Depression, Major Depressive Disorder, MDD
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 for 52 weeks with another antidepressant medicine.
Interventions
DRUGTC-5214
Tablet, oral, twice daily for 52 weeks
DRUGPlacebo
Tablet, oral, twice daily for 52 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. * Outpatient status at enrollment and randomization.
Exclusion criteria
* Patients with a lifetime history of bipolar disorder, psychotic disorder or post-traumatic stress disorder. * Patients with a history of suicide attempts in the past year and/or seen by the investigator as having a significant history of risk of suicide or homicide. * Patients with significant liver, kidney, lung, heart, neurological, or any other medical conditions that might confound the study or put the patient at greater risk during study participation.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Frequency of Patients Experiencing at Least One Adverse Event (AE) | Randomization (Week 0) to end of the follow-up period (Week 54) | The frequency of patients experiencing at least one AE during the randomized treatment or follow-up periods was calculated. |
| Frequency of Patients Experiencing AEs That Resulted in Discontinuation of Investigational Product (IP) | Randomization (Week 0) to end of the follow-up period (Week 54) | The frequency of patients experiencing AEs that resulted in discontinuation of IP during the randomized treatment or follow-up periods was calculated. |
| Frequency of Patients Experiencing Serious Adverse Events (SAEs) | Randomization (Week 0) to end of the follow-up period (Week 54) | The frequency of patients experiencing serious adverse events (SAEs) during the randomized treatment or follow-up periods was calculated. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change in Functional Impairment From Randomization (Week 0) to End of Treatment (Week 52) as Measured by the Sheehan Disability Scale (SDS) Total Score | Randomization (Week 0) to end of treatment (Week 52) | Sheehan Disability Scale (SDS) is 5-item, self-administered scale that measures the extent a patient is impaired by their disease. Higher scores indicate more severe impairment. The SDS total score is calculated as the sum of the score for the 3 inter-correlated domains (school/work, social life, and family life/home responsibilities) and ranges from 0 (unimpaired) to 30 (highly impaired). |
| Sustained Efficacy at 3 Months, Defined as a Montgomery-Asberg Depression Rating Scale (MADRS) Total Score of ≤12 at Week 12 and All Visits up to and Including Week 24 | Week 12 to Week 24 | The percentage of patients with a a MADRS total score of ≤12 at Week 12 and all visits up to and including Week 24 was calculated. One intermediate occurrence of a MADRS total score \>12 but ≤16 or missing was allowed from Week 16 to Week 20. A 10-item scale for the evaluation of depressive symptoms. Each MADRS item is rated on a 0 to 6 scale. The MADRS total score is calculated as the sum of the 10 individual item scores; the total score can range from 0 to 60. Higher MADRS scores indicate higher levels of depressive symptoms. |
| Change in EuroQol - 5 Dimensions (EQ-5D) From Randomization (Week 0) to End of Treatment (Week 52) | Randomization (Week 0) to end of treatment (Week 52) | A self-assessment questionnaire that provides 2 measures of health status. The EQ-5D index score is a weighted linear combination over 5 dimensions of health status. The score for each of the 5 dimensions can range from 1 to 3, and an equation is used to calculate the EQ-5D index score. The EQ-5D index score can range from possible negative values to a maximum of 1.0. The EQ-VAS is a visual analog scale with a range of 0 to 100. For both variables, a higher score indicates a better health state. |
| Change in Overall Quality of Life and Satisfaction From Randomization (Week 0) to End of Treatment (Week 52) by Assessing the Quality of Life Enjoyment and Satisfaction Questionnaire-Short Form (Q-LES-Q-SF) % Maximum Total Score | Randomization (Week 0) to end of treatment (Week 52) | The Q-LES-Q-SF total score is derived by summing item scores 1 to 14. Higher scores are indicative of greater enjoyment or satisfaction in each domain. The Q-LES-Q-SF % maximum total score is calculated as 100% × (Q-LES-Q-SF total score - 14) / 56, and can range from 0% to 100%. |
| Sustained Efficacy at 9 Months, Defined as a MADRS Total Score of ≤12 at Week 12 and at All Visits up to and Including Week 52 | Week 12 to Week 52 | The percentage of patients with a MADRS total score of ≤12 at Week 12 and at all visits up to and including Week 52 was calculated. Two intermediate occurrences (not consecutive) of a MADRS \>12 but ≤16 or missing were allowed from Week 16 to Week 48. A 10-item scale for the evaluation of depressive symptoms. Each MADRS item is rated on a 0 to 6 scale. The MADRS total score is calculated as the sum of the 10 individual item scores; the total score can range from 0 to 60. Higher MADRS scores indicate higher levels of depressive symptoms. |
| Change in the Clinician-rated Global Outcome of Severity as Measured by the Clinical Global Impression-Severity (CGI-S) Score From Randomization (Week 0) to End of Treatment (Week 52) | Randomization (Week 0) to end of treatment (Week 52) | A 3-part, clinician-administered scale that rates the improvement or worsening of the patient's illness from randomization (baseline). Each item is scored on a 1 to 7 scale. Higher CGI-S scores indicate greater illness severity. |
Countries
Puerto Rico, United States
Participant flow
Recruitment details
This multicenter study was conducted in the US between 22 June 2010 and 07 February 2012.
Pre-assignment details
The study had an up to 21-day screening/washout period, and an 6-week prospective open-label antidepressant treatment (ADT) period to identify the target patient population of inadequate responders to ADT (a HAMD-17 total score of ≥10 and a CGI-S score ≥3).
Participants by arm
| Arm | Count |
|---|---|
| TC-5214 Selective serotonin reuptake inhibitor (SSRI)/Serotonin/norepinephrine reuptake inhibitor (SNRI) + TC-5214, 1-4 mg BID | 610 |
| Placebo Selective serotonin reuptake inhibitor (SSRI)/Serotonin/norepinephrine reuptake inhibitor (SNRI) + Placebo BID | 203 |
| Total | 813 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 67 | 14 |
| Overall Study | Condition under investigation worsened | 5 | 2 |
| Overall Study | Death | 1 | 1 |
| Overall Study | Eligiblity criteria not fulfilled | 0 | 1 |
| Overall Study | Lack of Efficacy | 20 | 3 |
| Overall Study | Lost to Follow-up | 87 | 32 |
| Overall Study | Other | 28 | 8 |
| Overall Study | Severe non-compliance to protocol | 36 | 14 |
| Overall Study | Study-specific withdrawal criteria | 17 | 8 |
| Overall Study | Withdrawal by Subject | 73 | 28 |
Baseline characteristics
| Characteristic | Placebo | Total | TC-5214 |
|---|---|---|---|
| Age, Continuous | 42.8 years STANDARD_DEVIATION 11.75 | 43.1 years STANDARD_DEVIATION 11.69 | 43.2 years STANDARD_DEVIATION 11.68 |
| Hamilton Rating Scale for Depression-17 items (HAMD-17) total score at randomization | 18.6 Scores on a scale STANDARD_DEVIATION 4.61 | 18.5 Scores on a scale STANDARD_DEVIATION 4.52 | 18.4 Scores on a scale STANDARD_DEVIATION 4.49 |
| Montgomery-Asberg Depression Rating Scale (MADRS) total score at randomization | 23.4 Scores on a scale STANDARD_DEVIATION 5.85 | 23.4 Scores on a scale STANDARD_DEVIATION 6.21 | 23.5 Scores on a scale STANDARD_DEVIATION 6.34 |
| Race/Ethnicity, Customized American Indian or Alaska Native | 2 participants | 2 participants | 0 participants |
| Race/Ethnicity, Customized Asian | 4 participants | 14 participants | 10 participants |
| Race/Ethnicity, Customized Black or African American | 44 participants | 165 participants | 121 participants |
| Race/Ethnicity, Customized Native Hawaiian or other Pacific Islander | 0 participants | 1 participants | 1 participants |
| Race/Ethnicity, Customized Other | 4 participants | 15 participants | 11 participants |
| Race/Ethnicity, Customized White | 149 participants | 616 participants | 467 participants |
| Sex: Female, Male Female | 148 Participants | 566 Participants | 418 Participants |
| Sex: Female, Male Male | 55 Participants | 247 Participants | 192 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 151 / 201 | 451 / 607 |
| serious Total, serious adverse events | 5 / 201 | 22 / 607 |
Outcome results
Primary
Frequency of Patients Experiencing AEs That Resulted in Discontinuation of Investigational Product (IP)
The frequency of patients experiencing AEs that resulted in discontinuation of IP during the randomized treatment or follow-up periods was calculated.
Time frame: Randomization (Week 0) to end of the follow-up period (Week 54)
Population: Safety analysis set including all randomized patients who received at least 1 dose of investigational product (TC-5214 or placebo) and for whom any postdose data were available.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| TC-5214 | Frequency of Patients Experiencing AEs That Resulted in Discontinuation of Investigational Product (IP) | 10.5 percentage of participants analyzed |
| Placebo | Frequency of Patients Experiencing AEs That Resulted in Discontinuation of Investigational Product (IP) | 7.0 percentage of participants analyzed |
Primary
Frequency of Patients Experiencing at Least One Adverse Event (AE)
The frequency of patients experiencing at least one AE during the randomized treatment or follow-up periods was calculated.
Time frame: Randomization (Week 0) to end of the follow-up period (Week 54)
Population: Safety analysis set including all randomized patients who received at least 1 dose of investigational product (TC-5214 or placebo) and for whom any postdose data were available.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| TC-5214 | Frequency of Patients Experiencing at Least One Adverse Event (AE) | 82.4 percentage of participants analyzed |
| Placebo | Frequency of Patients Experiencing at Least One Adverse Event (AE) | 84.6 percentage of participants analyzed |
Primary
Frequency of Patients Experiencing Serious Adverse Events (SAEs)
The frequency of patients experiencing serious adverse events (SAEs) during the randomized treatment or follow-up periods was calculated.
Time frame: Randomization (Week 0) to end of the follow-up period (Week 54)
Population: Safety analysis set including all randomized patients who received at least 1 dose of investigational product (TC-5214 or placebo) and for whom any postdose data were available.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| TC-5214 | Frequency of Patients Experiencing Serious Adverse Events (SAEs) | 3.6 percentage of participants analyzed |
| Placebo | Frequency of Patients Experiencing Serious Adverse Events (SAEs) | 2.5 percentage of participants analyzed |
Secondary
Change in EuroQol - 5 Dimensions (EQ-5D) From Randomization (Week 0) to End of Treatment (Week 52)
A self-assessment questionnaire that provides 2 measures of health status. The EQ-5D index score is a weighted linear combination over 5 dimensions of health status. The score for each of the 5 dimensions can range from 1 to 3, and an equation is used to calculate the EQ-5D index score. The EQ-5D index score can range from possible negative values to a maximum of 1.0. The EQ-VAS is a visual analog scale with a range of 0 to 100. For both variables, a higher score indicates a better health state.
Time frame: Randomization (Week 0) to end of treatment (Week 52)
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 total MADRS score at randomization and a total HAMD-17 score ≥16 and a CGI-S score ≥4 at randomization.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| TC-5214 | Change in EuroQol - 5 Dimensions (EQ-5D) From Randomization (Week 0) to End of Treatment (Week 52) | EQ-5D index score | 0.081 units on a scale | Standard Deviation 0.2021 |
| TC-5214 | Change in EuroQol - 5 Dimensions (EQ-5D) From Randomization (Week 0) to End of Treatment (Week 52) | EQ-5D VAS score | 8.7 units on a scale | Standard Deviation 20.04 |
| Placebo | Change in EuroQol - 5 Dimensions (EQ-5D) From Randomization (Week 0) to End of Treatment (Week 52) | EQ-5D index score | 0.071 units on a scale | Standard Deviation 0.15 |
| Placebo | Change in EuroQol - 5 Dimensions (EQ-5D) From Randomization (Week 0) to End of Treatment (Week 52) | EQ-5D VAS score | 11.9 units on a scale | Standard Deviation 21.06 |
Secondary
Change in Functional Impairment From Randomization (Week 0) to End of Treatment (Week 52) 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 0) to end of treatment (Week 52)
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 total MADRS score at randomization and a total HAMD-17 score ≥16 and a CGI-S score ≥4 at randomization.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| TC-5214 | Change in Functional Impairment From Randomization (Week 0) to End of Treatment (Week 52) as Measured by the Sheehan Disability Scale (SDS) Total Score | -6.98 units on a scale | Standard Deviation 7.909 |
| Placebo | Change in Functional Impairment From Randomization (Week 0) to End of Treatment (Week 52) as Measured by the Sheehan Disability Scale (SDS) Total Score | -7.44 units on a scale | Standard Deviation 7.53 |
Secondary
Change in Overall Quality of Life and Satisfaction From Randomization (Week 0) to End of Treatment (Week 52) by Assessing the Quality of Life Enjoyment and Satisfaction Questionnaire-Short Form (Q-LES-Q-SF) % Maximum Total Score
The Q-LES-Q-SF total score is derived by summing item scores 1 to 14. Higher scores are indicative of greater enjoyment or satisfaction in each domain. The Q-LES-Q-SF % maximum total score is calculated as 100% × (Q-LES-Q-SF total score - 14) / 56, and can range from 0% to 100%.
Time frame: Randomization (Week 0) to end of treatment (Week 52)
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 total MADRS score at randomization and a total HAMD-17 score ≥16 and a CGI-S score ≥4 at randomization.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| TC-5214 | Change in Overall Quality of Life and Satisfaction From Randomization (Week 0) to End of Treatment (Week 52) by Assessing the Quality of Life Enjoyment and Satisfaction Questionnaire-Short Form (Q-LES-Q-SF) % Maximum Total Score | 10.83 units on a scale | Standard Deviation 18.744 |
| Placebo | Change in Overall Quality of Life and Satisfaction From Randomization (Week 0) to End of Treatment (Week 52) by Assessing the Quality of Life Enjoyment and Satisfaction Questionnaire-Short Form (Q-LES-Q-SF) % Maximum Total Score | 11.62 units on a scale | Standard Deviation 17.006 |
Secondary
Change in the Clinician-rated Global Outcome of Severity as Measured by the Clinical Global Impression-Severity (CGI-S) Score From Randomization (Week 0) to End of Treatment (Week 52)
A 3-part, clinician-administered scale that rates the improvement or worsening of the patient's illness from randomization (baseline). Each item is scored on a 1 to 7 scale. Higher CGI-S scores indicate greater illness severity.
Time frame: Randomization (Week 0) to end of treatment (Week 52)
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 total MADRS score at randomization and a total HAMD-17 score ≥16 and a CGI-S score ≥4 at randomization.
| Arm | Measure | Value (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 0) to End of Treatment (Week 52) | -1.8 units on a scale | Standard Deviation 1.17 |
| Placebo | Change in the Clinician-rated Global Outcome of Severity as Measured by the Clinical Global Impression-Severity (CGI-S) Score From Randomization (Week 0) to End of Treatment (Week 52) | -1.6 units on a scale | Standard Deviation 1.17 |
Secondary
Sustained Efficacy at 3 Months, Defined as a Montgomery-Asberg Depression Rating Scale (MADRS) Total Score of ≤12 at Week 12 and All Visits up to and Including Week 24
The percentage of patients with a a MADRS total score of ≤12 at Week 12 and all visits up to and including Week 24 was calculated. One intermediate occurrence of a MADRS total score \>12 but ≤16 or missing was allowed from Week 16 to Week 20. A 10-item scale for the evaluation of depressive symptoms. Each MADRS item is rated on a 0 to 6 scale. The MADRS total score is calculated as the sum of the 10 individual item scores; the total score can range from 0 to 60. Higher MADRS scores indicate higher levels of depressive symptoms.
Time frame: Week 12 to Week 24
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 total MADRS score at randomization and a total HAMD-17 score ≥16 and a CGI-S score ≥4 at randomization.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| TC-5214 | Sustained Efficacy at 3 Months, Defined as a Montgomery-Asberg Depression Rating Scale (MADRS) Total Score of ≤12 at Week 12 and All Visits up to and Including Week 24 | 18.2 percentage of participants analyzed |
| Placebo | Sustained Efficacy at 3 Months, Defined as a Montgomery-Asberg Depression Rating Scale (MADRS) Total Score of ≤12 at Week 12 and All Visits up to and Including Week 24 | 20.6 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: 0.69795% CI: [0.54, 1.5]Regression, Logistic
Secondary
Sustained Efficacy at 9 Months, Defined as a MADRS Total Score of ≤12 at Week 12 and at All Visits up to and Including Week 52
The percentage of patients with a MADRS total score of ≤12 at Week 12 and at all visits up to and including Week 52 was calculated. Two intermediate occurrences (not consecutive) of a MADRS \>12 but ≤16 or missing were allowed from Week 16 to Week 48. A 10-item scale for the evaluation of depressive symptoms. Each MADRS item is rated on a 0 to 6 scale. The MADRS total score is calculated as the sum of the 10 individual item scores; the total score can range from 0 to 60. Higher MADRS scores indicate higher levels of depressive symptoms.
Time frame: Week 12 to Week 52
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 total MADRS score at randomization and a total HAMD-17 score ≥16 and a CGI-S score ≥4 at randomization.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| TC-5214 | Sustained Efficacy at 9 Months, Defined as a MADRS Total Score of ≤12 at Week 12 and at All Visits up to and Including Week 52 | 9.7 percentage of patients analyzed |
| Placebo | Sustained Efficacy at 9 Months, Defined as a MADRS Total Score of ≤12 at Week 12 and at All Visits up to and Including Week 52 | 12.5 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: 0.58295% CI: [0.45, 1.57]Regression, Logistic