Treatment-Resistant Depression Registry

• Sponsor: Cyberonics, Inc. (Industry)
• Overall Status: Completed
• CT.gov ID: NCT00320372
• Collaborator: (none)
• Enrollment: 795
• Locations: 55
• Duration (Months): 111.9
• Patients Per Site: 14.5
• Patients Per Site Per Month: 0.1

Study Details

Study Description

Brief Summary

This registry will collect information about patients with treatment-resistant depression (TRD) who are currently in a major depressive episode. For the purposes of this study, TRD is defined as an ongoing depression lasting at least 2 years or that has recurred at least 3 times, to include the current episode, during the patient's lifetime AND has not adequately responded to 4 or more adequate antidepressive treatments. The registry will follow the clinical course and outcomes for patients with TRD who are treated with and without adjunctive (used along with other treatments for depression) vagus nerve stimulation (VNS) therapy.

Condition or Disease	Intervention/Treatment	Phase
Major Depressive Disorder

Detailed Description

Enrollment of TRD patients treated with VNS Therapy will consist of patients originally enrolled in the registry as well as patients who have completed the D-21 Dosing Study and are enrolled in the Registry for Long-Term Follow-up. Sites will maintain a screening log of all patients who have been screened for original TRD Registry patients.

Please note that because this is a post-approval registry, Cyberonics does not cover the cost of VNS Therapy implantation.

Study Design

• Study Type: Observational
• Actual Enrollment: 795 participants
• Time Perspective: Prospective
• Official Title: A Long-term, Prospective, Observational, Multi-center Patient Outcome Registry to Collect Data in Patients With Treatment-resistant Depression (TRD) Who Are Currently in a Major Depressive Episode.
• Study Start Date: Jan 1, 2006
• Actual Primary Completion Date: Mar 1, 2015
• Actual Study Completion Date: May 1, 2015

Arms and Interventions

Arm	Intervention/Treatment
1. 500 VNS Patients VNS Patients - Treatment-resistant depression patients treated with VNS Therapy.
2. 300 Non-VNS Patients Non-VNS Patients - Treatment-resistant depression patients not receiving VNS Therapy.

Outcome Measures

Primary Outcome Measures

1. Montgomery Asberg Depression Rating Scale (MADRS)% Responders (>/= 50% Improvement From Baseline) [3-Month Through 60-Month (Post Baseline)]

   Response Rate was computed and summarized as the proportion of patients that achieved ≥ 50% reduction from baseline in MADRS total score at each post-baseline visit. The MADRS is a ten-item diagnostic questionnaire used to measure the severity of depressive episodes in patients with mood disorders. Higher MADRS score indicates more severe depression, and each item yields a score of 0 to 6. The overall score ranges from 0 to 60. The lower a score the less symptom severity is seen. A patient was considered a "Responder" (Yes = 1) if achieved ≥ 50% reduction from baseline in MADRS total score at visit month assessment post-baseline. A "Non-Responder" (No = 0) was any patient who did not achieve ≥ 50% reduction from baseline in MADRS score at visit month assessment post-baseline. Total number of patients in each group may be lower than ITT in a case of missing assessment data.

Secondary Outcome Measures

1. Time Until Recurrence (TUR) for Patients That Achieved Remission, Based on Montgomery Asberg Depression Rating Scale (MADRS) [3-Month Through 60-Month (Post Baseline)]

   Recurrence based on MADRS is defined as first time attained MADRS total score ≥ 20 after achieving remission. Remission is a binary outcome response variable (Yes/No in-remission) defined as MADRS total score </= 9 at visit month assessment post-baseline. Duration of remission Computed as recorded date of the first recurrence/relapse (MADRS score >/= 20) minus the recorded date of first achieved remission (MADRS score </=9). Only a subpopulation that achieved remission will be included in the summary. Time-to-event analyses were summarized using Kaplan-Meier curves. Patients who did not achieve recurrence at the end of the study were censored on the last visit date recorded. Additionally, patients who discontinued early were censored on last date of contact. Censored observations and confidence intervals for the estimated median times were calculated.

2. Montgomery Asberg Depression Rating Scale (MADRS)% Remitters (MADRS Total Score ≤9 at Visit Month Assessment Post-Baseline) [3-Month Through 60-Month (Post Baseline)]

   Remission is a binary outcome response variable (Yes/No Inremission) defined as MADRS total score < 9 at visit month assessment post-baseline. The MADRS is a ten-item diagnostic questionnaire used to measure the severity of depressive episodes in patients with mood disorders. Higher MADRS score indicates more severe depression, and each item yields a score of 0 to 6. The overall score ranges from 0 to 60. The lower a score the less symptom severity is seen and in general it is accepted that a score between 0-6 is indicative of a normal/symptom-free individual; 7-19 is indicative of a patient with mild depression; 20-34 is indicative of a patient with moderate depression; and >34 is indicative of a patient with severe depression. Total number of patients in each group may be lower than ITT in a case of missing assessment data.

3. Predictors of Suicidality Based on Montgomery Asberg Depression Rating Scale (MADRS) Item 10 Score - Baseline MADRS Item 10 Suicidal Ideation [1 Week Pre-Baseline]

   This assessment was completed telephonically by a third party rater (Central Rater Group). The rating was based on a clinical interview moving from broadly phrased questions about symptoms to more detailed ones, which allowed a precise rating of severity. The rater decided whether the rating lied on the defined scale steps (0, 2, 4, 6) or between them (1, 3, 5) and then checked the appropriate selection on the MADRS Item 10 Suicidal Thoughts (Ideation). Total number of patients analyzed may be lower than ITT in a case of missing assessment data.

4. Predictors of Suicidality Based on Montgomery Asberg Depression Rating Scale (MADRS) Item 10 Score - Medical Threat to Life of Most Recent Suicidal Gesture [Baseline]

   This assessment was completed by the physician at the baseline visit in a clinical interview. The physician decided which category (as shown in outcome measure data table) best characterized the patient's medical threat to life of their most recent suicidal gesture or attempt. Total number of patients analyzed may be lower than ITT in a case of missing assessment data.

5. Predictors of Suicidality Based on Montgomery Asberg Depression Rating Scale (MADRS) Item 10 Score - Intent of Most Recent Suicidal Gesture [Baseline]

   This assessment was completed by the physician at the baseline visit in a clinical interview. The physician decided which category (as shown in outcome measure data table) best characterized the patient's intent of their most recent suicidal gesture or attempt. Total number of patients analyzed may be lower than ITT in a case of missing assessment data.

6. Predictors of Suicidality Based on Montgomery Asberg Depression Rating Scale (MADRS) Item 10 Score - Primary Diagnosis of MDE [Screening]

   This assessment was completed by the physician at the screening visit. The physician decided which DSM-IV Diagnosis (as shown in outcome measure data table) best characterized the patient's primary diagnosis of MDE.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Patient diagnosed with a current major depressive episode according to DSM-IV-TR criteria.

• For D-21 patients only who have completed the D-21 dosing Study without any D-21 inclusion and exclusion protocol deviation.

• Patient has been in the current depressive episode for 2 years or longer, or has had at least 3 lifetime episodes including the current MDE.

• Patient has had an inadequate response to 4 or more adequate antidepressive treatments.

• The patient has a CGI severity of illness score of moderately ill (score of 4) or greater.

• The patient must be able to provide informed consent and complete all forms.

Exclusion Criteria:

• Patient has a history of schizophrenia, schizoaffective disorder, any other psychotic disorder, or a current major depressive episode that includes psychotic features; or is currently psychotic.

• Patient is currently enrolled in a double blind investigational study; patients who have completed the double-blind D-21 study will be allowed to enter the Registry for Long Term Follow-up

• Other than those patients who were enrolled in the D-21 study, patient has previously received VNS therapy.

• Patient has a history of rapid cycling bipolar disorder.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	University of Arizona	Tucson	Arizona	United States	85724
2	Cedars-Sinai Hospital	Beverly Hills	California	United States
3	Mark Zetin, MD - Private Practice	Garden Grove	California	United States	92840
4	Loma Linda University	Loma Linda	California	United States
5	Sutter Institute for Medical Research	Sacramento	California	United States	95816
6	Fair Oaks Psychiatric Associates	Sacramento	California	United States
7	University of Connecticut Health Center	Farmington	Connecticut	United States	06030-1410
8	Florida Atlantic University	Boca Raton	Florida	United States	33431
9	University of Florida	Gainesville	Florida	United States	32610-0256
10	MG Martelli, MD, PC and Associates	Brunswick	Georgia	United States	31520
11	Arthur Holt, Private Practice	Columbus	Georgia	United States
12	Pact Atlanta, LLC	Decatur	Georgia	United States	30030
13	Private Practice	Macon	Georgia	United States	31201
14	Northwest Behavioral Research Center	Marietta	Georgia	United States	30060
15	Valdosta Psychiatric Associates LLC	Valdosta	Georgia	United States	31602
16	Northshore University Health System	Evanston	Illinois	United States	60201
17	McGrath Clinic	Evergreen Park	Illinois	United States
18	Alexian Brothers Behavioral Health Hospital	Hoffman Estates	Illinois	United States
19	Psychiatric Medicine Associates, LLC	Skokie	Illinois	United States	60076
20	Dupage Mental Health Services	Wheaton	Illinois	United States	60187
21	3c Methodist Hospital	Indianapolis	Indiana	United States
22	Clinical Research Institute	Wichita	Kansas	United States
23	Louisiana Clinical Research, LLC	Shreveport	Louisiana	United States	71115
24	Pharmasite Research Inc.	Baltimore	Maryland	United States	21208
25	Sheppard Pratt Health Systems, Inc.	Baltimore	Maryland	United States	21285
26	Clinical Insights	Glen Burnie	Maryland	United States	21061
27	Massachusetts General Hospital	Charlestown	Massachusetts	United States	02129
28	University of Massachusetts Medical School	Worcester	Massachusetts	United States	01605
29	Rochester Center for Behavioral Medicine	Rochester Hills	Michigan	United States	48307
30	Psychiatric Recovery	St. Paul	Minnesota	United States	55114
31	Precise Research Centers	Flowood	Mississippi	United States
32	Washington University in St. Louis	St. Louis	Missouri	United States	63110
33	Psych Care Consultants Research	St. Louis	Missouri	United States	63128
34	Dent Neurologic Institute	Amherst	New York	United States	14226
35	Suburban Psychiatric Associates	Amherst	New York	United States	14228
36	Jamaica Hospital Medical Center	Jamaica	New York	United States	11418
37	Columbia University	New York	New York	United States	10032
38	SUNY UMU at Syracuse	Syracuse	New York	United States	13210
39	Wake Forest University - Health Sciences	Winston Salem	North Carolina	United States	27157
40	University Hospitals Case Medical Center	Cleveland	Ohio	United States	44106
41	Century Health	Findlay	Ohio	United States	45840
42	Oregon Health & Science University	Portland	Oregon	United States	97239
43	University of Pennsylvania	Philadelphia	Pennsylvania	United States	19104
44	Western Psychiatric Institute & Clinic (WPIC)	Pittsburgh	Pennsylvania	United States	15213
45	Medical University of South Carolina	Charleston	South Carolina	United States	29403
46	UT Southwestern Medical Center at Dallas	Dallas	Texas	United States	75390-8898
47	Claghorn-Lesem Reserach Clinic, Ltd.	Houston	Texas	United States	77008
48	Baylor College of Medicine	Houston	Texas	United States
49	The Mech Center	Plano	Texas	United States
50	University of Texas Health Science Center at San Antonio	San Antonio	Texas	United States	78229
51	Alamo Superior Research	San Antonio	Texas	United States
52	Psychiatric & Behavioral Solutions	Salt Lake City	Utah	United States	84105
53	Virginia Commonwealth University	Richmond	Virginia	United States	23298
54	Center for Anxiety and Depression	Mercer Island	Washington	United States	98040
55	Medical College of Wisconsin	Milwaukee	Wisconsin	United States	53226

Sponsors and Collaborators

• Cyberonics, Inc.

Investigators

• Principal Investigator: Adam K. Ashton, MD, Suburban Psychiatric Associates
• Principal Investigator: Herbert Ward, MD, University of Florida
• Principal Investigator: Thomas Schwartz, MD, SUNY UMU at Syracuse
• Principal Investigator: Mark Zetin, MD, Private Practice
• Principal Investigator: Darin D. Dougherty, MD, Massachusetts General Hospital
• Principal Investigator: George Keepers, MD, Oregon Health and Science University
• Principal Investigator: Mustafa M. Husain, MD, UT Southwestern Medical Center at Dallas
• Principal Investigator: Leighton Y. Huey, MD, UConn Health
• Principal Investigator: James Kimball, MD, Wake Forest University Health Sciences
• Principal Investigator: Peter J. Holland, MD, Florida Atlantic University
• Principal Investigator: Robert Howland, MD, Western Psychiatric Institute & Clinic (WPIC)
• Principal Investigator: Anthony Rothschild, MD, University of Massachusetts, Worcester
• Principal Investigator: Craig J Vine, MD, Psychiatric Recovery
• Principal Investigator: Joel Young, MD, Rochester Center for Behavioral Science
• Principal Investigator: Lawrence W Adler, MD, Clinical Insights
• Principal Investigator: Harold Harsch, MD, Medical College of Wisconsin
• Principal Investigator: Syed Ali, MD, Dupage Mental Health Services
• Principal Investigator: Keming Gao, MD, University Hospitals Cleveland Medical Center
• Principal Investigator: Todd M. Antin, M.D., DFAPA, Pact Atlanta, LLC
• Principal Investigator: Basanti Basu, M.D., Century Health
• Principal Investigator: Dwight Bearden, MD, Private Practice
• Principal Investigator: David L. Dunner, MD, Center for Anxiety and Depression
• Principal Investigator: Azfar Malik, MD, Psych Care Consultants Research
• Principal Investigator: Joel Morgan, MD, Valdosta Psychiatric Associates LLC
• Principal Investigator: Mark George, MD, Medical University of South Carolina
• Principal Investigator: Frederick W. Reimherr, MD, Psychiatric & Behavorial Solutions
• Principal Investigator: John Zajecka, MD, Psychiatric Medicine Associates, LLC
• Principal Investigator: Michael Banov, MD, Northwest Behavioral Research Center
• Principal Investigator: Robert Lehman, MD, Pharmasite Research, Inc.
• Principal Investigator: Scott Aaronson, MD, Sheppard Pratt Health Systems, Inc.
• Principal Investigator: Jaishree Narayanan, MD, NorthShore University HealthSystem
• Principal Investigator: Greg Seal, MD, Louisiana Clinical Research, LLC
• Principal Investigator: Horacio Capote, MD, Dent Neurologic Institute
• Principal Investigator: Charles Conway, MD, Washington University School of Medicine
• Principal Investigator: Michael Lesem, MD, Claghorn-Lesem Reserach Clinic, Ltd.
• Principal Investigator: Miguel Martelli, MD, MG Martelli, MD, PC and Associates
• Principal Investigator: Ananda Pandurangi, MD, Virginia Commonwealth University
• Principal Investigator: Peter Thompson, MD, The University of Texas Health Science Center at San Antonio
• Principal Investigator: Theodore Goodman, MD, Sutter Institute for Medical Research
• Principal Investigator: Francisco Moreno, MD, University of Arizona
• Principal Investigator: Martha Edelman, MD, Jamaica Hospital Medical Center
• Principal Investigator: Peter Bulow, MD, Columbia University
• Study Director: Mark Bunker, Cyberonics, Inc.
• Principal Investigator: Mahendra Bhati, MD, University of Pennsylvania
• Principal Investigator: Ronald Warnell, MD, Loma Linda University
• Principal Investigator: Robert Cohen, MD, Cedars-Sinai Hospital
• Principal Investigator: Janak Mehtani, MD, Fair Oaks Psychiatric Associates
• Principal Investigator: Mounir Soliman, MD, University of California, San Diego
• Principal Investigator: Francisco Fernandez, MD, University of South Florida
• Principal Investigator: Arthur Holt, MD, Arthur Holt, Private Practice
• Principal Investigator: Harold McGrath, MD, McGarth Clinic
• Principal Investigator: Anthony D'Agostino, MD, Alexian Brothers Behavioral Health Hospital
• Principal Investigator: Anne Gilbert, MD, 3c Methodist Hospital
• Principal Investigator: Michael Burke, MD, Clinical Research Institute
• Principal Investigator: Ed Coffey, MD, Henry Ford Health Services
• Principal Investigator: Joseph Kwentus, MD, University of Mississippi Medical Center
• Principal Investigator: David Ginsberg, MD, New York University of Medical Center
• Principal Investigator: Melissa Martinez, MD, Baylor College of Medicine
• Principal Investigator: Arnold Mech, MD, The Mech Center
• Principal Investigator: Joseph Simpson, MD, Alamo Superior Research

Study Documents (Full-Text)

None provided.

More Information

Publications

• Bajbouj M, Merkl A, Schlaepfer TE, Frick C, Zobel A, Maier W, O'Keane V, Corcoran C, Adolfsson R, Trimble M, Rau H, Hoff HJ, Padberg F, Müller-Siecheneder F, Audenaert K, van den Abbeele D, Matthews K, Christmas D, Eljamel S, Heuser I. Two-year outcome of vagus nerve stimulation in treatment-resistant depression. J Clin Psychopharmacol. 2010 Jun;30(3):273-81. doi: 10.1097/JCP.0b013e3181db8831.
• George MS, Rush AJ, Marangell LB, Sackeim HA, Brannan SK, Davis SM, Howland R, Kling MA, Moreno F, Rittberg B, Dunner D, Schwartz T, Carpenter L, Burke M, Ninan P, Goodnick P. A one-year comparison of vagus nerve stimulation with treatment as usual for treatment-resistant depression. Biol Psychiatry. 2005 Sep 1;58(5):364-73.
• Rush AJ, Marangell LB, Sackeim HA, George MS, Brannan SK, Davis SM, Howland R, Kling MA, Rittberg BR, Burke WJ, Rapaport MH, Zajecka J, Nierenberg AA, Husain MM, Ginsberg D, Cooke RG. Vagus nerve stimulation for treatment-resistant depression: a randomized, controlled acute phase trial. Biol Psychiatry. 2005 Sep 1;58(5):347-54.
• Rush AJ, Sackeim HA, Marangell LB, George MS, Brannan SK, Davis SM, Lavori P, Howland R, Kling MA, Rittberg B, Carpenter L, Ninan P, Moreno F, Schwartz T, Conway C, Burke M, Barry JJ. Effects of 12 months of vagus nerve stimulation in treatment-resistant depression: a naturalistic study. Biol Psychiatry. 2005 Sep 1;58(5):355-63.

• Responsible Party: Cyberonics, Inc.
• ClinicalTrials.gov Identifier: NCT00320372
• Other Study ID Numbers: TRD Registry; NCT00657215
• First Posted: May 3, 2006
• Last Update Posted: Dec 23, 2015
• Last Verified: Dec 1, 2015

• Keywords provided by Cyberonics, Inc.: Major Depressive Disorder; Treatment-resistant Depression
• Additional relevant MeSH terms: Depression; Depressive Disorder; Depressive Disorder, Major; Depressive Disorder, Treatment-Resistant

Study Results

Participant Flow

Recruitment Details	The TRD Registry was to enroll over a maximum period of 6 years & patients were to be followed for at least 60 months. All sites were to first recruit patients who had agreed to have adjunctive VNS Therapy. Sites were also asked to enroll patients with TRD who would not be implanted with VNS Therapy and would act as a concurrent control group.
Pre-assignment Detail	A total of 878 subjects were screened in the TRD Registry Study. Thirty-seven were not eligible and 46 were eligible but not treated for various reasons. This left a total of 795 patients in the Safety Population (SP).

Arm/Group Title	VNS Therapy	Treatment as Usual (TAU)
Arm/Group Description	Disposition of study patients from baseline to the end of the study. The VNS Therapy arm, was comprised of D-23 Original patients (Patients that entered the TRD Registry without previous VNS Therapy treatment and selected the VNS Therapy study arm) and D-21 Rollover patients (Patients that entered the TRD Registry, having previously participated in the D-21 study-NCT00305565 and still being treated with VNS Therapy).	Disposition of study patients from baseline to the end of the study. The TAU arm were subjects that entered the TRD Registry without previous VNS Therapy treatment and selected the TAU study arm.
Period Title: Overall Study
STARTED	494	301
VNS Therapy D-23 Original	335	0
VNS Therapy D-21 (NCT00305565) Rollovers	159	0
COMPLETED	299	138
NOT COMPLETED	195	163

Baseline Characteristics

Arm/Group Title	VNS Therapy D-23 Original	VNS Therapy D-21 Rollover	Treatment as Usual (TAU)	Total
Arm/Group Description	Subjects that entered the TRD Registry without previous VNS Therapy treatment and selected the VNS Therapy study arm.	Subjects that entered the TRD Registry, having previously participated in the D-21 study and still being treated with VNS Therapy treatment were included within the VNS Therapy group. Based on the duration from initial implant to enrollment date, the D-21 rollover patients entered at the appropriate D-23 follow-up interval (i.e., patient enrolls at 24 months post implant for their first D-23 follow up visit. This 24 month visit corresponds to the 24 month follow up in the TRD Registry). Starting with the first TRD Registry visit, the D-21 long-term patients were to follow the same data collection schedule as other Original VNS and TAU Registry patients.	Non-VNS Patients - Treatment-resistant depression patients not receiving VNS Therapy. Subjects that entered the TRD Registry without previous VNS Therapy treatment and selected the TAU study arm.	Total of all reporting groups
Overall Participants	335	159	301	795
Age, Customized (Years) [Mean (Standard Deviation) ]
Age at Baseline (n=335, n=159, n=301)	48.9 (10.41)	48.9 (9.51)	49.9 (11.07)	49.3 (10.49)
Age-Initial Onset of Depression(n=334,n=159,n=301)	20.8 (12.13)	21.1 (11.11)	21.1 (11.40)	21.0 (11.64)
Age-Initial Dx. of Depression(n=334,n=159,n=301)	29.0 (10.95)	28.6 (10.50)	29.5 (11.89)	29.1 (11.22)
Sex: Female, Male (Count of Participants)
Female	231 69%	119 74.8%	211 70.1%	561 70.6%
Male	104 31%	40 25.2%	90 29.9%	234 29.4%
Race/Ethnicity, Customized (Number) [Number]
Caucasian	323 96.4%	155 97.5%	274 91%	752 94.6%
African-American	4 1.2%	4 2.5%	6 2%	14 1.8%
Hispanic	3 0.9%	0 0%	19 6.3%	22 2.8%
Asian	2 0.6%	0 0%	1 0.3%	3 0.4%
Other	3 0.9%	0 0%	1 0.3%	4 0.5%
Lifetime Episodes of Depression Diagnosed (n=335, n=0, n=301) (Lifetime Episodes of Depression) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [Lifetime Episodes of Depression]	14.9 (24.14)	NA (NA)	12.0 (23.86)	13.5 (24.03)
Number of Failed Treatments (n=335, n=159, n=301) (Number of Failed Treatments) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [Number of Failed Treatments]	8.0 (3.05)	8.6 (3.74)	7.3 (2.92)	7.9 (3.19)
Suicide Attempts in Lifetime (n=335, n=159, n=301) (Number of Suicide Attempts in a Lifetime) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [Number of Suicide Attempts in a Lifetime]	2.1 (4.38)	1.2 (2.95)	1.2 (2.41)	1.6 (3.49)
Diagnosis Disorder (Major Depressive Disorder (MDD) or Bipolar Disorder (BPD) (Number) [Number]
MDD, Recurrent, Moderate Severity	42 12.5%	21 13.2%	69 22.9%	132 16.6%
MDD, Recurrent, Severe w/o Psychotic Features	135 40.3%	90 56.6%	95 31.6%	320 40.3%
MDD, Single Episode, Moderate Severity	12 3.6%	4 2.5%	30 10%	46 5.8%
MDD, Single Episode, Severe w/o Psychotic Features	49 14.6%	7 4.4%	36 12%	92 11.6%
BPD I, MRE Depressed, Moderate Severity	19 5.7%	6 3.8%	21 7%	46 5.8%
BPD I, MRE Depressed,Severe w/o Psychotic Features	46 13.7%	16 10.1%	12 4%	74 9.3%
BPD II, MRE Depressed	32 9.6%	15 9.4%	38 12.6%	85 10.7%

Outcome Measures

1. Primary Outcome

Title	Montgomery Asberg Depression Rating Scale (MADRS)% Responders (>/= 50% Improvement From Baseline)
Description	Response Rate was computed and summarized as the proportion of patients that achieved ≥ 50% reduction from baseline in MADRS total score at each post-baseline visit. The MADRS is a ten-item diagnostic questionnaire used to measure the severity of depressive episodes in patients with mood disorders. Higher MADRS score indicates more severe depression, and each item yields a score of 0 to 6. The overall score ranges from 0 to 60. The lower a score the less symptom severity is seen. A patient was considered a "Responder" (Yes = 1) if achieved ≥ 50% reduction from baseline in MADRS total score at visit month assessment post-baseline. A "Non-Responder" (No = 0) was any patient who did not achieve ≥ 50% reduction from baseline in MADRS score at visit month assessment post-baseline. Total number of patients in each group may be lower than ITT in a case of missing assessment data.
Time Frame	3-Month Through 60-Month (Post Baseline)

Outcome Measure Data

Analysis Population Description

Intent-To-Treat (ITT) Population: VNS Therapy Population (n=489 (D-23=330 + D-21=159)) + (n= 276) TAU population

Arm/Group Title	VNS Therapy	Treatment As Usual (TAU)
Arm/Group Description	MADRS % Responders (Percentage of Responders)	MADRS % Responders (Percentage of Responders)
Measure Participants	489	276
3-Month (n=454, n=249)	24 7.2%	8.8 5.5%
6-Month (n=432, n=224)	28 8.4%	13.8 8.7%
9-Month (n=408, n=193)	33.8 10.1%	13.5 8.5%
12-Month (n=403, n=194)	38.2 11.4%	17.5 11%
18-Month (n=223, n=162)	34.1 10.2%	15.4 9.7%
24-Month (n=233, n=146)	38.6 11.5%	18.5 11.6%
30-Month (n=224, n=138)	34.8 10.4%	22.5 14.2%
36-Month (n=245, n=133)	38.8 11.6%	17.3 10.9%
42-Month (n=245, n=121)	41.2 12.3%	19.0 11.9%
48-Month (n=246, n=109)	46.3 13.8%	22.0 13.8%
54-Month (n=222, n=102)	48.2 14.4%	27.5 17.3%
60-Month (n=250, n=116)	49.6 14.8%	25.9 16.3%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	VNS Therapy
	Comments	Null Hypothesis: Percentage of responders across groups is the same. Alternate Hypothesis: Percentage of responders across groups is different.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	MMRM Least Squares Mean
	Estimated Value	38.1
	Confidence Interval	(2-Sided) 95%; 36.3 to 39.9
	Parameter Dispersion	Type: Value:
	Estimation Comments	Mixed Model Repeated Measure analysis on MADRS responders (binary variable with 1=yes, 0=no) as the response variable in the model. The covariates are treatment, visit and propensity quintile. This analysis of covariance produced least square means.

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Treatment As Usual (TAU)
	Comments	Null Hypothesis: Percentage of responders across groups is the same. Alternate Hypothesis: Percentage of responders across groups is different.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	MMRM Least Squares Mean
	Estimated Value	17.0
	Confidence Interval	(2-Sided) 95%; 15.2 to 19.0
	Parameter Dispersion	Type: Value:
	Estimation Comments	Mixed Model Repeated Measure analysis on MADRS responders (binary variable with 1=yes, 0=no) as the response variable in the model. The covariates are treatment, visit and propensity quintile. This analysis of covariance produced least square means.

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	VNS Therapy, Treatment As Usual (TAU)
	Comments	Null Hypothesis: Percentage of responders across groups is the same. Alternate Hypothesis: Percentage of responders across groups is different.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<.0001
	Comments
	Method	ANCOVA
	Comments

2. Secondary Outcome

Title	Time Until Recurrence (TUR) for Patients That Achieved Remission, Based on Montgomery Asberg Depression Rating Scale (MADRS)
Description	Recurrence based on MADRS is defined as first time attained MADRS total score ≥ 20 after achieving remission. Remission is a binary outcome response variable (Yes/No in-remission) defined as MADRS total score </= 9 at visit month assessment post-baseline. Duration of remission Computed as recorded date of the first recurrence/relapse (MADRS score >/= 20) minus the recorded date of first achieved remission (MADRS score </=9). Only a subpopulation that achieved remission will be included in the summary. Time-to-event analyses were summarized using Kaplan-Meier curves. Patients who did not achieve recurrence at the end of the study were censored on the last visit date recorded. Additionally, patients who discontinued early were censored on last date of contact. Censored observations and confidence intervals for the estimated median times were calculated.
Time Frame	3-Month Through 60-Month (Post Baseline)

Outcome Measure Data

Analysis Population Description

Intent-To-Treat (ITT) Population: VNS Therapy Population (n=489 (D-23=330 + D-21=159)) + (n= 276) TAU population

Arm/Group Title	VNS Therapy	Treatment As Usual (TAU)
Arm/Group Description	Time until recurrence based on the MADRS	Time until recurrence based on the MADRS
Measure Participants	204	70
Measure Censored Patients	151	46
1st Quartile (25%);Time (Mo.) Until Recurrence	14	9
Kaplan-Meier Median;Time (Mo.) Until Recurrence	40	19

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	VNS Therapy, Treatment As Usual (TAU)
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.1015
	Comments	Comparison for Kaplan Meier Median Time until recurrence
	Method	Log Rank
	Comments	Null hypothesis: median TUR between 2 groups is not different. Alternate hypothesis: median TUR between 2 groups is different.

3. Secondary Outcome

Title	Montgomery Asberg Depression Rating Scale (MADRS)% Remitters (MADRS Total Score ≤9 at Visit Month Assessment Post-Baseline)
Description	Remission is a binary outcome response variable (Yes/No Inremission) defined as MADRS total score < 9 at visit month assessment post-baseline. The MADRS is a ten-item diagnostic questionnaire used to measure the severity of depressive episodes in patients with mood disorders. Higher MADRS score indicates more severe depression, and each item yields a score of 0 to 6. The overall score ranges from 0 to 60. The lower a score the less symptom severity is seen and in general it is accepted that a score between 0-6 is indicative of a normal/symptom-free individual; 7-19 is indicative of a patient with mild depression; 20-34 is indicative of a patient with moderate depression; and >34 is indicative of a patient with severe depression. Total number of patients in each group may be lower than ITT in a case of missing assessment data.
Time Frame	3-Month Through 60-Month (Post Baseline)

Outcome Measure Data

Analysis Population Description

Intent-To-Treat (ITT) Population: VNS Therapy Population (n=489 (D-23=330 + D-21=159)) + (n= 276) TAU population

Arm/Group Title	VNS Therapy	Treatment As Usual (TAU)
Arm/Group Description	MADRS % Remitters (Percentage of Subjects in Remission)	MADRS % Remitters (Percentage of Subjects in Remission)
Measure Participants	489	276
3-Month (n=454, n=249)	8.6 2.6%	2.8 1.8%
6-Month (n=432, n=224)	15 4.5%	6.3 4%
9-Month (n=408, n=193)	16.2 4.8%	5.7 3.6%
12-Month (n=403, n=194)	19.4 5.8%	8.2 5.2%
18-Month (n=223, n=162)	14.3 4.3%	7.4 4.7%
24-Month (n=233, n=146)	21.9 6.5%	11 6.9%
30-Month (n=224, n=138)	20.5 6.1%	12.3 7.7%
36-Month (n=245, n=133)	19.2 5.7%	11.3 7.1%
42-Month (n=245, n=121)	24.9 7.4%	13.2 8.3%
48-Month (n=246, n=109)	25.6 7.6%	14.7 9.2%
54-Month (n=222, n=102)	28.4 8.5%	13.7 8.6%
60-Month (n=250, n=116)	27.6 8.2%	19 11.9%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	VNS Therapy
	Comments	Null Hypothesis: Percentage of remitters across groups is the same. Alternate Hypothesis: Percentage of remitters across groups is different.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	MMRM Least Squares Mean
	Estimated Value	19.8
	Confidence Interval	(2-Sided) 95%; 18.4 to 21.3
	Parameter Dispersion	Type: Value:
	Estimation Comments	Mixed Model Repeated Measure analysis on MADRS remitters (binary variable with 1=yes, 0=no) as the response variable in the model. The covariates are treatment, visit and propensity quintile. This analysis of covariance produced least square means.

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Treatment As Usual (TAU)
	Comments	Null Hypothesis: Percentage of remitters across groups is the same. Alternate Hypothesis: Percentage of remitters across groups is different.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	MMRM Least Squares Mean
	Estimated Value	8.1
	Confidence Interval	(2-Sided) 95%; 6.9 to 9.5
	Parameter Dispersion	Type: Value:
	Estimation Comments	Mixed Model Repeated Measure analysis on MADRS remitters (binary variable with 1=yes, 0=no) as the response variable in the model. The covariates are treatment, visit and propensity quintile. This analysis of covariance produced least square means.

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	VNS Therapy, Treatment As Usual (TAU)
	Comments	Null Hypothesis: Percentage of responders across groups is the same. Alternate Hypothesis: Percentage of responders across groups is different.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<.0001
	Comments
	Method	ANCOVA
	Comments

4. Post-Hoc Outcome

Title	Mortality and Suicidality in Safety Population (Total Number of Deaths)
Description	The number of deaths on the study were collected from the baseline visit.
Time Frame	3-Month (baseline or implantation) Through 60-Month (Post Baseline)

Outcome Measure Data

Analysis Population Description

Safety Population (SP): VNS Therapy Population (n=494 (D-23=335 + D-21=159)) + (n= 301) TAU population

Arm/Group Title	VNS Therapy	Treatment as Usual (TAU)
Arm/Group Description	VNS Patients - Treatment-resistant depression patients treated with VNS Therapy	Non-VNS Patients - Treatment-resistant depression patients not receiving VNS Therapy
Measure Participants	494	301
Number [Number of Deaths]	7	8

5. Post-Hoc Outcome

Title	Mortality and Suicidality in Safety Population (Total Patient Years Exposed)
Description	Treatment exposure time in years for all patients for all treatment groups were calculated in 1000 person year measure.
Time Frame	3-Month Through 60-Month (Post Baseline)

Outcome Measure Data

Analysis Population Description

Safety Population (SP): VNS Therapy Population (n=494 (D-23=335 + D-21=159)) + (n= 301) TAU population

Arm/Group Title	VNS Therapy	Treatment as Usual (TAU)
Arm/Group Description	VNS Patients - Treatment-resistant depression patients treated with VNS Therapy	Non-VNS Patients - Treatment-resistant depression patients not receiving VNS Therapy
Measure Participants	494	301
Number [Exposure Per 1000 Patient Years]	1985.083	926.493

6. Post-Hoc Outcome

Title	Mortality and Suicidality in Safety Population (All-Cause Mortality/1000 Person Years)
Description	All cause mortality is defined as the number of deaths per calculated 1000 person years.
Time Frame	3-Month Through 60-Month (Post Baseline)

Outcome Measure Data

Analysis Population Description

Safety Population (SP): VNS Therapy Population (n=494 (D-23=335 + D-21=159)) + (n= 301) TAU population

Arm/Group Title	VNS Therapy	Treatment as Usual (TAU)
Arm/Group Description	VNS Patients - Treatment-resistant depression patients treated with VNS Therapy	Non-VNS Patients - Treatment-resistant depression patients not receiving VNS Therapy
Measure Participants	494	301
Number [Deaths Per 1000 Person Years]	3.53	8.63

7. Post-Hoc Outcome

Title	Mortality and Suicidality in Safety Population (Number of Suicides)
Description	The number suicides on the study were collected from the baseline visit.
Time Frame	3-Month Through 60-Month (Post Baseline)

Outcome Measure Data

Analysis Population Description

Safety Population (SP): VNS Therapy Population (n=494 (D-23=335 + D-21=159)) + (n= 301) TAU population

Arm/Group Title	VNS Therapy	Treatment as Usual (TAU)
Arm/Group Description	VNS Patients - Treatment-resistant depression patients treated with VNS Therapy	Non-VNS Patients - Treatment-resistant depression patients not receiving VNS Therapy
Measure Participants	494	301
Number [Number of Suicides]	2	2

8. Post-Hoc Outcome

Title	Mortality and Suicidality in Safety Population (Suicides/1000 Person Years)
Description	The number of suicides per calculated 1000 person years.
Time Frame	3-Month Through 60-Month (Post Baseline)

Outcome Measure Data

Analysis Population Description

Safety Population (SP): VNS Therapy Population (n=494 (D-23=335 + D-21=159)) + (n= 301) TAU population

Arm/Group Title	VNS Therapy	Treatment as Usual (TAU)
Arm/Group Description	VNS Patients - Treatment-resistant depression patients treated with VNS Therapy	Non-VNS Patients - Treatment-resistant depression patients not receiving VNS Therapy
Measure Participants	494	301
Number [Number of Suicides Per 1000 Person Years]	1.01	2.20

9. Secondary Outcome

Title	Predictors of Suicidality Based on Montgomery Asberg Depression Rating Scale (MADRS) Item 10 Score - Baseline MADRS Item 10 Suicidal Ideation
Description	This assessment was completed telephonically by a third party rater (Central Rater Group). The rating was based on a clinical interview moving from broadly phrased questions about symptoms to more detailed ones, which allowed a precise rating of severity. The rater decided whether the rating lied on the defined scale steps (0, 2, 4, 6) or between them (1, 3, 5) and then checked the appropriate selection on the MADRS Item 10 Suicidal Thoughts (Ideation). Total number of patients analyzed may be lower than ITT in a case of missing assessment data.
Time Frame	1 Week Pre-Baseline

Outcome Measure Data

Analysis Population Description

D-23 Original + TAU [(n= 330) + (n= 276)] minus 2 missing assessment data. These risk factors assessed at baseline and pre-baseline were not collected with respect to treatment, therefore this information is not presented by treatment arm.

Arm/Group Title	ITT Population
Arm/Group Description	VNS Therapy and Treatment as Usual (TAU)
Measure Participants	763
0 Enjoys Life	6.03
1	28.83
2 Weary of Life	25.56
3	18.87
4 Probably Better Off Dead	14.81
5	4.72
6 Explicit Plans for Suicide	1.18

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	VNS Therapy
	Comments	The statistical modeling of predictors of suicide attempts and suicidal ideations considered 15 variables, defined in the protocol a priori to determine which ones were predictive of suicide attempts and suicidal ideations. Four variables representing the baseline disease and patient factors were considered predictors of suicidality. This outcome measure presents the underlying data collected and the corresponding correlation coefficient for one of the 4 variables identified.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments	Null hypothesis: There is a correlation between MADRS follow-up suicidal thoughts and baseline suicidal thoughts. Alternate hypothesis: There is no correlation between MADRS follow-up suicidal thoughts and baseline suicidal thoughts.
	Method	Pearson Correlation Coefficients
	Comments
Method of Estimation	Estimation Parameter	Pearson Correlation Coefficients
	Estimated Value	.34997
	Confidence Interval	(2-Sided) %; to
	Parameter Dispersion	Type: Value:
	Estimation Comments

10. Post-Hoc Outcome

Title	Quality of Life Enjoyment and Satisfaction Questionnaire - Short Form (Q-LES-Q-SF) Change From Baseline by Visit Month
Description	The Q-LES-Q-SF is a self-report scale to assess the degree of enjoyment and satisfaction experienced by the patient during the past week. There are 2 forms of this instrument: the short form and the long form. The short form employs the 14 general activities included in the long form, as well as 2 global items. Five-point item scores (1 to 5) are aggregated, with higher scores indicative of greater enjoyment or satisfaction in each domain. The scoring of the Q-LESQ-SF involves summing only the first 14 items to yield a raw total score. The last 2 items are not included in the total score but stand alone. The raw total score ranges from 14 (worst score) to 70 (best score). Higher Q-LES-QSF score indicates more enjoyment and satisfaction (Endicott, Nee et al. 1993).
Time Frame	3-Month Through 60-Month (Post Baseline)

Outcome Measure Data

Analysis Population Description

ITT Population minus D-21 Subjects: VNS Therapy Population (D-23=330) + (n= 276) TAU population. The total number of patients in each group is lower than ITT due to missing assessment data, for which a large portion is that of D-21 subjects. The Q-LES-Q-SF was not collected in the D-21 Study.

Arm/Group Title	VNS Therapy	Treatment As Usual (TAU)
Arm/Group Description	Change from Baseline Score	Change from Baseline Score
Measure Participants	330	276
3 Months (n=322, n=261)	7.92 (16.20)	1.38 (16.61)
6 Months (n=298, n=239)	9.11 (15.66)	4.36 (17.46)
9 Months (n=270, n=216)	10.50 (16.74)	3.97 (17.07)
12 Months (n=266, n=211)	11.04 (18.36)	5.49 (17.56)
18 Months (n=264, n=179)	11.40 (18.29)	3.88 (16.03)
24 Months (n=240, n=159)	13.15 (18.13)	7.50 (16.73)
30 Months (n=223, n=147)	13.06 (18.63)	8.13 (16.73)
36 Months (n=219, n=149)	15.59 (18.43)	8.34 (16.11)
42 Months (n=196, n=141)	14.67 (17.46)	8.55 (17.95)
48 Months (n=179, n=127)	14.70 (19.02)	9.88 (17.28)
54 Months (n=156, n=128)	16.44 (18.63)	10.49 (16.74)
60 Months (n=173, n=136)	17.20 (17.59)	10.11 (17.93)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	VNS Therapy, Treatment As Usual (TAU)
	Comments	3 Month Time point
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<.0001
	Comments	Null Hypothesis: Difference between change from baseline value of two treatment groups equals zero. Alternate Hypothesis: Difference between change from baseline value of two treatment groups is not equal to zero.
	Method	F-Test
	Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	VNS Therapy, Treatment As Usual (TAU)
	Comments	6 Month Time point
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	.0068
	Comments	Null Hypothesis: Difference between change from baseline value of two treatment groups equals zero. Alternate Hypothesis: Difference between change from baseline value of two treatment groups is not equal to zero.
	Method	F-Test
	Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	VNS Therapy, Treatment As Usual (TAU)
	Comments	9 Month Time point
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	.0008
	Comments	Null Hypothesis: Difference between change from baseline value of two treatment groups equals zero. Alternate Hypothesis: Difference between change from baseline value of two treatment groups is not equal to zero.
	Method	F-Test
	Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	VNS Therapy, Treatment As Usual (TAU)
	Comments	12 Month Time point
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	.0003
	Comments	Null Hypothesis: Difference between change from baseline value of two treatment groups equals zero. Alternate Hypothesis: Difference between change from baseline value of two treatment groups is not equal to zero.
	Method	F-Test
	Comments

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	VNS Therapy, Treatment As Usual (TAU)
	Comments	18 Month Time point
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<.0001
	Comments	Null Hypothesis: Difference between change from baseline value of two treatment groups equals zero. Alternate Hypothesis: Difference between change from baseline value of two treatment groups is not equal to zero.
	Method	F-Test
	Comments

Statistical Analysis 6

Statistical Analysis Overview	Comparison Group Selection	VNS Therapy, Treatment As Usual (TAU)
	Comments	24 Month Time point
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	.0059
	Comments	Null Hypothesis: Difference between change from baseline value of two treatment groups equals zero. Alternate Hypothesis: Difference between change from baseline value of two treatment groups is not equal to zero.
	Method	F-Test
	Comments

Statistical Analysis 7

Statistical Analysis Overview	Comparison Group Selection	VNS Therapy, Treatment As Usual (TAU)
	Comments	30 Month Time point
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	.0028
	Comments	Null Hypothesis: Difference between change from baseline value of two treatment groups equals zero. Alternate Hypothesis: Difference between change from baseline value of two treatment groups is not equal to zero.
	Method	F-Test
	Comments

Statistical Analysis 8

Statistical Analysis Overview	Comparison Group Selection	VNS Therapy, Treatment As Usual (TAU)
	Comments	36 Month Time point
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	.0002
	Comments	Null Hypothesis: Difference between change from baseline value of two treatment groups equals zero. Alternate Hypothesis: Difference between change from baseline value of two treatment groups is not equal to zero.
	Method	F-Test
	Comments

Statistical Analysis 9

Statistical Analysis Overview	Comparison Group Selection	VNS Therapy, Treatment As Usual (TAU)
	Comments	42 Month Time point
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	.0051
	Comments	Null Hypothesis: Difference between change from baseline value of two treatment groups equals zero. Alternate Hypothesis: Difference between change from baseline value of two treatment groups is not equal to zero.
	Method	F-Test
	Comments

Statistical Analysis 10

Statistical Analysis Overview	Comparison Group Selection	VNS Therapy, Treatment As Usual (TAU)
	Comments	48 Month Time point
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	.0363
	Comments	Null Hypothesis: Difference between change from baseline value of two treatment groups equals zero. Alternate Hypothesis: Difference between change from baseline value of two treatment groups is not equal to zero.
	Method	F-Test
	Comments

Statistical Analysis 11

Statistical Analysis Overview	Comparison Group Selection	VNS Therapy, Treatment As Usual (TAU)
	Comments	54 Month Time point
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	.0048
	Comments	Null Hypothesis: Difference between change from baseline value of two treatment groups equals zero. Alternate Hypothesis: Difference between change from baseline value of two treatment groups is not equal to zero.
	Method	F-Test
	Comments

Statistical Analysis 12

Statistical Analysis Overview	Comparison Group Selection	VNS Therapy, Treatment As Usual (TAU)
	Comments	60 Month Time point
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	.0009
	Comments	Null Hypothesis: Difference between change from baseline value of two treatment groups equals zero. Alternate Hypothesis: Difference between change from baseline value of two treatment groups is not equal to zero.
	Method	F-Test
	Comments

Statistical Analysis 13

Statistical Analysis Overview	Comparison Group Selection	VNS Therapy
	Comments	Null Hypothesis: Difference between change from baseline value of two treatment groups equals zero. Alternate Hypothesis: Difference between change from baseline value of two treatment groups is not equal to zero.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	MMRM Least Squares Mean
	Estimated Value	12.1009
	Confidence Interval	(2-Sided) 95%; 10.8979 to 13.3039
	Parameter Dispersion	Type: Value:
	Estimation Comments	Mixed Model Repeated Measure analysis on Q-LES-Q change from baseline score (continuous var) as the response variable in the model. The covariates are treatment, visit and propensity quintile. This analysis of covariance produced least square means.

Statistical Analysis 14

Statistical Analysis Overview	Comparison Group Selection	Treatment As Usual (TAU)
	Comments	Null Hypothesis: Difference between change from baseline value of two treatment groups equals zero. Alternate Hypothesis: Difference between change from baseline value of two treatment groups is not equal to zero.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	MMRM Least Squares Mean
	Estimated Value	7.5964
	Confidence Interval	(2-Sided) 95%; 6.1327 to 9.0602
	Parameter Dispersion	Type: Value:
	Estimation Comments	Mixed Model Repeated Measure analysis on Q-LES-Q change from baseline score (continuous var) as the response variable in the model. The covariates are treatment, visit and propensity quintile. This analysis of covariance produced least square means.

Statistical Analysis 15

Statistical Analysis Overview	Comparison Group Selection	VNS Therapy, Treatment As Usual (TAU)
	Comments	Null Hypothesis: Difference between change from baseline value of two treatment groups equals zero. Alternate Hypothesis: Difference between change from baseline value of two treatment groups is not equal to zero.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<.0001
	Comments
	Method	ANCOVA
	Comments

11. Secondary Outcome

Title	Predictors of Suicidality Based on Montgomery Asberg Depression Rating Scale (MADRS) Item 10 Score - Medical Threat to Life of Most Recent Suicidal Gesture
Description	This assessment was completed by the physician at the baseline visit in a clinical interview. The physician decided which category (as shown in outcome measure data table) best characterized the patient's medical threat to life of their most recent suicidal gesture or attempt. Total number of patients analyzed may be lower than ITT in a case of missing assessment data.
Time Frame	Baseline

Outcome Measure Data

Analysis Population Description

D-23 Original + TAU [(n= 330) + (n= 276)] minus 159 missing assessment data. These risk factors assessed at baseline and pre-baseline were not collected with respect to treatment, therefore this information is not presented by treatment arm.

Arm/Group Title	ITT Population
Arm/Group Description	VNS Therapy and Treatment as Usual (TAU)
Measure Participants	606
Patient Never Made an Attempt	46.70
No Information or Not Sure	3.14
No Danger	5.61
Minimal	3.47
Mild	8.91
Moderate	18.15
Severe	11.39
Extreme	2.64

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	VNS Therapy
	Comments	The statistical modeling of predictors of suicide attempts and suicidal ideations considered 15 variables, defined in the protocol a priori to determine which ones were predictive of suicide attempts and suicidal ideations. Four variables representing the baseline disease and patient factors were considered predictors of suicidality. This outcome measure presents the underlying data collected and the corresponding correlation coefficient for one of the 4 variables identified.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<.0001
	Comments	Null hypothesis: There is a correlation between MADRS follow-up suicidal thoughts and baseline medical threat to life. Alternate hypothesis: There is no correlation between MADRS follow-up suicidal thoughts and baseline medical threat to life.
	Method	Pearson Correlation Coefficients
	Comments
Method of Estimation	Estimation Parameter	Pearson Correlation Coefficients
	Estimated Value	.14837
	Confidence Interval	(2-Sided) %; to
	Parameter Dispersion	Type: Value:
	Estimation Comments

12. Secondary Outcome

Title	Predictors of Suicidality Based on Montgomery Asberg Depression Rating Scale (MADRS) Item 10 Score - Intent of Most Recent Suicidal Gesture
Description	This assessment was completed by the physician at the baseline visit in a clinical interview. The physician decided which category (as shown in outcome measure data table) best characterized the patient's intent of their most recent suicidal gesture or attempt. Total number of patients analyzed may be lower than ITT in a case of missing assessment data.
Time Frame	Baseline

Outcome Measure Data

Analysis Population Description

D-23 Original + TAU [(n= 330) + (n= 276)] minus 159 missing assessment data. These risk factors assessed at baseline and pre-baseline were not collected with respect to treatment, therefore this information is not presented by treatment arm.

Arm/Group Title	ITT Population
Arm/Group Description	VNS Therapy and Treatment as Usual (TAU)
Measure Participants	606
Patient Never Made an Attempt	46.86
No Information or Not Sure	3.80
Obviously no Intent	2.31
Not Sure or Only Minimal Intent	5.12
Definite But Very Ambivalent	11.06
Serious	12.05
Very Serious	9.57
Extreme	9.24

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	VNS Therapy
	Comments	The statistical modeling of predictors of suicide attempts and suicidal ideations considered 15 variables, defined in the protocol a priori to determine which ones were predictive of suicide attempts and suicidal ideations. Four variables representing the baseline disease and patient factors were considered predictors of suicidality. This outcome measure presents the underlying data collected and the corresponding correlation coefficient for one of the 4 variables identified.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<.0001
	Comments	Null hypothesis: There is a correlation between MADRS f/u suicidal thoughts and baseline intent of suicidal gesture. Alternate hypothesis: There is no correlation between MADRS f/u suicidal thoughts and baseline intent of suicidal gesture.
	Method	Pearson Correlation Coefficients
	Comments
Method of Estimation	Estimation Parameter	Pearson Correlation Coefficients
	Estimated Value	.14819
	Confidence Interval	(2-Sided) %; to
	Parameter Dispersion	Type: Value:
	Estimation Comments

13. Secondary Outcome

Title	Predictors of Suicidality Based on Montgomery Asberg Depression Rating Scale (MADRS) Item 10 Score - Primary Diagnosis of MDE
Description	This assessment was completed by the physician at the screening visit. The physician decided which DSM-IV Diagnosis (as shown in outcome measure data table) best characterized the patient's primary diagnosis of MDE.
Time Frame	Screening

Outcome Measure Data

Analysis Population Description

D-23 Original + TAU [(n= 330) + (n= 276)]. These risk factors assessed at baseline and pre-baseline were not collected with respect to treatment, therefore this information is not presented by treatment arm.

Arm/Group Title	ITT Population
Arm/Group Description	VNS Therapy and Treatment as Usual (TAU)
Measure Participants	765
MDD, Recurrent, Moderate Severity	16.99
MDD, Recurrent, Severe w/o Psychotic Features	40.39
MDD, Single Episode, Moderate Severity	5.88
MDD, Single Episode, Severe w/o Psychotic Features	11.24
BPD I, MRE Depressed, Moderate Severity	5.75
BPD I, MRE Depressed,Severe w/o Psychotic Features	9.41
BPD II, MRE Depressed	10.33

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	VNS Therapy
	Comments	The statistical modeling of predictors of suicide attempts and suicidal ideations considered 15 variables, defined in the protocol a priori to determine which ones were predictive of suicide attempts and suicidal ideations. Four variables representing the baseline disease and patient factors were considered predictors of suicidality. This outcome measure presents the underlying data collected and the corresponding correlation coefficient for one of the 4 variables identified.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	.0012
	Comments	Null hypothesis: There is a correlation between MADRS follow-up suicidal thoughts and baseline primary diagnosis of MDE. Alternate hypothesis: There is no correlation between MADRS follow-up suicidal thoughts and baseline primary diagnosis of MDE.
	Method	Pearson Correlation Coefficients
	Comments
Method of Estimation	Estimation Parameter	Pearson Correlation Coefficients
	Estimated Value	.04625
	Confidence Interval	(2-Sided) %; to
	Parameter Dispersion	Type: Value:
	Estimation Comments

Adverse Events

Time Frame	N/A (Adverse event information was not collected as part of the TRD Registry Protocol)
Adverse Event Reporting Description	Physicians were instructed to notify Cyberonics' Clinical Technical Support (CTS) department of all Medical Devices Reporting (MDR) events that occurred in TRD Registry participants receiving VNS Therapy.
Arm/Group Title	Safety Events
Arm/Group Description	N/A (not collected)
All Cause Mortality
	Safety Events
	Affected / at Risk (%)	# Events
Total	/ (NaN)
Serious Adverse Events
	Safety Events
	Affected / at Risk (%)	# Events
Total	0/0 (NaN)
Other (Not Including Serious) Adverse Events
	Safety Events
	Affected / at Risk (%)	# Events
Total	0/0 (NaN)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.