RECOVER: 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

Sponsor

LivaNova (Industry)

Overall Status

Recruiting

CT.gov ID

NCT03887715

Collaborator

(none)

6,800

Enrollment

Locations

Arms

135.2

Anticipated Duration (Months)

77.3

Patients Per Site

0.6

Patients Per Site Per Month

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Treatment Resistant Depression	Device: Vagus Nerve Stimulation (VNS)	N/A

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).

Study Design

Study Type:

Interventional

Anticipated Enrollment :

6800 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Intervention Model Description:

1:1 randomization of active stimulation vs. no stimulation for 12 months post randomization.1:1 randomization of active stimulation vs. no stimulation for 12 months post randomization.

Masking:

Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)

Masking Description:

Central Rater and sponsor are blinded in the RCT phase. Sites will need to have an unblinded programmer who is only programming the device and not collecting outcomes data.

Primary Purpose:

Treatment

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

Actual Study Start Date :

Sep 26, 2019

Anticipated Primary Completion Date :

Aug 31, 2022

Anticipated Study Completion Date :

Dec 31, 2030

Arms and Interventions

Arm	Intervention/Treatment
Active Comparator: Active Group will have VNS activated 2 weeks post implant.	Device: Vagus Nerve Stimulation (VNS) VNS is an implantable device that delivers stimulation to the vagal nerve. Other Names: VNS
Sham Comparator: Control 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) VNS is an implantable device that delivers stimulation to the vagal nerve. Other Names: VNS

Arm

Intervention/Treatment

Active Comparator: Active

Group will have VNS activated 2 weeks post implant.

Device: Vagus Nerve Stimulation (VNS)

VNS is an implantable device that delivers stimulation to the vagal nerve.

Other Names:

VNS

Sham Comparator: Control

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)

VNS is an implantable device that delivers stimulation to the vagal nerve.

Other Names:

VNS

Outcome Measures

Primary Outcome Measures

Montgomery Åsberg Depression Rating Scale (MADRS) Rate of Response [12 months post randomization]
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.
Montgomery Åsberg Depression Rating Scale (MADRS) Time to First response [Baseline up to 12 Months]
Time from randomization to the first observed MADRS response.
Montgomery Åsberg Depression Rating Scale (MADRS) Time to First Remission [Baseline up to 12 Months]
Time from randomization to the first observed MADRS remission.
Montgomery Åsberg Depression Rating Scale (MADRS) Duration of Response [Baseline up to 12 Months]
Duration of MADRS response, defined as the number of consecutive months from first observed MADRS response to the first assessment of MADRS response relapse.
Montgomery Åsberg Depression Rating Scale (MADRS) Rate of Remission [Baseline up to 12 Months]
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
Montgomery Åsberg Depression Rating Scale (MADRS) Maximum duration of Response [Baseline up to 12 Months]
Maximum duration of MADRS response, defined as the maximum number of consecutive months in response (only for subjects experiencing MADRS response).
Montgomery Åsberg Depression Rating Scale (MADRS) Duration of Remission [Baseline up to 12 Months]
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).
Montgomery Åsberg Depression Rating Scale (MADRS) Maximum duration of Remission [Baseline up to 12 Months]
Maximum duration of MADRS remission, defined as the maximum number of consecutive months in remission (only for subjects experiencing MADRS remission).
Assess all Adverse Events [Implant to 12 Months]
All adverse events, with a focus on device or procedure-related serious adverse events.
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 [12 months post randomization]
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.
Sheehan Suicidality Tracking Scale (S-STS) Changes in Suicidality [Implant to 12 Months]
Suicide attempts as measured by items #10 & #12 in S-STS scale

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	University of Alabama at Birmingham	Birmingham	Alabama	United States	35294
2	Access Multi Specialty Medical Clinic, Inc	Burlingame	California	United States	94010
3	CMB Clinical Trials	Colton	California	United States	92324
4	ATP Clinical Research, Inc.	Costa Mesa	California	United States	92626
5	Kaizen Brain Center	La Jolla	California	United States	92037
6	Keck Hospital of USC	Los Angeles	California	United States	90033
7	University of California San Diego	San Diego	California	United States	92103
8	SF-CARE, Inc.	San Rafael	California	United States	94901
9	Syrentis Clinical Research	Santa Ana	California	United States	92705
10	Sunrise Research Institute	Boca Raton	Florida	United States	33325
11	Mindful Behavioral Health	Boca Raton	Florida	United States	33431
12	Medycal Research, Inc	Brooksville	Florida	United States	34609
13	Galiz Research LLC	Hialeah	Florida	United States	33016
14	Florida Behavioral Psych	Largo	Florida	United States	33770
15	Segal Trials Corporate	Lauderhill	Florida	United States	33319
16	Ocean Blue Medical Research Center	Miami Springs	Florida	United States	33166
17	Central Miami Medical Institute, LLC	Miami	Florida	United States	33125
18	Clintex Research Group, Inc.	Miami	Florida	United States	33135
19	Research Center Of Florida, Inc	Miami	Florida	United States	33135
20	APG Research, LLC	Orlando	Florida	United States	32803
21	Nova Psychiatry Inc.	Orlando	Florida	United States	32803
22	Florida Center for TMS	Orlando	Florida	United States	32806
23	Millenia Psychiatry & Research, Inc	Orlando	Florida	United States	32819
24	Quantum Laboratories Inc.	Pompano Beach	Florida	United States	33064
25	Advanced Mental Health Care Inc.	Royal Palm Beach	Florida	United States	33411
26	Florida Center for TMS	Saint Augustine	Florida	United States	94901
27	Stedman Clinical Trials	Tampa	Florida	United States	33613
28	Psychiatric Specialty Center	West Palm Beach	Florida	United States	33409
29	Emory University	Atlanta	Georgia	United States	30322
30	Medical College of Georgia, Augusta University	Augusta	Georgia	United States	30912
31	PACT Atlanta LLC	Decatur	Georgia	United States	30030
32	IACT Health	Grayson	Georgia	United States	30017
33	Psych Atlanta	Marietta	Georgia	United States	30060
34	Pearl Health Clinic	Ammon	Idaho	United States	83406
35	Joliet Center For Clinical Research	Joliet	Illinois	United States	60435
36	AMR- Baber Research, Inc.	Naperville	Illinois	United States	60563
37	Psychiatric Medicine Associates, LLC	Skokie	Illinois	United States	60076
38	Southern Illinois University School of Medicine	Springfield	Illinois	United States	62794
39	Neuroscience Research Institute	Winfield	Illinois	United States	60910
40	Advanced Research Institute, Inc.	Indianapolis	Indiana	United States	56268
41	Beacon Medical Group Behavioral Health	South Bend	Indiana	United States	46601
42	University Of Kansas Cancer Center	Kansas City	Kansas	United States	66160
43	Sheppard Pratt Health System, Inc.	Baltimore	Maryland	United States	21204
44	Clinical Insights	Glen Burnie	Maryland	United States	21061
45	Massachusetts General Hospital	Boston	Massachusetts	United States	02114
46	Michigan Clinical Research Institute PC	Ann Arbor	Michigan	United States	48105
47	University of Minnesota	Minneapolis	Minnesota	United States	55416
48	Precise Research Centers	Flowood	Mississippi	United States	39232
49	Andrew Bishop, MD	Jackson	Mississippi	United States	39216
50	University of Missouri	Columbia	Missouri	United States	65212
51	Psychiatric Care and Research	O'Fallon	Missouri	United States	633668
52	Barnes-Jewish Hospital	Saint Louis	Missouri	United States	63110
53	PsychCare Consultants Research	Saint Louis	Missouri	United States	63128
54	Alivation Research, LLC	Lincoln	Nebraska	United States	68526
55	University of New Mexico - Psychiatric Center	Albuquerque	New Mexico	United States	87102
56	Dent Neurological Institute	Amherst	New York	United States	14226
57	Erie County Medical Center/State University of New York (SUNY) at Buffalo Affiliate	Buffalo	New York	United States	14215
58	Trinity Medical	Lewiston	New York	United States	14092
59	Hapworth Research Inc.	New York	New York	United States	10019
60	Icahn School of Medicine at Mount Sinai	New York	New York	United States	10029
61	Richmond Behavioral Associates	Staten Island	New York	United States	10312
62	Stony Brook University Hospital	Stony Brook	New York	United States	11794
63	State University Of New York Upstate Medical University	Syracuse	New York	United States	13210
64	Wake Forest University Health Science	Winston-Salem	North Carolina	United States	27103
65	The Ohio State University	Columbus	Ohio	United States	43210
66	Signature Research Associates, Inc.	Fairlawn	Ohio	United States	44333
67	Charak Center for Health and Wellness	Garfield Heights	Ohio	United States	44125
68	NPC Research	Oklahoma City	Oklahoma	United States	73109-3834
69	Rivus Wellness & Research Institute	Oklahoma City	Oklahoma	United States	73112
70	University of Oklahoma School of Community Medicine	Tulsa	Oklahoma	United States	74135
71	Scranton Medical Institutes	Moosic	Pennsylvania	United States	18507
72	University of Pennsylvania	Philadelphia	Pennsylvania	United States	19104
73	Medical University of South Carolina	Charleston	South Carolina	United States	29425
74	Neuroscience and TMS Treatment Center	Brentwood	Tennessee	United States	37027
75	UT Health Austin, Mulva Clinic for the Neurosciences	Austin	Texas	United States	78712
76	BioBehavioral Research of Austin	Austin	Texas	United States	78759
77	Texas Tech University Health Science Center	El Paso	Texas	United States	79905
78	The University Of Texas Medical School At Houston - UT Center Of Excellence On Mood Disorders	Houston	Texas	United States	77054
79	Houston Clinical Trials	Houston	Texas	United States	77401
80	Northpointe Psychiatry	Lewisville	Texas	United States	75057
81	Rise Clinical Research, LLC	Missouri City	Texas	United States	77459
82	The University of Utah	Salt Lake City	Utah	United States	84108
83	Neuropsychiatric Associates, Plc	Woodstock	Vermont	United States	05091
84	Carilion Clinic	Roanoke	Virginia	United States	24014
85	Center For Anxiety and Depression	Mercer Island	Washington	United States	98040
86	Seattle Neuropsychiatric Treatment Center	Seattle	Washington	United States	98104
87	Marshall University Joan C. Edwards School of Medicine	Huntington	West Virginia	United States	25701
88	West Virginia Clinical and Translational Science Institute	Morgantown	West Virginia	United States	26506