Major Depressive Disorder
Conditions
Keywords
Major depressive disorder, Placebo-controlled, Active reference, Multicenter study, Randomised study, Acute treatment
Brief summary
The purpose of the study is to evaluate the efficacy, tolerability and the safety of two fixed doses of vortioxetine in the treatment of major depressive disorder.
Interventions
DRUGPlacebo
capsules, daily, orally
encapsulated tablets, daily, orally
DRUGDuloxetine
encapsulated 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 75 Years
Healthy volunteers
No
Inclusion criteria
* The patient has recurrent MDD as the primary diagnosis according to DSM-IV-TR™ criteria (classification code 296.3x) * The patient has a MADRS total score \>=26 * The patient has a CGI-S score \>=4 * The patient has had the current episode of MDE for \>3 months
Exclusion criteria
* Any current anxiety psychiatric disorder as defined in the 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 alcohol or other substance abuse or dependence (excluding nicotine or caffeine) as defined in the DSM-IV TR * Use of any psychoactive medication 2 weeks prior to screening and during the study * The patient 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 Other protocol-defined inclusion and
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in MADRS Total Score After 8 Weeks of Treatment. | Baseline and Week 8 | 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 |
|---|---|---|
| Proportion of Responders at Week 8 (Response Defined as a >=50% Decrease in the MADRS Total Score From Baseline) | Week 8 | — |
| Change in Clinical Status Using CGI-I Score at Week 8 | Week 8 | 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. |
| Change From Baseline in MADRS Total Score After 8 Weeks of Treatment in Patients With Baseline HAM-A Total Score ≥20 | Baseline and Week 8 | — |
| Proportion of Remitters at Week 8 (Remission Defined as a MADRS Total Score <=10) | Week 8 | — |
| Change From Baseline in ASEX Total Score After 8 Weeks of Treatment | Baseline and Week 8 | The Arizona Sexual Experience Scale (ASEX) is a 5-item, patient self-rated scale that evaluates a patient's recent sexual experience. Patients are asked to assess their own experience over the last week (for example, How strong is your sex drive?, Are your orgasms satisfying?) and respond on a 6-point scale for each item. The ASEX is used to identify individuals with sexual dysfunction. Possible total score ranges from 5 to 30, with the higher score indicating more patient sexual dysfunction. A negative change indicates a lower sexual dysfunction. |
| Potential Discontinuation Symptoms After Abrupt Discontinuation of Treatment With Vortioxetine | Change from Week 8 in DESS total score analyzed at Week 10 | The Discontinuation-Emergent Signs and Symptoms Scale (DESS) was designed to evaluate possible effects of discontinuation of antidepressant therapy. It is a clinician-rated instrument that queries for signs and symptoms on a 43-item checklist (for example, agitation, insomnia, fatigue, and dizziness) to assess whether the item (event) is discontinuation-emergent. A new or worsened event reported after discontinuation of therapy scores 1 point on the checklist, and the DESS total score is the sum of all positive scores on the checklist. A higher score indicates more symptoms. |
| Change From Baseline in SDS Total Score After 8 Weeks of Treatment | Baseline and Week 8 | The Sheehan Disability Scale (SDS) comprises self-rated items designed to measure impairment. The patient rates the extent to which his or her (1) work, (2) social life or leisure activities and (3) home life or family responsibilities are impaired on a 10-point visual analogue scales, on which 0 = normal functioning and 10 = severe functional impairment. The three items may be summed into a single dimensional measure of global functional impairment that ranges from 0 (unimpaired) to 30 (highly impaired). The higher the score, the more severe. |
Participant flow
Recruitment details
Patients were selected from psychiatric settings (private practices), outpatient clinics, and inpatient hospitals.
Pre-assignment details
At the Baseline Visit, patients who fulfilled the selection criteria were assigned to treatment with either placebo, vortioxetine 15 or 20 mg/day, or duloxetine 60 mg/day in a 1:1:1:1 ratio.
Participants by arm
| Arm | Count |
|---|---|
| Placebo capsules, daily, orally | 158 |
| Vortioxetine 15 mg encapsulated tablets, daily, orally | 151 |
| Vortioxetine 20 mg encapsulated tablets, daily, orally | 151 |
| Duloxetine 60 mg encapsulated capsules, daily, orally | 147 |
| Total | 607 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| Overall Study | Administrative or other reason | 0 | 5 | 3 | 2 |
| Overall Study | Adverse Event | 7 | 10 | 17 | 7 |
| Overall Study | Lack of Efficacy | 6 | 8 | 2 | 1 |
| Overall Study | Lost to Follow-up | 1 | 1 | 0 | 2 |
| Overall Study | Non-compliance | 0 | 1 | 0 | 1 |
| Overall Study | Protocol Violation | 5 | 3 | 2 | 1 |
| Overall Study | Withdrawal of consent | 6 | 6 | 2 | 2 |
Baseline characteristics
| Characteristic | Vortioxetine 15 mg | Vortioxetine 20 mg | Placebo | Duloxetine 60 mg | Total |
|---|---|---|---|---|---|
| Age, Continuous | 47.0 years STANDARD_DEVIATION 14.6 | 46.2 years STANDARD_DEVIATION 13.4 | 48.1 years STANDARD_DEVIATION 13.1 | 45.6 years STANDARD_DEVIATION 13.6 | 46.7 years STANDARD_DEVIATION 13.7 |
| CGI-S baseline severity score | 4.9 units on a scale STANDARD_DEVIATION 0.6 | 4.8 units on a scale STANDARD_DEVIATION 0.7 | 4.9 units on a scale STANDARD_DEVIATION 0.7 | 4.8 units on a scale STANDARD_DEVIATION 0.7 | 4.8 units on a scale STANDARD_DEVIATION 0.7 |
| HAM-A baseline total score | 21.3 units on a scale STANDARD_DEVIATION 6.8 | 20.4 units on a scale STANDARD_DEVIATION 6.9 | 20.8 units on a scale STANDARD_DEVIATION 6.6 | 20.5 units on a scale STANDARD_DEVIATION 6.7 | 20.8 units on a scale STANDARD_DEVIATION 6.7 |
| MADRS baseline total score | 31.8 units on a scale STANDARD_DEVIATION 3.4 | 31.2 units on a scale STANDARD_DEVIATION 3.4 | 31.5 units on a scale STANDARD_DEVIATION 3.6 | 31.2 units on a scale STANDARD_DEVIATION 3.5 | 31.4 units on a scale STANDARD_DEVIATION 3.5 |
| SDS total baseline score | 20.6 units on a scale STANDARD_DEVIATION 5.3 | 20.7 units on a scale STANDARD_DEVIATION 4.8 | 19.8 units on a scale STANDARD_DEVIATION 6 | 20.5 units on a scale STANDARD_DEVIATION 4.4 | 20.4 units on a scale STANDARD_DEVIATION 5.2 |
| Sex: Female, Male Female | 97 Participants | 91 Participants | 110 Participants | 102 Participants | 400 Participants |
| Sex: Female, Male Male | 54 Participants | 60 Participants | 48 Participants | 45 Participants | 207 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 | 44 / 158 | 61 / 151 | 70 / 151 | 67 / 147 |
| serious Total, serious adverse events | 0 / 158 | 0 / 151 | 2 / 151 | 3 / 147 |
Outcome results
Primary
Change From Baseline in MADRS Total Score After 8 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 8
Population: Full-analysis set (FAS), mixed model for repeated measurements (MMRM)
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Change From Baseline in MADRS Total Score After 8 Weeks of Treatment. | -11.70 units on a scale | Standard Error 0.76 |
| Vortioxetine 15 mg | Change From Baseline in MADRS Total Score After 8 Weeks of Treatment. | -17.23 units on a scale | Standard Error 0.79 |
| Vortioxetine 20 mg | Change From Baseline in MADRS Total Score After 8 Weeks of Treatment. | -18.79 units on a scale | Standard Error 0.78 |
| Duloxetine 60 mg | Change From Baseline in MADRS Total Score After 8 Weeks of Treatment. | -21.15 units on a scale | Standard Error 0.77 |
Comparison: As soon as an endpoint was non-significant at the 0.025 level of significance, the testing procedure was stopped for all subsequent endpoints.p-value: <0.000195% CI: [-7.66, -3.4]MMRM
Comparison: As soon as an endpoint was non-significant at the 0.025 level of significance, the testing procedure was stopped for all subsequent endpoints.p-value: <0.000195% CI: [-9.21, -4.97]MMRM
p-value: <0.000195% CI: [-11.55, -7.35]MMRM
Secondary
Change From Baseline in ASEX Total Score After 8 Weeks of Treatment
The Arizona Sexual Experience Scale (ASEX) is a 5-item, patient self-rated scale that evaluates a patient's recent sexual experience. Patients are asked to assess their own experience over the last week (for example, How strong is your sex drive?, Are your orgasms satisfying?) and respond on a 6-point scale for each item. The ASEX is used to identify individuals with sexual dysfunction. Possible total score ranges from 5 to 30, with the higher score indicating more patient sexual dysfunction. A negative change indicates a lower sexual dysfunction.
Time frame: Baseline and Week 8
Population: FAS, MMRM
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Change From Baseline in ASEX Total Score After 8 Weeks of Treatment | 0.28 units on a scale | Standard Error 0.42 |
| Vortioxetine 15 mg | Change From Baseline in ASEX Total Score After 8 Weeks of Treatment | -0.39 units on a scale | Standard Error 0.43 |
| Vortioxetine 20 mg | Change From Baseline in ASEX Total Score After 8 Weeks of Treatment | -0.20 units on a scale | Standard Error 0.43 |
| Duloxetine 60 mg | Change From Baseline in ASEX Total Score After 8 Weeks of Treatment | -1.25 units on a scale | Standard Error 0.42 |
p-value: 0.252495% CI: [-1.83, 0.48]MMRM
p-value: 0.418695% CI: [-1.64, 0.68]MMRM
Secondary
Change From Baseline in MADRS Total Score After 8 Weeks of Treatment in Patients With Baseline HAM-A Total Score ≥20
Time frame: Baseline and Week 8
Population: FAS, MMRM
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Change From Baseline in MADRS Total Score After 8 Weeks of Treatment in Patients With Baseline HAM-A Total Score ≥20 | -12.20 units on a scale | Standard Error 1.09 |
| Vortioxetine 15 mg | Change From Baseline in MADRS Total Score After 8 Weeks of Treatment in Patients With Baseline HAM-A Total Score ≥20 | -17.44 units on a scale | Standard Error 1.08 |
| Vortioxetine 20 mg | Change From Baseline in MADRS Total Score After 8 Weeks of Treatment in Patients With Baseline HAM-A Total Score ≥20 | -18.62 units on a scale | Standard Error 1.15 |
| Duloxetine 60 mg | Change From Baseline in MADRS Total Score After 8 Weeks of Treatment in Patients With Baseline HAM-A Total Score ≥20 | -20.91 units on a scale | Standard Error 1.1 |
Comparison: As soon as an endpoint was non-significant at the 0.025 level of significance, the testing procedure was stopped for all subsequent endpoints.p-value: 0.000795% CI: [-8.25, -2.22]MMRM
Comparison: As soon as an endpoint was non-significant at the 0.025 level of significance, the testing procedure was stopped for all subsequent endpoints.p-value: <0.000195% CI: [-9.53, -3.31]MMRM
p-value: <0.000195% CI: [-11.73, -5.69]MMRM
Secondary
Change From Baseline in SDS Total Score After 8 Weeks of Treatment
The Sheehan Disability Scale (SDS) comprises self-rated items designed to measure impairment. The patient rates the extent to which his or her (1) work, (2) social life or leisure activities and (3) home life or family responsibilities are impaired on a 10-point visual analogue scales, on which 0 = normal functioning and 10 = severe functional impairment. The three items may be summed into a single dimensional measure of global functional impairment that ranges from 0 (unimpaired) to 30 (highly impaired). The higher the score, the more severe.
Time frame: Baseline and Week 8
Population: FAS, MMRM
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Change From Baseline in SDS Total Score After 8 Weeks of Treatment | -4.46 units on a scale | Standard Error 0.82 |
| Vortioxetine 15 mg | Change From Baseline in SDS Total Score After 8 Weeks of Treatment | -7.70 units on a scale | Standard Error 0.89 |
| Vortioxetine 20 mg | Change From Baseline in SDS Total Score After 8 Weeks of Treatment | -8.38 units on a scale | Standard Error 0.85 |
| Duloxetine 60 mg | Change From Baseline in SDS Total Score After 8 Weeks of Treatment | -11.39 units on a scale | Standard Error 0.85 |
Comparison: As soon as an endpoint was non-significant at the 0.025 level of significance, the testing procedure was stopped for all subsequent endpoints.p-value: 0.005495% CI: [-5.51, -0.97]MMRM
Comparison: As soon as an endpoint was non-significant at the 0.025 level of significance, the testing procedure was stopped for all subsequent endpoints.p-value: 0.000595% CI: [-6.11, -1.73]MMRM
p-value: <0.000195% CI: [-9.16, -4.7]MMRM
Secondary
Change in Clinical Status Using CGI-I Score at Week 8
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 8
Population: FAS, MMRM
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Change in Clinical Status Using CGI-I Score at Week 8 | 2.86 units on a scale | Standard Error 0.09 |
| Vortioxetine 15 mg | Change in Clinical Status Using CGI-I Score at Week 8 | 2.18 units on a scale | Standard Error 0.09 |
| Vortioxetine 20 mg | Change in Clinical Status Using CGI-I Score at Week 8 | 1.92 units on a scale | Standard Error 0.09 |
| Duloxetine 60 mg | Change in Clinical Status Using CGI-I Score at Week 8 | 1.75 units on a scale | Standard Error 0.09 |
Comparison: As soon as an endpoint was non-significant at the 0.025 level of significance, the testing procedure was stopped for all subsequent endpoints.p-value: <0.000195% CI: [-0.94, -0.44]MMRM
Comparison: As soon as an endpoint was non-significant at the 0.025 level of significance, the testing procedure was stopped for all subsequent endpoints.p-value: <0.000195% CI: [-1.2, -0.7]MMRM
p-value: <0.000195% CI: [-1.36, -0.87]MMRM
Secondary
Potential Discontinuation Symptoms After Abrupt Discontinuation of Treatment With Vortioxetine
The Discontinuation-Emergent Signs and Symptoms Scale (DESS) was designed to evaluate possible effects of discontinuation of antidepressant therapy. It is a clinician-rated instrument that queries for signs and symptoms on a 43-item checklist (for example, agitation, insomnia, fatigue, and dizziness) to assess whether the item (event) is discontinuation-emergent. A new or worsened event reported after discontinuation of therapy scores 1 point on the checklist, and the DESS total score is the sum of all positive scores on the checklist. A higher score indicates more symptoms.
Time frame: Change from Week 8 in DESS total score analyzed at Week 10
Population: All Patients Completed Set (APCS), OC, Analysis of Covariance (ANCOVA)
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Potential Discontinuation Symptoms After Abrupt Discontinuation of Treatment With Vortioxetine | 0.15 units on a scale | Standard Error 0.3 |
| Vortioxetine 15 mg | Potential Discontinuation Symptoms After Abrupt Discontinuation of Treatment With Vortioxetine | 0.01 units on a scale | Standard Error 0.31 |
| Vortioxetine 20 mg | Potential Discontinuation Symptoms After Abrupt Discontinuation of Treatment With Vortioxetine | 0.72 units on a scale | Standard Error 0.31 |
| Duloxetine 60 mg | Potential Discontinuation Symptoms After Abrupt Discontinuation of Treatment With Vortioxetine | 2.28 units on a scale | Standard Error 0.3 |
p-value: 0.737295% CI: [-0.95, 0.67]ANCOVA
p-value: 0.16995% CI: [-0.24, 1.37]ANCOVA
Secondary
Proportion of Remitters at Week 8 (Remission Defined as a MADRS Total Score <=10)
Time frame: Week 8
Population: FAS, LOCF, Logistic Regression
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo | Proportion of Remitters at Week 8 (Remission Defined as a MADRS Total Score <=10) | 19 percentage of patients |
| Vortioxetine 15 mg | Proportion of Remitters at Week 8 (Remission Defined as a MADRS Total Score <=10) | 35 percentage of patients |
| Vortioxetine 20 mg | Proportion of Remitters at Week 8 (Remission Defined as a MADRS Total Score <=10) | 38 percentage of patients |
| Duloxetine 60 mg | Proportion of Remitters at Week 8 (Remission Defined as a MADRS Total Score <=10) | 54 percentage of patients |
Comparison: As soon as an endpoint was non-significant at the 0.025 level of significance, the testing procedure was stopped for all subsequent endpoints.p-value: 0.001695% CI: [1.37, 3.91]Adjusted Odds Ratio
Comparison: As soon as an endpoint was non-significant at the 0.025 level of significance, the testing procedure was stopped for all subsequent endpoints.p-value: 0.000295% CI: [1.58, 4.44]Adjusted Odds Ratio
p-value: <0.000195% CI: [2.99, 8.37]Adjusted for Odds Ratio
Secondary
Proportion of Responders at Week 8 (Response Defined as a >=50% Decrease in the MADRS Total Score From Baseline)
Time frame: Week 8
Population: FAS, last observation carried forward (LOCF), Logistic Regression
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo | Proportion of Responders at Week 8 (Response Defined as a >=50% Decrease in the MADRS Total Score From Baseline) | 32 percentage of patients |
| Vortioxetine 15 mg | Proportion of Responders at Week 8 (Response Defined as a >=50% Decrease in the MADRS Total Score From Baseline) | 57 percentage of patients |
| Vortioxetine 20 mg | Proportion of Responders at Week 8 (Response Defined as a >=50% Decrease in the MADRS Total Score From Baseline) | 62 percentage of patients |
| Duloxetine 60 mg | Proportion of Responders at Week 8 (Response Defined as a >=50% Decrease in the MADRS Total Score From Baseline) | 74 percentage of patients |
Comparison: As soon as an endpoint was non-significant at the 0.025 level of significance, the testing procedure was stopped for all subsequent endpoints.p-value: <0.000195% CI: [1.76, 4.47]Adjusted Odds Ratio
Comparison: As soon as an endpoint was non-significant at the 0.025 level of significance, the testing procedure was stopped for all subsequent endpoints.p-value: <0.000195% CI: [2.1, 5.36]Adjusted Odds Ratio
p-value: <0.000195% CI: [3.61, 9.78]Adjusted Odds Ratio