Efficacy Study of Deep Brain Stimulation in Patients With Treatment Resistant Major Depression

Study Overview
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Brief Summary
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The primary objective of this multicenter, randomized, sham-controlled, double blind (patient and observer blinded) clinical trial is to assess the antidepressant effect of Deep Brain Stimulation (DBS) in patients with treatment resistant major depression using the Boston Scientific implantable Vercise™ GEVIA™ DBS system compared to sham.

Detailed Description
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The main objective of this clinical trial is to assess the putative antidepressant efficacy of a therapeutic method called Deep Brain Stimulation (DBS) in patients suffering from severe, treatment-resistant depression, i.e. in patients who have not sufficiently improved under established antidepressant therapies (such as psychotherapy, antidepressant drug therapy, and electroconvulsive therapy). DBS, also known as brain pacemaker therapy, is a neurosurgical therapeutic method that is widely established for the treatment of other conditions such as Parkinson's disease. However, DBS is not yet approved for the treatment of patients with depression. In order to initiate DBS treatment, a neurosurgical procedure is performed in which electrodes are placed in a brain region termed 'medial forebrain bundle' (MFB). The electrodes are then used to stimulate this region with electric pulses. From previous investigations and studies with small numbers of patients, it is believed that DBS might have a positive effect on depressive symptoms in patients treated with the method.

Official Title
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Controlled Randomized Clinical Trial to Assess Efficacy of Deep Brain Stimulation (DBS) of the slMFB in Patients With Treatment Resistant Major Depression

Conditions
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Treatment-resistant Depression

Intervention / Treatment
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* Device: Vercise GEVIA deep brain stimulation (DBS) system


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Major depression (MD), severe, unipolar, or bipolar in an acute depression episode. German mother tongue or fluent. Male or female patients ≥20 and ≤75 years. Hamilton Depression Rating Scale (HDRS-28) score of >21. Global Assessment of Function (GAF) score of <45. At least 4 episodes of depression or one chronic episode >2 years. Failure to respond to adequate trials of primary antidepressants from at least 3 different classes (>5 weeks at the maximum recommended or tolerated dose) and adequate trials of augmentation/combination of a primary antidepressant (>3 weeks at the usually recommended or maximum tolerated dose) using at least 2 different augmenting/combination agents (lithium, T3, stimulants, neuroleptics, anticonvulsants, buspirone, or a second primary antidepressant) and an adequate trial of electroconvulsive therapy (ECT) (>6 treatments) and an adequate trial of individual psychotherapy (>20 sessions with an experienced psychotherapist). Able to give written informed consent. Compliance to participate in the study. Drug free or on stable drug regimen at least 6 weeks before study entry. Exclusion Criteria: Current or past non-affective psychotic disorder. Any current clinically significant neurological disorder or medical illness affecting brain function, other than motor tics or Gilles de la Tourette syndrome. Any clinically significant abnormality on preoperative magnetic resonance imaging (MRI), any contraindications to perform a planned MRI to visualize the slMFB. Any surgical contraindications to undergoing DBS like deformed or displaced or not discernable target region, scarring after brain disease (infarction), need for continuous anticoagulation that cannot be bridged in order to obtain normal coagulation, present risks for anesthesia or any brain or scalp injury (even after intracranial surgery). Current or unstably remitted substance abuse (aside from nicotine). Pregnancy, women of childbearing age not using effective contraception and breast feeding women. History of severe personality disorder. Acute suicidal ideation. Patients with advanced stage cardiovascular disease. Patients under immunosuppressive or chemo therapy because of malignant disease. Patients who had previous intracranial surgery. Patients who are currently under DBS therapy or have implanted any kind of stimulator already. Patients with aneurysm clips. Patients with cochlear implants. Patients with planned diathermy. Persons who are in a relationship of dependence/employment with the sponsor or the investigator. Simultaneous participation or previous participation within 30 days prior to start of screening in a clinical trial involving investigational medicinal product(s) or investigational medical device(s).

Ages Eligible for Study
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Minimum Age: 20 Years
Maximum Age: 75 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: multicenter, randomized, sham-controlled, double blind (patient and observer blinded)
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Group A: DBS onset in week 1<br>Implantation of Vercise GEVIA deep brain stimulation (DBS) system. DBS onset in week 1. 2ND STAGE: After 6 months DBS ON, patients will be assessed whether they are responders or non-responders. In the subgroup of eligible responders, patients will be randomized to either DBS OFF* (for max. 3 months) or continued DBS for another 6 months. *DBS OFF until worsening of clinical depression, event (defined as > 5 points augmentation in MADRS in two consecutive visits) or for a maximum of 3 months. After DBS OFF, re-onset of DBS will be performed, followed by 6 months continuous DBS. Non-responders will also receive another 6 months DBS therapy in the 2nd stage. At sites other than Freiburg/Bonn, the 2nd stage consists of 6 months DBS therapy only. | Device: Vercise GEVIA deep brain stimulation (DBS) system<br>* DBS to the superolateral branch of the Medial Forebrain Bundle (slMFB)<br>|
| Sham Comparator: Group B: DBS off, followed by DBS onset in week 17<br>Implantation of Vercise GEVIA deep brain stimulation (DBS) system. 4 months OFF after implantation followed by DBS onset in first week of month 5. 2ND STAGE: See group A. | Device: Vercise GEVIA deep brain stimulation (DBS) system<br>* DBS to the superolateral branch of the Medial Forebrain Bundle (slMFB)<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Montgomery-Asberg Depression Rating Scale (MADRS) total score | Primary outcome (Efficacy). MADRS is an established instrument to rate symptoms of depression. The questionnaire includes questions on the following symptoms 1. Apparent sadness 2. Reported sadness 3. Inner tension 4. Reduced sleep 5. Reduced appetite 6. Concentration difficulties 7. Lassitude 8. Inability to feel 9. Pessimistic thoughts 10. Suicidal thoughts Each of the 10 items yields a score of 0 to 6. These item scores are summed up to yield a total score. The range of the total score is thus 0 to 60; higher total scores indicate more severe depressive symptoms. Usual cutoff points are: 0 to 6 - normal/symptom absent; 7 to 19 - mild depression; 20 to 34 - moderate depression; >34 - severe depression | 16 weeks after surgery | 
| Time to Montgomery-Asberg Depression Rating Scale (MADRS) augmentation of >5 points or clinical worsening in two consecutive visits after DBS termination | Primary outcome in 2nd stage; Description MADRS: see above. | Up to 3 months | 
| Assessment of (Serious) Adverse Events related to Investigational Medical Device and / or surgical procedures | Primary outcome (Safety); (Serious) adverse events seen will be reported using standard descriptive statistical methods. | From IMD implantation until the end of study; assessed up to 77 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Hamilton Depression Rating Scale (HDRS-28) total score | HDRS is an established instrument to rate symptoms of depression. Different versions exist, using between 17 and 29 items. In this study, the 28-item version (HDRS-28) is used. The patient is rated by a clinician, items are scored either on a 3-point or 5-point Likert-type scale. Single item scores are summed up to yield a total score. The total score ranges from 0 to 85; a higher total score indicates more severe depressive symptoms. | 16 weeks after surgery | 
| Clinical Global Impression Score (CGI) total score | The CGI is a scale that measures the global severity of illness, the global improvement relative to the beginning of the study as well as the therapeutic effect and adverse reactions, score ranges from 0 to 7 for severity of illness and global improvement, a higher score indicates more severe symptoms and a worsening of symptoms; score ranges from 0 to 8 for the efficacy index, 0 means that the efficacy can't be evaluated, a score of 2 means best efficacy while a score of 8 means no therapeutic effect and more adverse reactions | 16 weeks after surgery | 
| Global Assessment of Functioning (GAF) total score | Score ranges from 100 (high functioning) to 1 (severly impaired) | 16 weeks after surgery | 
| Beck Depression Inventory (BDI-II) total score | Score ranges from 0 to 63; a higher total score indicates more severe depressive symptoms | 16 weeks after surgery | 
| 36-Item Short Form Health Survey (SF-36) total score | Health-related quality of life questionnaire; 8 subscales: General health perceptions, physical functioning, role limitations due to physical problems, bodily pain, vitality, general mental health, role limitations due to emotional problems, social functioning. The score in each subscale ranges from 0 to 100; subscores add up to two total scores, physical health and mental health, each with a score range of 0-400. Higher scores indicate better health-related quality of life. | 16 weeks after surgery | 
| Change over time in HDRS total score after DBS surgery with DB stimulation OFF compared to stimulation ON | HDRS: see above | assessed weekly for 16 weeks after surgery | 
| Change over time in CGI total score after DBS surgery with DB stimulation OFF compared to stimulation ON | CGI: see above | assessed weekly for 16 weeks after surgery | 
| Change over time in GAF total score after DBS surgery with DB stimulation OFF compared to stimulation ON | GAF: see above | assessed weekly for 16 weeks after surgery | 
| Change over time in BDI-II total score after DBS surgery with DB stimulation OFF compared to stimulation ON | BDI-II: see above | assessed weekly for 16 weeks after surgery | 
| Change over time in SF-36 total score after DBS surgery with DB stimulation OFF compared to stimulation ON | SF-36: see above | assessed weekly for 16 weeks after surgery | 
| Neuropsychological Assessments: Rey Complex Figure Test (CFT) | Score range 0-36, higher scores indicate better cognitive performance | at 4 months after implantation | 
| Neuropsychological Assessments: d2 concentration test (d2) | Higher scores indicate better cognitive performance (total of right answers minus errors) | at 4 months after implantation | 
| Neuropsychological Assessments: 5-Point-Test | Score range 0-35, higher scores indicate better cognitive performance | at 4 months after implantation | 
| Neuropsychological Assessments: Wechsler Adult Intelligence Scale (WAIS) (vocabulary, similarities) | Score range vocabulary: 0-32, Score range finding similarities: 0-32, higher scores indicate better cognitive performance | at 4 months after implantation | 
| Neuropsychological Assessments: Mini-Mental-Status-Test (MMST) | Score range 0-30, higher scores indicate better cognitive performance | at 4 months after implantation | 
| Neuropsychological Assessments: Multiple-Choice Vocabulary Intelligence Test (MWT-B) | Score range 0-37, higher scores indicate better cognitive performance | at 4 months after implantation | 
| Neuropsychological Assessments: Rey Visual Design Learning Test (RVDLT) | Score range 0-75, higher scores indicate better cognitive performance | at 4 months after implantation | 
| Neuropsychological Assessments: Word Fluency Test | No maximum scores, patient has two minutes to produce answers, higher scores indicate better cognitive performance | at 4 months after implantation | 
| Neuropsychological Assessments: Stroop-Test | Time in s, low scores (less seconds) indicate better cognitive performance | at 4 months after implantation | 
| Neuropsychological Assessments: Test for Attentional Performance (TAP) | Reaction times as well as correct or false responses and omissions are measured, higher cognitive performance is indicated by fast responses, few errors and high no. of correct responses | at 4 months after implantation | 
| Neuropsychological Assessments: Trail-Making Test (TMT) | Time in s, low scores (less seconds) indicate better cognitive performance | at 4 months after implantation | 
| Neuropsychological Assessments: Verbal Memory and Learning Ability Test | Score range 0-75, higher scores indicate better cognitive performance | at 4 months after implantation | 
| Neuropsychological Assessments: Hopper Visual Organization Test (VOT) | Score range 0-30, higher scores indicate better cognitive performance | at 4 months after implantation | 
| Neuropsychological Assessments: Digit-Span and Block-Span Test | Score range 0-12 for each of for dimensions: Digit span forward, digit span backward, block span forward, block span backward. Higher scores indicate better cognitive performance | at 4 months after implantation | 
| MADRS total score during long-term follow-up compared to baseline | MADRS: see above | at 12 months stimulation | 
| HDRS total score during long-term follow-up compared to baseline | see above | at 12 months stimulation | 
| CGI total score | see above | at 6 and 12 months DB stimulation compared to baseline | 
| GAF total score | see above | at 6 and 12 months DB stimulation compared to baseline | 
| BDI-II total score | see above | at 6 and 12 months DB stimulation compared to baseline | 
| SF-36 total score | see above | at 6 and 12 months DB stimulation compared to baseline | 
| Neuropsychological Assessments: Rey Complex Figure Test (CFT) | see above | at 6 months DBS compared to baseline and at end of the study compared to baseline, assessed up to 77 weeks | 
| Neuropsychological Assessments: d2 concentration test (d2) | see above | at 6 months DBS compared to baseline and at end of the study compared to baseline, assessed up to 77 weeks | 
| Neuropsychological Assessments: 5-Point-Test | see above | at 6 months DBS compared to baseline and at end of the study compared to baseline, assessed up to 77 weeks | 
| Neuropsychological Assessments: Wechsler Adult Intelligence Scale (WAIS) (vocabulary, similarities) | see above | at 6 months DBS compared to baseline and at end of the study compared to baseline, assessed up to 77 weeks | 
| Neuropsychological Assessments: Mini-Mental-Status-Test (MMST) | see above | at 6 months DBS compared to baseline and at end of the study compared to baseline, assessed up to 77 weeks | 
| Neuropsychological Assessments: Multiple-Choice Vocabulary Intelligence Test (MWT-B) | see above | at 6 months DBS compared to baseline and at end of the study compared to baseline, assessed up to 77 weeks | 
| Neuropsychological Assessments: Rey Visual Design Learning Test (RVDLT) | see above | at 6 months DBS compared to baseline and at end of the study compared to baseline, assessed up to 77 weeks | 
| Neuropsychological Assessments: Word Fluency Test | see above | at 6 months DBS compared to baseline and at end of the study compared to baseline, assessed up to 77 weeks | 
| Neuropsychological Assessments: Stroop-Test | see above | at 6 months DBS compared to baseline and at end of the study compared to baseline, assessed up to 77 weeks | 
| Neuropsychological Assessments: Test for Attentional Performance (TAP) | see above | at 6 months DBS compared to baseline and at end of the study compared to baseline, assessed up to 77 weeks | 
| Neuropsychological Assessments: Trail-Making Test (TMT) | see above | at 6 months DBS compared to baseline and at end of the study compared to baseline, assessed up to 77 weeks | 
| Neuropsychological Assessments: Verbal Memory and Learning Ability Test | see above | at 6 months DBS compared to baseline and at end of the study compared to baseline, assessed up to 77 weeks | 
| Neuropsychological Assessments: Hopper Visual Organization Test (VOT) | see above | at 6 months DBS compared to baseline and at end of the study compared to baseline, assessed up to 77 weeks | 
| Neuropsychological Assessments: Digit-Span and Block-Span Test | see above | at 6 months DBS compared to baseline and at end of the study compared to baseline, assessed up to 77 weeks | 
| Incidence of relapse into clinical depression after tapering down of DBS | The incidence of relapse into clinical depression after discontinuation of DBS will be assessed. | From discontinuation of DBS until the date of first documented relapse, assessed up to 12 weeks | 
| Pattern of metabolic activity as measured by FDG-PET at 1 week and 4 months after implantation compared to baseline | Change of metabolic activity in the prefrontal and orbitofrontal cortex as well as in subcortical regions (nucl. accumbens, amygdala) (exploratory endpoint) | at 1 week and 4 months after implantation compared to baseline | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Deep Brain Stimulation, Treatment-resistant depression, Medial forebrain bundle