Trial Review

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Trial registered on ANZCTR


Registration number
ACTRN12615001309572
Ethics application status
Approved
Date submitted
3/08/2015
Date registered
30/11/2015
Date last updated
31/10/2022
Date data sharing statement initially provided
8/01/2019
Date results provided
21/10/2019
Type of registration
Retrospectively registered

Titles & IDs
Public title
Deep Brain Stimulation for Patients with Treatment-Resistant Obsessive Compulsive Disorder: Identifying electrophysiological biomarkers
Scientific title
Deep Brain Stimulation for Patients with Treatment-Resistant Obsessive Compulsive Disorder: Identifying electrophysiological biomarkers
Secondary ID [1] 287204 0
None
Universal Trial Number (UTN)
U1111-1146-0992
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Treatment-Resistant Obsessive Compulsive Disorder 295797 0
Condition category
Condition code
Mental Health 296063 296063 0 0
Other mental health disorders

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
The study will consist of 5 different phases including:
1. Baseline (assessment and pre-surgery)
2 Surgery & Randomisation
3 Recovery (day 1 post-surgery to 1 month post-surgery)
4 Double blind phase (1 month post-surgery to 4 months post-surgery)
5 Open label phase (4 months post-surgery to 24 months post-surgery)

Baseline:
Participants are assessed by 2 neuropsychiatrists and their eligibility for Deep Brain Stimulation (DBS) is considered by an independent mental health review tribunal. Successful participants are enrolled in the trial and complete the following:
Neuropsychological rating scales
Magnetic resonance imaging (MRI) brain scan
Electroencephalography (EEG)
Computerised reward task (Monetary Incentive Delay task)
Computerised symptom provocation (International Affective Picture Scale)

Surgery & Randomisation:
At surgery, patients are implanted with the Activa PC+S (Medtronic, Minneapolis, USA) device. Product description is as follows:

The Model 37604 Activa PC+S system is a multiprogrammable device that both delivers electrical stimulation and records bioelectric data through one or two leads implanted in the brain. Activa PC+S electrical stimulation is based on the Model 37610 Activa PC neurostimulator but adds the functionality of bioelectrical data recording (sensing). Activa PC and Activa PC+S share the same therapy and form factor. There are no new tissue contacting materials in the Activa PC+S.

Stimulation is provided by controlled delivery of current from a battery in an implantable neurostimulator (INS) to metal electrodes surgically implanted in the brain in the same manner as ACTIVA PC. The INS is typically placed in the pectoral location. Current is conducted to the electrodes via electrical conduits, including extensions and leads, which are tunnelled sub dermally through the neck, travel through the skull, and terminate in a neural structure appropriate to the neurological disease being treated.

Like Activa PC, The Active PC+S system is capable of providing stimulation to 2 leads, each with 4 electrode contacts. Stimulation parameters are adjusted to optimise therapy for the patient. They can be independently controlled and include the following: active electrodes(s), electrode polarity, pulse, width, amplitude, and frequency. The stimulation settings are stored in programs. A program is a specific combination of pulse width, rate and amplitude settings acting on a specific electrode combination on a lead, or on a lead and the INS, in unipolar mode. Up to four programs can be combined into a group.

Pulse width, amplitude and electrode polarity are independently programmed for each program within a group. Rate, rate limits and cycling for each program within a group must have the same values.

Stimulation is delivered to a maximum of two implanted leads (one lead per hemisphere), with a maximum of 4 electrodes per lead. Rate is limited to 250 Hz, pulse width is limited to 450 micro-sec, amplitude is limited to 10.5 V (or 22.5 mA) and the charge density warning threshold is 30 micro-Coulomb/cm^2/phase.

Stimulation programs are controlled by the clinician via the N'Vision Clinician Programmer. Sensing functions. The recording of bioelectric data is controlled by a separate sensing clinician programmer.
The total procedure is approximately 3.5 hours in duration.
Patients are woken intra-operatively to complete the following tasks:
Computerised reward task (Monetary Incentive Delay task)
Computerised symptom provocation (International Affective Picture Scale)
Randomisation to ON or OFF stimulation in the blinded phase will occur at this time point in a 50:50 ratio. Randomisation will take place externally and allocation will be concealed from participants and investigators, excepting those responsible for DBS programming.

Recovery:
Participants are assessed fortnightly during the recovery phase and will complete:
Neuropsychological rating scales
Computerised reward task (Monetary Incentive Delay task)
Computerised symptom provocation (International Affective Picture Scale)
Neuronal recordings

Double Blind Phase
Participants are initially assessed weekly and this will increase to fortnightly. They will complete:
Neuropsychological rating scales
Computerised reward task (Monetary Incentive Delay task)
Computerised symptom provocation (International Affective Picture Scale)
Participants randomised into the ON stimulation group will begin active treatment during this phase. Active treatment is continuous stimulation. This will commence using predetermined stimulation parameters with increments at each visit according to a titration protocol, with regard to prevailing symptoms. Those participants in the OFF stimulation group will receive sham treatment during this phase.

Open Label Phase
Participants will initially be assessed fortnightly and this will increase in increments to a maximum of 3-monthly. They will complete:
Neuropsychological rating scales
Computerised reward task (Monetary Incentive Delay task)
Computerised symptom provocation (International Affective Picture Scale)
Neuronal recordings
Cognitive behavioural therapy (CBT)
All participants will receive active treatment during this phase. Active treatment is continuous stimulation. Stimulation parameters may be adjusted at each visit, with regard to prevailing symptoms.

Further information on data collected at each visit is described below:

Neuropsychological rating scales

1 Yale-Brown Obsessive-Compulsive Scale (Y-BOCS) – A 10 item scale, administered as a semi structured interview for assessing the severity of obsessions and compulsions. This test is considered the “gold standard” for rating OCD. Each item is rated on a 5 point severity scale (0-4), giving a maximum total score of 40. Scores above 24 are considered “severe”. Assessments will be completed at Visit 1,2,6,7,10,12,14,17,19, 21, 23-28.

2 Vancouver Obsessive-Compulsive Inventory (VOCI), a self-report questionnaire comprised of six subscales, including Contamination (12 items), Checking (6 items), Obsessions (12 items), Hoarding (7 items), Just Right (12 items), and Indecisiveness (6 items). Assessments will be completed from Visit 1,2,6,7,10,12,14,17,19, 21, 23-28.

3 Montgomery-Asberg Depression Rating Scale - A 10 item rating scale, completed by the clinician for assessing overall depression severity. Assessments will be completed at Visit 1,2,6,7,10,12,14,17,19, 21, 23-28.

4 Spielberger State-trait Anxiety Inventory (STA-I) – For assessing comorbid anxiety symptoms. Assessments will be completed at Visit 1,2,6,7,10,12,14,17,19, 21, 23-28.

5 Clinical Global Impression (CGI) – The raters’ clinical impression of the patient’s condition, rated on a 7-point scale. Assessments will be completed at Visit 1,2,6,7,10,12,14,17,19, 21, 23-28.

6 NEO-Five Factor Inventory (NEO-FFI-3) – a 60-item measure of the personality traits of Extraversion, Agreeableness, Conscientiousness, Neuroticism and Openness to Experience. Assessments will be completed at Visit 1,2, 19, 24, 28.

7 Quality of Life Enjoyment and Satisfaction Questionnaire (Q-LES-Q-SF) – a 16 item self-report measure of enjoyment and satisfaction in the past week. Assessments will be completed at Visit 1,2, 19, 24, 28.

8 Assessment of tics - We will administer a brief, 8-item, screening questionnaire to ascertain the presence of tics, either currently or in the past. If patient is clinically judged to have tics as per this brief screen, then the Yale Global Tic Severity Scale (YGTSS) will be administered. Assessments will be completed at Visit 1 and not thereafter if there are no tics. If Tics, then at 1,2,6,7,10,12,14,17,19, 21, 23-28.

9 YGTSS (Yale Global Tic Severity Scale) - This is a validated, standardized rating scale for motor and phonic tics, yielding a total possible tic severity score of 50 and a total possible functional tic-related impairment score of 50, for a final total possible score of 100. Higher scores indicate a greater number and severity of tics and a higher degree of functional impairment. Assessments will be completed at Visit 1 and not thereafter if there are no tics. If Tics, then at 1,2,6,7,10,12,14,17,19, 21, 23-28.


Neuronal Recordings
Local field potentials from the implanted DBS electrodes are recorded directly during postoperative visits at rest and during the performance of the computerised tasks below. Additionally, the device is programmed to record short (30 second) field potentials every 12 hours between visits. This data is subsequently downloaded at each scheduled assessment.

Computerised Tasks
Computerised Symptom Provocation
Patients view a series of images with neutral, negative or positive emotional connotations. The images are chosen from a standardised image database called the International Affective Picture System (IAPS). Each patient in the cohort for this clinical trial has different emotional triggers salient to their specific obsessions, so for our purposes, these images are divided into 18 different categories with different emotional significance. Images are chosen randomly from each category. At the start of each image trial, the image is displayed. Inter-trial interval is 3 seconds for the MRI condition to allow a short time for separability of BOLD responses, and 0 seconds for the other conditions.

Monetary Incentive Delay Task
The ‘Monetary Incentive Delay’ (MID) task has been used in a large number of brain-imaging studies. This task has been used to implicate the striatum in the neural response to anticipation of reward delivery. In the task, subjects see a cue that indicates the amount of monetary reward or loss at stake on a given trial, followed by a target to which they must make a speeded response, followed, finally, by feedback indicating whether or not they received the reward or lost money.

Participants undertake these tasks at all stages of the trial. At baseline the trials are additionally conducted during functional MRI imaging and EEG. They are conducted during surgery. Post-operatively the tasks are conducted during recording of neuronal activity from the DBS device. The total duration of the tasks is determined by the number of trial blocks, but typically takes approximately 20 minutes to complete. The intraoperative task is much shorter (5 minutes).

The tasks will be conducted during the imaging assessments and intraoperatively to investigate patterns of electrophysiological brain activity with specific focus on the nucleus accumbens (NAcc). These two measures will provide detailed information on the response of the patients to specific reward stimuli and we will be able to assess the impact of DBS protocols on this activity to subsequently correlate with clinical outcome.

Cognitive Behavioural Therapy:
Participants will receive 8-12 individual OCD-oriented CBT sessions with a clinical psychologist with expertise in OCD, using the principles of exposure and response prevention. The duration of these sessions will be approximately 1 hour. CBT will commence during the open label phase when the response to active treatment with neurostimulation has plateaued (3 consecutive Yale-Brown Obsessive-Compulsive Scale scores within 3 point range). Sessions will be initially weekly and will extend to fortnightly and then monthly depending on patient response. Adherence will be monitored as part of the trial protocol using a register.

The CBT sessions will include assessments and therapy with the device switched on. Cognitive Behaviour Therapy (CBT) is a relatively short term, focused approach to the treatment of many types of emotional, behavioural and psychiatric problems. The application of CBT varies according to the problem being addressed, but is essentially a collaborative and individualized program that helps individuals to identify unhelpful thoughts and behaviours and learn or re-learn healthier skills and habits.
Intervention code [1] 292489 0
Treatment: Other
Intervention code [2] 293111 0
Treatment: Devices
Comparator / control treatment
The study will follow a randomised, placebo controlled, double blind, staggered onset design. All participants will have a deep brain stimulation device inserted and this will not be turned on for one month. At four weeks post surgery, the participants randomly selected to the "on" stimulation group will have their devices switched on. At four months post surgery, participants selected to the "off" stimulation group will have their devices switched on.
Control group
Placebo

Outcomes
Primary outcome [1] 295737 0
The primary clinical outcome is the proportion of patients who achieve a 25-35% improvement in the Yale-Brown Obsessive Compulsive Scale (YBOCS), 12 and 24 months after the DBS device has been switched on.
Timepoint [1] 295737 0
12 and 24 months after the device has been switched on.
Primary outcome [2] 295792 0
This primary outcome is a composite primary outcome. Correlation between clinical outcome (assessed using the Y-BOCS) and electrophysiological activity in the nucleus accumbens (NAc) identified intra-operatively using neuronal recordings. This will assist in target selection for future patients. Electrophysiological responses to reward and visual stimulation of neural pathways in the NAc will be recorded intra-operatively. Y-BOCS data is collected during the follow up - see previous section.
Timepoint [2] 295792 0
The intra-operative electrophysiological data is collected intra-operatively, as described above. Y-BOCS data to be used in this analysis will be taken 12 and 24 months after the DBS device has been switched on.
Primary outcome [3] 296677 0
This primary outcome is a composite primary outcome. Correlation between clinical outcome (assessed using the Y-BOCS) and electrophysiological activity in the nucleus accumbens (NAc) identified post-operatively using neuronal recordings made with the Activa PC+S (see previous section for description of this device). Electrophysiological responses to reward and visual stimulation of neural pathways in the NAc will be recorded post-operatively using the Activa PC+S (see previous section for description). Y-BOCS data is collected during the follow up - see previous section.
Timepoint [3] 296677 0
The post-operative electrophysiological data will be correlated with Y-BOCS data 12 and 24 months after DBS device implantation.
Secondary outcome [1] 316362 0
Quality of life assessed by using the Quality of Life Enjoyment and Satisfaction Questionnaire - Short Form (Q-LES-Q-SF).
Timepoint [1] 316362 0
12 and 24 months after the DBS device has been switched on.
Secondary outcome [2] 319091 0
The proportion of patients achieving a 50% reduction in depressive symptoms as assessed by the MADRS.
Timepoint [2] 319091 0
12 and 24 months after the DBS device has been switched on.
Secondary outcome [3] 330484 0
To measure the change in each (i) participant and (ii) nominated carer’s Quality Adjusted Life Years (QALY).

To develop an economic database comprising of:

1. Direct costs:

a) Bottom up costing approach, which utilises health service invoices from St Andrews War Memorial Hospital.
b) 5 years of MBS and PBS item numbers.

2. EuroQol 5 Dimension (EQ-5D-5L): A validated Health Related Quality of Life instrument for the participant.

3. Health Service Utilisation and Labour Market Participation Survey, for the participant.

4. EuroQol 5 Dimension (EQ-5D-5L): A validated Health Related Quality of Life instrument for the participant’s nominated carer.

5. Health Service Utilisation and Labour Market Participation Survey, for the participant’s nominated carer.
Timepoint [3] 330484 0
24 months after the device has been switched on.

Secondary outcome [4] 330485 0
To calculate the Incremental Cost effectiveness ratio (ICER) for treating severe OCD with DBS.

To develop an economic database comprising of:

1. Direct costs:

a) Bottom up costing approach, which utilises health service invoices from St Andrews War Memorial Hospital.
b) 5 years of MBS and PBS item numbers.

2. EuroQol 5 Dimension (EQ-5D-5L): A validated Health Related Quality of Life instrument for the participant.

3. Health Service Utilisation and Labour Market Participation Survey, for the participant.

4. EuroQol 5 Dimension (EQ-5D-5L): A validated Health Related Quality of Life instrument for the participant’s nominated carer.

5. Health Service Utilisation and Labour Market Participation Survey, for the participant’s nominated carer.
Timepoint [4] 330485 0
24 months after the device has been switched on.

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

1. Diagnosis - Patient is diagnosed with primary obsessive-compulsive disorder (OCD) according to DSM-IV diagnostic criteria derived from the SCID.

2. Severity - Patient 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 an 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 antipsychotic for 8 weeks in combination with the one of the abovementioned drugs plus
* 1 CBT trial (Exposure and response prevention or ERP), confirmed by patient or psychotherapist, for an adequate number of sessions as determined by a neuropsychiatrist.

5.Patient is aged between 18-70 years.

6. Patient is a male or non-pregnant female adequately protected from conception. Females of childbearing potential must use an acceptable method of birth control. Abstinence is an acceptable means of birth control.

7. Patient is able to comply with all testing and follow-up visit requirements defined by the Study Protocol.

8. Patient has voluntarily signed an informed consent in accordance with institutional policies.

9. Patient’s medication regime has remained stable for at least 6 weeks prior to study inclusion.
Minimum age
18 Years
Maximum age
70 Years
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
Patients 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 disorders).

2. Diagnosed manic episode within the last 3 years.

3. Clinical history consistent with severe personality disorder.

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. Current clinically significant medical illness or neurological disorder, excluding tic disorder.

6. Clinically significant abnormality on pre-operative MRI.

7.Any labelled contraindication to having DBS surgery, and/ or inability to undergo preoperative MRI.

8. Pregnancy.

9. Patient meets any of the following:

* 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.

10. Patient had received general anesthesia in a 30 day period prior to DBS implantation.

11. Patient is currently enrolled in another investigational study or is using another investigational device.

12. Patient has a history of, or evidence of, significant brain malformation or significant head injury or clinically apparent cerebral vascular events, or prior brain surgery such as cingulotomy.

13. Patient has a cardiac pacemaker, implantable defibrillator, or other implantable stimulator.

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)
Participants will be screened for medical history and diagnosis of OCD using the Structured Clinical Interview for Diagnosis (SCID) for DSM-IV. Eligible participants will be identified by the neurologist, neurosurgeon and psychiatry team. All consented participants are required to attend the Mental Health Review Tribunal (MHRT) and be presented to the MHRT as required under the Queensland Mental Health Act (2000). This will be a further independent check on the validity of consent and the advisability of the procedure as assessed by experienced psychiatrists, neurologists and neurosurgeons enabling objectivity at distance from the treating team.

Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Participants will be randomly assigned on the day of surgery a participant ID and a treatment group by the Principal Investigator. Participant IDs will be randomly assigned using an on-line randomisation for clinical trials at https://www.sealedenvelope.com/simple-randomiser/v1/lists. An external party will use the generated randomised list and allocate 01 – 10 in sealed envelopes. Participants will be randomly allocated into their treatment groups with a known end-point that 5 participants will be in the On Stimulation Group and 5 in the Off Stimulation Group.
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
Other
Other design features
The study will follow a randomised, placebo controlled, double blind, staggered onset design with single blind, open label and 2 follow-up. Following initial screening and enrolment, participants will undergo standard stereotactic DBS surgery based on MRI plus CT image fusion and utilising Cosman Roberts Wells stereotactic frame in conjunction with microelectrode recording.
There will be two unblinded people during the duration of the trial - the PI and a DBS programmer.
Phase
Not Applicable
Type of endpoint/s
Safety/efficacy
Statistical methods / analysis
The primary outcome measure of OCD symptoms will be the Y-BOCS, a 10-item clinician rated measure. Inter-rater reliability on this measure will be established. The small sample size may limit the statistical power of parametric inferential statistics, so effect size measures (Cohen's d) will be used to give a non-sample size dependent measure of the treatment effect, in addition to repeated samples t-tests. Additionally the treatment effect for individual participants will be examined using the reliable change index (Jacobsen & Truax, 1991). Clinical significance of the treatment for individuals will also be assessed (Jacobsen & Truax, 1991).

Sample size calculations were based on effect size for treatment with pharmacotherapy plus cognitive behavioural therapy as stated in the meta-analysis by Eddy et al. (2004), in which the effect size was 1.72. Specifying an alpha level of 0.05 and a priori power of 0.8, a total sample size of 4 is required to detect the large treatment effect. A sample size of N=4 will yield an actual power of 0.83. As previously mentioned, non-sample-size dependent effect size measures for the treatment effect will also be computed.

A sample size of 10 is targeted due to the additional primary outcome of defining electrophysiological biomarkers for OCD targeting. This is a novel methodology and additional patients are recruited in the absence of existing data regarding effect size and variance.

For the electrophysiological statistical analysis, neuronal recordings will be sorted manually for spike detection and analysed using custom software written for MATLAB (Mathworks). The Wilcoxon rank-sum test (significance level p=0.01 will be used during different experimental conditions for each neuron for individual spike train analysis.

Recruitment
Recruitment status
Completed
Date of first participant enrolment
Anticipated
Actual
5/08/2015
Date of last participant enrolment
Anticipated
1/07/2019
Actual
21/05/2019
Date of last data collection
Anticipated
31/12/2021
Actual
29/07/2021
Sample size
Target
10
Accrual to date
Final
10
Recruitment in Australia
Recruitment state(s)
QLD
Recruitment postcode(s) [1] 10058 0
4000 - Spring Hill

Funding & Sponsors
Funding source category [1] 291777 0
University
Name [1] 291777 0
The University of Queensland
Country [1] 291777 0
Australia
Primary sponsor type
University
Name
The University Of Queensland
Address
University of Queensland Asia Pacific Centre for Neuromodulation (APCN), Building 71/918 Herston QLD 4029 Australia QLD 4029 Australia
Country
Australia
Secondary sponsor category [1] 290443 0
None
Name [1] 290443 0
Address [1] 290443 0
Country [1] 290443 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 293294 0
Uniting Care Health Human Research Ethics Committee
Ethics committee address [1] 293294 0
Ethics committee country [1] 293294 0
Australia
Date submitted for ethics approval [1] 293294 0
02/09/2013
Approval date [1] 293294 0
26/11/2013
Ethics approval number [1] 293294 0
1320
Ethics committee name [2] 293295 0
The University of Queensland
Ethics committee address [2] 293295 0
Ethics committee country [2] 293295 0
Australia
Date submitted for ethics approval [2] 293295 0
05/12/2013
Approval date [2] 293295 0
11/12/2013
Ethics approval number [2] 293295 0
2013001560

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

Contacts
Principal investigator
Name 59274 0
Prof Peter Silburn
Address 59274 0
Asia-Pacific Centre for Neuromodulation, The University of Queensland, St Andrew’s Place, Brisbane QLD 4072
Country 59274 0
Australia
Phone 59274 0
+617 3831 2393
Fax 59274 0
+61 7 3346 5599
Email 59274 0
[email protected]
Contact person for public queries
Name 59275 0
Janet Voight
Address 59275 0
Asia-Pacific Centre for Neuromodulation, The University of Queensland, St Andrew’s Place, Brisbane QLD 4072
Country 59275 0
Australia
Phone 59275 0
+61 429 901 530
Fax 59275 0
+61 7 3346 6301
Email 59275 0
[email protected]
Contact person for scientific queries
Name 59276 0
Pankaj Sah
Address 59276 0
The Queensland Brain Institute
The University of Queensland
QBI Building (#79)
St Lucia, QLD 4072
Australia
Country 59276 0
Australia
Phone 59276 0
+61 7 334 66311
Fax 59276 0
+61 7 3346 6301
Email 59276 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
Not included in study set-up, no resources to support this.


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.