Major Depressive Disorder
Conditions
Keywords
Major Depressive Disorder, MDD, Monotherapy, Inadequate Response to Antidepressant Therapy
Brief summary
The purpose of this study is to assess the safety and effect of TC-5214 as a single therapy in patients with major depressive disorder who exhibit inadequate response to antidepressants.
Interventions
DRUGTC-5214
Tablet, oral, twice daily for 8 weeks
DRUGDuloxetine
Capsule, oral, once daily
DRUGPlacebo
Tablet, oral, twice daily for 8 weeks
Sponsors
AstraZeneca
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, 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. * Women of child-bearing potential must have a negative urine pregnancy test and confirmed use of a highly effective form of birth control before enrollment and until 3 months after their last dose of study drug. * 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 any significant unstable hepatic, renal, pulmonary, cardiovascular, ophthalmologic, neurologic, or any other medical conditions that might confound the study or put the patient at greater risk during study participation. * History of stroke or transient ischemic attack, seizures or seizure disorder, head trauma including closed head injury. * Pregnancy or lactation.
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 Montgomery Asberg Depression Rating Scale (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
Estonia, Finland, India, Japan, United States
Participant flow
Recruitment details
This multicenter study was conducted in Europe, Asia, and North America between 4 February 2011 and 26 April 2012.
Pre-assignment details
21-day screening/washout and 8-week prospective open-label SSRI(selective serotonin reuptake inhibitors)/SNRI(selective serotonin and norepinephrine reuptake inhibitors) periods to identify population of inadequate responders(\<50% reduction in Hamilton Rating Scale for Depression total score of ≥16 and a Clinical Global Impression-Severity ≥4).
Participants by arm
| Arm | Count |
|---|---|
| 1 mg BID TC-5214 | 37 |
| 4 mg BID TC-5214 | 36 |
| 60 mg QD Duloxetine | 37 |
| Placebo | 35 |
| Total | 145 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| Overall Study | Adverse Event | 2 | 1 | 2 | 3 |
| Overall Study | Condition under Investigation Worsened | 0 | 0 | 0 | 1 |
| Overall Study | Lack of Efficacy | 2 | 2 | 0 | 2 |
| Overall Study | Lost to Follow-up | 1 | 1 | 1 | 0 |
| Overall Study | Other or Study Termination | 11 | 15 | 14 | 8 |
| Overall Study | Severe Non-Compliance to Protocol | 1 | 3 | 1 | 3 |
| Overall Study | Study-Specific Withdrawal Criteria | 1 | 1 | 0 | 0 |
| Overall Study | Withdrawal by Subject | 2 | 4 | 1 | 0 |
Baseline characteristics
| Characteristic | 4 mg BID TC-5214 | Total | Placebo | 60 mg QD Duloxetine | 1 mg BID TC-5214 |
|---|---|---|---|---|---|
| Age Continuous | 40.3 years STANDARD_DEVIATION 12.5 | 41.7 years STANDARD_DEVIATION 12.24 | 40.1 years STANDARD_DEVIATION 10.49 | 41.8 years STANDARD_DEVIATION 12.7 | 44.5 years STANDARD_DEVIATION 13.03 |
| Hamilton Rating Scale for Depression-17 items (HAMD-17) total score at randomization | 21.371 Scores on a scale STANDARD_DEVIATION 3.606 | 21.372 Scores on a scale STANDARD_DEVIATION 3.632 | 21.344 Scores on a scale STANDARD_DEVIATION 4.1 | 21.857 Scores on a scale STANDARD_DEVIATION 3.499 | 20.914 Scores on a scale STANDARD_DEVIATION 3.425 |
| Montgomery-Asberg Depression Rating Scale (MADRS) total score at randomization | 26.857 Scores on a scale STANDARD_DEVIATION 5.542 | 27.577 Scores on a scale STANDARD_DEVIATION 5.734 | 27.625 Scores on a scale STANDARD_DEVIATION 5.32 | 28.600 Scores on a scale STANDARD_DEVIATION 6.796 | 27.228 Scores on a scale STANDARD_DEVIATION 5.202 |
| Race/Ethnicity, Customized American Indian or Alaska Native | 0 participants | 0 participants | 0 participants | 0 participants | 0 participants |
| Race/Ethnicity, Customized Asian | 10 participants | 40 participants | 9 participants | 9 participants | 12 participants |
| Race/Ethnicity, Customized Black or African American | 4 participants | 14 participants | 5 participants | 4 participants | 1 participants |
| Race/Ethnicity, Customized Native Hawaiian or other Pacific Islander | 0 participants | 0 participants | 0 participants | 0 participants | 0 participants |
| Race/Ethnicity, Customized Other | 2 participants | 5 participants | 1 participants | 1 participants | 1 participants |
| Race/Ethnicity, Customized White | 20 participants | 86 participants | 20 participants | 23 participants | 23 participants |
| Sex: Female, Male Female | 26 Participants | 91 Participants | 19 Participants | 22 Participants | 24 Participants |
| Sex: Female, Male Male | 10 Participants | 54 Participants | 16 Participants | 15 Participants | 13 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 22 / 37 | 27 / 35 | 21 / 37 | 24 / 35 |
| serious Total, serious adverse events | 1 / 37 | 0 / 35 | 0 / 37 | 1 / 35 |
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 Montgomery Asberg Depression Rating Scale (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, duloxetine or placebo) and who had a randomization and at least 1 post-randomization MADRS total score.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| 1 mg BID TC-5214 | Change in the Montgomery Asberg Depression Rating Scale (MADRS) Total Score From Randomization to End of Treatment | -9.1 units on a scale | Standard Error 2.15 |
| 4 mg BID TC-5214 | Change in the Montgomery Asberg Depression Rating Scale (MADRS) Total Score From Randomization to End of Treatment | -11.2 units on a scale | Standard Error 2.56 |
| 60 mg QD Duloxetine | Change in the Montgomery Asberg Depression Rating Scale (MADRS) Total Score From Randomization to End of Treatment | -11.4 units on a scale | Standard Error 2.14 |
| Placebo | Change in the Montgomery Asberg Depression Rating Scale (MADRS) Total Score From Randomization to End of Treatment | -7.6 units on a scale | Standard Error 2.19 |
Comparison: Mixed model repeated measures (MMRM) includes treatment, pooled center, visit, treatment by visit interaction, region, responsiveness, and region by responsiveness as explanatory variables and the randomization MADRS total score as a covariate. Treatment, visit treatment by visit interaction, region, responsiveness, and region by responsiveness are fixed effects in the model; pooled center is a random effect.p-value: 0.61795% CI: [-7.35, 4.39]MMRM
Comparison: Mixed model repeated measures (MMRM) includes treatment, pooled center, visit, treatment by visit interaction, region, responsiveness, and region by responsiveness as explanatory variables and the randomization MADRS total score as a covariate. Treatment, visit, treatment by visit interaction, region, responsiveness, and region by responsiveness are fixed effects in the model; pooled center is a random effect.p-value: 0.27795% CI: [-10.06, 2.91]MMRM
Comparison: Mixed model repeated measures (MMRM) includes treatment, pooled center, visit, treatment by visit interaction, region, responsiveness, and region by responsiveness as explanatory variables and the randomization MADRS total score as a covariate. Treatment, visit, treatment by visit interaction, region, responsiveness, and region by responsiveness are fixed effects in the model; pooled center is a random effect.p-value: 0.19495% CI: [-9.72, 2]MMRM