Efficacy and Safety of Vortioxetine (Lu AA21004) for Treatment of Generalized Anxiety Disorder in Adults.

Study Overview
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Brief Summary
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The purpose of this study is to evaluate the efficacy and safety of vortioxetine, once daily (QD), in adults with Generalized Anxiety Disorders.

Detailed Description
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The drug that was tested in this study is called Vortioxetine. Vortioxetine is being tested to treat anxiety in adults who have general anxiety disorder (GAD). This study looked at GAD relief in people who took vortioxetine. The study enrolled 301 patients. Participants were randomly assigned (by chance, like flipping a coin) to one of the two treatment groups-which remained undisclosed to the patient and study doctor during the study (unless there was an urgent medical need): Vortioxetine 5 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-center trial was conducted in Europe. The overall time to participate in this study was up to 13 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 a Single Dose of Lu AA21004 in Acute Treatment of Adults With Generalized Anxiety Disorder

Conditions
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Generalized Anxiety 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: Suffers from a primary diagnosis of Generalized Anxiety Disorder according to Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision (DSM-IV-TR) criteria. Has a Hamilton Anxiety Scale total score ≥20 at Screening and Baseline. Has a Hamilton Anxiety Scale score ≥2 on both Item 1 (anxious mood) and Item 2 (tension) at Screening and Baseline. Has a Montgomery-Åsberg Depression Rating Scale total score ≤16 at Screening and Baseline. Male and females of childbearing potential who are sexually active agree 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 received any investigational compound <30 days before Screening or 5 half-lives prior to Screening. Has received Lu AA21004 in a previous clinical study or as a therapeutic agent. Has 1 or more of the following: Any current psychiatric disorder other than Generalized Anxiety 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's disease, Parkinson's disease, multiple sclerosis, Huntington disease, etc). Any Axis II disorder that might compromise the study. Is required to take excluded medications or it is anticipated that the participant will require treatment with at least 1 of the disallowed concomitant medications during the study including: Nonsteroidal anti-inflammatory drugs Rifampin Macrolide antibiotics Hormones Hypoglycemic agents and Insulin Systemic steroids Antineoplastics Antiobesity agents Antidiarrheal agents (episodic use allowed) Antifungal agents (episodic topical use allowed) Antihistamines (episodic use of loratadine, desloratadine, cetirizine allowed) Cough/cold agents (episodic use allowed but preparations containing pseudoephedrine and narcotics are NOT allowed) Diuretics (episodic use allowed) 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. 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. Is currently receiving formal cognitive or behavioral therapy, systematic psychotherapy, or plans to initiate such therapy during the study. Has a clinically significant unstable illness, for example, hepatic impairment or renal insufficiency, or a cardiovascular, pulmonary, gastrointestinal, endocrine, neurological, rheumatologic, immunologic, infectious, skin and subcutaneous tissue disorders, or metabolic disturbance. Has an alanine aminotransferase, aspartate aminotransferase or bilirubin level >1.5 times the upper limits of normal. Has a serum creatinine of >1.5 times the upper limits of normal. Has a previous history of cancer that had been in remission for less than 5 years prior to the first dose of study medication. This criterion does not include those participants with basal cell or stage I squamous cell carcinoma of the skin. Has clinically significant abnormal vital signs as determined by the investigator. Has 1 or more laboratory values outside the normal range, based on the blood or urine samples taken at Screening, that are considered by the investigator to be clinically significant. Has thyroid stimulating hormone value outside the normal range at Screening and is deemed clinically significant by the investigator. Has an abnormal electrocardiogram as determined by the central reader and confirmed as clinically significant by the investigator. Has a disease or takes medication that, in the opinion of the investigator, could interfere with the assessments of safety, tolerability, or efficacy. Has previously participated in this study.

Ages Eligible for Study
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Minimum Age: 18 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: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: Placebo<br>Vortioxetine placebo-matching capsules, orally, once daily for up to 8 weeks. | Drug: Placebo<br>* Vortioxetine placebo-matching capsules<br>|
| Experimental: Vortioxetine 5 mg<br>Vortioxetine 5 mg, encapsulated tablets, orally, once daily for up to 8 weeks. | 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 |
| --- | --- | --- |
| Change From Baseline in the Hamilton Anxiety Scale (HAM-A) Total Score at Week 8 | 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. Least Squares (LS) means were 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 the Hospital Anxiety and Depression (HAD) Anxiety Subscale at Week 8 | The Hospital Anxiety and Depression (HAD) Anxiety sub-scale consists of 7 items that are assessed on a scale from 0 (no anxiety) to 3 (severe feeling of anxiety). The anxiety subscale determines a state of generalized anxiety including anxious mood, restlessness, anxious thoughts and panic attacks. Scores are summed and range from 0 to 21 (maximal severity). LS means were from a 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 were from a MMRM with baseline-by-week, center, week and week-by-treatment as factors in the analysis. | Baseline to Week 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 a 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-A Total Score at Week 8 | Response was defined as participants with a ≥ 50% decrease 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 (symptoms absent) to 56 (maximum severity). | Baseline and Week 8 | 
| Change From Baseline in the Hamilton Anxiety Scale (HAM-A) Total Score at Week 8 in Participants With Baseline HAM-A ≥25 | 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 were from a MMRM with Baseline-by-week, center, week and week-by-treatment as factors in the analysis. | Baseline to Week 8 | 
| Change From Baseline in 36-Item Short-Form Health Survey (SF-36) Social Functioning Subscore at Week 8 | 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 were from a MMRM with Baseline-by-week, center, week and week-by-treatment as factors in the analysis. | Baseline to Week 8 | 
| Change From Baseline in Hamilton Anxiety Scale (HAM-A) Total Score at Other Weeks 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 were from a MMRM with Baseline-by-week, center, week and week-by-treatment as factors in the analysis. | Baseline to Weeks 1, 2, 4 and 6. | 
| Change From Baseline in the Hospital Anxiety and Depression (HAD) Anxiety Subscale at Other Weeks Assessed | The Hospital Anxiety and Depression (HAD) Anxiety sub-scale consists of 7 items that are assessed on a scale from 0 (no anxiety) to 3 (severe feeling of anxiety). The anxiety subscale determines a state of generalized anxiety including anxious mood, restlessness, anxious thoughts and panic attacks. Scores are summed and range from 0 to 21 (maximal severity). LS means were from a MMRM with Baseline-by-week, center, week and week-by-treatment as factors in the analysis. | Baseline to Weeks 1 and 4 | 
| Clinical Global Impression Scale-Global Improvement at Other Weeks Assessed | 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 a MMRM with Baseline-by-week, center, week and week-by-treatment as factors in the analysis. | Baseline to 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 were from a MMRM with Baseline-by-week, center, week and week-by-treatment as factors in the analysis. | Baseline to Weeks 1, 2 and 4 | 
| Percentage of Responders in HAM-A Total Score at Other Weeks Assessed | Response was defined as participants with a ≥ 50% decrease 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 (symptoms absent) to 56 (maximum severity). | Baseline and Weeks 1, 2, 4 and 6 | 
| Change From Baseline in the Hamilton Anxiety Scale (HAM-A) Total Score at Other Weeks Assessed in Participants With Baseline HAM-A ≥25 | 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 were from a MMRM with Baseline-by-week, center, week and week-by-treatment as factors in the analysis. | Baseline to Weeks 1, 2, 4 and 6 | 
| Percentage of Participants in HAM-A Remission at Each Week Assessed | Remission is defined as a Hamilton Anxiety Scale (HAM-A) total score ≤ 7. 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 (symptoms absent) to 56 (maximum severity). | 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 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 a MMRM with Baseline-by-week, center, week and week-by-treatment as factors in the analysis. | Baseline to Weeks 1, 2, 4, 6 and 8 | 
| Change From Baseline in the Hospital Anxiety and Depression (HAD) Depression Subscale at Each Week Assessed | The HAD-Depression subscale is completed by the participant and measures depression, focusing on the state of lost interest and diminished pleasure response. The subscale is made up of 7 items that are assessed on a scale from 0 (no depression) to 3 (severe feeling of depression). Participants are required to indicate the response which most accurately reflects the way they have felt over the last few days. The item scores are summed and the total subscore ranges from 0 to 21 (maximal severity). LS means were from a MMRM with Baseline-by-week, center, week and week-by-treatment as factors in the analysis. | Baseline to Weeks 1, 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 were from a MMRM with Baseline-by-week, center, week and week-by-treatment as factors in the analysis. | Baseline to Weeks 2 and 4 | 
| Change From Baseline in 36-Item Short-Form Health Survey (SF-36) Physical Functioning Subscore at Each Week 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 were from a MMRM with Baseline-by-week, center, week and week-by-treatment as factors in the analysis. | Baseline to Weeks 2, 4 and 8 | 
| Change From Baseline in 36-Item Short-Form Health Survey (SF-36) Role-Physical Subscore at Each Week 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 were from a MMRM with Baseline-by-week, center, week and week-by-treatment as factors in the analysis. | Baseline to Weeks 2, 4 and 8 | 
| Change From Baseline in 36-Item Short-Form Health Survey (SF-36) Bodily Pain Subscore at Each Week 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 were from a MMRM with Baseline-by-week, center, week and week-by-treatment as factors in the analysis. | Baseline to Weeks 2, 4 and 8 | 
| Change From Baseline in 36-Item Short-Form Health Survey (SF-36) General Health Subscore at Each Week 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 were from a MMRM with Baseline-by-week, center, week and week-by-treatment as factors in the analysis. | Baseline to Weeks 2, 4 and 8 | 
| Change From Baseline in 36-Item Short-Form Health Survey (SF-36) Vitality Subscore at Each Week 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 were from a MMRM with Baseline-by-week, center, week and week-by-treatment as factors in the analysis. | Baseline to Weeks 2, 4 and 8 | 
| Change From Baseline in 36-Item Short-Form Health Survey (SF-36) Role-Emotional Subscore at Each Week 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 were from a MMRM with Baseline-by-week, center, week and week-by-treatment as factors in the analysis. | Baseline to Weeks 2, 4 and 8 | 
| Change From Baseline in 36-Item Short-Form Health Survey (SF-36) Mental Health Subscore at Each Week 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 were from a MMRM with Baseline-by-week, center, week and week-by-treatment as factors in the analysis. | Baseline to Weeks 2, 4 and 8 | 
| Health Care 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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Generalized Anxiety Disorder, Anxiety Disorders, Drug Therapy