Efficacy of Vortioxetine (Lu AA21004) in Treating Generalized Anxiety Disorder

Study Overview
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Brief Summary
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The purpose of this study is to determine the safety and efficacy of vortioxetine, once daily (QD), in adults with generalized anxiety disorder.

Detailed Description
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Participants in this study will be randomly assigned to receive either 2.5 mg, 5 mg or 10 mg of vortioxetine, once daily, 60 mg of duloxetine once daily, or a placebo once daily for eight weeks. Participants will be seen weekly during the first 2 weeks of treatment, and then every 2 weeks up to the end of the 8-week treatment period. Participants who complete the 8-week treatment period will enter a 2-week discontinuation period in order to assess potential discontinuation symptoms. Total commitment time is up to 12 weeks.

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 3 Doses 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: Placebo
* Drug: Vortioxetine
* Drug: Duloxetine


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Has a primary diagnosis of generalized anxiety disorder according to the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision (DSM-IV-TR®) criteria (classification code 300.02). Has a Hamilton Anxiety Scale total score ≥ 20. Has a Hamilton Anxiety Scale score ≥2 on both item 1 (anxious mood) and item 2 (tension). Has a Montgomery-Åsberg Depression Rating Scale total score ≤16. Exclusion Criteria: Had received any investigational compound <30 days before Screening or 5 half-lives prior to Screening, whichever is longer. Received Lu AA21004 in a previous clinical study. Was a study site employee, or an immediate family member (ie, spouse, parent, child, or sibling) of a study site employee involved in conduct of this study. Has 1 or more of the following: Any current psychiatric disorder other than Generalized Anxiety Disorder as defined in the DSM-IV-TR® (as assessed by the Mini International Neuropsychiatric Interview [MINI]). 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® and must have a 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). Any Axis II disorder that might compromise the study. Has known sensitivity to duloxetine. Is taking excluded medications 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 inhibitor 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 known history of or currently has increased intraocular pressure or is at risk of acute narrow-angle glaucoma. 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 total bilirubin level >1.5 times the upper limit of normal. Has a serum creatinine level >1.5 upper limit of normal. Has a previous history of cancer that had been in remission for less than 5 years. Hasclinically significant abnormal vital signs as determined by the investigator. Has a history of lack of response to previous adequate treatment with duloxetine for any Generalized Anxiety Disorder episode. Has 1 or more laboratory values outside the normal range, based on the blood or urine samples taken at the Screening Visit Has a thyroid stimulating hormone value outside the normal range. Has an abnormal electrocardiogram. has a disease or was taking medications that, in the opinion of the investigator, could have interfered with the assessments of safety, tolerability, or efficacy. The patient, in the opinion of the investigator, was unlikely to comply with the clinical study protocol or was unsuitable for any reason. Had previously been enrolled in this study.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 65 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 |
| --- | --- |
| Placebo Comparator: Placebo<br>Placebo-matching capsules, orally, once daily for up to 9 weeks. | Drug: Placebo<br>* Placebo-matching capsules<br>|
| Experimental: Vortioxetine 2.5 mg<br>Vortioxetine 2.5 mg encapsulated tablets, orally, once daily, for 8 weeks, followed by placebo-matching capsules, orally, once daily, for 1 week. | Drug: Placebo<br>* Placebo-matching capsules<br>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 8 weeks, followed by placebo-matching capsules, orally, once daily, for 1 week. | Drug: Placebo<br>* Placebo-matching capsules<br>Drug: Vortioxetine<br>* Encapsulated vortioxetine immediate release tablets<br>* Other names: Brintellix®;|
| Experimental: Vortioxetine 10 mg<br>Vortioxetine 10 mg encapsulated tablets, orally, once daily, for 8 weeks, followed by placebo-matching capsules, orally, once daily, for 1 week. | Drug: Placebo<br>* Placebo-matching capsules<br>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 8 weeks, followed by duloxetine 30 mg capsules, orally, once daily, for 1 week. | Drug: Duloxetine<br>* Overencapsulated duloxetine capsules<br>* Other names: Cymbalta;|

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 (HAM-A) Scale 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 week, Baseline score-by-week and treatment-by-week interaction as factors. | Baseline to Week 8 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in Hospital Anxiety and Depression (HAD) - Anxiety Subscale at Week 8 | The HAD-Anxiety subscale is completed by the participant and measures anxiety, including anxious mood, restlessness, anxious thoughts, and panic attacks. The subscale is made up of 7 items that are assessed on a scale from 0 (no anxiety) to 3 (severe feeling of anxiety). Participants are required to indicate the response which most accurately reflects the way they have felt over the last few days. Scores are summed and range from 0 to 21 (maximal severity). LS means were from a mixed model for repeated measurements (MMRM) with week, Baseline score-by-week and treatment-by-week interaction as factors. | Baseline to Week 8 | 
| Mean Clinical Global Impression Scale-Global Improvement (CGI-I) at Week 8 | The Clinical Global Impression - Global Improvement scale measures the participant's improvement (or worsening) as assessed by the investigator 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 mixed model for repeated measurements (MMRM) with week, Baseline score-by-week and treatment-by-week interaction as factors. | Baseline to Week 8 | 
| Change From Baseline in Sheehan Disability Scale (SDS) 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 mixed model for repeated measurements (MMRM) with week, Baseline score-by-week and treatment-by-week interaction as factors. | 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 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). | 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 mixed model for repeated measurements (MMRM) with week, Baseline score-by-week and treatment-by-week interaction as factors. | 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 mixed model for repeated measurements (MMRM) with week, Baseline score-by-week and treatment-by-week interaction as factors. | Baseline to Weeks 1, 2, 4 and 6 | 
| Change From Baseline in Hospital Anxiety and Depression (HAD) - Anxiety Subscale at Other Weeks Assessed | The HAD-Anxiety subscale is completed by the participant and measures anxiety, including anxious mood, restlessness, anxious thoughts, and panic attacks. The subscale is made up of 7 items that are assessed on a scale from 0 (no anxiety) to 3 (severe feeling of anxiety). Participants are required to indicate the response which most accurately reflects the way they have felt over the last few days. Scores are summed and range from 0 to 21 (maximal severity). LS means were from a mixed model for repeated measurements (MMRM) with week, Baseline score-by-week and treatment-by-week interaction as factors. | Baseline to Weeks 1 and 4 | 
| Mean Clinical Global Impression Scale-Global Improvement (CGI-I) at Other Weeks Assessed | The Clinical Global Impression - Global Improvement scale measures 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 mixed model for repeated measurements (MMRM) with week, Baseline score-by-week and treatment-by-week interaction as factors. | Baseline to Weeks 1, 2, 4 and 6 | 
| Change From Baseline in Sheehan Disability Scale (SDS) 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 mixed model for repeated measurements (MMRM) with week, Baseline score-by-week and treatment-by-week interaction as factors. | 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 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 mixed model for repeated measurements (MMRM) with week, Baseline score-by-week and treatment-by-week interaction as factors. | 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 (CGI-S) | 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 mixed model for repeated measurements (MMRM) with week, Baseline score-by-week and treatment-by-week interaction as factors. | Baseline to Weeks 1, 2, 4, 6 and 8 | 
| Change From Baseline in Hospital Anxiety and Depression (HAD) - Depression Subscale at All Weeks 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 mixed model for repeated measurements (MMRM) model with week, Baseline score-by-week and treatment-by-week interaction as factors. | Baseline to Weeks 1, 4 and 8 | 
| 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 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, Mood Disorder, Affective Disorder, Anxiety Disorder, Drug Therapy