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Closed-Loop Deep Brain Stimulation for Major Depression (PReSiDio)

Primary Purpose

Major Depressive Disorder

Status
Recruiting
Phase
Not Applicable
Locations
United States
Study Type
Interventional
Intervention
Stimulation-ON
Stimulation-OFF
Stimulation-ON Active Control
Sponsored by
Andrew Krystal
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Major Depressive Disorder focused on measuring Major Depressive Disorder, Depression, Treatment-resistance, Deep brain stimulation, Closed-loop, Biomarker, Responsive neurostimulation, Brain surgery

Eligibility Criteria

22 Years - 70 Years (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

  • Age 22-70
  • Meet the Diagnostic and Statistical Manual of Mental Disorders (DSM-V) diagnostic criteria for Major Depressive Disorder (MDD) without psychosis based on a Structured Clinical Interview for DSM-V (SCID) with current episode ≥ 2 years that is treatment- resistant (4 adequate trials (including ECT), 3 classes of medications, one augmentation strategy, psychotherapy) as measured by the antidepressant treatment history form (ATHF).
  • Failed electroconvulsive therapy (ECT) due to inability to achieve sustained response (2 failed attempts to discontinue ECT treatment) or discontinued due to intolerable side effects.
  • Has MADRS score of > 26 at both baseline and screening visit
  • The presence of variability on repeated administrations of MDD rating scales (minimum of 2-point variation on the HAMD-6 administered 3 times a day for 3 days), which is required for the identification of a neural biomarker.
  • If patient is on a regimen of psychotropic medication, no changes in this regimen should be made during the 4 weeks prior to entry into and the duration of the study.
  • Willing and able to undergo invasive brain recording/stimulation study
  • Willing and able to attend multiple research visits and perform at-home research protocol
  • Willing and able to provide informed consent
  • Ability to speak and read English

Exclusion Criteria:

  • Meets DSM-V criteria for a psychotic disorder, eating disorder, panic disorder, posttraumatic stress disorder, bipolar disorder, obsessive compulsive disorder, tic disorder, or another comorbid psychiatric disorder other than MDD or generalized anxiety disorder based on a SCID
  • Generalized anxiety disorder is the primary DSM-V disorder during the current MDD episode
  • Active suicidal ideation with intent and plan as defined by a score of 5 on the Columbia-Suicide Severity Rating Scale (C-SSRS)
  • History of suicide attempt requiring hospitalization in previous 2 years.
  • Meets criteria for alcohol or substance abuse or dependence (other than caffeine) in previous 6 months, determined by the SCID
  • Has a personality disorder based on the investigator's assessment that the investigator believes will adversely impact subject compliance or safety
  • Fibromyalgia or chronic fatigue syndrome
  • Current condition requiring chronic narcotic use
  • History of traumatic brain injury, another neurological disorder, or developmental delay
  • History of seizures
  • MRI (done within one year of the first visit) with significant abnormalities
  • Previous ablative intracranial surgery or previously implanted deep brain stimulation system or any previously implanted device treatment involving brain stimulation
  • Implantable hardware not compatible with MRI or with the study
  • Major medical co-morbidities increasing the risk of surgery including severe diabetes, major organ system failure, history of hemorrhagic stroke, need for chronic anticoagulation other than aspirin, active infection, intracranial space occupying lesion, increased intracranial pressure, cardiovascular accident within the last month, aneurysm/abnormality, retinal detachment, unstable cardiovascular disease (recent myocardial infarction, severe ischemia, severe or uncontrolled hypertension), immunocompromised state, or malignancy with < 5 years life expectancy
  • Inability to stop Coumadin or platelet anti-aggregation therapy for surgery and after surgery. - Patients taking these medications will need to discuss the need/risk of continuing these medications with their physicians and the PI or study personnel may contact the treating physician(s) to discuss the risks of anticoagulation/antiaggregation therapy discontinuation
  • Coagulopathy. Patients will be excluded unless assessed and cleared by hematology
  • Allergies or known hypersensitivity to materials in the NeuroPace RNS® System (i.e. titanium, polyurethane, silicone, polyetherimide, stainless steel)
  • Subject lives alone without possibility of caregiver support post-hospital stay
  • Inability to comply with study follow-up visits
  • Women who are pregnant, plan to become pregnant, or breast feeding
  • Inability to speak and/or read English
  • Inability to give consent
  • Significant cognitive impairment or dementia (MoCA < 25)
  • Likely to require ECT during the course of the study

Sites / Locations

  • University of California, San FranciscoRecruiting

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm Type

Experimental

Sham Comparator

Active Comparator

Arm Label

Arm 1: Intervention (stimulation ON)

Arm 2: Sham Control (stimulation OFF)

Arm 3: Active Control (stimulation ON triggered by sham biomarker)

Arm Description

This is a crossover trial. Each patient will receive 6 wks of stimulation ON (arm 1), stimulation OFF (arm 2), and Stimulation ON Active Control (sham biomarker) (arm 3) in random order. After 6 months of intervening therapy, this 3-period crossover study will be repeated.

This is a crossover trial. Each patient will receive 6 wks of stimulation ON (arm 1), stimulation OFF (arm 2), and Stimulation ON Active Control (sham biomarker) (arm 3) in random order. After 6 months of intervening therapy, this 3-period crossover study will be repeated.

This is a crossover trial. Each patient will receive 6 wks of stimulation ON (arm 1), stimulation OFF (arm 2), and stimulation ON Active Control (sham biomarker) (arm 3) in random order. After 6 months of intervening therapy, this 3-period crossover study will be repeated.

Outcomes

Primary Outcome Measures

change in MADRS score
Effect size of active compared to sham stimulation (mean difference in Montgomery Asberg Depression Rating Scale (MADRS) score before and after the sham and treatment periods). Higher MADRS score indicates more severe depression; the overall score ranges from 0 to 60.

Secondary Outcome Measures

change in Montgomery Asberg Depression Rating Scale (MADRS) score after 1 year
Effect size of active compared to sham stimulation (mean difference in Montgomery Asberg Depression Rating Scale (MADRS) score before and after the sham and treatment periods at the end of Stage 3. Higher MADRS score indicates more severe depression; the overall score ranges from 0 to 60.
difference in Hamilton Depression Rating Scale (HAMD-17) score
Mean difference in Hamilton Depression Rating Scale (HAMD-17) score across the two 6-week cross-over periods. The score for Hamilton Depression Rating Scale ranges from 0-50, with a higher score indicating more severe depression.
difference in Hamilton Depression Rating Scale (HAMD-17) score after 1 year
Mean difference in Hamilton Depression Rating Scale (HAMD-17) score across the two 6-week cross-over periods at 1 year. The score for Hamilton Depression Rating Scale ranges from 0-50, with a higher score indicating more severe depression.
difference in the Inventory of Depressive Symptomatology Self-Report (IDS-SR) score
Mean difference in Inventory of Depressive Symptomatology Self-Report (IDS-SR) score across the two 6-week cross-over periods. The scores range from 0 to 27, with higher scores indicating more depressive symptoms.
difference in Inventory of Depressive Symptomatology Self-Report (IDS-SR) score after 1 year
Mean difference in Inventory of Depressive Symptomatology Self-Report (IDS-SR) score across the two 6-week cross-over periods at the of Stage 3. The scores range from 0 to 27, with higher scores indicating more depressive symptoms.

Full Information

First Posted
June 26, 2019
Last Updated
April 27, 2023
Sponsor
Andrew Krystal
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1. Study Identification

Unique Protocol Identification Number
NCT04004169
Brief Title
Closed-Loop Deep Brain Stimulation for Major Depression
Acronym
PReSiDio
Official Title
Closed-Loop Deep Brain Stimulation for Treatment-Resistant Depression
Study Type
Interventional

2. Study Status

Record Verification Date
April 2023
Overall Recruitment Status
Recruiting
Study Start Date
July 18, 2019 (Actual)
Primary Completion Date
June 28, 2030 (Anticipated)
Study Completion Date
June 28, 2035 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor-Investigator
Name of the Sponsor
Andrew Krystal

4. Oversight

Studies a U.S. FDA-regulated Drug Product
No
Studies a U.S. FDA-regulated Device Product
Yes
Data Monitoring Committee
Yes

5. Study Description

Brief Summary
Neurons are specialized types of cells that are responsible for carrying out the functions of the brain. Neurons communicate with electrical signals. In diseases such as major depression this electrical communication can go awry. One way to change brain function is using electrical stimulation to help alter the communication between groups of neurons in the brain. The purpose of this study is to test a personalized approach to brain stimulation as an intervention for depression. The study researchers will use a surgically implanted device to measure each individual's brain activity related to his/her depression. The researchers will then use small electrical impulses to alter that brain activity and measure whether these changes help reduce depression symptoms. This study is intended for patients with major depression whose symptoms have not been adequately treated with currently available therapies. The device used in this study is called the NeuroPace Responsive Neurostimulation (RNS) System. It is currently FDA approved to treat patients with epilepsy. The study will test whether personalized responsive neurostimulation can safely and effectively treat depression.
Detailed Description
This is a single-center 3-stage feasibility study of personalized closed-loop stimulation for treatment resistant Major Depressive Disorder. Depending on participant's results at each stage, he/she might not be eligible to proceed to all 3 stages. Stage 1 of the study will involve surgically implanting small, thin electrodes in brain regions that regulate depression in order to identify personalized treatment sites. The researchers will test stimulation in the different brain regions and their effect on depression symptoms. The electrodes will be surgically removed at the end of Stage 1. Stage 2 will involve a second brain surgery to implant the NeuroPace RNS® System. Researchers will use information from Stage 1 to decide where to implant the electrodes of the RNS System. Over the next ~4-12 months, participants will have regular study visits in the clinic where the researchers will determine a personalized brain activity pattern that correlates with depression symptoms and can be paired with stimulation to improve depression symptoms. Stage 3 will be 12 months long and will involve turning ON and OFF the intervention to test its effectiveness. Over the course of a year, the participant will have two 6-week periods with no stimulation and will receive the intervention for the remainder of the time. At the end of this stage the participant can choose to continue with long-term follow-up or have the RNS System surgically removed.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Major Depressive Disorder
Keywords
Major Depressive Disorder, Depression, Treatment-resistance, Deep brain stimulation, Closed-loop, Biomarker, Responsive neurostimulation, Brain surgery

7. Study Design

Primary Purpose
Treatment
Study Phase
Not Applicable
Interventional Study Model
Crossover Assignment
Masking
ParticipantCare ProviderOutcomes Assessor
Allocation
Randomized
Enrollment
12 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title
Arm 1: Intervention (stimulation ON)
Arm Type
Experimental
Arm Description
This is a crossover trial. Each patient will receive 6 wks of stimulation ON (arm 1), stimulation OFF (arm 2), and Stimulation ON Active Control (sham biomarker) (arm 3) in random order. After 6 months of intervening therapy, this 3-period crossover study will be repeated.
Arm Title
Arm 2: Sham Control (stimulation OFF)
Arm Type
Sham Comparator
Arm Description
This is a crossover trial. Each patient will receive 6 wks of stimulation ON (arm 1), stimulation OFF (arm 2), and Stimulation ON Active Control (sham biomarker) (arm 3) in random order. After 6 months of intervening therapy, this 3-period crossover study will be repeated.
Arm Title
Arm 3: Active Control (stimulation ON triggered by sham biomarker)
Arm Type
Active Comparator
Arm Description
This is a crossover trial. Each patient will receive 6 wks of stimulation ON (arm 1), stimulation OFF (arm 2), and stimulation ON Active Control (sham biomarker) (arm 3) in random order. After 6 months of intervening therapy, this 3-period crossover study will be repeated.
Intervention Type
Device
Intervention Name(s)
Stimulation-ON
Intervention Description
Active neurostimulation from the NeuroPace RNS® System triggered by a biomarker
Intervention Type
Device
Intervention Name(s)
Stimulation-OFF
Intervention Description
No neurostimulation from the NeuroPace RNS® System
Intervention Type
Device
Intervention Name(s)
Stimulation-ON Active Control
Intervention Description
Active neurostimulation from the NeuroPace RNS® System triggered by a sham biomarker
Primary Outcome Measure Information:
Title
change in MADRS score
Description
Effect size of active compared to sham stimulation (mean difference in Montgomery Asberg Depression Rating Scale (MADRS) score before and after the sham and treatment periods). Higher MADRS score indicates more severe depression; the overall score ranges from 0 to 60.
Time Frame
administered at baseline and every 2 weeks for the first 18 weeks of stage 3
Secondary Outcome Measure Information:
Title
change in Montgomery Asberg Depression Rating Scale (MADRS) score after 1 year
Description
Effect size of active compared to sham stimulation (mean difference in Montgomery Asberg Depression Rating Scale (MADRS) score before and after the sham and treatment periods at the end of Stage 3. Higher MADRS score indicates more severe depression; the overall score ranges from 0 to 60.
Time Frame
administered at Weeks 30 and every 2 weeks for the last 18 weeks of Stage 3
Title
difference in Hamilton Depression Rating Scale (HAMD-17) score
Description
Mean difference in Hamilton Depression Rating Scale (HAMD-17) score across the two 6-week cross-over periods. The score for Hamilton Depression Rating Scale ranges from 0-50, with a higher score indicating more severe depression.
Time Frame
administered at baseline and every 2 weeks for the first 18 weeks of stage 3
Title
difference in Hamilton Depression Rating Scale (HAMD-17) score after 1 year
Description
Mean difference in Hamilton Depression Rating Scale (HAMD-17) score across the two 6-week cross-over periods at 1 year. The score for Hamilton Depression Rating Scale ranges from 0-50, with a higher score indicating more severe depression.
Time Frame
administered at Weeks 30 and every 2 weeks for the last 18 weeks of Stage 3
Title
difference in the Inventory of Depressive Symptomatology Self-Report (IDS-SR) score
Description
Mean difference in Inventory of Depressive Symptomatology Self-Report (IDS-SR) score across the two 6-week cross-over periods. The scores range from 0 to 27, with higher scores indicating more depressive symptoms.
Time Frame
administered at baseline and every 2 weeks for the first 18 weeks of stage 3
Title
difference in Inventory of Depressive Symptomatology Self-Report (IDS-SR) score after 1 year
Description
Mean difference in Inventory of Depressive Symptomatology Self-Report (IDS-SR) score across the two 6-week cross-over periods at the of Stage 3. The scores range from 0 to 27, with higher scores indicating more depressive symptoms.
Time Frame
administered at Weeks 30 and every 2 weeks for the last 18 weeks of Stage 3
Other Pre-specified Outcome Measures:
Title
Stimulation site identification
Description
Over 50% of patients move from Stage 1 to Stage 2 (stimulation site that acutely improved mood identified)
Time Frame
Final study visit of Stage 1 (roughly 3-6 months after initial enrollment)
Title
Biomarker identification in Stage 1
Description
The number of patients in whom we can identify a neural biomarker that accounts for a significant amount of variance in depression symptom severity
Time Frame
Final study visit of Stage 1 (roughly 3-6 months after initial enrollment)
Title
Number of patients who had viable biomarker(s) identified in Stage 2
Description
The number of patients in whom we can identify a neural biomarker utilizing the RNS system that accounts for a significant amount of variance in depression symptom severity
Time Frame
Final study visit of Stage 2 (up to 1 year duration)
Title
The number of patients in whom we can identify a neural biomarker utilizing the RNS system that accounts for a significant amount of variance in depression symptom severity
Description
The number of patients in whom we can find a personalized biomarker of depression in terms of accounting for significant variance in depression
Time Frame
Assessed at the final study visit of Stage 3 (1 year duration)
Title
The number and type of serious adverse events for patients that occur in closed-loop deep brain stimulation with the device
Description
The number and type of serious adverse events that occur in comparison to comparable open-loop deep brain stimulation trials
Time Frame
Safety will be monitored continuously throughout the ~2 years of trial enrollment
Title
Relationship of biomarkers identified in Stage 2 and Stage 1
Description
The number of subjects for whom the biomarker identified with Stage 1 data is able to be replicated in Stage 2 in terms of a measure obtained from the same recording site and in a comparable frequency range accounting for a significant amount of variance in depression severity.
Time Frame
Assessed at the end of Stage 2 (up to 1.5 year duration)
Title
Achievement of Long-Term Symptom Control
Description
Number of subjects who achieve long-term symptom control with treatment in terms of being in remission at the end of the 3 months of active therapy between the two randomized trials in Stage 3.
Time Frame
Assessed at end of Stage 3 (up to 1 year duration)
Title
Non-inferiority of closed loop vs open-loop intermittent stimulation therapy and sham stimulation
Description
Number of subjects for whom active closed-loop therapy is associated with equal or lower MADRS scores compared with: 1) active intermittent stimulation driven by a sham biomarker control and 2) sham stimulation control.
Time Frame
administered at baseline and every 2 weeks for the first 18 weeks of stage 3

10. Eligibility

Sex
All
Minimum Age & Unit of Time
22 Years
Maximum Age & Unit of Time
70 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: Age 22-70 Meet the Diagnostic and Statistical Manual of Mental Disorders (DSM-V) diagnostic criteria for Major Depressive Disorder (MDD) without psychosis based on a Structured Clinical Interview for DSM-V (SCID) with current episode ≥ 2 years that is treatment- resistant (4 adequate trials (including ECT), 3 classes of medications, one augmentation strategy, psychotherapy) as measured by the antidepressant treatment history form (ATHF). Failed electroconvulsive therapy (ECT) due to inability to achieve sustained response (2 failed attempts to discontinue ECT treatment) or discontinued due to intolerable side effects. Has MADRS score of > 26 at both baseline and screening visit The presence of variability on repeated administrations of MDD rating scales (minimum of 2-point variation on the HAMD-6 administered 3 times a day for 3 days), which is required for the identification of a neural biomarker. If patient is on a regimen of psychotropic medication, no changes in this regimen should be made during the 4 weeks prior to entry into and the duration of the study. Willing and able to undergo invasive brain recording/stimulation study Willing and able to attend multiple research visits and perform at-home research protocol Willing and able to provide informed consent Ability to speak and read English Exclusion Criteria: Meets DSM-V criteria for a psychotic disorder, eating disorder, panic disorder, posttraumatic stress disorder, bipolar disorder, obsessive compulsive disorder, tic disorder, or another comorbid psychiatric disorder other than MDD or generalized anxiety disorder based on a SCID Generalized anxiety disorder is the primary DSM-V disorder during the current MDD episode Active suicidal ideation with intent and plan as defined by a score of 5 on the Columbia-Suicide Severity Rating Scale (C-SSRS) History of suicide attempt requiring hospitalization in previous 2 years. Meets criteria for alcohol or substance abuse or dependence (other than caffeine) in previous 6 months, determined by the SCID Has a personality disorder based on the investigator's assessment that the investigator believes will adversely impact subject compliance or safety Fibromyalgia or chronic fatigue syndrome Current condition requiring chronic narcotic use History of traumatic brain injury, another neurological disorder, or developmental delay History of seizures MRI (done within one year of the first visit) with significant abnormalities Previous ablative intracranial surgery or previously implanted deep brain stimulation system or any previously implanted device treatment involving brain stimulation Implantable hardware not compatible with MRI or with the study Major medical co-morbidities increasing the risk of surgery including severe diabetes, major organ system failure, history of hemorrhagic stroke, need for chronic anticoagulation other than aspirin, active infection, intracranial space occupying lesion, increased intracranial pressure, cardiovascular accident within the last month, aneurysm/abnormality, retinal detachment, unstable cardiovascular disease (recent myocardial infarction, severe ischemia, severe or uncontrolled hypertension), immunocompromised state, or malignancy with < 5 years life expectancy Inability to stop Coumadin or platelet anti-aggregation therapy for surgery and after surgery. - Patients taking these medications will need to discuss the need/risk of continuing these medications with their physicians and the PI or study personnel may contact the treating physician(s) to discuss the risks of anticoagulation/antiaggregation therapy discontinuation Coagulopathy. Patients will be excluded unless assessed and cleared by hematology Allergies or known hypersensitivity to materials in the NeuroPace RNS® System (i.e. titanium, polyurethane, silicone, polyetherimide, stainless steel) Subject lives alone without possibility of caregiver support post-hospital stay Inability to comply with study follow-up visits Women who are pregnant, plan to become pregnant, or breast feeding Inability to speak and/or read English Inability to give consent Significant cognitive impairment or dementia (MoCA < 25) Likely to require ECT during the course of the study
Central Contact Person:
First Name & Middle Initial & Last Name or Official Title & Degree
Katherine Scangos, MD, PhD
Phone
415-476-7439
Email
trdepression@ucsf.edu
First Name & Middle Initial & Last Name or Official Title & Degree
Rebecca Martinez, MS
Phone
415-476-7439
Email
rebecca.martinez@ucsf.edu
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Andrew Krystal, MD, MS
Organizational Affiliation
University of California, San Francisco
Official's Role
Principal Investigator
Facility Information:
Facility Name
University of California, San Francisco
City
San Francisco
State/Province
California
ZIP/Postal Code
94143
Country
United States
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Katherine Scangos, MD, PhD
Phone
415-476-7439
Email
trdepression@ucsf.edu
First Name & Middle Initial & Last Name & Degree
Rebecca Martinez, MS
Phone
415- 476-7439
Email
rebecca.martinez@ucsf.edu
First Name & Middle Initial & Last Name & Degree
Katherine Scangos, MD, PhD
First Name & Middle Initial & Last Name & Degree
Andrew Krystal, MD, MS
First Name & Middle Initial & Last Name & Degree
Edward Chang, MD
First Name & Middle Initial & Last Name & Degree
Philip Starr, MD

12. IPD Sharing Statement

Plan to Share IPD
No

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Closed-Loop Deep Brain Stimulation for Major Depression

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