Long-term, Open-label, Flexible-dose, Extension Study of Vortioxetine in Child and Adolescent Participants With Major Depressive Disorder (MDD) From 7 to 18 Years of Age

Study Overview
=================
Brief Summary
-----------------
Evaluation of the long-term safety and tolerability of vortioxetine in child and adolescent participants with a Diagnostic and Statistical Manual of Mental Disorders, 5th edition (DSM-5™) diagnosis of MDD.

Official Title
-----------------
Long-term, Open-label, Flexible-dose, Extension Study of Vortioxetine in Child and Adolescent Patients With Major Depressive Disorder (MDD) From 7 to 18 Years of Age

Conditions
-----------------
Depressive Disorder, Major

Intervention / Treatment
-----------------
* Drug: Vortioxetine


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: The participant is a male or female child aged ≥7 and <12 years or adolescent aged ≥12 and ≤18 years in the lead-in study (12709A and 12710A). The participant must have completed Study 12709A or 12710A (Visit 12, Completion Visit) immediately prior to enrolment into this extension study. The participant had a primary diagnosis of MDD at entry in study 12709A or 12710A, diagnosed according to DSM-5™. The participant is indicated for long-term treatment with vortioxetine according to the clinical opinion of the Investigator. For participants aged ≥7 and ≤17 years at the Baseline visit; the participant is able to understand the Informed Assent Form, and parent(s)/legal representative(s) are able to read and understand the Informed Consent Form. For participants who turned 18 years during the lead-in study 12710A; the participant has signed the Informed Consent Form. Exclusion Criteria: The participant has been diagnosed with another psychiatric disorder (for example mania, bipolar disorder, schizophrenia or any psychotic disorder) during study 12709A or 12710A. The participant has an attention-deficit/hyperactivity disorder (ADHD) that requires a pharmacological treatment other than a stimulant medication. Other protocol-defined inclusion and exclusion criteria may apply

Ages Eligible for Study
-----------------
Minimum Age: 7 Years
Maximum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

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 tablets for 26 weeks. Single dose of vortioxetine oral drops (only a subset of participants). | Drug: Vortioxetine<br>* Target dose is 10 mg/day, however, the dose can be down- or uptitrated to 5, 15, or 20 mg/day.<br>* Other names: Lu AA21004;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Treatment-Emergent Adverse Events (TEAEs) | An adverse event (AE) was defined as any untoward medical occurrence that develops or worsens in severity during the conduct of a clinical study and does not necessarily have a causal relationship to the study drug. SAEs included death, a life-threatening adverse event, inpatient hospitalization or prolongation of existing hospitalization, persistent or significant disability or incapacity, a congenital anomaly or birth defect, or an important medical event that jeopardized the participant and required medical intervention to prevent 1 of the outcomes listed in this definition. TEAE was defined as an AE that started or increased in intensity on or after the date of first dose of study drug in this study 12712A. A summary of serious and non-serious AEs regardless of causality is located in 'Reported Adverse Events module'. | Baseline up to Week 30 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in Children Depression Rating Scale - Revised (CDRS-R) Total Score at Week 26 | CDRS-R consisted of 17 items out of which 3 items rated nonverbal observations (listless speech, hypoactivity, and depressed affect). Fourteen items were rated on a 7-point scale from 1 to 7, and 3 items (sleep disturbance, appetite disturbance, and listless speech) were scored on a 5-point scale from 1 to 5. A rating of 1 indicated normal functioning and a higher number indicated a greater degree of depression. Total score ranged from 17 (normal) to 113 (severe depression). Least square (LS) mean was calculated using a restricted maximum likelihood-based mixed model for repeated measurements (MMRM) approach. | Baseline, Week 26 | 
| Time to First Relapse | Relapse was defined as a total score ≥40 on the CDRS-R. CDRS-R consisted of 17 items out of which 3 items rated nonverbal observations (listless speech, hypoactivity, and depressed affect). Fourteen items were rated on a 7-point scale from 1 to 7, and 3 items (sleep disturbance, appetite disturbance, and listless speech) were scored on a 5-point scale from 1 to 5. A rating of 1 indicated normal functioning and a higher number indicated a greater degree of depression. Total score ranged from 17 (normal) to 113 (severe depression). | Baseline up to Week 26 | 
| Time to First Loss of Remission | Remission was defined as a total score ≤28 on the CDRS-R. CDRS-R consisted of 17 items out of which 3 items rated nonverbal observations (listless speech, hypoactivity, and depressed affect). Fourteen items were rated on a 7-point scale from 1 to 7, and 3 items (sleep disturbance, appetite disturbance, and listless speech) were scored on a 5-point scale from 1 to 5. A rating of 1 indicated normal functioning and a higher number indicated a greater degree of depression. Total score ranged from 17 (normal) to 113 (severe depression). | Baseline up to Week 26 | 
| Change From Baseline in Clinical Global Impression - Severity of Illness (CGI-S) Score at Week 26 | The CGI-S provides the clinician's impression of the participant's current state of mental illness. The clinician uses his or her clinical experience of this participant population to rate the severity of the participant's current mental illness on a 7-point scale ranging from 1 (normal - not at all ill) to 7 (among the most extremely ill participants). LS mean was calculated using a restricted maximum likelihood-based MMRM approach. | Baseline, Week 26 | 
| Clinical Global Impression - Global Improvement (CGI-I) Score | The CGI-I provides the clinician's impression of the participant's improvement (or worsening). The clinician assesses the participant's condition relative to a baseline on a 7-point scale ranging from 1 (very much improved) to 7 (very much worse). LS mean was calculated using a restricted maximum likelihood-based MMRM approach. | Week 26 | 
| Children (7-11 Years): Change From Baseline in Behaviour Rating Inventory of Executive Function - Preschool (BRIEF-P) Using the Global Executive Composite (GEC) Score at Week 26 | BRIEF form is an 86-item measure with symptoms rated on a 3-point likert scale of 1 never, 2 sometimes or 3 often. These items cover 8 non-overlapping clinical scales. For BRIEF-P form, only the first 72 items (Inhibit [10], Shift [8], Emotional Control [10], Initiate [8], Working Memory [10], Plan/Organize [12], Organization of Materials [6], Monitor [8]) were included in clinical scales. Clinical scales combined to form 2 indexes, Behavioural Regulation Index (BRI) and Metacognition Index (MI), and 1 composite summary score, the GEC, that incorporates all 8 clinical scales. GEC score was calculated as the sum of index scores ranging from 72-216; higher scores indicating greater impairment in executive functions. Raw scores converted to T-scores as detailed in T-score conversion tables for BRIEF-P. Conversion was based on gender and age group. T-scores ranged between 30 to 101, with a lower score indicating better functioning. | Baseline, Week 26 | 
| Adolescents (12-18 Years): Change From Baseline in Behaviour Rating Inventory of Executive Function - Self-report (BRIEF-SR) Using the GEC Score at Week 26 | BRIEF form is an 86-item measure that assesses impairment in executive function with symptoms rated on a 3-point likert scale of 1 never, 2 sometimes or 3 often. These items cover 8 non-overlapping clinical scales. For BRIEF-SR form, only 80 items (Inhibit [13], Shift [10], Emotional Control [10], Initiate [5], Working Memory [12], Plan/Organize [13], Organization of Materials [7], Monitor [10]) were included in clinical scales. Clinical scales combined to form 2 indexes, the BRI and the MI, and 1 composite summary score, the GEC, that incorporates all 8 clinical scales. GEC score was calculated as the sum of index scores and ranges from 80-240 with higher scores indicating greater impairment in functions. Raw scores converted to T-scores as detailed in T-score conversion tables for BRIEF-SR. The conversion was based on gender and the age group. T-scores ranged between 29 to 104, with a lower score indicating better functioning. | Baseline, Week 26 | 
| Children (7-11 Years): Change From Baseline in BRIEF-P Using the MI Score at Week 26 | BRIEF form is an 86-item measure that assesses impairment in executive function with symptoms rated on a 3-point likert scale of 1 never, 2 sometimes or 3 often. These items cover 8 non-overlapping clinical scales. Clinical scales combined to form 2 indexes, the BRI and the MI. For BRIEF-P, MI is comprised of Initiate (8), Working Memory (10), Plan/Organize (12), Organization of Materials (6), and Monitor (8) scales. The MI scores are calculated as the sum of the total 44 items ranging from 44 to 132 with lower scores reflecting better functioning. Raw scores converted to T-scores as detailed in T-score conversion tables for BRIEF-P. The conversion was based on gender and the age group. T-scores ranged between 30 to 98, with a lower score indicating better functioning. | Baseline, Week 26 | 
| Adolescents (12-18 Years): Change From Baseline in BRIEF-SR Using the MI Score at Week 26 | BRIEF form is an 86-item measure that assesses impairment in executive function with symptoms rated on a 3-point likert scale of 1 never, 2 sometimes or 3 often. These items cover 8 non-overlapping clinical scales. Clinical scales combined to form 2 indexes, the BRI and the MI. For BRIEF-SR, MI is comprised of Working Memory (12), Plan/Organize (13), Organization of Materials (7), and Task Completion (10) scales. The MI scores are calculated as the sum of the total 42 items ranging from 42 to 126 with lower scores reflecting better functioning. Raw scores converted to T-scores as detailed in T-score conversion tables for BRIEF-SR. The conversion was based on gender and the age group. T-scores ranged between 31 to 100, with a lower score indicating better functioning. | Baseline, Week 26 | 
| Change From Baseline in Children's Global Assessment Scale (CGAS) Score at Week 26 | The CGAS is a clinician-rated global scale to measure the lowest level of functioning for a child (4 to 16 years) during a specified time period. The CGAS contains behaviourally-oriented descriptors at each anchor point that depict behaviours and life situations applicable to a child. The score ranges from 1 (most functionally impaired child) to 100 (the healthiest). A score greater than 70 indicates normal function. | Baseline, Week 26 | 
| Change From Baseline in Pediatric Quality of Life Inventory Present Functioning Visual Analogue Scale (PedsQL VAS) Total Score at Week 26 | The PedsQL™ VAS is designed to measure at-that-moment functioning in children and adolescents. The PedsQL™ VAS consists of 6 domains: anxiety, sadness, anger, worry, fatigue, and pain using VAS. The functionality for each domain is measured on a 10 cm line with a happy face at one end and a sad face at the other (0-10 points). The participants are asked to mark on the line how they feel. The total score is the average of all 6 items ranging from 0 to 10, where a lower value represents a better outcome. | Baseline, Week 26 | 
| Number of Participants With Response to the Palatability Questionnaire | The palatability of vortioxetine oral drops was assessed after intake of a single dose (5 to 20 mg) corresponding to the participant's current vortioxetine dose (replacing the vortioxetine tablet on that day). The palatability assessment included 4 questions on the overall appreciation of a medicinal product in relation to its taste (What do you think of the taste), mouthfeel (How does medicine feel in your mouth), aftertaste (What do you think of the after taste), and smell (What do you think of the smell). The items were rated on a 5-point hedonic scale; really bad, bad, neither good or bad, good, or very good. The oral drops were considered acceptable if the mean hedonic scores were ≤3 for each aspect of palatability (taste, aftertaste, smell, and mouthfeel). | assessed at Baseline up to Week 26, Week 26 reported | 
| Number of Participants With Response to the Acceptability Questionnaire | The acceptability of vortioxetine oral drops was assessed after intake of a single dose (5 to 20 mg) corresponding to the participant's current vortioxetine dose (replacing the vortioxetine tablet on that day). The acceptability assessment was based on 3 items; acceptability of the taste, whether the drops were perceived as easy to take, willingness to take the drops every day (provided it was the only available formulation). For each item the response options were no, not sure, and yes. The oral drops were considered acceptable if <60% of participants responded no to each of the 3 questions regarding acceptability. | assessed at Baseline up to Week 26, Week 26 reported | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
adolescent, children