Efficacy Study of Vortioxetine (Lu AA21004) in Adults With Major Depressive Disorder

Study Overview
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Brief Summary
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The purpose of this study is to determine the effectiveness and safety of vortioxetine, once daily (QD), in patients with Major Depressive Disorder.

Detailed Description
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The drug that was tested in this study is called vortioxetine. Vortioxetine is being tested to treat depression in adults who have major depressive disorder (MDD). This study looked at MDD relief in people who took varying dosages of vortioxetine. The study enrolled 560 patients. Participants were randomly assigned (by chance, like flipping a coin) to one of the four treatment groups-which remained undisclosed to the patient and study doctor during the study (unless there was an urgent medical need): Vortioxetine 1 mg Vortioxetine 5 mg Vortioxetine 10 mg Placebo (dummy inactive pill) - this was a capsule that looked like the study drug but had no active ingredient. All participants were asked to take one capsule at the same time each day throughout the study. This multi-centre trial was conducted in Europe, Asia, Australia, and South Africa. The overall time to participate in this study was up to 14 weeks. Participants made 7 visits to the clinic, and were contacted by telephone 4 weeks after the last dose of study drug for a follow-up assessment.

Official Title
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A Randomized, Double-blind, Parallel-Group, Placebo-Controlled, Fixed-Dose Study Comparing the Efficacy and Safety of 3 Doses of Lu AA21004 in Acute Treatment of Adults With Major Depressive Disorder

Conditions
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Major Depressive Disorder

Intervention / Treatment
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* Drug: Vortioxetine
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Has a primary diagnosis of major depressive episode according to the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision (DSM-IV-TR) criteria. The reported duration of the current major depressive episode is at least 3 months. Has a Montgomery Åsberg Depression Rating Scale (MADRS) total score ≥26. A male or a female of childbearing potential who is sexually active agrees to use adequate contraception from Screening throughout the duration of the study and for 1 month after the last dose of study medication. Exclusion Criteria: Has 1 or more the following: Any current psychiatric disorder other than major depressive disorder as defined in the DSM-IV-TR. Current or past 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. Any substance disorder (except nicotine and caffeine) within the previous 6 months as defined in the DSM-IV-TR. (must have negative urine drug screen prior to Baseline). Presence or history of a clinically significant neurological disorder (including epilepsy). Neurodegenerative disorder (Alzheimer disease, Parkinson disease, multiple sclerosis, Huntington disease, etc). Has a significant risk of suicide according to the investigator's opinion or has a score ≥5 on item 10 (suicidal thoughts) of the Montgomery Åsberg Depression Rating Scale, or has made a suicide attempt in the previous 6 months. Currently receiving formal cognitive or behavioral therapy, systematic psychotherapy, or plans to initiate such therapy during the study. Has a clinically significant unstable illness. Has previously failed to respond to adequate treatment with selective serotonin reuptake inhibitors and/or serotonin-norepinephrine reuptake inhibitors. Has received electroconvulsive therapy within 6 months prior to Screening. Has an alanine aminotransferase, aspartate aminotransferase, or total bilirubin level > 1.5 times the upper limit of normal. Has a serum creatinine of > 1.5 × upper limit of normal. Has a previous history of cancer that had been in remission for less than 5 years. Has thyroid stimulating hormone value outside the normal range. Has an abnormal electrocardiogram.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 75 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Vortioxetine 1 mg<br>Vortioxetine 1 mg, encapsulated tablets, orally, once daily for up 8 weeks. | Drug: Vortioxetine<br>* Encapsulated immediate-release vortioxetine tablets<br>* Other names: Brintellix®;|
| Experimental: Vortioxetine 5 mg<br>Vortioxetine 5 mg, encapsulated tablets, orally, once daily for up 8 weeks. | Drug: Vortioxetine<br>* Encapsulated immediate-release vortioxetine tablets<br>* Other names: Brintellix®;|
| Experimental: Vortioxetine 10 mg<br>Vortioxetine 10 mg, encapsulated tablets, orally, once daily for up 8 weeks. | Drug: Vortioxetine<br>* Encapsulated immediate-release vortioxetine tablets<br>* Other names: Brintellix®;|
| Placebo Comparator: Placebo<br>Vortioxetine placebo-matching capsules, orally, once daily for up to 8 weeks. | Drug: Placebo<br>* Vortioxetine placebo-matching capsules<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in the 24-item Hamilton Depression Scale Total Score At Week 8 | The 24-item Hamilton Depression Scale (HAM-D24) is a clinician-rated 24-item scale for assessing the severity of depression symptoms. The scores for each item range from 0 to 4 or 0 to 2, where 0 represents no symptoms. The rating is based on the past 7 days prior to the time of assessment. The total score range is from 0 to 74 where a higher score indicates a greater depressive state. Least squares (LS) means are from a mixed model for repeated measurements (MMRM) with Baseline-by-week, center, week, and week-by-treatment as factors in the analysis. | Baseline to Week 8 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in Sheehan Disability Scale (SDS) Total Score at Week 8 | The Sheehan Disability Scale assesses functional impairment in 3 domains: work/school, social life or leisure activities, and home life or family responsibilities. The participant rates the extent to which each aspect is impaired on a 10-point visual analog scale, from 0 (not at all) to 10 (extremely). The 3 scores are added together to calculate the total score, which ranges from 0 to 30, with higher scores indicating more impairment. LS means are from a mixed model for repeated measurements (MMRM) with Baseline-by-week, center, week, and week-by-treatment as factors in the analysis. | Baseline to Week 8 | 
| Clinical Global Impression Scale-Global Improvement at Week 8 | The Clinical Global Impression - Global Improvement scale assesses the participant's improvement (or worsening) as assessed by the clinician relative to Baseline on a 7-point scale: 1, very much improved; 2, much improved; 3, minimally improved; 4, no change; 5, minimally worse; 6, much worse; or 7, very much worse. LS means are from a mixed model for repeated measurements (MMRM) with Baseline-by-week, center, week, and week-by-treatment as factors in the analysis. | Baseline to Week 8 | 
| Percentage of Responders in HAM-D24 Total Score at Week 8 | A responder is defined as a participant with a ≥50% decrease from Baseline in HAM-D24 total score. The HAM-D24 is a clinician-rated 24-item scale for assessing the severity of depression symptoms. The scores for each item range from 0 to 4 or 0 to 2, where 0 represents no symptoms. The rating is based on the past 7 days prior to the time of assessment. The total score ranges from 0 to 74, where a higher score indicates a greater depressive state. | Baseline and Week 8 | 
| Change From Baseline in HAM-D24 Total Score at Week 8 in Participants With Baseline HAM-A Score ≥20 | The HAM-D24 is a clinician-rated 24-item scale for assessing the severity of depression symptoms. The scores for each item range from 0 to 4 or 0 to 2, where 0 represents no symptoms. The rating is based on the past 7 days prior to the time of assessment. The total score ranges from 0 to 74 where a higher score indicates a greater depressive state. The Hamilton Anxiety Scale (HAM-A) is an anxiety rating scale consisting of 14 items that assess anxious mood, tension, fear, insomnia, intellectual (cognitive) symptoms, depressed mood, behavior 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 scores range from 0 (symptoms absent) to 56 (severe symptoms). LS means are from a mixed model for repeated measurements (MMRM) with Baseline-by-week, center, week, and week-by-treatment as factors in the analysis. | Baseline to Week 8 | 
| Percentage of Participants in MADRS Remission at Week 8 | Remission is defined as a participant with a Montgomery Åsberg Depression Rating Scale (MADRS) total score ≤10. The MADRS is a depression rating scale consisting of 10 items, each rated 0 to 6. The 10 items represent the core symptoms of depressive illness. The overall score ranges from 0 (symptoms absent) to 60 (severe depression). Decrease in the total score or on individual items indicates improvement. | Week 8 | 
| Change From Baseline in the 24-item Hamilton Depression Scale Total Score at Other Weeks Assessed | The HAM-D24 is a clinician-rated 24-item scale for assessing the severity of depression symptoms. The scores for each item range from 0 to 4 or 0 to 2, where 0 represents no symptoms. The rating is based on the past 7 days prior to the time of assessment. The total score range is from 0 to 74 where a higher score indicates a greater depressive state. LS means are from a mixed model for repeated measurements (MMRM) with Baseline-by-week, center, week, and week-by-treatment as factors in the analysis. | Baseline and Weeks 1, 2, 4 and 6 | 
| Change From Baseline in Sheehan Disability Scale (SDS) Total Score at Other Weeks Assessed | The Sheehan Disability Scale assesses functional impairment in 3 domains: work/school, social life or leisure activities, and home life or family responsibilities. The participant rates the extent to which each aspect is impaired on a 10-point visual analog scale, from 0 (not at all) to 10 (extremely). The 3 scores are added together to calculate the total score, which ranges from 0 to 30, with higher scores indicating more impairment. LS means are from a mixed model for repeated measurements (MMRM) with Baseline-by-week, center, week, and week-by-treatment as factors in the analysis. | Baseline and Weeks 1, 2 and 6 | 
| Clinical Global Impression Scale-Global Improvement at Other Weeks Assessed | The Clinical Global Impression - global improvement assesses the participant's improvement (or worsening) as assessed by the clinician relative to Baseline on a 7-point scale: 1, very much improved; 2, much improved; 3, minimally improved; 4, no change; 5, minimally worse; 6, much worse; or 7, very much worse. LS means are from a mixed model for repeated measurements (MMRM) with Baseline-by-week, center, week, and week-by-treatment as factors in the analysis. | Baseline and Weeks 1, 2, 4 and 6 | 
| Percentage of Responders in HAM-D24 Total Score at Other Weeks Assessed | A responder is defined as a participant with a ≥50% decrease from Baseline in HAM-D24 total score. The HAM-D24 is a clinician-rated 24-item scale for assessing the severity of depression symptoms. The scores for each item range from 0 to 4 or 0 to 2, where 0 represents no symptoms. The rating is based on the past 7 days prior to the time of assessment. The total score ranges from 0 to 74, where a higher score indicates a greater depressive state. | Baseline and Weeks 1, 2, 4 and 6 | 
| Change From Baseline in HAM-D24 Total Score at Other Weeks Assessed in Participants With a Baseline HAM-A Score ≥20 | The HAM-D24 is a clinician-rated 24-item scale for assessing the severity of depression symptoms. The scores for each item range from 0 to 4 or 0 to 2, where 0 represents no symptoms. The rating is based on the past 7 days prior to the time of assessment. The total score range from 0 to 74 where a higher score indicates a greater depressive state. The Hamilton Anxiety Scale (HAM-A) is an anxiety rating scale consisting of 14 items that assess anxious mood, tension, fear, insomnia, intellectual (cognitive) symptoms, depressed mood, behavior 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 scores range from 0 (symptoms absent) to 56 (symptoms severe). LS means are from a mixed model for repeated measurements (MMRM) with Baseline-by-week, center, week, and week-by-treatment as factors in the analysis. | Baseline and Weeks 1, 2, 4 and 6 | 
| Percentage of Participants in MADRS Remission at Other Weeks Assessed | Remission is defined as a participant with a Montgomery Åsberg Depression Rating Scale (MADRS) total score ≤10. The MADRS is a depression rating scale consisting of 10 items, each rated 0 to 6. The 10 items represent the core symptoms of depressive illness. The overall score ranges from 0 (symptoms absent) to 60 (severe depression). Decrease in the total score or on individual items indicates improvement. | Weeks 1, 2, 4 and 6 | 
| Percentage of Participants With a Sustained Response in HAM-D24 Total Score | A sustained response is defined as a ≥20% decrease from Baseline in HAM-D24 total score obtained at Week 1 and sustained through Week 7 and at least 50% decrease from Baseline at Week 8. | From Baseline through Week 8 | 
| Change From Baseline in Montgomery Åsberg Depression Rating Scale (MADRS) Total Score at Each Week | The MADRS is a depression rating scale consisting of 10 items, each rated 0 to 6. The 10 items represent the core symptoms of depressive illness. The overall score ranges from 0 (symptoms absent) to 60 (severe depression). A decrease in the total score or on individual items indicates improvement. LS means are from a mixed model for repeated measurements (MMRM) with Baseline-by-week, center, week, and week-by-treatment as factors in the analysis. | Baseline and Weeks 1, 2, 4, 6, and 8 | 
| Change From Baseline in Hamilton Anxiety Scale (HAM-A) Total Score at Each Week Assessed | The HAM-A is an anxiety rating scale consisting of 14 items that assess anxious mood, tension, fear, insomnia, intellectual (cognitive) symptoms, depressed mood, behavior 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 scores range from 0 to 56, where <17 indicates mild severity, 18-24 mild to moderate severity and 25-30 moderate to severe. Total scores above 30 are rare, but indicate very severe anxiety. LS means are from a mixed model for repeated measurements (MMRM) with Baseline-by-week, center, week, and week-by-treatment as factors in the analysis. | Baseline and Weeks 1, 2, 4, 6, and 8 | 
| Change From Baseline in Clinical Global Impression Scale-Severity of Illness at Each Week Assessed | The Clinical Global Impression - Severity scale (CGI-S) is a 7-point scale that requires the clinician to rate the severity of the participant's illness at the time of assessment, relative to the clinician's past experience with patients who have the same diagnosis. Considering total clinical experience, a patient is assessed on severity of mental illness on the following scale: 1, normal, not at all ill; 2, borderline mentally ill; 3, mildly ill; 4, moderately ill; 5, markedly ill; 6, severely ill; or 7, extremely ill. LS means are from a mixed model for repeated measurements (MMRM) with Baseline-by-week, center, week, and week-by-treatment as factors in the analysis. | Baseline and Weeks 1, 2, 4, 6, and 8 | 
| Change From Baseline in Hospital Anxiety and Depression (HAD) Scales at Each Week Assessed | The HAD scale is completed by the participant and comprises two subscales, one measuring depression (focusing on the state of lost interest and diminished pleasure response) and one measuring anxiety (including anxious mood, restlessness, anxious thoughts, panic attacks). Each subscale is made up of 7 items that are assessed on a scale of 0 = no anxiety/depression to 3 = severe feeling of anxiety/depression. Participants are required to indicate the response which most accurately reflects the way they have felt over the last few days. Scores for the depression and anxiety subscales are summed separately and not combined, with each score ranging from 0 to 21 (maximal severity). LS means are from a mixed model for repeated measurements (MMRM) with Baseline-by-week, center, week, and week-by-treatment as factors in the analysis | Baseline and Weeks 1, 4, and 8 | 
| Change From Baseline in 36-Item Short-Form Health Survey (SF-36) Physical Functioning Subscore at All Weeks Assessed | The Medical Outcomes Study SF-36 is a participant self-rated questionnaire that is a general measure of perceived health status comprising 36 questions, which yields an 8-scale health profile. The physical functioning subscale assesses limitations in physical activities because of health problems. The sub-score scale ranges from 0 (best) - 100 (worst). LS means are from a mixed model for repeated measurements (MMRM) with Baseline-by-week, center, week, and week-by-treatment as factors in the analysis. | Baseline and Weeks 2, 4 and 8 | 
| Change From Baseline in 36-Item Short-Form Health Survey (SF-36) Role-Physical Subscore at All Weeks Assessed | The Medical Outcomes Study SF-36 is a participant self-rated questionnaire that is a general measure of perceived health status comprising 36 questions, which yields an 8-scale health profile. The role-physical subscale assesses limitations in usual role activities because of physical health problems. The sub-score scale ranges from 0 (best) - 100 (worst). LS means are from a mixed model for repeated measurements (MMRM) with Baseline-by-week, center, week, and week-by-treatment as factors in the analysis. | Baseline and Weeks 2, 4 and 8 | 
| Change From Baseline in 36-Item Short-Form Health Survey (SF-36) Bodily Pain Subscore at All Weeks Assessed | The Medical Outcomes Study SF-36 is a participant self-rated questionnaire that is a general measure of perceived health status comprising 36 questions, which yields an 8-scale health profile. The bodily pain sub-score scale ranges from 0 (best) - 100 (worst). LS means are from a mixed model for repeated measurements (MMRM) with Baseline-by-week, center, week, and week-by-treatment as factors in the analysis. | Baseline and Weeks 2, 4 and 8 | 
| Change From Baseline in 36-Item Short-Form Health Survey (SF-36) General Health Subscore at All Weeks Assessed | The Medical Outcomes Study SF-36 is a participant self-rated questionnaire that is a general measure of perceived health status comprising 36 questions, which yields an 8-scale health profile. The general health sub-score scale ranges from 0 (best) - 100 (worst). LS means are from a mixed model for repeated measurements (MMRM) with Baseline-by-week, center, week, and week-by-treatment as factors in the analysis. | Baseline and Weeks 2, 4 and 8 | 
| Change From Baseline in 36-Item Short-Form Health Survey (SF-36) Vitality Subscore at All Weeks Assessed | The Medical Outcomes Study SF-36 is a participant self-rated questionnaire that is a general measure of perceived health status comprising 36 questions, which yields an 8-scale health profile. The vitality sub-score assesses energy and fatigue, and ranges from 0 (best) - 100 (worst). LS means are from a mixed model for repeated measurements (MMRM) with Baseline-by-week, center, week, and week-by-treatment as factors in the analysis. | Baseline and Weeks 2, 4 and 8 | 
| Change From Baseline in 36-Item Short-Form Health Survey (SF-36) Social Functioning Subscore at Other Weeks Assessed | The Medical Outcomes Study SF-36 is a participant self-rated questionnaire that is a general measure of perceived health status comprising 36 questions, which yields an 8-scale health profile. The social functioning subscale assesses limitations in social activities because of physical or emotional problems. The sub-score scale ranges from 0 (best) - 100 (worst). LS means are from a mixed model for repeated measurements (MMRM) with Baseline-by-week, center, week, and week-by-treatment as factors in the analysis. | Baseline and Weeks 2 and 4 | 
| Change From Baseline in 36-Item Short-Form Health Survey (SF-36) Role-Emotional Subscore at All Weeks Assessed | The Medical Outcomes Study SF-36 is a participant self-rated questionnaire that is a general measure of perceived health status comprising 36 questions, which yields an 8-scale health profile. The role-emotional subscale assesses limitations in usual role activities because of emotional problems. The sub-score scale ranges from 0 (best) - 100 (worst). LS means are from a mixed model for repeated measurements (MMRM) with Baseline-by-week, center, week, and week-by-treatment as factors in the analysis. | Baseline and Weeks 2, 4 and 8 | 
| Change From Baseline in 36-Item Short-Form Health Survey (SF-36) Mental Health Subscore at All Weeks Assessed | The Medical Outcomes Study SF-36 is a participant self-rated questionnaire that is a general measure of perceived health status comprising 36 questions, which yields an 8-scale health profile. The mental health sub-score assesses general mental health (psychological distress and well-being) and ranges from 0 (best) - 100 (worst). LS means are from a mixed model for repeated measurements (MMRM) with Baseline-by-week, center, week, and week-by-treatment as factors in the analysis. | Baseline and Weeks 2, 4 and 8 | 
| Healthcare Resource Utilization as Assessed by the Health Economic Assessment Questionnaire. | Healthcare resource utilization was assessed by the Health Economic Assessment (HEA) questionnaire, which monitors the participants' absenteeism from work, as well as resource use such as visits to a general practitioner, outpatient and inpatient services, hospitalization, medications, and other relevant services over the past 8 weeks. | Baseline and Week 8 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Depression, Depressive Disorder, Mood Disorder, Mental Disorder, Melancholia, Involutional, Paraphrenia, Involutional, Drug Therapy