Investigating the Effect of Vortioxetine in Adult ADHD Patients

Study Overview
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Brief Summary
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The purpose is to determine the effect of vortioxetine treatment on ADHD symptoms in adult patients with ADHD in a 12 weeks study.

Detailed Description
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The study employed the Sequential Parallel Comparison Design (SPCD), a clinical study design which intend to increase signal detection by using two stages of treatment: Stage 1 - first 6 weeks of the 12-weeks treatment period (Visit 2/Baseline 1 to Visit 5/Week 6) Stage 2 - last 6 weeks of the 12-weeks treatment period (Visit 5/Baseline 2 to Visit 8/Week 12) In Stage 1, patients were randomized to placebo or vortioxetine 10 or 20mg. Patients on vortioxetine 10 or 20mg/day during Stage 1 remained on the same treatment in Stage 2. Responders to placebo in Stage 1 remained on Placebo in Stage 2. Patients who were placebo non-responders during Stage 1, defined as patients with a <30% reduction in AISRS total score from Baseline 1, were re-randomized to placebo or vortioxetine 10 or 20mg/day in Stage 2.

Official Title
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Interventional, Randomised, Double-blind, Placebo-controlled, Fixed-dose Study of Vortioxetine in Adults With Attention Deficit Hyperactivity Disorder (ADHD)

Conditions
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Attention Deficit Hyperactivity Disorder

Intervention / Treatment
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* Drug: vortioxetine 10 mg tablet
* Drug: vortioxetine 20 mg tablet
* Other: Placebo tablet


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: The patient is willing and able to attend study appointments within the specified time windows. The patient is an outpatient. The patient is diagnosed with a primary diagnosis of ADHD according to the DSM-5™ classification. The patient has an AISRS total score ≥24. The patient has a CGI-S rating ≥4 (moderately ill or worse). Exclusion Criteria: The patient has previously been treated with vortioxetine. The patient has any current psychiatric disorder (DSM-IV-TR™ criteria), other than ADHD, as assessed using the Mini International Neuropsychiatric Interview (MINI). The patient has a known first-degree relative with bipolar disorder. The patient suffers from intellectual disability as evaluated by the Wechsler Abbreviated Scale of Intelligence (WASI) II vocabulary and matrix. The patient suffers from organic mental disorders, or mental disorders due to a general medical condition (DSM-5™ criteria). The patient has reported current use of, or has tested positive for, drugs of abuse (opiates, methadone, cocaine, amphetamines [including ecstasy], barbiturates, benzodiazepines, and cannabinoids). If a patient tests positive for opiates due to incidental use of codeine containing medication, as assessed in a clinical interview, the drug screen may be repeated up to three weeks later but the retest result must be available from the central laboratory latest at Visit 2 and has to be negative for this patient to be eligible for enrolment. If a patient tests positive for amphetamines due to his/her ADHD current treatment, as confirmed by a clinical interview, the patient is eligible for enrolment provided this treatment is discontinued two weeks prior to the Baseline Visit. The patient has a history of two prior failed (<50% improvement in symptoms) adequate trials of ADHD treatment. The patient has any other disorder for which the treatment takes priority over treatment of ADHD or is likely to interfere with study treatment or impair treatment compliance. The patient has a history of moderate or severe head trauma or other neurological disorders or systemic medical diseases that are, in the investigator's opinion, likely to affect central nervous system functioning. The patient has attempted suicide within the last 6 months or is at significant risk of suicide (either in the opinion of the Investigator or defined as a yes to suicidal ideation questions 4 or 5 or answering yes to suicidal behaviour on the Columbia-Suicide Rating Scale (C-SSRS) within the last 12 months). Other protocol defined inclusion and exclusion criteria do apply

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 55 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 |
| --- | --- |
| Experimental: vortioxetine 10 mg tablet<br>In Stage 1, patients will receive vortioxetine 10mg/day for 6 weeks. In Stage 2, patients who received vortioxetine 10mg/day in Stage 1 will continue on the same treatment for additionally 6 weeks. Placebo non-responders will be re-randomized to placebo, or vortioxetine 10 or 20mg/day for additionally 6 weeks. | Drug: vortioxetine 10 mg tablet<br>* Oral tablets, once daily<br>* Other names: Trintellix®;|
| Experimental: vortioxetine 20 mg tablet<br>In Stage 1, patients will receive vortioxetine 20mg/day for 6 weeks. In Stage 2, patients who received vortioxetine 20mg/day in Stage 1 will continue on the same treatment for additionally 6 weeks. Placebo non-responders will be re-randomized to placebo, or vortioxetine 10 or 20mg/day for additionally 6 weeks. | Drug: vortioxetine 20 mg tablet<br>* Oral tablets, once daily<br>* Other names: Trintellix®;|
| Placebo Comparator: Placebo tablet<br>In Stage 1, the patients will receive placebo for 6 weeks. In Stage 2, placebo responders will continue on placebo for additionally 6 weeks. Placebo non-responders will be re-randomized to placebo, or vortioxetine 10 or 20mg/day for additionally 6 weeks. | Other: Placebo tablet<br>* Oral tablets, once daily<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in ADHD Investigator Symptom Rating Scale (AISRS) Total Score | AISRS: an 18-item scale administered by the investigator. It included 9 items that evaluated symptoms of inattention and 9 items that evaluated symptoms of impulsivity and hyperactivity. Each item was rated from 0 (none) to 3 (severe). AISRS total score was calculated as sum of all the items on the scale and ranged from 0 to 54. A higher score corresponded to a worse severity of ADHD. | Baseline to Week 6 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Inattention/Meta-cognition: Change in Behavior Rating Inventory of Executive Function - Adult Version (BRIEF-A) Using Metacognition Index | The Metacognition Index (MI) is an index score of the BRIEF-A consisting of 5 scales: initiate, working memory, plan/organise, task monitor, and organization of materials. Each item is rated on a 3-point scale with the numeric score of 1 to 3. Raw scale scores are used to generate T-scores. A reduction in score indicates less impairment. | Baseline to Week 6 | 
| Cognitive Function/Global Executive Function: Change in BRIEF-A Using the Global Executive Composite Score | BRIEF-A is a validated questionnaire composed of 75-item within nine non-overlapping scales: 4 scales in the Behavioral Regulation Index (BRI) (inhibit, shift, emotional control, and self-monitor), and 5 scales in the Metacognition Index (MI) (initiate, working memory, plan/organise, task monitor, and organization of materials). Each item is rated on a 3-point scale with the numeric score of 1 to 3. The BRIEF-A yields an overall score (Global Executive Composite) composed of two index scores, the MI and the BRI. Raw scale scores are used to generate T-scores. A reduction in score indicates less impairment. | Baseline to Week 6 | 
| Overall Functioning: Change in Sheehan Disability Scale (SDS) Total Score | The SDS comprises a series of patient rated scales designed to measure impairment. The patient rates the extent to which his or her (1) work, (2) social life or leisure activities and 3) home life or family responsibilities are impaired on a 10-point visual analogue scale, on which 0 = normal functioning and 10 = severe functional impairment. The number of days lost and the number of underproductive days last from work/school due to symptoms are also captured. The total score is calculated as a sum of the 3 visual analogue scales, ranges from 0 to 30. A higher score represents more severe functional impairment. A reduction in score indicates less impairment. | Baseline to Week 6 | 
| Productivity: Change in Work Limitations Questionnaire (WLQ) Productivity Loss Score | The WLQ is a patient self-rated scale designed to assess on-the-job impact of chronic health problems and/or treatment. The WLQ consists of 25 items in 4 dimensions: limitations handling time (5 items), physical work demands (6 items), mental-interpersonal work demands (9 items), and output demands (5 items). Each item is rated on a 5-point scale from All of the Time (score 5) to None of the Time (score 0), or Does Not Apply to My Job. The WLQ Productivity Loss Score is derived from the Global Productivity Index, which is calculated as a weighed sum of the 4 dimensions. Reduction in WLQ Productivity Loss score indicates less work limitation and represents the estimated percentage of productivity loss in the past two weeks due to presenteeism relative to a healthy benchmark sample. WLQ Productivity Loss Score ranges from 0% to 24,9%. | Baseline to Week 6 | 
| Change in AISRS Inattention Sub-score | The AISRS inattentive subscale score consists of 9 items from the AISRS which address inattention. Each item is rated from 0 to 3. The AISRS inattentive subscale score can range from 0 to 27. A higher score corresponds to a worse severity of ADHD inattentiveness. | Baseline to Week 6 | 
| Change AISRS Hyperactivity/Impulsivity Sub-score | The AISRS hyperactive/impulsive subscale score consists of 9 items from the AISRS which address hyperactivity and impulsivity. Each item is rated from 0 to 3. The AISRS hyperactive/impulsive subscale score can range from 0 to 27. A higher score corresponds to a worse severity of ADHD hyperactivity/impulsivity. | Baseline to Week 6 | 
| Percentage of Patients Responding (Response Defined as 30% or Greater Reduction From Baseline in AISRS Total Score) | AISRS: an 18-item scale administered by the investigator. It included 9 items that evaluated symptoms of inattention and 9 items that evaluated symptoms of impulsivity and hyperactivity. Each item was rated from 0 (none) to 3 (severe). AISRS total score was calculated as sum of all the items on the scale and ranged from 0 to 54. A higher score corresponded to a worse severity of ADHD. | Baseline to Week 6 | 
| Change in Adult ADHD Self-Report Scale (ASRS) Total Score | The Adult ADHD Self-Report Scale (ASRS) is a patient-rated scale designed to assess the ADHD symptoms in adults based on the diagnostic criteria of DSM-IVTM. The ASRS consist of 18 items, each rated on a 5-point scale from Never to Very Often. The categories Never and Rarely were combined when calculating the total score to mirror the scoring of the AISRS, with 0 representing Never/Rarely and 3 representing Very Often. The Total Score ranges from 0 to 54. A reduction in score indicates less severity of ADHD. | Baseline to Week 6 | 
| Change in Clinical Global Impression - Severity of Illness (CGI-S) Score | The Clinical Global Impression - Severity of Illness (CGI-S) provides the clinician's impression of the patient's current state of mental illness. The clinician uses his or her clinical experience of this patient population to rate the severity of the patient's current mental illness on a 7-point scale ranging from 1 (Normal - not at all ill) to 7 (among the most extremely ill patients). Higher scores indicate worsening. | Baseline to Week 6 | 
| Clinical Global Impression - Global Improvement (CGI-I) Score | The Clinical Global Impression - Global Improvement (CGI-I) provides the clinician's impression of the patient's improvement (or worsening). The clinician assesses the patient's condition relative to a baseline on a 7-point scale ranging from 1 (very much improved) to 7 (very much worse). Higher scores indicate worsening. | Week 6 | 
| Response (Defined as a CGI-I Score of 1 or 2), Stage 1 | The Clinical Global Impression - Global Improvement (CGI-I) provides the clinician's impression of the patient's improvement (or worsening). The clinician assesses the patient's condition relative to a baseline on a 7-point scale ranging from 1 (very much improved) to 7 (very much worse). Higher scores indicate worsening. | Week 6 | 
| Change in BRIEF-A Using the Behavioural Regulation Index | The Behavioral Regulation Index (BRI) is an index score of the BRIEF-A and consists of 4 scales: inhibit, shift, emotional control, and self-monitor). Each item is rated on a 3-point scale with the numeric score of 1 to 3. Raw scale scores are used to generate T-scores. A reduction in score indicates less impairment. | Baseline to Week 6 | 
| Change in BRIEF-A Subscales - Inhibit | The BRIEF-A subscale Inhibit is a subscale within the Behavioural Regulation Index (BRI). Each item is rated on a 3-point scale ranging from 1 (never) to 3 (often). Raw scale scores are used to generate T-scores. A reduction in score indicates less impairment. | Baseline to Week 6 | 
| Change BRIEF-A Subscales - Initiate | The BRIEF-A subscale Initiate is a subscale within the Behavioural Regulation Index (BRI). Each item is rated on a 3-point scale ranging from 1 (never) to 3 (often). Raw scale scores are used to generate T-scores. A reduction in score indicates less impairment. | Baseline to Week 6 | 
| Change in BRIEF-A Subscales - Organization of Materials | The BRIEF-A subscale Organization of Materials is a subscale within the Behavioural Regulation Index (BRI). Each item is rated on a 3-point scale ranging from 1 (never) to 3 (often). Raw scale scores are used to generate T-scores. A reduction in score indicates less impairment. | Baseline to Week 6 | 
| Change in BRIEF-A Subscales - Planning/Organize | The BRIEF-A subscale Planning/Organize is a subscale within the Behavioural Regulation Index (BRI). Each item is rated on a 3-point scale ranging from 1 (never) to 3 (often). Raw scale scores are used to generate T-scores. A reduction in score indicates less impairment. | Baseline to Week 6 | 
| Change in BRIEF-A Subscales - Shift | The BRIEF-A subscale Shift is a subscale within the Behavioural Regulation Index (BRI). Each item is rated on a 3-point scale ranging from 1 (never) to 3 (often). Raw scale scores are used to generate T-scores. A reduction in score indicates less impairment. | Baseline to Week 6 | 
| Change in BRIEF-A Subscales - Self Monitor | The BRIEF-A subscale Self Monitor is a subscale within the Behavioural Regulation Index (BRI). Each item is rated on a 3-point scale ranging from 1 (never) to 3 (often). Raw scale scores are used to generate T-scores. A reduction in score indicates less impairment. | Baseline to Week 6 | 
| Change in BRIEF-A Subscales - Task Monitor | The BRIEF-A subscale Task Monitor is a subscale within the Behavioural Regulation Index (BRI). Each item is rated on a 3-point scale ranging from 1 (never) to 3 (often). Raw scale scores are used to generate T-scores. A reduction in score indicates less impairment. | Baseline to Week 6 | 
| Change in BRIEF-A Subscales - Working Memory | The BRIEF-A subscale Working Memory is a subscale within the Behavioural Regulation Index (BRI). Each item is rated on a 3-point scale ranging from 1 (never) to 3 (often). Raw scale scores are used to generate T-scores. A reduction in score indicates less impairment. | Baseline to Week 6 | 
| Change in BRIEF-A Subscales - Emotional Control | The BRIEF-A subscale Emotional Control is a subscale within the Behavioural Regulation Index (BRI). Each item is rated on a 3-point scale ranging from 1 (never) to 3 (often). Raw scale scores are used to generate T-scores. A reduction in score indicates less impairment. | Baseline to Week 6 | 
| Change in Perceived Deficits Questionnaire - Depression (PDQ-D) Total Score | The PDQ-D is a patient-rated scale designed to assess cognitive impairment/dysfunction adapted for MDD. Each item is rated on a scale from 0 (never) to 4 (almost always). The total score of the 20 items ranges from 0 to 80 with higher scores reflect greater subjective cognitive impairment. A reduction in score indicates less impairment. | Baseline to Week 6 | 
| Change in PDQ-D Subscales - Attention and Concentration Sub-score | The PDQ-D attention/concentration sub-score consists of items 1, 5, 9, 13, and 17 of the PDQ with a score ranging from 0 to 20. A higher score reflects greater subjective cognitive impairment. A reduction in score indicates less cognitive impairment. | Baseline to Week 6 | 
| Change in PDQ-D Sub-scales - Retrospective Memory Sub-score | The PDQ-D retrospective memory sub-score consists of items 2, 6, 10, 14, and 18 of the PDQ (see Outcome 23) with a score ranging from 0 to 20. A higher score reflects greater subjective cognitive impairment. A reduction in score indicates less cognitive impairment. | Baseline to Week 6 | 
| Change in PDQ-D Sub-scales - Prospective Memory Sub-score | The PDQ-D prospective memory sub-score consists of items 3, 7, 11, 15, and 19 of the PDQ (see Outcome 23) with a score ranging from 0 to 20. A higher score reflects greater subjective cognitive impairment. A reduction in score indicates less cognitive impairment. | Baseline to Week 6 | 
| Change in PDQ-D Sub-scales - Planning and Organisation Sub-score | The PDQ-D planning and organisation sub-score consists of items 4, 8, 12, 16, and 20 of the PDQ (see Outcome 23) with a score ranging from 0 to 20. A higher score reflects greater subjective cognitive impairment. A reduction in score indicates less cognitive impairment. | Baseline to Week 6 | 
| Change in SDS Item Scores - Family | The SDS item family is rated from 0 = normal functioning to 10 = severe functional impairment (see outcome 4). A higher score represents more severe functional impairment. A reduction in score indicates less impairment. | Baseline to Week 6 | 
| Change in SDS Item Scores - Work | The SDS item work is rated from 0 = normal functioning to 10 = severe functional impairment (see outcome 4). A higher score represents more severe functional impairment. A reduction in score indicates less impairment. | Baseline to Week 6 | 
| Change in SDS Item Scores - Social Life | The SDS item social life is rated from 0 = normal functioning to 10 = severe functional impairment (see outcome 4). A higher score represents more severe functional impairment. A reduction in score indicates less impairment. | Baseline to Week 6 | 
| Change in SDS Item Scores - Number of Days Lost | This SDS item captures days lost from school or work (see outcome 4). | Baseline to Week 6 | 
| Change in SDS Item Scores - Number of Underproductive Days | This SDS item captures the number of underproductive days (see outcome 4) | Baseline to Week 6 | 
| Change in WLQ Using the Global Productivity Index | The WLQ is a patient self-rated scale designed to assess on-the-job impact of chronic health problems and/or treatment. The WLQ consists of 25 items in 4 dimensions: limitations handling time (5 items), physical work demands (6 items), mental-interpersonal work demands (9 items), and output demands (5 items). Each item is rated on a 5-point scale from All of the Time (score 5) to None of the Time (score 0), or Does Not Apply to My Job. The Global Productivity Index is calculated as a weighed sum of the 4 dimensions, and ranges from 0.000 to 0.286. Reduction in score indicates less work limitation. | Baseline to Week 6 | 
| Change in WLQ Domain Scores - Limitations Handling Time | Limitations Handling Time is scored on a scale of 0 (limited at work none of the time) to 100 (limited at work all of the time) based on a converted mean score. A reduction in score indicates less work limitation. | Baseline to Week 6 | 
| Change in WLQ Domain Scores - Mental-Interpersonal Work Demands | Mental-Interpersonal Work Demands is scored on a scale of 0 (limited at work none of the time) to 100 (limited at work all of the time) based on a converted mean score. A reduction in score indicates less work limitation. | Baseline to Week 6 | 
| Change in WLQ Domain Scores - Physical Demands | Physical Demands is scored on a scale of 0 (limited at work none of the time) to 100 (limited at work all of the time) based on a converted mean score. A reduction in score indicates less work limitation. | Baseline to Week 6 | 
| Change in WLQ Domain Scores - Output Demands | Output Demands is scored on a scale of 0 (limited at work none of the time) to 100 (limited at work all of the time) based on a converted mean score. A reduction in score indicates less work limitation. | Baseline to Week 6 | 
| Change in Adult ADHD Quality of Life Measure (AAQoL) Total Score | The AAQoL is a patient-rated scale designed to assess health-related quality of life in adults with ADHD. The AAQoL consists of 29 items, each item is rated on a 5-point scale from 1 (not at all/never) to 5 (extremely/very often). The AAQoL Total score is based on all 29 items and ranges from 29 to 145. A reduction in score indicates less impairment. | Baseline to Week 6 | 
| Change in AAQoL Subscales - Life Productivity Sub-score | The AAQoL is a patient-rated scale designed to assess health-related quality of life in adults with ADHD. The AAQoL consists of 29 items, each item is rated on a 5-point scale from 1 (not at all/never) to 5 (extremely/very often). The AAQoL Life productivity subscale is based on 11 items and ranges from 11 to 55. A reduction in score indicates less impairment. | Baseline to Week 6 | 
| Change in AAQoL Subscales - Psychological Health Sub-score | The AAQoL is a patient-rated scale designed to assess health-related quality of life in adults with ADHD. The AAQoL consists of 29 items, each item is rated on a 5-point scale from 1 (not at all/never) to 5 (extremely/very often). The AAQoL Psychological Health subscale is based on 6 items and ranges from 6 to 30. A reduction in score indicates less impairment. | Baseline to Week 6 | 
| Change in AAQoL Subscales - Life Outlook Sub-score | The AAQoL is a patient-rated scale designed to assess health-related quality of life in adults with ADHD. The AAQoL consists of 29 items, each item is rated on a 5-point scale from 1 (not at all/never) to 5 (extremely/very often). The AAQoL Life Outlook subscale is based on 7 items and ranges from 7 to 35. A reduction in score indicates less impairment. | Baseline to Week 6 | 
| Change in AAQoL Subscales - Relationships Sub-score | The AAQoL is a patient-rated scale designed to assess health-related quality of life in adults with ADHD. The AAQoL consists of 29 items, each item is rated on a 5-point scale from 1 (not at all/never) to 5 (extremely/very often). The AAQoL Relationship subscale is based on 5 items and ranges from 5 to 25. A reduction in score indicates less impairment. | Baseline to Week 6 |