A Prospective, Multi-center, Randomized Controlled Blinded Trial Demonstrating the Safety and Effectiveness of VNS Therapy® System as Adjunctive Therapy Versus a No Stimulation Control in Subjects With Treatment-Resistant Depression

Study Overview
=================
Brief Summary
-----------------
Objectives of this study are to determine whether active VNS Therapy treatment is superior to a no stimulation control in producing a reduction in baseline depressive symptom severity, based on multiple depression scale assessment tools at 12 months from randomization.

Detailed Description
-----------------
A prospective, multi-center, randomized, controlled, blinded trial of subjects implanted with VNS Therapy. Active treatment and no stimulation control are randomized, at least two weeks after implantation and observed for 12-months. After completing the 12 month endpoint in the RCT portion of the study, all RECOVER subjects will transition into the prospective, open-label, longitudinal portion of the study. Subjects in the control arm of RECOVER will be activated after completing the 12 month endpoint. After completion of enrollment in the RCT portion or meeting of interim success criterion (whichever comes first), up to 5,800 new subjects may enroll directly into the open-label,prospective, longitudinal study. These subjects will participate in the study for approximately 5 years. The study has been designed in accordance with The Centers for Medicare and Medicaid Services coverage with evidence development (CED) decision entitled Decision Memo for Vagus Nerve Stimulation (VNS) for Treatment Resistant Depression (TRD) (CAG-00313R2).

Official Title
-----------------
A Prospective, Multi-center, Randomized Controlled Blinded Trial Demonstrating the Safety and Effectiveness of VNS Therapy® System as Adjunctive Therapy Versus a No Stimulation Control in Subjects With Treatment-Resistant Depression

Conditions
-----------------
Treatment Resistant Depression

Intervention / Treatment
-----------------
* Device: Vagus Nerve Stimulation (VNS)


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: The patient must be in a major depressive disorder (MDD) episode for ≥ two years or have had at least four episodes of MDD, including the current episode. The patient's depressive illness meets a minimum criterion of four prior failed treatments of adequate dose and duration as measured by a tool designed for this purpose. The patient is experiencing a major depressive episode (MDE) as measured by a guideline recommended depression scale assessment tool on two visits, within a 45-day span prior to implantation of the VNS device. Patients must maintain a stable medication regimen for at least four weeks before device implantation. Exclusion Criteria: Current or lifetime history of psychotic features in any MDE; Current or lifetime history of schizophrenia or schizoaffective disorder; Current or lifetime history of any other psychotic disorder; Current or lifetime history of rapid cycling bipolar disorder; Current secondary diagnosis of delirium, dementia, amnesia, or other cognitive disorder; Current suicidal intent; or Treatment with another investigational device or investigational drugs.

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: 1:1 randomization of active stimulation vs. no stimulation for 12 months post randomization.
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Active<br>Group will have VNS activated 2 weeks post implant. | Device: Vagus Nerve Stimulation (VNS)<br>* VNS is an implantable device that delivers stimulation to the vagal nerve.<br>* Other names: VNS;|
| Sham Comparator: Control<br>Group will be implanted with VNS but device is not activated for the first 12 months. After 12 months, this group can receive stimulation. | Device: Vagus Nerve Stimulation (VNS)<br>* VNS is an implantable device that delivers stimulation to the vagal nerve.<br>* Other names: VNS;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Montgomery Åsberg Depression Rating Scale (MADRS) Rate of Response | The rate of response defined as person months of response/total months of study participation where response is at least a 50% reduction from baseline in MADRS total score. Subjects discontinuing the study before the endpoint assessment will be considered as non-responders for each successive month after discontinuance. | 12 months post randomization | 
| Montgomery Åsberg Depression Rating Scale (MADRS) Time to First response | Time from randomization to the first observed MADRS response. | Baseline up to 12 Months | 
| Montgomery Åsberg Depression Rating Scale (MADRS) Time to First Remission | Time from randomization to the first observed MADRS remission. | Baseline up to 12 Months | 
| Montgomery Åsberg Depression Rating Scale (MADRS) Duration of Response | Duration of MADRS response, defined as the number of consecutive months from first observed MADRS response to the first assessment of MADRS response relapse. | Baseline up to 12 Months | 
| Montgomery Åsberg Depression Rating Scale (MADRS) Rate of Remission | The rate of remission is defined as total number of months in remission divided by total months of expected study participation. Subjects discontinuing the study before the endpoint assessment will be considered as non-in-remission for each successive month after discontinuance | Baseline up to 12 Months | 
| Montgomery Åsberg Depression Rating Scale (MADRS) Maximum duration of Response | Maximum duration of MADRS response, defined as the maximum number of consecutive months in response (only for subjects experiencing MADRS response). | Baseline up to 12 Months | 
| Montgomery Åsberg Depression Rating Scale (MADRS) Duration of Remission | Duration of MADRS remission, defined as the number of consecutive months from first observed MADRS remission to the first assessment of MADRS remission relapse (defined score > 20). | Baseline up to 12 Months | 
| Montgomery Åsberg Depression Rating Scale (MADRS) Maximum duration of Remission | Maximum duration of MADRS remission, defined as the maximum number of consecutive months in remission (only for subjects experiencing MADRS remission). | Baseline up to 12 Months | 
| Assess all Adverse Events | All adverse events, with a focus on device or procedure-related serious adverse events. | Implant to 12 Months | 
| WHO Disability Assessment Schedule (WHODAS) Changes in scores over time |  | Baseline to 12 Months | 
| Health Outcome Scale (EQ-5D-L) Changes in scores over time |  | Baseline to 12 Months | 
| Clinical Global Impressions Scale - Improvement (CGI-I) Response | A CGI-I score ≤ 2 at 12 months from randomization. Subjects discontinuing the study before the 12 months assessment will be considered as not in response for each successive month after discontinuance. | 12 months post randomization | 
| Sheehan Suicidality Tracking Scale (S-STS) Changes in Suicidality | Suicide attempts as measured by items #10 & #12 in S-STS scale | Implant to 12 Months | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
VNS, Depression, TRD