A Study to Assess the Efficacy and Safety of TC-5214 as an Adjunct Therapy in Patients With Major Depressive Disorder (MDD)

• Sponsor: AstraZeneca (Industry)
• Overall Status: Completed
• CT.gov ID: NCT01157078
• Collaborator: Targacept Inc. (Industry)
• Enrollment: 319
• Locations: 51
• Arms: 2
• Duration (Months): 17
• Patients Per Site: 6.3
• 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 together with another antidepressant.

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

Detailed Description

A multicenter, randomized, double-blind, parallel group, placebo-controlled, phase III efficacy and safety study of TC-5214 (S-mecamylamine) in flexible doses as an adjunct to an antidepressant in patients with major depressive disorder with an inadequate response to antidepressant therapy.

Study Design

• Study Type: Interventional
• Actual Enrollment: 319 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 Efficacy and Safety Study of TC-5214 (S-mecamylamine) in Flexible Doses as an Adjunct to an Antidepressant in Patients With Major Depressive Disorder With an Inadequate Response to Antidepressant Therapy
• Study Start Date: Jun 1, 2010
• Actual Primary Completion Date: Nov 1, 2011
• Actual Study Completion Date: Nov 1, 2011

Arms and Interventions

Arm	Intervention/Treatment
Experimental: TC-5214 Selective serotonin reuptake inhibitor (SSRI)/Serotonin/norepinephrine reuptake inhibitor (SNRI) + TC-5214, 1-4 mg BID	Drug: TC-5214; Tablet, oral, twice daily for 8 weeks
Placebo Comparator: Placebo Selective serotonin reuptake inhibitor (SSRI)/Serotonin/norepinephrine reuptake inhibitor (SNRI) + Placebo BID	Drug: Placebo; Tablet, oral, twice daily for 8 weeks

Outcome Measures

Primary Outcome Measures

1. Change in the Montgomery-Asberg Depression Rating Scale (MADRS) Total Score From Randomization to End of Treatment. [Randomization (Week 8) to end of treatment (Week 16)]

   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.

Secondary Outcome Measures

1. Response in Depressive Symptoms of Major Depressive Disorder (MDD), Defined as a ≥50% Reduction From Randomization (Week 8) in MADRS Total Score at End of Treatment (Week 16) [Randomization (Week 8) to end of treatment (Week 16)]

   The percentage of patients with a ≥50% reduction from randomization (Week 8) in MADRS total score at end of treatment (Week 16) was calculated. MADRS is 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. Remission in Depressive Symptoms of MDD, Defined as MADRS Total Score of ≤8 at End of Treatment (Week 16) [Week 16]

   The percentage of patients with a MADRS total score of ≤8 at end of treatment (Week 16) was calculated. MADRS is 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. Early and Sustained Response, Defined as a ≥50% Reduction From Randomization (Week 8) in MADRS Total Score and a MADRS Total Score of ≤12 at Week 10, Week 12, Week 14, and End of Treatment (Week 16) [Randomization (Week 8) to end of treatment (Week 16); Week 10, Week 12, Week 14, and Week 16]

   The percentage of patients with a ≥50% reduction from randomization (Week 8) in MADRS total score and a MADRS total score of ≤12 at Week 10, Week 12, Week 14, and end of treatment (Week 16) was calculated. MADRS is 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.

4. Sustained Response, Defined as a ≥50% Reduction From Randomization (Week 8) in MADRS Total Score and a MADRS Total Score of ≤12 at Week 12, Week 14, and End of Treatment (Week 16) [Randomization (Week 8) to end of treatment (Week 16); Week 12, Week 14, and Week 16]

   The percentage of patients with a ≥50% reduction from randomization (Week 8) in MADRS total score and a MADRS total score of ≤12 at Week 12, Week 14, and end of treatment (Week 16) was calculated. MADRS is 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.

5. Sustained Remission, Defined as a MADRS Total Score of ≤8 at Week 12, Week 14, and End of Treatment (Week 16) [Week 12, Week 14, Week 16]

   The percentage of patients with a MADRS total score of ≤8 at Week 12, Week 14, and end of treatment (Week 16)was calculated. MADRS is 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.

6. Change in Depressive Symptoms From Randomization (Week 8) to End of Treatment (Week 16) as Measured by Hamilton Rating Scale for Depression-17 Items (HAMD-17) Total Score [Randomization (Week 8) to end of treatment (Week 16)]

   A 17-item, clinician-rated scale that assesses depressive symptoms. The HAMD-17 consists of 17 symptoms, each of which is rated from 0 to 2 or 0 to 4, where 0 is none/absent. The HAMD-17 total score is calculated as the sum of the 17 individual symptom scores; the total score can range from 0 to 52. Higher HAMD-17 scores indicate more severe depression.

7. Change in the Clinician-rated Global Outcome of Severity as Measured by the Clinical Global Impression-Severity (CGI-S) Score From Randomization (Week 8) to End of Treatment (Week 16) [Randomization (Week 8) to end of treatment (Week 16)]

   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.

8. Response in the Clinical Global Impression-Improvement (CGI-I) Defined as CGI-I Rating of "Very Much Improved" or "Much Improved" From Randomization (Week 8) to End of Treatment (Week 16) [Randomization (Week 8) to end of treatment (Week 16)]

   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. CGI-I scores >4 indicate worsening, while scores <4 indicate improvement.

9. Change in MADRS Total Score From Randomization (Week 8) to Week 9 [Randomization (Week 8) to Week 9]

   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. MADRS is 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.

10. Change in MADRS Total Score From Randomization (Week 8) to Week 10 [Randomization (Week 8) to Week 10]

    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.

11. Change in MADRS Total Score From Randomization (Week 8) to Week 12 [Randomization (Week 8) to Week 12]

    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.

12. Change in MADRS Total Score From Randomization (Week 8) to Week 14 [Randomization (Week 8) to Week 14]

    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.

13. Change in Functional Impairment From Randomization (Week 8) to End of Treatment (Week 16) as Measured by the Sheehan Disability Scale (SDS) Total Score [Randomization (Week 8) to end of treatment (Week 16)]

    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).

14. Change in Functional Impairment From Randomization (Week 8) to End of Treatment (Week 16) as Measured by SDS Work/School Domain Score [Randomization (Week 8) to end of treatment (Week 16)]

    A 5-item, self-administered scale that measures the extent a patient is impaired by their disease. Higher scores indicate more severe impairment. The 3 inter-correlated domains are school/work, social life, and family life/home responsibilities. The numerical rating for the work/school domain score is 0- 10, where 10 is considered to be 'highly impaired'.

15. Change in Functional Impairment From Randomization (Week 8) to End of Treatment (Week 16) as Measured by SDS Social Life Domain Score [Randomization (Week 8) to end of treatment (Week 16)]

    A 5-item, self-administered scale that measures the extent a patient is impaired by their disease. Higher scores indicate more severe impairment. The 3 inter-correlated domains are school/work, social life, and family life/home responsibilities. The numerical rating for the SDS social life domain score is 0- 10, where 10 is considered to be 'highly impaired'.

16. Change in Functional Impairment From Randomization (Week 8) to End of Treatment (Week 16) as Measured by SDS Family Life/Home Responsibilities Domain Score [Randomization (Week 8) to end of treatment (Week 16)]

    A 5-item, self-administered scale that measures the extent a patient is impaired by their disease. Higher scores indicate more severe impairment. The 3 inter-correlated domains are school/work, social life, and family life/home responsibilities. The numerical rating for the SDS family life/home responsibilities domain score is 0- 10, where 10 is considered to be 'highly impaired'.

17. Change in Overall Quality of Life and Satisfaction From Randomization (Week 8) to End of Treatment (Week 16) by Assessing the Quality of Life Enjoyment and Satisfaction Questionnaire-Short Form (Q-LES-Q-SF) % Maximum Total Score [Randomization (Week 8) to end of treatment (Week 16)]

    The Q-LES-Q-SF (Quality of Life Enjoyment and Satisfaction Questionnaire-Short Form)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%.

18. Change From Randomization (Week 8) to End of Treatment (Week 16) in Quality of Life Enjoyment and Satisfaction Questionnaire-Short Form (Q LES-Q-SF) Item 15 [Randomization (Week 8) to end of treatment (Week 16)]

    The Q-LES-Q-SF (Quality of Life Enjoyment and Satisfaction Questionnaire-Short Form) measures the patient's satisfaction with medication and overall quality of life. The 15th item queries respondents' satisfaction with the medication they are taking, rated on a 1 to 4 scale, score 0 indicates that no medication was taken. Higher scores are indicative of greater satisfaction.

19. Change From Randomization (Week 8) to End of Treatment (Week 16) in Quality of Life Enjoyment and Satisfaction Questionnaire-Short Form (Q LES-Q-SF) Item 16 [Randomization (Week 8) to end of treatment (Week 16)]

    The Q-LES-Q-SF (Quality of Life Enjoyment and Satisfaction Questionnaire-Short Form) measures the patient's satisfaction with medication and overall quality of life. The 16th item is a global rating of overall life satisfaction and contentment, rated on a 1 to 5 scale. Higher scores are indicative of greater satisfaction.

20. Change in Irritability Symptoms as Measured by the Sheehan Irritability Scale (SIS) Total Score From Randomization (Week 8) to End of Treatment (Week 16) [Randomization (Week 8) to end of treatment (Week 16)]

    A self-administered scale to be used by clinical subjects to rate suffering over the past week with regard to irritability symptoms. The total SIS score is the sum of 7 items, and ranges from 0 to 70. Each item is assessed on an 11-point scale where 0=not at all, 1-3=mildly, 4-6=moderately, 7-9=markedly, and 10=extremely. The SIS also records the number of days impaired by irritability.

21. Change in EuroQol - 5 Dimensions (EQ-5D) From Randomization (Week 8) to End of Treatment (Week 16) [Randomization (Week 8) to end of treatment (Week 16)]

    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 (minimum -0.415) 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.

• Out-patient 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.

• History of renal insufficiency or impairment or conditions that could affect absorption or metabolism of the investigational product in this patient population

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Research Site	Tuscaloosa	Alabama	United States
2	Research Site	Tucson	Arizona	United States
3	Research Site	Little Rock	Arkansas	United States
4	Research Site	Chino	California	United States
5	Research Site	Costa Mesa	California	United States
6	Research Site	Encino	California	United States
7	Research Site	Escondido	California	United States
8	Research Site	Los Alamitos	California	United States
9	Research Site	Oceanside	California	United States
10	Research Site	Pico Rivera	California	United States
11	Research Site	San Diego	California	United States
12	Research Site	Torrance	California	United States
13	Research Site	Hamden	Connecticut	United States
14	Research Site	Coral Springs	Florida	United States
15	Research Site	Jacksonville	Florida	United States
16	Research Site	Orange City	Florida	United States
17	Research Site	Orlando	Florida	United States
18	Research Site	Tampa	Florida	United States
19	Research Site	Chicago	Illinois	United States
20	Research Site	Prairie Village	Kansas	United States
21	Research Site	Florence	Kentucky	United States
22	Research Site	Shreveport	Louisiana	United States
23	Research Site	St. Louis	Missouri	United States
24	Research Site	New York	New York	United States
25	Research Site	Rochester	New York	United States
26	Research Site	Staten Island	New York	United States
27	Research Site	Cincinnati	Ohio	United States
28	Research Site	Dayton	Ohio	United States
29	Research Site	Middleburg Heights	Ohio	United States
30	Research Site	Portland	Oregon	United States
31	Research Site	Salem	Oregon	United States
32	Research Site	Norristown	Pennsylvania	United States
33	Research Site	Charleston	South Carolina	United States
34	Research Site	Dallas	Texas	United States
35	Research Site	Houston	Texas	United States
36	Research Site	Woodstock	Vermont	United States
37	Research Site	Seattle	Washington	United States
38	Research Site	Visakhapatnam	Andh Prad	India
39	Research Site	Guntur	Andhra Pradesh	India
40	Research Site	Ahmedabad	Gujarat	India
41	Research Site	Rajkot	Gujrat	India
42	Research Site	Mangalore	Karnataka	India
43	Research Site	Aurangabad	Maharashtra	India
44	Research Site	Pune	Maharashtra	India
45	Research Site	Nashik	Mahara	India
46	Research Site	Jaipur	Rajasthan	India
47	Research Site	Khatipura	Rajasthan	India
48	Research Site	Madurai	Tamilnadu	India
49	Research Site	Varanasi	Uttar Prad	India
50	Research Site	Kanpur		India
51	Research Site	Mysore		India

Sponsors and Collaborators

• AstraZeneca
• Targacept Inc.

Investigators

• Study Director: Hans A. Eriksson, MD, Ph.D, MBA, AstraZeneca R&D
• Principal Investigator: Bernadette D'Souza, MD, Midwest Clinical Research Center, Ohio

Study Documents (Full-Text)

None provided.

More Information

Additional Information:

• CSR-D4130C00002.pdf
• D4130C00002_Clinical_Study_Protocol

Publications

None provided.

• Responsible Party: AstraZeneca
• ClinicalTrials.gov Identifier: NCT01157078
• Other Study ID Numbers: D4130C00002
• First Posted: Jul 5, 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 United States and India between 22 June 2010 and 17 November 2011.
Pre-assignment Detail	The study had an up to 21-day screening/washout period, and an 8-week prospective open-label antidepressant treatment (ADT) period to identify the target patient population of inadequate responders to ADT (<50% reduction in HAMD-17 total score during the prospective open-label ADT period, a HAMD-17 total score of ≥16 and a CGI-S score ≥4).

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	159	160
Received Treatment	157	159
COMPLETED	124	124
NOT COMPLETED	35	36

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	159	160	319
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	39.7 (11.37)	41.0 (11.53)	40.4 (11.45)
Sex: Female, Male (Count of Participants)
Female	101 63.5%	99 61.9%	200 62.7%
Male	58 36.5%	61 38.1%	119 37.3%
Race/Ethnicity, Customized (participants) [Number]
White	99 62.3%	100 62.5%	199 62.4%
Black or African American	11 6.9%	19 11.9%	30 9.4%
Asian	48 30.2%	37 23.1%	85 26.6%
Native Hawaiian or other Pacific Islander	0 0%	0 0%	0 0%
American Indian or Alaska Native	0 0%	1 0.6%	1 0.3%
Other	1 0.6%	3 1.9%	4 1.3%
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]	22.0 (4.13)	21.1 (3.81)	21.5 (3.98)
Montgomery-Asberg Depression Rating Scale (MADRS) total score at randomization (Scores on a scale) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [Scores on a scale]	27.4 (5.58)	26.6 (5.63)	27.0 (5.61)

Outcome Measures

1. Primary Outcome

Title	Change in the Montgomery-Asberg Depression Rating Scale (MADRS) Total Score From Randomization to End of Treatment.
Description	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	Randomization (Week 8) to end of treatment (Week 16)

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 randomization and at least 1 post-randomization MADRS total score.

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	151	157
Least Squares Mean (Standard Error) [units on a scale]	-12.7 (0.80)	-11.7 (0.80)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	TC-5214, Placebo
	Comments	Mixed model repeated measures (MMRM) includes treatment, pooled center, visit and treatment by visit interaction as explanatory variables and the randomization MADRS total score as a covariate. Treatment, visit and treatment by visit interaction are fixed effects in the model; pooled center is a random effect.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.349
	Comments	The adjusted p-value protects the overall family-wise error rate by taking into account the multiple comparisons between the TC-5214 doses for both the primary efficacy variable (MADRS) and the key secondary efficacy variable (SDS).
	Method	MMRM
	Comments
Method of Estimation	Estimation Parameter	LS mean
	Estimated Value	-1.0
	Confidence Interval	(2-Sided) 95%; -3.14 to 1.11
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 1.08
	Estimation Comments

2. Secondary Outcome

Title	Response in Depressive Symptoms of Major Depressive Disorder (MDD), Defined as a ≥50% Reduction From Randomization (Week 8) in MADRS Total Score at End of Treatment (Week 16)
Description	The percentage of patients with a ≥50% reduction from randomization (Week 8) in MADRS total score at end of treatment (Week 16) was calculated. MADRS is 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	Randomization (Week 8) to end of treatment (Week 16)

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 randomization and at least 1 post-randomization MADRS total score.

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	151	157
Number [percentage of participants analyzed]	42.0 26.4%	47.0 29.4%

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	0.444
	Comments
	Method	Regression, Logistic
	Comments
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	1.20
	Confidence Interval	(2-Sided) 95%; 0.75 to 1.92
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.29
	Estimation Comments	TC-5214 is the numerator in the OR, OR>1 represents a result in favor of TC-5214.

3. Secondary Outcome

Title	Remission in Depressive Symptoms of MDD, Defined as MADRS Total Score of ≤8 at End of Treatment (Week 16)
Description	The percentage of patients with a MADRS total score of ≤8 at end of treatment (Week 16) was calculated. MADRS is 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 16

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 randomization and at least 1 post-randomization MADRS total score.

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	151	157
Number [percentage of participants analyzed]	30.5 19.2%	24.2 15.1%

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	0.130
	Comments
	Method	Regression, Logistic
	Comments
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	1.52
	Confidence Interval	(2-Sided) 95%; 0.88 to 2.61
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.42
	Estimation Comments	TC-5214 is the numerator in the OR, OR>1 represents a result in favor of TC-5214.

4. Secondary Outcome

Title	Early and Sustained Response, Defined as a ≥50% Reduction From Randomization (Week 8) in MADRS Total Score and a MADRS Total Score of ≤12 at Week 10, Week 12, Week 14, and End of Treatment (Week 16)
Description	The percentage of patients with a ≥50% reduction from randomization (Week 8) in MADRS total score and a MADRS total score of ≤12 at Week 10, Week 12, Week 14, and end of treatment (Week 16) was calculated. MADRS is 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	Randomization (Week 8) to end of treatment (Week 16); Week 10, Week 12, Week 14, and Week 16

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 randomization and at least 1 post-randomization MADRS total score.

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	150	153
Number [percentage of participants analyzed]	6.0 3.8%	3.9 2.4%

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	0.307
	Comments
	Method	Regression, Logistic
	Comments
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	1.75
	Confidence Interval	(2-Sided) 95%; 0.60 to 5.14
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.96
	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 Response, Defined as a ≥50% Reduction From Randomization (Week 8) in MADRS Total Score and a MADRS Total Score of ≤12 at Week 12, Week 14, and End of Treatment (Week 16)
Description	The percentage of patients with a ≥50% reduction from randomization (Week 8) in MADRS total score and a MADRS total score of ≤12 at Week 12, Week 14, and end of treatment (Week 16) was calculated. MADRS is 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	Randomization (Week 8) to end of treatment (Week 16); Week 12, Week 14, and Week 16

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 randomization and at least 1 post-randomization MADRS total score.

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	148	152
Number [percentage of patients analyzed]	14.2	11.8

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	0.313
	Comments
	Method	Regression, Logistic
	Comments
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	1.44
	Confidence Interval	(2-Sided) 95%; 0.71 to 2.94
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.52
	Estimation Comments	TC-5214 is the numerator in the OR, OR>1 represents a result in favor of TC-5214.

6. Secondary Outcome

Title	Sustained Remission, Defined as a MADRS Total Score of ≤8 at Week 12, Week 14, and End of Treatment (Week 16)
Description	The percentage of patients with a MADRS total score of ≤8 at Week 12, Week 14, and end of treatment (Week 16)was calculated. MADRS is 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, Week 14, Week 16

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 randomization and at least 1 post-randomization MADRS total score.

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	148	153
Number [percentage of participants analyzed]	9.5 6%	6.5 4.1%

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	0.201
	Comments
	Method	Regression, Logistic
	Comments
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	1.77
	Confidence Interval	(2-Sided) 95%; 0.74 to 4.24
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.79
	Estimation Comments	TC-5214 is the numerator in the OR, OR>1 represents a result in favor of TC-5214.

7. Secondary Outcome

Title	Change in Depressive Symptoms From Randomization (Week 8) to End of Treatment (Week 16) as Measured by Hamilton Rating Scale for Depression-17 Items (HAMD-17) Total Score
Description	A 17-item, clinician-rated scale that assesses depressive symptoms. The HAMD-17 consists of 17 symptoms, each of which is rated from 0 to 2 or 0 to 4, where 0 is none/absent. The HAMD-17 total score is calculated as the sum of the 17 individual symptom scores; the total score can range from 0 to 52. Higher HAMD-17 scores indicate more severe depression.
Time Frame	Randomization (Week 8) to end of treatment (Week 16)

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 randomization and at least 1 post-randomization MADRS total score.

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	139	145
Least Squares Mean (Standard Error) [units on a scale]	-9.7 (0.96)	-9.3 (0.96)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	TC-5214, Placebo
	Comments	Analysis of covariance (ANCOVA) with randomization HAMD-17 total score as covariate, treatment as a fixed effect and pooled center as a random effect.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.552
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	LS mean
	Estimated Value	-0.5
	Confidence Interval	(2-Sided) 95%; -2.10 to 1.12
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.82
	Estimation Comments

8. 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 8) to End of Treatment (Week 16)
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 8) to end of treatment (Week 16)

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 randomization and at least 1 post-randomization MADRS total score.

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	151	157
Least Squares Mean (Standard Error) [units on a scale]	-1.4 (0.11)	-1.3 (0.11)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	TC-5214, Placebo
	Comments	MMRM model includes treatment, pooled center, visit, and treatment by visit interaction as explanatory variables and the randomization CGI-S total score as a covariate. Treatment, visit, and treatment by visit interaction are fixed effects in the model; pooled center is a random effect.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.803
	Comments
	Method	MMRM
	Comments
Method of Estimation	Estimation Parameter	LS mean
	Estimated Value	0.0
	Confidence Interval	() 95%; -0.31 to 0.24
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.14
	Estimation Comments

9. Secondary Outcome

Title	Response in the Clinical Global Impression-Improvement (CGI-I) Defined as CGI-I Rating of "Very Much Improved" or "Much Improved" From Randomization (Week 8) to End of Treatment (Week 16)
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. CGI-I scores >4 indicate worsening, while scores <4 indicate improvement.
Time Frame	Randomization (Week 8) to end of treatment (Week 16)

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 randomization and at least 1 post-randomization MADRS total score.

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	151	157
Number [percentage of participants analyzed]	56.3 35.4%	51.0 31.9%

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 Clinical Global Impression Severity (CGI-S) as a covariate.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.440
	Comments
	Method	Regression, Logistic
	Comments
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	1.20
	Confidence Interval	(2-Sided) 95%; 0.75 to 1.91
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.28
	Estimation Comments	TC-5214 is the numerator in the OR, OR>1 represents a result in favor of TC-5214.

10. Secondary Outcome

Title	Change in MADRS Total Score From Randomization (Week 8) to Week 9
Description	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. MADRS is 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	Randomization (Week 8) to Week 9

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 randomization and at least 1 post-randomization MADRS total score.

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	142	151
Least Squares Mean (Standard Error) [units on a scale]	-3.6 (0.45)	-3.8 (0.45)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	TC-5214, Placebo
	Comments	MMRM model includes treatment, pooled center, visit and treatment by visit interaction as explanatory variables and the randomization MADRS total score as a covariate. Treatment, visit and treatment by visit interaction are fixed effects in the model; pooled center is a random effect.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.768
	Comments	Analysis for change in MADRS total score from randomization to Week 9.
	Method	MMRM
	Comments
Method of Estimation	Estimation Parameter	LS mean
	Estimated Value	0.2
	Confidence Interval	(2-Sided) 95%; -0.91 to 1.23
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.55
	Estimation Comments

11. Secondary Outcome

Title	Change in MADRS Total Score From Randomization (Week 8) to Week 10
Description	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	Randomization (Week 8) to Week 10

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 randomization and at least 1 post-randomization MADRS total score.

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	147	146
Least Squares Mean (Standard Error) [units on a scale]	-6.1 (0.60)	-6.8 (0.60)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	TC-5214, Placebo
	Comments	MMRM model includes treatment, pooled center, visit and treatment by visit interaction as explanatory variables and the randomization MADRS total score as a covariate. Treatment, visit and treatment by visit interaction are fixed effects in the model; pooled center is a random effect.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.373
	Comments
	Method	MMRM
	Comments
Method of Estimation	Estimation Parameter	LS mean
	Estimated Value	0.7
	Confidence Interval	(2-Sided) 95%; -0.84 to 2.24
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.78
	Estimation Comments

12. Secondary Outcome

Title	Change in MADRS Total Score From Randomization (Week 8) to Week 12
Description	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	Randomization (Week 8) to Week 12

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 randomization and at least 1 post-randomization MADRS total score.

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	139	144
Least Squares Mean (Standard Error) [units on a scale]	-8.7 (0.68)	-8.0 (0.67)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	TC-5214, Placebo
	Comments	MMRM model includes treatment, pooled center, visit and treatment by visit interaction as explanatory variables and the randomization MADRS total score as a covariate. Treatment, visit and treatment by visit interaction are fixed effects in the model; pooled center is a random effect.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.435
	Comments
	Method	MMRM
	Comments
Method of Estimation	Estimation Parameter	LS mean
	Estimated Value	-0.7
	Confidence Interval	(2-Sided) 95%; -2.47 to 1.07
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.90
	Estimation Comments

13. Secondary Outcome

Title	Change in MADRS Total Score From Randomization (Week 8) to Week 14
Description	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	Randomization (Week 8) to Week 14

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 randomization and at least 1 post-randomization MADRS total score.

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	133	136
Least Squares Mean (Standard Error) [units on a scale]	-11.1 (0.72)	-10.5 (0.72)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	TC-5214, Placebo
	Comments	MMRM model includes treatment, pooled center, visit and treatment by visit interaction as explanatory variables and the randomization MADRS total score as a covariate. Treatment, visit and treatment by visit interaction are fixed effects the model; pooled center is a random effect.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.501
	Comments
	Method	MMRM
	Comments
Method of Estimation	Estimation Parameter	LS mean
	Estimated Value	-0.7
	Confidence Interval	(2-Sided) 95%; -2.56 to 1.25
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.97
	Estimation Comments

14. Secondary Outcome

Title	Change in Functional Impairment From Randomization (Week 8) to End of Treatment (Week 16) 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 8) to end of treatment (Week 16)

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 randomization and at least 1 post-randomization MADRS total score.

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	143	151
Least Squares Mean (Standard Error) [units on a scale]	-6.09 (0.696)	-5.47 (0.700)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	TC-5214, Placebo
	Comments	MMRM model includes treatment, pooled center, visit, and treatment by visit interaction as explanatory variables and the randomization SDS total score as a covariate. Treatment, visit and treatment by visit interaction are fixed effects in the model; pooled center is a random effect.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.424
	Comments	The adjusted p-value protects the overall family-wise error rate by taking into account the multiple comparisons between the TC-5214 doses for both the primary efficacy variable (MADRS) and the key secondary efficacy variable (SDS).
	Method	MMRM
	Comments
Method of Estimation	Estimation Parameter	LS mean
	Estimated Value	-0.62
	Confidence Interval	(2-Sided) 95%; -2.134 to 0.901
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.771
	Estimation Comments

15. Secondary Outcome

Title	Change in Functional Impairment From Randomization (Week 8) to End of Treatment (Week 16) as Measured by SDS Work/School Domain Score
Description	A 5-item, self-administered scale that measures the extent a patient is impaired by their disease. Higher scores indicate more severe impairment. The 3 inter-correlated domains are school/work, social life, and family life/home responsibilities. The numerical rating for the work/school domain score is 0- 10, where 10 is considered to be 'highly impaired'.
Time Frame	Randomization (Week 8) to end of treatment (Week 16)

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 randomization and at least 1 post-randomization MADRS total score.

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	124	134
Least Squares Mean (Standard Error) [units on a scale]	-2.0 (0.24)	-1.7 (0.24)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	TC-5214, Placebo
	Comments	MMRM model includes treatment, pooled center, visit and treatment by visit interaction as explanatory variables and the randomization SDS work/school domain score as a covariate. Treatment, visit and treatment by visit interaction are fixed effects in the model; pooled center is a random effect.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.214
	Comments	Analysis for change in SDS work/school domain score from randomization (Week 8) to end of treatment (Week 16)
	Method	MMRM
	Comments
Method of Estimation	Estimation Parameter	LS mean
	Estimated Value	-0.4
	Confidence Interval	(2-Sided) 95%; -0.96 to 0.22
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.30
	Estimation Comments

16. Secondary Outcome

Title	Change in Functional Impairment From Randomization (Week 8) to End of Treatment (Week 16) as Measured by SDS Social Life Domain Score
Description	A 5-item, self-administered scale that measures the extent a patient is impaired by their disease. Higher scores indicate more severe impairment. The 3 inter-correlated domains are school/work, social life, and family life/home responsibilities. The numerical rating for the SDS social life domain score is 0- 10, where 10 is considered to be 'highly impaired'.
Time Frame	Randomization (Week 8) to end of treatment (Week 16)

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 randomization and at least 1 post-randomization MADRS total score.

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	143	151
Least Squares Mean (Standard Error) [units on a scale]	-1.9 (0.24)	-1.9 (0.24)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	TC-5214, Placebo
	Comments	MMRM model includes treatment, pooled center, visit and treatment by visit interaction as explanatory variables and the randomization SDS social life domain score. Treatment, visit and treatment by visit interaction are fixed effects in the model; pooled center is a random effect.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.931
	Comments
	Method	MMRM
	Comments
Method of Estimation	Estimation Parameter	LS mean
	Estimated Value	0.0
	Confidence Interval	(2-Sided) 95%; -0.59 to 0.54
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.29
	Estimation Comments

17. Secondary Outcome

Title	Change in Functional Impairment From Randomization (Week 8) to End of Treatment (Week 16) as Measured by SDS Family Life/Home Responsibilities Domain Score
Description	A 5-item, self-administered scale that measures the extent a patient is impaired by their disease. Higher scores indicate more severe impairment. The 3 inter-correlated domains are school/work, social life, and family life/home responsibilities. The numerical rating for the SDS family life/home responsibilities domain score is 0- 10, where 10 is considered to be 'highly impaired'.
Time Frame	Randomization (Week 8) to end of treatment (Week 16)

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 randomization and at least 1 post-randomization MADRS total score.

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	143	151
Least Squares Mean (Standard Error) [units on a scale]	-2.1 (0.28)	-2.0 (0.28)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	TC-5214, Placebo
	Comments	MMRM model includes treatment, pooled center, visit and treatment by visit interaction as explanatory variables and the randomization SDS family life/home responsibilities domain score. Treatment, visit and treatment by visit interaction are effects in the model; pooled center is a random effect.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.755
	Comments
	Method	MMRM
	Comments
Method of Estimation	Estimation Parameter	LS mean
	Estimated Value	-0.1
	Confidence Interval	(2-Sided) 95%; -0.60 to 0.44
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.26
	Estimation Comments

18. Secondary Outcome

Title	Change in Overall Quality of Life and Satisfaction From Randomization (Week 8) to End of Treatment (Week 16) 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 (Quality of Life Enjoyment and Satisfaction Questionnaire-Short Form)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 8) to end of treatment (Week 16)

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 randomization and at least 1 post-randomization MADRS total score.

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	141	148
Least Squares Mean (Standard Error) [units on a scale]	12.47 (1.736)	11.65 (1.738)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	TC-5214, Placebo
	Comments	ANCOVA with randomization Q-LES-Q-SF % maximum total score as covariate, treatment as a fixed effect and pooled center as a random effect.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.646
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	LS mean
	Estimated Value	0.82
	Confidence Interval	(2-Sided) 95%; -2.699 to 4.346
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 1.789
	Estimation Comments

19. Secondary Outcome

Title	Change From Randomization (Week 8) to End of Treatment (Week 16) in Quality of Life Enjoyment and Satisfaction Questionnaire-Short Form (Q LES-Q-SF) Item 15
Description	The Q-LES-Q-SF (Quality of Life Enjoyment and Satisfaction Questionnaire-Short Form) measures the patient's satisfaction with medication and overall quality of life. The 15th item queries respondents' satisfaction with the medication they are taking, rated on a 1 to 4 scale, score 0 indicates that no medication was taken. Higher scores are indicative of greater satisfaction.
Time Frame	Randomization (Week 8) to end of treatment (Week 16)

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 randomization and at least 1 post-randomization MADRS total score.

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	123	126
Least Squares Mean (Standard Error) [units on a scale]	0.2 (0.08)	0.3 (0.08)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	TC-5214, Placebo
	Comments	An analysis of covariance (ANCOVA) with randomization Q-LES-Q-SF item 15 score as covariate, treatment as a fixed effect and pooled center as a random effect.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.446
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	LS mean
	Estimated Value	-0.1
	Confidence Interval	(2-Sided) 95%; -0.31 to 0.14
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.12
	Estimation Comments

20. Secondary Outcome

Title	Change From Randomization (Week 8) to End of Treatment (Week 16) in Quality of Life Enjoyment and Satisfaction Questionnaire-Short Form (Q LES-Q-SF) Item 16
Description	The Q-LES-Q-SF (Quality of Life Enjoyment and Satisfaction Questionnaire-Short Form) measures the patient's satisfaction with medication and overall quality of life. The 16th item is a global rating of overall life satisfaction and contentment, rated on a 1 to 5 scale. Higher scores are indicative of greater satisfaction.
Time Frame	Randomization (Week 8) to end of treatment (Week 16)

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 randomization and at least 1 post-randomization MADRS total score.

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	140	148
Least Squares Mean (Standard Error) [units on a scale]	0.7 (0.08)	0.5 (0.08)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	TC-5214, Placebo
	Comments	An analysis of covariance (ANCOVA) with randomization Q-LES-Q-SF item 16 as a fixed effect and pooled center as a random effect.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.178
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	LS mean
	Estimated Value	0.1
	Confidence Interval	(2-Sided) 95%; -0.06 to 0.33
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.10
	Estimation Comments

21. Secondary Outcome

Title	Change in Irritability Symptoms as Measured by the Sheehan Irritability Scale (SIS) Total Score From Randomization (Week 8) to End of Treatment (Week 16)
Description	A self-administered scale to be used by clinical subjects to rate suffering over the past week with regard to irritability symptoms. The total SIS score is the sum of 7 items, and ranges from 0 to 70. Each item is assessed on an 11-point scale where 0=not at all, 1-3=mildly, 4-6=moderately, 7-9=markedly, and 10=extremely. The SIS also records the number of days impaired by irritability.
Time Frame	Randomization (Week 8) to end of treatment (Week 16)

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 randomization and at least 1 post-randomization MADRS total score.

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	144	151
Least Squares Mean (Standard Error) [units on a scale]	-12.6 (1.96)	-11.5 (1.97)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	TC-5214, Placebo
	Comments	MMRM model includes treatment, pooled center, visit, and treatment by visit interaction as explanatory variables and the randomization SIS total score as a covariate. Treatment, visit and treatment by visit interaction are fixed effects in the model; pooled center is a random effect.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.515
	Comments
	Method	MMRM
	Comments
Method of Estimation	Estimation Parameter	LS Mean
	Estimated Value	-1.1
	Confidence Interval	(2-Sided) 95%; -4.22 to 2.12
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 1.61
	Estimation Comments

22. Secondary Outcome

Title	Change in EuroQol - 5 Dimensions (EQ-5D) From Randomization (Week 8) to End of Treatment (Week 16)
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 (minimum -0.415) 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 8) to end of treatment (Week 16)

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 randomization and at least 1 post-randomization MADRS total score.

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	144	151
EQ-5D index score	0.113 (0.0199)	0.089 (0.0199)
EQ-5D VAS score	13.3 (2.03)	11.6 (2.03)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	TC-5214, Placebo
	Comments	MMRM model includes treatment, pooled center, visit and treatment by visit interaction as explanatory variables and the randomization EQ-5D total score as a covariate. Treatment, visit and treatment by visit interaction are fixed effects in the model; pooled center is a random effect.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.298
	Comments	Analysis for change in EQ-5D index score from randomization (Week 8) to end of treatment (Week 16)
	Method	MMRM
	Comments
Method of Estimation	Estimation Parameter	LS mean
	Estimated Value	0.024
	Confidence Interval	(2-Sided) 95%; -0.0209 to 0.0680
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.0226
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	TC-5214, Placebo
	Comments	MMRM model includes treatment, pooled center, visit and treatment by visit interaction as explanatory variables and the randomization EQ-5D VAS total score as a covariate. Treatment, visit and treatment by visit interaction are fixed effects in the model; pooled center is a random effect.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.484
	Comments	Analysis of change in EQ-5D VAS score from randomization (Week 8) to end of treatment (Week 16)
	Method	MMRM
	Comments
Method of Estimation	Estimation Parameter	LS mean
	Estimated Value	1.6
	Confidence Interval	(2-Sided) 95%; -2.98 to 6.26
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 2.34
	Estimation Comments

Adverse Events

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
All Cause Mortality
	TC-5214		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	TC-5214		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	1/157 (0.6%)		0/159 (0%)
Nervous system disorders
Headache	1/157 (0.6%)	1	0/159 (0%)	0
Other (Not Including Serious) Adverse Events
	TC-5214		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	80/157 (51%)		77/159 (48.4%)
Gastrointestinal disorders
Constipation	19/157 (12.1%)	19	10/159 (6.3%)	12
Nausea	12/157 (7.6%)	13	6/159 (3.8%)	6
Dry Mouth	7/157 (4.5%)	7	6/159 (3.8%)	6
Diarrhoea	15/157 (9.6%)	18	10/159 (6.3%)	10
Vomiting	4/157 (2.5%)	4	3/159 (1.9%)	3
General disorders
Fatigue	9/157 (5.7%)	9	7/159 (4.4%)	7
Infections and infestations
Nasopharyngitis	3/157 (1.9%)	3	6/159 (3.8%)	8
Upper respiratory tract infection	8/157 (5.1%)	9	5/159 (3.1%)	5
Investigations
Weight increased	5/157 (3.2%)	5	3/159 (1.9%)	3
Musculoskeletal and connective tissue disorders
Musculoskeletal stiffness	1/157 (0.6%)	1	4/159 (2.5%)	5
Nervous system disorders
Headache	19/157 (12.1%)	22	17/159 (10.7%)	17
Dizziness	7/157 (4.5%)	9	13/159 (8.2%)	18
Somnolence	7/157 (4.5%)	7	8/159 (5%)	8
Tremor	0/157 (0%)	0	4/159 (2.5%)	5
Dizziness postural	2/157 (1.3%)	2	5/159 (3.1%)	7
Psychiatric disorders
Insomnia	5/157 (3.2%)	5	10/159 (6.3%)	12
Anxiety	4/157 (2.5%)	4	2/159 (1.3%)	2
Abnormal dreams	6/157 (3.8%)	6	8/159 (5%)	8
Agitation	2/157 (1.3%)	2	4/159 (2.5%)	5
Nightmare	2/157 (1.3%)	2	4/159 (2.5%)	4
Skin and subcutaneous tissue disorders
Hyperhidrosis	3/157 (1.9%)	3	4/159 (2.5%)	4
Vascular disorders
Orthostatic Hypotension	6/157 (3.8%)	7	5/159 (3.1%)	10

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.