Major Depressive Disorder
Conditions
Keywords
Drug Therapy
Brief summary
The purpose of this study is to assess the efficacy, safety and tolerability of 8-week treatment with Vortioxetine (Lu AA21004), once daily (QD), in Japanese participants with major depressive disorder. The purpose of this study is to assess the efficacy, safety and tolerability of 8-week treatment with Lu AA21004, once daily (QD), in Japanese participants with major depressive disorder.
Detailed description
Lu AA21004 was discovered by H. Lundbeck A/S, and is under co-development by H. Lundbeck A/S and Takeda for the treatment of major depressive disorder and general anxiety disorder. Major depressive disorder (MDD) is a chronic, recurring disease with considerable morbidity in the general population. The estimated lifetime prevalence of major depression in the adult population is 5 to 25%, with approximately 2-fold higher prevalence in women than in men. The hallmark of the disease is a depressed mood, with additional symptoms including sleep disturbances, psychomotor agitation or retardation, sexual dysfunction, weight loss, concentration difficulties and delusional ideas. In addition to direct ill effects, MDD causes suicide or job loss and exerts indirect influence on social economy. This study will assess the efficacy and the safety of Lu AA21004. This study consists of a 1-week screening period, an 8-week double-blind treatment period, 4-week safety follow-up.The duration of the study is 13 weeks in total. Blood samples will be collected from participants, and a safety follow-up contact (visit or phone call) will be made 4 weeks after completion of the 8-week double-blind treatment period. Subjects who complete the 8-week double-blind treatment period can successively enter a long-term extension study (Lu AA21004/OCT-001; NCT01395147; hereinafter, OCT-001), if they meet all inclusion criteria and none of exclusion criteria of the OCT-001 study and are willing to participate in the OCT-001 study. Subjects who will enter the OCT-001 will not be requested to safety follow-up after completion of the 8-week double-blind treatment period. Lu AA21004 was discovered by H. Lundbeck A/S, and is under co-development by H. Lundbeck A/S and Takeda for the treatment of major depressive disorder and general anxiety disorder. Major depressive disorder (MDD) is a chronic, recurring disease with considerable morbidity in the general population. The estimated lifetime prevalence of major depression in the adult population is 5 to 25%, with approximately 2-fold higher prevalence in women than in men. The hallmark of the disease is a depressed mood, with additional symptoms including sleep disturbances, psychomotor agitation or retardation, sexual dysfunction, weight loss, concentration difficulties and delusional ideas. In addition to direct ill effects, MDD causes suicide or job loss and exerts indirect influence on social economy. This study will assess the efficacy and the safety of Lu AA21004. This study consists of a 1-week screening period, an 8-week double-blind treatment period, 4-week s safety follow-up.The duration of the study is 13 weeks in total. Blood samples will be collected from participants, and a safety follow-up contact (visit or phone call) will be made 4 weeks after completion of the 8-week double-blind treatment period. Subjects who complete the 8-week double-blind treatment period can successively enter a long-term extension study (Lu AA21004/OCT-001; NCT01395147; hereinafter, OCT-001), if they meet all inclusion criteria and none of exclusion criteria of the OCT-001 study and are willing to participate in the OCT-001 study. Subjects who will enter the OCT-001 will not be requested to safety follow-up after completion of the 8-week double-blind treatment period.
Interventions
DRUGVortioxetine
Vortioxetine tablets
DRUGPlacebo
Vortioxetine placebo
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 75 Years
Healthy volunteers
No
Inclusion criteria
1. The subject suffers from Major Depressive Disorder (MDD) as the primary diagnosis according to the 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. The subject has a Montgomery-Åsberg Depression Rating Scale (MADRS) total score ≥26 at the Screening and Baseline Visits. 4. The subject has a Clinical Global Impression Scale-Severity (CGI-S) score ≥4 at the Screening and Baseline Visits
Exclusion criteria
1. The subject has one or more of the following conditions: * Any current psychiatric disorder other than MDD as defined in the DSM-IV-TR. A subject who exhibits symptoms of anxiety is eligible unless the subject fulfills 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. * 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 subject are considered by the investigator to have been resistant to 2 adequate antidepressant treatments of at least 6 weeks duration each. 3. The subject is at significant risk of suicide or has a score ≥5 on Item 10 (suicidal thoughts) of the MADRS at the Screening and Baseline Visit, 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 After 8 Weeks of Treatment | Baseline, Week 8 | MADRS is a 10-item clinician rated scale that measures overall severity of depressive symptoms (such as apparent sadness, reported sadness, inner tension) rated on a 7-point Likert scale from 0 (symptoms absent) to 6 (severe depression) with a total possible score range from 0 to 60. Higher scores indicate greater severity of symptoms. A negative change from Baseline indicates that symptoms have improved. An analysis of covariance (ANCOVA) model was used with change in MADRS total score as a dependent variable, treatment as a fixed effect and the baseline MADRS total score as a covariate. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Patients With MADRS Response After 8 Weeks of Treatment | Baseline, Week 8 | MADRS is a 10-item clinician rated scale to measure overall severity of depressive symptoms (such as apparent sadness, reported sadness, inner tension) rated on a 7-point Likert scale from 0 (symptoms absent) to 6 (severe depression) with a total possible score range from 0 to 60. Higher scores indicate greater severity of symptoms. Response is defined as a ≥50% decrease in the MADRS Total Score from Baseline. |
| Percentage of Patients With MADRS Remission After 8 Weeks of Treatment | Week 8 | MADRS is a 10-item clinician rated scale to measure overall severity of depressive symptoms (such as apparent sadness, reported sadness, inner tension) rated on a 7-point Likert scale from 0 (symptoms absent) to 6 (severe depression) with a total possible score range from 0 to 60. Higher scores indicate greater severity of symptoms. Remission is defined as a MADRS Total Score ≤10. |
| Change From Baseline in the Hamilton Depression Scale (HAM-D17) Total Score After 8 Weeks of Treatment | Baseline, Week 8 | The HAM-D17 is a 17-item rating scale that assesses depressed mood, agitation and somatic symptoms of depression, rated on a 5-point scale from 0 (absent) to 4 (very severe) with a total score range from 0 to 52. Higher scores indicate greater severity of depression symptoms. A negative change from Baseline indicates that symptoms have improved. ANCOVA model was used with treatment as a fixed effect and the baseline HAM-D17 score as a covariate. |
| Clinical Global Impression Scale-Improvement (CGI-I) Score After 8 Weeks of Treatment | Baseline, Week 8 | The CGI-I assesses the clinician's impression of the participant's state of mental illness improvement and consists of one question for the investigator: Compared to his condition at the start of the study, how much has this patient changed? which is rated on a seven-point scale (1=very much improved; 2=much improved; 3=minimally improved; 4=no change from baseline; 5=minimally worse; 6= much worse; 7=very much worse). Higher scores indicate greater severity of illness. Values closest to 1 for this outcome measure indicate the greatest improvement of symptoms. ANCOVA model was used with treatment as a fixed effect and the baseline CGI-Severity (CGI-S) score as a covariate. |
| Change From Baseline in Sheehan Disability Scale (SDS) Total Score After 8 Weeks of Treatment | Baseline, Week 8 | The SDS is a 3 item rating scale to assess functional impairment (panic, anxiety, phobic and depressive symptoms) over three inter-related domains (work/school, social life, and family life/home responsibilities) rated on an 11 point scale from 0 (not at all) to 10 (extremely) with a total score range from 0 to 30. Higher scores indicate greater severity of impairment. A negative change from Baseline indicates that symptoms have improved. ANCOVA model was used with treatment as a fixed effect and the Baseline SDS total score as a covariate. |
Countries
Japan
Participant flow
Recruitment details
Participants took part in the study at 32 investigative sites throughout Japan from 13 May 2011 to 21 December 2012.
Pre-assignment details
Participants with a diagnosis of major depressive disorder were enrolled equally in 1 of 3 treatment groups: once a day 5 mg or 10 mg vortioxetine (Lu AA21004) or placebo.
Participants by arm
| Arm | Count |
|---|---|
| Vortioxetine 5 mg Vortioxetine 5 mg, tablets, orally, once daily for up to 8 weeks. | 119 |
| Vortioxetine 10 mg Vortioxetine 10 mg, tablets, orally, once daily for up to 8 weeks. | 123 |
| Placebo Vortioxetine placebo-matching tablets, orally, once daily for up to 8 weeks. | 124 |
| Total | 366 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Lack of Efficacy | 2 | 1 | 1 |
| Overall Study | Lost to Follow-up | 0 | 0 | 1 |
| Overall Study | Major Protocol Deviation | 0 | 1 | 0 |
| Overall Study | Non Compliance with Study Medication | 0 | 1 | 0 |
| Overall Study | Pretreatment Event or Adverse Event | 3 | 4 | 6 |
| Overall Study | Withdrawal of Consent | 2 | 3 | 3 |
Baseline characteristics
| Characteristic | Placebo | Vortioxetine 5 mg | Vortioxetine 10 mg | Total |
|---|---|---|---|---|
| Age, Continuous | 37.6 years STANDARD_DEVIATION 10.67 | 38.8 years STANDARD_DEVIATION 10.85 | 38.8 years STANDARD_DEVIATION 10.99 | 38.4 years STANDARD_DEVIATION 10.83 |
| Body Mass Index (BMI) | 22.57 kg/m^2 STANDARD_DEVIATION 4.016 | 22.59 kg/m^2 STANDARD_DEVIATION 3.366 | 22.42 kg/m^2 STANDARD_DEVIATION 4.306 | 22.53 kg/m^2 STANDARD_DEVIATION 3.911 |
| Clinical Global Impression - Severity Scale Score | 4.6 scores on a scale STANDARD_DEVIATION 0.69 | 4.5 scores on a scale STANDARD_DEVIATION 0.65 | 4.5 scores on a scale STANDARD_DEVIATION 0.64 | 4.5 scores on a scale STANDARD_DEVIATION 0.66 |
| Cytochrome p450 (CYP)2D6 Phenotype Extensive Metabolizer (EM) | 96 participants | 91 participants | 97 participants | 284 participants |
| Cytochrome p450 (CYP)2D6 Phenotype Intermediate Metabolizer (IM) | 21 participants | 25 participants | 20 participants | 66 participants |
| Cytochrome p450 (CYP)2D6 Phenotype Poor Metabolizer (PM) | 0 participants | 0 participants | 1 participants | 1 participants |
| Cytochrome p450 (CYP)2D6 Phenotype Ultra-rapid Metabolizer (UM) | 2 participants | 1 participants | 1 participants | 4 participants |
| Cytochrome p450 (CYP)2D6 Phenotype Unknown | 5 participants | 2 participants | 4 participants | 11 participants |
| Hamilton Depression Scale (HAM-D17) Total Score | 21.5 scores on a scale STANDARD_DEVIATION 4.48 | 20.9 scores on a scale STANDARD_DEVIATION 4.12 | 21.2 scores on a scale STANDARD_DEVIATION 4.43 | 21.2 scores on a scale STANDARD_DEVIATION 4.34 |
| Height | 163.9 cm STANDARD_DEVIATION 8.46 | 165.7 cm STANDARD_DEVIATION 8.45 | 165.6 cm STANDARD_DEVIATION 8.51 | 165.1 cm STANDARD_DEVIATION 8.49 |
| History of Alcohol Consumption 2 to 6 Times/Week | 15 participants | 21 participants | 20 participants | 56 participants |
| History of Alcohol Consumption Daily | 8 participants | 15 participants | 11 participants | 34 participants |
| History of Alcohol Consumption Never | 41 participants | 34 participants | 32 participants | 107 participants |
| History of Alcohol Consumption Once a Week | 20 participants | 16 participants | 20 participants | 56 participants |
| History of Alcohol Consumption Once Monthly or Less Often | 40 participants | 33 participants | 40 participants | 113 participants |
| Montgomery Åsberg Depression Rating Scale (MADRS) Total Score | 32.5 scores on a scale STANDARD_DEVIATION 4.5 | 32.2 scores on a scale STANDARD_DEVIATION 4.81 | 32.5 scores on a scale STANDARD_DEVIATION 4.93 | 32.4 scores on a scale STANDARD_DEVIATION 4.74 |
| Pharmacotherapy for Current Major Depressive Episode No | 50 participants | 51 participants | 55 participants | 156 participants |
| Pharmacotherapy for Current Major Depressive Episode Yes | 74 participants | 68 participants | 68 participants | 210 participants |
| Region of Enrollment Japan | 124 participants | 119 participants | 123 participants | 366 participants |
| Sex: Female, Male Female | 67 Participants | 50 Participants | 54 Participants | 171 Participants |
| Sex: Female, Male Male | 57 Participants | 69 Participants | 69 Participants | 195 Participants |
| Sheehan Disability Scale (SDS) - Total Score | 15.4 scores on a scale STANDARD_DEVIATION 5.45 | 15.5 scores on a scale STANDARD_DEVIATION 6.12 | 15.2 scores on a scale STANDARD_DEVIATION 5.97 | 15.4 scores on a scale STANDARD_DEVIATION 5.83 |
| Smoking Classification Current smoker | 40 participants | 39 participants | 41 participants | 120 participants |
| Smoking Classification Ex-smoker | 24 participants | 26 participants | 24 participants | 74 participants |
| Smoking Classification Never Smoked | 60 participants | 54 participants | 58 participants | 172 participants |
| Status of Major Depressive Episode (MDE) Recurrent episode | 48 participants | 49 participants | 55 participants | 152 participants |
| Status of Major Depressive Episode (MDE) Single episode | 76 participants | 70 participants | 68 participants | 214 participants |
| Weight | 60.86 kg STANDARD_DEVIATION 12.69 | 62.18 kg STANDARD_DEVIATION 11.357 | 62.11 kg STANDARD_DEVIATION 15.883 | 61.71 kg STANDARD_DEVIATION 13.441 |
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 | 80 / 119 | 93 / 122 | 78 / 124 |
| serious Total, serious adverse events | 1 / 119 | 1 / 122 | 1 / 124 |
Outcome results
Primary
Change From Baseline in Montgomery-Åsberg Depression Rating Scale (MADRS) Total Score After 8 Weeks of Treatment
MADRS is a 10-item clinician rated scale that measures overall severity of depressive symptoms (such as apparent sadness, reported sadness, inner tension) rated on a 7-point Likert scale from 0 (symptoms absent) to 6 (severe depression) with a total possible score range from 0 to 60. Higher scores indicate greater severity of symptoms. A negative change from Baseline indicates that symptoms have improved. An analysis of covariance (ANCOVA) model was used with change in MADRS total score as a dependent variable, treatment as a fixed effect and the baseline MADRS total score as a covariate.
Time frame: Baseline, Week 8
Population: Participants from the Full Analysis Set (FAS), defined as all participants who were randomized and received at least 1 dose of study drug; who had data available for this outcome measure. One participant in the Vortioxetine 10 mg group was excluded due to a major protocol deviation. Last observation carried forward.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Vortioxetine 5 mg | Change From Baseline in Montgomery-Åsberg Depression Rating Scale (MADRS) Total Score After 8 Weeks of Treatment | -15.84 scores on a scale | Standard Error 0.885 |
| Vortioxetine 10 mg | Change From Baseline in Montgomery-Åsberg Depression Rating Scale (MADRS) Total Score After 8 Weeks of Treatment | -14.85 scores on a scale | Standard Error 0.874 |
| Placebo | Change From Baseline in Montgomery-Åsberg Depression Rating Scale (MADRS) Total Score After 8 Weeks of Treatment | -13.81 scores on a scale | Standard Error 0.87 |
p-value: 0.103195% CI: [-4.467, 0.413]ANCOVA
p-value: 0.400895% CI: [-3.461, 1.387]ANCOVA
Secondary
Change From Baseline in Sheehan Disability Scale (SDS) Total Score After 8 Weeks of Treatment
The SDS is a 3 item rating scale to assess functional impairment (panic, anxiety, phobic and depressive symptoms) over three inter-related domains (work/school, social life, and family life/home responsibilities) rated on an 11 point scale from 0 (not at all) to 10 (extremely) with a total score range from 0 to 30. Higher scores indicate greater severity of impairment. A negative change from Baseline indicates that symptoms have improved. ANCOVA model was used with treatment as a fixed effect and the Baseline SDS total score as a covariate.
Time frame: Baseline, Week 8
Population: Participants from the Full Analysis Set (FAS), defined as all participants who were randomized and received at least 1 dose of study drug, who had data available for this outcome measure. One participant in the Vortioxetine 10 mg group was excluded due to a major protocol deviation. Last Observation Carried Forward (LOCF).
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Vortioxetine 5 mg | Change From Baseline in Sheehan Disability Scale (SDS) Total Score After 8 Weeks of Treatment | -5.01 scores on a scale | Standard Error 0.51 |
| Vortioxetine 10 mg | Change From Baseline in Sheehan Disability Scale (SDS) Total Score After 8 Weeks of Treatment | -4.02 scores on a scale | Standard Error 0.506 |
| Placebo | Change From Baseline in Sheehan Disability Scale (SDS) Total Score After 8 Weeks of Treatment | -2.91 scores on a scale | Standard Error 0.504 |
Secondary
Change From Baseline in the Hamilton Depression Scale (HAM-D17) Total Score After 8 Weeks of Treatment
The HAM-D17 is a 17-item rating scale that assesses depressed mood, agitation and somatic symptoms of depression, rated on a 5-point scale from 0 (absent) to 4 (very severe) with a total score range from 0 to 52. Higher scores indicate greater severity of depression symptoms. A negative change from Baseline indicates that symptoms have improved. ANCOVA model was used with treatment as a fixed effect and the baseline HAM-D17 score as a covariate.
Time frame: Baseline, Week 8
Population: Participants from the Full Analysis Set (FAS), defined as all participants who were randomized and received at least 1 dose of study drug, who had data available for this outcome measure. One participant in the Vortioxetine 10 mg group was excluded due to a major protocol deviation. Last Observation Carried Forward.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Vortioxetine 5 mg | Change From Baseline in the Hamilton Depression Scale (HAM-D17) Total Score After 8 Weeks of Treatment | -9.56 scores on a scale | Standard Error 0.586 |
| Vortioxetine 10 mg | Change From Baseline in the Hamilton Depression Scale (HAM-D17) Total Score After 8 Weeks of Treatment | -8.54 scores on a scale | Standard Error 0.58 |
| Placebo | Change From Baseline in the Hamilton Depression Scale (HAM-D17) Total Score After 8 Weeks of Treatment | -8.40 scores on a scale | Standard Error 0.578 |
Secondary
Clinical Global Impression Scale-Improvement (CGI-I) Score After 8 Weeks of Treatment
The CGI-I assesses the clinician's impression of the participant's state of mental illness improvement and consists of one question for the investigator: Compared to his condition at the start of the study, how much has this patient changed? which is rated on a seven-point scale (1=very much improved; 2=much improved; 3=minimally improved; 4=no change from baseline; 5=minimally worse; 6= much worse; 7=very much worse). Higher scores indicate greater severity of illness. Values closest to 1 for this outcome measure indicate the greatest improvement of symptoms. ANCOVA model was used with treatment as a fixed effect and the baseline CGI-Severity (CGI-S) score as a covariate.
Time frame: Baseline, Week 8
Population: Participants from the Full Analysis Set (FAS), defined as all participants who were randomized and received at least 1 dose of study drug, who had data available for this outcome measure. One participant in the Vortioxetine 10 mg group was excluded due to a major protocol deviation. Last Observation Carried Forward (LOCF).
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Vortioxetine 5 mg | Clinical Global Impression Scale-Improvement (CGI-I) Score After 8 Weeks of Treatment | 2.44 scores on a scale | Standard Error 0.1 |
| Vortioxetine 10 mg | Clinical Global Impression Scale-Improvement (CGI-I) Score After 8 Weeks of Treatment | 2.57 scores on a scale | Standard Error 0.099 |
| Placebo | Clinical Global Impression Scale-Improvement (CGI-I) Score After 8 Weeks of Treatment | 2.66 scores on a scale | Standard Error 0.099 |
Secondary
Percentage of Patients With MADRS Remission After 8 Weeks of Treatment
MADRS is a 10-item clinician rated scale to measure overall severity of depressive symptoms (such as apparent sadness, reported sadness, inner tension) rated on a 7-point Likert scale from 0 (symptoms absent) to 6 (severe depression) with a total possible score range from 0 to 60. Higher scores indicate greater severity of symptoms. Remission is defined as a MADRS Total Score ≤10.
Time frame: Week 8
Population: Participants from the Full Analysis Set (FAS), defined as all participants who were randomized and received at least 1 dose of study drug, who had data available for this outcome measure. One participant in the Vortioxetine 10 mg group was excluded due to a major protocol deviation.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Vortioxetine 5 mg | Percentage of Patients With MADRS Remission After 8 Weeks of Treatment | 29.4 percentage of participants |
| Vortioxetine 10 mg | Percentage of Patients With MADRS Remission After 8 Weeks of Treatment | 28.7 percentage of participants |
| Placebo | Percentage of Patients With MADRS Remission After 8 Weeks of Treatment | 22.0 percentage of participants |
Secondary
Percentage of Patients With MADRS Response After 8 Weeks of Treatment
MADRS is a 10-item clinician rated scale to measure overall severity of depressive symptoms (such as apparent sadness, reported sadness, inner tension) rated on a 7-point Likert scale from 0 (symptoms absent) to 6 (severe depression) with a total possible score range from 0 to 60. Higher scores indicate greater severity of symptoms. Response is defined as a ≥50% decrease in the MADRS Total Score from Baseline.
Time frame: Baseline, Week 8
Population: Participants from the Full Analysis Set (FAS), defined as all participants who were randomized and received at least 1 dose of study drug, who had data available for this outcome measure. One participant in the Vortioxetine 10 mg group was excluded due to a major protocol deviation.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Vortioxetine 5 mg | Percentage of Patients With MADRS Response After 8 Weeks of Treatment | 51.3 percentage of participants |
| Vortioxetine 10 mg | Percentage of Patients With MADRS Response After 8 Weeks of Treatment | 45.9 percentage of participants |
| Placebo | Percentage of Patients With MADRS Response After 8 Weeks of Treatment | 39.8 percentage of participants |