 1 treatment trial with clomipramine at maximum tolerated dosage for at least 12 weeks, plus
• 1 augmentation trial with an atypical antipsychotic for 8 weeks in combination with one of the above mentioned drugs, plus
• 1 attempted psychotherapy trial (exposure and response prevention or ERP), confirmed by psychotherapist.
5) Aged between 20-55 years.
6) Participant is male or non-pregnant female adequately protected by conception. Females of childbearing potential must use an acceptable method of birth control for the duration of participation in the trial. Abstinence is an acceptable means of birth control.
7) Participant is able to comply with all testing and follow-up visit requirements defined by the Study Protocol.
8) Participant has voluntarily signed an informed consent.
9) Participant’s medication regimen has remained stable for at least 6 weeks prior to study enrolment.
Minimum age
20 Years
Maximum age
55 Years
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
Participants with any of the following will not be eligible for enrolment:

1) A lifetime diagnosis of psychotic disorder, current or past (such as schizophrenia, schizoaffective disorder or delusional disorder).
2) Diagnosed manic episode within the last 3 years.
3) Clinical history consistent with severe personality disorder of any type.
4) Current, or unstably remitted substance abuse disorder, the latter being defined by history consistent with substance dependence in the last 12 months, or abuse in the last 6 months, other than nicotine dependence or abuse.
5) Participant is at high risk of suicide:
• Has made a suicide attempt within the previous 12 months that required medical treatment, or
• Has made two suicide attempts in the past 12 months, or
• Has a clear-cut plan for suicide and states that he/she cannot guarantee that he/she will call his/her regular psychiatrist or the investigator if the impulse to implement the plan becomes substantial during the study, or
• Is likely to attempt suicide within the next six months, in the investigator’s opinion.
6) Current clinically-significant medical illness or neurological disorder, excluding tic disorder.
7) Clinically-significant abnormality on pre-operative MRI.
8) Any labelled contraindication to having DBS surgery, and/or inability to undergo pre-operative MRI.
9) Pregnancy.
10) Participant has received general anaesthesia in a 30 day period prior to the DBS implantation.
11) Participant is currently enrolled in another investigational study or is using another investigational device.

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)
During the crossover phase, the order of treatment period (sham or active stimulation first) will be allocated randomly, in a counterbalanced manner, with three participants to be allocated to sham then active and two to active then sham. The study statistician will generate the randomisation sequence in a statistical software package and will provide this to the chief investigator, who will manage the stimulation settings during this phase.
The chief investigator will be involved in determining the participant's eligibility for inclusion in the study.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Simple randomisation using a randomisation table created by computer software (i.e. computerised sequence generation)
Masking / blinding
Blinded (masking used)
Who is / are masked / blinded?
The people receiving the treatment/s

The people assessing the outcomes
Intervention assignment
Crossover
Other design features
Phase
Not Applicable
Type of endpoint/s
Efficacy
Statistical methods / analysis
A total of 5 participants will be enrolled. The sample size is constrained by the cost of the DBS implants and the total pool of funding available. Our group previously demonstrated a statistically-significant benefit from active DBS in a small sample size (n = 9, Mosley et al Translational Psychiatry 2021). With 80% power and a=0.05, the primary analysis of the blinded cross-over phase of the trial will be able to detect a large effect (Cohen’s d>1.68).

Recruitment
Recruitment status
Recruiting
Date of first participant enrolment
Anticipated
1/06/2023
Actual
7/09/2023
Date of last participant enrolment
Anticipated
31/12/2024
Actual
Date of last data collection
Anticipated
1/09/2025
Actual
Sample size
Target
5
Accrual to date
4
Final
Recruitment in Australia
Recruitment state(s)
ACT,NSW,NT,QLD,SA,TAS,WA,VIC
Recruitment postcode(s) [1] 40191 0
4000 - Spring Hill

Funding & Sponsors
Funding source category [1] 313708 0
Government body
Name [1] 313708 0
National Health and Medical Research Council
Country [1] 313708 0
Australia
Primary sponsor type
Other
Name
QIMR Berghofer Medical Research Institute
Address
300 Herston Road
Herston
Brisbane
QLD 4006
Country
Australia
Secondary sponsor category [1] 315517 0
None
Name [1] 315517 0
Address [1] 315517 0
Country [1] 315517 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 312881 0
Uniting Care Health Human Research Ethics Committee
Ethics committee address [1] 312881 0
Ethics committee country [1] 312881 0
Australia
Date submitted for ethics approval [1] 312881 0
13/01/2023
Approval date [1] 312881 0
23/03/2023
Ethics approval number [1] 312881 0
202301

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

Contacts
Principal investigator
Name 126202 0
Dr Philip Mosley
Address 126202 0
QIMR Berghofer Medical Research Institute
300 Herston Road
Herston
Brisbane
QLD 4006
Country 126202 0
Australia
Phone 126202 0
+61 7 3362 0222
Fax 126202 0
Email 126202 0
[email protected]
Contact person for public queries
Name 126203 0
Philip Mosley
Address 126203 0
QIMR Berghofer Medical Research Institute
300 Herston Road
Herston
Brisbane
QLD 4006
Country 126203 0
Australia
Phone 126203 0
+61 7 3362 0222
Fax 126203 0
Email 126203 0
[email protected]
Contact person for scientific queries
Name 126204 0
Philip Mosley
Address 126204 0
QIMR Berghofer Medical Research Institute
300 Herston Road
Herston
Brisbane
QLD 4006
Country 126204 0
Australia
Phone 126204 0
+61 7 3362 0222
Fax 126204 0
Email 126204 0
[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 investigator Dr Philip Mosley ([email protected]).


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.