Major Depressive Disorder
Conditions
Keywords
Relapse prevention, Antidepressants, Placebo-controlled, Double-blind, Multicentre study
Brief summary
This study will evaluate the efficacy of Vortioxetine in the prevention of relapse of major depressive episodes in patients who responded to open-label treatment with Vortioxetine.
Interventions
DRUGPlacebo
capsules, daily, orally
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
* Major Depressive Episode (MDE) as the primary diagnosis according to DSM-IV TR criteria * At least one other MDE before the current one * Moderate to severe depression
Exclusion criteria
* Any current psychiatric disorder other than Major Depressive Disorder (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 Randomisation Criteria: Patients in remission (MADRS total score \<=10) at both Week 10 and Week 12 Other protocol-defined inclusion and
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Relapse Within First 24 Weeks of the Double-blind Period Based on a MADRS Total Score >=22 or an Unsatisfactory Treatment Effect (Lack of Efficacy) as Judged by the Investigator | Within first 24 weeks of the double-blind period | 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 Double-blind Baseline in MADRS Total Score After 24 Weeks of Double-blind Treatment | Double-blind Baseline and Week 24 of the double-blind period | — |
| Change From Double-blind Baseline in HAM-D-17 Total Score After 24 Weeks of Double-blind Treatment | Double-blind Baseline and Week 24 of the double-blind period | The Hamilton Depression Scale - 17 items (HAM-D-17) measures depression severity. Items are rated on a scale from 0 (symptoms not present) to a maximum of 2 to 4 (symptom extremely severe) for a total score range of 0 to 52. The higher the score, the more severe. |
| Change From Double-blind Baseline in HAM-A Total Score After 24 Weeks of Double-blind Treatment | Double-blind Baseline and Week 24 of the double-blind period | 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. |
| Relapse During the Entire Double-blind Period Based on a MADRS Total Score >=22 or an Unsatisfactory Treatment Effect (Lack of Efficacy) as Judged by the Investigator | Within 64 weeks of the double-blind period | — |
| Proportion of Responders at Week 24 of the Double-blind Period (Response Defined as a >=50% Reduction in MADRS Total Score From Open-label Baseline) | Week 24 of the double-blind period (Counted From Open-label Baseline) | — |
| Proportion of Remitters at Week 24 of the Double-blind Period (Remission Defined as a MADRS Total Score <=10) | Week 24 of the double-blind period | — |
| Change From Double-blind Baseline in SDS Total Score at Week 24 of the Double-blind Period | Week 24 of the double-blind period (Counted From Double-blind Baseline) | 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. |
| Change From Double-blind Baseline in CGI-S Score After 24 Weeks of Double-blind Treatment | Double-blind Baseline and Week 24 of the double-blind period | 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. |
Participant flow
Recruitment details
Patients were in- and outpatients from psychiatric settings.
Pre-assignment details
The study consisted of two consecutive periods: a 12-week open-label treatment period with Vortioxetine and a double-blind, fixed-dose, placebo-controlled treatment period of at least 24 weeks.
Participants by arm
| Arm | Count |
|---|---|
| Open-label Period (APTS) | 639 |
| Placebo - Double-blind Period (FAS) Placebo : capsules, daily, orally | 192 |
| Vortioxetine: 5 or 10 mg - Double-blind Period (FAS) Vortioxetine (Lu AA21004) : encapsulated tablets, daily, orally | 204 |
| Total | 1,035 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Double-blind Period | Adverse Event | 5 | 16 |
| Double-blind Period | Lack of Efficacy | 52 | 28 |
| Double-blind Period | Lost to Follow-up | 0 | 2 |
| Double-blind Period | Non-compliance With Study Product | 3 | 4 |
| Double-blind Period | Other Reasons | 10 | 18 |
| Double-blind Period | Protocol Violation | 11 | 8 |
| Double-blind Period | Withdrawal of Consent | 7 | 3 |
| Open-label Period | Adverse Event | 0 | 49 |
| Open-label Period | Lack of Efficacy | 0 | 33 |
| Open-label Period | Other Reasons | 0 | 65 |
| Open-label Period to Double-blind Period | Adverse Event | 0 | 5 |
| Open-label Period to Double-blind Period | Lack of Efficacy | 0 | 24 |
| Open-label Period to Double-blind Period | Not Eligible | 0 | 49 |
| Open-label Period to Double-blind Period | Other Reasons | 0 | 14 |
Baseline characteristics
| Characteristic | Open-label Period (APTS) | Placebo - Double-blind Period (FAS) | Vortioxetine: 5 or 10 mg - Double-blind Period (FAS) | Total |
|---|---|---|---|---|
| Age, Continuous | 44.6 years STANDARD_DEVIATION 12.4 | 45.1 years STANDARD_DEVIATION 12.1 | 44.8 years STANDARD_DEVIATION 12.4 | 45.0 years STANDARD_DEVIATION 12.3 |
| CGI-S | 4.8 units on a scale STANDARD_DEVIATION 0.7 | 1.54 units on a scale STANDARD_DEVIATION 0.69 | 1.56 units on a scale STANDARD_DEVIATION 0.68 | 1.55 units on a scale STANDARD_DEVIATION 0.69 |
| HAM-A | 22.6 units on a scale STANDARD_DEVIATION 6.6 | 4.60 units on a scale STANDARD_DEVIATION 3.6 | 5.09 units on a scale STANDARD_DEVIATION 3.83 | 4.85 units on a scale STANDARD_DEVIATION 3.72 |
| HAM-D-17 | 22.8 units on a scale STANDARD_DEVIATION 4.5 | 3.96 units on a scale STANDARD_DEVIATION 3.15 | 4.46 units on a scale STANDARD_DEVIATION 3.27 | 4.21 units on a scale STANDARD_DEVIATION 3.21 |
| MADRS | 32.3 units on a scale STANDARD_DEVIATION 4.1 | 4.66 units on a scale STANDARD_DEVIATION 3.16 | 4.89 units on a scale STANDARD_DEVIATION 3 | 4.78 units on a scale STANDARD_DEVIATION 3.08 |
| SDS | 20.8 units on a scale STANDARD_DEVIATION 5.7 | 8.37 units on a scale STANDARD_DEVIATION 7.44 | 8.95 units on a scale STANDARD_DEVIATION 7.09 | 8.66 units on a scale STANDARD_DEVIATION 7.27 |
| Sex/Gender, Customized Female (Double-blind Period) | 0 participants | 120 participants | 130 participants | 250 participants |
| Sex/Gender, Customized Female (Open-label Period) | 397 participants | NA participants | NA participants | NA participants |
| Sex/Gender, Customized Male (Double-blind Period) | 0 participants | 72 participants | 74 participants | 146 participants |
| Sex/Gender, Customized Male (Open-label Period) | 242 participants | NA participants | NA participants | NA participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — |
| other Total, other adverse events | 337 / 639 | 73 / 192 | 79 / 204 |
| serious Total, serious adverse events | 14 / 639 | 6 / 192 | 7 / 204 |
Outcome results
Primary
Relapse Within First 24 Weeks of the Double-blind Period Based on a MADRS Total Score >=22 or an Unsatisfactory Treatment Effect (Lack of Efficacy) as Judged by the Investigator
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: Within first 24 weeks of the double-blind period
Population: FAS
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo | Relapse Within First 24 Weeks of the Double-blind Period Based on a MADRS Total Score >=22 or an Unsatisfactory Treatment Effect (Lack of Efficacy) as Judged by the Investigator | 26.0 percentage of patients who relapsed |
| Vortioxetine: 5 or 10 mg | Relapse Within First 24 Weeks of the Double-blind Period Based on a MADRS Total Score >=22 or an Unsatisfactory Treatment Effect (Lack of Efficacy) as Judged by the Investigator | 13.2 percentage of patients who relapsed |
p-value: 0.003595% CI: [1.26, 3.21]Cox-model
Secondary
Change From Double-blind Baseline in CGI-S Score After 24 Weeks of Double-blind 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: Double-blind Baseline and Week 24 of the double-blind period
Population: FAS; OC
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Change From Double-blind Baseline in CGI-S Score After 24 Weeks of Double-blind Treatment | 0.24 units on a scale | Standard Error 0.08 |
| Vortioxetine: 5 or 10 mg | Change From Double-blind Baseline in CGI-S Score After 24 Weeks of Double-blind Treatment | -0.14 units on a scale | Standard Error 0.08 |
p-value: 0.000295% CI: [-0.57, -0.18]ANCOVA
Secondary
Change From Double-blind Baseline in HAM-A Total Score After 24 Weeks of Double-blind 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: Double-blind Baseline and Week 24 of the double-blind period
Population: FAS; OC
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Change From Double-blind Baseline in HAM-A Total Score After 24 Weeks of Double-blind Treatment | 0.89 units on a scale | Standard Error 0.5 |
| Vortioxetine: 5 or 10 mg | Change From Double-blind Baseline in HAM-A Total Score After 24 Weeks of Double-blind Treatment | -0.23 units on a scale | Standard Error 0.46 |
p-value: 0.061295% CI: [-2.3, 0.05]ANCOVA
Secondary
Change From Double-blind Baseline in HAM-D-17 Total Score After 24 Weeks of Double-blind Treatment
The Hamilton Depression Scale - 17 items (HAM-D-17) measures depression severity. Items are rated on a scale from 0 (symptoms not present) to a maximum of 2 to 4 (symptom extremely severe) for a total score range of 0 to 52. The higher the score, the more severe.
Time frame: Double-blind Baseline and Week 24 of the double-blind period
Population: FAS; OC
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Change From Double-blind Baseline in HAM-D-17 Total Score After 24 Weeks of Double-blind Treatment | 1.61 units on a scale | Standard Error 0.46 |
| Vortioxetine: 5 or 10 mg | Change From Double-blind Baseline in HAM-D-17 Total Score After 24 Weeks of Double-blind Treatment | 0.30 units on a scale | Standard Error 0.42 |
p-value: 0.017195% CI: [-2.39, -0.24]ANCOVA
Secondary
Change From Double-blind Baseline in MADRS Total Score After 24 Weeks of Double-blind Treatment
Time frame: Double-blind Baseline and Week 24 of the double-blind period
Population: FAS; observed cases (OC)
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Change From Double-blind Baseline in MADRS Total Score After 24 Weeks of Double-blind Treatment | 1.45 units on a scale | Standard Error 0.55 |
| Vortioxetine: 5 or 10 mg | Change From Double-blind Baseline in MADRS Total Score After 24 Weeks of Double-blind Treatment | -0.62 units on a scale | Standard Error 0.51 |
p-value: 0.00295% CI: [-3.36, -0.77]ANCOVA
Secondary
Change From Double-blind Baseline in SDS Total Score at Week 24 of the Double-blind Period
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: Week 24 of the double-blind period (Counted From Double-blind Baseline)
Population: FAS; OC
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Change From Double-blind Baseline in SDS Total Score at Week 24 of the Double-blind Period | 0.14 units on a scale | Standard Error 0.58 |
| Vortioxetine: 5 or 10 mg | Change From Double-blind Baseline in SDS Total Score at Week 24 of the Double-blind Period | -0.53 units on a scale | Standard Error 0.57 |
p-value: 0.364295% CI: [-2.12, 0.78]ANCOVA
Secondary
Proportion of Remitters at Week 24 of the Double-blind Period (Remission Defined as a MADRS Total Score <=10)
Time frame: Week 24 of the double-blind period
Population: FAS; OC
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo | Proportion of Remitters at Week 24 of the Double-blind Period (Remission Defined as a MADRS Total Score <=10) | 82.6 percentage of patients |
| Vortioxetine: 5 or 10 mg | Proportion of Remitters at Week 24 of the Double-blind Period (Remission Defined as a MADRS Total Score <=10) | 94.7 percentage of patients |
p-value: 0.00295% CI: [4.73, 19.52]Fisher Exact
Secondary
Proportion of Responders at Week 24 of the Double-blind Period (Response Defined as a >=50% Reduction in MADRS Total Score From Open-label Baseline)
Time frame: Week 24 of the double-blind period (Counted From Open-label Baseline)
Population: FAS; OC
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo | Proportion of Responders at Week 24 of the Double-blind Period (Response Defined as a >=50% Reduction in MADRS Total Score From Open-label Baseline) | 91.7 percentage of patients |
| Vortioxetine: 5 or 10 mg | Proportion of Responders at Week 24 of the Double-blind Period (Response Defined as a >=50% Reduction in MADRS Total Score From Open-label Baseline) | 98.0 percentage of patients |
p-value: 0.02595% CI: [1.13, 11.56]Fisher Exact
Secondary
Relapse During the Entire Double-blind Period Based on a MADRS Total Score >=22 or an Unsatisfactory Treatment Effect (Lack of Efficacy) as Judged by the Investigator
Time frame: Within 64 weeks of the double-blind period
Population: FAS
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo | Relapse During the Entire Double-blind Period Based on a MADRS Total Score >=22 or an Unsatisfactory Treatment Effect (Lack of Efficacy) as Judged by the Investigator | 30.2 percentage of patients who relapsed |
| Vortioxetine: 5 or 10 mg | Relapse During the Entire Double-blind Period Based on a MADRS Total Score >=22 or an Unsatisfactory Treatment Effect (Lack of Efficacy) as Judged by the Investigator | 15.2 percentage of patients who relapsed |
p-value: 0.00195% CI: [1.35, 3.23]Cox-Model