Depressive Disorder, Major
Conditions
Keywords
Major Depressive Disorder, Depression, Melancholia, Drug Therapy
Brief summary
The purpose of this study is to assess the efficacy and safety of multiple doses of vortioxetine, once daily (QD), in participants with major depressive disorder.
Detailed description
The drug that was tested in this study is called vortioxetine. Vortioxetine is being tested to treat depression in adults who have major depressive disorder (MDD). This study looked at MDD relief in people who took varying doses of vortioxetine. The study enrolled 600 patients. Participants were randomly assigned (by chance, like flipping a coin) to one of the four treatment groups-which remained undisclosed to the patient and study doctor during the study (unless there was an urgent medical need): * Vortioxetine 5 mg * Vortioxetine 10 mg * Vortioxetine 20 mg * Placebo (dummy inactive pill) - this was a capsule that looked like the study drug but had no active ingredient. All participants were asked to take one capsule at the same time each day throughout the study. This multi-center trial was conducted in 14 countries in Europe and Asia. The overall time to participate in this study was up to 13 weeks. Participants made weekly visits to the clinic during the first 2 weeks of the 8-week treatment period and then every 2 weeks up to the end of the 8-week treatment period. Participants who completed the 8-week treatment period entered a 2-week discontinuation period to assess potential discontinuation symptoms 1 and 2 weeks after the end of the 8-week treatment period. A safety follow-up contact (visit or phone call) was made 4 weeks after completion of the 8-week double-blind treatment period (2 weeks after the end of the 2-week discontinuation period).
Interventions
DRUGVortioxetine
Vortioxetine tablets
DRUGPlacebo
Vortioxetine placebo-matching tablets
Sponsors
Takeda
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
20 Years to 64 Years
Healthy volunteers
No
Inclusion criteria
1. Suffers from Major Depressive Disorder as the primary diagnosis according to Diagnostic and Statistical Manual of Mental Disorders, 4th Edition, Text Revision (DSM-IV-TR) criteria (classification code 296.2x and 296.3x). 2. The reported duration of the current major depressive episode is at least 3 months at the Screening Visit. 3. Has a Montgomery-Åsberg Depression Rating Scale (MADRS) total score ≥26 at the Screening and Baseline Visits. 4. Has a Clinical Global Impression Scale-Severity (CGI-S) score ≥4 at the Screening and Baseline Visits.
Exclusion criteria
1. Has one or more of the following conditions: * Any current psychiatric disorder other than Major Depressive Disorder as defined in the Diagnostic and Statistical Manual of Mental Disorders, 4th Edition, Text Revision (DSM-IV-TR; assessed by the Mini International Neuropsychiatric Interview: MINI). A participant who exhibits symptoms of anxiety is eligible unless fulfilling the diagnostic criteria for a current anxiety disorder per DSM-IV-TR. * Current diagnosis or history of manic or hypomanic episode, schizophrenia or any other psychotic disorder, including major depression with psychotic features, mental retardation, organic mental disorders, or mental disorders due to a general medical condition as defined in the DSM-IV-TR. * Current diagnosis or history of any substance-related disorder (except nicotine and caffeine-related disorders) as defined in the DSM-IV-TR. Participant with confirmed positive urine drug screens (except prescribed medications or a medication that does not constitute drug abuse) will be excluded. * Presence or history of a clinically significant neurological disorder (including epilepsy). * Neurodegenerative disorder. (Alzheimer's disease, Parkinson's disease, multiple sclerosis, Huntington's disease, etc.) * Any DSM-IV-TR axis II disorder that might compromise the study. 2. The current depressive symptoms of the participant are considered by the investigator to have been resistant to 2 adequate antidepressant treatments of at least 6 weeks duration each. 3. Has received electroconvulsive, vagal nerve stimulation, or repetitive transcranial magnetic stimulation therapy within 6 months prior to the Screening Visit. 4. Is currently receiving formal cognitive or behavioral therapy, systematic psychotherapy, or plans to initiate such therapy during the study. 5. Is at significant risk of suicide or has a score ≥5 on Item 10 (suicidal thoughts) of the MADRS, or has attempted suicide within 6 months prior to the Screening Visit.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in Montgomery-Åsberg Depression Rating Scale (MADRS) Total Score | Baseline and Week 8 | The MADRS is a depression rating scale consisting of 10 items, each rated 0 (normal) to 6 (most abnormal). The 10 items represent the core symptoms of depressive illness. The overall score ranges from 0 (symptoms absent) to 60 (severe depression). A decrease in the total score or on individual items indicates improvement. Least squares (LS) means were from an Analysis of Covariance (ANCOVA) model with treatment as a fixed factor and the Baseline value as a covariate. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants With a MADRS Response at Week 8 | Baseline and Week 8 | Response is defined as a participant with a ≥50% decrease in Montgomery Åsberg Depression Rating Scale (MADRS) total score from Baseline. The MADRS is a depression rating scale consisting of 10 items, each rated 0 to 6. The 10 items represent the core symptoms of depressive illness. The overall score ranges from 0 (symptoms absent) to 60 (severe depression). Decrease in the total score or on individual items indicates improvement. |
| Percentage of Participants in MADRS Remission at Week 8 | Week 8 | Remission is defined as a participant with a Montgomery Åsberg Depression Rating Scale (MADRS) total score ≤10. The MADRS is a depression rating scale consisting of 10 items, each rated 0 to 6. The 10 items represent the core symptoms of depressive illness. The overall score ranges from 0 (symptoms absent) to 60 (severe depression). Decrease in the total score or on individual items indicates improvement. |
| Mean Clinical Global Impression Scale - Improvement (CGI-I) Score at Week 8 | Week 8 | The Clinical Global Impression - Global Improvement scale assesses the participant's improvement (or worsening) as assessed by the clinician relative to Baseline on a 7-point scale: 1, very much improved; 2, much improved; 3, minimally improved; 4, no change; 5, minimally worse; 6, much worse; or 7, very much worse. LS means were from an ANCOVA model with treatment as a fixed factor and the Baseline Clinical Global Impression-Severity of Illness (CGI-S) score as a covariate. |
| Change From Baseline in Sheehan Disability Scale (SDS) Total Score at Week 8 | Baseline and Week 8 | The Sheehan Disability Scale assesses functional impairment in 3 domains: work/school, social life or leisure activities, and family life or home responsibilities. The participant rates the extent to which each aspect is impaired on a 10-point visual analog scale, from 0 (not at all) to 10 (extremely). The 3 scores are added together to calculate the total score, which ranges from 0 to 30, with higher scores indicating more impairment. LS means were from an ANCOVA model with treatment as a fixed factor and the Baseline value as a covariate. |
Countries
Croatia, Finland, Germany, Hong Kong, India, Japan, Latvia, Malaysia, Philippines, Poland, Romania, Russia, Serbia, South Korea, Taiwan, Ukraine
Participant flow
Recruitment details
Participants took part in the study at 90 investigative sites in Japan, Europe and Asia/Oceania from 18 November 2010 to 25 April 2012.
Pre-assignment details
Participants with a diagnosis of major depressive disorder were enrolled equally in 1 of 4 treatment groups, once a day placebo, 5 mg, 10 mg, or 20 mg vortioxetine.
Participants by arm
| Arm | Count |
|---|---|
| Placebo Vortioxetine placebo-matching tablets, orally, once daily for up to 10 weeks. | 152 |
| Vortioxetine 5 mg Vortioxetine 5 mg, tablets, orally, once daily for 8 weeks, followed by vortioxetine placebo-matching tablets, orally, once daily for 2 weeks. | 144 |
| Vortioxetine 10 mg Vortioxetine 10 mg, tablets, orally, once daily for 8 weeks, followed by vortioxetine placebo-matching tablets, orally, once daily for 2 weeks. | 150 |
| Vortioxetine 20 mg Vortioxetine 10 mg, tablets, orally, once daily for 1 week, followed by vortioxetine 20 mg, tablets, orally, once daily for 7 weeks, followed by vortioxetine placebo-matching tablets, orally, once daily, for 2 weeks. | 154 |
| Total | 600 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| Overall Study | Lack of Efficacy | 2 | 2 | 2 | 2 |
| Overall Study | Lost to Follow-up | 1 | 2 | 4 | 2 |
| Overall Study | Major Protocol Deviation | 1 | 1 | 0 | 4 |
| Overall Study | Noncompliance with Study Drug | 3 | 1 | 0 | 0 |
| Overall Study | Pregnancy | 0 | 0 | 0 | 1 |
| Overall Study | Pretreatment Event or Adverse Event (AE) | 6 | 2 | 9 | 9 |
| Overall Study | Withdrawal of Consent | 3 | 9 | 3 | 4 |
Baseline characteristics
| Characteristic | Total | Vortioxetine 5 mg | Vortioxetine 10 mg | Placebo | Vortioxetine 20 mg |
|---|---|---|---|---|---|
| Age Continuous | 44.4 years STANDARD_DEVIATION 11.54 | 44.2 years STANDARD_DEVIATION 11.89 | 45.7 years STANDARD_DEVIATION 10.9 | 43.6 years STANDARD_DEVIATION 11.57 | 44.0 years STANDARD_DEVIATION 11.79 |
| Body Mass Index (BMI) | 25.15 kg/m^2 STANDARD_DEVIATION 5.313 | 25.06 kg/m^2 STANDARD_DEVIATION 5.432 | 25.93 kg/m^2 STANDARD_DEVIATION 5.462 | 24.82 kg/m^2 STANDARD_DEVIATION 5.129 | 24.82 kg/m^2 STANDARD_DEVIATION 5.206 |
| Clinical Global Impression - Severity scale score | 4.70 scores on a scale STANDARD_DEVIATION 0.65 | 4.7 scores on a scale STANDARD_DEVIATION 0.65 | 4.7 scores on a scale STANDARD_DEVIATION 0.66 | 4.7 scores on a scale STANDARD_DEVIATION 0.66 | 4.7 scores on a scale STANDARD_DEVIATION 0.65 |
| Hamilton Anxiety Scale Total Score | 18.7 scores on a scale STANDARD_DEVIATION 6.53 | 18.9 scores on a scale STANDARD_DEVIATION 6.55 | 18.8 scores on a scale STANDARD_DEVIATION 6.66 | 18.6 scores on a scale STANDARD_DEVIATION 6.83 | 18.5 scores on a scale STANDARD_DEVIATION 6.12 |
| Height | 167.3 cm STANDARD_DEVIATION 9.33 | 167.2 cm STANDARD_DEVIATION 9.64 | 167.5 cm STANDARD_DEVIATION 9.4 | 167.1 cm STANDARD_DEVIATION 8.75 | 167.5 cm STANDARD_DEVIATION 9.61 |
| History of Alcohol Consumption 2 to 6 times per week | 46 participants | 9 participants | 10 participants | 14 participants | 13 participants |
| History of Alcohol Consumption Daily | 41 participants | 10 participants | 10 participants | 11 participants | 10 participants |
| History of Alcohol Consumption Never | 230 participants | 62 participants | 54 participants | 58 participants | 56 participants |
| History of Alcohol Consumption Once a week | 83 participants | 22 participants | 22 participants | 17 participants | 22 participants |
| History of Alcohol Consumption Once monthly or less often | 200 participants | 41 participants | 54 participants | 52 participants | 53 participants |
| Montgomery Åsberg Depression Rating Scale (MADRS) Total Score | 31.7 scores on a scale STANDARD_DEVIATION 3.74 | 31.6 scores on a scale STANDARD_DEVIATION 3.67 | 31.8 scores on a scale STANDARD_DEVIATION 4.02 | 31.6 scores on a scale STANDARD_DEVIATION 3.56 | 31.7 scores on a scale STANDARD_DEVIATION 3.73 |
| Pharmacotherapy for Current Major Depressive Episode No | 323 participants | 84 participants | 81 participants | 79 participants | 79 participants |
| Pharmacotherapy for Current Major Depressive Episode Yes | 277 participants | 60 participants | 69 participants | 73 participants | 75 participants |
| Race/Ethnicity, Customized Asian | 186 participants | 43 participants | 46 participants | 48 participants | 49 participants |
| Race/Ethnicity, Customized Caucasian (or White, including Hispanic) | 414 participants | 101 participants | 104 participants | 104 participants | 105 participants |
| Region of Enrollment Croatia | 3 participants | 1 participants | 0 participants | 0 participants | 2 participants |
| Region of Enrollment Finland | 20 participants | 5 participants | 5 participants | 5 participants | 5 participants |
| Region of Enrollment Germany | 199 participants | 50 participants | 50 participants | 50 participants | 49 participants |
| Region of Enrollment India | 11 participants | 3 participants | 3 participants | 3 participants | 2 participants |
| Region of Enrollment Japan | 129 participants | 32 participants | 31 participants | 33 participants | 33 participants |
| Region of Enrollment Latvia | 10 participants | 2 participants | 2 participants | 3 participants | 3 participants |
| Region of Enrollment Malaysia | 4 participants | 0 participants | 0 participants | 2 participants | 2 participants |
| Region of Enrollment Philippines | 13 participants | 2 participants | 4 participants | 4 participants | 3 participants |
| Region of Enrollment Poland | 79 participants | 18 participants | 20 participants | 20 participants | 21 participants |
| Region of Enrollment Romania | 18 participants | 4 participants | 6 participants | 5 participants | 3 participants |
| Region of Enrollment Russia | 51 participants | 13 participants | 12 participants | 13 participants | 13 participants |
| Region of Enrollment Serbia | 9 participants | 2 participants | 3 participants | 2 participants | 2 participants |
| Region of Enrollment South Korea | 27 participants | 6 participants | 7 participants | 6 participants | 8 participants |
| Region of Enrollment Ukraine | 27 participants | 6 participants | 7 participants | 6 participants | 8 participants |
| Sex: Female, Male Female | 375 Participants | 98 Participants | 93 Participants | 91 Participants | 93 Participants |
| Sex: Female, Male Male | 225 Participants | 46 Participants | 57 Participants | 61 Participants | 61 Participants |
| Sheehan Disability Scale (SDS) - Total score | 18.2 scores on a scale STANDARD_DEVIATION 5.65 | 17.9 scores on a scale STANDARD_DEVIATION 6.27 | 18.5 scores on a scale STANDARD_DEVIATION 5.42 | 18.2 scores on a scale STANDARD_DEVIATION 5.28 | 18.2 scores on a scale STANDARD_DEVIATION 5.7 |
| Smoking Classification Current smoker | 207 participants | 50 participants | 50 participants | 51 participants | 56 participants |
| Smoking Classification Ex-smoker | 73 participants | 19 participants | 21 participants | 22 participants | 11 participants |
| Smoking Classification Never smoked | 320 participants | 75 participants | 79 participants | 79 participants | 87 participants |
| Status of Major Depressive Episode (MDE) Recurrent episode | 396 participants | 89 participants | 101 participants | 101 participants | 105 participants |
| Status of Major Depressive Episode (MDE) Single episode | 204 participants | 55 participants | 49 participants | 51 participants | 49 participants |
| Weight | 70.95 kg STANDARD_DEVIATION 18.095 | 70.57 kg STANDARD_DEVIATION 18.214 | 73.37 kg STANDARD_DEVIATION 19.014 | 69.70 kg STANDARD_DEVIATION 16.901 | 70.21 kg STANDARD_DEVIATION 18.189 |
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 | 97 / 151 | 96 / 144 | 93 / 148 | 106 / 150 |
| serious Total, serious adverse events | 1 / 151 | 2 / 144 | 2 / 148 | 3 / 150 |
Outcome results
Primary
Change From Baseline in Montgomery-Åsberg Depression Rating Scale (MADRS) Total Score
The MADRS is a depression rating scale consisting of 10 items, each rated 0 (normal) to 6 (most abnormal). The 10 items represent the core symptoms of depressive illness. The overall score ranges from 0 (symptoms absent) to 60 (severe depression). A decrease in the total score or on individual items indicates improvement. Least squares (LS) means were from an Analysis of Covariance (ANCOVA) model with treatment as a fixed factor and the Baseline value as a covariate.
Time frame: Baseline and Week 8
Population: The full analysis set included all randomized participants who received at least 1 dose of study drug. One patient in the placebo arm was excluded from all datasets due to enrollment in another clinical study. Only participants with Baseline and at least 1 post-baseline value are included. Last observation carried forward (LOCF) was used.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Change From Baseline in Montgomery-Åsberg Depression Rating Scale (MADRS) Total Score | -13.99 scores on a scale | Standard Error 0.783 |
| Vortioxetine 5 mg | Change From Baseline in Montgomery-Åsberg Depression Rating Scale (MADRS) Total Score | -14.61 scores on a scale | Standard Error 0.805 |
| Vortioxetine 10 mg | Change From Baseline in Montgomery-Åsberg Depression Rating Scale (MADRS) Total Score | -15.68 scores on a scale | Standard Error 0.791 |
| Vortioxetine 20 mg | Change From Baseline in Montgomery-Åsberg Depression Rating Scale (MADRS) Total Score | -15.82 scores on a scale | Standard Error 0.786 |
Comparison: All statistical tests were 2-sided with the estimated P-values at the 5% level of significance.p-value: 0.90795% CI: [-3.258, 2.035]ANCOVA
p-value: 0.300695% CI: [-4.31, 0.938]ANCOVA
p-value: 0.239995% CI: [-4.436, 0.794]ANCOVA
Secondary
Change From Baseline in Sheehan Disability Scale (SDS) Total Score at Week 8
The Sheehan Disability Scale assesses functional impairment in 3 domains: work/school, social life or leisure activities, and family life or home responsibilities. The participant rates the extent to which each aspect is impaired on a 10-point visual analog scale, from 0 (not at all) to 10 (extremely). The 3 scores are added together to calculate the total score, which ranges from 0 to 30, with higher scores indicating more impairment. LS means were from an ANCOVA model with treatment as a fixed factor and the Baseline value as a covariate.
Time frame: Baseline and Week 8
Population: Full analysis set, only participants with Baseline and at least 1 post-baseline value are included. LOCF was used.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Change From Baseline in Sheehan Disability Scale (SDS) Total Score at Week 8 | -6.20 scores on a scale | Standard Error 0.602 |
| Vortioxetine 5 mg | Change From Baseline in Sheehan Disability Scale (SDS) Total Score at Week 8 | -6.38 scores on a scale | Standard Error 0.647 |
| Vortioxetine 10 mg | Change From Baseline in Sheehan Disability Scale (SDS) Total Score at Week 8 | -7.97 scores on a scale | Standard Error 0.633 |
| Vortioxetine 20 mg | Change From Baseline in Sheehan Disability Scale (SDS) Total Score at Week 8 | -7.26 scores on a scale | Standard Error 0.622 |
Secondary
Mean Clinical Global Impression Scale - Improvement (CGI-I) Score at Week 8
The Clinical Global Impression - Global Improvement scale assesses the participant's improvement (or worsening) as assessed by the clinician relative to Baseline on a 7-point scale: 1, very much improved; 2, much improved; 3, minimally improved; 4, no change; 5, minimally worse; 6, much worse; or 7, very much worse. LS means were from an ANCOVA model with treatment as a fixed factor and the Baseline Clinical Global Impression-Severity of Illness (CGI-S) score as a covariate.
Time frame: Week 8
Population: Full analysis set, only participants with Baseline and at least 1 post-baseline value are included. LOCF was used.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Mean Clinical Global Impression Scale - Improvement (CGI-I) Score at Week 8 | 2.54 scores on a scale | Standard Error 0.087 |
| Vortioxetine 5 mg | Mean Clinical Global Impression Scale - Improvement (CGI-I) Score at Week 8 | 2.37 scores on a scale | Standard Error 0.089 |
| Vortioxetine 10 mg | Mean Clinical Global Impression Scale - Improvement (CGI-I) Score at Week 8 | 2.27 scores on a scale | Standard Error 0.088 |
| Vortioxetine 20 mg | Mean Clinical Global Impression Scale - Improvement (CGI-I) Score at Week 8 | 2.36 scores on a scale | Standard Error 0.087 |
Secondary
Percentage of Participants in MADRS Remission at Week 8
Remission is defined as a participant with a Montgomery Åsberg Depression Rating Scale (MADRS) total score ≤10. The MADRS is a depression rating scale consisting of 10 items, each rated 0 to 6. The 10 items represent the core symptoms of depressive illness. The overall score ranges from 0 (symptoms absent) to 60 (severe depression). Decrease in the total score or on individual items indicates improvement.
Time frame: Week 8
Population: Full analysis set, only participants with Baseline and at least 1 post-baseline value are included. LOCF was used.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo | Percentage of Participants in MADRS Remission at Week 8 | 26.7 percentage of participants |
| Vortioxetine 5 mg | Percentage of Participants in MADRS Remission at Week 8 | 24.6 percentage of participants |
| Vortioxetine 10 mg | Percentage of Participants in MADRS Remission at Week 8 | 29.3 percentage of participants |
| Vortioxetine 20 mg | Percentage of Participants in MADRS Remission at Week 8 | 30.9 percentage of participants |
Secondary
Percentage of Participants With a MADRS Response at Week 8
Response is defined as a participant with a ≥50% decrease in Montgomery Åsberg Depression Rating Scale (MADRS) total score from Baseline. The MADRS is a depression rating scale consisting of 10 items, each rated 0 to 6. The 10 items represent the core symptoms of depressive illness. The overall score ranges from 0 (symptoms absent) to 60 (severe depression). Decrease in the total score or on individual items indicates improvement.
Time frame: Baseline and Week 8
Population: Full analysis set, only participants with Baseline and at least 1 post-baseline value are included. LOCF was used.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo | Percentage of Participants With a MADRS Response at Week 8 | 39.3 percentage of participants |
| Vortioxetine 5 mg | Percentage of Participants With a MADRS Response at Week 8 | 49.3 percentage of participants |
| Vortioxetine 10 mg | Percentage of Participants With a MADRS Response at Week 8 | 54.4 percentage of participants |
| Vortioxetine 20 mg | Percentage of Participants With a MADRS Response at Week 8 | 51.0 percentage of participants |