Major Depressive Disorder
Conditions
Keywords
Major depressive disorder, Placebo-controlled, Active reference, Multicenter study, Randomised study, Acute treatment
Brief summary
The purpose of this Venlafaxine-referenced study is to evaluate the efficacy, safety and tolerability of two fixed doses of Vortioxetine in the acute treatment of Major Depressive Disorder (MDD).
Interventions
DRUGPlacebo
capsules, daily, orally
encapsulated tablets, daily, orally
DRUGVenlafaxine XL
capsules, daily, orally
Sponsors
H. Lundbeck A/S
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to 65 Years
Healthy volunteers
No
Inclusion criteria
* MDE as primary diagnosis according to DSM-IV-TR criteria (classification code 296.xx) * Current MDE duration of at least 3 months and less than 12 months * The patient has a MADRS total score \>=30
Exclusion criteria
* Any current psychiatric disorder other than MDD as defined in the DSM-IV TR * Any substance disorder within the previous 6 months * Female patients of childbearing potential who are not using effective contraception * Use of any psychoactive medication 2 weeks prior to screening and during the study Other protocol-defined inclusion and
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in MADRS Total Score After 6 Weeks of Treatment | Baseline and Week 6 | The Montgomery Åsberg Depression Rating Scale (MADRS) is a depression rating scale consisting of 10 items, each rated 0 (no symptom) to 6 (severe symptom). The 10 items represent the core symptoms of depressive illness. The rating should be based on a clinical interview with the patient, moving from broadly phrased questions about symptoms to more detailed ones, which allow a precise rating of severity, covering the last 7 days. Total score from 0 to 60. The higher the score, the more severe. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in HAM-D 24 Total Score After 6 Weeks of Treatment | Baseline and Week 6 | The 24-item Hamilton Depression Rating Scale (HAM-D) is based on the 21-item HAM-D plus an additional 3 items (helplessness, hopelessness, and worthlessness). The observer makes his/her assessment on the basis of a specific statement, content, tone, facial expression, and gestures of the patient during the interview, and scores each item from 0 to 2 or 0 to 4. Total score from 0 to 76. The higher the score, the more severe. |
| Change From Baseline in HAM-A Total Score After 6 Weeks of Treatment | Baseline and Week 6 | The Hamilton Anxiety Rating Scale (HAM-A) consists of 14 items that assess anxious mood, tension, fear, insomnia, intellectual (cognitive) symptoms, depressed mood, behaviour at interview, somatic (sensory), cardiovascular, respiratory, gastrointestinal, genitourinary, autonomic, and somatic (muscular) symptoms. Each symptom is rated from 0 (absent) to 4 (maximum severity). Total score from 0 to 56. The higher the score, the more severe. |
| Change From Baseline in CGI-S Score After 6 Weeks of Treatment | Baseline and Week 6 | The Clinical Global Impression - Severity of Illness (CGI-S) is a 7-point scale rated from 1 (normal, not at all ill) to 7 (among the most extremely ill patients). The investigator should use his/her total clinical experience with this patient population to judge how mentally ill the patient is at the time of rating. |
| Change From Baseline in MADRS Total Score After 1 Week of Treatment | Baseline and Week 1 | — |
| Proportion of Responders at Week 6 (Response Defined as a >=50% Decrease in the MADRS Total Score From Baseline) | Week 6 | — |
| Proportion of Remitters at Week 6 (Remission is Defined as a MADRS Total Score <=10) | Week 6 | — |
| Change in Clinical Status Using CGI-I Score at Week 6 | Week 6 | The Clinical Global Impression - Global Improvement (CGI-I) is a 7-point scale rated from 1 (very much improved) to 7 (very much worse). The investigator rated the patient's overall improvement relative to baseline, whether or not, in the opinion of the investigator, this was entirely due to the drug treatment. |
Participant flow
Recruitment details
Outpatients with Major Depressive Episode (MDE) were recruited from psychiatric settings.
Pre-assignment details
Eligible patients were randomised equally (1:1:1:1) to one of the 4 treatment arms for a 6-week double-blind treatment period. The doses of Vortioxetine were 5 mg/day or 10 mg/day for 6 weeks. The dose of venlafaxine was 75 mg/day for 4 days, 150 mg/day for the following 3 days, and 225 mg/day for the remainder of the treatment period.
Participants by arm
| Arm | Count |
|---|---|
| Placebo capsules, daily, orally | 105 |
| Vortioxetine 5 mg encapsulated tablets, daily, orally | 108 |
| Vortioxetine 10 mg encapsulated tablets, daily, orally | 100 |
| Venlafaxine 225 mg capsules, daily, orally | 113 |
| Total | 426 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| Overall Study | Administrative or other reasons | 3 | 0 | 1 | 0 |
| Overall Study | Adverse Event | 4 | 3 | 7 | 16 |
| Overall Study | Lack of Efficacy | 6 | 6 | 3 | 2 |
| Overall Study | Lost to Follow-up | 1 | 0 | 1 | 0 |
| Overall Study | Non-compliance | 0 | 0 | 0 | 1 |
| Overall Study | Protocol Violation | 0 | 1 | 2 | 0 |
| Overall Study | Withdrawal of consent | 4 | 0 | 4 | 1 |
Baseline characteristics
| Characteristic | Placebo | Vortioxetine 5 mg | Vortioxetine 10 mg | Venlafaxine 225 mg | Total |
|---|---|---|---|---|---|
| Age, Continuous | 42.0 years STANDARD_DEVIATION 10.9 | 43.8 years STANDARD_DEVIATION 11.6 | 42.3 years STANDARD_DEVIATION 13.1 | 45.0 years STANDARD_DEVIATION 10.3 | 43.3 years STANDARD_DEVIATION 11.5 |
| Baseline 24-item HAM-D Total Score | 29.7 units on a scale STANDARD_DEVIATION 5 | 29.9 units on a scale STANDARD_DEVIATION 5.4 | 29.3 units on a scale STANDARD_DEVIATION 5.6 | 29.4 units on a scale STANDARD_DEVIATION 5 | 29.6 units on a scale STANDARD_DEVIATION 5.2 |
| CGI-S: Baseline Severity Score | 5.1 units on a scale STANDARD_DEVIATION 0.7 | 5.2 units on a scale STANDARD_DEVIATION 0.7 | 5.1 units on a scale STANDARD_DEVIATION 0.7 | 5.2 units on a scale STANDARD_DEVIATION 0.7 | 5.2 units on a scale STANDARD_DEVIATION 0.7 |
| HAM-A: Baseline Total Score | 22.9 units on a scale STANDARD_DEVIATION 5.9 | 21.7 units on a scale STANDARD_DEVIATION 6.2 | 22.3 units on a scale STANDARD_DEVIATION 5.6 | 22.0 units on a scale STANDARD_DEVIATION 5.5 | 22.2 units on a scale STANDARD_DEVIATION 5.8 |
| MADRS: Baseline Total Score | 33.9 units on a scale STANDARD_DEVIATION 2.7 | 34.1 units on a scale STANDARD_DEVIATION 2.6 | 34.0 units on a scale STANDARD_DEVIATION 2.8 | 34.2 units on a scale STANDARD_DEVIATION 3.1 | 34.0 units on a scale STANDARD_DEVIATION 2.8 |
| Sex: Female, Male Female | 69 Participants | 70 Participants | 66 Participants | 62 Participants | 267 Participants |
| Sex: Female, Male Male | 36 Participants | 38 Participants | 34 Participants | 51 Participants | 159 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 | 53 / 105 | 63 / 108 | 66 / 100 | 78 / 113 |
| serious Total, serious adverse events | 0 / 105 | 0 / 108 | 2 / 100 | 1 / 113 |
Outcome results
Primary
Change From Baseline in MADRS Total Score After 6 Weeks of Treatment
The Montgomery Åsberg Depression Rating Scale (MADRS) is a depression rating scale consisting of 10 items, each rated 0 (no symptom) to 6 (severe symptom). The 10 items represent the core symptoms of depressive illness. The rating should be based on a clinical interview with the patient, moving from broadly phrased questions about symptoms to more detailed ones, which allow a precise rating of severity, covering the last 7 days. Total score from 0 to 60. The higher the score, the more severe.
Time frame: Baseline and Week 6
Population: Full-analysis set (FAS) - all patients in the all-patients-treated set (APTS) who had at least one valid baseline and one valid post-baseline assessment of the MADRS total score; Last Observation Carried Forward (LOCF)
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Change From Baseline in MADRS Total Score After 6 Weeks of Treatment | -14.50 units on a scale | Standard Error 1.03 |
| Vortioxetine 5 mg | Change From Baseline in MADRS Total Score After 6 Weeks of Treatment | -20.40 units on a scale | Standard Error 1.01 |
| Vortioxetine 10 mg | Change From Baseline in MADRS Total Score After 6 Weeks of Treatment | -20.20 units on a scale | Standard Error 1.04 |
| Venlafaxine 225 mg | Change From Baseline in MADRS Total Score After 6 Weeks of Treatment | -20.92 units on a scale | Standard Error 0.99 |
Comparison: The statistical model was an analysis of covariance (ANCOVA) of the change from baseline in MADRS total score (FAS, LOCF) with treatment and centre as fixed factors and the baseline MADRS score as a covariate.~Null hypothesis: No difference between 10 mg Vortioxetine and placebo at Week 6.~With 96 patients in each treatment arm and a standard deviation of 9 points, the power to detect a true effect of 3.7 points on the MADRS total score at Week 6 will be 80%.p-value: <0.000195% CI: [-8.49, -2.91]ANCOVA
Comparison: The statistical model was ANCOVA of the change from baseline in MADRS total score (FAS, LOCF) with treatment and centre as fixed factors and the baseline MADRS score as a covariate.~Null hypothesis: No difference between 5 mg Vortioxetine and placebo at Week 6.p-value: <0.000195% CI: [-8.64, -3.17]ANCOVA
p-value: <0.000195% CI: [-9.13, -3.72]ANCOVA
Secondary
Change From Baseline in CGI-S Score After 6 Weeks of Treatment
The Clinical Global Impression - Severity of Illness (CGI-S) is a 7-point scale rated from 1 (normal, not at all ill) to 7 (among the most extremely ill patients). The investigator should use his/her total clinical experience with this patient population to judge how mentally ill the patient is at the time of rating.
Time frame: Baseline and Week 6
Population: FAS, LOCF
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Change From Baseline in CGI-S Score After 6 Weeks of Treatment | -1.55 units on a scale | Standard Error 0.14 |
| Vortioxetine 5 mg | Change From Baseline in CGI-S Score After 6 Weeks of Treatment | -2.45 units on a scale | Standard Error 0.14 |
| Vortioxetine 10 mg | Change From Baseline in CGI-S Score After 6 Weeks of Treatment | -2.51 units on a scale | Standard Error 0.15 |
| Venlafaxine 225 mg | Change From Baseline in CGI-S Score After 6 Weeks of Treatment | -2.58 units on a scale | Standard Error 0.14 |
p-value: <0.000195% CI: [-1.28, -0.52]ANCOVA
p-value: <0.000195% CI: [-1.34, -0.56]ANCOVA
Secondary
Change From Baseline in HAM-A Total Score After 6 Weeks of Treatment
The Hamilton Anxiety Rating Scale (HAM-A) consists of 14 items that assess anxious mood, tension, fear, insomnia, intellectual (cognitive) symptoms, depressed mood, behaviour at interview, somatic (sensory), cardiovascular, respiratory, gastrointestinal, genitourinary, autonomic, and somatic (muscular) symptoms. Each symptom is rated from 0 (absent) to 4 (maximum severity). Total score from 0 to 56. The higher the score, the more severe.
Time frame: Baseline and Week 6
Population: FAS, LOCF
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Change From Baseline in HAM-A Total Score After 6 Weeks of Treatment | -8.41 units on a scale | Standard Error 0.74 |
| Vortioxetine 5 mg | Change From Baseline in HAM-A Total Score After 6 Weeks of Treatment | -11.71 units on a scale | Standard Error 0.75 |
| Vortioxetine 10 mg | Change From Baseline in HAM-A Total Score After 6 Weeks of Treatment | -11.41 units on a scale | Standard Error 0.77 |
| Venlafaxine 225 mg | Change From Baseline in HAM-A Total Score After 6 Weeks of Treatment | -11.29 units on a scale | Standard Error 0.73 |
p-value: 0.001195% CI: [-5.27, -1.33]ANCOVA
p-value: 0.003495% CI: [-5.01, -1]ANCOVA
Secondary
Change From Baseline in HAM-D 24 Total Score After 6 Weeks of Treatment
The 24-item Hamilton Depression Rating Scale (HAM-D) is based on the 21-item HAM-D plus an additional 3 items (helplessness, hopelessness, and worthlessness). The observer makes his/her assessment on the basis of a specific statement, content, tone, facial expression, and gestures of the patient during the interview, and scores each item from 0 to 2 or 0 to 4. Total score from 0 to 76. The higher the score, the more severe.
Time frame: Baseline and Week 6
Population: FAS, LOCF
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Change From Baseline in HAM-D 24 Total Score After 6 Weeks of Treatment | -12.23 units on a scale | Standard Error 0.9 |
| Vortioxetine 5 mg | Change From Baseline in HAM-D 24 Total Score After 6 Weeks of Treatment | -17.51 units on a scale | Standard Error 0.89 |
| Vortioxetine 10 mg | Change From Baseline in HAM-D 24 Total Score After 6 Weeks of Treatment | -17.57 units on a scale | Standard Error 0.92 |
| Venlafaxine 225 mg | Change From Baseline in HAM-D 24 Total Score After 6 Weeks of Treatment | -17.32 units on a scale | Standard Error 0.88 |
p-value: <0.000195% CI: [-7.69, -2.88]ANCOVA
p-value: <0.000195% CI: [-7.79, -2.88]ANCOVA
Secondary
Change From Baseline in MADRS Total Score After 1 Week of Treatment
Time frame: Baseline and Week 1
Population: FAS, LOCF. Please note that 1 patient in each Vortioxetine group did not have a valid MADRS assessment at Week 1, but were included in the analysis because they had a valid MADRS assessment after Week 1.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Change From Baseline in MADRS Total Score After 1 Week of Treatment | -5.04 units on a scale | Standard Error 0.5 |
| Vortioxetine 5 mg | Change From Baseline in MADRS Total Score After 1 Week of Treatment | -5.26 units on a scale | Standard Error 0.49 |
| Vortioxetine 10 mg | Change From Baseline in MADRS Total Score After 1 Week of Treatment | -5.86 units on a scale | Standard Error 0.51 |
| Venlafaxine 225 mg | Change From Baseline in MADRS Total Score After 1 Week of Treatment | -4.50 units on a scale | Standard Error 0.48 |
Comparison: The statistical model was ANCOVA of the change from baseline in MADRS total score (FAS, LOCF) with treatment and centre as fixed factors and the baseline MADRS score as a covariate.~Null hypothesis: No difference between 10 mg Vortioxetine and placebo at Week 1.p-value: 0.237795% CI: [-2.17, 0.54]ANCOVA
Comparison: The statistical model was ANCOVA of the change from baseline in MADRS total score (FAS, LOCF) with treatment and centre as fixed factors and the baseline MADRS score as a covariate.~Null hypothesis: No difference between 5 mg Vortioxetine and placebo at Week 1.p-value: 0.748995% CI: [-1.54, 1.11]ANCOVA
p-value: 0.414295% CI: [-0.77, 1.85]ANCOVA
Secondary
Change in Clinical Status Using CGI-I Score at Week 6
The Clinical Global Impression - Global Improvement (CGI-I) is a 7-point scale rated from 1 (very much improved) to 7 (very much worse). The investigator rated the patient's overall improvement relative to baseline, whether or not, in the opinion of the investigator, this was entirely due to the drug treatment.
Time frame: Week 6
Population: FAS, LOCF
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Change in Clinical Status Using CGI-I Score at Week 6 | 2.64 units on a scale | Standard Error 0.12 |
| Vortioxetine 5 mg | Change in Clinical Status Using CGI-I Score at Week 6 | 2.05 units on a scale | Standard Error 0.12 |
| Vortioxetine 10 mg | Change in Clinical Status Using CGI-I Score at Week 6 | 2.04 units on a scale | Standard Error 0.12 |
| Venlafaxine 225 mg | Change in Clinical Status Using CGI-I Score at Week 6 | 1.96 units on a scale | Standard Error 0.12 |
p-value: 0.000395% CI: [-0.9, -0.27]ANCOVA
p-value: 0.000395% CI: [-0.92, -0.27]ANCOVA
Secondary
Proportion of Remitters at Week 6 (Remission is Defined as a MADRS Total Score <=10)
Time frame: Week 6
Population: FAS, LOCF
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo | Proportion of Remitters at Week 6 (Remission is Defined as a MADRS Total Score <=10) | 26.7 percentage of patients |
| Vortioxetine 5 mg | Proportion of Remitters at Week 6 (Remission is Defined as a MADRS Total Score <=10) | 49.1 percentage of patients |
| Vortioxetine 10 mg | Proportion of Remitters at Week 6 (Remission is Defined as a MADRS Total Score <=10) | 49.0 percentage of patients |
| Venlafaxine 225 mg | Proportion of Remitters at Week 6 (Remission is Defined as a MADRS Total Score <=10) | 55.4 percentage of patients |
p-value: 0.00195% CI: [9.74, 35.07]Fisher Exact
p-value: 0.00195% CI: [9.39, 35.28]Fisher Exact
Secondary
Proportion of Responders at Week 6 (Response Defined as a >=50% Decrease in the MADRS Total Score From Baseline)
Time frame: Week 6
Population: FAS, LOCF
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo | Proportion of Responders at Week 6 (Response Defined as a >=50% Decrease in the MADRS Total Score From Baseline) | 44.8 percentage of patients |
| Vortioxetine 5 mg | Proportion of Responders at Week 6 (Response Defined as a >=50% Decrease in the MADRS Total Score From Baseline) | 66.7 percentage of patients |
| Vortioxetine 10 mg | Proportion of Responders at Week 6 (Response Defined as a >=50% Decrease in the MADRS Total Score From Baseline) | 68.0 percentage of patients |
| Venlafaxine 225 mg | Proportion of Responders at Week 6 (Response Defined as a >=50% Decrease in the MADRS Total Score From Baseline) | 72.3 percentage of patients |
p-value: 0.00295% CI: [8.89, 34.92]Fisher Exact
p-value: 0.00195% CI: [10.05, 36.43]Fisher Exact