Major Depressive Disorder
Conditions
Keywords
Depression, Multimodal antidepressant
Brief summary
The objective of the present study is to evaluate whether vortioxetine (10 or 20 mg/day) is at least as effective as agomelatine (25 to 50 mg/day) in patients with depressive symptoms that showed inadequate response to Serotonin Reuptake Inhibitors (SRI) antidepressants.
Interventions
encapsulated tablets, daily, orally
DRUGAgomelatine
encapsulated tablets, 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 is being treated with a serotonin reuptake inhibitor (SRI) antidepressant (monotherapy) that was prescribed to treat Major Depressive Episode (DSM-IV-TR criteria) * The response to the current SRI treatment is inadequate and patient agrees to discontinue the current SRI at the baseline * Montgomery Åsberg Depression Rating Scale (MADRS) total score ≥22 at the Screening Visit and Baseline * The patient, if a woman, must: agree not to try to become pregnant during the study, AND use adequate, highly effective contraception
Exclusion criteria
* The patient has any current Axis I disorders (DSM-IV criteria) other than Major Depressive Disorder (MDD), General Anxiety Disorder (GAD) and Social Anxiety Disorder (SAD) * The patient is at significant risk of suicide * The patient is currently receiving formal psychotherapy or other psychoactive medications Other protocol-defined inclusion and
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in MADRS Total Score at Week 8 | 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, thus, a negative change (or decrease) from baseline indicates a reduction (or improvement) in symptoms. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in HAM-A Total Score at Week 8 | Baseline and Week 8 | 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; higher score indicates greater anxiety, thus, a negative change (or decrease) from baseline indicates a reduction (or improvement) in symptoms. |
| Change From Baseline in HAM-A Total Score at Week 12 | Baseline and Week 12 | — |
| Change From Baseline in CGI-S Score at Week 8 | Baseline and Week 8 | 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. Higher score indicates that the subject is more ill, thus, a negative change (or decrease) from baseline indicates a reduction (or improvement) in symptoms. |
| Change From Baseline in CGI-S Score at Week 12 | Baseline and Week 12 | — |
| 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. Higher score = more affected. |
| Change in Clinical Status Using CGI-I Score at Week 12 | Week 12 | — |
| Change From Baseline in MADRS Total Score at Week 12 | Baseline and Week 12 | — |
| Proportion of Patients Who Respond at Week 12 (Response Defined as a >=50% Decrease in the MADRS Total Score From Baseline) | Baseline and Week 12 | — |
| Proportion of Patients Who Are in Remission at Week 8 (Remission is Defined as a MADRS Total Score <=10) | Week 8 | — |
| Proportion of Patients Who Are in Remission at Week 12 (Remission is Defined as a MADRS Total Score <=10) | Week 12 | — |
| Change From Baseline in SDS Total Score at Week 8 | 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, thus, a negative change (or decrease) from baseline indicates a reduction (or improvement) in symptoms. |
| Change From Baseline in SDS Total Score at Week 12 | Baseline and Week 12 | — |
| Proportion of Patients Who Respond at Week 8 (Response Defined as a >=50% Decrease in the MADRS Total Score From Baseline) | Baseline and Week 8 | — |
Participant flow
Recruitment details
In- or outpatients who had been treated with antidepressant selective serotonin reuptake inhibitor (SSRI) or selective noradrenaline reuptake inhibitor (SNRI) monotherapy that was prescribed to treat a single episode of Major Depressive Disorder (MDD) or recurrent MDD.
Pre-assignment details
The study will consist of a screening period of 4 to 10 days before the Baseline Visit, followed by a 12-week treatment period with vortioxetine or agomelatine. A safety follow-up will be done approximately 4 weeks after the Completion/Withdrawal Visit.
Participants by arm
| Arm | Count |
|---|---|
| Vortioxetine 10 mg or 20 mg encapsulated tablets, daily, orally | 253 |
| Agomelatine 25 mg or 50 mg encapsulated tablets, daily, orally | 242 |
| Total | 495 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Administrative or Other Reason(s) | 5 | 4 |
| Overall Study | Adverse Event | 15 | 23 |
| Overall Study | Lack of Efficacy | 11 | 17 |
| Overall Study | Lost to Follow-up | 1 | 0 |
| Overall Study | Non-compliance with study drug | 2 | 0 |
| Overall Study | Protocol Violation | 5 | 7 |
| Overall Study | Withdrawal of Consent | 14 | 12 |
Baseline characteristics
| Characteristic | Agomelatine 25 mg or 50 mg | Vortioxetine 10 mg or 20 mg | Total |
|---|---|---|---|
| Age, Continuous | 45.6 years STANDARD_DEVIATION 12.4 | 47.0 years STANDARD_DEVIATION 12.4 | 46.3 years STANDARD_DEVIATION 12.4 |
| CGI-S Baseline Severity Score | 4.4 units on a scale STANDARD_DEVIATION 0.6 | 4.4 units on a scale STANDARD_DEVIATION 0.6 | 4.4 units on a scale STANDARD_DEVIATION 0.6 |
| HAM-A: Baseline Total Score | 21.4 units on a scale STANDARD_DEVIATION 6.2 | 21.6 units on a scale STANDARD_DEVIATION 6.3 | 21.5 units on a scale STANDARD_DEVIATION 6.2 |
| MADRS: Baseline Total Score | 28.7 units on a scale STANDARD_DEVIATION 4 | 29.1 units on a scale STANDARD_DEVIATION 4.4 | 28.9 units on a scale STANDARD_DEVIATION 4.2 |
| SDS Total Baseline Score | 19.3 units on a scale STANDARD_DEVIATION 5.2 | 19.2 units on a scale STANDARD_DEVIATION 5.3 | 19.3 units on a scale STANDARD_DEVIATION 5.3 |
| Sex: Female, Male Female | 175 Participants | 195 Participants | 370 Participants |
| Sex: Female, Male Male | 67 Participants | 58 Participants | 125 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 82 / 253 | 77 / 242 |
| serious Total, serious adverse events | 3 / 253 | 4 / 242 |
Outcome results
Primary
Change From Baseline in MADRS Total Score at 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, thus, a negative change (or decrease) from baseline indicates a reduction (or improvement) in symptoms.
Time frame: Baseline and Week 8
Population: full-analysis set (FAS)
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Vortioxetine 10 mg or 20 mg | Change From Baseline in MADRS Total Score at Week 8 | -16.53 units on a scale | Standard Error 0.48 |
| Agomelatine 25 mg or 50 mg | Change From Baseline in MADRS Total Score at Week 8 | -14.38 units on a scale | Standard Error 0.51 |
p-value: 0.001895% CI: [-3.51, -0.81]Mixed Models Analysis
Secondary
Change From Baseline in CGI-S Score at Week 12
Time frame: Baseline and Week 12
Population: FAS
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Vortioxetine 10 mg or 20 mg | Change From Baseline in CGI-S Score at Week 12 | -2.20 units on a scale | Standard Error 0.07 |
| Agomelatine 25 mg or 50 mg | Change From Baseline in CGI-S Score at Week 12 | -1.93 units on a scale | Standard Error 0.07 |
p-value: 0.007595% CI: [-0.47, -0.07]Mixed Models Analysis
Secondary
Change From Baseline in CGI-S Score at Week 8
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. Higher score indicates that the subject is more ill, thus, a negative change (or decrease) from baseline indicates a reduction (or improvement) in symptoms.
Time frame: Baseline and Week 8
Population: FAS
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Vortioxetine 10 mg or 20 mg | Change From Baseline in CGI-S Score at Week 8 | -1.84 units on a scale | Standard Error 0.07 |
| Agomelatine 25 mg or 50 mg | Change From Baseline in CGI-S Score at Week 8 | -1.55 units on a scale | Standard Error 0.07 |
p-value: 0.002395% CI: [-0.48, -0.11]Mixed Models Analysis
Secondary
Change From Baseline in HAM-A Total Score at Week 12
Time frame: Baseline and Week 12
Population: FAS
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Vortioxetine 10 mg or 20 mg | Change From Baseline in HAM-A Total Score at Week 12 | -13.52 units on a scale | Standard Error 0.4 |
| Agomelatine 25 mg or 50 mg | Change From Baseline in HAM-A Total Score at Week 12 | -11.59 units on a scale | Standard Error 0.42 |
p-value: 0.000795% CI: [-3.04, -0.81]Mixed Models Analysis
Secondary
Change From Baseline in HAM-A Total Score at Week 8
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; higher score indicates greater anxiety, thus, a negative change (or decrease) from baseline indicates a reduction (or improvement) in symptoms.
Time frame: Baseline and Week 8
Population: FAS
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Vortioxetine 10 mg or 20 mg | Change From Baseline in HAM-A Total Score at Week 8 | -11.68 units on a scale | Standard Error 0.39 |
| Agomelatine 25 mg or 50 mg | Change From Baseline in HAM-A Total Score at Week 8 | -9.79 units on a scale | Standard Error 0.42 |
p-value: 0.000895% CI: [-2.98, -0.8]Mixed Models Analysis
Secondary
Change From Baseline in MADRS Total Score at Week 12
Time frame: Baseline and Week 12
Population: FAS
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Vortioxetine 10 mg or 20 mg | Change From Baseline in MADRS Total Score at Week 12 | -18.95 units on a scale | Standard Error 0.5 |
| Agomelatine 25 mg or 50 mg | Change From Baseline in MADRS Total Score at Week 12 | -16.92 units on a scale | Standard Error 0.53 |
p-value: 0.005495% CI: [-3.45, -0.6]Mixed Models Analysis
Secondary
Change From Baseline in SDS Total Score at Week 12
Time frame: Baseline and Week 12
Population: FAS
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Vortioxetine 10 mg or 20 mg | Change From Baseline in SDS Total Score at Week 12 | -10.99 units on a scale | Standard Error 0.55 |
| Agomelatine 25 mg or 50 mg | Change From Baseline in SDS Total Score at Week 12 | -9.24 units on a scale | Standard Error 0.58 |
p-value: 0.020995% CI: [-3.23, -0.27]Mixed Models Analysis
Secondary
Change From Baseline in SDS Total Score at 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, thus, a negative change (or decrease) from baseline indicates a reduction (or improvement) in symptoms.
Time frame: Baseline and Week 8
Population: FAS
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Vortioxetine 10 mg or 20 mg | Change From Baseline in SDS Total Score at Week 8 | -9.28 units on a scale | Standard Error 0.53 |
| Agomelatine 25 mg or 50 mg | Change From Baseline in SDS Total Score at Week 8 | -7.06 units on a scale | Standard Error 0.55 |
p-value: 0.002195% CI: [-3.63, -0.81]Mixed Models Analysis
Secondary
Change in Clinical Status Using CGI-I Score at Week 12
Time frame: Week 12
Population: FAS
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Vortioxetine 10 mg or 20 mg | Change in Clinical Status Using CGI-I Score at Week 12 | 1.74 units on a scale | Standard Error 0.06 |
| Agomelatine 25 mg or 50 mg | Change in Clinical Status Using CGI-I Score at Week 12 | 1.99 units on a scale | Standard Error 0.07 |
p-value: 0.005595% CI: [-0.42, -0.07]Mixed Models Analysis
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. Higher score = more affected.
Time frame: Week 8
Population: FAS
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Vortioxetine 10 mg or 20 mg | Change in Clinical Status Using CGI-I Score at Week 8 | 1.97 units on a scale | Standard Error 0.06 |
| Agomelatine 25 mg or 50 mg | Change in Clinical Status Using CGI-I Score at Week 8 | 2.22 units on a scale | Standard Error 0.07 |
p-value: 0.004895% CI: [-0.42, -0.08]Mixed Models Analysis
Secondary
Proportion of Patients Who Are in Remission at Week 12 (Remission is Defined as a MADRS Total Score <=10)
Time frame: Week 12
Population: FAS, LOCF
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Vortioxetine 10 mg or 20 mg | Proportion of Patients Who Are in Remission at Week 12 (Remission is Defined as a MADRS Total Score <=10) | 55.2 percentage of participants |
| Agomelatine 25 mg or 50 mg | Proportion of Patients Who Are in Remission at Week 12 (Remission is Defined as a MADRS Total Score <=10) | 39.4 percentage of participants |
p-value: 0.000295% CI: [1.39, 2.9]Regression, Logistic
Secondary
Proportion of Patients Who Are in Remission at Week 8 (Remission is Defined as a MADRS Total Score <=10)
Time frame: Week 8
Population: FAS, LOCF
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Vortioxetine 10 mg or 20 mg | Proportion of Patients Who Are in Remission at Week 8 (Remission is Defined as a MADRS Total Score <=10) | 40.5 percentage of participants |
| Agomelatine 25 mg or 50 mg | Proportion of Patients Who Are in Remission at Week 8 (Remission is Defined as a MADRS Total Score <=10) | 29.5 percentage of participants |
p-value: 0.005495% CI: [1.17, 2.52]Regression, Logistic
Secondary
Proportion of Patients Who Respond at Week 12 (Response Defined as a >=50% Decrease in the MADRS Total Score From Baseline)
Time frame: Baseline and Week 12
Population: FAS, LOCF
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Vortioxetine 10 mg or 20 mg | Proportion of Patients Who Respond at Week 12 (Response Defined as a >=50% Decrease in the MADRS Total Score From Baseline) | 69.8 percentage of participants |
| Agomelatine 25 mg or 50 mg | Proportion of Patients Who Respond at Week 12 (Response Defined as a >=50% Decrease in the MADRS Total Score From Baseline) | 56.0 percentage of participants |
p-value: 0.001495% CI: [1.26, 2.65]Regression, Logistic
Secondary
Proportion of Patients Who Respond at Week 8 (Response Defined as a >=50% Decrease in the MADRS Total Score From Baseline)
Time frame: Baseline and Week 8
Population: FAS, last observation carried forward (LOCF)
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Vortioxetine 10 mg or 20 mg | Proportion of Patients Who Respond at Week 8 (Response Defined as a >=50% Decrease in the MADRS Total Score From Baseline) | 61.5 percentage of participants |
| Agomelatine 25 mg or 50 mg | Proportion of Patients Who Respond at Week 8 (Response Defined as a >=50% Decrease in the MADRS Total Score From Baseline) | 47.3 percentage of participants |
p-value: 0.001295% CI: [1.26, 2.6]Regression, Logistic