Efficacy Study of Deep Brain Stimulation in Patients With Treatment Resistant Major Depression (FORESEE III)

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

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.

Study Overview

• Status: Recruiting
• Conditions: Treatment-resistant Depression
• Intervention / Treatment: Device: Vercise GEVIA deep brain stimulation (DBS) system

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Anticipated): 47
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Thomas E Schlaepfer, Prof. Dr.; Phone Number: 68820 +49761270; Email: thomas.schlaepfer@uniklinik-freiburg.de
• Study Contact Backup: Name: Volker A Coenen, Prof. Dr.; Phone Number: 50630 +49761270; Email: volker.coenen@uniklinik-freiburg.de

Study Locations

• France
  • Grenoble, France, 38043
    • Recruiting
    • Université Grenoble Alpes
    • Contact: Mircea Polosan, Prof; Phone Number: 04 76 76 54 14; Email: MPolosan@chu-grenoble.fr
    • Contact: Stephan Chabardès, Prof; Phone Number: 0476767759; Email: SChabardes@chu-grenoble.fr
    • Principal Investigator: Mircea Polosan, Prof
• Germany
  • Baden-Württemberg
    • Freiburg, Baden-Württemberg, Germany, 79106
      • Recruiting
      • University Hospital Freiburg

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 20 years to 75 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

1. Major depression (MD), severe, unipolar, or bipolar in an acute depression episode.
2. German mother tongue or fluent.
3. Male or female patients ≥20 and ≤75 years.
4. Hamilton Depression Rating Scale (HDRS-28) score of >21.
5. Global Assessment of Function (GAF) score of <45.
6. At least 4 episodes of depression or one chronic episode >2 years.

7. Failure to respond to

   1. adequate trials of primary antidepressants from at least 3 different classes (>5 weeks at the maximum recommended or tolerated dose) and
   2. 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
   3. an adequate trial of electroconvulsive therapy (ECT) (>6 treatments) and an adequate trial of individual psychotherapy (>20 sessions with an experienced psychotherapist).
8. Able to give written informed consent.
9. Compliance to participate in the study.
10. Drug free or on stable drug regimen at least 6 weeks before study entry.

Exclusion Criteria:

1. Current or past non-affective psychotic disorder.
2. Any current clinically significant neurological disorder or medical illness affecting brain function, other than motor tics or Gilles de la Tourette syndrome.
3. Any clinically significant abnormality on preoperative magnetic resonance imaging (MRI), any contraindications to perform a planned MRI to visualize the slMFB.
4. 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).
5. Current or unstably remitted substance abuse (aside from nicotine).
6. Pregnancy, women of childbearing age not using effective contraception and breast feeding women.
7. History of severe personality disorder.
8. Acute suicidal ideation.
9. Patients with advanced stage cardiovascular disease.
10. Patients under immunosuppressive or chemo therapy because of malignant disease.
11. Patients who had previous intracranial surgery.
12. Patients who are currently under DBS therapy or have implanted any kind of stimulator already.
13. Patients with aneurysm clips.
14. Patients with cochlear implants.
15. Patients with planned diathermy.
16. Persons who are in a relationship of dependence/employment with the sponsor or the investigator.
17. 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).

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Double

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Group A: DBS onset in week 1; 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; DBS to the superolateral branch of the Medial Forebrain Bundle (slMFB)
Sham Comparator: Group B: DBS off, followed by DBS onset in week 17; 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; DBS to the superolateral branch of the Medial Forebrain Bundle (slMFB)

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: University Hospital Freiburg
• Collaborators: Boston Scientific Corporation
• Investigators: Principal Investigator: Thomas E Schlaepfer, Prof. Dr., University Hospital Freiburg

Study record dates

Study Major Dates

• Study Start (Actual): September 3, 2018
• Primary Completion (Anticipated): June 2, 2025
• Study Completion (Anticipated): June 2, 2025

Study Registration Dates

• First Submitted: August 22, 2018
• First Submitted That Met QC Criteria: August 30, 2018
• First Posted (Actual): August 31, 2018

Study Record Updates

• Last Update Posted (Actual): November 3, 2022
• Last Update Submitted That Met QC Criteria: November 2, 2022
• Last Verified: November 1, 2022

More Information

Terms related to this study

• Keywords: Deep Brain Stimulation; Treatment-resistant depression; Medial forebrain bundle
• Additional Relevant MeSH Terms: Behavioral Symptoms; Mental Disorders; Mood Disorders; Depression; Depressive Disorder; Depressive Disorder, Treatment-Resistant
• Other Study ID Numbers: P000767; DRKS00014947 (Registry Identifier: German Clinical Trials Register); CIV-17-07-020746 (Other Identifier: Eudamed Number)

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No