Depression, Major Depressive Disorder
Conditions
Keywords
Major Depressive Disorder, MDD, Depression, Safety, add-on therapy
Brief summary
The purpose of this study is to determine if TC-5214 or placebo (a tablet that looks like medicine tablet or capsule, but contains no active medicine) is safe and effective when taken together with another antidepressant.
Detailed description
A Multicenter, Randomized, Double-Blind, Parallel Group, Placebo-Controlled, Phase III Efficacy and Safety Study of TC-5214 (S-mecamylamine) in Flexible Doses as an Adjunct to an Antidepressant in Patients with Major Depressive Disorder Who Exhibit an Inadequate Response to Antidepressant Therapy
Interventions
DRUGTC-5214
Tablet, oral, twice daily for 8 weeks
DRUGPlacebo
Tablet, oral, twice daily for 8 weeks
Sponsors
Targacept Inc.
AstraZeneca
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to 65 Years
Healthy volunteers
No
Inclusion criteria
* Provision of signed and dated informed consent before initiation of any study-related procedures. * The patient must have a clinical diagnosis of major depressive disorder (MDD) with inadequate response to no more than one antidepressant. * Out-patient status at enrollment and randomization.
Exclusion criteria
* Patients with a lifetime history of bipolar disorder, psychotic disorder or post-traumatic stress disorder. * Patients with a history of suicide attempts in the past year and/or seen by the investigator as having a significant history of risk of suicide or homicide. * History of renal insufficiency or impairment or conditions that could affect absorption or metabolism of the investigational product in this patient population
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change in the Montgomery-Asberg Depression Rating Scale (MADRS) Total Score From Randomization to End of Treatment. | Randomization (Week 8) to end of treatment (Week 16) | A 10-item scale for the evaluation of depressive symptoms. Each MADRS item is rated on a 0 to 6 scale. The MADRS total score is calculated as the sum of the 10 individual item scores; the total score can range from 0 to 60. Higher MADRS scores indicate higher levels of depressive symptoms. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Remission in Depressive Symptoms of MDD, Defined as MADRS Total Score of ≤8 at End of Treatment (Week 16) | Week 16 | The percentage of patients with a MADRS total score of ≤8 at end of treatment (Week 16) was calculated. 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. |
| Early and Sustained Response, Defined as a ≥50% Reduction From Randomization (Week 8) in MADRS Total Score and a MADRS Total Score of ≤12 at Week 10, Week 12, Week 14, and End of Treatment (Week 16) | Randomization (Week 8) to end of treatment (Week 16); Week 10, Week 12, Week 14, and Week 16 | The percentage of patients with a ≥50% reduction from randomization (Week 8) in MADRS total score and a MADRS total score of ≤12 at Week 10, Week 12, Week 14, and end of treatment (Week 16) was calculated. 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. |
| Sustained Response, Defined as a ≥50% Reduction From Randomization (Week 8) in MADRS Total Score and a MADRS Total Score of ≤12 at Week 12, Week 14, and End of Treatment (Week 16) | Randomization (Week 8) to end of treatment (Week 16); Week 12, Week 14, and Week 16 | The percentage of patients with a ≥50% reduction from randomization (Week 8) in MADRS total score and a MADRS total score of ≤12 at Week 12, Week 14, and end of treatment (Week 16) was calculated. 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. |
| Sustained Remission, Defined as a MADRS Total Score of ≤8 at Week 12, Week 14, and End of Treatment (Week 16) | Week 12, Week 14, Week 16 | The percentage of patients with a MADRS total score of ≤8 at Week 12, Week 14, and end of treatment (Week 16)was calculated. 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. |
| Change in Depressive Symptoms From Randomization (Week 8) to End of Treatment (Week 16) as Measured by Hamilton Rating Scale for Depression-17 Items (HAMD-17) Total Score | Randomization (Week 8) to end of treatment (Week 16) | A 17-item, clinician-rated scale that assesses depressive symptoms. The HAMD-17 consists of 17 symptoms, each of which is rated from 0 to 2 or 0 to 4, where 0 is none/absent. The HAMD-17 total score is calculated as the sum of the 17 individual symptom scores; the total score can range from 0 to 52. Higher HAMD-17 scores indicate more severe depression. |
| Change in the Clinician-rated Global Outcome of Severity as Measured by the Clinical Global Impression-Severity (CGI-S) Score From Randomization (Week 8) to End of Treatment (Week 16) | Randomization (Week 8) to end of treatment (Week 16) | A 3-part, clinician-administered scale that rates the improvement or worsening of the patient's illness from randomization (baseline). Each item is scored on a 1 to 7 scale. Higher CGI-S scores indicate greater illness severity. |
| Response in the Clinical Global Impression-Improvement (CGI-I) Defined as CGI-I Rating of Very Much Improved or Much Improved From Randomization (Week 8) to End of Treatment (Week 16) | Randomization (Week 8) to end of treatment (Week 16) | A 3-part, clinician-administered scale that rates the improvement or worsening of the patient's illness from randomization (baseline). Each item is scored on a 1 to 7 scale. CGI-I scores \>4 indicate worsening, while scores \<4 indicate improvement. |
| Change in MADRS Total Score From Randomization (Week 8) to Week 9 | Randomization (Week 8) to Week 9 | A 10-item scale for the evaluation of depressive symptoms. Each MADRS item is rated on a 0 to 6 scale. The MADRS total score is calculated as the sum of the 10 individual item scores; the total score can range from 0 to 60. Higher MADRS scores indicate higher levels of depressive symptoms. |
| Change in MADRS Total Score From Randomization (Week 8) to Week 10 | Randomization (Week 8) to Week 10 | A 10-item scale for the evaluation of depressive symptoms. Each MADRS item is rated on a 0 to 6 scale. The MADRS total score is calculated as the sum of the 10 individual item scores; the total score can range from 0 to 60. Higher MADRS scores indicate higher levels of depressive symptoms. |
| Response in Depressive Symptoms of Major Depressive Disorder (MDD), Defined as a ≥50% Reduction From Randomization (Week 8) in MADRS Total Score at End of Treatment (Week 16) | Randomization (Week 8) to end of treatment (Week 16) | The percentage of patients with a ≥50% reduction from randomization (Week 8) in MADRS total score at end of treatment (Week 16) was calculated. 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. |
| Change in MADRS Total Score From Randomization (Week 8) to Week 14 | Randomization (Week 8) to Week 14 | A 10-item scale for the evaluation of depressive symptoms. Each MADRS item is rated on a 0 to 6 scale. The MADRS total score is calculated as the sum of the 10 individual item scores; the total score can range from 0 to 60. Higher MADRS scores indicate higher levels of depressive symptoms. |
| Change in Functional Impairment From Randomization (Week 8) to End of Treatment (Week 16) as Measured by the Sheehan Disability Scale (SDS) Total Score | Randomization (Week 8) to end of treatment (Week 16) | Sheehan Disability Scale (SDS) is 5-item, self-administered scale that measures the extent a patient is impaired by their disease. Higher scores indicate more severe impairment. The SDS total score is calculated as the sum of the score for the 3 inter-correlated domains (school/work, social life, and family life/home responsibilities) and ranges from 0 (unimpaired) to 30 (highly impaired). |
| Change in Functional Impairment From Randomization (Week 8) to End of Treatment (Week 16) as Measured by SDS Work/School Domain Score | Randomization (Week 8) to end of treatment (Week 16) | A 5-item, self-administered scale that measures the extent a patient is impaired by their disease. Higher scores indicate more severe impairment. The 3 inter-correlated domains are school/work, social life, and family life/home responsibilities. The numerical rating for the work/school domain score is 0- 10, where 10 is considered to be 'highly impaired'. |
| Change in Functional Impairment From Randomization (Week 8) to End of Treatment (Week 16) as Measured by SDS Social Life Domain Score | Randomization (Week 8) to end of treatment (Week 16) | A 5-item, self-administered scale that measures the extent a patient is impaired by their disease. Higher scores indicate more severe impairment. The 3 inter-correlated domains are school/work, social life, and family life/home responsibilities. The numerical rating for the SDS social life domain score is 0- 10, where 10 is considered to be 'highly impaired'. |
| Change in Functional Impairment From Randomization (Week 8) to End of Treatment (Week 16) as Measured by SDS Family Life/Home Responsibilities Domain Score | Randomization (Week 8) to end of treatment (Week 16) | A 5-item, self-administered scale that measures the extent a patient is impaired by their disease. Higher scores indicate more severe impairment. The 3 inter-correlated domains are school/work, social life, and family life/home responsibilities. The numerical rating for the SDS family life/home responsibilities domain score is 0- 10, where 10 is considered to be 'highly impaired'. |
| Change in Overall Quality of Life and Satisfaction From Randomization (Week 8) to End of Treatment (Week 16) by Assessing the Quality of Life Enjoyment and Satisfaction Questionnaire-Short Form (Q-LES-Q-SF) % Maximum Total Score | Randomization (Week 8) to end of treatment (Week 16) | The Q-LES-Q-SF (Quality of Life Enjoyment and Satisfaction Questionnaire-Short Form)total score is derived by summing item scores 1 to 14. Higher scores are indicative of greater enjoyment or satisfaction in each domain. The Q-LES-Q-SF % maximum total score is calculated as 100% × (Q-LES-Q-SF total score - 14) / 56, and can range from 0% to 100%. |
| Change From Randomization (Week 8) to End of Treatment (Week 16) in Quality of Life Enjoyment and Satisfaction Questionnaire-Short Form (Q LES-Q-SF) Item 15 | Randomization (Week 8) to end of treatment (Week 16) | The Q-LES-Q-SF (Quality of Life Enjoyment and Satisfaction Questionnaire-Short Form) measures the patient's satisfaction with medication and overall quality of life. The 15th item queries respondents' satisfaction with the medication they are taking, rated on a 1 to 4 scale, score 0 indicates that no medication was taken. Higher scores are indicative of greater satisfaction. |
| Change From Randomization (Week 8) to End of Treatment (Week 16) in Quality of Life Enjoyment and Satisfaction Questionnaire-Short Form (Q LES-Q-SF) Item 16 | Randomization (Week 8) to end of treatment (Week 16) | The Q-LES-Q-SF (Quality of Life Enjoyment and Satisfaction Questionnaire-Short Form) measures the patient's satisfaction with medication and overall quality of life. The 16th item is a global rating of overall life satisfaction and contentment, rated on a 1 to 5 scale. Higher scores are indicative of greater satisfaction. |
| Change in EuroQol - 5 Dimensions (EQ-5D) From Randomization (Week 8) to End of Treatment (Week 16) | Randomization (Week 8) to end of treatment (Week 16) | A self-assessment questionnaire that provides 2 measures of health status. The EQ-5D index score is a weighted linear combination over 5 dimensions of health status. The score for each of the 5 dimensions can range from 1 to 3, and an equation is used to calculate the EQ-5D index score. The EQ-5D index score can range from possible negative values (minimum -0.415) to a maximum of 1.0. The EQ-VAS is a visual analog scale with a range of 0 to 100. For both variables, a higher score indicates a better health state. |
| Change in MADRS Total Score From Randomization (Week 8) to Week 12 | Randomization (Week 8) to Week 12 | A 10-item scale for the evaluation of depressive symptoms. Each MADRS item is rated on a 0 to 6 scale. The MADRS total score is calculated as the sum of the 10 individual item scores; the total score can range from 0 to 60. Higher MADRS scores indicate higher levels of depressive symptoms. |
Countries
Czechia, Estonia, Finland, France, Germany, Hungary, Latvia, Lithuania, Poland, Sweden
Participant flow
Recruitment details
This multicenter study was conducted in Europe between 2 September 2010 and 27 September 2011.
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).
Participants by arm
| Arm | Count |
|---|---|
| TC-5214 Selective serotonin reuptake inhibitor (SSRI)/Serotonin/norepinephrine reuptake inhibitor (SNRI) + TC-5214, 1-4 mg BID | 147 |
| Placebo Selective serotonin reuptake inhibitor (SSRI)/Serotonin/norepinephrine reuptake inhibitor (SNRI) + Placebo BID | 148 |
| Total | 295 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 12 | 10 |
| Overall Study | Condition under investigation worsened | 2 | 1 |
| Overall Study | Eligibility criteria not fulfilled | 0 | 2 |
| Overall Study | Lack of Efficacy | 2 | 0 |
| Overall Study | Lost to Follow-up | 2 | 3 |
| Overall Study | Other | 0 | 1 |
| Overall Study | Severe non-compliance to protocol | 1 | 2 |
| Overall Study | Study-specific withdrawal criteria | 1 | 2 |
| Overall Study | Withdrawal by Subject | 5 | 6 |
Baseline characteristics
| Characteristic | Placebo | Total | TC-5214 |
|---|---|---|---|
| Age, Continuous | 43.4 years STANDARD_DEVIATION 11.31 | 44.8 years STANDARD_DEVIATION 11.34 | 46.1 years STANDARD_DEVIATION 11.25 |
| Hamilton Rating Scale for Depression-17 items (HAMD-17) total score at randomization | 20.5 Scores on a scale STANDARD_DEVIATION 3.41 | 20.2 Scores on a scale STANDARD_DEVIATION 3.11 | 20.0 Scores on a scale STANDARD_DEVIATION 2.77 |
| Montgomery-Asberg Depression Rating Scale (MADRS) total score at randomization | 25.1 Scores on a scale STANDARD_DEVIATION 4.72 | 24.7 Scores on a scale STANDARD_DEVIATION 4.82 | 24.3 Scores on a scale STANDARD_DEVIATION 4.92 |
| Race/Ethnicity, Customized American Indian or Alaska Native | 0 participants | 0 participants | 0 participants |
| Race/Ethnicity, Customized Asian | 0 participants | 0 participants | 0 participants |
| Race/Ethnicity, Customized Black or African American | 0 participants | 0 participants | 0 participants |
| Race/Ethnicity, Customized Native Hawaiian or other Pacific Islander | 0 participants | 0 participants | 0 participants |
| Race/Ethnicity, Customized Other | 0 participants | 1 participants | 1 participants |
| Race/Ethnicity, Customized White | 148 participants | 294 participants | 146 participants |
| Sex: Female, Male Female | 95 Participants | 189 Participants | 94 Participants |
| Sex: Female, Male Male | 53 Participants | 106 Participants | 53 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 83 / 147 | 65 / 146 |
| serious Total, serious adverse events | 1 / 147 | 2 / 146 |
Outcome results
Primary
Change in the Montgomery-Asberg Depression Rating Scale (MADRS) Total Score From Randomization to End of Treatment.
A 10-item scale for the evaluation of depressive symptoms. Each MADRS item is rated on a 0 to 6 scale. The MADRS total score is calculated as the sum of the 10 individual item scores; the total score can range from 0 to 60. Higher MADRS scores indicate higher levels of depressive symptoms.
Time frame: Randomization (Week 8) to end of treatment (Week 16)
Population: 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 | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| TC-5214 | Change in the Montgomery-Asberg Depression Rating Scale (MADRS) Total Score From Randomization to End of Treatment. | -11.7 units on a scale | Standard Error 0.71 |
| Placebo | Change in the Montgomery-Asberg Depression Rating Scale (MADRS) Total Score From Randomization to End of Treatment. | -11.6 units on a scale | Standard Error 0.7 |
Comparison: 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.p-value: 0.94495% CI: [-1.86, 1.73]MMRM
Secondary
Change From Randomization (Week 8) to End of Treatment (Week 16) in Quality of Life Enjoyment and Satisfaction Questionnaire-Short Form (Q LES-Q-SF) Item 15
The Q-LES-Q-SF (Quality of Life Enjoyment and Satisfaction Questionnaire-Short Form) measures the patient's satisfaction with medication and overall quality of life. The 15th item queries respondents' satisfaction with the medication they are taking, 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)
Population: 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 | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| TC-5214 | 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 | 0.3 units on a scale | Standard Error 0.08 |
| Placebo | 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 | 0.4 units on a scale | Standard Error 0.07 |
Comparison: 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.p-value: 0.34595% CI: [-0.3, 0.1]ANCOVA
Secondary
Change From Randomization (Week 8) to End of Treatment (Week 16) in Quality of Life Enjoyment and Satisfaction Questionnaire-Short Form (Q LES-Q-SF) Item 16
The Q-LES-Q-SF (Quality of Life Enjoyment and Satisfaction Questionnaire-Short Form) measures the patient's satisfaction with medication and overall quality of life. The 16th item is a global rating of overall life satisfaction and contentment, 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)
Population: 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 | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| TC-5214 | 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 | 0.7 units on a scale | Standard Error 0.08 |
| Placebo | 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 | 0.7 units on a scale | Standard Error 0.08 |
Comparison: An analysis of covariance (ANCOVA) with randomization Q-LES-Q-SF item 16 as a fixed effect and pooled center as a random effect.p-value: 0.94295% CI: [-0.2, 0.19]ANCOVA
Secondary
Change in Depressive Symptoms From Randomization (Week 8) to End of Treatment (Week 16) as Measured by Hamilton Rating Scale for Depression-17 Items (HAMD-17) Total Score
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)
Population: 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 | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| TC-5214 | 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 | -9.4 units on a scale | Standard Error 0.56 |
| Placebo | 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 | -9.8 units on a scale | Standard Error 0.55 |
Comparison: Analysis of covariance (ANCOVA) with randomization HAMD-17 total score as covariate, treatment as a fixed effect and pooled center as a random effect.p-value: 0.52595% CI: [-0.96, 1.89]ANCOVA
Secondary
Change in EuroQol - 5 Dimensions (EQ-5D) From Randomization (Week 8) to End of Treatment (Week 16)
A self-assessment questionnaire that provides 2 measures of health status. The EQ-5D index score is a weighted linear combination over 5 dimensions of health status. The score for each of the 5 dimensions can range from 1 to 3, and an equation is used to calculate the EQ-5D index score. The EQ-5D index score can range from possible negative values (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)
Population: 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 | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| TC-5214 | Change in EuroQol - 5 Dimensions (EQ-5D) From Randomization (Week 8) to End of Treatment (Week 16) | EQ-5D index score | 0.109 units on a scale | Standard Error 0.0154 |
| TC-5214 | Change in EuroQol - 5 Dimensions (EQ-5D) From Randomization (Week 8) to End of Treatment (Week 16) | EQ-5D VAS score | 13.6 units on a scale | Standard Error 1.59 |
| Placebo | Change in EuroQol - 5 Dimensions (EQ-5D) From Randomization (Week 8) to End of Treatment (Week 16) | EQ-5D index score | 0.120 units on a scale | Standard Error 0.015 |
| Placebo | Change in EuroQol - 5 Dimensions (EQ-5D) From Randomization (Week 8) to End of Treatment (Week 16) | EQ-5D VAS score | 14.0 units on a scale | Standard Error 1.54 |
Comparison: 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.p-value: 0.57695% CI: [-0.05, 0.0279]MMRM
Comparison: 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.p-value: 0.84295% CI: [-4.58, 3.73]MMRM
Secondary
Change in Functional Impairment From Randomization (Week 8) to End of Treatment (Week 16) as Measured by SDS Family Life/Home Responsibilities Domain Score
A 5-item, self-administered scale that measures the extent a patient is impaired by their disease. Higher scores indicate more severe impairment. The 3 inter-correlated domains are school/work, social life, and family life/home responsibilities. The numerical rating for the SDS family life/home responsibilities domain score is 0- 10, where 10 is considered to be 'highly impaired'.
Time frame: Randomization (Week 8) to end of treatment (Week 16)
Population: 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 | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| TC-5214 | Change in Functional Impairment From Randomization (Week 8) to End of Treatment (Week 16) as Measured by SDS Family Life/Home Responsibilities Domain Score | -1.9 units on a scale | Standard Error 0.2 |
| Placebo | Change in Functional Impairment From Randomization (Week 8) to End of Treatment (Week 16) as Measured by SDS Family Life/Home Responsibilities Domain Score | -2.0 units on a scale | Standard Error 0.19 |
Comparison: 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.p-value: 0.6295% CI: [-0.4, 0.68]MMRM
Secondary
Change in Functional Impairment From Randomization (Week 8) to End of Treatment (Week 16) as Measured by SDS Social Life Domain Score
A 5-item, self-administered scale that measures the extent a patient is impaired by their disease. Higher scores indicate more severe impairment. The 3 inter-correlated domains are school/work, social life, and family life/home responsibilities. The numerical rating for the SDS social life domain score is 0- 10, where 10 is considered to be 'highly impaired'.
Time frame: Randomization (Week 8) to end of treatment (Week 16)
Population: 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 | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| TC-5214 | Change in Functional Impairment From Randomization (Week 8) to End of Treatment (Week 16) as Measured by SDS Social Life Domain Score | -2.0 units on a scale | Standard Error 0.19 |
| Placebo | Change in Functional Impairment From Randomization (Week 8) to End of Treatment (Week 16) as Measured by SDS Social Life Domain Score | -1.9 units on a scale | Standard Error 0.19 |
Comparison: 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.p-value: 0.75695% CI: [-0.62, 0.45]MMRM
Secondary
Change in Functional Impairment From Randomization (Week 8) to End of Treatment (Week 16) as Measured by SDS Work/School Domain Score
A 5-item, self-administered scale that measures the extent a patient is impaired by their disease. Higher scores indicate more severe impairment. The 3 inter-correlated domains are school/work, social life, and family life/home responsibilities. The numerical rating for the work/school domain score is 0- 10, where 10 is considered to be 'highly impaired'.
Time frame: Randomization (Week 8) to end of treatment (Week 16)
Population: 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 | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| TC-5214 | Change in Functional Impairment From Randomization (Week 8) to End of Treatment (Week 16) as Measured by SDS Work/School Domain Score | -2.2 units on a scale | Standard Error 0.25 |
| Placebo | Change in Functional Impairment From Randomization (Week 8) to End of Treatment (Week 16) as Measured by SDS Work/School Domain Score | -1.8 units on a scale | Standard Error 0.24 |
Comparison: 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.p-value: 0.20195% CI: [-0.98, 0.21]MMRM
Secondary
Change in Functional Impairment From Randomization (Week 8) to End of Treatment (Week 16) as Measured by the Sheehan Disability Scale (SDS) Total Score
Sheehan Disability Scale (SDS) is 5-item, self-administered scale that measures the extent a patient is impaired by their disease. Higher scores indicate more severe impairment. The SDS total score is calculated as the sum of the score for the 3 inter-correlated domains (school/work, social life, and family life/home responsibilities) and ranges from 0 (unimpaired) to 30 (highly impaired).
Time frame: Randomization (Week 8) to end of treatment (Week 16)
Population: 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 | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| TC-5214 | Change in Functional Impairment From Randomization (Week 8) to End of Treatment (Week 16) as Measured by the Sheehan Disability Scale (SDS) Total Score | -5.79 units on a scale | Standard Error 0.548 |
| Placebo | Change in Functional Impairment From Randomization (Week 8) to End of Treatment (Week 16) as Measured by the Sheehan Disability Scale (SDS) Total Score | -5.75 units on a scale | Standard Error 0.536 |
Comparison: 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.p-value: 0.95695% CI: [-1.549, 1.466]MMRM
Secondary
Change in MADRS Total Score From Randomization (Week 8) to Week 10
A 10-item scale for the evaluation of depressive symptoms. Each MADRS item is rated on a 0 to 6 scale. The MADRS total score is calculated as the sum of the 10 individual item scores; the total score can range from 0 to 60. Higher MADRS scores indicate higher levels of depressive symptoms.
Time frame: Randomization (Week 8) to Week 10
Population: 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 | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| TC-5214 | Change in MADRS Total Score From Randomization (Week 8) to Week 10 | -4.9 units on a scale | Standard Error 0.56 |
| Placebo | Change in MADRS Total Score From Randomization (Week 8) to Week 10 | -5.4 units on a scale | Standard Error 0.56 |
Comparison: 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.p-value: 0.46895% CI: [-0.84, 1.82]MMRM
Secondary
Change in MADRS Total Score From Randomization (Week 8) to Week 12
A 10-item scale for the evaluation of depressive symptoms. Each MADRS item is rated on a 0 to 6 scale. The MADRS total score is calculated as the sum of the 10 individual item scores; the total score can range from 0 to 60. Higher MADRS scores indicate higher levels of depressive symptoms.
Time frame: Randomization (Week 8) to Week 12
Population: 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 | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| TC-5214 | Change in MADRS Total Score From Randomization (Week 8) to Week 12 | -7.2 units on a scale | Standard Error 0.62 |
| Placebo | Change in MADRS Total Score From Randomization (Week 8) to Week 12 | -8.2 units on a scale | Standard Error 0.62 |
Comparison: 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.p-value: 0.18795% CI: [-0.49, 2.52]MMRM
Secondary
Change in MADRS Total Score From Randomization (Week 8) to Week 14
A 10-item scale for the evaluation of depressive symptoms. Each MADRS item is rated on a 0 to 6 scale. The MADRS total score is calculated as the sum of the 10 individual item scores; the total score can range from 0 to 60. Higher MADRS scores indicate higher levels of depressive symptoms.
Time frame: Randomization (Week 8) to Week 14
Population: 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 | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| TC-5214 | Change in MADRS Total Score From Randomization (Week 8) to Week 14 | -9.1 units on a scale | Standard Error 0.68 |
| Placebo | Change in MADRS Total Score From Randomization (Week 8) to Week 14 | -10.3 units on a scale | Standard Error 0.67 |
Comparison: 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.p-value: 0.14595% CI: [-0.44, 2.95]MMRM
Secondary
Change in MADRS Total Score From Randomization (Week 8) to Week 9
A 10-item scale for the evaluation of depressive symptoms. Each MADRS item is rated on a 0 to 6 scale. The MADRS total score is calculated as the sum of the 10 individual item scores; the total score can range from 0 to 60. Higher MADRS scores indicate higher levels of depressive symptoms.
Time frame: Randomization (Week 8) to Week 9
Population: 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 | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| TC-5214 | Change in MADRS Total Score From Randomization (Week 8) to Week 9 | -3.0 units on a scale | Standard Error 0.47 |
| Placebo | Change in MADRS Total Score From Randomization (Week 8) to Week 9 | -3.1 units on a scale | Standard Error 0.46 |
Comparison: 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.p-value: 0.83295% CI: [-0.89, 1.11]MMRM
Secondary
Change in Overall Quality of Life and Satisfaction From Randomization (Week 8) to End of Treatment (Week 16) by Assessing the Quality of Life Enjoyment and Satisfaction Questionnaire-Short Form (Q-LES-Q-SF) % Maximum Total Score
The Q-LES-Q-SF (Quality of Life Enjoyment and Satisfaction Questionnaire-Short Form)total score is derived by summing item scores 1 to 14. Higher scores are indicative of greater enjoyment or satisfaction in each domain. The Q-LES-Q-SF % maximum total score is calculated as 100% × (Q-LES-Q-SF total score - 14) / 56, and can range from 0% to 100%.
Time frame: Randomization (Week 8) to end of treatment (Week 16)
Population: 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 | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| TC-5214 | 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 | 11.22 units on a scale | Standard Error 1.246 |
| Placebo | 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 | 11.07 units on a scale | Standard Error 1.217 |
Comparison: ANCOVA with randomization Q-LES-Q-SF % maximum total score as covariate, treatment as a fixed effect and pooled center as a random effect.p-value: 0.92495% CI: [-2.981, 3.286]ANCOVA
Secondary
Change in the Clinician-rated Global Outcome of Severity as Measured by the Clinical Global Impression-Severity (CGI-S) Score From Randomization (Week 8) to End of Treatment (Week 16)
A 3-part, clinician-administered scale that rates the improvement or worsening of the patient's illness from randomization (baseline). Each item is scored on a 1 to 7 scale. Higher CGI-S scores indicate greater illness severity.
Time frame: Randomization (Week 8) to end of treatment (Week 16)
Population: 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 | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| TC-5214 | 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) | -1.6 units on a scale | Standard Error 0.11 |
| Placebo | 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) | -1.6 units on a scale | Standard Error 0.11 |
Comparison: 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.p-value: 0.96495% CI: [-0.28, 0.26]MMRM
Secondary
Early and Sustained Response, Defined as a ≥50% Reduction From Randomization (Week 8) in MADRS Total Score and a MADRS Total Score of ≤12 at Week 10, Week 12, Week 14, and End of Treatment (Week 16)
The percentage of patients with a ≥50% reduction from randomization (Week 8) in MADRS total score and a MADRS total score of ≤12 at Week 10, Week 12, Week 14, and end of treatment (Week 16) was calculated. 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
Population: 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 | Measure | Value (NUMBER) |
|---|---|---|
| TC-5214 | 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) | 7.6 percentage of participants analyzed |
| Placebo | 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) | 6.3 percentage of participants analyzed |
Comparison: Logistic regression model including treatment and pooled center as fixed effects and the randomization MADRS total score as a covariate.p-value: 0.46195% CI: [0.55, 3.78]Regression, Logistic
Secondary
Remission in Depressive Symptoms of MDD, Defined as MADRS Total Score of ≤8 at End of Treatment (Week 16)
The percentage of patients with a MADRS total score of ≤8 at end of treatment (Week 16) was calculated. 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
Population: 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 | Measure | Value (NUMBER) |
|---|---|---|
| TC-5214 | Remission in Depressive Symptoms of MDD, Defined as MADRS Total Score of ≤8 at End of Treatment (Week 16) | 33.8 percentage of participants analyzed |
| Placebo | Remission in Depressive Symptoms of MDD, Defined as MADRS Total Score of ≤8 at End of Treatment (Week 16) | 26.9 percentage of participants analyzed |
Comparison: Logistic regression model including treatment and pooled center as fixed effects and the randomization MADRS total score as a covariate.p-value: 0.18495% CI: [0.84, 2.53]Regression, Logistic
Secondary
Response in Depressive Symptoms of Major Depressive Disorder (MDD), Defined as a ≥50% Reduction From Randomization (Week 8) in MADRS Total Score at End of Treatment (Week 16)
The percentage of patients with a ≥50% reduction from randomization (Week 8) in MADRS total score at end of treatment (Week 16) was calculated. 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)
Population: 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 | Measure | Value (NUMBER) |
|---|---|---|
| TC-5214 | 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) | 48.3 percentage of participants analyzed |
| Placebo | 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) | 49.0 percentage of participants analyzed |
Comparison: Logistic regression model including treatment and pooled center as fixed effects and the randomization MADRS total score as a covariate.p-value: 0.97495% CI: [0.61, 1.66]Regression, Logistic
Secondary
Response in the Clinical Global Impression-Improvement (CGI-I) Defined as CGI-I Rating of Very Much Improved or Much Improved From Randomization (Week 8) to End of Treatment (Week 16)
A 3-part, clinician-administered scale that rates the improvement or worsening of the patient's illness from randomization (baseline). Each item is scored on a 1 to 7 scale. CGI-I scores \>4 indicate worsening, while scores \<4 indicate improvement.
Time frame: Randomization (Week 8) to end of treatment (Week 16)
Population: 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 | Measure | Value (NUMBER) |
|---|---|---|
| TC-5214 | 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) | 64.8 percentage of participants analyzed |
| Placebo | 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) | 65.5 percentage of participants analyzed |
Comparison: Logistic regression model including treatment and pooled center as fixed effects and the randomization Clinical Global Impression Severity (CGI-S) as a covariate.p-value: 0.78395% CI: [0.54, 1.58]Regression, Logistic
Secondary
Sustained Remission, Defined as a MADRS Total Score of ≤8 at Week 12, Week 14, and End of Treatment (Week 16)
The percentage of patients with a MADRS total score of ≤8 at Week 12, Week 14, and end of treatment (Week 16)was calculated. 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
Population: 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 | Measure | Value (NUMBER) |
|---|---|---|
| TC-5214 | Sustained Remission, Defined as a MADRS Total Score of ≤8 at Week 12, Week 14, and End of Treatment (Week 16) | 7.9 percentage of participants analyzed |
| Placebo | Sustained Remission, Defined as a MADRS Total Score of ≤8 at Week 12, Week 14, and End of Treatment (Week 16) | 9.2 percentage of participants analyzed |
Comparison: Logistic regression model including treatment and pooled center as fixed effects and the randomization MADRS total score as a covariate.p-value: 0.83195% CI: [0.35, 2.32]Regression, Logistic
Secondary
Sustained Response, Defined as a ≥50% Reduction From Randomization (Week 8) in MADRS Total Score and a MADRS Total Score of ≤12 at Week 12, Week 14, and End of Treatment (Week 16)
The percentage of patients with a ≥50% reduction from randomization (Week 8) in MADRS total score and a MADRS total score of ≤12 at Week 12, Week 14, and end of treatment (Week 16) was calculated. 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
Population: 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 | Measure | Value (NUMBER) |
|---|---|---|
| TC-5214 | 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) | 14.5 percentage of patients analyzed |
| Placebo | 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) | 16.3 percentage of patients analyzed |
Comparison: Logistic regression model including treatment and pooled center as fixed effects and the randomization MADRS total score as a covariate.p-value: 0.68995% CI: [0.43, 1.75]Regression, Logistic