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

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ClinicalTrials.gov Identifier: NCT01153347
Recruitment Status : Completed
First Posted : June 30, 2010
Results First Posted : November 20, 2012
Last Update Posted : April 11, 2014
Sponsor:
Collaborator:
Targacept Inc.
Information provided by (Responsible Party):
AstraZeneca

Study Type Interventional
Study Design Allocation: Randomized;   Intervention Model: Parallel Assignment;   Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor);   Primary Purpose: Treatment
Conditions Major Depressive Disorder
Depression
Interventions Drug: TC-5214
Drug: Placebo
Enrollment 2409
Recruitment Details This multicenter study was conducted in the US and India between 15 June 2010 and 31 January 2012.
Pre-assignment Details 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 0.5 mg BID TC-5214 2 mg BID TC-5214 4 mg BID TC-5214 Placebo
Hide Arm/Group Description Selective serotonin reuptake inhibitor (SSRI)/Serotonin/norepinephrine reuptake inhibitor (SNRI) + TC-5214, 0.5 mg BID Selective serotonin reuptake inhibitor (SSRI)/Serotonin/norepinephrine reuptake inhibitor (SNRI) + TC-5214, 2 mg BID Selective serotonin reuptake inhibitor (SSRI)/Serotonin/norepinephrine reuptake inhibitor (SNRI) + TC-5214, 4 mg BID Selective serotonin reuptake inhibitor (SSRI)/Serotonin/norepinephrine reuptake inhibitor (SNRI) + Placebo BID
Period Title: Overall Study
Started 160 160 160 161
Received Treatment 160 158 158 160
Completed 127 116 110 129
Not Completed 33 44 50 32
Reason Not Completed
Withdrawal by Subject             7             7             7             7
Eligibility criteria not fulfilled             0             1             2             1
Adverse Event             3             9             21             7
Severe non-compliance to protocol             6             7             4             3
Condition under investigation worsened             1             1             0             0
Lack of Efficacy             2             2             0             4
Study-specific withdrawal criteria             4             3             1             2
Lost to Follow-up             4             9             11             8
Not specified             5             5             4             0
Death             1             0             0             0
Arm/Group Title 0.5 mg BID TC-5214 2 mg BID TC-5214 4 mg BID TC-5214 Placebo Total
Hide Arm/Group Description Selective serotonin reuptake inhibitor (SSRI)/Serotonin/norepinephrine reuptake inhibitor (SNRI) + TC-5214, 0.5 mg BID Selective serotonin reuptake inhibitor (SSRI)/Serotonin/norepinephrine reuptake inhibitor (SNRI) + TC-5214, 2 mg BID Selective serotonin reuptake inhibitor (SSRI)/Serotonin/norepinephrine reuptake inhibitor (SNRI) + TC-5214, 4 mg BID Selective serotonin reuptake inhibitor (SSRI)/Serotonin/norepinephrine reuptake inhibitor (SNRI) + Placebo BID Total of all reporting groups
Overall Number of Baseline Participants 160 160 160 161 641
Hide Baseline Analysis Population Description
[Not Specified]
Age, Continuous  
Mean (Standard Deviation)
Unit of measure:  Years
Number Analyzed 160 participants 160 participants 160 participants 161 participants 641 participants
40.6  (11.78) 42.1  (11.77) 42.1  (11.35) 43.2  (11.92) 42.0  (11.72)
Sex: Female, Male  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 160 participants 160 participants 160 participants 161 participants 641 participants
Female
85
  53.1%
91
  56.9%
93
  58.1%
96
  59.6%
365
  56.9%
Male
75
  46.9%
69
  43.1%
67
  41.9%
65
  40.4%
276
  43.1%
Race/Ethnicity, Customized  
Measure Type: Number
Unit of measure:  Participants
Number Analyzed 160 participants 160 participants 160 participants 161 participants 641 participants
White 87 100 91 103 381
Black or African American 20 23 27 14 84
Asian 50 35 40 42 167
Native Hawaiian or other Pacific Islander 0 0 0 1 1
American Indian or Alaska Native 0 1 0 0 1
Other 3 1 2 1 7
Hamilton Rating Scale for Depression-17 items (HAMD-17) total score at randomization   [1] 
Mean (Standard Deviation)
Unit of measure:  Scores on a scale
Number Analyzed 160 participants 160 participants 160 participants 161 participants 641 participants
22.3  (3.98) 21.5  (3.74) 22.0  (4.07) 22.1  (4.08) 22.0  (3.97)
[1]
Measure 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.
Montgomery-Asberg Depression Rating Scale (MADRS) total score at randomization   [1] 
Mean (Standard Deviation)
Unit of measure:  Scores on a scale
Number Analyzed 160 participants 160 participants 160 participants 161 participants 641 participants
26.86  (6.331) 26.37  (6.036) 27.06  (5.854) 26.70  (6.809) 26.75  (6.261)
[1]
Measure 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.
1.Primary Outcome
Title Change in the Montgomery-Asberg Depression Rating Scale (MADRS) Total Score From Randomization to End of Treatment.
Hide 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)
Show Outcome Measure DataHide Outcome Measure Data
Hide 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 0.5 mg BID TC-5214 2 mg BID TC-5214 4 mg BID TC-5214 Placebo
Hide Arm/Group Description:
Selective serotonin reuptake inhibitor (SSRI)/Serotonin/norepinephrine reuptake inhibitor (SNRI) + TC-5214, 0.5 mg BID
Selective serotonin reuptake inhibitor (SSRI)/Serotonin/norepinephrine reuptake inhibitor (SNRI) + TC-5214, 2 mg BID
Selective serotonin reuptake inhibitor (SSRI)/Serotonin/norepinephrine reuptake inhibitor (SNRI) + TC-5214, 4 mg BID
Selective serotonin reuptake inhibitor (SSRI)/Serotonin/norepinephrine reuptake inhibitor (SNRI) + Placebo BID
Overall Number of Participants Analyzed 155 156 152 157
Least Squares Mean (Standard Error)
Unit of Measure: units on a scale
-12.1  (0.81) -11.8  (0.83) -11.3  (0.84) -11.2  (0.80)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection 0.5 mg BID 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 [Not Specified]
Statistical Test of Hypothesis P-Value 1.000
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 [Not Specified]
Method of Estimation Estimation Parameter LS mean
Estimated Value -0.9
Confidence Interval (2-Sided) 95%
-2.96 to 1.24
Parameter Dispersion
Type: Standard Error of the mean
Value: 1.07
Estimation Comments [Not Specified]
Show Statistical Analysis 2 Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection 2 mg BID 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 [Not Specified]
Statistical Test of Hypothesis P-Value 1.000
Comments [Not Specified]
Method MMRM
Comments [Not Specified]
Method of Estimation Estimation Parameter LS mean
Estimated Value -0.6
Confidence Interval (2-Sided) 95%
-2.67 to 1.57
Parameter Dispersion
Type: Standard Error of the mean
Value: 1.08
Estimation Comments [Not Specified]
Show Statistical Analysis 3 Hide Statistical Analysis 3
Statistical Analysis Overview Comparison Group Selection 4 mg BID 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 [Not Specified]
Statistical Test of Hypothesis P-Value 1.000
Comments [Not Specified]
Method MMRM
Comments [Not Specified]
Method of Estimation Estimation Parameter LS mean
Estimated Value -0.1
Confidence Interval (2-Sided) 95%
-2.26 to 2.04
Parameter Dispersion
Type: Standard Error of the mean
Value: 1.09
Estimation Comments [Not Specified]
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)
Hide 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.

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)
Show Outcome Measure DataHide Outcome Measure Data
Hide 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 0.5 mg BID TC-5214 2 mg BID TC-5214 4 mg BID TC-5214 Placebo
Hide Arm/Group Description:
Selective serotonin reuptake inhibitor (SSRI)/Serotonin/norepinephrine reuptake inhibitor (SNRI) + TC-5214, 0.5 mg BID
Selective serotonin reuptake inhibitor (SSRI)/Serotonin/norepinephrine reuptake inhibitor (SNRI) + TC-5214, 2 mg BID
Selective serotonin reuptake inhibitor (SSRI)/Serotonin/norepinephrine reuptake inhibitor (SNRI) + TC-5214, 4 mg BID
Selective serotonin reuptake inhibitor (SSRI)/Serotonin/norepinephrine reuptake inhibitor (SNRI) + Placebo BID
Overall Number of Participants Analyzed 155 156 152 157
Measure Type: Number
Unit of Measure: percentage of participants analyzed
43.9 39.7 38.8 42.7
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection 0.5 mg BID 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 [Not Specified]
Statistical Test of Hypothesis P-Value 0.967
Comments [Not Specified]
Method Regression, Logistic
Comments [Not Specified]
Method of Estimation Estimation Parameter Odds Ratio (OR)
Estimated Value 1.01
Confidence Interval (2-Sided) 95%
0.64 to 1.60
Parameter Dispersion
Type: Standard Error of the mean
Value: 0.24
Estimation Comments TC-5214 is the numerator in the OR, OR>1 represents a result in favor of TC-5214.
Show Statistical Analysis 2 Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection 2 mg BID 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 [Not Specified]
Statistical Test of Hypothesis P-Value 0.670
Comments [Not Specified]
Method Regression, Logistic
Comments [Not Specified]
Method of Estimation Estimation Parameter Odds Ratio (OR)
Estimated Value 0.90
Confidence Interval (2-Sided) 95%
0.57 to 1.43
Parameter Dispersion
Type: Standard Error of the mean
Value: 0.21
Estimation Comments TC-5214 is the numerator in the OR, OR>1 represents a result in favor of TC-5214.
Show Statistical Analysis 3 Hide Statistical Analysis 3
Statistical Analysis Overview Comparison Group Selection 4 mg BID 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 [Not Specified]
Statistical Test of Hypothesis P-Value 0.544
Comments [Not Specified]
Method Regression, Logistic
Comments [Not Specified]
Method of Estimation Estimation Parameter Odds Ratio (OR)
Estimated Value 0.87
Confidence Interval (2-Sided) 95%
0.54 to 1.38
Parameter Dispersion
Type: Standard Error of the mean
Value: 0.21
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)
Hide Description

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

A 10-item scale for the evaluation of depressive symptoms. Each MADRS item is rated on a 0 to 6 scale. The MADRS total score is calculated as the sum of the 10 individual item scores; the total score can range from 0 to 60. Higher MADRS scores indicate higher levels of depressive symptoms.

Time Frame Week 16
Show Outcome Measure DataHide Outcome Measure Data
Hide 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 0.5 mg BID TC-5214 2 mg BID TC-5214 4 mg BID TC-5214 Placebo
Hide Arm/Group Description:
Selective serotonin reuptake inhibitor (SSRI)/Serotonin/norepinephrine reuptake inhibitor (SNRI) + TC-5214, 0.5 mg BID
Selective serotonin reuptake inhibitor (SSRI)/Serotonin/norepinephrine reuptake inhibitor (SNRI) + TC-5214, 2 mg BID
Selective serotonin reuptake inhibitor (SSRI)/Serotonin/norepinephrine reuptake inhibitor (SNRI) + TC-5214, 4 mg BID
Selective serotonin reuptake inhibitor (SSRI)/Serotonin/norepinephrine reuptake inhibitor (SNRI) + Placebo BID
Overall Number of Participants Analyzed 155 156 152 157
Measure Type: Number
Unit of Measure: percentage of participants analyzed
29.0 26.9 23.7 29.9
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection 0.5 mg BID 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 [Not Specified]
Statistical Test of Hypothesis P-Value 0.730
Comments [Not Specified]
Method Regression, Logistic
Comments [Not Specified]
Method of Estimation Estimation Parameter Odds Ratio (OR)
Estimated Value 0.91
Confidence Interval (2-Sided) 95%
0.55 to 1.53
Parameter Dispersion
Type: Standard Error of the mean
Value: 0.24
Estimation Comments TC-5214 is the numerator in the OR, OR>1 represents a result in favor of TC-5214.
Show Statistical Analysis 2 Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection 2 mg BID 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 [Not Specified]
Statistical Test of Hypothesis P-Value 0.671
Comments [Not Specified]
Method Regression, Logistic
Comments [Not Specified]
Method of Estimation Estimation Parameter Odds Ratio (OR)
Estimated Value 0.89
Confidence Interval (2-Sided) 95%
0.53 to 1.50
Parameter Dispersion
Type: Standard Error of the mean
Value: 0.23
Estimation Comments TC-5214 is the numerator in the OR, OR>1 represents a result in favor of TC-5214.
Show Statistical Analysis 3 Hide Statistical Analysis 3
Statistical Analysis Overview Comparison Group Selection 4 mg BID 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 [Not Specified]
Statistical Test of Hypothesis P-Value 0.308
Comments [Not Specified]
Method Regression, Logistic
Comments [Not Specified]
Method of Estimation Estimation Parameter Odds Ratio (OR)
Estimated Value 0.76
Confidence Interval (2-Sided) 95%
0.45 to 1.29
Parameter Dispersion
Type: Standard Error of the mean
Value: 0.20
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)
Hide 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.

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); Week 10, Week 12, Week 14, and Week 16
Show Outcome Measure DataHide Outcome Measure Data
Hide 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 0.5 mg BID TC-5214 2 mg BID TC-5214 4 mg BID TC-5214 Placebo
Hide Arm/Group Description:
Selective serotonin reuptake inhibitor (SSRI)/Serotonin/norepinephrine reuptake inhibitor (SNRI) + TC-5214, 0.5 mg BID
Selective serotonin reuptake inhibitor (SSRI)/Serotonin/norepinephrine reuptake inhibitor (SNRI) + TC-5214, 2 mg BID
Selective serotonin reuptake inhibitor (SSRI)/Serotonin/norepinephrine reuptake inhibitor (SNRI) + TC-5214, 4 mg BID
Selective serotonin reuptake inhibitor (SSRI)/Serotonin/norepinephrine reuptake inhibitor (SNRI) + Placebo BID
Overall Number of Participants Analyzed 148 153 145 153
Measure Type: Number
Unit of Measure: percentage of participants analyzed
8.8 7.8 8.3 8.5
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection 0.5 mg BID 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 [Not Specified]
Statistical Test of Hypothesis P-Value 0.905
Comments [Not Specified]
Method Regression, Logistic
Comments [Not Specified]
Method of Estimation Estimation Parameter Odds Ratio (OR)
Estimated Value 0.95
Confidence Interval (2-Sided) 95%
0.42 to 2.15
Parameter Dispersion
Type: Standard Error of the mean
Value: 0.40
Estimation Comments TC-5214 is the numerator in the OR, OR>1 represents a result in favor of TC-5214.
Show Statistical Analysis 2 Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection 2 mg BID 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 [Not Specified]
Statistical Test of Hypothesis P-Value 0.864
Comments [Not Specified]
Method Regression, Logistic
Comments [Not Specified]
Method of Estimation Estimation Parameter Odds Ratio (OR)
Estimated Value 0.93
Confidence Interval (2-Sided) 95%
0.41 to 2.14
Parameter Dispersion
Type: Standard Error of the mean
Value: 0.39
Estimation Comments TC-5214 is the numerator in the OR, OR>1 represents a result in favor of TC-5214.
Show Statistical Analysis 3 Hide Statistical Analysis 3
Statistical Analysis Overview Comparison Group Selection 4 mg BID 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 [Not Specified]
Statistical Test of Hypothesis P-Value 0.958
Comments [Not Specified]
Method Regression, Logistic
Comments [Not Specified]
Method of Estimation Estimation Parameter Odds Ratio (OR)
Estimated Value 0.98
Confidence Interval (2-Sided) 95%
0.43 to 2.25
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.
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)
Hide 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.

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); Week 12, Week 14, and Week 16
Show Outcome Measure DataHide Outcome Measure Data
Hide 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 0.5 mg BID TC-5214 2 mg BID TC-5214 4 mg BID TC-5214 Placebo
Hide Arm/Group Description:
Selective serotonin reuptake inhibitor (SSRI)/Serotonin/norepinephrine reuptake inhibitor (SNRI) + TC-5214, 0.5 mg BID
Selective serotonin reuptake inhibitor (SSRI)/Serotonin/norepinephrine reuptake inhibitor (SNRI) + TC-5214, 2 mg BID
Selective serotonin reuptake inhibitor (SSRI)/Serotonin/norepinephrine reuptake inhibitor (SNRI) + TC-5214, 4 mg BID
Selective serotonin reuptake inhibitor (SSRI)/Serotonin/norepinephrine reuptake inhibitor (SNRI) + Placebo BID
Overall Number of Participants Analyzed 145 150 143 151
Measure Type: Number
Unit of Measure: percentage of patients analyzed
15.9 18.7 14.0 15.9
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection 0.5 mg BID 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 [Not Specified]
Statistical Test of Hypothesis P-Value 0.778
Comments [Not Specified]
Method Regression, Logistic
Comments [Not Specified]
Method of Estimation Estimation Parameter Odds Ratio (OR)
Estimated Value 0.91
Confidence Interval (2-Sided) 95%
0.48 to 1.73
Parameter Dispersion
Type: Standard Error of the mean
Value: 0.30
Estimation Comments TC-5214 is the numerator in the OR, OR>1 represents a result in favor of TC-5214.
Show Statistical Analysis 2 Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection 2 mg BID 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 [Not Specified]
Statistical Test of Hypothesis P-Value 0.532
Comments [Not Specified]
Method Regression, Logistic
Comments [Not Specified]
Method of Estimation Estimation Parameter Odds Ratio (OR)
Estimated Value 1.22
Confidence Interval (2-Sided) 95%
0.66 to 2.24
Parameter Dispersion
Type: Standard Error of the mean
Value: 0.38
Estimation Comments TC-5214 is the numerator in the OR, OR>1 represents a result in favor of TC-5214.
Show Statistical Analysis 3 Hide Statistical Analysis 3
Statistical Analysis Overview Comparison Group Selection 4 mg BID 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 [Not Specified]
Statistical Test of Hypothesis P-Value 0.633
Comments [Not Specified]
Method Regression, Logistic
Comments [Not Specified]
Method of Estimation Estimation Parameter Odds Ratio (OR)
Estimated Value 0.85
Confidence Interval (2-Sided) 95%
0.44 to 1.64
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.
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)
Hide 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.

A 10-item scale for the evaluation of depressive symptoms. Each MADRS item is rated on a 0 to 6 scale. The MADRS total score is calculated as the sum of the 10 individual item scores; the total score can range from 0 to 60. Higher MADRS scores indicate higher levels of depressive symptoms.

Time Frame Week 12, Week 14, Week 16
Show Outcome Measure DataHide Outcome Measure Data
Hide 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 0.5 mg BID TC-5214 2 mg BID TC-5214 4 mg BID TC-5214 Placebo
Hide Arm/Group Description:
Selective serotonin reuptake inhibitor (SSRI)/Serotonin/norepinephrine reuptake inhibitor (SNRI) + TC-5214, 0.5 mg BID
Selective serotonin reuptake inhibitor (SSRI)/Serotonin/norepinephrine reuptake inhibitor (SNRI) + TC-5214, 2 mg BID
Selective serotonin reuptake inhibitor (SSRI)/Serotonin/norepinephrine reuptake inhibitor (SNRI) + TC-5214, 4 mg BID
Selective serotonin reuptake inhibitor (SSRI)/Serotonin/norepinephrine reuptake inhibitor (SNRI) + Placebo BID
Overall Number of Participants Analyzed 146 150 144 152
Measure Type: Number
Unit of Measure: percentage of participants analyzed
10.3 12.7 7.6 9.2
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection 0.5 mg BID 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 [Not Specified]
Statistical Test of Hypothesis P-Value 0.949
Comments [Not Specified]
Method Regression, Logistic
Comments [Not Specified]
Method of Estimation Estimation Parameter Odds Ratio (OR)
Estimated Value 1.03
Confidence Interval (2-Sided) 95%
0.46 to 2.31
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.
Show Statistical Analysis 2 Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection 2 mg BID 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 [Not Specified]
Statistical Test of Hypothesis P-Value 0.253
Comments [Not Specified]
Method Regression, Logistic
Comments [Not Specified]
Method of Estimation Estimation Parameter Odds Ratio (OR)
Estimated Value 1.57
Confidence Interval (2-Sided) 95%
0.72 to 3.40
Parameter Dispersion
Type: Standard Error of the mean
Value: 0.62
Estimation Comments TC-5214 is the numerator in the OR, OR>1 represents a result in favor of TC-5214.
Show Statistical Analysis 3 Hide Statistical Analysis 3
Statistical Analysis Overview Comparison Group Selection 4 mg BID 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 [Not Specified]
Statistical Test of Hypothesis P-Value 0.763
Comments [Not Specified]
Method Regression, Logistic
Comments [Not Specified]
Method of Estimation Estimation Parameter Odds Ratio (OR)
Estimated Value 0.88
Confidence Interval (2-Sided) 95%
0.37 to 2.08
Parameter Dispersion
Type: Standard Error of the mean
Value: 0.39
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
Hide 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)
Show Outcome Measure DataHide Outcome Measure Data
Hide 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 0.5 mg BID TC-5214 2 mg BID TC-5214 4 mg BID TC-5214 Placebo
Hide Arm/Group Description:
Selective serotonin reuptake inhibitor (SSRI)/Serotonin/norepinephrine reuptake inhibitor (SNRI) + TC-5214, 0.5 mg BID
Selective serotonin reuptake inhibitor (SSRI)/Serotonin/norepinephrine reuptake inhibitor (SNRI) + TC-5214, 2 mg BID
Selective serotonin reuptake inhibitor (SSRI)/Serotonin/norepinephrine reuptake inhibitor (SNRI) + TC-5214, 4 mg BID
Selective serotonin reuptake inhibitor (SSRI)/Serotonin/norepinephrine reuptake inhibitor (SNRI) + Placebo BID
Overall Number of Participants Analyzed 147 144 142 150
Least Squares Mean (Standard Error)
Unit of Measure: units on a scale
-10.1  (0.79) -9.7  (0.79) -9.5  (0.79) -9.1  (0.78)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection 0.5 mg BID 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 [Not Specified]
Statistical Test of Hypothesis P-Value 0.207
Comments [Not Specified]
Method ANCOVA
Comments [Not Specified]
Method of Estimation Estimation Parameter LS mean
Estimated Value -1.0
Confidence Interval (2-Sided) 95%
-2.51 to 0.55
Parameter Dispersion
Type: Standard Error of the mean
Value: 0.78
Estimation Comments [Not Specified]
Show Statistical Analysis 2 Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection 2 mg BID 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 [Not Specified]
Statistical Test of Hypothesis P-Value 0.427
Comments [Not Specified]
Method ANCOVA
Comments [Not Specified]
Method of Estimation Estimation Parameter LS mean
Estimated Value -0.6
Confidence Interval (2-Sided) 95%
-2.16 to 0.91
Parameter Dispersion
Type: Standard Error of the mean
Value: 0.78
Estimation Comments [Not Specified]
Show Statistical Analysis 3 Hide Statistical Analysis 3
Statistical Analysis Overview Comparison Group Selection 4 mg BID 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 [Not Specified]
Statistical Test of Hypothesis P-Value 0.591
Comments [Not Specified]
Method ANCOVA
Comments [Not Specified]
Method of Estimation Estimation Parameter LS mean
Estimated Value -0.4
Confidence Interval (2-Sided) 95%
-1.96 to 1.12
Parameter Dispersion
Type: Standard Error of the mean
Value: 0.78
Estimation Comments [Not Specified]
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)
Hide 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)
Show Outcome Measure DataHide Outcome Measure Data
Hide 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 0.5 mg BID TC-5214 2 mg BID TC-5214 4 mg BID TC-5214 Placebo
Hide Arm/Group Description:
Selective serotonin reuptake inhibitor (SSRI)/Serotonin/norepinephrine reuptake inhibitor (SNRI) + TC-5214, 0.5 mg BID
Selective serotonin reuptake inhibitor (SSRI)/Serotonin/norepinephrine reuptake inhibitor (SNRI) + TC-5214, 2 mg BID
Selective serotonin reuptake inhibitor (SSRI)/Serotonin/norepinephrine reuptake inhibitor (SNRI) + TC-5214, 4 mg BID
Selective serotonin reuptake inhibitor (SSRI)/Serotonin/norepinephrine reuptake inhibitor (SNRI) + Placebo BID
Overall Number of Participants Analyzed 155 156 152 157
Least Squares Mean (Standard Error)
Unit of Measure: units on a scale
-1.3  (0.10) -1.3  (0.11) -1.2  (0.11) -1.2  (0.10)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection 0.5 mg BID 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 [Not Specified]
Statistical Test of Hypothesis P-Value 0.551
Comments [Not Specified]
Method MMRM
Comments [Not Specified]
Method of Estimation Estimation Parameter LS mean
Estimated Value -0.1
Confidence Interval 95%
-0.34 to 0.18
Parameter Dispersion
Type: Standard Error of the mean
Value: 0.13
Estimation Comments [Not Specified]
Show Statistical Analysis 2 Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection 2 mg BID 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 [Not Specified]
Statistical Test of Hypothesis P-Value 0.487
Comments [Not Specified]
Method MMRM
Comments [Not Specified]
Method of Estimation Estimation Parameter LS mean
Estimated Value -0.1
Confidence Interval (2-Sided) 95%
-0.36 to 0.17
Parameter Dispersion
Type: Standard Error of the mean
Value: 0.13
Estimation Comments [Not Specified]
Show Statistical Analysis 3 Hide Statistical Analysis 3
Statistical Analysis Overview Comparison Group Selection 4 mg BID 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 [Not Specified]
Statistical Test of Hypothesis P-Value 0.780
Comments [Not Specified]
Method MMRM
Comments [Not Specified]
Method of Estimation Estimation Parameter LS mean
Estimated Value 0.0
Confidence Interval (2-Sided) 95%
-0.23 to 0.31
Parameter Dispersion
Type: Standard Error of the mean
Value: 0.14
Estimation Comments [Not Specified]
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)
Hide 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)
Show Outcome Measure DataHide Outcome Measure Data
Hide 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 0.5 mg BID TC-5214 2 mg BID TC-5214 4 mg BID TC-5214 Placebo
Hide Arm/Group Description:
Selective serotonin reuptake inhibitor (SSRI)/Serotonin/norepinephrine reuptake inhibitor (SNRI) + TC-5214, 0.5 mg BID
Selective serotonin reuptake inhibitor (SSRI)/Serotonin/norepinephrine reuptake inhibitor (SNRI) + TC-5214, 2 mg BID
Selective serotonin reuptake inhibitor (SSRI)/Serotonin/norepinephrine reuptake inhibitor (SNRI) + TC-5214, 4 mg BID
Selective serotonin reuptake inhibitor (SSRI)/Serotonin/norepinephrine reuptake inhibitor (SNRI) + Placebo BID
Overall Number of Participants Analyzed 155 156 152 157
Measure Type: Number
Unit of Measure: percentage of participants analyzed
48.4 49.4 37.5 47.8
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection 0.5 mg BID 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 [Not Specified]
Statistical Test of Hypothesis P-Value 0.908
Comments [Not Specified]
Method Regression, Logistic
Comments [Not Specified]
Method of Estimation Estimation Parameter Odds Ratio (OR)
Estimated Value 0.97
Confidence Interval (2-Sided) 95%
0.62 to 1.53
Parameter Dispersion
Type: Standard Error of the mean
Value: 0.23
Estimation Comments TC-5214 is the numerator in the OR, OR>1 represents a result in favor of TC-5214.
Show Statistical Analysis 2 Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection 2 mg BID 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 [Not Specified]
Statistical Test of Hypothesis P-Value 0.803
Comments [Not Specified]
Method Regression, Logistic
Comments [Not Specified]
Method of Estimation Estimation Parameter Odds Ratio (OR)
Estimated Value 1.06
Confidence Interval (2-Sided) 95%
0.67 to 1.67
Parameter Dispersion
Type: Standard Error of the mean
Value: 0.24
Estimation Comments TC-5214 is the numerator in the OR, OR>1 represents a result in favor of TC-5214.
Show Statistical Analysis 3 Hide Statistical Analysis 3
Statistical Analysis Overview Comparison Group Selection 4 mg BID 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 [Not Specified]
Statistical Test of Hypothesis P-Value 0.066
Comments [Not Specified]
Method Regression, Logistic
Comments [Not Specified]
Method of Estimation Estimation Parameter Odds Ratio (OR)
Estimated Value 0.65
Confidence Interval (2-Sided) 95%
0.41 to 1.03
Parameter Dispersion
Type: Standard Error of the mean
Value: 0.15
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 Hamilton Anxiety Scale (HAM-A) Total Score From Randomization (Week 8) to End of Treatment (Week 16)
Hide Description A 14-item clinician-administered scale for the evaluation of anxiety symptoms. Each HAM-A item is rated on a 0 to 4 scale, the total score can range from 0 to 56. Higher HAM-A scores indicate higher levels of anxiety.
Time Frame Randomization (Week 8) to end of treatment (Week 16)
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
[Not Specified]
Arm/Group Title 0.5 mg BID TC-5214 2 mg BID TC-5214 4 mg BID TC-5214 Placebo
Hide Arm/Group Description:
Selective serotonin reuptake inhibitor (SSRI)/Serotonin/norepinephrine reuptake inhibitor (SNRI) + TC-5214, 0.5 mg BID
Selective serotonin reuptake inhibitor (SSRI)/Serotonin/norepinephrine reuptake inhibitor (SNRI) + TC-5214, 2 mg BID
Selective serotonin reuptake inhibitor (SSRI)/Serotonin/norepinephrine reuptake inhibitor (SNRI) + TC-5214, 4 mg BID
Selective serotonin reuptake inhibitor (SSRI)/Serotonin/norepinephrine reuptake inhibitor (SNRI) + Placebo BID
Overall Number of Participants Analyzed 147 144 142 150
Least Squares Mean (Standard Error)
Unit of Measure: units on a scale
-7.07  (0.648) -6.46  (0.652) -6.75  (0.655) -6.24  (0.641)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection 0.5 mg BID TC-5214, Placebo
Comments 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.
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.202
Comments [Not Specified]
Method ANCOVA
Comments [Not Specified]
Method of Estimation Estimation Parameter LS mean
Estimated Value -0.82
Confidence Interval (2-Sided) 95%
-2.091 to 0.442
Parameter Dispersion
Type: Standard Error of the mean
Value: 0.645
Estimation Comments [Not Specified]
Show Statistical Analysis 2 Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection 2 mg BID TC-5214, Placebo
Comments 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.
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.738
Comments [Not Specified]
Method ANCOVA
Comments [Not Specified]
Method of Estimation Estimation Parameter LS mean
Estimated Value -0.22
Confidence Interval (2-Sided) 95%
-1.487 to 1.055
Parameter Dispersion
Type: Standard Error of the mean
Value: 0.647
Estimation Comments [Not Specified]
Show Statistical Analysis 3 Hide Statistical Analysis 3
Statistical Analysis Overview Comparison Group Selection 4 mg BID TC-5214, Placebo
Comments 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.
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.433
Comments [Not Specified]
Method ANCOVA
Comments [Not Specified]
Method of Estimation Estimation Parameter LS mean
Estimated Value -0.51
Confidence Interval (2-Sided) 95%
-1.787 to 0.767
Parameter Dispersion
Type: Standard Error of the mean
Value: 0.650
Estimation Comments [Not Specified]
11.Secondary Outcome
Title Change in MADRS Total Score From Randomization (Week 8) to Week 9
Hide 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 9
Show Outcome Measure DataHide Outcome Measure Data
Hide 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 0.5 mg BID TC-5214 2 mg BID TC-5214 4 mg BID TC-5214 Placebo
Hide Arm/Group Description:
Selective serotonin reuptake inhibitor (SSRI)/Serotonin/norepinephrine reuptake inhibitor (SNRI) + TC-5214, 0.5 mg BID
Selective serotonin reuptake inhibitor (SSRI)/Serotonin/norepinephrine reuptake inhibitor (SNRI) + TC-5214, 2 mg BID
Selective serotonin reuptake inhibitor (SSRI)/Serotonin/norepinephrine reuptake inhibitor (SNRI) + TC-5214, 4 mg BID
Selective serotonin reuptake inhibitor (SSRI)/Serotonin/norepinephrine reuptake inhibitor (SNRI) + Placebo BID
Overall Number of Participants Analyzed 152 150 146 152
Least Squares Mean (Standard Error)
Unit of Measure: units on a scale
-4.0  (0.52) -5.1  (0.52) -4.0  (0.52) -5.0  (0.52)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection 0.5 mg BID 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 [Not Specified]
Statistical Test of Hypothesis P-Value 0.097
Comments [Not Specified]
Method MMRM
Comments [Not Specified]
Method of Estimation Estimation Parameter LS mean
Estimated Value 1.0
Confidence Interval (2-Sided) 95%
-0.18 to 2.22
Parameter Dispersion
Type: Standard Error of the mean
Value: 0.61
Estimation Comments [Not Specified]
Show Statistical Analysis 2 Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection 2 mg BID 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 [Not Specified]
Statistical Test of Hypothesis P-Value 0.882
Comments [Not Specified]
Method MMRM
Comments [Not Specified]
Method of Estimation Estimation Parameter LS mean
Estimated Value -0.1
Confidence Interval (2-Sided) 95%
-1.29 to 1.11
Parameter Dispersion
Type: Standard Error of the mean
Value: 0.61
Estimation Comments [Not Specified]
Show Statistical Analysis 3 Hide Statistical Analysis 3
Statistical Analysis Overview Comparison Group Selection 4 mg BID 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 [Not Specified]
Statistical Test of Hypothesis P-Value 0.100
Comments [Not Specified]
Method MMRM
Comments [Not Specified]
Method of Estimation Estimation Parameter LS mean
Estimated Value 1.0
Confidence Interval (2-Sided) 95%
-0.19 to 2.23
Parameter Dispersion
Type: Standard Error of the mean
Value: 0.62
Estimation Comments [Not Specified]
12.Secondary Outcome
Title Change in MADRS Total Score From Randomization (Week 8) to Week 10
Hide 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
Show Outcome Measure DataHide Outcome Measure Data
Hide 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 0.5 mg BID TC-5214 2 mg BID TC-5214 4 mg BID TC-5214 Placebo
Hide Arm/Group Description:
Selective serotonin reuptake inhibitor (SSRI)/Serotonin/norepinephrine reuptake inhibitor (SNRI) + TC-5214, 0.5 mg BID
Selective serotonin reuptake inhibitor (SSRI)/Serotonin/norepinephrine reuptake inhibitor (SNRI) + TC-5214, 2 mg BID
Selective serotonin reuptake inhibitor (SSRI)/Serotonin/norepinephrine reuptake inhibitor (SNRI) + TC-5214, 4 mg BID
Selective serotonin reuptake inhibitor (SSRI)/Serotonin/norepinephrine reuptake inhibitor (SNRI) + Placebo BID
Overall Number of Participants Analyzed 150 146 139 148
Least Squares Mean (Standard Error)
Unit of Measure: units on a scale
-6.3  (0.60) -6.9  (0.60) -7.3  (0.61) -7.1  (0.60)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection 0.5 mg BID 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 [Not Specified]
Statistical Test of Hypothesis P-Value 0.303
Comments [Not Specified]
Method MMRM
Comments [Not Specified]
Method of Estimation Estimation Parameter LS mean
Estimated Value 0.8
Confidence Interval (2-Sided) 95%
-0.69 to 2.22
Parameter Dispersion
Type: Standard Error of the mean
Value: 0.74
Estimation Comments [Not Specified]
Show Statistical Analysis 2 Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection 2 mg BID 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 [Not Specified]
Statistical Test of Hypothesis P-Value 0.793
Comments [Not Specified]
Method MMRM
Comments [Not Specified]
Method of Estimation Estimation Parameter LS mean
Estimated Value 0.2
Confidence Interval (2-Sided) 95%
-1.26 to 1.65
Parameter Dispersion
Type: Standard Error of the mean
Value: 0.74
Estimation Comments [Not Specified]
Show Statistical Analysis 3 Hide Statistical Analysis 3
Statistical Analysis Overview Comparison Group Selection 4 mg BID 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 [Not Specified]
Statistical Test of Hypothesis P-Value 0.762
Comments [Not Specified]
Method MMRM
Comments [Not Specified]
Method of Estimation Estimation Parameter LS mean
Estimated Value -0.2
Confidence Interval (2-Sided) 95%
-1.70 to 1.25
Parameter Dispersion
Type: Standard Error of the mean
Value: 0.75
Estimation Comments [Not Specified]
13.Secondary Outcome
Title Change in MADRS Total Score From Randomization (Week 8) to Week 12
Hide 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
Show Outcome Measure DataHide Outcome Measure Data
Hide 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 0.5 mg BID TC-5214 2 mg BID TC-5214 4 mg BID TC-5214 Placebo
Hide Arm/Group Description:
Selective serotonin reuptake inhibitor (SSRI)/Serotonin/norepinephrine reuptake inhibitor (SNRI) + TC-5214, 0.5 mg BID
Selective serotonin reuptake inhibitor (SSRI)/Serotonin/norepinephrine reuptake inhibitor (SNRI) + TC-5214, 2 mg BID
Selective serotonin reuptake inhibitor (SSRI)/Serotonin/norepinephrine reuptake inhibitor (SNRI) + TC-5214, 4 mg BID
Selective serotonin reuptake inhibitor (SSRI)/Serotonin/norepinephrine reuptake inhibitor (SNRI) + Placebo BID
Overall Number of Participants Analyzed 142 135 128 145
Least Squares Mean (Standard Error)
Unit of Measure: units on a scale
-9.4  (0.70) -9.4  (0.71) -8.9  (0.73) -8.5  (0.70)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection 0.5 mg BID 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 [Not Specified]
Statistical Test of Hypothesis P-Value 0.339
Comments [Not Specified]
Method MMRM
Comments [Not Specified]
Method of Estimation Estimation Parameter LS mean
Estimated Value -0.9
Confidence Interval (2-Sided) 95%
-2.65 to 0.92
Parameter Dispersion
Type: Standard Error of the mean
Value: 0.91
Estimation Comments [Not Specified]
Show Statistical Analysis 2 Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection 2 mg BID 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 [Not Specified]
Statistical Test of Hypothesis P-Value 0.321
Comments [Not Specified]
Method MMRM
Comments [Not Specified]
Method of Estimation Estimation Parameter LS mean
Estimated Value -0.9
Confidence Interval (2-Sided) 95%
-2.70 to 0.89
Parameter Dispersion
Type: Standard Error of the mean
Value: 0.91
Estimation Comments [Not Specified]
Show Statistical Analysis 3 Hide Statistical Analysis 3
Statistical Analysis Overview Comparison Group Selection 4 mg BID 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 [Not Specified]
Statistical Test of Hypothesis P-Value 0.680
Comments [Not Specified]
Method MMRM
Comments [Not Specified]
Method of Estimation Estimation Parameter LS mean
Estimated Value -0.4
Confidence Interval (2-Sided) 95%
-2.20 to 1.43
Parameter Dispersion
Type: Standard Error of the mean
Value: 0.92
Estimation Comments [Not Specified]
14.Secondary Outcome
Title Change in MADRS Total Score From Randomization (Week 8) to Week 14
Hide 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
Show Outcome Measure DataHide Outcome Measure Data
Hide 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 0.5 mg BID TC-5214 2 mg BID TC-5214 4 mg BID TC-5214 Placebo
Hide Arm/Group Description:
Selective serotonin reuptake inhibitor (SSRI)/Serotonin/norepinephrine reuptake inhibitor (SNRI) + TC-5214, 0.5 mg BID
Selective serotonin reuptake inhibitor (SSRI)/Serotonin/norepinephrine reuptake inhibitor (SNRI) + TC-5214, 2 mg BID
Selective serotonin reuptake inhibitor (SSRI)/Serotonin/norepinephrine reuptake inhibitor (SNRI) + TC-5214, 4 mg BID
Selective serotonin reuptake inhibitor (SSRI)/Serotonin/norepinephrine reuptake inhibitor (SNRI) + Placebo BID
Overall Number of Participants Analyzed 140 127 119 134
Least Squares Mean (Standard Error)
Unit of Measure: units on a scale
-11.0  (0.74) -11.3  (0.76) -10.6  (0.77) -10.7  (0.74)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection 0.5 mg BID 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 [Not Specified]
Statistical Test of Hypothesis P-Value 0.737
Comments [Not Specified]
Method MMRM
Comments [Not Specified]
Method of Estimation Estimation Parameter LS mean
Estimated Value -0.3
Confidence Interval (2-Sided) 95%
-2.23 to 1.58
Parameter Dispersion
Type: Standard Error of the mean
Value: 0.97
Estimation Comments [Not Specified]
Show Statistical Analysis 2 Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection 2 mg BID 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 [Not Specified]
Statistical Test of Hypothesis P-Value 0.547
Comments [Not Specified]
Method MMRM
Comments [Not Specified]
Method of Estimation Estimation Parameter LS mean
Estimated Value -0.6
Confidence Interval (2-Sided) 95%
-2.52 to 1.33
Parameter Dispersion
Type: Standard Error of the mean
Value: 0.98
Estimation Comments [Not Specified]
Show Statistical Analysis 3 Hide Statistical Analysis 3
Statistical Analysis Overview Comparison Group Selection 4 mg BID 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 [Not Specified]
Statistical Test of Hypothesis P-Value 0.953
Comments [Not Specified]
Method MMRM
Comments [Not Specified]
Method of Estimation Estimation Parameter LS mean
Estimated Value 0.1
Confidence Interval (2-Sided) 95%
-1.89 to 2.01
Parameter Dispersion
Type: Standard Error of the mean
Value: 0.99
Estimation Comments [Not Specified]
15.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
Hide 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)
Show Outcome Measure DataHide Outcome Measure Data
Hide 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 0.5 mg BID TC-5214 2 mg BID TC-5214 4 mg BID TC-5214 Placebo
Hide Arm/Group Description:
Selective serotonin reuptake inhibitor (SSRI)/Serotonin/norepinephrine reuptake inhibitor (SNRI) + TC-5214, 0.5 mg BID
Selective serotonin reuptake inhibitor (SSRI)/Serotonin/norepinephrine reuptake inhibitor (SNRI) + TC-5214, 2 mg BID
Selective serotonin reuptake inhibitor (SSRI)/Serotonin/norepinephrine reuptake inhibitor (SNRI) + TC-5214, 4 mg BID
Selective serotonin reuptake inhibitor (SSRI)/Serotonin/norepinephrine reuptake inhibitor (SNRI) + Placebo BID
Overall Number of Participants Analyzed 152 148 149 153
Least Squares Mean (Standard Error)
Unit of Measure: units on a scale
-5.53  (0.631) -5.45  (0.643) -4.53  (0.651) -4.93  (0.627)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection 0.5 mg BID 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 [Not Specified]
Statistical Test of Hypothesis P-Value 1.000
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 [Not Specified]
Method of Estimation Estimation Parameter LS mean
Estimated Value -0.60
Confidence Interval (2-Sided) 95%
-2.069 to 0.864
Parameter Dispersion
Type: Standard Error of the mean
Value: 0.746
Estimation Comments [Not Specified]
Show Statistical Analysis 2 Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection 2 mg BID 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 [Not Specified]
Statistical Test of Hypothesis P-Value 1.000
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 [Not Specified]
Method of Estimation Estimation Parameter LS mean
Estimated Value -0.52
Confidence Interval (2-Sided) 95%
-2.004 to 0.960
Parameter Dispersion
Type: Standard Error of the mean
Value: 0.755
Estimation Comments [Not Specified]
Show Statistical Analysis 3 Hide Statistical Analysis 3
Statistical Analysis Overview Comparison Group Selection 4 mg BID 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 [Not Specified]
Statistical Test of Hypothesis P-Value 1.000
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 [Not Specified]
Method of Estimation Estimation Parameter LS mean
Estimated Value 0.40
Confidence Interval (2-Sided) 95%
-1.095 to 1.896
Parameter Dispersion
Type: Standard Error of the mean
Value: 0.761
Estimation Comments [Not Specified]
16.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
Hide 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)
Show Outcome Measure DataHide Outcome Measure Data
Hide 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 0.5 mg BID TC-5214 2 mg BID TC-5214 4 mg BID TC-5214 Placebo
Hide Arm/Group Description:
Selective serotonin reuptake inhibitor (SSRI)/Serotonin/norepinephrine reuptake inhibitor (SNRI) + TC-5214, 0.5 mg BID
Selective serotonin reuptake inhibitor (SSRI)/Serotonin/norepinephrine reuptake inhibitor (SNRI) + TC-5214, 2 mg BID
Selective serotonin reuptake inhibitor (SSRI)/Serotonin/norepinephrine reuptake inhibitor (SNRI) + TC-5214, 4 mg BID
Selective serotonin reuptake inhibitor (SSRI)/Serotonin/norepinephrine reuptake inhibitor (SNRI) + Placebo BID
Overall Number of Participants Analyzed 132 123 134 137
Least Squares Mean (Standard Error)
Unit of Measure: units on a scale
-1.7  (0.21) -1.8  (0.22) -1.7  (0.21) -1.7  (0.21)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection 0.5 mg BID 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 [Not Specified]
Statistical Test of Hypothesis P-Value 0.953
Comments [Not Specified]
Method MMRM
Comments [Not Specified]
Method of Estimation Estimation Parameter LS mean
Estimated Value 0.0
Confidence Interval (2-Sided) 95%
-0.56 to 0.59
Parameter Dispersion
Type: Standard Error of the mean
Value: 0.29
Estimation Comments [Not Specified]
Show Statistical Analysis 2 Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection 2 mg BID 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 [Not Specified]
Statistical Test of Hypothesis P-Value 0.868
Comments [Not Specified]
Method MMRM
Comments [Not Specified]
Method of Estimation Estimation Parameter LS mean
Estimated Value 0.0
Confidence Interval (2-Sided) 95%
-0.64 to 0.54
Parameter Dispersion
Type: Standard Error of the mean
Value: 0.30
Estimation Comments [Not Specified]
Show Statistical Analysis 3 Hide Statistical Analysis 3
Statistical Analysis Overview Comparison Group Selection 4 mg BID 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 [Not Specified]
Statistical Test of Hypothesis P-Value 0.792
Comments [Not Specified]
Method MMRM
Comments [Not Specified]
Method of Estimation Estimation Parameter LS mean
Estimated Value 0.1
Confidence Interval (2-Sided) 95%
-0.50 to 0.66
Parameter Dispersion
Type: Standard Error of the mean
Value: 0.30
Estimation Comments [Not Specified]
17.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
Hide 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)
Show Outcome Measure DataHide Outcome Measure Data
Hide 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 0.5 mg BID TC-5214 2 mg BID TC-5214 4 mg BID TC-5214 Placebo
Hide Arm/Group Description:
Selective serotonin reuptake inhibitor (SSRI)/Serotonin/norepinephrine reuptake inhibitor (SNRI) + TC-5214, 0.5 mg BID
Selective serotonin reuptake inhibitor (SSRI)/Serotonin/norepinephrine reuptake inhibitor (SNRI) + TC-5214, 2 mg BID
Selective serotonin reuptake inhibitor (SSRI)/Serotonin/norepinephrine reuptake inhibitor (SNRI) + TC-5214, 4 mg BID
Selective serotonin reuptake inhibitor (SSRI)/Serotonin/norepinephrine reuptake inhibitor (SNRI) + Placebo BID
Overall Number of Participants Analyzed 152 148 149 153
Least Squares Mean (Standard Error)
Unit of Measure: units on a scale
-1.9  (0.22) -1.9  (0.23) -1.6  (0.23) -1.9  (0.22)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection 0.5 mg BID 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 [Not Specified]
Statistical Test of Hypothesis P-Value 0.915
Comments [Not Specified]
Method MMRM
Comments [Not Specified]
Method of Estimation Estimation Parameter LS mean
Estimated Value 0.0
Confidence Interval (2-Sided) 95%
-0.54 to 0.48
Parameter Dispersion
Type: Standard Error of the mean
Value: 0.26
Estimation Comments [Not Specified]
Show Statistical Analysis 2 Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection 2 mg BID 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 [Not Specified]
Statistical Test of Hypothesis P-Value 0.972
Comments [Not Specified]
Method MMRM
Comments [Not Specified]
Method of Estimation Estimation Parameter LS mean
Estimated Value 0.0
Confidence Interval (2-Sided) 95%
-0.51 to 0.53
Parameter Dispersion
Type: Standard Error of the mean
Value: 0.26
Estimation Comments [Not Specified]
Show Statistical Analysis 3 Hide Statistical Analysis 3
Statistical Analysis Overview Comparison Group Selection 4 mg BID 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 [Not Specified]
Statistical Test of Hypothesis P-Value 0.237
Comments [Not Specified]
Method MMRM
Comments [Not Specified]
Method of Estimation Estimation Parameter LS mean
Estimated Value 0.3
Confidence Interval (2-Sided) 95%
-0.21 to 0.84
Parameter Dispersion
Type: Standard Error of the mean
Value: 0.27
Estimation Comments [Not Specified]
18.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
Hide 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)
Show Outcome Measure DataHide Outcome Measure Data
Hide 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 0.5 mg BID TC-5214 2 mg BID TC-5214 4 mg BID TC-5214 Placebo
Hide Arm/Group Description:
Selective serotonin reuptake inhibitor (SSRI)/Serotonin/norepinephrine reuptake inhibitor (SNRI) + TC-5214, 0.5 mg BID
Selective serotonin reuptake inhibitor (SSRI)/Serotonin/norepinephrine reuptake inhibitor (SNRI) + TC-5214, 2 mg BID
Selective serotonin reuptake inhibitor (SSRI)/Serotonin/norepinephrine reuptake inhibitor (SNRI) + TC-5214, 4 mg BID
Selective serotonin reuptake inhibitor (SSRI)/Serotonin/norepinephrine reuptake inhibitor (SNRI) + Placebo BID
Overall Number of Participants Analyzed 152 148 149 153
Least Squares Mean (Standard Error)
Unit of Measure: units on a scale
-1.9  (0.22) -1.8  (0.23) -1.6  (0.23) -1.6  (0.22)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection 0.5 mg BID 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 [Not Specified]
Statistical Test of Hypothesis P-Value 0.213
Comments [Not Specified]
Method MMRM
Comments [Not Specified]
Method of Estimation Estimation Parameter LS mean
Estimated Value -0.3
Confidence Interval (2-Sided) 95%
-0.87 to 0.19
Parameter Dispersion
Type: Standard Error of the mean
Value: 0.27
Estimation Comments [Not Specified]
Show Statistical Analysis 2 Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection 2 mg BID 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 [Not Specified]
Statistical Test of Hypothesis P-Value 0.343
Comments [Not Specified]
Method MMRM
Comments [Not Specified]
Method of Estimation Estimation Parameter LS mean
Estimated Value -0.3
Confidence Interval (2-Sided) 95%
-0.80 to 0.28
Parameter Dispersion
Type: Standard Error of the mean
Value: 0.27
Estimation Comments [Not Specified]
Show Statistical Analysis 3 Hide Statistical Analysis 3
Statistical Analysis Overview Comparison Group Selection 4 mg BID 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 [Not Specified]
Statistical Test of Hypothesis P-Value 0.971
Comments [Not Specified]
Method MMRM
Comments [Not Specified]
Method of Estimation Estimation Parameter LS mean
Estimated Value 0.0
Confidence Interval (2-Sided) 95%
-0.55 to 0.53
Parameter Dispersion
Type: Standard Error of the mean
Value: 0.28
Estimation Comments [Not Specified]
19.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
Hide Description The Q-LES-Q-SF total score is derived by summing item scores 1 to 14. Higher scores are indicative of greater enjoyment or satisfaction in each domain. The Q-LES-Q-SF % maximum total score is calculated as 100% × (Q-LES-Q-SF total score – 14) / 56, and can range from 0% to 100%.
Time Frame Randomization (Week 8) to end of treatment (Week 16)
Show Outcome Measure DataHide Outcome Measure Data
Hide 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 0.5 mg BID TC-5214 2 mg BID TC-5214 4 mg BID TC-5214 Placebo
Hide Arm/Group Description:
Selective serotonin reuptake inhibitor (SSRI)/Serotonin/norepinephrine reuptake inhibitor (SNRI) + TC-5214, 0.5 mg BID
Selective serotonin reuptake inhibitor (SSRI)/Serotonin/norepinephrine reuptake inhibitor (SNRI) + TC-5214, 2 mg BID
Selective serotonin reuptake inhibitor (SSRI)/Serotonin/norepinephrine reuptake inhibitor (SNRI) + TC-5214, 4 mg BID
Selective serotonin reuptake inhibitor (SSRI)/Serotonin/norepinephrine reuptake inhibitor (SNRI) + Placebo BID
Overall Number of Participants Analyzed 152 148 144 151
Least Squares Mean (Standard Error)
Unit of Measure: units on a scale
12.81  (1.470) 11.42  (1.483) 8.83  (1.499) 10.71  (1.467)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection 0.5 mg BID 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 [Not Specified]
Statistical Test of Hypothesis P-Value 0.215
Comments [Not Specified]
Method ANCOVA
Comments [Not Specified]
Method of Estimation Estimation Parameter LS mean
Estimated Value 2.10
Confidence Interval (2-Sided) 95%
-1.224 to 5.431
Parameter Dispersion
Type: Standard Error of the mean
Value: 1.694
Estimation Comments [Not Specified]
Show Statistical Analysis 2 Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection 2 mg BID 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 [Not Specified]
Statistical Test of Hypothesis P-Value 0.673
Comments [Not Specified]
Method ANCOVA
Comments [Not Specified]
Method of Estimation Estimation Parameter LS mean
Estimated Value 0.72
Confidence Interval (2-Sided) 95%
-2.624 to 4.062
Parameter Dispersion
Type: Standard Error of the mean
Value: 1.702
Estimation Comments [Not Specified]
Show Statistical Analysis 3 Hide Statistical Analysis 3
Statistical Analysis Overview Comparison Group Selection 4 mg BID 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 [Not Specified]
Statistical Test of Hypothesis P-Value 0.275
Comments [Not Specified]
Method ANCOVA
Comments [Not Specified]
Method of Estimation Estimation Parameter LS mean
Estimated Value -1.88
Confidence Interval (2-Sided) 95%
-5.248 to 1.494
Parameter Dispersion
Type: Standard Error of the mean
Value: 1.716
Estimation Comments [Not Specified]
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 15
Hide 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)
Show Outcome Measure DataHide Outcome Measure Data
Hide 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 0.5 mg BID TC-5214 2 mg BID TC-5214 4 mg BID TC-5214 Placebo
Hide Arm/Group Description:
Selective serotonin reuptake inhibitor (SSRI)/Serotonin/norepinephrine reuptake inhibitor (SNRI) + TC-5214, 0.5 mg BID
Selective serotonin reuptake inhibitor (SSRI)/Serotonin/norepinephrine reuptake inhibitor (SNRI) + TC-5214, 2 mg BID
Selective serotonin reuptake inhibitor (SSRI)/Serotonin/norepinephrine reuptake inhibitor (SNRI) + TC-5214, 4 mg BID
Selective serotonin reuptake inhibitor (SSRI)/Serotonin/norepinephrine reuptake inhibitor (SNRI) + Placebo BID
Overall Number of Participants Analyzed 142 136 124 138
Least Squares Mean (Standard Error)
Unit of Measure: units on a scale
0.3  (0.08) 0.4  (0.08) 0.2  (0.08) 0.4  (0.08)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection 0.5 mg BID 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 [Not Specified]
Statistical Test of Hypothesis P-Value 0.412
Comments [Not Specified]
Method ANCOVA
Comments [Not Specified]
Method of Estimation Estimation Parameter LS mean
Estimated Value -0.1
Confidence Interval (2-Sided) 95%
-0.28 to 0.11
Parameter Dispersion
Type: Standard Error of the mean
Value: 0.10
Estimation Comments [Not Specified]
Show Statistical Analysis 2 Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection 2 mg BID 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 [Not Specified]
Statistical Test of Hypothesis P-Value 0.928
Comments [Not Specified]
Method ANCOVA
Comments [Not Specified]
Method of Estimation Estimation Parameter LS mean
Estimated Value 0.0
Confidence Interval (2-Sided) 95%
-0.19 to 0.21
Parameter Dispersion
Type: Standard Error of the mean
Value: 0.10
Estimation Comments [Not Specified]
Show Statistical Analysis 3 Hide Statistical Analysis 3
Statistical Analysis Overview Comparison Group Selection 4 mg BID 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 [Not Specified]
Statistical Test of Hypothesis P-Value 0.033
Comments [Not Specified]
Method ANCOVA
Comments [Not Specified]
Method of Estimation Estimation Parameter LS mean
Estimated Value -0.2
Confidence Interval (2-Sided) 95%
-0.42 to -0.02
Parameter Dispersion
Type: Standard Error of the mean
Value: 0.10
Estimation Comments [Not Specified]
21.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
Hide 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)
Show Outcome Measure DataHide Outcome Measure Data
Hide 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 0.5 mg BID TC-5214 2 mg BID TC-5214 4 mg BID TC-5214 Placebo
Hide Arm/Group Description:
Selective serotonin reuptake inhibitor (SSRI)/Serotonin/norepinephrine reuptake inhibitor (SNRI) + TC-5214, 0.5 mg BID
Selective serotonin reuptake inhibitor (SSRI)/Serotonin/norepinephrine reuptake inhibitor (SNRI) + TC-5214, 2 mg BID
Selective serotonin reuptake inhibitor (SSRI)/Serotonin/norepinephrine reuptake inhibitor (SNRI) + TC-5214, 4 mg BID
Selective serotonin reuptake inhibitor (SSRI)/Serotonin/norepinephrine reuptake inhibitor (SNRI) + Placebo BID
Overall Number of Participants Analyzed 152 148 144 151
Least Squares Mean (Standard Error)
Unit of Measure: units on a scale
0.6  (0.08) 0.5  (0.08) 0.4  (0.08) 0.5  (0.08)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection 0.5 mg BID 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 [Not Specified]
Statistical Test of Hypothesis P-Value 0.353
Comments [Not Specified]
Method ANCOVA
Comments [Not Specified]
Method of Estimation Estimation Parameter LS mean
Estimated Value 0.1
Confidence Interval (2-Sided) 95%
-0.10 to 0.28
Parameter Dispersion
Type: Standard Error of the mean
Value: 0.10
Estimation Comments [Not Specified]
Show Statistical Analysis 2 Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection 2 mg BID 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 [Not Specified]
Statistical Test of Hypothesis P-Value 0.721
Comments [Not Specified]
Method ANCOVA
Comments [Not Specified]
Method of Estimation Estimation Parameter LS mean
Estimated Value 0.0
Confidence Interval (2-Sided) 95%
-0.16 to 0.23
Parameter Dispersion
Type: Standard Error of the mean
Value: 0.10
Estimation Comments [Not Specified]
Show Statistical Analysis 3 Hide Statistical Analysis 3
Statistical Analysis Overview Comparison Group Selection 4 mg BID 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 [Not Specified]
Statistical Test of Hypothesis P-Value 0.666
Comments [Not Specified]
Method ANCOVA
Comments [Not Specified]
Method of Estimation Estimation Parameter LS mean
Estimated Value 0.0
Confidence Interval (2-Sided) 95%
-0.24 to 0.15
Parameter Dispersion
Type: Standard Error of the mean
Value: 0.10
Estimation Comments [Not Specified]
22.Secondary Outcome
Title Change in EuroQol - 5 Dimensions (EQ-5D) From Randomization (Week 8) to End of Treatment (Week 16)
Hide 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)
Show Outcome Measure DataHide Outcome Measure Data
Hide 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 0.5 mg BID TC-5214 2 mg BID TC-5214 4 mg BID TC-5214 Placebo
Hide Arm/Group Description:
Selective serotonin reuptake inhibitor (SSRI)/Serotonin/norepinephrine reuptake inhibitor (SNRI) + TC-5214, 0.5 mg BID
Selective serotonin reuptake inhibitor (SSRI)/Serotonin/norepinephrine reuptake inhibitor (SNRI) + TC-5214, 2 mg BID
Selective serotonin reuptake inhibitor (SSRI)/Serotonin/norepinephrine reuptake inhibitor (SNRI) + TC-5214, 4 mg BID
Selective serotonin reuptake inhibitor (SSRI)/Serotonin/norepinephrine reuptake inhibitor (SNRI) + Placebo BID
Overall Number of Participants Analyzed 152 147 147 153
Least Squares Mean (Standard Error)
Unit of Measure: units on a scale
EQ-5D index score 0.114  (0.0169) 0.107  (0.0173) 0.106  (0.0176) 0.120  (0.0168)
EQ-5D VAS score 13.4  (1.69) 12.9  (1.73) 10.3  (1.76) 11.5  (1.68)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection 0.5 mg BID 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 [Not Specified]
Statistical Test of Hypothesis P-Value 0.747
Comments Analysis for change in EQ-5D index score from randomization (Week 8) to end of treatment (Week 16)
Method MMRM
Comments [Not Specified]
Method of Estimation Estimation Parameter LS mean
Estimated Value -0.006
Confidence Interval (2-Sided) 95%
-0.0459 to 0.0329
Parameter Dispersion
Type: Standard Error of the mean
Value: 0.0201
Estimation Comments [Not Specified]
Show Statistical Analysis 2 Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection 2 mg BID 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 [Not Specified]
Statistical Test of Hypothesis P-Value 0.524
Comments Analysis for change in EQ-5D index score from randomization (Week 8) to end of treatment (Week 16)
Method MMRM
Comments [Not Specified]
Method of Estimation Estimation Parameter LS mean
Estimated Value -0.013
Confidence Interval (2-Sided) 95%
-0.0529 to 0.0270
Parameter Dispersion
Type: Standard Error of the mean
Value: 0.0203
Estimation Comments [Not Specified]
Show Statistical Analysis 3 Hide Statistical Analysis 3
Statistical Analysis Overview Comparison Group Selection 4 mg BID 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 [Not Specified]
Statistical Test of Hypothesis P-Value 0.502
Comments Analysis for change in EQ-5D index score from randomization (Week 8) to end of treatment (Week 16)
Method MMRM
Comments [Not Specified]
Method of Estimation Estimation Parameter LS mean
Estimated Value -0.014
Confidence Interval (2-Sided) 95%
-0.0543 to 0.0267
Parameter Dispersion
Type: Standard Error of the mean
Value: 0.0206
Estimation Comments [Not Specified]
Show Statistical Analysis 4 Hide Statistical Analysis 4
Statistical Analysis Overview Comparison Group Selection 0.5 mg BID 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 [Not Specified]
Statistical Test of Hypothesis P-Value 0.345
Comments Analysis of change in EQ-5D VAS score from randomization (Week 8) to end of treatment (Week 16)
Method MMRM
Comments [Not Specified]
Method of Estimation Estimation Parameter LS mean
Estimated Value 1.9
Confidence Interval (2-Sided) 95%
-2.10 to 6.00
Parameter Dispersion
Type: Standard Error of the mean
Value: 2.06
Estimation Comments [Not Specified]
Show Statistical Analysis 5 Hide Statistical Analysis 5
Statistical Analysis Overview Comparison Group Selection 2 mg BID 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 [Not Specified]
Statistical Test of Hypothesis P-Value 0.486
Comments Analysis of change in EQ-5D VAS score from randomization (Week 8) to end of treatment (Week 16)
Method MMRM
Comments [Not Specified]
Method of Estimation Estimation Parameter LS mean
Estimated Value 1.5
Confidence Interval (2-Sided) 95%
-2.65 to 5.56
Parameter Dispersion
Type: Standard Error of the mean
Value: 2.09
Estimation Comments [Not Specified]
Show Statistical Analysis 6 Hide Statistical Analysis 6
Statistical Analysis Overview Comparison Group Selection 4 mg BID 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 [Not Specified]
Statistical Test of Hypothesis P-Value 0.564
Comments Analysis of change in EQ-5D VAS score from randomization (Week 8) to end of treatment (Week 16)
Method MMRM
Comments [Not Specified]
Method of Estimation Estimation Parameter LS mean
Estimated Value -1.2
Confidence Interval (2-Sided) 95%
-5.39 to 2.94
Parameter Dispersion
Type: Standard Error of the mean
Value: 2.12
Estimation Comments [Not Specified]
23.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)
Hide 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)
Show Outcome Measure DataHide Outcome Measure Data
Hide 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 0.5 mg BID TC-5214 2 mg BID TC-5214 4 mg BID TC-5214 Placebo
Hide Arm/Group Description:
Selective serotonin reuptake inhibitor (SSRI)/Serotonin/norepinephrine reuptake inhibitor (SNRI) + TC-5214, 0.5 mg BID
Selective serotonin reuptake inhibitor (SSRI)/Serotonin/norepinephrine reuptake inhibitor (SNRI) + TC-5214, 2 mg BID
Selective serotonin reuptake inhibitor (SSRI)/Serotonin/norepinephrine reuptake inhibitor (SNRI) + TC-5214, 4 mg BID
Selective serotonin reuptake inhibitor (SSRI)/Serotonin/norepinephrine reuptake inhibitor (SNRI) + Placebo BID
Overall Number of Participants Analyzed 152 148 149 153
Least Squares Mean (Standard Error)
Unit of Measure: units on a scale
-10.2  (1.46) -10.1  (1.49) -8.3  (1.50) -8.8  (1.46)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection 0.5 mg BID 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 [Not Specified]
Statistical Test of Hypothesis P-Value 0.350
Comments [Not Specified]
Method MMRM
Comments [Not Specified]
Method of Estimation Estimation Parameter LS mean
Estimated Value -1.4
Confidence Interval (2-Sided) 95%
-4.48 to 1.59
Parameter Dispersion
Type: Standard Error of the mean
Value: 1.55
Estimation Comments [Not Specified]
Show Statistical Analysis 2 Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection 2 mg BID 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 [Not Specified]
Statistical Test of Hypothesis P-Value 0.393
Comments [Not Specified]
Method MMRM
Comments [Not Specified]
Method of Estimation Estimation Parameter LS mean
Estimated Value -1.3
Confidence Interval (2-Sided) 95%
-4.41 to 1.73
Parameter Dispersion
Type: Standard Error of the mean
Value: 1.56
Estimation Comments [Not Specified]
Show Statistical Analysis 3 Hide Statistical Analysis 3
Statistical Analysis Overview Comparison Group Selection 4 mg BID 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 [Not Specified]
Statistical Test of Hypothesis P-Value 0.745
Comments [Not Specified]
Method MMRM
Comments [Not Specified]
Method of Estimation Estimation Parameter LS mean
Estimated Value 0.5
Confidence Interval (2-Sided) 95%
-2.59 to 3.62
Parameter Dispersion
Type: Standard Error of the mean
Value: 1.58
Estimation Comments [Not Specified]
Time Frame [Not Specified]
Adverse Event Reporting Description [Not Specified]
 
Arm/Group Title Placebo 0.5 mg BID TC-5214 2 mg BID TC-5214 4 mg BID TC-5214
Hide Arm/Group Description Selective serotonin reuptake inhibitor (SSRI)/Serotonin/norepinephrine reuptake inhibitor (SNRI) + Placebo Selective serotonin reuptake inhibitor (SSRI)/Serotonin/norepinephrine reuptake inhibitor (SNRI) + TC-5214, 0.5 mg BID Selective serotonin reuptake inhibitor (SSRI)/Serotonin/norepinephrine reuptake inhibitor (SNRI) + TC-5214, 2 mg BID Selective serotonin reuptake inhibitor (SSRI)/Serotonin/norepinephrine reuptake inhibitor (SNRI) + TC-5214, 4 mg BID
All-Cause Mortality
Placebo 0.5 mg BID TC-5214 2 mg BID TC-5214 4 mg BID TC-5214
Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%)
Total   --/--      --/--      --/--      --/--    
Show Serious Adverse Events Hide Serious Adverse Events
Placebo 0.5 mg BID TC-5214 2 mg BID TC-5214 4 mg BID TC-5214
Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total   2/160 (1.25%)      2/160 (1.25%)      0/158 (0.00%)      5/158 (3.16%)    
General disorders         
Non-Cardiac Chest Pain  1  1/160 (0.63%)  1 0/160 (0.00%)  0 0/158 (0.00%)  0 0/158 (0.00%)  0
Infections and infestations         
Upper Respiratory Tract Infection  1  0/160 (0.00%)  0 0/160 (0.00%)  0 0/158 (0.00%)  0 1/158 (0.63%)  1
Injury, poisoning and procedural complications         
Clavicle Fracture  1  0/160 (0.00%)  0 0/160 (0.00%)  0 0/158 (0.00%)  0 1/158 (0.63%)  1
Rib Fracture  1  0/160 (0.00%)  0 0/160 (0.00%)  0 0/158 (0.00%)  0 1/158 (0.63%)  1
Scapula Fracture  1  0/160 (0.00%)  0 0/160 (0.00%)  0 0/158 (0.00%)  0 1/158 (0.63%)  1
Nervous system disorders         
Convulsion  1  0/160 (0.00%)  0 0/160 (0.00%)  0 0/158 (0.00%)  0 1/158 (0.63%)  1
Psychiatric disorders         
Major Depression  1  0/160 (0.00%)  0 1/160 (0.63%)  1 0/158 (0.00%)  0 1/158 (0.63%)  1
Suicidal Ideation  1  0/160 (0.00%)  0 1/160 (0.63%)  1 0/158 (0.00%)  0 0/158 (0.00%)  0
Renal and urinary disorders         
Obstructive Uropathy  1  0/160 (0.00%)  0 0/160 (0.00%)  0 0/158 (0.00%)  0 1/158 (0.63%)  1
Renal Failure Acute  1  0/160 (0.00%)  0 0/160 (0.00%)  0 0/158 (0.00%)  0 1/158 (0.63%)  1
Reproductive system and breast disorders         
Benign Prostatic Hyperplasia  1  0/160 (0.00%)  0 0/160 (0.00%)  0 0/158 (0.00%)  0 1/158 (0.63%)  1
Endometriosis  1  1/160 (0.63%)  1 0/160 (0.00%)  0 0/158 (0.00%)  0 0/158 (0.00%)  0
Respiratory, thoracic and mediastinal disorders         
Pulmonary Fibrosis  1  0/160 (0.00%)  0 1/160 (0.63%)  1 0/158 (0.00%)  0 0/158 (0.00%)  0
Indicates events were collected by systematic assessment
1
Term from vocabulary, MedDRA 14.1
Show Other (Not Including Serious) Adverse Events Hide Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events 2%
Placebo 0.5 mg BID TC-5214 2 mg BID TC-5214 4 mg BID TC-5214
Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total   76/160 (47.50%)      80/160 (50.00%)      88/158 (55.70%)      99/158 (62.66%)    
Eye disorders         
Vision Blurred  1  0/160 (0.00%)  0 1/160 (0.63%)  1 3/158 (1.90%)  3 6/158 (3.80%)  7
Gastrointestinal disorders         
Constipation  1  7/160 (4.38%)  8 12/160 (7.50%)  13 25/158 (15.82%)  28 45/158 (28.48%)  48
Nausea  1  10/160 (6.25%)  11 7/160 (4.38%)  7 13/158 (8.23%)  13 10/158 (6.33%)  11
Dry Mouth  1  2/160 (1.25%)  3 6/160 (3.75%)  6 11/158 (6.96%)  11 11/158 (6.96%)  11
Diarrhoea  1  10/160 (6.25%)  10 10/160 (6.25%)  11 8/158 (5.06%)  8 10/158 (6.33%)  11
Abdominal Distension  1  1/160 (0.63%)  1 2/160 (1.25%)  2 5/158 (3.16%)  5 3/158 (1.90%)  3
Vomiting  1  5/160 (3.13%)  5 1/160 (0.63%)  1 5/158 (3.16%)  6 4/158 (2.53%)  4
Dyspepsia  1  1/160 (0.63%)  1 4/160 (2.50%)  5 2/158 (1.27%)  2 3/158 (1.90%)  3
Flatulence  1  0/160 (0.00%)  0 2/160 (1.25%)  2 4/158 (2.53%)  4 3/158 (1.90%)  3
General disorders         
Fatigue  1  6/160 (3.75%)  6 2/160 (1.25%)  2 4/158 (2.53%)  4 7/158 (4.43%)  8
Pyrexia  1  1/160 (0.63%)  2 5/160 (3.13%)  5 1/158 (0.63%)  1 0/158 (0.00%)  0
Asthenia  1  0/160 (0.00%)  0 1/160 (0.63%)  1 1/158 (0.63%)  1 4/158 (2.53%)  4
Pain  1  3/160 (1.88%)  3 4/160 (2.50%)  4 1/158 (0.63%)  2 3/158 (1.90%)  3
Infections and infestations         
Nasopharyngitis  1  7/160 (4.38%)  7 6/160 (3.75%)  6 7/158 (4.43%)  8 5/158 (3.16%)  5
Bronchitis  1  6/160 (3.75%)  6 0/160 (0.00%)  0 0/158 (0.00%)  0 4/158 (2.53%)  4
Upper Respiratory Tract Infection  1  6/160 (3.75%)  6 2/160 (1.25%)  2 6/158 (3.80%)  6 3/158 (1.90%)  3
Sinusitis  1  4/160 (2.50%)  5 2/160 (1.25%)  2 3/158 (1.90%)  3 0/158 (0.00%)  0
Aspartate Aminotransferase Increased  1  1/160 (0.63%)  1 1/160 (0.63%)  1 4/158 (2.53%)  4 0/158 (0.00%)  0
Metabolism and nutrition disorders         
Increased Appetite  1  1/160 (0.63%)  1 1/160 (0.63%)  1 4/158 (2.53%)  4 2/158 (1.27%)  2
Musculoskeletal and connective tissue disorders         
Back Pain  1  4/160 (2.50%)  4 2/160 (1.25%)  2 2/158 (1.27%)  2 1/158 (0.63%)  1
Muscle Spasms  1  2/160 (1.25%)  2 0/160 (0.00%)  0 1/158 (0.63%)  1 4/158 (2.53%)  4
Muscle Tightness  1  0/160 (0.00%)  0 1/160 (0.63%)  1 0/158 (0.00%)  0 4/158 (2.53%)  4
Myalgia  1  3/160 (1.88%)  3 4/160 (2.50%)  4 3/158 (1.90%)  3 2/158 (1.27%)  2
Nervous system disorders         
Headache  1  22/160 (13.75%)  25 14/160 (8.75%)  19 15/158 (9.49%)  17 13/158 (8.23%)  14
Dizziness  1  3/160 (1.88%)  3 11/160 (6.88%)  11 8/158 (5.06%)  8 14/158 (8.86%)  14
Somnolence  1  5/160 (3.13%)  5 6/160 (3.75%)  6 4/158 (2.53%)  4 8/158 (5.06%)  8
Dizziness Postural  1  2/160 (1.25%)  2 1/160 (0.63%)  1 3/158 (1.90%)  5 5/158 (3.16%)  7
Akathisia  1  4/160 (2.50%)  4 0/160 (0.00%)  0 3/158 (1.90%)  3 1/158 (0.63%)  1
Psychiatric disorders         
Insomnia  1  9/160 (5.63%)  10 8/160 (5.00%)  8 8/158 (5.06%)  8 6/158 (3.80%)  7
Abnormal Dreams  1  3/160 (1.88%)  3 2/160 (1.25%)  2 6/158 (3.80%)  6 2/158 (1.27%)  2
Agitation  1  4/160 (2.50%)  4 5/160 (3.13%)  5 4/158 (2.53%)  4 2/158 (1.27%)  2
Anxiety  1  1/160 (0.63%)  1 3/160 (1.88%)  3 4/158 (2.53%)  4 2/158 (1.27%)  2
Renal and urinary disorders         
Pollakiuria  1  0/160 (0.00%)  0 1/160 (0.63%)  1 0/158 (0.00%)  0 5/158 (3.16%)  5
Vascular disorders         
Orthostatic Hypotension  1  2/160 (1.25%)  3 1/160 (0.63%)  1 1/158 (0.63%)  5 5/158 (3.16%)  5
Hypertension  1  4/160 (2.50%)  4 3/160 (1.88%)  3 1/158 (0.63%)  1 1/158 (0.63%)  1
Indicates events were collected by systematic assessment
1
Term from vocabulary, MedDRA 14.1
Certain Agreements
Principal Investigators are NOT employed by the organization sponsoring the study.
There IS an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.
Results Point of Contact
Name/Title: Gerard Lynch
Organization: AstraZeneca
Responsible Party: AstraZeneca
ClinicalTrials.gov Identifier: NCT01153347     History of Changes
Other Study ID Numbers: D4130C00004
First Submitted: June 23, 2010
First Posted: June 30, 2010
Results First Submitted: June 26, 2012
Results First Posted: November 20, 2012
Last Update Posted: April 11, 2014