A Study to Assess the Long- Term Safety of TC-5214 as an Adjunct Therapy in Patients With Major Depressive Disorder

• Sponsor: AstraZeneca (Industry)
• Overall Status: Completed
• CT.gov ID: NCT01152554
• Collaborator: Targacept Inc. (Industry)
• Enrollment: 813
• Locations: 94
• Arms: 2
• Duration (Months): 20
• Patients Per Site: 8.6
• Patients Per Site Per Month: 0.4

Study Details

Study Description

Brief Summary

The purpose of this study is to determine if TC-5214 or placebo (a tablet that looks like medicine tablet or capsule, but contains no active medicine) is safe and effective when taken for 52 weeks with another antidepressant medicine.

Condition or Disease	Intervention/Treatment	Phase
Major Depressive Disorder; MDD; Depression	Drug: TC-5214; Drug: Placebo	Phase 3

Study Design

• Study Type: Interventional
• Actual Enrollment: 813 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: A Multicenter, Randomized, Double-blind, Parallel Group, Placebo-controlled, Phase III, Long-Term Safety and Tolerability Study of TC-5214 (S-mecamylamine) as an Adjunct to an Antidepressant in Patients With Major Depressive Disorder Who Exhibit an Inadequate Response to Antidepressant Therapy
• Study Start Date: Jun 1, 2010
• Actual Primary Completion Date: Feb 1, 2012
• Actual Study Completion Date: Feb 1, 2012

Arms and Interventions

Arm	Intervention/Treatment
Experimental: SSRI/Serotonin/SNRI + TC-5214 1-4 mg Selective serotonin reuptake inhibitor (SSRI)/Serotonin/norepinephrine reuptake inhibitor (SNRI) + TC-5214 1-4 mg BID	Drug: TC-5214; Tablet, oral, twice daily for 52 weeks
Placebo Comparator: SSRI/Serotonin/SNRI + placebo Selective serotonin reuptake inhibitor (SSRI)/Serotonin/norepinephrine reuptake inhibitor (SNRI) + placebo BID	Drug: Placebo; Tablet, oral, twice daily for 52 weeks

Outcome Measures

Primary Outcome Measures

1. Frequency of Patients Experiencing at Least One Adverse Event (AE) [Randomization (Week 0) to end of the follow-up period (Week 54)]

   The frequency of patients experiencing at least one AE during the randomized treatment or follow-up periods was calculated.

2. Frequency of Patients Experiencing AEs That Resulted in Discontinuation of Investigational Product (IP) [Randomization (Week 0) to end of the follow-up period (Week 54)]

   The frequency of patients experiencing AEs that resulted in discontinuation of IP during the randomized treatment or follow-up periods was calculated.

3. Frequency of Patients Experiencing Serious Adverse Events (SAEs) [Randomization (Week 0) to end of the follow-up period (Week 54)]

   The frequency of patients experiencing serious adverse events (SAEs) during the randomized treatment or follow-up periods was calculated.

Secondary Outcome Measures

1. Sustained Efficacy at 3 Months, Defined as a Montgomery-Asberg Depression Rating Scale (MADRS) Total Score of ≤12 at Week 12 and All Visits up to and Including Week 24 [Week 12 to Week 24]

   The percentage of patients with a a MADRS total score of ≤12 at Week 12 and all visits up to and including Week 24 was calculated. One intermediate occurrence of a MADRS total score >12 but ≤16 or missing was allowed from Week 16 to Week 20. A 10-item scale for the evaluation of depressive symptoms. Each MADRS item is rated on a 0 to 6 scale. The MADRS total score is calculated as the sum of the 10 individual item scores; the total score can range from 0 to 60. Higher MADRS scores indicate higher levels of depressive symptoms.

2. Sustained Efficacy at 9 Months, Defined as a MADRS Total Score of ≤12 at Week 12 and at All Visits up to and Including Week 52 [Week 12 to Week 52]

   The percentage of patients with a MADRS total score of ≤12 at Week 12 and at all visits up to and including Week 52 was calculated. Two intermediate occurrences (not consecutive) of a MADRS >12 but ≤16 or missing were allowed from Week 16 to Week 48. A 10-item scale for the evaluation of depressive symptoms. Each MADRS item is rated on a 0 to 6 scale. The MADRS total score is calculated as the sum of the 10 individual item scores; the total score can range from 0 to 60. Higher MADRS scores indicate higher levels of depressive symptoms.

3. Change in the Clinician-rated Global Outcome of Severity as Measured by the Clinical Global Impression-Severity (CGI-S) Score From Randomization (Week 0) to End of Treatment (Week 52) [Randomization (Week 0) to end of treatment (Week 52)]

   A 3-part, clinician-administered scale that rates the improvement or worsening of the patient's illness from randomization (baseline). Each item is scored on a 1 to 7 scale. Higher CGI-S scores indicate greater illness severity.

4. Change in Functional Impairment From Randomization (Week 0) to End of Treatment (Week 52) as Measured by the Sheehan Disability Scale (SDS) Total Score [Randomization (Week 0) to end of treatment (Week 52)]

   Sheehan Disability Scale (SDS) is 5-item, self-administered scale that measures the extent a patient is impaired by their disease. Higher scores indicate more severe impairment. The SDS total score is calculated as the sum of the score for the 3 inter-correlated domains (school/work, social life, and family life/home responsibilities) and ranges from 0 (unimpaired) to 30 (highly impaired).

5. Change in Overall Quality of Life and Satisfaction From Randomization (Week 0) to End of Treatment (Week 52) by Assessing the Quality of Life Enjoyment and Satisfaction Questionnaire-Short Form (Q-LES-Q-SF) % Maximum Total Score [Randomization (Week 0) to end of treatment (Week 52)]

   The Q-LES-Q-SF total score is derived by summing item scores 1 to 14. Higher scores are indicative of greater enjoyment or satisfaction in each domain. The Q-LES-Q-SF % maximum total score is calculated as 100% × (Q-LES-Q-SF total score - 14) / 56, and can range from 0% to 100%.

6. Change in EuroQol - 5 Dimensions (EQ-5D) From Randomization (Week 0) to End of Treatment (Week 52) [Randomization (Week 0) to end of treatment (Week 52)]

   A self-assessment questionnaire that provides 2 measures of health status. The EQ-5D index score is a weighted linear combination over 5 dimensions of health status. The score for each of the 5 dimensions can range from 1 to 3, and an equation is used to calculate the EQ-5D index score. The EQ-5D index score can range from possible negative values to a maximum of 1.0. The EQ-VAS is a visual analog scale with a range of 0 to 100. For both variables, a higher score indicates a better health state.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 65 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Provision of signed and dated informed consent before initiation of any study-related procedures.

• The patient must have a clinical diagnosis of major depressive disorder (MDD) with inadequate response to no more than one antidepressant.

• Outpatient status at enrollment and randomization.

Exclusion Criteria:

• Patients with a lifetime history of bipolar disorder, psychotic disorder or post-traumatic stress disorder.

• Patients with a history of suicide attempts in the past year and/or seen by the investigator as having a significant history of risk of suicide or homicide.

• Patients with significant liver, kidney, lung, heart, neurological, or any other medical conditions that might confound the study or put the patient at greater risk during study participation.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Research Site	Birmingham	Alabama	United States
2	Research Site	Tuscaloosa	Alabama	United States
3	Research Site	Tucson	Arizona	United States
4	Research Site	Little Rock	Arkansas	United States
5	Research Site	Arcadia	California	United States
6	Research Site	Beverly Hills	California	United States
7	Research Site	Carson	California	United States
8	Research Site	Cerritos	California	United States
9	Research Site	Chino	California	United States
10	Research Site	Costa Mesa	California	United States
11	Research Site	Encino	California	United States
12	Research Site	Escondido	California	United States
13	Research Site	Garden Grove	California	United States
14	Research Site	Irvine	California	United States
15	Research Site	Los Alamitos	California	United States
16	Research Site	Los Angeles	California	United States
17	Research Site	Newport Beach	California	United States
18	Research Site	Pico Rivera	California	United States
19	Research Site	Riverside	California	United States
20	Research Site	Sherman Oaks	California	United States
21	Research Site	Torrance	California	United States
22	Research Site	Upland	California	United States
23	Research Site	Denver	Colorado	United States
24	Research Site	Norwalk	Connecticut	United States
25	Research Site	Norwich	Connecticut	United States
26	Research Site	Bradenton	Florida	United States
27	Research Site	Coral Springs	Florida	United States
28	Research Site	Ft Myers	Florida	United States
29	Research Site	Gainsville	Florida	United States
30	Research Site	Jacksonville	Florida	United States
31	Research Site	Maitland	Florida	United States
32	Research Site	North Miami	Florida	United States
33	Research Site	Orange City	Florida	United States
34	Research Site	Orlando	Florida	United States
35	Research Site	Pinecrest	Florida	United States
36	Research Site	Plantation	Florida	United States
37	Research Site	St Petersburg	Florida	United States
38	Research Site	Tampa	Florida	United States
39	Research Site	West Palm Beach	Florida	United States
40	Research Site	Roswell	Georgia	United States
41	Research Site	Chicago	Illinois	United States
42	Research Site	Hoffman Estates	Illinois	United States
43	Research Site	Joliet	Illinois	United States
44	Research Site	Schaumburg	Illinois	United States
45	Research Site	Skokie	Illinois	United States
46	Research Site	Lafayette	Indiana	United States
47	Research Site	Valparaiso	Indiana	United States
48	Research Site	Prairie Village	Kansas	United States
49	Research Site	Wichita	Kansas	United States
50	Research Site	Florence	Kentucky	United States
51	Research Site	Shreveport	Louisiana	United States
52	Research Site	Baltimore	Maryland	United States
53	Research Site	Gaithersburg	Maryland	United States
54	Research Site	Glen Burnie	Maryland	United States
55	Research Site	Rockville	Maryland	United States
56	Research Site	Weymouth	Massachusetts	United States
57	Research Site	Flowood	Mississippi	United States
58	Research Site	Creve Coeur	Missouri	United States
59	Research Site	St. Louis	Missouri	United States
60	Research Site	Lincoln	Nebraska	United States
61	Research Site	Toms River	New Jersey	United States
62	Research Site	Willingboro	New Jersey	United States
63	Research Site	Albuquerque	New Mexico	United States
64	Research Site	Fresh Meadows	New York	United States
65	Research Site	Mount Kisco	New York	United States
66	Research Site	New York	New York	United States
67	Research Site	Rochester	New York	United States
68	Research Site	Staten Island	New York	United States
69	Research Site	Charlotte	North Carolina	United States
70	Research Site	Wilmington	North Carolina	United States
71	Research Site	Beechwood	Ohio	United States
72	Research Site	Canton	Ohio	United States
73	Research Site	Dayton	Ohio	United States
74	Research Site	Dublin	Ohio	United States
75	Research Site	Mason	Ohio	United States
76	Research Site	Middleburg Heights	Ohio	United States
77	Research Site	Toledo	Ohio	United States
78	Research Site	Portland	Oregon	United States
79	Research Site	Salem	Oregon	United States
80	Research Site	Jenkintown	Pennsylvania	United States
81	Research Site	Norristown	Pennsylvania	United States
82	Research Site	Pittsburgh	Pennsylvania	United States
83	Research Site	Charleston	South Carolina	United States
84	Research Site	Austin	Texas	United States
85	Research Site	Dallas	Texas	United States
86	Research Site	Friendswood	Texas	United States
87	Research Site	Irving	Texas	United States
88	Research Site	Lake Jackson	Texas	United States
89	Research Site	San Antonio	Texas	United States
90	Research Site	Woodstock	Vermont	United States
91	Research Site	Seattle	Washington	United States
92	Research Site	South Kirkland	Washington	United States
93	Research Site	Middleton	Wisconsin	United States
94	Research Site	San Juan		Puerto Rico

Sponsors and Collaborators

• AstraZeneca
• Targacept Inc.

Investigators

• Study Director: Hans A. Eriksson, MD, Ph.D, MBA, AstraZeneca
• Principal Investigator: Andrew . J Cutler, MD, Florida Clinical Research Center, LLC

Study Documents (Full-Text)

None provided.

More Information

Additional Information:

• CSR-D4130C00007.pdf
• D4130C00007/Clinical Study Protocol

Publications

None provided.

• Responsible Party: AstraZeneca
• ClinicalTrials.gov Identifier: NCT01152554
• Other Study ID Numbers: D4130C00007
• First Posted: Jun 29, 2010
• Last Update Posted: Apr 11, 2014
• Last Verified: Mar 1, 2014

• Keywords provided by AstraZeneca: Major Depressive Disorder; MDD; Depression; Safety; add-on therapy
• Additional relevant MeSH terms: Disease; Depression; Depressive Disorder; Depressive Disorder, Major

Study Results

Participant Flow

Recruitment Details	This multicenter study was conducted in the US between 22 June 2010 and 07 February 2012.
Pre-assignment Detail	The study had an up to 21-day screening/washout period, and an 6-week prospective open-label antidepressant treatment (ADT) period to identify the target patient population of inadequate responders to ADT (a HAMD-17 total score of ≥10 and a CGI-S score ≥3).

Arm/Group Title	TC-5214	Placebo
Arm/Group Description	Selective serotonin reuptake inhibitor (SSRI)/Serotonin/norepinephrine reuptake inhibitor (SNRI) + TC-5214, 1-4 mg BID	Selective serotonin reuptake inhibitor (SSRI)/Serotonin/norepinephrine reuptake inhibitor (SNRI) + Placebo BID
Period Title: Overall Study
STARTED	610	203
Received Treatment	607	201
COMPLETED	276	92
NOT COMPLETED	334	111

Baseline Characteristics

Arm/Group Title	TC-5214	Placebo	Total
Arm/Group Description	Selective serotonin reuptake inhibitor (SSRI)/Serotonin/norepinephrine reuptake inhibitor (SNRI) + TC-5214, 1-4 mg BID	Selective serotonin reuptake inhibitor (SSRI)/Serotonin/norepinephrine reuptake inhibitor (SNRI) + Placebo BID	Total of all reporting groups
Overall Participants	610	203	813
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	43.2 (11.68)	42.8 (11.75)	43.1 (11.69)
Sex: Female, Male (Count of Participants)
Female	418 68.5%	148 72.9%	566 69.6%
Male	192 31.5%	55 27.1%	247 30.4%
Race/Ethnicity, Customized (participants) [Number]
White	467 76.6%	149 73.4%	616 75.8%
Black or African American	121 19.8%	44 21.7%	165 20.3%
Asian	10 1.6%	4 2%	14 1.7%
Native Hawaiian or other Pacific Islander	1 0.2%	0 0%	1 0.1%
American Indian or Alaska Native	0 0%	2 1%	2 0.2%
Other	11 1.8%	4 2%	15 1.8%
Hamilton Rating Scale for Depression-17 items (HAMD-17) total score at randomization (Scores on a scale) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [Scores on a scale]	18.4 (4.49)	18.6 (4.61)	18.5 (4.52)
Montgomery-Asberg Depression Rating Scale (MADRS) total score at randomization (Scores on a scale) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [Scores on a scale]	23.5 (6.34)	23.4 (5.85)	23.4 (6.21)

Outcome Measures

1. Primary Outcome

Title	Frequency of Patients Experiencing at Least One Adverse Event (AE)
Description	The frequency of patients experiencing at least one AE during the randomized treatment or follow-up periods was calculated.
Time Frame	Randomization (Week 0) to end of the follow-up period (Week 54)

Outcome Measure Data

Analysis Population Description

Safety analysis set including all randomized patients who received at least 1 dose of investigational product (TC-5214 or placebo) and for whom any postdose data were available.

Arm/Group Title	TC-5214	Placebo
Arm/Group Description	Selective serotonin reuptake inhibitor (SSRI)/Serotonin/norepinephrine reuptake inhibitor (SNRI) + TC-5214, 1-4 mg BID	Selective serotonin reuptake inhibitor (SSRI)/Serotonin/norepinephrine reuptake inhibitor (SNRI) + Placebo BID
Measure Participants	607	201
Number [percentage of participants analyzed]	82.4 13.5%	84.6 41.7%

2. Primary Outcome

Title	Frequency of Patients Experiencing AEs That Resulted in Discontinuation of Investigational Product (IP)
Description	The frequency of patients experiencing AEs that resulted in discontinuation of IP during the randomized treatment or follow-up periods was calculated.
Time Frame	Randomization (Week 0) to end of the follow-up period (Week 54)

Outcome Measure Data

Analysis Population Description

Safety analysis set including all randomized patients who received at least 1 dose of investigational product (TC-5214 or placebo) and for whom any postdose data were available.

Arm/Group Title	TC-5214	Placebo
Arm/Group Description	Selective serotonin reuptake inhibitor (SSRI)/Serotonin/norepinephrine reuptake inhibitor (SNRI) + TC-5214, 1-4 mg BID	Selective serotonin reuptake inhibitor (SSRI)/Serotonin/norepinephrine reuptake inhibitor (SNRI) + Placebo BID
Measure Participants	607	201
Number [percentage of participants analyzed]	10.5 1.7%	7.0 3.4%

3. Primary Outcome

Title	Frequency of Patients Experiencing Serious Adverse Events (SAEs)
Description	The frequency of patients experiencing serious adverse events (SAEs) during the randomized treatment or follow-up periods was calculated.
Time Frame	Randomization (Week 0) to end of the follow-up period (Week 54)

Outcome Measure Data

Analysis Population Description

Safety analysis set including all randomized patients who received at least 1 dose of investigational product (TC-5214 or placebo) and for whom any postdose data were available.

Arm/Group Title	TC-5214	Placebo
Arm/Group Description	Selective serotonin reuptake inhibitor (SSRI)/Serotonin/norepinephrine reuptake inhibitor (SNRI) + TC-5214, 1-4 mg BID	Selective serotonin reuptake inhibitor (SSRI)/Serotonin/norepinephrine reuptake inhibitor (SNRI) + Placebo BID
Measure Participants	607	201
Number [percentage of participants analyzed]	3.6 0.6%	2.5 1.2%

4. Secondary Outcome

Title	Sustained Efficacy at 3 Months, Defined as a Montgomery-Asberg Depression Rating Scale (MADRS) Total Score of ≤12 at Week 12 and All Visits up to and Including Week 24
Description	The percentage of patients with a a MADRS total score of ≤12 at Week 12 and all visits up to and including Week 24 was calculated. One intermediate occurrence of a MADRS total score >12 but ≤16 or missing was allowed from Week 16 to Week 20. A 10-item scale for the evaluation of depressive symptoms. Each MADRS item is rated on a 0 to 6 scale. The MADRS total score is calculated as the sum of the 10 individual item scores; the total score can range from 0 to 60. Higher MADRS scores indicate higher levels of depressive symptoms.
Time Frame	Week 12 to Week 24

Outcome Measure Data

Analysis Population Description

Modified intent-to-treat analysis set including all randomized patients who received at least 1 dose of investigational product (TC-5214 or placebo) and who had a total MADRS score at randomization and a total HAMD-17 score ≥16 and a CGI-S score ≥4 at randomization.

Arm/Group Title	TC-5214	Placebo
Arm/Group Description	Selective serotonin reuptake inhibitor (SSRI)/Serotonin/norepinephrine reuptake inhibitor (SNRI) + TC-5214, 1-4 mg BID	Selective serotonin reuptake inhibitor (SSRI)/Serotonin/norepinephrine reuptake inhibitor (SNRI) + Placebo BID
Measure Participants	391	136
Number [percentage of participants analyzed]	18.2 3%	20.6 10.1%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	TC-5214, Placebo
	Comments	Logistic regression model including treatment and pooled center as fixed effects and the randomization MADRS total score as a covariate.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.697
	Comments
	Method	Regression, Logistic
	Comments
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	0.90
	Confidence Interval	(2-Sided) 95%; 0.54 to 1.50
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.24
	Estimation Comments	TC-5214 is the numerator in the OR, OR>1 represents a result in favor of TC-5214.

5. Secondary Outcome

Title	Sustained Efficacy at 9 Months, Defined as a MADRS Total Score of ≤12 at Week 12 and at All Visits up to and Including Week 52
Description	The percentage of patients with a MADRS total score of ≤12 at Week 12 and at all visits up to and including Week 52 was calculated. Two intermediate occurrences (not consecutive) of a MADRS >12 but ≤16 or missing were allowed from Week 16 to Week 48. A 10-item scale for the evaluation of depressive symptoms. Each MADRS item is rated on a 0 to 6 scale. The MADRS total score is calculated as the sum of the 10 individual item scores; the total score can range from 0 to 60. Higher MADRS scores indicate higher levels of depressive symptoms.
Time Frame	Week 12 to Week 52

Outcome Measure Data

Analysis Population Description

Modified intent-to-treat analysis set including all randomized patients who received at least 1 dose of investigational product (TC-5214 or placebo) and who had a total MADRS score at randomization and a total HAMD-17 score ≥16 and a CGI-S score ≥4 at randomization.

Arm/Group Title	TC-5214	Placebo
Arm/Group Description	Selective serotonin reuptake inhibitor (SSRI)/Serotonin/norepinephrine reuptake inhibitor (SNRI) + TC-5214, 1-4 mg BID	Selective serotonin reuptake inhibitor (SSRI)/Serotonin/norepinephrine reuptake inhibitor (SNRI) + Placebo BID
Measure Participants	391	136
Number [percentage of patients analyzed]	9.7	12.5

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	TC-5214, Placebo
	Comments	Logistic regression model including treatment and pooled center as fixed effects and the randomization MADRS total score as a covariate.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.582
	Comments
	Method	Regression, Logistic
	Comments
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	0.84
	Confidence Interval	(2-Sided) 95%; 0.45 to 1.57
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.27
	Estimation Comments	TC-5214 is the numerator in the OR, OR>1 represents a result in favor of TC-5214.

6. Secondary Outcome

Title	Change in the Clinician-rated Global Outcome of Severity as Measured by the Clinical Global Impression-Severity (CGI-S) Score From Randomization (Week 0) to End of Treatment (Week 52)
Description	A 3-part, clinician-administered scale that rates the improvement or worsening of the patient's illness from randomization (baseline). Each item is scored on a 1 to 7 scale. Higher CGI-S scores indicate greater illness severity.
Time Frame	Randomization (Week 0) to end of treatment (Week 52)

Outcome Measure Data

Analysis Population Description

Modified intent-to-treat analysis set including all randomized patients who received at least 1 dose of investigational product (TC-5214 or placebo) and who had a total MADRS score at randomization and a total HAMD-17 score ≥16 and a CGI-S score ≥4 at randomization.

Arm/Group Title	TC-5214	Placebo
Arm/Group Description	Selective serotonin reuptake inhibitor (SSRI)/Serotonin/norepinephrine reuptake inhibitor (SNRI) + TC-5214, 1-4 mg BID	Selective serotonin reuptake inhibitor (SSRI)/Serotonin/norepinephrine reuptake inhibitor (SNRI) + Placebo BID
Measure Participants	176	68
Mean (Standard Deviation) [units on a scale]	-1.8 (1.17)	-1.6 (1.17)

7. Secondary Outcome

Title	Change in Functional Impairment From Randomization (Week 0) to End of Treatment (Week 52) as Measured by the Sheehan Disability Scale (SDS) Total Score
Description	Sheehan Disability Scale (SDS) is 5-item, self-administered scale that measures the extent a patient is impaired by their disease. Higher scores indicate more severe impairment. The SDS total score is calculated as the sum of the score for the 3 inter-correlated domains (school/work, social life, and family life/home responsibilities) and ranges from 0 (unimpaired) to 30 (highly impaired).
Time Frame	Randomization (Week 0) to end of treatment (Week 52)

Outcome Measure Data

Analysis Population Description

Modified intent-to-treat analysis set including all randomized patients who received at least 1 dose of investigational product (TC-5214 or placebo) and who had a total MADRS score at randomization and a total HAMD-17 score ≥16 and a CGI-S score ≥4 at randomization.

Arm/Group Title	TC-5214	Placebo
Arm/Group Description	Selective serotonin reuptake inhibitor (SSRI)/Serotonin/norepinephrine reuptake inhibitor (SNRI) + TC-5214, 1-4 mg BID	Selective serotonin reuptake inhibitor (SSRI)/Serotonin/norepinephrine reuptake inhibitor (SNRI) + Placebo BID
Measure Participants	185	70
Mean (Standard Deviation) [units on a scale]	-6.98 (7.909)	-7.44 (7.530)

8. Secondary Outcome

Title	Change in Overall Quality of Life and Satisfaction From Randomization (Week 0) to End of Treatment (Week 52) by Assessing the Quality of Life Enjoyment and Satisfaction Questionnaire-Short Form (Q-LES-Q-SF) % Maximum Total Score
Description	The Q-LES-Q-SF total score is derived by summing item scores 1 to 14. Higher scores are indicative of greater enjoyment or satisfaction in each domain. The Q-LES-Q-SF % maximum total score is calculated as 100% × (Q-LES-Q-SF total score - 14) / 56, and can range from 0% to 100%.
Time Frame	Randomization (Week 0) to end of treatment (Week 52)

Outcome Measure Data

Analysis Population Description

Modified intent-to-treat analysis set including all randomized patients who received at least 1 dose of investigational product (TC-5214 or placebo) and who had a total MADRS score at randomization and a total HAMD-17 score ≥16 and a CGI-S score ≥4 at randomization.

Arm/Group Title	TC-5214	Placebo
Arm/Group Description	Selective serotonin reuptake inhibitor (SSRI)/Serotonin/norepinephrine reuptake inhibitor (SNRI) + TC-5214, 1-4 mg BID	Selective serotonin reuptake inhibitor (SSRI)/Serotonin/norepinephrine reuptake inhibitor (SNRI) + Placebo BID
Measure Participants	184	70
Mean (Standard Deviation) [units on a scale]	10.83 (18.744)	11.62 (17.006)

9. Secondary Outcome

Title	Change in EuroQol - 5 Dimensions (EQ-5D) From Randomization (Week 0) to End of Treatment (Week 52)
Description	A self-assessment questionnaire that provides 2 measures of health status. The EQ-5D index score is a weighted linear combination over 5 dimensions of health status. The score for each of the 5 dimensions can range from 1 to 3, and an equation is used to calculate the EQ-5D index score. The EQ-5D index score can range from possible negative values to a maximum of 1.0. The EQ-VAS is a visual analog scale with a range of 0 to 100. For both variables, a higher score indicates a better health state.
Time Frame	Randomization (Week 0) to end of treatment (Week 52)

Outcome Measure Data

Analysis Population Description

Modified intent-to-treat analysis set including all randomized patients who received at least 1 dose of investigational product (TC-5214 or placebo) and who had a total MADRS score at randomization and a total HAMD-17 score ≥16 and a CGI-S score ≥4 at randomization.

Arm/Group Title	TC-5214	Placebo
Arm/Group Description	Selective serotonin reuptake inhibitor (SSRI)/Serotonin/norepinephrine reuptake inhibitor (SNRI) + TC-5214, 1-4 mg BID	Selective serotonin reuptake inhibitor (SSRI)/Serotonin/norepinephrine reuptake inhibitor (SNRI) + Placebo BID
Measure Participants	177	68
EQ-5D index score	0.081 (0.2021)	0.071 (0.1500)
EQ-5D VAS score	8.7 (20.04)	11.9 (21.06)

Adverse Events

Arm/Group Title	Placebo		TC-5214
Arm/Group Description	Selective serotonin reuptake inhibitor (SSRI)/Serotonin/norepinephrine reuptake inhibitor (SNRI) + Placebo		Selective serotonin reuptake inhibitor (SSRI)/Serotonin/norepinephrine reuptake inhibitor (SNRI) + TC-5214, 1-4 mg BID
All Cause Mortality
	Placebo		TC-5214
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	Placebo		TC-5214
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	5/201 (2.5%)		22/607 (3.6%)
Cardiac disorders
Bradycardia	0/201 (0%)	0	1/607 (0.2%)	1
Gastrointestinal disorders
Abdominal Hernia	0/201 (0%)	0	1/607 (0.2%)	1
Diverticulum	0/201 (0%)	0	1/607 (0.2%)	1
Haemorrhoids	0/201 (0%)	0	1/607 (0.2%)	1
Small Intestinal Obstruction	0/201 (0%)	0	1/607 (0.2%)	1
Infections and infestations
Cellulitis	0/201 (0%)	0	2/607 (0.3%)	2
Oral Infection	0/201 (0%)	0	1/607 (0.2%)	1
Pneumonia	0/201 (0%)	0	1/607 (0.2%)	1
Injury, poisoning and procedural complications
Brain Contusion	0/201 (0%)	0	1/607 (0.2%)	1
Cervical Vertebral Fracture	0/201 (0%)	0	1/607 (0.2%)	1
Contusion	0/201 (0%)	0	1/607 (0.2%)	1
Facial Bones Fracture	0/201 (0%)	0	1/607 (0.2%)	1
Fibula Fracture	0/201 (0%)	0	1/607 (0.2%)	1
Intentional Overdose	1/201 (0.5%)	1	0/607 (0%)	0
Tibia Fracture	0/201 (0%)	0	1/607 (0.2%)	1
Toxicity To Various Agents	0/201 (0%)	0	1/607 (0.2%)	1
Metabolism and nutrition disorders
Diabetic Ketoacidosis	1/201 (0.5%)	1	0/607 (0%)	0
Musculoskeletal and connective tissue disorders
Musculoskeletal Chest Pain	0/201 (0%)	0	1/607 (0.2%)	1
Nervous system disorders
Subarachnoid Haemorrhage	1/201 (0.5%)	1	0/607 (0%)	0
Pregnancy, puerperium and perinatal conditions
Abortion Spontaneous	1/201 (0.5%)	1	1/607 (0.2%)	1
Psychiatric disorders
Alcohol Withdrawal Syndrome	0/201 (0%)	0	1/607 (0.2%)	1
Psychotic Disorder	0/201 (0%)	0	1/607 (0.2%)	1
Suicidal Ideation	0/201 (0%)	0	2/607 (0.3%)	2
Suicide Attempt	0/201 (0%)	0	2/607 (0.3%)	2
Reproductive system and breast disorders
Ovarian Torsion	0/201 (0%)	0	1/607 (0.2%)	1
Vaginal Haemorrhage	1/201 (0.5%)	1	0/607 (0%)	0
Respiratory, thoracic and mediastinal disorders
Atelectasis	1/201 (0.5%)	1	0/607 (0%)	0
Vascular disorders
Hypertensive Crisis	0/201 (0%)	0	1/607 (0.2%)	1
Other (Not Including Serious) Adverse Events
	Placebo		TC-5214
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	151/201 (75.1%)		451/607 (74.3%)
Gastrointestinal disorders
Constipation	12/201 (6%)	14	120/607 (19.8%)	147
Diarrhoea	20/201 (10%)	23	65/607 (10.7%)	80
Nausea	24/201 (11.9%)	27	64/607 (10.5%)	79
Dry Mouth	10/201 (5%)	11	59/607 (9.7%)	61
Vomiting	13/201 (6.5%)	21	32/607 (5.3%)	40
Abdominal Pain	4/201 (2%)	4	12/607 (2%)	12
Abdominal Pain Upper	2/201 (1%)	2	14/607 (2.3%)	16
Flatulence	4/201 (2%)	4	14/607 (2.3%)	15
Abdominal Distension	4/201 (2%)	5	5/607 (0.8%)	5
General disorders
Fatigue	17/201 (8.5%)	18	39/607 (6.4%)	43
Immune system disorders
Seasonal Allergy	5/201 (2.5%)	5	11/607 (1.8%)	12
Infections and infestations
Upper Respiratory Tract Infection	30/201 (14.9%)	39	104/607 (17.1%)	122
Nasopharyngitis	22/201 (10.9%)	26	59/607 (9.7%)	70
Sinusitis	11/201 (5.5%)	14	28/607 (4.6%)	32
Urinary Tract Infection	10/201 (5%)	11	26/607 (4.3%)	30
Influenza	7/201 (3.5%)	8	19/607 (3.1%)	22
Bronchitis	5/201 (2.5%)	5	12/607 (2%)	12
Gastroenteritis	5/201 (2.5%)	6	14/607 (2.3%)	14
Gastroenteritis Viral	5/201 (2.5%)	5	13/607 (2.1%)	13
Injury, poisoning and procedural complications
Contusion	6/201 (3%)	6	5/607 (0.8%)	5
Muscle Strain	4/201 (2%)	4	7/607 (1.2%)	7
Weight Increased	14/201 (7%)	14	27/607 (4.4%)	27
Blood Pressure Increased	5/201 (2.5%)	6	8/607 (1.3%)	9
Metabolism and nutrition disorders
Increased Appetite	5/201 (2.5%)	5	11/607 (1.8%)	13
Musculoskeletal and connective tissue disorders
Arthralgia	10/201 (5%)	12	26/607 (4.3%)	35
Back Pain	18/201 (9%)	21	20/607 (3.3%)	23
Muscle Spasms	5/201 (2.5%)	5	15/607 (2.5%)	16
Musculoskeletal Pain	6/201 (3%)	7	13/607 (2.1%)	13
Neck Pain	4/201 (2%)	4	11/607 (1.8%)	11
Pain In Extremity	4/201 (2%)	5	11/607 (1.8%)	11
Myalgia	7/201 (3.5%)	8	9/607 (1.5%)	11
Nervous system disorders
Headache	34/201 (16.9%)	52	102/607 (16.8%)	170
Dizziness	16/201 (8%)	24	75/607 (12.4%)	99
Dizziness Postural	3/201 (1.5%)	3	28/607 (4.6%)	43
Somnolence	9/201 (4.5%)	9	31/607 (5.1%)	33
Sedation	4/201 (2%)	4	12/607 (2%)	12
Memory Impairment	4/201 (2%)	4	5/607 (0.8%)	6
Migraine	5/201 (2.5%)	5	8/607 (1.3%)	8
Paraesthesia	5/201 (2.5%)	6	7/607 (1.2%)	7
Tremor	4/201 (2%)	4	5/607 (0.8%)	5
Psychiatric disorders
Insomnia	18/201 (9%)	20	47/607 (7.7%)	52
Abnormal Dreams	7/201 (3.5%)	7	28/607 (4.6%)	29
Agitation	5/201 (2.5%)	6	21/607 (3.5%)	22
Anxiety	1/201 (0.5%)	1	15/607 (2.5%)	17
Bruxism	4/201 (2%)	4	3/607 (0.5%)	3
Respiratory, thoracic and mediastinal disorders
Cough	5/201 (2.5%)	5	15/607 (2.5%)	15
Nasal Congestion	4/201 (2%)	5	11/607 (1.8%)	12
Oropharyngeal Pain	5/201 (2.5%)	5	13/607 (2.1%)	13
Wheezing	4/201 (2%)	4	1/607 (0.2%)	1
Skin and subcutaneous tissue disorders
Hyperhidrosis	5/201 (2.5%)	5	17/607 (2.8%)	19
Rash	4/201 (2%)	4	6/607 (1%)	6
Vascular disorders
Hypertension	9/201 (4.5%)	9	15/607 (2.5%)	15
Orthostatic Hypotension	0/201 (0%)	0	13/607 (2.1%)	15

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

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

The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is more than 60 days but less than or equal to 180 days. The sponsor cannot require changes to the communication and cannot extend the embargo.