Efficacy and Safety of Vortioxetine (Lu AA21004) in the Treatment of Patients 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 efficacy and safety of vortioxetine, once daily (QD), in adults 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 611 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 2.5 mg Vortioxetine 5 mg Duloxetine 10 mg Placebo (dummy inactive capsule) - 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-center trial was conducted in the United States. The overall time to participate in this study was up to 12 weeks. Participants made 8 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, Active-Referenced, Fixed-Dose Study Comparing the Efficacy and Safety of 2 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: Duloxetine
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Suffers from a major depressive episode as the primary diagnosis according to Diagnostic and Statistical Manual of Mental Disorders, 4th Edition, Text Revision (DSM-IV-TR) criteria. The reported duration of the current major depressive episode is at least 3 months. 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. Presence or history of a clinically significant neurological disorder (including epilepsy). Neurodegenerative disorder (Alzheimer disease, Parkinson disease, multiple sclerosis, Huntington disease, etc). Any Axis II disorder that might compromise the study. 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 (MADRS) or has made a suicide attempt in the previous 6 months. The current depressive symptoms of the patient are considered by the investigator to have been resistant to 2 adequate antidepressant treatments of at least 6 weeks duration each. Has received electroconvulsive therapy within 6 months prior to Screening. Is currently receiving formal cognitive or behavioral therapy, systematic psychotherapy, or plans to initiate such therapy during the study.

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 2.5 mg<br>Vortioxetine 2.5 mg, encapsulated tablets, orally, once daily for up to 8 weeks, then placebo-matching capsules, orally, once daily, for 1 week following the treatment period. | Drug: Vortioxetine<br>* Encapsulated vortioxetine immediate-release tablets<br>* Other names: Brintellix®;|
| Experimental: Vortioxetine 5 mg<br>Vortioxetine 5 mg, encapsulated tablets, orally, once daily for up to 8 weeks, then placebo-matching capsules, orally, once daily, for 1 week following the treatment period. | Drug: Vortioxetine<br>* Encapsulated vortioxetine immediate-release tablets<br>* Other names: Brintellix®;|
| Active Comparator: Duloxetine 60 mg<br>Duloxetine 60 mg, capsules, orally, once daily for up to 8 weeks, then duloxetine 30 mg capsules, orally, once daily for 1 week after the treatment period. | Drug: Duloxetine<br>* Duloxetine capsules<br>* Other names: Cymbalta®;|
| Placebo Comparator: Placebo<br>Placebo-matching capsules, orally, once daily for up to 9 weeks. | Drug: Placebo<br>* 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 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. Least squares (LS) means were from an Analysis of Covariance (ANCOVA) model with terms for treatment and center as factors and the Baseline rank value as a covariate. | Baseline and Week 8 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 ranges from 0 to 74 where a higher score indicates a greater depressive state. LS means were from an ANCOVA model with terms for treatment and center as factors and the Baseline rank value as a covariate. | Baseline and Weeks 1, 2, 4, and 6 | 
| Percentage of Responders in HAM-D 24 Total Score by Study Visit | 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, 6 and 8. | 
| Percentage of Participants With a Sustained Response in HAM-D24 | 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. | 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 Montgomery Åsberg Depression Rating Scale (MADRS) Total Score | 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 an ANCOVA model with treatment and center as fixed factors and the Baseline value as a covariate. | Baseline and Weeks 1, 2, 4, 6 and 8 | 
| Clinical Global Impression Scale-Global Improvement Scale | 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 were from an ANCOVA model with treatment and center as fixed factors and the CGI-S Baseline value as a covariate. | Baseline and Weeks 1, 2, 4, 6 and 8. | 
| Change From Baseline in Montgomery-Åsberg Depression Rating Scale - Self-assessment (MADRS-S) | The MADRS-S is a patient-reported outcome measure based on MADRS, administered to evaluate treatment effectiveness in depression. This scale consists of 9 items assessing patients' mood, feelings of unease, sleep, appetite, ability to concentrate, initiative, emotional involvement, pessimism and zest for life. Each item is scored between 0 (best) and 3 (worst). The total score is calculated by summing the answers of the nine items, ranging between 0 and 27 (higher scores indicate increased impairment). LS means are from an ANCOVA model with treatment and center as fixed factors and the Baseline value as a covariate. | Baseline and Weeks 1, 4 and 8 | 
| Change From Baseline in the Hamilton Anxiety Scale (HAM-A) Total Score | 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 an ANCOVA model with treatment and center as fixed factors and the Baseline value as a covariate. | Baseline and Weeks 1, 2, 4, 6 and 8. | 
| Change From Baseline in the Clinical Global Impression Scale-Severity of Illness Scale | The Clinical Global Impression - Severity scale (CGI-S) is a 7-point scale that requires the clinician to rate the severity of the patient'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 were from an ANCOVA model with treatment and center as fixed factors and the Baseline value as a covariate. | Baseline and Weeks 1, 2, 4, 6 and 8. | 
| 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 were from an ANCOVA model with treatment and center as fixed factors and the Baseline value as a covariate. | Baseline and Week 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 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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Major Depressive Disorder, Depression, Drug Therapy, Major Depressive Episode