Trial Review

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Trial registered on ANZCTR


Registration number
ACTRN12618002047279
Ethics application status
Approved
Date submitted
13/12/2018
Date registered
21/12/2018
Date last updated
2/12/2019
Date data sharing statement initially provided
21/12/2018
Type of registration
Prospectively registered

Titles & IDs
Public title
Deep Brain Stimulation (DBS) of the Nucleus Accumbens for Treatment Resistant Severe and Enduring Anorexia Nervosa: A Phase 1 Open Trial
Scientific title
Efficacy and safety of Deep Brain Stimulation (DBS) of the Nucleus Accumbens for Treatment Resistant Severe and Enduring Anorexia Nervosa: A Phase 1 Open Trial
Secondary ID [1] 296873 0
Nil
Universal Trial Number (UTN)
U1111-1219-9348
Trial acronym
DBS-SEAN
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Anorexia Nervosa 310796 0
Condition category
Condition code
Surgery 309466 309466 0 0
Surgical techniques
Mental Health 309515 309515 0 0
Eating disorders

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
The aims of this study are to determine the efficacy of Deep Brain Stimulation in treatment-resistant severe and enduring anorexia nervosa.

Surgical Procedure:
Participants will have the Vercise Gevia Deep Brain Stimulation System surgically implanted by a neurosurgeon according to standard stereotactic procedures. All patients will undergo bilateral implantation. Device implantation is permanent and participants will have the option to continue with the therapy post-trial or have the device switched or and/or removed.

The device provides electrical stimulation to the Nucleus Accumbens (NAcc). Stimulation is provided by controlled delivery of current from a battery in an implantable neurostimulator (INS) connected by extension leads from the body through the neck to electrodes surgically implanted in the brain.

Stimulation programs are controlled by the neurologist via the clinical programmer. The total procedure is approximately 3.5 hours in duration. As in the standard procedure patients are woken intra-operatively and will also complete an image recognition task.

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.

Post-operatively participants will undergo a CT scan to verify electrode positioning.

Stimulation / Programming:
Participants will visit the centre for programming of the device by the neuropsychiatrist. Programming sessions will last approximately 30 minutes and are initially weekly, becoming less frequent when parameters are stable. Initial stimulation will commence bilateral stimulation, monopolar configuration. The clinician will initially review the response at weekly-fortnightly intervals. During initial phase aim is to increase stimulation amplitude by 0.5mA to 1mA per visit until a target amplitude of 4MA is reached.

If there is an insufficient response after initial phase amplitude will be increased in 0.2mA to 0.5mA increments.

Clinical Assessments:
Assessment sessions are scheduled every 3 months. The following will be administered:
* Eating Disorder Examination Questionnaire (EDE-Q 6.0)
* Depression Anxiety and Stress Scale (DASS)
* Yale-Brown Obsessive Compulsive Scale (Y-BOCS)
* Montreal Cognitive Assessment (MoCA)
* Clinical Impairment Assessment Questionnaire (CIA)
* Body Mass Index (BMI)

Patients will attend a clinic at the Royal Brisbane & Women's Hospital. The clinic will take approximately 1 hour and will be with the trial's psychologist.

Image Recognition Task:
Every 3 months participants will also undergo an EEG with a researcher at the Queensland Brain Institute. Under the EEG condition participants will complete an image presentation task. This session will take approximately 1 hour.
Intervention code [1] 313150 0
Treatment: Devices
Intervention code [2] 313170 0
Treatment: Surgery
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
Active

Outcomes
Primary outcome [1] 308432 0
The primary outcome is any serious adverse events, or adverse events leading to permanent discontinuation, related to the implantation of or activation of the deep brain stimulation device.

Conditions present at screening and do not deteriorate will not be considered adverse events.

Hospitalisation due to progression of disease will not be considered a serious adverse event for the purposes of this study.

At every study visit patients will be asked how they have been since their last visit in order to elicit any medically related changes in their well-being. Hospitalisations, new medication or changed concomitant medication regimens. In addition, adverse events will be documented from physical examination findings, clinically significant lab results or other documents related to patient safety.

The following are possible known adverse events: depression, hypermania, mixed bipolar, cardiac air emblous, postopeartive fever, postopeartive infection, headache.
Timepoint [1] 308432 0
Adverse events will be recorded from the time the patient signs the informed consent until the final study visit 18 months post-surgery.
Secondary outcome [1] 354951 0
Body Mass Index (BMI)

The proportion of patients attaining a healthy BMI range of equal to or greater than 18.5.

A measure of relative size based on the height and weight of the individual, calculated as the weight in kilograms divided by the height in metres squared (i.e. kg/m2). Diagnostic and Statistical Manual 5 uses BMI, as a measure of severity of AN. BMI is to be collected preoperatively, whilst baseline BMIs are to be calculated based on patient interviews, weight diaries and medical records.
Timepoint [1] 354951 0
Pre-operatively (2 weeks)
1 month post-surgery
4 months post-surgery
7 months post-surgery
10 months post-surgery
13 months post-surgery
16 months post-surgery
18 months post-surgery
Secondary outcome [2] 355046 0
Eating Disorder Examination Questionnaire (EDE-Q 6.0)

The proportion of patients attaining an EDE-Q global score that is less than 1 standard deviation above community norms < 2.74)
Timepoint [2] 355046 0
Pre-operatively (2 weeks)
1 month post-surgery
4 months post-surgery
7 months post-surgery
10 months post-surgery
13 months post-surgery
16 months post-surgery
18 months post-surgery
Secondary outcome [3] 355047 0
Clinical Impairment Assessment (CIA)

The proportion of patients attaining a CIA global score that is less than 1 standard deviation above community norms < 13.9
Timepoint [3] 355047 0
Pre-operatively (2 weeks)
1 month post-surgery
4 months post-surgery
7 months post-surgery
10 months post-surgery
13 months post-surgery
16 months post-surgery
18 months post-surgery
Secondary outcome [4] 355048 0
Depression, Anxiety and Stress Scale (DASS)

The proportion of patients attaining a 50% reduction in global score, which is considered clinically significant
Timepoint [4] 355048 0
Pre-operatively (2 weeks)
1 month post-surgery
4 months post-surgery
7 months post-surgery
10 months post-surgery
13 months post-surgery
16 months post-surgery
18 months post-surgery
Secondary outcome [5] 355049 0
Yale-Brown Obsessive Compulsive Scale (Y-BOCS)

The proportion of patients attaining a 35% reduction in global score, which is considered clinically significant
Timepoint [5] 355049 0
Pre-operatively (2 weeks)
1 month post-surgery
4 months post-surgery
7 months post-surgery
10 months post-surgery
13 months post-surgery
16 months post-surgery
18 months post-surgery
Secondary outcome [6] 355050 0
Montreal Cognitive Assessment (MoCA)

The proportion of patients scoring in the cognitively impaired range post-intervention (< 26)
Timepoint [6] 355050 0
Pre-operatively (2 weeks)
1 month post-surgery
4 months post-surgery
7 months post-surgery
10 months post-surgery
13 months post-surgery
16 months post-surgery
18 months post-surgery
Secondary outcome [7] 355051 0
Cost of healthcare and service utilisation - Medicare service use up to five years post DBS implant
Timepoint [7] 355051 0
5 years post DBS implantation.

Eligibility
Key inclusion criteria
Participants will be selected initially on psychiatric criteria for fulfilling a clear diagnosis of, restricting or binge-purging subtype, as defined in the Diagnostic and Statistical Manual of Mental Disorders (DSM-5)

Be of a severe, enduring and treatment-resistant AN:
* BMI between 13 to 17.5
* Duration of severe AN of at least 7 years
* Treatment resistance: lack of response to at least two treatments such as evidence-based psychotherapy, day treatment and inpatient weight regain

• Significant functional impairment
• Age 18-65 years
• Able to freely provide verbal and written informed consent
• Able to comply with all assessment, protocols and follow-ups
• Approved for treatment by the Mental Health Review Tribunal (MHRT)
Minimum age
18 Years
Maximum age
65 Years
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
• Active neurological disease such as epilepsy
• Pregnancy
• Any past or present evidence of psychosis; current severe depressive disorder; past or present diagnosis of bipolar disorder, Antisocial Personality Disorder or severe Borderline Personality Disorder
• Unstable physical condition contraindicating surgery or anaesthesia
• Alcohol or substance use disorder in the previous six months, excluding nicotine and caffeine
• Any contradiction to MRI scanning
• Likely to move or relocate during the study’s 18-month duration
• Participant on an Involuntary Treatment Order under Mental Health Act

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)
Sealed envelope
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Participant treatment group allocation will be randomly assigned using an on-line randomisation for clinical trials at https://www.sealedenvelope.com/simple-randomiser/v1/lists of block sizes of 10. An external party will use the generated randomised list and allocate 01 – 10 in sealed envelopes. Randomisation will occur the day of surgery by the trial’s neurologist. Participants will be randomly allocated a computer-generated study ID and treatment group with a known end-point that five participants will be in the “On Stimulation Group” and five 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
Parallel
Other design features
During the blinded phase of the trial the only people who will know the intervention the participant is receiving will be the neurologist and neuropsychiatrist. Those doing the assessments and analysis will not know the patient is receiving the intervention.
Phase
Not Applicable
Type of endpoint/s
Safety/efficacy
Statistical methods / analysis
The primary aim of this study is to determine the safety, tolerability and efficacy of DBS of the NAcc in ten persons with severe, chronic and treatment-refractory AN. The statistical analyses are critical to the efficacy component of the trial with the primary response variable being BMI (as presented in Lipsman et al., 2013). BMI is a good choice for a primary response variable because it is continuous, is easily measured and objective, and has direct relevance to the classification of the disorder.

The initial analysis post completion of the trial will begin with an exploratory analysis via data visualisation in the R programming language. This will include a visualization of the time series for all primary and secondary variables across the 8 visits of the 18-month study. Additionally, tables including the mean, median, and quantiles for the control and treatment groups for each of the time points will be calculated using the R programming language.

Recruitment
Recruitment status
Not yet recruiting
Date of first participant enrolment
Anticipated
1/02/2020
Actual
Date of last participant enrolment
Anticipated
1/01/2021
Actual
Date of last data collection
Anticipated
1/01/2026
Actual
Sample size
Target
10
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
QLD
Recruitment postcode(s) [1] 28677 0
4072 - University Of Queensland

Funding & Sponsors
Funding source category [1] 301442 0
Commercial sector/Industry
Name [1] 301442 0
Boston Scientific Group Plc
Country [1] 301442 0
Netherlands
Primary sponsor type
University
Name
The University of Queensland
Address
Queensland Brain Institute
Building #79
St Lucia
QLD 4072
Country
Australia
Secondary sponsor category [1] 301130 0
None
Name [1] 301130 0
Address [1] 301130 0
Country [1] 301130 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 302175 0
Royal Brisbane & Women's Hospital HREC
Ethics committee address [1] 302175 0
Ethics committee country [1] 302175 0
Australia
Date submitted for ethics approval [1] 302175 0
24/09/2018
Approval date [1] 302175 0
14/01/2019
Ethics approval number [1] 302175 0
HREC/2018/QRBW/46642
Ethics committee name [2] 302177 0
Uniting Care Health HREC
Ethics committee address [2] 302177 0
Ethics committee country [2] 302177 0
Australia
Date submitted for ethics approval [2] 302177 0
23/10/2018
Approval date [2] 302177 0
12/02/2019
Ethics approval number [2] 302177 0
1822
Ethics committee name [3] 302178 0
The University of Queensland HREC
Ethics committee address [3] 302178 0
Ethics committee country [3] 302178 0
Australia
Date submitted for ethics approval [3] 302178 0
28/01/2019
Approval date [3] 302178 0
14/03/2019
Ethics approval number [3] 302178 0
2019000440

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

Contacts
Principal investigator
Name 89378 0
A/Prof Warren Ward
Address 89378 0
University of Queensland
St Lucia
QLD 4072
Country 89378 0
Australia
Phone 89378 0
+61 07 3346 6353
Fax 89378 0
Email 89378 0
apcn.an.trial@uq.edu.au
Contact person for public queries
Name 89379 0
Warren Ward
Address 89379 0
University of Queensland
St Lucia
QLD 4072
Country 89379 0
Australia
Phone 89379 0
+61 07 3346 6353
Fax 89379 0
Email 89379 0
apcn.an.trial@uq.edu.au
Contact person for scientific queries
Name 89380 0
Warren Ward
Address 89380 0
University of Queensland
St Lucia
QLD 4072
Country 89380 0
Australia
Phone 89380 0
+61 07 3346 6353
Fax 89380 0
Email 89380 0
apcn.an.trial@uq.edu.au

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?

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.