Safety and Tolerability 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 long-term 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 people who have major depressive disorder (MDD). This study looked at MDD relief in people who took vortioxetine. The study enrolled 836 patients that had completed one of two other vortioxetine studies. Participants received 5 mg of vortioxetine for the first week of treatment. After completing the first week of treatment, the dose could be increased to 10 mg/day or decreased to 2.5 mg/day based on participant's response as judged by the doctor. All participants were asked to take one encapsulated tablet at the same time each day throughout the study. This multi-center trial was conducted worldwide. The overall time to participate in this study was up to 56 weeks. Participants made 13 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 Long-Term, Open-Label, Flexible-Dose, Extension Study Evaluating the Safety and Tolerability of Lu AA21004 in Subjects With Major Depressive Disorder

Conditions
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Major Depressive Disorder

Intervention / Treatment
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* Drug: Vortioxetine


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Has completed the double blind treatment period of either study Lu AA21004_304 (NCT00672620) or LuAA21004_305 (NCT00735709) immediately prior to enrollment in the extension study (ie, the baseline visit is the same visit as the completion visit of the double blind treatment of the preceding protocol). 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 (classification code 296.xx) at entry into the prior Lu AA21004_304 or Lu AA21004_305 study. Exclusion Criteria: In addition to meeting the exclusion criteria for studies Lu AA21004_304 or Lu AA21004_305 at the time of enrollment into those studies respectively, with the exception of the criteria prohibiting previous exposure to Lu AA21004 and investigational drugs, and the criteria prohibiting patients with increased intraocular pressure, or risk of acute narrow-angle glaucoma, the following exclusion criteria apply: Has Major Depressive Disorder for whom other psychiatric disorders (mania, bipolar disorder, schizophrenia, or any psychotic disorder) have been diagnosed during the prior study. The participant, in the investigator's opinion, has a significant risk of suicide and/or a score of ≥5 points on item 10 (suicidal thoughts) of the Montgomery Åsberg Depression Rating Scale. The participant, in the opinion of the investigator, is unlikely to comply with the clinical study protocol or is unsuitable for any reason. Has a clinically significant moderate or severe ongoing adverse event related to study medication from the prior study. Has used/uses disallowed concomitant medication.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 76 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
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Vortioxetine<br>Vortioxetine 2.5 mg, 5 mg or 10 mg, encapsulated tablets, orally, once daily for up to 52 weeks. For the first week of treatment all participants received 5 mg/day vortioxetine, thereafter, the dose could be increased to 10 mg/day or decreased to 2.5 mg/day, based on participant's response and tolerability as judged by the investigator. | Drug: Vortioxetine<br>* Encapsulated vortioxetine immediate-release tablets<br>* Other names: Brintellix®;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Physical Examination Findings | Physical examination consisted of the following body systems: (1) appearance; (2) extremities; (3) skin; (4) head and neck; (5) eyes, ears, nose, and throat; (6) lungs and chest; (7) heart and cardiovascular system; (8) abdomen; and (9) musculoskeletal system. An assessment of the nervous system was conducted; any findings were captured under the appropriate body area. Each system was assessed as normal or abnormal. | Baseline and Week 52 | 
| Number of Participants With Potentially Clinically Significant Laboratory Evaluation Findings | Participants with at least one post-baseline potentially clinically significant (as defined in the table below) serum chemistry, hematology or urinalysis result. ULN = upper limit of normal; LLN = Lower limit of normal. | Weeks 4, 8, 12, 20, 28, 36, 44 and 52 | 
| Number of Participants With Potentially Clinically Significant Electrocardiogram (ECG) Findings | A standard 12-lead ECG was performed at the designated study visits. The central reader reviewed and recorded the intervals (PR, QRS, RR, QT, and corrected QT interval [QTc]), and interpreted the ECG using 1 of the following categories: within normal limits or abnormal. The number of participants with at least one post-baseline potentially clinically significant ECG finding is reported. bpm = beats per minute; QTcB = QT interval corrected using Bazett's formula; QTcF = QT interval corrected using Fridericia's formula. | Weeks 4, 12, 24, 36 and 52 | 
| Number of Participants With Adverse Events (AEs) | The intensity (severity) of each AE was defined as: Mild: caused minimal discomfort and did not interfere in a significant manner with normal activities. Moderate: sufficiently uncomfortable to produce some impairment of normal activities. Severe: incapacitating, preventing the patient from participating in normal activities. The causal relationship between an AE and study drug was assessed by the investigator as Probable, Possible or Not Related; Related=AEs with causality of Possibly or Probably. A serious AE (SAE) was defined as any untoward medical occurrence that resulted in death, was life-threatening, required inpatient hospitalization or prolongation of existing hospitalization, resulted in persistent or significant disability/incapacity, led to a congenital anomaly/birth defect, or was an important medical event that either jeopardized the patient, required intervention to prevent any of the SAEs defined above, a suicide attempt or an abortion. | From the first dose of open-label study drug until 4 weeks after the last dose (up to 56 weeks) | 
| Number of Participants With Potentially Clinically Significant Vital Sign Findings | Participants with at least one potentially clinically significant post-baseline vital sign finding. The definition of clinically significant is included in the table below for each parameter. SSBP = supine systolic blood pressure; SDBP = supine diastolic blood pressure. | Weeks 1, 2, 4, 8, 12, 16, 20, 24, 28, 36, 44 and 52 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in Hamilton Depression Scale-24 Item (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. Final Visit includes data from Week 52 or earlier for participants who didn't complete the 52 weeks. | Baseline and Weeks 1, 2, 4, 8, 12, 16, 20, 24, 28, 36, 44 and 52. | 
| 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). Decrease in the total score or on individual items indicates improvement. Final Visit includes data from Week 52 or earlier for participants who didn't complete the 52 weeks. | Baseline and Weeks 4, 24 and 52 | 
| 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. Final Visit includes data from Week 52 or earlier for participants who didn't complete the 52 weeks. | Baseline and Weeks 4, 24 and 52 | 
| Change From Baseline in the Clinical Global Impression of 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. Final Visit includes data from Week 52 or earlier for participants who didn't complete the 52 weeks. | Baseline and Weeks 4, 24 and 52 | 
| Change From Baseline to the Final Visit in 36-item Short-form Health Survey (SF-36) | 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 8 health concepts are: 1. Limitation in physical activities because of health problems. 2. Limitations in usual role activities because of physical health problems. 3. Bodily pain. 4. Limitations in social activities because of physical or emotional problems. 5. General mental health (psychological distress and well-being). 6. Limitations in usual role activities because of emotional problems. 7. Vitality (energy and fatigue). 8. General health perception. Each scale ranges from 0 (best) - 100 (worst). | Baseline and Week 52 | 
| Change From Baseline to the Final Visit in the Sheehan Disability Scale | The Sheehan Disability Scale (SDS) 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. | Baseline and Week 52 | 
| Health Care Resource Utilization 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 52 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Major Depressive Disorder, Depression, Melancholia, Mood Disorder, Dysthymic Disorder, Drug Therapy