A Study to Assess the Efficacy and Safety of TC-5214 as a... | NCT01197508

Name	Class
Targacept Inc.	INDUSTRY

A Study to Assess the Efficacy and Safety of TC-5214 as a... | NCT01197508 | Trialant

Arms/Interventions Module

Arm Groups

Label	Type	Description	Intervention Names
0.1 mg BID TC-5214	Experimental	Selective serotonin reuptake inhibitor (SSRI)/Serotonin/norepinephrine reuptake inhibitor (SNRI) + TC-5214, 0.1 mg BID	Drug: TC-5214
1 mg BID TC-5214	Experimental	Selective serotonin reuptake inhibitor (SSRI)/Serotonin/norepinephrine reuptake inhibitor (SNRI) + TC-5214, 1 mg BID	Drug: TC-5214
4 mg BID TC-5214	Experimental	Selective serotonin reuptake inhibitor (SSRI)/Serotonin/norepinephrine reuptake inhibitor (SNRI) + TC-5214, 4 mg BID	Drug: TC-5214
Placebo	Placebo Comparator	Selective serotonin reuptake inhibitor (SSRI)/Serotonin/norepinephrine reuptake inhibitor (SNRI) + Placebo BID	Drug: Placebo

Name	Type	Description	Arm Group Labels	Other Names
TC-5214	Drug	Twice daily for 8 weeks.	0.1 mg BID TC-5214 1 mg BID TC-5214 4 mg BID TC-5214

Outcomes Module

Primary Outcomes

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

Secondary Outcomes

Measure	Description	Time Frame
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)	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.

Contacts/Locations Module

Name	Affiliation	Role
Hans A Eriksson, MD,PhD, MBA	AstraZeneca R&D	Study Director
Hans-Jürgen Möller, Prof. Dr.	University Hospital München	Principal Investigator

Facility	Status	City	State	ZIP	Country	Contacts
Research Site		Buenos Aires	Buenos Aires F.D.		Argentina
Research Site

References Module

Citations

PubMed Identifier	Type	Citation	Retractions
25602163	Derived	Moller HJ, Demyttenaere K, Olausson B, Szamosi J, Wilson E, Hosford D, Dunbar G, Tummala R, Eriksson H. Two Phase III randomised double-blind studies of fixed-dose TC-5214 (dexmecamylamine) adjunct to ongoing antidepressant therapy in patients with major depressive disorder and an inadequate response to prior antidepressant therapy. World J Biol Psychiatry. 2015 Oct;16(7):483-501. doi: 10.3109/15622975.2014.989261. Epub 2015 Jan 20.

Label	URL
CSR-D4130C00005.pdf	View source

Results Section

Participant Flow Module

Arm/Group Information

ID	Title	Description
FG000	0.1 mg BID TC-5214	Selective serotonin reuptake inhibitor (SSRI)/Serotonin/norepinephrine reuptake inhibitor (SNRI) + TC-5214, 0.1 mg BID
FG001	1 mg BID TC-5214	Selective serotonin reuptake inhibitor (SSRI)/Serotonin/norepinephrine reuptake inhibitor (SNRI) + TC-5214, 1 mg BID

Baseline Characteristics Module

Outcome Measures Module

Adverse Events Module

More Info Module

Type	Comment	Reasons
Withdrawal by Subject		FG0008 subjects FG0017 subjects FG00215 subjects FG0034 subjects
Eligiblity criteria not fulfilled		FG0000 subjects FG0010 subjects FG0022 subjects FG0030 subjects
Adverse Event		FG00010 subjects FG00113 subjects FG00223 subjects FG0033 subjects
Severe non-compliance to protocol		FG0000 subjects FG0013 subjects FG0021 subjects FG0033 subjects
Condition under investigation worsened		FG0001 subjects FG0011 subjects FG0021 subjects FG0031 subjects
Lack of Efficacy		FG0001 subjects FG0012 subjects FG0022 subjects FG0031 subjects
Study-specific withdrawal criteria		FG0000 subjects FG0010 subjects FG0021 subjects FG0032 subjects
Lost to Follow-up		FG0001 subjects FG0011 subjects FG0022 subjects FG0030 subjects
Other		FG0002 subjects FG0013 subjects FG0022 subjects FG0032 subjects

Arm/Group Information

ID	Title	Description
BG000	0.1 mg BID TC-5214	Selective serotonin reuptake inhibitor (SSRI)/Serotonin/norepinephrine reuptake inhibitor (SNRI) + TC-5214, 0.1 mg BID
BG001	1 mg BID TC-5214	Selective serotonin reuptake inhibitor (SSRI)/Serotonin/norepinephrine reuptake inhibitor (SNRI) + TC-5214, 1 mg BID
BG002	4 mg BID TC-5214	Selective serotonin reuptake inhibitor (SSRI)/Serotonin/norepinephrine reuptake inhibitor (SNRI) + TC-5214, 4 mg BID
BG003	Placebo	Selective serotonin reuptake inhibitor (SSRI)/Serotonin/norepinephrine reuptake inhibitor (SNRI) + Placebo BID
BG004	Total	Total of all reporting groups

Baseline Measures

Title

Description

Population Description

Parameter Type

Dispersion Type

Unit of Measure

Calculate Percentage

Denominator Units Selected

Denominators

Classes

Age, Continuous

Mean

Standard Deviation

years

Title

Denominators

Categories

Title	Measurements
	BG00046.0± 10.66 BG00145.0± 11.72 BG00245.6± 10.72 BG003

Sex: Female, Male

Count of Participants

Participants

Title

Denominators

Categories

Title	Measurements
Female	BG000127 BG001125 BG002

Race/Ethnicity, Customized

Number

participants

Title

Denominators

Categories

White

Title	Measurements
	BG000161 BG001156 BG002

Hamilton Rating Scale for Depression-17 items (HAMD-17) total score at randomization

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.

Mean

Standard Deviation

Scores on a scale

Title

Denominators

Categories

Title	Measurements
	BG00021.49± 3.587 BG001

Montgomery-Asberg Depression Rating Scale (MADRS) total score at randomization

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.

Mean

Standard Deviation

Scores on a scale

Title

Denominators

Categories

Title	Measurements
	BG00024.69± 5.086 BG001

Type

Title

Description

Population Description

Reporting Status

Anticipated Posting Date

Parameter Type

Dispersion Type

Unit of Measure

Calculate Percentage

Time Frame

Units Analyzed

Denominator Units Selected

Arm/Group Information

Denominators

Classes

Analyses

Primary

Change in the Montgomery-Asberg Depression Rating Scale (MADRS) Total Score From Randomization to End of Treatment.

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.

Posted

Least Squares Mean

Standard Error

units on a scale

Randomization (Week 8) to end of treatment (Week 16)

ID	Title	Description
OG000	0.1 mg BID TC-5214	Selective serotonin reuptake inhibitor (SSRI)/Serotonin/norepinephrine reuptake inhibitor (SNRI) + TC-5214, 0.1 mg BID
OG001	1 mg BID TC-5214	Selective serotonin reuptake inhibitor (SSRI)/Serotonin/norepinephrine reuptake inhibitor (SNRI) + TC-5214, 1 mg BID
OG002	4 mg BID TC-5214	Selective serotonin reuptake inhibitor (SSRI)/Serotonin/norepinephrine reuptake inhibitor (SNRI) + TC-5214, 4 mg BID
OG003	Placebo	Selective serotonin reuptake inhibitor (SSRI)/Serotonin/norepinephrine reuptake inhibitor (SNRI) + Placebo BID

Units	Counts
Participants	OG000173 OG001174 OG002170 OG003

Title

Denominators

Categories

Title	Measurements
	OG000-11.6± 0.65 OG001-12.2± 0.66 OG002-12.2± 0.69 OG003

Group IDs	Group Description	Statistical Method	Statistical Comment	P-Value	P-Value Comment	Parameter Type	Parameter Value	Dispersion Type	Dispersion Value	Confidence Interval Sides	Confidence Interval %	CI Lower Limit	CI Upper Limit	CI Lower Limit Comment	CI Upper Limit Comment	Estimate Comment	Tested Non-Inferiority	Non-Inferiority Type	Non-Inferiority Comment	Other Analysis Description
OG000 OG003	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.	MMRM		1.000	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).	LS mean	1.1	Standard Error of the Mean	0.84	2-Sided	95	-0.53	2.79				No

Secondary

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)

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.

Posted

Number

percentage of participants analyzed

Randomization (Week 8) to end of treatment (Week 16)

ID	Title	Description
OG000	0.1 mg BID TC-5214	Selective serotonin reuptake inhibitor (SSRI)/Serotonin/norepinephrine reuptake inhibitor (SNRI) + TC-5214, 0.1 mg BID
OG001	1 mg BID TC-5214	Selective serotonin reuptake inhibitor (SSRI)/Serotonin/norepinephrine reuptake inhibitor (SNRI) + TC-5214, 1 mg BID
OG002	4 mg BID TC-5214

Secondary

Remission in Depressive Symptoms of MDD, Defined as MADRS Total Score of ≤8 at End of Treatment (Week 16)

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

Posted

Number

percentage of participants analyzed

Week 16

ID	Title	Description
OG000	0.1 mg BID TC-5214	Selective serotonin reuptake inhibitor (SSRI)/Serotonin/norepinephrine reuptake inhibitor (SNRI) + TC-5214, 0.1 mg BID
OG001	1 mg BID TC-5214	Selective serotonin reuptake inhibitor (SSRI)/Serotonin/norepinephrine reuptake inhibitor (SNRI) + TC-5214, 1 mg BID
OG002	4 mg BID TC-5214	Selective serotonin reuptake inhibitor (SSRI)/Serotonin/norepinephrine reuptake inhibitor (SNRI) + TC-5214, 4 mg BID

Secondary

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)

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.

Posted

Number

percentage of participants analyzed

Randomization (Week 8) to end of treatment (Week 16); Week 10, Week 12, Week 14, and Week 16

ID	Title	Description
OG000	0.1 mg BID TC-5214	Selective serotonin reuptake inhibitor (SSRI)/Serotonin/norepinephrine reuptake inhibitor (SNRI) + TC-5214, 0.1 mg BID
OG001	1 mg BID TC-5214	Selective serotonin reuptake inhibitor (SSRI)/Serotonin/norepinephrine reuptake inhibitor (SNRI) + TC-5214, 1 mg BID

Secondary

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)

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.

Posted

Number

percentage of patients analyzed

Randomization (Week 8) to end of treatment (Week 16); Week 12, Week 14, and Week 16

ID	Title	Description
OG000	0.1 mg BID TC-5214	Selective serotonin reuptake inhibitor (SSRI)/Serotonin/norepinephrine reuptake inhibitor (SNRI) + TC-5214, 0.1 mg BID
OG001	1 mg BID TC-5214	Selective serotonin reuptake inhibitor (SSRI)/Serotonin/norepinephrine reuptake inhibitor (SNRI) + TC-5214, 1 mg BID
OG002

Secondary

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

Posted

Number

percentage of participants analyzed

Week 12, Week 14, Week 16

ID	Title	Description
OG000	0.1 mg BID TC-5214	Selective serotonin reuptake inhibitor (SSRI)/Serotonin/norepinephrine reuptake inhibitor (SNRI) + TC-5214, 0.1 mg BID
OG001	1 mg BID TC-5214	Selective serotonin reuptake inhibitor (SSRI)/Serotonin/norepinephrine reuptake inhibitor (SNRI) + TC-5214, 1 mg BID
OG002	4 mg BID TC-5214	Selective serotonin reuptake inhibitor (SSRI)/Serotonin/norepinephrine reuptake inhibitor (SNRI) + TC-5214, 4 mg BID

Secondary

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

Posted

Least Squares Mean

Standard Error

units on a scale

Randomization (Week 8) to end of treatment (Week 16)

ID	Title	Description
OG000	0.1 mg BID TC-5214	Selective serotonin reuptake inhibitor (SSRI)/Serotonin/norepinephrine reuptake inhibitor (SNRI) + TC-5214, 0.1 mg BID
OG001	1 mg BID TC-5214	Selective serotonin reuptake inhibitor (SSRI)/Serotonin/norepinephrine reuptake inhibitor (SNRI) + TC-5214, 1 mg BID
OG002	4 mg BID TC-5214

Secondary

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)

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.

Posted

Least Squares Mean

Standard Error

units on a scale

Randomization (Week 8) to end of treatment (Week 16)

ID	Title	Description
OG000	0.1 mg BID TC-5214	Selective serotonin reuptake inhibitor (SSRI)/Serotonin/norepinephrine reuptake inhibitor (SNRI) + TC-5214, 0.1 mg BID
OG001	1 mg BID TC-5214	Selective serotonin reuptake inhibitor (SSRI)/Serotonin/norepinephrine reuptake inhibitor (SNRI) + TC-5214, 1 mg BID
OG002	4 mg BID TC-5214	Selective serotonin reuptake inhibitor (SSRI)/Serotonin/norepinephrine reuptake inhibitor (SNRI) + TC-5214, 4 mg BID

Secondary

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)

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.

Posted

Number

percentage of participants analyzed

Randomization (Week 8) to end of treatment (Week 16)

ID	Title	Description
OG000	0.1 mg BID TC-5214	Selective serotonin reuptake inhibitor (SSRI)/Serotonin/norepinephrine reuptake inhibitor (SNRI) + TC-5214, 0.1 mg BID
OG001	1 mg BID TC-5214	Selective serotonin reuptake inhibitor (SSRI)/Serotonin/norepinephrine reuptake inhibitor (SNRI) + TC-5214, 1 mg BID
OG002	4 mg BID TC-5214	Selective serotonin reuptake inhibitor (SSRI)/Serotonin/norepinephrine reuptake inhibitor (SNRI) + TC-5214, 4 mg BID

Secondary

Change in Hamilton Anxiety Scale (HAM-A) Total Score From Randomization (Week 8) to End of Treatment (Week 16)

A 14-item clinician-administered scale for the evaluation of anxiety symptoms. Each HAM-A item is rated on a 0 to 4 scale. Higher HAM-A scores indicate higher levels of anxiety.

Posted

Least Squares Mean

Standard Error

units on a scale

Randomization (Week 8) to end of treatment (Week 16)

ID	Title	Description
OG000	0.1 mg BID TC-5214	Selective serotonin reuptake inhibitor (SSRI)/Serotonin/norepinephrine reuptake inhibitor (SNRI) + TC-5214, 0.1 mg BID
OG001	1 mg BID TC-5214	Selective serotonin reuptake inhibitor (SSRI)/Serotonin/norepinephrine reuptake inhibitor (SNRI) + TC-5214, 1 mg BID
OG002	4 mg BID TC-5214	Selective serotonin reuptake inhibitor (SSRI)/Serotonin/norepinephrine reuptake inhibitor (SNRI) + TC-5214, 4 mg BID
OG003	Placebo	Selective serotonin reuptake inhibitor (SSRI)/Serotonin/norepinephrine reuptake inhibitor (SNRI) + Placebo BID

Secondary

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

Posted

Least Squares Mean

Standard Error

units on a scale

Randomization (Week 8) to Week 9

ID	Title	Description
OG000	0.1 mg BID TC-5214	Selective serotonin reuptake inhibitor (SSRI)/Serotonin/norepinephrine reuptake inhibitor (SNRI) + TC-5214, 0.1 mg BID
OG001	1 mg BID TC-5214	Selective serotonin reuptake inhibitor (SSRI)/Serotonin/norepinephrine reuptake inhibitor (SNRI) + TC-5214, 1 mg BID
OG002	4 mg BID TC-5214	Selective serotonin reuptake inhibitor (SSRI)/Serotonin/norepinephrine reuptake inhibitor (SNRI) + TC-5214, 4 mg BID

Secondary

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

Posted

Least Squares Mean

Standard Error

units on a scale

Randomization (Week 8) to Week 10

ID	Title	Description
OG000	0.1 mg BID TC-5214	Selective serotonin reuptake inhibitor (SSRI)/Serotonin/norepinephrine reuptake inhibitor (SNRI) + TC-5214, 0.1 mg BID
OG001	1 mg BID TC-5214	Selective serotonin reuptake inhibitor (SSRI)/Serotonin/norepinephrine reuptake inhibitor (SNRI) + TC-5214, 1 mg BID
OG002	4 mg BID TC-5214	Selective serotonin reuptake inhibitor (SSRI)/Serotonin/norepinephrine reuptake inhibitor (SNRI) + TC-5214, 4 mg BID

Secondary

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

Posted

Least Squares Mean

Standard Error

units on a scale

Randomization (Week 8) to Week 12

ID	Title	Description
OG000	0.1 mg BID TC-5214	Selective serotonin reuptake inhibitor (SSRI)/Serotonin/norepinephrine reuptake inhibitor (SNRI) + TC-5214, 0.1 mg BID
OG001	1 mg BID TC-5214	Selective serotonin reuptake inhibitor (SSRI)/Serotonin/norepinephrine reuptake inhibitor (SNRI) + TC-5214, 1 mg BID
OG002	4 mg BID TC-5214	Selective serotonin reuptake inhibitor (SSRI)/Serotonin/norepinephrine reuptake inhibitor (SNRI) + TC-5214, 4 mg BID

Secondary

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

Posted

Least Squares Mean

Standard Error

units on a scale

Randomization (Week 8) to Week 14

ID	Title	Description
OG000	0.1 mg BID TC-5214	Selective serotonin reuptake inhibitor (SSRI)/Serotonin/norepinephrine reuptake inhibitor (SNRI) + TC-5214, 0.1 mg BID
OG001	1 mg BID TC-5214	Selective serotonin reuptake inhibitor (SSRI)/Serotonin/norepinephrine reuptake inhibitor (SNRI) + TC-5214, 1 mg BID
OG002	4 mg BID TC-5214	Selective serotonin reuptake inhibitor (SSRI)/Serotonin/norepinephrine reuptake inhibitor (SNRI) + TC-5214, 4 mg BID

Secondary

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

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).

Posted

Least Squares Mean

Standard Error

units on a scale

Randomization (Week 8) to end of treatment (Week 16)

ID	Title	Description
OG000	0.1 mg BID TC-5214	Selective serotonin reuptake inhibitor (SSRI)/Serotonin/norepinephrine reuptake inhibitor (SNRI) + TC-5214, 0.1 mg BID
OG001	1 mg BID TC-5214	Selective serotonin reuptake inhibitor (SSRI)/Serotonin/norepinephrine reuptake inhibitor (SNRI) + TC-5214, 1 mg BID
OG002	4 mg BID TC-5214

Secondary

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

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'.

Posted

Least Squares Mean

Standard Error

units on a scale

Randomization (Week 8) to end of treatment (Week 16)

ID	Title	Description
OG000	0.1 mg BID TC-5214	Selective serotonin reuptake inhibitor (SSRI)/Serotonin/norepinephrine reuptake inhibitor (SNRI) + TC-5214, 0.1 mg BID
OG001	1 mg BID TC-5214	Selective serotonin reuptake inhibitor (SSRI)/Serotonin/norepinephrine reuptake inhibitor (SNRI) + TC-5214, 1 mg BID
OG002	4 mg BID TC-5214	Selective serotonin reuptake inhibitor (SSRI)/Serotonin/norepinephrine reuptake inhibitor (SNRI) + TC-5214, 4 mg BID

Secondary

Change in Functional Impairment From Randomization (Week 8) to End of Treatment (Week 16) as Measured by SDS Social Life Domain Score

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'.

Posted

Least Squares Mean

Standard Error

units on a scale

Randomization (Week 8) to end of treatment (Week 16)

ID	Title	Description
OG000	0.1 mg BID TC-5214	Selective serotonin reuptake inhibitor (SSRI)/Serotonin/norepinephrine reuptake inhibitor (SNRI) + TC-5214, 0.1 mg BID
OG001	1 mg BID TC-5214	Selective serotonin reuptake inhibitor (SSRI)/Serotonin/norepinephrine reuptake inhibitor (SNRI) + TC-5214, 1 mg BID
OG002	4 mg BID TC-5214	Selective serotonin reuptake inhibitor (SSRI)/Serotonin/norepinephrine reuptake inhibitor (SNRI) + TC-5214, 4 mg BID

Secondary

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

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'.

Posted

Least Squares Mean

Standard Error

units on a scale

Randomization (Week 8) to end of treatment (Week 16)

ID	Title	Description
OG000	0.1 mg BID TC-5214	Selective serotonin reuptake inhibitor (SSRI)/Serotonin/norepinephrine reuptake inhibitor (SNRI) + TC-5214, 0.1 mg BID
OG001	1 mg BID TC-5214	Selective serotonin reuptake inhibitor (SSRI)/Serotonin/norepinephrine reuptake inhibitor (SNRI) + TC-5214, 1 mg BID
OG002	4 mg BID TC-5214

Secondary

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

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%.

Posted

Least Squares Mean

Standard Error

units on a scale

Randomization (Week 8) to end of treatment (Week 16)

ID	Title	Description
OG000	0.1 mg BID TC-5214	Selective serotonin reuptake inhibitor (SSRI)/Serotonin/norepinephrine reuptake inhibitor (SNRI) + TC-5214, 0.1 mg BID
OG001	1 mg BID TC-5214	Selective serotonin reuptake inhibitor (SSRI)/Serotonin/norepinephrine reuptake inhibitor (SNRI) + TC-5214, 1 mg BID
OG002	4 mg BID TC-5214

Secondary

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

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. Higher scores are indicative of greater enjoyment or satisfaction in each domain.

Posted

Least Squares Mean

Standard Error

units on a scale

Randomization (Week 8) to end of treatment (Week 16)

ID	Title	Description
OG000	0.1 mg BID TC-5214	Selective serotonin reuptake inhibitor (SSRI)/Serotonin/norepinephrine reuptake inhibitor (SNRI) + TC-5214, 0.1 mg BID
OG001	1 mg BID TC-5214	Selective serotonin reuptake inhibitor (SSRI)/Serotonin/norepinephrine reuptake inhibitor (SNRI) + TC-5214, 1 mg BID
OG002	4 mg BID TC-5214	Selective serotonin reuptake inhibitor (SSRI)/Serotonin/norepinephrine reuptake inhibitor (SNRI) + TC-5214, 4 mg BID

Secondary

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

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. Higher scores are indicative of greater enjoyment or satisfaction in each domain.

Posted

Least Squares Mean

Standard Error

units on a scale

Randomization (Week 8) to end of treatment (Week 16)

ID	Title	Description
OG000	0.1 mg BID TC-5214	Selective serotonin reuptake inhibitor (SSRI)/Serotonin/norepinephrine reuptake inhibitor (SNRI) + TC-5214, 0.1 mg BID
OG001	1 mg BID TC-5214	Selective serotonin reuptake inhibitor (SSRI)/Serotonin/norepinephrine reuptake inhibitor (SNRI) + TC-5214, 1 mg BID
OG002	4 mg BID TC-5214	Selective serotonin reuptake inhibitor (SSRI)/Serotonin/norepinephrine reuptake inhibitor (SNRI) + TC-5214, 4 mg BID

Secondary

Change in EuroQol - 5 Dimensions (EQ-5D) From 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 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.

Posted

Least Squares Mean

Standard Error

units on a scale

Randomization (Week 8) to end of treatment (Week 16)

ID	Title	Description
OG000	0.1 mg BID TC-5214	Selective serotonin reuptake inhibitor (SSRI)/Serotonin/norepinephrine reuptake inhibitor (SNRI) + TC-5214, 0.1 mg BID
OG001	1 mg BID TC-5214	Selective serotonin reuptake inhibitor (SSRI)/Serotonin/norepinephrine reuptake inhibitor (SNRI) + TC-5214, 1 mg BID
OG002	4 mg BID TC-5214

Arm/Groups

ID	Title	Description	Serious Events (Affected)	Serious Events (At Risk)	Other Events (Affected)	Other Events (At Risk)
EG000	Placebo	Selective serotonin reuptake inhibitor (SSRI)/Serotonin/norepinephrine reuptake inhibitor (SNRI) + Placebo	2	174	64	174
EG001	0.1 mg BID TC-5214	Selective serotonin reuptake inhibitor (SSRI)/Serotonin/norepinephrine reuptake inhibitor (SNRI) + TC-5214, 0.1 mg BID	2	174	68	174
EG002	1 mg BID TC-5214	Selective serotonin reuptake inhibitor (SSRI)/Serotonin/norepinephrine reuptake inhibitor (SNRI) + TC-5214, 1 mg BID	4	174	72	174
EG003	4 mg BID TC-5214	Selective serotonin reuptake inhibitor (SSRI)/Serotonin/norepinephrine reuptake inhibitor (SNRI) + TC-5214, 4 mg BID	2	171	94	171

Serious Adverse Events

Term	Organ System	Source Vocabulary	Assessment Type	Statistical Information
Food Poisoning	Gastrointestinal disorders	MedDRA 14.1	Systematic Assessment	EG0000 events0 affected174 at risk EG0010 events0 affected174 at risk EG0021 events1 affected174 at risk EG0030 events0 affected171 at risk
Pneumonia	Infections and infestations	MedDRA 14.1	Systematic Assessment	EG0000 events0 affected174 at risk EG0010 events0 affected174 at risk EG0021 events1 affected174 at risk EG003
Urinary Tract Infection	Infections and infestations	MedDRA 14.1	Systematic Assessment	EG0000 events0 affected174 at risk EG0010 events0 affected174 at risk EG0021 events1 affected174 at risk EG003
Toxicity To Various Agents	Injury, poisoning and procedural complications	MedDRA 14.1	Systematic Assessment	EG0000 events0 affected174 at risk EG0011 events1 affected174 at risk EG0020 events0 affected174 at risk EG003
Cervix Carcinoma	Neoplasms benign, malignant and unspecified (incl cysts and polyps)	MedDRA 14.1	Systematic Assessment	EG0001 events1 affected174 at risk EG0010 events0 affected174 at risk EG0020 events0 affected174 at risk EG003
Abortion Spontaneous	Pregnancy, puerperium and perinatal conditions	MedDRA 14.1	Systematic Assessment	EG0001 events1 affected174 at risk EG0010 events0 affected174 at risk EG0020 events0 affected174 at risk EG003
Depression	Psychiatric disorders	MedDRA 14.1	Systematic Assessment	EG0000 events0 affected174 at risk EG0010 events0 affected174 at risk EG0021 events1 affected174 at risk EG003
Suicidal Ideation	Psychiatric disorders	MedDRA 14.1	Systematic Assessment	EG0000 events0 affected174 at risk EG0010 events0 affected174 at risk EG0020 events0 affected174 at risk EG003
Suicide Attempt	Psychiatric disorders	MedDRA 14.1	Systematic Assessment	EG0000 events0 affected174 at risk EG0012 events2 affected174 at risk EG0021 events1 affected174 at risk EG003

Other Adverse Events

Term	Organ System	Source Vocabulary	Assessment Type	Statistical Information
Vertigo	Ear and labyrinth disorders	MedDRA 14.1	Systematic Assessment	EG0000 events0 affected174 at risk EG0011 events1 affected174 at risk EG0022 events2 affected174 at risk EG0036 events6 affected171 at risk
Constipation	Gastrointestinal disorders	MedDRA 14.1	Systematic Assessment	EG00011 events11 affected174 at risk EG00113 events13 affected174 at risk EG00214 events13 affected174 at risk EG003
Dry Mouth	Gastrointestinal disorders	MedDRA 14.1	Systematic Assessment	EG0004 events3 affected174 at risk EG0015 events5 affected174 at risk EG0025 events5 affected174 at risk EG003
Diarrhoea	Gastrointestinal disorders	MedDRA 14.1	Systematic Assessment	EG00013 events12 affected174 at risk EG0011 events1 affected174 at risk EG0024 events3 affected174 at risk EG003
Nausea	Gastrointestinal disorders	MedDRA 14.1	Systematic Assessment	EG00010 events9 affected174 at risk EG0018 events7 affected174 at risk EG0027 events6 affected174 at risk EG003
Vomiting	Gastrointestinal disorders	MedDRA 14.1	Systematic Assessment	EG0003 events3 affected174 at risk EG0011 events1 affected174 at risk EG0022 events2 affected174 at risk EG003
Abdominal Pain Upper	Gastrointestinal disorders	MedDRA 14.1	Systematic Assessment	EG0004 events4 affected174 at risk EG0011 events1 affected174 at risk EG0025 events4 affected174 at risk EG003
Fatigue	General disorders	MedDRA 14.1	Systematic Assessment	EG0004 events4 affected174 at risk EG0016 events6 affected174 at risk EG00210 events10 affected174 at risk EG003
Influenza	Infections and infestations	MedDRA 14.1	Systematic Assessment	EG0008 events8 affected174 at risk EG0012 events2 affected174 at risk EG0026 events6 affected174 at risk EG003
Nasopharyngitis	Infections and infestations	MedDRA 14.1	Systematic Assessment	EG0005 events5 affected174 at risk EG0014 events3 affected174 at risk EG0021 events1 affected174 at risk EG003
Urinary Tract Infection	Infections and infestations	MedDRA 14.1	Systematic Assessment	EG0000 events0 affected174 at risk EG0012 events2 affected174 at risk EG0022 events1 affected174 at risk EG003
Alanine Aminotransferase Increased	Infections and infestations	MedDRA 14.1	Systematic Assessment	EG0000 events0 affected174 at risk EG0011 events1 affected174 at risk EG0024 events4 affected174 at risk EG003
Increased Appetite	Metabolism and nutrition disorders	MedDRA 14.1	Systematic Assessment	EG0000 events0 affected174 at risk EG0011 events1 affected174 at risk EG0024 events4 affected174 at risk EG003
Headache	Nervous system disorders	MedDRA 14.1	Systematic Assessment	EG00027 events23 affected174 at risk EG00127 events22 affected174 at risk EG00241 events24 affected174 at risk EG003
Dizziness	Nervous system disorders	MedDRA 14.1	Systematic Assessment	EG0009 events7 affected174 at risk EG0019 events9 affected174 at risk EG00213 events13 affected174 at risk EG003
Somnolence	Nervous system disorders	MedDRA 14.1	Systematic Assessment	EG0005 events5 affected174 at risk EG0015 events5 affected174 at risk EG0027 events7 affected174 at risk EG003
Dysgeusia	Nervous system disorders	MedDRA 14.1	Systematic Assessment	EG0000 events0 affected174 at risk EG0011 events1 affected174 at risk EG0021 events1 affected174 at risk EG003
Insomnia	Psychiatric disorders	MedDRA 14.1	Systematic Assessment	EG0001 events1 affected174 at risk EG0016 events6 affected174 at risk EG00211 events9 affected174 at risk EG003
Agitation	Psychiatric disorders	MedDRA 14.1	Systematic Assessment	EG0004 events4 affected174 at risk EG0013 events3 affected174 at risk EG0023 events3 affected174 at risk EG003
Nervousness	Psychiatric disorders	MedDRA 14.1	Systematic Assessment	EG0000 events0 affected174 at risk EG0010 events0 affected174 at risk EG0024 events4 affected174 at risk EG003
Nightmare	Psychiatric disorders	MedDRA 14.1	Systematic Assessment	EG0002 events2 affected174 at risk EG0014 events4 affected174 at risk EG0021 events1 affected174 at risk EG003
Hyperhidrosis	Skin and subcutaneous tissue disorders	MedDRA 14.1	Systematic Assessment	EG0001 events1 affected174 at risk EG0015 events5 affected174 at risk EG0024 events4 affected174 at risk EG003
Pruritus	Skin and subcutaneous tissue disorders	MedDRA 14.1	Systematic Assessment	EG0005 events4 affected174 at risk EG0010 events0 affected174 at risk EG0020 events0 affected174 at risk EG003
Orthostatic Hypotension	Vascular disorders	MedDRA 14.1	Systematic Assessment	EG0001 events1 affected174 at risk EG0011 events1 affected174 at risk EG0020 events0 affected174 at risk EG003
Hypotension	Vascular disorders	MedDRA 14.1	Systematic Assessment	EG0000 events0 affected174 at risk EG0011 events1 affected174 at risk EG0020 events0 affected174 at risk EG003
Hypertension	Vascular disorders	MedDRA 14.1	Systematic Assessment	EG0002 events2 affected174 at risk EG0013 events2 affected174 at risk EG0023 events3 affected174 at risk EG003

Group IDs	Group Description	Statistical Method	P-Value	Parameter Type	Parameter Value	Dispersion Type	Dispersion Value	Confidence Interval Sides	Confidence Interval %	CI Lower Limit	CI Upper Limit	Estimate Comment	Tested Non-Inferiority	Non-Inferiority Type
OG000 OG003	Logistic regression model including treatment and pooled center as fixed effects and the randomization MADRS total score as a covariate.	Regression, Logistic	0.144	Odds Ratio (OR)	0.71	Standard Error of the Mean	0.17	2-Sided	95	0.45	1.12	TC-5214 is the numerator in the OR, OR>1 represents a result in favor of TC-5214.	No	Superiority or Other
OG001 OG003	Logistic regression model including treatment and pooled center as fixed effects and the randomization MADRS total score as a covariate.	Regression, Logistic	0.203	Odds Ratio (OR)	0.74	Standard Error of the Mean	0.17	2-Sided	95	0.47	1.17	TC-5214 is the numerator in the OR, OR>1 represents a result in favor of TC-5214.	No	Superiority or Other
OG002 OG003	Logistic regression model including treatment and pooled center as fixed effects and the randomization MADRS total score as a covariate.	Regression, Logistic	0.005	Odds Ratio (OR)	0.52	Standard Error of the Mean	0.12	2-Sided	95	0.32	0.82	TC-5214 is the numerator in the OR, OR>1 represents a result in favor of TC-5214.	No	Superiority or Other

Group IDs	Group Description	Statistical Method	P-Value	Parameter Type	Parameter Value	Dispersion Type	Dispersion Value	Confidence Interval Sides	Confidence Interval %	CI Lower Limit	CI Upper Limit	Estimate Comment	Tested Non-Inferiority	Non-Inferiority Type
OG000 OG003	Logistic regression model including treatment and pooled center as fixed effects and the randomization MADRS total score as a covariate.	Regression, Logistic	0.636	Odds Ratio (OR)	0.89	Standard Error of the Mean	0.22	2-Sided	95	0.54	1.45	TC-5214 is the numerator in the OR, OR>1 represents a result in favor of TC-5214.	No	Superiority or Other
OG001 OG003	Logistic regression model including treatment and pooled center as fixed effects and the randomization MADRS total score as a covariate.	Regression, Logistic	0.215	Odds Ratio (OR)	0.73	Standard Error of the Mean	0.19	2-Sided	95	0.44	1.20	TC-5214 is the numerator in the OR, OR>1 represents a result in favor of TC-5214.	No	Superiority or Other
OG002 OG003	Logistic regression model including treatment and pooled center as fixed effects and the randomization MADRS total score as a covariate.	Regression, Logistic	0.034	Odds Ratio (OR)	0.58	Standard Error of the Mean	0.15	2-Sided	95	0.35	0.96	TC-5214 is the numerator in the OR, OR>1 represents a result in favor of TC-5214.	No	Superiority or Other

Group IDs	Group Description	Statistical Method	P-Value	Parameter Type	Parameter Value	Dispersion Type	Dispersion Value	Confidence Interval Sides	Confidence Interval %	CI Lower Limit	CI Upper Limit	Estimate Comment	Tested Non-Inferiority	Non-Inferiority Type
OG000 OG003	Logistic regression model including treatment and pooled center as fixed effects and the randomization MADRS total score as a covariate.	Regression, Logistic	0.711	Odds Ratio (OR)	0.85	Standard Error of the Mean	0.37	2-Sided	95	0.36	1.99	TC-5214 is the numerator in the OR, OR>1 represents a result in favor of TC-5214.	No	Superiority or Other
OG001 OG003	Logistic regression model including treatment and pooled center as fixed effects and the randomization MADRS total score as a covariate.	Regression, Logistic	0.594	Odds Ratio (OR)	0.79	Standard Error of the Mean	0.34	2-Sided	95	0.34	1.85	TC-5214 is the numerator in the OR, OR>1 represents a result in favor of TC-5214.	No	Superiority or Other
OG002 OG003	Logistic regression model including treatment and pooled center as fixed effects and the randomization MADRS total score as a covariate.	Regression, Logistic	0.749	Odds Ratio (OR)	1.15	Standard Error of the Mean	0.49	2-Sided	95	0.50	2.65	TC-5214 is the numerator in the OR, OR>1 represents a result in favor of TC-5214.	No	Superiority or Other

Group IDs	Group Description	Statistical Method	P-Value	Parameter Type	Parameter Value	Dispersion Type	Dispersion Value	Confidence Interval Sides	Confidence Interval %	CI Lower Limit	CI Upper Limit	Estimate Comment	Tested Non-Inferiority	Non-Inferiority Type
OG000 OG003	Logistic regression model including treatment and pooled center as fixed effects and the randomization MADRS total score as a covariate.	Regression, Logistic	0.037	Odds Ratio (OR)	0.52	Standard Error of the Mean	0.16	2-Sided	95	0.28	0.96	TC-5214 is the numerator in the OR, OR>1 represents a result in favor of TC-5214.	No	Superiority or Other
OG001 OG003	Logistic regression model including treatment and pooled center as fixed effects and the randomization MADRS total score as a covariate.	Regression, Logistic	0.222	Odds Ratio (OR)	0.69	Standard Error of the Mean	0.21	2-Sided	95	0.38	1.25	TC-5214 is the numerator in the OR, OR>1 represents a result in favor of TC-5214.	No	Superiority or Other
OG002 OG003	Logistic regression model including treatment and pooled center as fixed effects and the randomization MADRS total score as a covariate.	Regression, Logistic	0.042	Odds Ratio (OR)	0.52	Standard Error of the Mean	0.17	2-Sided	95	0.28	0.98	TC-5214 is the numerator in the OR, OR>1 represents a result in favor of TC-5214.	No	Superiority or Other

Group IDs	Group Description	Statistical Method	P-Value	Parameter Type	Parameter Value	Dispersion Type	Dispersion Value	Confidence Interval Sides	Confidence Interval %	CI Lower Limit	CI Upper Limit	Estimate Comment	Tested Non-Inferiority	Non-Inferiority Type
OG000 OG003	Logistic regression model including treatment and pooled center as fixed effects and the randomization MADRS total score as a covariate.	Regression, Logistic	0.913	Odds Ratio (OR)	1.04	Standard Error of the Mean	0.41	2-Sided	95	0.48	2.27	TC-5214 is the numerator in the OR, OR>1 represents a result in favor of TC-5214.	No	Superiority or Other
OG001 OG003	Logistic regression model including treatment and pooled center as fixed effects and the randomization MADRS total score as a covariate.	Regression, Logistic	0.841	Odds Ratio (OR)	0.92	Standard Error of the Mean	0.37	2-Sided	95	0.42	2.01	TC-5214 is the numerator in the OR, OR>1 represents a result in favor of TC-5214.	No	Superiority or Other
OG002 OG003	Logistic regression model including treatment and pooled center as fixed effects and the randomization MADRS total score as a covariate.	Regression, Logistic	0.239	Odds Ratio (OR)	0.61	Standard Error of the Mean	0.26	2-Sided	95	0.26	1.39	TC-5214 is the numerator in the OR, OR>1 represents a result in favor of TC-5214.	No	Superiority or Other

Group IDs	Group Description	Statistical Method	P-Value	Parameter Type	Parameter Value	Dispersion Type	Dispersion Value	Confidence Interval Sides	Confidence Interval %	CI Lower Limit	CI Upper Limit	Tested Non-Inferiority	Non-Inferiority Type
OG000 OG003	Analysis of covariance (ANCOVA) with randomization HAMD-17 total score as covariate, treatment as a fixed effect and pooled center as a random effect.	ANCOVA	0.120	LS mean	1.10	Standard Error of the Mean	0.705	2-Sided	95	-0.288	2.481	No	Superiority or Other
OG001 OG003	Analysis of covariance (ANCOVA) with randomization HAMD-17 total score as covariate, treatment as a fixed effect and pooled center as a random effect.	ANCOVA	0.184	LS mean	0.95	Standard Error of the Mean	0.715	2-Sided	95	-0.452	2.354	No	Superiority or Other
OG002 OG003	Analysis of covariance (ANCOVA) with randomization HAMD-17 total score as covariate, treatment as a fixed effect and pooled center as a random effect.	ANCOVA	0.003	LS mean	2.09	Standard Error of the Mean	0.711	2-Sided	95	0.692	3.484	No	Superiority or Other

Group IDs	Group Description	Statistical Method	P-Value	Parameter Type	Parameter Value	Dispersion Type	Dispersion Value	Confidence Interval Sides	Confidence Interval %	CI Lower Limit	CI Upper Limit	Tested Non-Inferiority	Non-Inferiority Type
OG000 OG003	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.	MMRM	0.131	LS mean	0.2	Standard Error of the Mean	0.12		95	-0.05	0.42	No	Superiority or Other
OG001 OG003	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.	MMRM	0.551	LS mean	0.1	Standard Error of the Mean	0.12	2-Sided	95	-0.17	0.31	No	Superiority or Other
OG002 OG003	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.	MMRM	0.645	LS mean	0.1	Standard Error of the Mean	0.12	2-Sided	95	-0.19	0.30	No	Superiority or Other

Group IDs	Group Description	Statistical Method	P-Value	Parameter Type	Parameter Value	Dispersion Type	Dispersion Value	Confidence Interval Sides	Confidence Interval %	CI Lower Limit	CI Upper Limit	Estimate Comment	Tested Non-Inferiority	Non-Inferiority Type
OG000 OG003	Logistic regression model including treatment and pooled center as fixed effects and the randomization Clinical Global Impression Severity (CGI-S) as a covariate.	Regression, Logistic	0.046	Odds Ratio (OR)	0.62	Standard Error of the Mean	0.15	2-Sided	95	0.38	0.99	TC-5214 is the numerator in the OR, OR>1 represents a result in favor of TC-5214.	No	Superiority or Other
OG001 OG003	Logistic regression model including treatment and pooled center as fixed effects and the randomization Clinical Global Impression Severity (CGI-S) as a covariate.	Regression, Logistic	0.051	Odds Ratio (OR)	0.62	Standard Error of the Mean	0.15	2-Sided	95	0.38	1.00	TC-5214 is the numerator in the OR, OR>1 represents a result in favor of TC-5214.	No	Superiority or Other
OG002 OG003	Logistic regression model including treatment and pooled center as fixed effects and the randomization Clinical Global Impression Severity (CGI-S) as a covariate.	Regression, Logistic	0.040	Odds Ratio (OR)	0.60	Standard Error of the Mean	0.15	2-Sided	95	0.37	0.98	TC-5214 is the numerator in the OR, OR>1 represents a result in favor of TC-5214.	No	Superiority or Other

Group IDs	Group Description	Statistical Method	P-Value	Parameter Type	Parameter Value	Dispersion Type	Dispersion Value	Confidence Interval Sides	Confidence Interval %	CI Lower Limit	CI Upper Limit	Tested Non-Inferiority	Non-Inferiority Type
OG000 OG003	An analysis of covariance (ANCOVA) with randomization HAM-A total score as covariate, treatment as a fixed effect and pooled center as a random effect.	ANCOVA	0.273	LS mean	0.7	Standard Error of the Mean	0.66	2-Sided	95	-0.58	2.03	No	Superiority or Other
OG001 OG003	An analysis of covariance (ANCOVA) with randomization HAM-A total score as covariate, treatment as a fixed effect and pooled center as a random effect.	ANCOVA	0.315	LS mean	0.7	Standard Error of the Mean	0.67	2-Sided	95	-0.65	2.00	No	Superiority or Other
OG002 OG003	An analysis of covariance (ANCOVA) with randomization HAM-A total score as covariate, treatment as a fixed effect and pooled center as a random effect.	ANCOVA	0.078	LS mean	1.2	Standard Error of the Mean	0.67	2-Sided	95	-0.13	2.51	No	Superiority or Other

Group IDs	Group Description	Statistical Method	P-Value	Parameter Type	Parameter Value	Dispersion Type	Dispersion Value	Confidence Interval Sides	Confidence Interval %	CI Lower Limit	CI Upper Limit	Tested Non-Inferiority	Non-Inferiority Type
OG000 OG003	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.	MMRM	0.590	LS mean	0.3	Standard Error of the Mean	0.47	2-Sided	95	-0.68	1.19	No	Superiority or Other
OG001 OG003	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.	MMRM	0.679	LS mean	0.2	Standard Error of the Mean	0.48	2-Sided	95	-0.74	1.14	No	Superiority or Other
OG002 OG003	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.	MMRM	0.215	LS mean	0.6	Standard Error of the Mean	0.48	2-Sided	95	-0.35	1.53	No	Superiority or Other

Group IDs	Group Description	Statistical Method	P-Value	Parameter Type	Parameter Value	Dispersion Type	Dispersion Value	Confidence Interval Sides	Confidence Interval %	CI Lower Limit	CI Upper Limit	Tested Non-Inferiority	Non-Inferiority Type
OG000 OG003	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.	MMRM	0.052	LS mean	1.2	Standard Error of the Mean	0.61	2-Sided	95	-0.01	2.38	No	Superiority or Other
OG001 OG003	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.	MMRM	0.874	LS mean	0.1	Standard Error of the Mean	0.61	2-Sided	95	-1.11	1.30	No	Superiority or Other
OG002 OG003	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.	MMRM	0.099	LS mean	1.0	Standard Error of the Mean	0.62	2-Sided	95	-0.19	2.24	No	Superiority or Other

Group IDs	Group Description	Statistical Method	P-Value	Parameter Type	Parameter Value	Dispersion Type	Dispersion Value	Confidence Interval Sides	Confidence Interval %	CI Lower Limit	CI Upper Limit	Tested Non-Inferiority	Non-Inferiority Type
OG000 OG003	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.	MMRM	0.394	LS mean	0.6	Standard Error of the Mean	0.69	2-Sided	95	-0.77	1.95	No	Superiority or Other
OG001 OG003	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.	MMRM	0.712	LS mean	0.3	Standard Error of the Mean	0.70	2-Sided	95	-1.11	1.63	No	Superiority or Other
OG002 OG003	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.	MMRM	0.167	LS mean	1.0	Standard Error of the Mean	0.71	2-Sided	95	-0.41	2.38	No	Superiority or Other

Group IDs	Group Description	Statistical Method	P-Value	Parameter Type	Parameter Value	Dispersion Type	Dispersion Value	Confidence Interval Sides	Confidence Interval %	CI Lower Limit	CI Upper Limit	Tested Non-Inferiority	Non-Inferiority Type
OG000 OG003	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.	MMRM	0.046	LS mean	1.5	Standard Error of the Mean	0.75	2-Sided	95	0.02	2.95	No	Superiority or Other
OG001 OG003	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.	MMRM	0.681	LS mean	0.3	Standard Error of the Mean	0.75	2-Sided	95	-1.17	1.79	No	Superiority or Other
OG002 OG003	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.	MMRM	0.087	LS mean	1.3	Standard Error of the Mean	0.77	2-Sided	95	-0.19	2.84	No	Superiority or Other

Group IDs	Group Description	Statistical Method	P-Value	P-Value Comment	Parameter Type	Parameter Value	Dispersion Type	Dispersion Value	Confidence Interval Sides	Confidence Interval %	CI Lower Limit	CI Upper Limit	Tested Non-Inferiority	Non-Inferiority Type
OG000 OG003	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.	MMRM	1.000	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).	LS mean	0.98	Standard Error of the Mean	0.736	2-Sided	95	-0.464	2.427	No	Superiority or Other
OG001 OG003	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.	MMRM	1.000	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).	LS mean	0.72	Standard Error of the Mean	0.746	2-Sided	95	-0.740	2.188	No	Superiority or Other
OG002 OG003	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.	MMRM	1.000	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).	LS mean	0.85	Standard Error of the Mean	0.762	2-Sided	95	-0.649	2.346	No	Superiority or Other

Group IDs	Group Description	Statistical Method	P-Value	Parameter Type	Parameter Value	Dispersion Type	Dispersion Value	Confidence Interval Sides	Confidence Interval %	CI Lower Limit	CI Upper Limit	Tested Non-Inferiority	Non-Inferiority Type
OG000 OG003	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.	MMRM	0.914	LS mean	0.0	Standard Error of the Mean	0.29	2-Sided	95	-0.54	0.61	No	Superiority or Other
OG001 OG003	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.	MMRM	0.446	LS mean	0.2	Standard Error of the Mean	0.30	2-Sided	95	-0.36	0.81	No	Superiority or Other
OG002 OG003	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.	MMRM	0.656	LS mean	0.1	Standard Error of the Mean	0.31	2-Sided	95	-0.47	0.75	No	Superiority or Other

Group IDs	Group Description	Statistical Method	P-Value	Parameter Type	Parameter Value	Dispersion Type	Dispersion Value	Confidence Interval Sides	Confidence Interval %	CI Lower Limit	CI Upper Limit	Tested Non-Inferiority	Non-Inferiority Type
OG000 OG003	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.	MMRM	0.248	LS mean	0.3	Standard Error of the Mean	0.26	2-Sided	95	-0.21	0.82	No	Superiority or Other
OG001 OG003	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.	MMRM	0.498	LS mean	0.2	Standard Error of the Mean	0.27	2-Sided	95	-0.34	0.70	No	Superiority or Other
OG002 OG003	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.	MMRM	0.441	LS mean	0.2	Standard Error of the Mean	0.27	2-Sided	95	-0.32	0.74	No	Superiority or Other

Group IDs	Group Description	Statistical Method	P-Value	Parameter Type	Parameter Value	Dispersion Type	Dispersion Value	Confidence Interval Sides	Confidence Interval %	CI Lower Limit	CI Upper Limit	Tested Non-Inferiority	Non-Inferiority Type
OG000 OG003	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.	MMRM	0.174	LS mean	0.4	Standard Error of the Mean	0.26	2-Sided	95	-0.16	0.87	No	Superiority or Other
OG001 OG003	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.	MMRM	0.402	LS mean	0.2	Standard Error of the Mean	0.27	2-Sided	95	-0.30	0.74	No	Superiority or Other
OG002 OG003	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.	MMRM	0.197	LS mean	0.3	Standard Error of the Mean	0.27	2-Sided	95	-0.18	0.88	No	Superiority or Other

Group IDs	Group Description	Statistical Method	P-Value	Parameter Type	Parameter Value	Dispersion Type	Dispersion Value	Confidence Interval Sides	Confidence Interval %	CI Lower Limit	CI Upper Limit	Tested Non-Inferiority	Non-Inferiority Type
OG000 OG003	ANCOVA with randomization Q-LES-Q-SF % maximum total score as covariate, treatment as a fixed effect and pooled center as a random effect.	ANCOVA	0.371	LS mean	-1.47	Standard Error of the Mean	1.643	2-Sided	95	-4.697	1.756	No	Superiority or Other
OG001 OG003	ANCOVA with randomization Q-LES-Q-SF % maximum total score as covariate, treatment as a fixed effect and pooled center as a random effect.	ANCOVA	0.432	LS mean	-1.32	Standard Error of the Mean	1.672	2-Sided	95	-4.597	1.967	No	Superiority or Other
OG002 OG003	ANCOVA with randomization Q-LES-Q-SF % maximum total score as covariate, treatment as a fixed effect and pooled center as a random effect.	ANCOVA	0.105	LS mean	-2.71	Standard Error of the Mean	1.672	2-Sided	95	-5.992	0.573	No	Superiority or Other

Group IDs	Group Description	Statistical Method	P-Value	Parameter Type	Parameter Value	Dispersion Type	Dispersion Value	Confidence Interval Sides	Confidence Interval %	CI Lower Limit	CI Upper Limit	Tested Non-Inferiority	Non-Inferiority Type
OG000 OG003	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.	ANCOVA	0.312	LS mean	-0.1	Standard Error of the Mean	0.10	2-Sided	95	-0.29	0.09	No	Superiority or Other
OG001 OG003	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.	ANCOVA	0.885	LS mean	0.0	Standard Error of the Mean	0.10	2-Sided	95	-0.18	0.21	No	Superiority or Other
OG002 OG003	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.	ANCOVA	0.067	LS mean	-0.2	Standard Error of the Mean	0.10	2-Sided	95	-0.37	0.01	No	Superiority or Other

Group IDs	Group Description	Statistical Method	P-Value	Parameter Type	Parameter Value	Dispersion Type	Dispersion Value	Confidence Interval Sides	Confidence Interval %	CI Lower Limit	CI Upper Limit	Tested Non-Inferiority	Non-Inferiority Type
OG000 OG003	An analysis of covariance (ANCOVA) with randomization Q-LES-Q-SF item 16 as a fixed effect and pooled center as a random effect.	ANCOVA	0.152	LS mean	-0.1	Standard Error of the Mean	0.10	2-Sided	95	-0.33	0.05	No	Superiority or Other
OG001 OG003	An analysis of covariance (ANCOVA) with randomization Q-LES-Q-SF item 16 as a fixed effect and pooled center as a random effect.	ANCOVA	0.078	LS mean	-0.2	Standard Error of the Mean	0.10	2-Sided	95	-0.37	0.02	No	Superiority or Other
OG002 OG003	An analysis of covariance (ANCOVA) with randomization Q-LES-Q-SF item 16 as a fixed effect and pooled center as a random effect.	ANCOVA	0.033	LS mean	-0.2	Standard Error of the Mean	0.10	2-Sided	95	-0.41	-0.02	No	Superiority or Other

Title

Denominators

Categories

EQ-5D index score

Title	Measurements
	OG0000.128± 0.0147 OG0010.139± 0.0149 OG0020.133± 0.0155 OG0030.139± 0.0146

EQ-5D VAS score

Title	Measurements
	OG00016.4± 1.52 OG00117.0± 1.54 OG00215.9± 1.61 OG003

Group IDs	Group Description	Statistical Method	P-Value	P-Value Comment	Parameter Type	Parameter Value	Dispersion Type	Dispersion Value	Confidence Interval Sides	Confidence Interval %	CI Lower Limit	CI Upper Limit	Tested Non-Inferiority	Non-Inferiority Type
OG000 OG003	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.	MMRM	0.543	Analysis for change in EQ-5D index score from randomization (Week 8) to end of treatment (Week 16)	LS mean	-0.011	Standard Error of the Mean	0.0181	2-Sided	95	-0.0465	0.0245	No	Superiority or Other
OG001 OG003	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.	MMRM	0.998	Analysis for change in EQ-5D index score from randomization (Week 8) to end of treatment (Week 16)	LS mean	0.000	Standard Error of the Mean	0.0183	2-Sided	95	-0.0360	0.0361	No	Superiority or Other
OG002 OG003	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.	MMRM	0.743	Analysis for change in EQ-5D index score from randomization (Week 8) to end of treatment (Week 16)	LS mean	-0.006	Standard Error of the Mean	0.0188	2-Sided	95	-0.0432	0.0308	No	Superiority or Other
OG000 OG003	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.	MMRM	0.244	Analysis of change in EQ-5D VAS score from randomization (Week 8) to end of treatment (Week 16)	LS mean	-2.3	Standard Error of the Mean	1.95	2-Sided	95	-6.10	1.56	No	Superiority or Other
OG001 OG003	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.	MMRM	0.389	Analysis of change in EQ-5D VAS score from randomization (Week 8) to end of treatment (Week 16)	LS mean	-1.7	Standard Error of the Mean	1.98	2-Sided	95	-5.59	2.18	No	Superiority or Other
OG002 OG003	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.	MMRM	0.165	Analysis of change in EQ-5D VAS score from randomization (Week 8) to end of treatment (Week 16)	LS mean	-2.8	Standard Error of the Mean	2.02	2-Sided	95	-6.79	1.16	No	Superiority or Other

ID	Term
D003866	Depressive Disorder
D019964	Mood Disorders
D001523	Mental Disorders
D001526	Behavioral Symptoms
D001519	Behavior