Clinical trial NCT05014919
Conditions: Depression
Sponsor: H. Lundbeck A/S
Start date: 2021-08-10; Completion date: 2022-04-28
Enrollment: 35 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of this study is to find out if vortioxetine is better than placebo (sugar pills) in preventing depression in children who improved when treated with vortioxetine.

Detailed description:
The study consists of a 12-week open-label, flexible-dose treatment period with vortioxetine, followed by a 26-week, randomized, double-blind, fixed-dose, placebo-controlled relapse-prevention period. There will be a safety follow up 4 weeks after the end of the 26-week double-blind treatment period.

The study population will include 'de novo' participants as well as 'rollover' participants from other paediatric vortioxetine studies 12709A (NCT02709655) and 12712A (NCT02871297), who, in the investigator's opinion, could benefit from continued treatment with vortioxetine.

Arms: arm 1: Vortioxetine - 5, 10, 15, and 20 mg/day, film-coated tablets, orally once daily.

Patients will receive a targeted dose of 10 mg/day vortioxetine, however the investigator has the possibility to adjust the dose in case of unsatisfactory response or in case of dose-limiting adverse events. arm 2: Vortioxetine - 5, 10, 15, and 20 mg/day, encapsulated film-coated tables, orally once daily.

In the double-blind period, the patients will continue on the same fixed dose as during the end of the open label period arm 3: Placebo - encapsulated tablets, orally once daily.
Interventions: intervention 1: Vortioxetine intervention 2: Placebo
Intervention descriptions: intervention 1: Tablets intervention 2: Tablets

Protocol documents:
SAP_003.pdf: 
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Statistical Analysis Plan 
 
A double blind, randomized, placebo-controlled, multicentre, 
relapse-prevention study of vortioxetine in paediatric patients 
aged 7 to 11 years with Major Depressive Disorder 
 
 
Vortioxetine 
 
 
 
Study No.:                       13546A 
 
Sponsor:                          H. Lundbeck A/S (Lundbeck) 
2500 Valby (Copenhagen), Denmark 
 
                 
 
 
SAP date:                         Final version 1.0, 09 April 2021 
 
 
 
 
 
 
 
 
 
This document is the property of H. Lundbeck A/S and H. Lundbeck A/S is the holder of any and all 
related intellectual property rights, including, but not limited to, copyrights.  This document is 
confidential.  It is not to be copied or distributed to other parties without prior written authorization 
from H. Lundbeck A/S.
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Table of Contents 
 
Appendices .............................................................................................................................................. 4 
List of Panels .......................................................................................................................................... 5 
List of Abbreviations and Definitions of Terms .................................................................................. 6 
1 
Introduction ................................................................................................................................... 7 
2 
Objectives and Endpoints ............................................................................................................ 8 
3 
Study Design .................................................................................................................................. 9 
3.1 
Open Label Period ............................................................................................................. 10 
3.2 
Double-Blind Treatment Period ........................................................................................ 11 
4 
Definitions .................................................................................................................................... 12 
4.1 
Definition of Baseline ....................................................................................................... 12 
4.2 
Definition of Periods ......................................................................................................... 13 
4.3 
Definition of Withdrawal .................................................................................................. 14 
5 
Analysis Sets ................................................................................................................................ 14 
6 
Descriptive Statistics ................................................................................................................... 14 
7 
Patient Disposition ...................................................................................................................... 14 
7.1 
Summary of Patient Disposition ........................................................................................ 14 
7.2 
Withdrawals ....................................................................................................................... 15 
8 
Demographics and Baseline Characteristics ............................................................................ 15 
9 
Recent and Concomitant Medication ........................................................................................ 15 
10 
Exposure ...................................................................................................................................... 16 
11 
Efficacy ......................................................................................................................................... 17 
11.1 
Overview of Planned Efficacy Analysis ............................................................................ 17 
11.2 
General Efficacy Analysis Methodology .......................................................................... 18 
11.3 
Analysis Methodology for the Primary Endpoint.............................................................. 18 
11.3.1 
Primary Analysis of the Primary Endpoint ........................................................ 18 
11.3.2 
Sensitivity Analyses of the Primary Endpoint ................................................... 19 
11.4 
Analysis Methodology for the Secondary Endpoints ........................................................ 20 
11.4.1 
Analysis of the Secondary Endpoint(s) .............................................................. 20 
11.5 
Analysis of the Exploratory Endpoints .............................................................................. 23 
11.6 
Pharmacokinetic Analyses................................................................................................. 23 
12 
Safety ............................................................................................................................................ 23 
12.1 
Adverse Events .................................................................................................................. 24 
12.1.1 
General Methodology for Adverse Events ......................................................... 24 
12.1.2 
Coding of Adverse Events ................................................................................. 24 
12.1.3 
Classification of Adverse Events ....................................................................... 24 
12.1.4 
Allocation of TEAEs to Treatment Periods ....................................................... 24 
12.1.5 
Presentation of Adverse Events ......................................................................... 25 
12.1.6 
Presentation of Pre-treatment Adverse Events ................................................... 25 
12.1.7 
Presentation of Treatment-emergent Adverse Events ........................................ 25 
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12.1.8 
Presentation of Deaths ....................................................................................... 26 
12.1.9 
Presentation of Serious Adverse Events ............................................................ 26 
12.1.10 Presentation of Adverse Events Leading to Withdrawal ................................... 26 
12.2 
General Methodology for Other Safety Data .................................................................... 26 
12.3 
Clinical Safety Laboratory Test Data ................................................................................ 27 
12.4 
ECG, Vital Signs and Weight ............................................................................................ 28 
12.5 
Other Safety Endpoints ..................................................................................................... 28 
12.5.1 
Columbia-Suicide Severity Rating Scale (C-SSRS) Scores .............................. 28 
12.5.2 
General Behavior Inventory (GBI) 10-Item Mania Scale .................................. 29 
13 
Interim Analyses ......................................................................................................................... 29 
14 
Sample Size Considerations ....................................................................................................... 30 
15 
Statistical Software ..................................................................................................................... 30 
16 
Details on Data Handling ........................................................................................................... 30 
16.1 
Assigning Data to Visits .................................................................................................... 30 
16.1.1 
Visit Window ..................................................................................................... 30 
16.1.2 
Safety Variables ................................................................................................. 31 
16.1.3 
Covid-19 impact ................................................................................................. 32 
16.2 
Handling Missing or Incomplete Dates/Times .................................................................. 32 
16.2.1 
IMP Start and Stop Dates ................................................................................... 32 
16.2.2 
Withdrawal Date ................................................................................................ 32 
16.2.3 
Medication Start and Stop Dates ........................................................................ 32 
16.2.4 
Adverse Event Start and Stop Dates .................................................................. 33 
16.3 
Data with Multiple Records............................................................................................... 34 
16.3.1 
Dose Changes in Medication ............................................................................. 34 
16.3.2 
Changes in Intensity or Seriousness of Adverse Events .................................... 34 
References ............................................................................................................................................. 35 
 
 
 
 
 
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Appendices 
Appendix I 
Statistical Analysis Plan Authentication and Authorization 
Appendix II 
Overview of Study Procedures 
Appendix III 
SAS® Code 
 
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List of Panels 
Panel 1 
Objectives and Endpoints .................................................................................................... 8 
Panel 2 
Schedule of Study Design ................................................................................................. 12 
Panel 3 
Overview of Planned Efficacy Analyses ........................................................................... 18 
Panel 4 
Clinical Safety Laboratory Tests ....................................................................................... 27 
Panel 5 
C-SSRS Scores .................................................................................................................. 29 
Panel 6 
Visit Windows ................................................................................................................... 31 
Panel 7 
Classification of Concomitant Medication ........................................................................ 33 
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List of Abbreviations and Definitions of Terms 
 
 
ANCOVA 
Analysis Of Covariance 
APES 
All-Patients-Enrolled Set 
APRS 
All-Patients-Randomized Set 
ATC 
Anatomical Therapeutic Chemical 
BMI 
Body Mass Index 
CDRS-R 
Children Depression Rating Scale Revised Version 
CGI-I 
Clinical Global Impression – Global Improvement 
CGI-S 
Clinical Global Impression – Severity Of Illness 
CI 
Confidence Interval 
COVID 
Coronavirus Disease 
C-SSRS 
Columbia-Suicide Severity Rating Scale  
DSM-5TM 
Diagnostic And Statistical Manual Of Mental Disorders, 5th Edition 
ECG 
Electrocardiogram 
eCRF 
Electronic Case Report Form 
FAS 
Full- Fda Analysis Set 
FSH 
Follicle-Stimulating Hormone 
GBI 
General Behaviour Inventory 
IMP 
Investigational Medicinal Product 
K-SADS-PL 
The Kiddie-Schedule For Affective Disorders And Schizophrenia For 
School-Aged Children, Present And Lifetime Version 
LH 
Luteinising Hormone 
LOCF 
Last Observation Carried Forward 
MDD 
Major Depressive Disorder 
MMRM 
Mixed Model For Repeated Measurements 
OCD 
Obsessive Compulsive Disorder 
PCS 
Potentially Clinically Significant 
PK 
Pharmacokinetic(s) 
PK 
Pharmacokinetics  
PQ-LES-Q 
Pediatric Quality Of Life Enjoyment And Satisfaction Questionnaire  
SAE 
Serious Adverse Event 
SAS® 
Statistical Software Package From The SAS® Institute 
SOC 
System Organ Class 
TEAE 
Treatment-Emergent Adverse Event 
 
 
 
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1 Introduction 
 
The purpose of this Statistical Analysis Plan (SAP) is to provide detailed descriptions of the 
statistical methods, data derivations and data displays for study protocol 13546A “A double 
blind, randomized, placebo-controlled, multicentre, relapse-prevention study of vortioxetine 
in paediatric patients aged 7 to 11 years with Major Depressive Disorder”. The table of 
contents and templates for the TFLs will be produced in a separate document. 
The analysis plan may change due to unforeseen circumstances. Any deviations from this 
SAP will be described and justified in an amendment or the Clinical Study Report (CSR). 
 
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2 Objectives and Endpoints 
 The study objectives and endpoints are summarized in Panel 1. 
Panel 1 
Objectives and Endpoints 
Objectives 
Endpoints 
Primary Objective 
• to evaluate the efficacy of vortioxetine in the 
prevention of relapse of major depressive 
episodes in paediatric patients with MDD 
 
 
Depressive Symptoms 
• Primary endpoint: 
− time to relapse in the Double-Blind Treatment Period  
• Secondary endpoint: 
− relapse in the Double-Blind Treatment Period 
Secondary Objectives 
• to evaluate efficacy of vortioxetine during 
continuation treatment of paediatric patients 
with MDD 
• to evaluate the efficacy of vortioxetine on: 
− clinical global impression 
− quality of life 
• to assess adherence to investigational 
medicinal product (IMP) through 
pharmacokinetic analysis  
 
Depressive Symptoms 
• Secondary endpoint: 
− change from baseline to Week 26 in the Children Depression 
Rating Scale Revised Version (CDRS-R) total score  
 
Global Clinical Impression 
• Secondary endpoints: 
− change from baseline to Week 26 in the Clinical Global 
Impression – Severity of Illness (CGI-S) score 
− Clinical Global Impression – Global Improvement (CGI-I) 
score at Week 26 
 
Quality of life 
• Secondary endpoint: 
− Change from baseline to Week 26 in Pediatric Quality of Life 
Enjoyment and Satisfaction Questionnaire (PQ­LES­Q) – 
total score of item 1-14 during the 26 weeks treatment period. 
− Change from baseline to Week 26 in Pediatric Quality of Life 
Enjoyment and Satisfaction Questionnaire (PQ­LES­Q) – 
overall evaluation score (item 15) during the 26 weeks 
treatment period. 
 
 
Pharmacokinetics 
• Secondary endpoints: 
− plasma exposure to vortioxetine 
− population pharmacokinetic parameter values  
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Objectives 
Endpoints 
Safety Objectives  
• to evaluate long-term safety and tolerability of 
vortioxetine in paediatric patients with MDD 
Safety Endpoints 
• adverse events 
• absolute values and changes from baseline in clinical safety 
laboratory test values (including estradiol [girls only], and 
luteinising hormone [LH], follicle-stimulating hormone [FSH]), 
vital signs, height, weight, Tanner staging, electrocardiogram 
(ECG) parameter values. Effects on menstrual cycle will be 
assessed. 
• potentially clinically significant clinical safety laboratory test 
values, vital signs, weight changes, and ECG parameter values 
• Columbia-Suicide Severity Rating Scale (C-SSRS) score 
• General Behaviour Inventory (GBI) using the 10-item mania 
subscale (parental version) 
 
 
 
3 Study Design 
This is an interventional, multi-national, multi-site, randomized, parallel-group, placebo-
controlled, relapse-prevention study in paediatric patients with MDD from 7 to 11 years of age.  
The study consists of a 12-week, open-label, flexible-dose treatment period with vortioxetine 
followed by a 26-week, randomized, Double Blind, fixed-dose, placebo-controlled 
relapse­prevention period. 
The study population will include de novo patients as well as rollover patients from other 
paediatric vortioxetine studies (Studies 12709A and 12712A), who, in the investigator’s opinion, 
could benefit from continued treatment with vortioxetine. To reach 80 randomized patients, 
approximately 150 patients recruited, either as de novo patients or rollover patients from Study 
12709A and 12712A, are estimated to be enrolled into the study. 
De novo patients  
• Patients meeting eligibility criteria for de novo patients will be enrolled in the 12-week, open-
label, flexible-dose treatment period. 
Rollover patients from Study 12709A (enrolled to the Open Label Period) 
• Patients may participate in the present study after completion of the randomized, 8-week, 
Double Blind, placebo-controlled treatment period of Study 12709A.  
• Eligible patients will be enrolled in the 12-week, open-label, flexible-dose treatment period. 
• The Baseline Visit of this study (Study 13546A) will take place at the same visit as Visit 12 
(Completion Visit) of Study 12709A. Participation in Study 12709A is considered completed 
when all assessments required at Visit 12 are completed. 
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De novo patients and rollover patients from study 12709A can be randomized to the Double-
Blind Treatment Period, if eligible. 
Rollover patients (remitters) from Study 12712A (randomized to the Double-Blind Treatment 
Period) 
• Patients who have received 8 to 12 weeks of treatment with vortioxetine in the open-label 
extension study 12712A may participate in the present study if they have remitted (CDRS­R 
total score ≤28) at the last 2 visits in Study 12712A prior to the rollover. In addition, the dose 
of vortioxetine must have been fixed for the last 4 weeks in Study 12712A prior to 
randomization in the present study. 
• Eligible patients will be randomized directly to the 26-week, Double Blind treatment period. 
An overview of the study is presented in the Schedule of Study Design (including the study 
periods) and the scheduled study procedures and assessments per study period are summarized in 
Appendix II. 
 
3.1 Open Label Period 
Open Label Period (for de novo patients and rollover patients from Study 12709A) 
• The duration of the open-label, flexible-dose treatment period will be 12 weeks. 
• The dosage of vortioxetine will be initiated at 5 mg/day for the first 2 days prior to receiving 
10 mg/day. 
• The target dose is 10 mg/day, however, the investigator has the possibility to increase the 
dose to a maximum of 20 mg/day in case of unsatisfactory response or decrease the dose 
to 5 mg/day in case of dose-limiting AEs. The dose can be up- or down-titrated with 
5 mg/day. The patient should receive the same dose for 2 days before being up- or down-
titrated to a new dose. Changes in dosing may occur at any visit during the first 8 weeks 
at the investigator's discretion. In addition, between Week 2 and Week 8, the patient 
and/or parent(s)/legal representative(s) can request an unscheduled visit to discuss their 
current dose. The minimum dose is 5 mg/day. 
• From Week 8 and onwards the dose has to remain fixed. 
• Patients in remission (CDRS-R total score ≤28) at both Weeks 10 and 12 or with an adequate 
clinical response (defined as ≥50% reduction in the CDRS-R total score compared to the 
baseline score in this study [subtracted 17 as 17 is the minimum CDRS-R Total Score] and a 
CDRS-R total score ≤35) at both Weeks 10 and 12 will be randomized in the Double Blind, 
placebo-controlled, fixed-dose period.  
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• Patients who do not fulfil randomization criteria for remission or adequate response at Week 
10 and/or Week 12 will be withdrawn from the study and will complete an early Withdrawal 
Visit. Non-remitters/non-responders who leave the study will be treated at the investigator’s 
discretion. 
A Safety Follow-up Visit will be performed approximately 4 weeks after withdrawal from the 
Open Label Period. 
3.2 Double-Blind Treatment Period 
Double-Blind Treatment Period (for all randomized patients) 
• Patients who fulfil the randomization criteria and do not meet any of the withdrawal criteria 
during the Open Label Period or at the time of randomization will be randomly assigned via a 
centralized randomization system to receive vortioxetine or placebo in a 1:1 ratio. 
Randomization will be stratified by patient inclusion sources (de novo patients, rollover 
patients from 12709A, or from 12712A).  
• Patients randomized to vortioxetine will continue on their final dose from the Open Label 
Period or the dose they had on their last visit in Study 12712A, as applicable.  
• The maximum duration of the Double-Blind Treatment Period will be 26 weeks.  
• Patients who relapse during the Double-Blind Treatment Period must be withdrawn from the 
study. The criterion for a relapse is a CDRS-R total score of ≥40 with a history of 2 weeks of 
clinical deterioration, or a clinical deterioration that in the investigator’s opinion warrants 
alteration of treatment to prevent full relapse.  
 
A Safety Follow-up Visit will be performed 4 weeks after withdrawal or completion of the 
Double-Blind Treatment Period. 
 
 
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Panel 2 
Schedule of Study Design 
 
 
 
 
 
* Patients in remission (CDRS total score ≤28) at the two last visits in the Open Label period / Study 12712A  
OR with an adequate clinical response (≥50% reduction in the CDRS-R total score compared to the baseline score and a CDRS-R 
total score ≤35) at the two last visits in the Open Label period 
**Relapse: CDRS-R total score of ≥40 with a history of 2 weeks of clinical deterioration, or a clinical deterioration that in the 
investigator’s opinion warrants alteration of treatment to prevent full relapse 
 
 
4 Definitions 
4.1 Definition of Baseline 
 
The primary analysis of the study focuses on the results of the Double-Blind Treatment Period. 
Therefore, baseline for the primary analysis will be defined as the randomization visit, i.e. the 
start of the Double-Blind treatment period. This baseline will be referred to as Randomization 
(Visit). 
 
For the analysis of safety, baseline is defined as the start of the Open Label Period for de novo 
and 12709A rollover patients. This baseline will be referred to as Baseline (Visit). For 12712A 
rollover patients baseline will be defined as the start of the Double-Blind Treatment Period, i.e. 
the randomization visit. 
 
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4.2 Definition of Periods 
The following periods can be identified: 
 
Screening period 
A Screening Visit will be performed only for de novo patients. Patients rolling over from 
Study 12709A will proceed directly to the Baseline Visit. Therefore, the screening period is not 
applicable for these patients. In addition, this period is not applicable for patients rolling over 
from Study 12712A, as these patients will enrol the study at the randomization visit. The 
screening period begins when the first screening assessment is done after written Informed 
Assent/Consent has been obtained, and ends at the Baseline Visit for the Open Label Period (visit 
2). 
 
 
Open Label Period 
De novo patients who continue to meet all inclusion criteria and none of the exclusion criteria 
(see section 5.3 of the study protocol) will be enrolled into a 12-week Open Label Period. For 
patients rolling over from Study 12709A, the Baseline Visit of the Open Label Period will be 
performed the same day as the Week 12 (Completion) Visit of Study 12709A.  
Patients eligible for entering the Open Label Period will start IMP (vortioxetine) at the Baseline 
Visit of the Open Label Period. 
The duration of the Open Label Period is 12 weeks or until the patient is withdrawn from the 
study, whichever comes first. If a patient withdraws from the study, the Open Label Period ends 
at the withdrawal visit.  
 
 
Double-Blind Treatment Period 
The Double-Blind Treatment Period starts at the randomization visit (visit 8) and ends after 26 
weeks of treatment (visit 17), or until the patient will be withdrawn from the study, whichever 
comes first. If a patient withdraws from the study the Double-Blind Treatment Period ends at the 
withdrawal visit.  
Patients rolling over from Study 12712A will have their first visit in this study at visit 8 (the 
Randomization Visit). For 12712A-patients the last available values from assessments and 
procedures (efficacy/safety, and use of concomitant medication) performed at either Visit 7 
(Week 8) and/or Visit 8 (Week 10), or Visit 9 (Week 12) in Study 12712A will be the 
Randomization Visit values for this study. 
 
 
Safety Follow-up Period 
The Safety Follow-up Period has a duration of 4 weeks after the last IMP intake. This period 
starts at the date of last IMP intake. 
A Safety Follow-up Period is planned at the end of the study (i.e. after completion of visit 17) 
and after withdrawal of a patient in either the Open Label Period or the Double-Blind Treatment 
Period. The end of the Safety Follow-up Period will be at visit 18 (SFU visit). 
 
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4.3 Definition of Withdrawal 
 
The patients who withdraw from the Open Label Period or the Double-Blind Treatment period 
will be described as withdrawn from the study. The remaining patients will be described as 
completed the study.  
5 Analysis Sets 
 
The following analysis sets will be used to analyze and present the data: 
   all-patients-enrolled (APES) – all-patients-enrolled to the 12-week Open Label Treatment 
Period who took at least one dose of IMP 
   all-patients-randomized set (APRS) – all patients randomized to the 26-week Double-Blind 
Treatment Period 
   full-analysis set (FAS) – all patients randomized to the 26-week Double-Blind Treatment 
Period who took at least one dose of Double Blind IMP 
 
 
The efficacy analyses will be based on the FAS and the safety analyses will be based on the 
APES (for de novo and 12709A rollover patients) and the APRS (for 12712A rollover patients). 
The patients and data will be classified into the analysis sets according to the definitions above 
during a Classification Meeting after the study database has been released, but before the blind 
has been broken. 
 
6 Descriptive Statistics 
 
In general, summary statistics (n, arithmetic mean, standard deviation, median, minimum and 
maximum values) will be presented for continuous variables. Counts and, if relevant, 
percentages will be presented for categorical variables. The denominator for the percentage 
calculation will be noted. 
 
Unless otherwise specified, data listings will include enrolment source, site, treatment group, 
patient screening number, sex, age, race, and baseline weight. 
 
7 Patient Disposition 
7.1 Summary of Patient Disposition 
 
The disposition data will be summarized for the Open Label Period (split out by de novo patients, 
rollover patients from Study 12709A and total), and the Double-Blind Treatment Period (split out 
by treatment groups and total) separately. The number of patients in APES and APRS who 
completed or withdrew from the study, as well as the number of patients in each analysis set 
(APES, APRS and FAS) will be presented.  
 
 
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7.2 Withdrawals 
 
The number of patients who withdrew from the Open Label Period will be summarized by de 
novo patients, rollover patients from Study 12709A and total. The number of patients who 
withdrew from the Double-Blind Treatment Period will be summarized by treatment group and 
total. The primary reason for withdrawal as well as all reasons for withdrawal will be presented 
per period. 
 
Patients who withdrew from the study will be listed and the listing will include the number of 
days in the study until withdrawal from the study, the number of days on IMP, the primary 
reason for withdrawal, and all reasons for withdrawal. 
 
8 Demographics and Baseline Characteristics 
 
Summary tables on demographic and baseline characteristics will be presented for both the Open 
Label Period and the Double-Blind Treatment Period separately. The baseline characteristics for 
the Open Label Period will be based on the APES and will be presented for de novo patients, 
rollover patients (from Study 12709A) and overall. 
 
For the Double-Blind Treatment Period the summary tables on demographics will be based on 
the FAS and results will be presented per treatment group (vortioxetine and placebo) and in total.  
 
Demographics (sex, age, ethnicity and race), baseline characteristics (height, weight and BMI), 
disease characteristics and baseline efficacy variables will be summarized.  
 
The following baseline (randomization) efficacy variables will be summarized: 
   CDRS-R total score 
   CGI-S score 
   PQ-LES-Q scores (total score and overall score (item 15))  
 
Disease characteristics will include MDE history (MDD history, including number of MDEs,  
duration of current episode, treatment type (physchotherapy / pharmacotherapy) for MDD. In 
addition, MDD treatment will be summarized. 
 
Medical history from the Medical History eCRF page will be coded with medical 
dictionary for regulatory activities (MedDRA) version 19.0 or above. All medical 
histories, data on major depressive disorder history and treatment, the family psychiatric 
history and the history of stimulant medication will be listed. 
 
9 Recent and Concomitant Medication 
 
Recent and concomitant medication will be coded using the WHO Drug Dictionary (WHO 
Global B3 Mar 2020). 
 
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Medications will be classified according to the start and stop time and summarized by 
anatomical therapeutic chemical (ATC) code, generic drug name: 
 
• 
medication discontinued prior to first dose of IMP in Open Label Period 
• 
concomitant medication continued after first dose of IMP in Open Label Period 
• 
concomitant medication started at or after first dose of IMP in Open Label Period 
       
• 
concomitant medication continued after first dose of IMP in Double-Blind 
Treatment Period 
• 
concomitant medication started at or after first dose of IMP in Double-Blind 
Treatment Period 
• 
concomitant medication started after last dose of IMP in Double-Blind Treatment 
Period 
 
Concomitant medications started after withdrawal from treatment will be listed separately. 
 
Two sets of tables will be produced; for the Open Label Period tables will be based on the 
APES and will present the de novo patients and 12709A rollover patients separately as 
well as in total. 
For the Double-Blind Treatment Period, tables will be based on the APRS and presented 
per treatment group as well as overall. 
 
10 Exposure 
 
Exposure and compliance will be calculated per patient and summarized for Open Label 
Period and Double-Blind Treatment Period separately. For the Open Label Period results will 
be summarized for de novo and 12709A rollover patients separately as well as in total, 
whereas for the Double-Blind Treatment Period results will be presented per treatment group 
and overall. 
 
Exposure (days) to IMP, irrespective of missing doses, in each period, will be calculated as: 
Date of last IMP intake – Date of first IMP intake in the respective period+ 1 
Exposure in weeks will be calculated as: Exposure in days/7 
 
The calculation will include the patient years of exposure (PYE). PYE will be calculated as 
the sum of the number of days of exposure to IMP for each patient, divided by 365.25 days. 
 
Compliance will be defined as the number of days in which a dose was taken related to the 
number of days the patient was expected to take IMP as per the protocol. 
 
Compliance in each treatment period will be calculated as:  
(the number of days of dose taken / the number of days a dose was planned)*100 
 
 
 
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Exposure and compliance will be summarized using standard summary statistics. In addition, 
exposure to IMP will be categorized in the following intervals: 
< 1 week 
1-2 weeks 
3-4 weeks 
5-8 weeks 
9-10 weeks 
11-12 weeks 
>12 weeks 
for the Open Label Period,  
and:  
< 1 week 
1-2 weeks 
3-4 weeks 
5-6 weeks 
7-10 weeks 
11-14 weeks 
15-18 weeks 
19-22 weeks 
23-26 weeks 
>26 weeks relative to randomisation for the Double-Blind Treatment Period. 
 
For the Open Label Period an overview of the dosing pattern per patient will be presented. 
 
For both the Double-Blind Treatment Period and the Open Label Period, summary statistics 
on the mean daily dose will be presented. The results for the Open Label Period will be 
presented for de novo and rollover patients separately, as well as in total.  For the Double-
Blind Treatment Period this will only be presented for the vortioxetine treated patients. 
  
The mean daily dose will be defined as: 
 
Total dose received during the Double-Blind Treatment Period / number of exposure days in 
the Double-Blind Treatment Period. 
 
For the Double-Blind Treatment Period a frequency count on the dosage received, including 
the number of patients withdrawn per dose, will be presented. 
 
Exposure will be summarized based on the APES for Open Label Period and on the APRS for 
Double-Blind Treatment Period.  
 
11 Efficacy 
 
11.1   Overview of Planned Efficacy Analysis 
An overview of all planned effectiveness analyses in provided in Panel 3. 
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Panel 3 
Overview of Planned Efficacy Analyses 
Variable (Analysis Set): 
Endpoint 
Type 
Descriptive 
Statisticsa 
Logistic 
Regression 
Cox 
Regression 
ANCOVA 
MMRM 
 
OC 
LOCF 
OC 
LOCF 
 
 
 
 
 
 
 
 
 
 
 
Time to relapse (FAS) 
4 
 
 
 
 
X 
 
 
 
Relapse (FAS) 
3 
X 
 
X 
X 
 
 
 
 
CDRS-R (FAS)  
-Total score  
 
1 
 
X 
 
X 
 
 
 
 
X 
 
X 
 
PQ-LES-Q (FAS) 
-Total score (sum of item 1-14) 
-Overall score (item 15) 
 
1 
1 
 
X 
X 
 
X 
X 
 
 
 
 
X 
X 
 
X 
X 
 
CGI-S (FAS)  
1/2 
X 
X 
 
 
 
X 
X 
CGI-I (FAS) score 
1/2 
X 
X 
 
 
 
X 
X 
 1 = continuous; 2 = categorical; 3 = binary; 4 = time to event 
a Including summaries of absolute values and changes from randomization for endpoints based on changes 
 
In addition to the planned efficacy analysis on the FAS, descriptive statistics and the change from 
randomization in the CDRS-R total score, per inclusion source, will be presented for the Open 
Label Period. 
Also the number of relapses will be summarized descriptively according to relapse criteria: 
CDRS-R total score ≥40 with 2 weeks of clinical deterioration, investigator’s judgement, or both. 
 
11.2    General Efficacy Analysis Methodology 
 
All the statistical tests of the efficacy endpoints will be one-sided tests performed at the 5% 
significance level and all confidence intervals (CIs) will be 95% CIs, unless otherwise 
specified. 
For all proposed analyses the applicable assumptions will be checked before the respective 
analysis is carried out. 
 
The efficacy analyses will be based on the FAS for the Double-Blind Treatment Period. 
The SAS code for the statistical analyses is provided in Appendix III. 
 
11.3    Analysis Methodology for the Primary Endpoint  
11.3.1 
Primary Analysis of the Primary Endpoint 
 
The primary efficacy analysis will compare the time to relapse in the Double-Blind Treatment 
Period between vortioxetine and placebo treated patients. Relapse will be defined as either a 
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total score ≥40 on the CDRS-R with a history of 2 weeks of clinical deterioration, or clinical 
deterioration as judged by the clinician and documented in the eCRF.  
 
The time to relapse is defined as the number of days from the start of the Double-Blind 
Treatment Period (Randomization visit) to the date of relapse. This will be calculated as 
follows: 
 
(Date of relapse – Date of start of Double-Blind Treatment Period)  
 
Patients who do not relapse before the end of the Double-Blind Treatment Period (26 weeks) 
will be censored at week 26. Patients who withdraw from the study for other reason(s) than 
relapse will be censored at the time of withdrawal. 
 
The two treatment groups will be compared using a Cox regression model with exact 
adjustment for ties.  
Cox Regression Model 
The time to relapse will be analysed using a Cox regression model that includes treatment as a 
fixed factor, and the randomization CDRS-R total score as covariate, and stratifying by inclusion 
source to allow for different baseline hazards for each inclusion group.  
The hazard ratio for vortioxetine compared to placebo will be estimated from the model and 
presented with p-values and 95% CIs. 
In case of non-convergence of the Cox regression model the strata will be grouped in a new 
stratum variable, and this variable will be defined at the classification meeting based on blinded 
treatment and relapses from the different enrolment sources. 
 
A one-sided 5% alpha level of confidence will be used. 
 
11.3.2 
Sensitivity Analyses of the Primary Endpoint 
 
The following sensitivity analyses will be performed: 
1. The primary analysis will be repeated ignoring relapses occurring during the first week, two 
weeks and four weeks of the Double-Blind Treatment Period, respectively.  
 
For the purpose of this sensitivity analysis 3 subsets of data will be defined: 
i) A subset excluding all patients with a relapse within the first 7 days after the start of 
the Double-Blind Treatment Period. 
ii) A subset excluding all patients with a relapse within the first 14 days after the start of 
the Double-Blind Treatment Period. 
iii) A subset excluding all patients with a relapse within the first 28 days after the start of 
the Double-Blind Treatment Period. 
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The primary analysis of the study, as described, will be repeated in each of the 3 subsets above 
and for each subset the hazard ratio for vortioxetine compared to placebo will be estimated from 
the model and presented with p-values and 95% CIs. 
 
 
2. The primary analysis will be repeated for the de novo patients and for the (pooled) 12709A 
patients and 12712A patients additionally.  
 
The hazard ratio’s for vortioxetine compared to placebo will be estimated from the model and 
presented with p-values and 95% CIs for de novo and rollover patients (pooled 12709A and 
12712A) separately. 
 
On an exploratory basis, if feasible, the impact of the use of psychotherapy, severity of illness, 
gender and age may be investigated. Therefore, these may be added as fixed factors or covariates 
to the Cox regression model, or subgroups may be created. 
 
11.4   Analysis Methodology for the Secondary Endpoints 
11.4.1 
Analysis of the Secondary Endpoint(s) 
 
Relapse 
The number of relapses will be summarized per visit, per treatment group and overall. The 
relapse criteria as defined in in section 11.3 will be used.  
 
The relapse over the 26 weeks Double-Blind Treatment Period will be analysed using logistic 
regression, with treatment and inclusion source as fixed factors and CDRS-R Total Score at 
randomization as covariate. In addition, the analysis will be repeated using the LOCF (Last 
Observation Carried Forward) approach for missing data. 
 
The odds ratio estimates with 95% confidence intervals will be presented. The odds ratio and 
the confidence limits will be based on the profile likelihood. 
 
Secondary efficacy variables (CDRS-R total score, PQ-LES-Q scores (total score and overall 
score), CGI-S and CGI-I) will be analysed on an exploratory basis over the 26-week Double-
Blind Treatment Period by Mixed Model Repeated Measurements (MMRM) and analysis of 
covariance (ANCOVA).  
 
For the purpose of the analysis the change from randomization in CDRS-R total score, PQ-
LES-Q scores, and in CGI-S score will be computed.  
 
For both the MMRM and the ANCOVA, the dependent variable will be the change from 
randomization in CDRS-R total score, change from randomization in PQ-LES-Q scores, change 
from Randomization in CGI-S score and the absolute CGI-I score, respectively. 
 
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The MMRM will have treatment, week and inclusion source as fixed factors and the 
randomization score will be added as a covariate. For CGI-I, the score at randomization for the 
CGI­S will be used as covariate.  
 
In addition, the interaction between treatment and week and between randomization score and 
week will be included and an unstructured covariance matrix will be applied. The Kenward-
Roger approximation will be used to estimate denominator degrees of freedom.  
 
In the ANCOVA treatment and inclusion source will be included as fixed factors and the 
respective randomization score will be included as a covariate. For CGI-I, the score at 
randomization for the CGI-S will be used as covariate. 
 
Only the observed cases (OC) approach will be used. 
 
 Paediatric Quality of Life Enjoyment and Satisfaction Questionnaire 
 
The PQ-LES-Q consist of 15 items, item 1 to 14 assess the degree of satisfaction experienced 
by patients in various areas of daily functioning and item 15 allows patients to summarize their 
experience in a global rating. 
 
Each item is rated on a 5-point scale from 1 (very poor) to 5 (very good). The total score range 
of item 1 to 14 is 14 to 70, with higher scores indicating greater satisfaction. It takes 5 to 10 
minutes to complete the scale. 
 
The same analysis as for item 1-14 will be applied on the global rating (item 15). 
 
Summary statistics on total score (items 1 -14) and the overall score (item 15) will be presented 
for each visit, per treatment group and overall. 
 
Children depression rating scale revised version (CDRS-R) 
 
The CDRS-R is a clinician-rated scale to measure the severity of depression of children and 
adolescents. The CDRS-R is rated by a clinician following interviews with the child and  
parent(s) and consists of 17 items: 14 items rate verbal observations, and 3 items rate non-
verbal observations (tempo of language, hypoactivity, and nonverbal expression of depressed 
affect). Items are rated for severity on a 7-point scale (1 to 7) for 14 items, and on a 
5-point scale (1 to 5) for 3 items (sleep disturbance, appetite disturbance, and listless speech). 
The total score ranges from 17 (normal) to 113 (severe depression). 
 
Summary statistics on total score and all items scores will be presented for each visit, per 
treatment group and overall. 
 
 
Clinical Global Impression 
 
The CGI is a clinician rated scale that consist of two subscales: severity of illness (CGI-S) and 
global improvement (CGI-I). 
 
CGI-S 
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The 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). 
 
 
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CGI-I 
The CGI-I provides the clinician’s impression of the patient’s improvement (or worsening). The 
clinician assesses the patient’s condition relative to randomization on a 7-point scale ranging 
from 1 (very much improved) to 7 (very much worse). 
 
For both the CGI-S as the CGI-I descriptive statistics as well as frequency counts and 
percentages will be given for each time point per treatment group and overall. 
 
11.5    Analysis of the Exploratory Endpoints 
 
No formal exploratory endpoints have been defined. 
 
On an exploratory basis, severity of illness, gender and age may be assessed as covariates or to 
generate subgroups for the Cox regression model as described in section 11.3.1.1. In addition, 
descriptive statistics will be used to compare patient populations and treatment outcome 
between the geographical regions. 
Also on an exploratory basis, the primary analysis of the study will be repeated for each of the 
two definitions of relapse below and the hazard ratio for vortioxetine compared to placebo will 
be estimated from the model and presented with p-values and 95% CIs: 
i) Relapse based on investigator judgement. 
ii) Relapse defined as CDRS-R total score ≥40 with 2 weeks of clinical deterioration  
11.6   Pharmacokinetic Analyses 
The pharmacokinetic analyses will be described in a separate population PK analysis plan.  
12 Safety 
The safety analyses will be performed for each period, based on the APES and the APRS. Unless 
otherwise specified the tables and listings of the Open Label Period are based on APES. The 
tables and listings of the Double-Blind Treatment Period are based on the APRS. 
All safety endpoints will be reported for the 12-week Open Label Period and the 26-week 
Double-Blind Treatment Period separately. The results of the safety analysis of the Open Label 
Period will be presented by patient group (de novo patients and rollover patients from Study 
12709A) and overall.  
The results of the safety analyses of the Double-Blind Treatment Period will be displayed by 
treatment group and overall.  
 
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12.1   Adverse Events 
12.1.1 
General Methodology for Adverse Events 
 
Tables by preferred term and tables by system organ class (SOC) and preferred term will be 
sorted in descending order based on the percentages of patients in the total column. 
 
Unless otherwise specified, the summaries of adverse events will include the total number 
and percentage of patients with an adverse event and the total number of AEs. 
In summaries of adverse events presented by intensity, the maximum intensity of the adverse 
event will be used for patients who have more than one intensity of that event. Adverse events 
for which information on intensity is missing will be classified as severe. 
 
Listings of adverse events will be sorted by site, patient screening number, and adverse event 
start date, and include period, preferred term, investigator term, adverse event start date, days 
since first dose of IMP, dose at onset of AE, duration of the adverse event, action taken, 
causality, intensity, seriousness, and outcome. For adverse events that change in intensity, each 
intensity will be included. 
12.1.2 
Coding of Adverse Events 
 
Adverse events will be coded using MedDRA, Version 23.0 or later. 
12.1.3 
Classification of Adverse Events 
 
Adverse events will be classified according to the time of onset of the adverse event: 
 
• pre-treatment adverse event – an adverse event that starts on or after the date the 
patient signed the Informed Consent Form and prior to the date of first dose of IMP. 
As such, this definition will only be used for de novo patients.  
• treatment-emergent adverse event (TEAE) – an adverse event that starts or increases 
in intensity and/or seriousness on or after the date of first dose of IMP 
Adverse events, sorted by system organ class (SOC) and preferred term, will be 
summarized by treatment group. 
 
An adverse event is considered causally related to the use of the IMP when the causality 
assessment by the investigator is probable or possible. For pre-treatment adverse events, a 
causality assessment is not relevant. 
12.1.4 
Allocation of TEAEs to Treatment Periods 
 
TEAEs will be allocated to treatment periods according to the time of onset of the adverse 
event: 
   Pre-treatment AEs – an adverse event that starts on or after the date the patient signed the 
Informed Consent Form and prior to the date of first dose of IMP in Open Label Period. This 
definition will only be used for de novo patients. 
 
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   TEAE in the Open Label Period – an AE that starts on or after the date of the first IMP 
intake in the Open Label Period and before the date of the end of Open Label Period. In 
addition, for de novo patients only, this also includes AEs that start before the date of 
the start of Open Label Period and worsens before the date of the end of the Open Label 
Period. 
 
   TEAE in the Double-Blind Treatment Period – a TEAE that starts on or after the date of 
the first IMP intake in the Double-Blind Treatment Period and before the date of the 
end of Double-Blind Treatment Period, OR starts before the date of the start of Double-
Blind Treatment Period and worsens on or after the date of the first IMP intake in the 
DB treatment period and before the date of the end of the Double-Blind Treatment 
Period 
 
   TEAE in the Safety Follow-up Period – an AE that starts on or after the date of the end of 
Double-Blind Treatment Period or on or after the date of withdrawal (in either the Open 
Label Period or the Double-Blind Treatment Period). 
 
Adverse events that are ongoing in either parent study at the time of entry into the current study 
will be included in the present study. All data will be transcribed and the rules as described above 
will apply. 
12.1.5 
Presentation of Adverse Events 
 
All adverse events will be listed for the APES and APRS for the Open Label Period and 
the Double-Blind Treatment Period, including a flag for TEAEs. The period in which the 
AE started will be displayed. 
 
For each period, an overview of the number and percentage of patients with TEAEs, serious 
adverse events (SAEs), or adverse events leading to withdrawal and patients who died during 
the study will be provided. 
This overview will be based on the APES for the Open Label Period and APRS for the 
Double-Blind Treatment Period. For TEAEs, SAEs, and adverse events leading to 
withdrawal, the total number of events will be included. 
12.1.6 
Presentation of Pre-treatment Adverse Events 
 
Pre-treatment adverse events will be summarized by preferred term based on APES. 
 
12.1.7 
Presentation of Treatment-emergent Adverse Events 
 
The following summaries will be provided for the Open Label Period (based on the APES) and 
for the Double-Blind Treatment Period (based on the APRS) separately: 
• 
TEAEs by SOC and preferred term 
• 
TEAEs by preferred term 
• 
TEAEs with an incidence ≥5% by preferred term 
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• 
Causally related TEAEs by SOC and preferred term 
• 
TEAEs by intensity (mild/moderate/severe), SOC, and preferred term 
• 
Causally related TEAEs by intensity, SOC, and preferred term 
    
12.1.8 
Presentation of Deaths 
 
All the adverse events in patients who died during the study will be listed for the APES in the 
Open Label Period and for the APRS in the Double-Blind Treatment Period.  
12.1.9 
Presentation of Serious Adverse Events 
 
All the SAEs will be listed for the APES in the Open Label Period and for the APRS in the 
Double-Blind Treatment Period. 
 
Treatment-emergent SAEs will be summarized for each treatment period by: 
• 
SOC and preferred term 
• 
Preferred term 
 A listing presenting all SAEs will be prepared. 
12.1.10 
Presentation of Adverse Events Leading to Withdrawal 
All the adverse events leading to withdrawal will be listed. TEAEs leading to 
withdrawal will be summarized per treatment period by: 
• 
SOC and preferred term 
• 
Preferred term  
   
12.2    General Methodology for Other Safety Data 
Unless otherwise specified, tables, graphs and listings will be based on the APES (Open Label 
Period) and the APRS (Double-Blind Treatment Period). 
 
All tables and graphs will be presented by inclusion source (Open Label Period) and treatment 
group (Double-Blind Treatment Period). 
All safety endpoints will be reported for the 12-week Open Label Period and the 26-week 
Double-Blind Treatment Period separately. 
The denominators for the summaries of a given variable will be based on the number of patients 
with non-missing values at a given visit or during the assessment period. 
Descriptive statistics for the safety variables, both absolute values and changes from baseline, 
will be presented by visit and for the last assessment. All available post-baseline assessments 
(including data collected at unscheduled visits) will be included in the identification of the last 
assessment. With respect to baseline, the definition as presented in section 4.1 will be used. 
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The number and percentage of patients with at least one potentially clinically significant (PCS) 
value at any post-baseline assessment time point will be summarized by variable. All available 
assessments will be included in the evaluation of PCS values.  
The number and percentage of patients with values out-of-reference range and/or PCS range will 
be summarized by variable, visit, and last post-baseline assessment. 
For patients with post-baseline PCS values, listings will be provided including all the values for 
those patients for the variable, with flagging of PCS values and out-of-reference-range values. 
The PCS values relating to the paediatric population in this study will be applied. 
Lundbeck standard criteria for identifying PCS values will be used. 
12.3    Clinical Safety Laboratory Test Data 
The clinical safety laboratory tests that are evaluated at baseline and post-baseline are included in 
the panel below. 
 
Panel 4 
Clinical Safety Laboratory Tests 
Haematology 
Clinical Chemistry 
Urine 
protein (dipstick) 
glucose (dipstick) 
blood (dipstick) 
 
haemoglobin 
erythrocyte count 
total leucocyte count 
neutrophilsa 
eosinophilsa 
basophilsa 
lymphocytesa 
monocytesa 
thrombocyte count 
 
total bilirubin 
conjugated bilirubin 
alkaline phosphatase 
alanine aminotransferase 
aspartate aminotransferase 
gamma-glutamyl transferase 
creatinine 
urea nitrogen 
sodium 
potassium 
calcium (total) 
albumin 
estradiol [girls only] 
luteinising hormone [LH] 
follicle-stimulating hormone [FSH]) 
prolactin [PROLCTN] 
glucose 
low density lipoprotein 
high density lipoprotein 
triglycerides 
cholesterol (total) 
 
Absolute and change from baseline in clinical safety laboratory tests will be summarized per 
treatment period. For the Open Label Period results will be presented per inclusion source and 
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overall, whereas for the Double-Blind Treatment Period the results will be summarized per 
treatment group and in total. 
 
Urine results (dipstick) will be listed only. The microscopy results will be listed for patients with 
findings by assessment time point. 
In case of any pregnancies these will be listed. 
PCS values on laboratory tests will be flagged and summarized for the Open Label Period and 
Double-Blind Treatment Period as described in section 12.2.  
12.4    ECG, Vital Signs and Weight 
Results on blood pressure, pulse rate, height and weight will be presented as described in section 
12.2.  
The results from the central ECG readings will include the RR, PR, QRS, QT, QTc, and QTcF 
intervals. All of the ECG parameters will be summarized as described in section 12.2.  
12.5    Other Safety Endpoints 
Tanner staging is a scale for assessing physical development and sexual maturity during onset 
and progress of puberty. The scale includes 5 stages of pubertal changes (called Tanner stages) 
separate for males and for females.  
Data on Tanner staging and menstrual cycle (age of menarche, length of the menstrual cycle and 
menstrual cycle regularity) will be listed only. 
12.5.1 
Columbia-Suicide Severity Rating Scale (C-SSRS) Scores 
The C-SSRS was administered: 
At screening using the Baseline Screening version to capture the baseline result (de novo patients 
only) and at every scheduled visit thereafter using the Since last Visit version to capture the C-
SSRS assessments after baseline. 
A summary capturing the patients with suicidal ideation, suicidal behaviour 
The numbers and percentages of patients with baseline, or post-baseline suicide-related events 
based on the C-SSRS will be summarized. For the post-baseline assessments, the most severe 
score (Panel 5) per patient related to suicidal ideation and/or behaviour will be summarized. 
The number and percentage of patients with no suicidal ideation or behaviour will be 
summarized. Patients in this category are those who: 
answered ‘no’ to all ideation and behaviour questions; that is, answered ‘no’ to items in Panel 8 
related to suicidal ideation and answered ‘no’ to items related to suicidal behaviour. 
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Panel 5 
C-SSRS Scores 
C-SSRS Score 
Related to: 
Wish to be dead 
Suicidal ideation 
Non-specific active suicidal thoughts 
 
Active suicidal ideation with any methods (not plan) without intent to act 
 
Active suicidal ideation with some intent to act, without specific plan 
 
Active suicidal ideation with specific plan and intent 
 
Preparatory acts or behaviour 
Suicidal behaviour 
Aborted attempt 
 
Interrupted attempt 
 
Non-fatal suicide attempt 
 
Completed suicide (only applicable for the post-baseline assessments) 
 
The C-SSRS scores will be summarized per study period and by visit based on the APES (Open 
Label Period) or APRS (Double- blind Period) for patients with at least one post-baseline 
C-SSRS assessment in the respective period, regardless of whether they had a baseline C-SSRS 
assessment. 
Missing C-SSRS scores will not be imputed. 
Positive responses to non-suicidal self-injurious behaviour will be summarized separately. 
For patients with any post-baseline suicidal behaviour (C-SSRS scores of 6 to 10), listings will 
be provided including all C-SSRS scores for those patients; C-SSRS scores related to suicidal 
behaviour will be flagged. 
In addition, a listing with (highest) suicidal behaviour in the study or a period based on C-SSRS 
scores for those patients, and all SAEs related to suicidality, will be prepared. 
12.5.2 
General Behavior Inventory (GBI) 10-Item Mania Scale 
The GBI 10-item mania scale is a parent- and patient-rated scale designed to screen for manic 
symptoms in children and adolescents. The ten items are rated on a 4-point scale from 0 
(never or hardly ever) to 3 (very often or almost constantly). The total score ranges from 0 to 
30, with higher scores indicating greater pathology. Only the parent-rated scale will be used in 
this study. 
Summary statistics on the total score, absolute scores as well as changes from baseline for 
each visit as well as the latest assessment will be presented per study period and inclusion 
source (Open Label Period) and treatment group (Double-Blind Treatment Period). 
13 Interim Analyses 
 
No interim analyses will be performed. 
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14 Sample Size Considerations 
 
The calculation of power is based on a log-rank test for the time to relapse at a one-sided 
5% level of significance using SAS Proc Power. A sample size of 80 randomized patients 
(40 patients per treatment group) will provide at least 80% power to find a difference 
between vortioxetine and placebo as statistically significant, when expecting cumulative 
relapse rates at 0.42 and 0.69 over 26 weeks, respectively corresponding to a hazard-ratio 
of 2.15. The assumption of relapse rates (42% and 69% over 6 months for vortioxetine and 
placebo, respectively) is based on observed rates from a similarly designed relapse-
prevention study of fluoxetine in pediatric patients with MDD who had an adequate 
response after 12 weeks of acute treatment1. 
 
It is anticipated that approximately 60% of de novo patients enrolled into the Open Label 
Period will qualify for the Double-Blind Treatment Period. To achieve 80 randomized 
patients, 150 patients are estimated to be enrolled into the study (depending on number and 
randomization rate of de novo and rollover patients). 
15 Statistical Software 
 
The statistical software used will be SAS®, Version 9.4 or later. 
16 Details on Data Handling 
 
An LOCF approach will be used for the Double-Blind Treatment Period of the following scales: 
 
CDRS-R, PQ-LES-Q, CGI-I and CGI-S. 
 
The LOCF approach will only be used for the total scores (if applicable). The last usable 
assessment in the Double-Blind Treatment Period (excluding the randomization assessment) 
will be used to impute missing values for the LOCF. See also section Section 16.1.3 for the 
handling of missing data related to COVID-19. 
16.1    Assigning Data to Visits 
 
16.1.1 
Visit Window 
 
The assessments at the scheduled visits will be used for the analyses. The assessment at the 
Withdrawal Visit for patients withdrawn from study will be assigned to a nominal visit in the 
Treatment Period, according to the visit windowing specified in Panel 6. If the assessment at 
the Withdrawal Visit is assigned to the same visit as an assessment at a scheduled visit, the 
assessment from the Withdrawal Visit, which by definition always will be the latest, will be 
used.
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Panel 6 
Visit Windows 
Nominal Visit Number 
Nomin
al Visit 
Week 
Nominal 
Visit Week 
(relative to 
randomizat
ion) 
Nominal 
Visit Day 
Time 
Window 
(days) 
Mapping 
Window 
(days) 
Open Label Period 
 
 
 
 
 
V1(screen) 
 
 
-15 
-5 to -15 
 
V2(baseline) 
0 
NA 
0 
- 
 
V3 
1 
NA 
7 
4 to 10 
1 to 10 
V4 
2 
NA 
14 
11 to 17 
11 to 21 
V5 
4 
NA 
28 
25 to 31 
22 to 42 
V6 
8 
NA 
56 
53 to 59 
43 to 63 
V7 
10 
NA 
70 
67 to 73 
64 to 77 
V8(end of Open Label Period) 
12 
NA 
84 
81 to 87 
78 to 86 
Safety follow-up (end of Open 
Label, for patients not entering 
Double-Blind Treatment Period) 
16 
NA 
112 
110 to 114 
>86 
Double-Blind Treatment Period 
 
 
 
 
 
V8(baseline of Double-Blind 
Treatment Period) 
12 
0 
84 
81 to 87 
78 to 86 
V9 
13 
1 
91 
88 to 93 
87 to 95 
V10 
14 
2 
98 
95 to 101 
96 to 105 
V11 
16 
4 
112 
107 to 117 
106 to 119 
V11, CGI-I only* 
16 
4 
112 
107 to 117 
101 to 133 
V12 
18 
6 
126 
121 to 131 
120 to 140 
V13 
22 
10 
154 
149 to 159 
141 to 168 
V13, CGI-I and PQ-LES-Q only* 
22 
10 
154 
149 to 159 
134 to 182 
V14 
26 
14 
182 
177 to 187 
169 to 196 
V15 
30 
18 
210 
205 to 215 
197 to 224 
V15, CGI-I and PQ-LES-Q only* 
30 
18 
210 
205 to 215 
183 to 238 
V16 
34 
22 
238 
233 to 243 
225 to 252 
V17 
38 
26 
266 
261 to 271 
253 to 280 
V18 - Safety follow-up (end of 
Double-Blind Treatment Period, 
for patients who completed the 
Double-Blind Treatment Period) 
42 
30 
294 
289 to 299 
>281 
*Different mapping for these variables only, due to a different schedule of assessments 
 
16.1.2 
Safety Variables 
 
For laboratory test values (including estradiol [girls only], and luteinizing hormone [LH], 
follicle-stimulating hormone [FSH]), vital signs, height, weight, Tanner staging, 
electrocardiogram (ECG) parameter values, GBI scores (using the 10-item mania subscale), and 
C-SSRS scores, missing values will be not be imputed. 
 
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16.1.3 
Covid-19 impact 
 
This study has been carried out during the pandemic of COVID-19. As a result, impact on 
assessments and the timing of assessments is expected. Data will be collected to evaluate the 
impact of COVID-19 on the conduct of the study. These data will be presented in listings and 
summarized if needed. 
 
Missing visits: 
 
Depending on the impact of COVID-19 on data collection, it will be decided whether data from 
missing visits due to COVID-19 will be imputed using the LOCF approach as well. 
 
Remote visits: 
 
Scheduled and unscheduled visits are allowed to take place remotely via voice call or voice 
and video call. All the data from scheduled visits recorded remotely will be included in the 
analysis at the designated visit. Visit windowing as explained in Panel 6 above will be 
applied to remote visits. 
 
A listing will be presented on the details of remote visits including which visit was conducted 
remotely, date of remote visit, and whether or not patient reported outcomes and clinician 
reported outcomes were assessed during the remote visit. 
16.2    Handling Missing or Incomplete Dates/Times 
16.2.1 
IMP Start and Stop Dates 
 
A missing IMP start date will be imputed with the date of baseline of Open Label Period for De 
novo patients, Rollover patients from Study 12709A; 
A missing IMP start date will be imputed with the date of baseline of Double-Blind Treatment 
Period for Rollover patients (remitters) from Study 12712A; 
A missing IMP stop date will be imputed using last attended visit date.  
16.2.2 
Withdrawal Date 
 
Missing withdrawal dates will not be imputed. 
 
16.2.3 
Medication Start and Stop Dates 
 
Following rules will be followed to classify recent and concomitant medications for each of the 
two periods: 
 
 
 
 
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Panel 7 
Classification of Concomitant Medication 
Medication Start Date 
in period 
Medication Stop Date 
Classification 
Unknown 
< Date of first dose of IMP in period 
Discontinued prior to first dose 
of IMP in period 
Unknown 
≥ date of first dose of IMP in period 
Started at or after first dose of 
IMP in period 
< Date of first dose of 
IMP in period 
Unknown 
Continued after first dose of 
IMP in period 
≥ date of first dose of 
IMP in period 
Unknown 
Started at or after first dose of 
IMP in period 
Unknown 
Unknown 
Started at or after first dose of 
IMP in period 
 
16.2.4 
Adverse Event Start and Stop Dates 
With regard to classification of adverse events with incomplete dates, the following rule will be 
used: 
If the start date is missing for an adverse event and the stop date is prior to the first dose of IMP, 
the adverse event will be classified as a pre-treatment adverse event. In all other cases of an 
adverse event with a missing start or stop date, the adverse event will be classified as a TEAE. 
 
For the calculation of duration, missing or incomplete start and/or stop dates will imputed as 
follows: 
 
If only day is missing in the end date of an AE, the last day of the month will be used, whereas 
for missing start days the first day of the month will be used. 
For ongoing adverse events, the date of the last study contact will be used as the stop date for the 
adverse event in the calculation of duration. For other adverse events with a missing start or stop 
date, the duration will not be calculated. 
 
 
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16.3    Data with Multiple Records 
16.3.1 
Dose Changes in Medication 
 
Dose changes in medications are recorded on multiple rows in the dataset, with different start 
and stop dates. When classifying medications into periods (prior to IMP, started or continued in 
treatment period), each dose is considered a separate medication, and the same medication can 
be assigned to several periods for the same patient. Within a period, multiple entries contribute 
as a single count. 
16.3.2 
Changes in Intensity or Seriousness of Adverse Events 
 
Changes in adverse event intensity or seriousness are recorded on multiple rows in the dataset. 
When classifying adverse events into periods, an event will be assigned to more than one period 
only if the intensity increases or if a non-serious event becomes serious. An adverse event that 
changes in intensity or seriousness in a period will contribute to the count of events as a single 
event. 
 
In summaries of adverse events presented by intensity, the maximum intensity of the adverse 
event will be used. The maximum intensity is searched for in events with changes, as well as 
over repeated events based on the preferred term. Adverse events for which information on 
intensity is missing will be classified as severe. 
 
Adverse events for which information on seriousness is missing will be classified as serious. 
 
 
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References 
1  
Emslie GJ, Ventura D, Korotzer A, Tourkodimitris S: Escitalopram in the treatment of 
adolescent depression: A randomized placebocontrolled multisite trial. J Am Acad Child Adolesc 
Psychiatry. 2009; 48: 721–729.
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Appendix I: Statistical Analysis Plan 
Authentication and Authorization 
 
 
 
 
Study title: 
A Double Blind, randomized, placebo-controlled, multicentre, relapse-
prevention study of vortioxetine in paediatric patients aged 7 to 11 years 
with Major Depressive Disorder 
Study No.: 
13546A 
SAP date: 
Final Version 1.0: 09 April 2021 
 
This document has been signed electronically. The signatories are listed below. 
 
 
Authentication 
 
 
H Lundbeck A/S 
 
 
 
 
 
ICON Plc 
 
 
Authorization 
 
 
 
 
H Lundbeck A/S 
 
 
 
 
H Lundbeck A/S 
 
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h The K-SADS-PL will be used to confirm diagnosis of MDD and to assess possible psychiatric co-morbidities. 
i 
Values from all assessments and procedures (efficacy/safety, including blood/urine samples and use of 
concomitant medication) performed at the Completion Visit (Visit 12) in Study 12709A will be the Baseline 
Visit values in Study 13546A.  
j 
Only for AEs ongoing at Withdrawal and new SAEs. 
k The hormones panel is to be collected at Visit 1 (estradiol in females only). 
l 
An extra tube of blood samples will be required for hormones at the Study 12709 Week 12 Visit. 
m Between Week 2 and Week 8, the patient and/or parents /legal representative can request an unscheduled site 
visit to discuss their current dose. AEs will be collected and C-SSRS, GBI-mania and CGI-S will be done at 
the unscheduled visit. 
n If the patient is a female patient of childbearing potential (defined as females aged ≥10 years old and younger 
girls who, at the discretion of the investigator, are deemed to be of reproductive potential), a urine pregnancy  
test is to be performed at screening and randomization, and at the Withdrawal Visit. 
o It is not mandatory to screen for drugs and/or alcohol. However, it can be performed at any visit, at the 
discretion of the investigator. 
 
 
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B) Study Procedures and Assessments – Double-Blind Treatment Period 
Visit 
Double-Blind Treatment Period 
(Relapse-prevention) 
Safety 
Follow-upb 
Randomi
zationa 
 
Completion or 
Withdrawal 
Visit Number 
8 
9 
10 
11 
12 
13 
14 
15 
16 
17 
18 
End of Week (relative to 
Baseline) 
12 
13 
14 
16 
18 
22 
26 
30 
34 
38 
42 
End of Week (relative to 
Randomization) 
0 
1 
2 
4 
6 
10 
14 
18 
22 
26 
30 
Visit Windowc (days 
relative to nominal visit) 
±3 
±3 
±3 
±5 
±5 
±5 
±5 
±  
±5 
 
±5 
±5 
Randomisation Procedures and Assessments 
Signed Informed 
Assent/Consent (rollover 
patients from 12712A only) 
√ 
 
 
 
 
 
 
 
 
 
 
Inclusion criteria 
√ 
 
 
 
 
 
 
 
 
 
 
Efficacy Assessments 
CDRS-R 
√d 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
 
CGI-S 
√d 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
 
CGI-I 
 
√ 
 
√ 
 
√ 
 
√ 
 
√ 
 
PQ-LES-Q (PRO) 
√ 
 
 
√ 
 
√ 
 
√ 
 
√ 
 
Pharmacokinetic Assessments 
Blood sampling for 
vortioxetine quantification  
√ 
 
 
 
 
√ 
 
 
 
√ 
 
Safety Assessments 
Adverse events 
√e 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√f 
Blood and urine sampling 
for clinical safety laboratory 
testsj 
√i 
 
 
 
 
√  
 
 
√ 
 
Vital signs 
√d 
√ 
√ 
√ 
√ 
√ 
 
√ 
 
√ 
 
Weight and height 
√d 
 
 
 
 
√ 
 
 
 
√ 
 
ECGs 
√ 
 
 
 
 
√ 
 
 
 
√ 
 
Examinations (physical and 
neurological) 
√d 
 
 
 
 
√ 
 
 
 
√ 
 
Menstrual cycle 
√d 
 
 
 
 
 
 
 
 
√ 
 
Tanner staging 
√d 
 
 
 
 
 
 
 
 
√ 
 
C-SSRS 
√d 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
 
GBI (mania subscale) 
√ 
 
√ 
 
√ 
√ 
 
√ 
 
√ 
 
Other Study Procedures 
IMP dispensed 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
 
 
IMP returned and IMP 
accountability 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
 
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CDRS-R = Children depression rating scale revised version; CGI-I = Clinical Global Impression – Global 
Improvement; CGI-S = Clinical Global Impression – Severity of Illness; C-SSRS = Columbia-Suicide Severity 
Rating Scale; eCRF = electronic case report form; ECG = electrocardiogram; GBI: General Behaviour 
Inventory; IMP = investigational medicinal product; K-SADS-PL = The Kiddie-Schedule for Affective 
Disorders and Schizophrenia for School-aged Children, Present and Lifetime version; PQ-LES-Q = Pediatric 
Quality of Life Enjoyment and Satisfaction Questionnaire – Patient rated; SAE = serious adverse event  
a Patients from Study 12712A who are in remission after 8 to 12 weeks of open-label treatment in study 12712A 
will enter directly into the Randomization Visit of this study. 
b This can be a telephone contact, unless an SAE has occurred since the last visit or unless there was a clinically 
significant abnormal safety laboratory test value at the last visit. In such cases, safety follow-up(s) must be 
scheduled to allow for a medical examination and/or blood sampling. Further safety follow-up visits beyond 30 
days may be needed as judged by the investigator (if further safety follow-up visits are performed, these must be 
recorded in the patient’s medical record, and not in the eCRF). 
c  If the date of a patient visit does not conform to the study plan, subsequent visits should be planned to maintain 
the visit schedule relative to the Randomization Visit (Visit 8). Consider that the number of days between 2 visits 
must not exceed the number of days for which the patient has been dispensed IMP. 
d For 12712A-patients, last available values from assessments and procedures (efficacy/safety, and use of 
concomitant medication) performed at either Visit 7 (Week 8) and/or Visit 8 (Week 10), or Visit 9 (Week 12) in 
Study 12712A will be the Randomization Visit values for this study, when applicable. For patients who rollover at 
Visit 7 or Visit 8, weight, height, Tanner staging, menstrual cycle, and examinations should be done at the 
Randomization Visits. 
e For 12712A-patients, ongoing AEs and concomitant medication from study 12712A will be used for eCRF. 
f 
Only for AEs ongoing at Completion/Withdrawal and new SAEs 
g If the patient is a female patient of childbearing potential (defined as females aged ≥10 years old and younger girls 
who, at the discretion of the investigator, were deemed to be of reproductive potential), a urine pregnancy test is to 
be performed at randomization, Visit 13 (Double-Blind Treatment Period Week 10) and at 
Completion/Withdrawal Visit. Additional pregnancy tests during the study will be performed according to local 
requirements.  
h It is not mandatory to screen for drugs and/or alcohol. However, it can be performed at any visit, at the discretion 
of the investigator.  
i 
Only for 12712A-patients who rollover into Double Blind phase. 
j 
The hormones panel is to be collected at Visit 8 (for 12712A-patients) and Completion/Withdrawal (for all 
patients). 
 
 
 
Recent and concomitant 
medication 
√e 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
 
Pregnancy testg 
√ 
 
 
 
 
√ 
 
 
 
√ 
 
Drug and alcohol screenh 
 
 
 
 
 
 
 
 
 
 
 
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Appendix III: SAS Codes 
 
 
 
 
 
Primary endpoint 
 
Cox regression Model proc phreg data=xyz; 
class treatment; 
strata inclusion; 
model time_to_relapse*censor(0)=treatment 
randomization_total_cdrs-r 
/ rl=both ties=exact; 
run; 
 
 
Secondary 
Endpoint(s) – Relapse 
 
Logistic Regression 
proc logistic data=xyz; 
class treatment(ref=’Placebo’) inclusion; 
model relapse=treatment inclusion 
cdrs_baseline / clodds=pl clparm=pl; 
run; 
 
 
CDRS-R total score 
PQ-LES-Q 
CGI-S 
CGI-I 
 
MMRM 
proc mixed data=xyz ic method=reml; 
class usubjid treatment(ref=’Placebo’) week 
inclusion; 
model Change=treatment week inclusion 
baseline treatment*week baseline*week / s 
ddfm=kr; 
repeated week / patient usubjid type=un; 
lsmeans treatment*week / cl alpha=0.05; 
 
 
CDRS-R total score 
PQ-LES-Q 
CGI-S 
CGI-I 
 
ANCOVA 
proc mixed data=xyz ic method=reml; 
class treatment inclusion; 
model Change=treatment inclusion baseline; 
lsmeans treatment / cl alpha=0.05; 
 
 
 
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Final: Version 1.0
PLUTO ID: CLI_01374315
Electronic Signature Page
Full Title
A double-blind, randomized, placebo-controlled, multicentre, relapse-prevention
study of vortioxetine in paediatric patients aged 7 to 11 years with Major Depressive
Disorder
Short Title
13546A - Protocol - Edition 1.0
Study Number
13546A
The following persons have electronically signed this document
Server Date and Time Signed By
07-Jan-2021 15:22:47
Reason for Signature
Correctness and Completeness
07-Jan-2021 15:48:43
Reason for Signature
Biostatistic Approval
07-Jan-2021 16:00:35
Reason for Signature
Clinical Approval
07-Jan-2021 16:24:16
Reason for Signature
Clinical Approval
08-Jan-2021 10:12:27
Reason for Signature
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Study 13546A – Clinical Study Protocol
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Clinical Study Protocol
A double-blind, randomized, placebo-controlled, multicentre, 
relapse-prevention study of vortioxetine in paediatric patients 
aged 7 to 11 years with Major Depressive Disorder
Vortioxetine
Study No.:
13546A
EudraCT No/IND.:
2010-020493-42/112581
Sponsor:
H. Lundbeck A/S (Lundbeck)
2500 Valby (Copenhagen), Denmark
Edition No.:
1.0
Date of edition:
7 January 2021
This document is the property of H. Lundbeck A/S and H. Lundbeck A/S is the holder of any and all 
related intellectual property rights, including, but not limited to, copyrights. This document is 
confidential. It is not to be copied or distributed to other parties without prior written authorization 
from H. Lundbeck A/S.
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Synopsis – Study 13546A
Sponsor
H. Lundbeck A/S
Investigational Medicinal Product
Vortioxetine
Study Title
A double-blind, randomized, placebo-controlled, multicentre, relapse-prevention study of vortioxetine in 
paediatric patients aged 7 to 11 years with Major Depressive Disorder (MDD)
Objectives and Endpoints
Objectives
Endpoints
Primary Objective
to evaluate the efficacy of vortioxetine in the 
prevention of relapse of major depressive 
episodes in paediatric patients with MDD
Depressive Symptoms
Primary endpoint:
time to relapse in the double-blind period
Secondary endpoint:
relapse rate in the double-blind period
Secondary Objectives
to evaluate efficacy of vortioxetine during 
continuation treatment of paediatric patients 
with MDD
to evaluate the efficacy of vortioxetine on:
clinical global impression
quality of life
to assess adherence to investigational 
medicinal product (IMP) through 
pharmacokinetic analysis 
Depressive Symptoms
Secondary endpoint:
change from baseline to Week 26 in the Children 
Depression Rating Scale Revised Version (CDRS-R) total 
score
Global Clinical Impression
Secondary endpoints:
change from baseline to Week 26 in the Clinical Global 
Impression – Severity of Illness (CGI-S) score
Clinical Global Impression – Global Improvement (CGI-I)
score at Week 26
Quality of life
• Secondary endpoint:
Change from baseline to Week 26 in Pediatric Quality of 
Life Enjoyment and Satisfaction Questionnaire 
(PQ-LES-Q) – Patient rated
Pharmacokinetics
Secondary endpoints:
plasma exposure to vortioxetine
population pharmacokinetic parameter values 
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Safety Objectives
to evaluate long-term safety and tolerability of 
vortioxetine in paediatric patients with MDD
Safety Endpoints
adverse events
absolute values and changes from baseline in clinical safety 
laboratory test values (including estradiol [girls only], and 
luteinising hormone [LH], follicle-stimulating hormone 
[FSH]), vital signs, height, weight, Tanner staging, 
electrocardiogram (ECG) parameter values. Effects on 
menstrual cycle will be assessed.
potentially clinically significant clinical safety laboratory 
test values, vital signs, weight changes, and ECG parameter 
values
Columbia-Suicide Severity Rating Scale (C-SSRS) score
General Behaviour Inventory (GBI) using the 10-item mania 
subscale (parental version)
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Study Methodology
This is an interventional, multi-national, multi-site, randomized, parallel-group, placebo-controlled, 
relapse-prevention study in paediatric patients with MDD from 7 to 11 years of age. 
The study consists of a 12-week, open-label, flexible-dose treatment period with vortioxetine followed by a 
26-week, randomized, double-blind, fixed-dose, placebo-controlled relapse-prevention period.
The study population will include de novo patients as well as rollover patients from other paediatric 
vortioxetine studies (Studies 12709A and 12712A), who, in the investigator’s opinion, could benefit from 
continued treatment with vortioxetine.
  De novo patients 
Patients meeting eligibility criteria for de novo patients will be enrolled in the 12-week, open-label, 
flexible-dose treatment period.
  Rollover patients from Study 12709A (enrolled to the open-label period)
Patients may participate in the present study after completion of the randomized, 8-week, double-blind, 
placebo-controlled treatment period of Study 12709A. 
Eligible patients will be enrolled in the 12-week, open-label, flexible-dose treatment period.
The Baseline Visit of this study (Study 13546A) will take place at the same visit as Visit 12 (Completion 
Visit) of Study 12709A. Participation in Study 12709A is considered completed when all assessments 
required at Visit 12 are completed.
  Rollover patients (remitters) from Study 12712A (randomized to the double-blind period)
Patients who have received 8 to 12 weeks of treatment with vortioxetine in the open-label extension study 
12712A may participate in the present study if they have remitted (CDRS-R total score ≤28) at the last 
2 visits in Study 12712A prior to the rollover. In addition, the dose of vortioxetine must have been fixed for 
the last 4 weeks in Study 12712A prior to randomization in the present study.
Eligible patients will be randomized directly to the 26-week, double-blind treatment period.
The study design is presented in Panel 1 (including the study periods) and the scheduled study procedures and 
assessments are summarized in Panel 2 and Panel 3.
Open-label Period (for de novo patients and rollover patients from Study 12709A)
The duration of the open-label, flexible-dose treatment period will be 12 weeks.
The dosage of vortioxetine will be initiated at 5 mg/day for the first 2 days prior to receiving 10 mg/day.
The target dose is 10 mg/day, however, the investigator has the possibility to increase the dose to a maximum 
of 20 mg/day in case of unsatisfactory response or decrease the dose to 5 mg/day in case of dose-limiting 
adverse events. The dose can be up- or down-titrated with 5 mg/day. The patient should receive the same dose 
for 2 days before being up- or down-titrated to a new dose. Changes in dosing may occur at any visit during 
the first 8 weeks at the investigator's discretion. In addition, between Week 2 and Week 8, the patient and/or 
parent(s)/legal representative(s) can request an unscheduled visit to discuss their current dose. 
From Week 8 onwards the dose has to remain fixed.
Patients in remission (CDRS-R total score ≤28) at both Weeks 10 and 12 or with an adequate clinical 
response (defined as ≥50% reduction in the CDRS-R total score compared to the baseline score in this study 
[subtracted 17 to avoid flooring effect] and a CDRS-R total score ≤35) at both Weeks 10 and 12 will be 
randomized in the double-blind, placebo-controlled, fixed-dose period. 
Patients who do not fulfil the randomization criteria at Week 10 and/or Week 12 will be withdrawn from the 
study and will complete an early Withdrawal Visit. Non-remitters who leave the study will be treated at the 
investigator’s discretion.
A Safety Follow-up Visit will be performed approximately 4 weeks after withdrawal from the open-label 
period.
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Double-Blind Period (for all patients)
A total of 80 patients who fulfil the randomization criteria will be randomly assigned via a centralized 
randomization system to receive vortioxetine or placebo in a 1:1 ratio. Randomization will be stratified by 
patient inclusion source (de novo patients, rollover patients from 12709A, or from 12712A).
Patients randomized to vortioxetine will continue on their final dose from the open-label period or the dose 
they had on their last visit in Study 12712A, as applicable. 
The duration of the double-blind, fixed-dose treatment period will be 26 weeks. 
Patients who relapse during the double-blind period must be withdrawn from the study. The criterion for a 
relapse is a CDRS-R total score of ≥40 with a history of 2 weeks of clinical deterioration, or a clinical 
deterioration that in the investigator’s opinion warrants alteration of treatment to prevent full relapse.
A Safety Follow-up Visit will be performed 4 weeks after withdrawal from or completion of the double-blind 
period. 
An independent Data Monitoring Committee (DMC) will monitor safety data at regular intervals as specified 
in the DMC Charter.
This study will be terminated if the result of the currently ongoing placebo-controlled, short-term study 
(12709A) in children is negative (that is, if vortioxetine fails to show a significant difference from placebo in 
acute treatment). In case of study termination, the participating patients will be treated at the discretion of the 
investigator in line with clinical practice.
Number of Patients Planned
Eighty (80) patients are planned for randomization to the 26-week double-blind period (including those who 
rollover from study 12712A): 40 in the vortioxetine group and 40 in the placebo group.
One-hundred fifty (150) patients recruited from specialist settings, mainly outpatient clinics, either as de novo
patients or rollover patients from Study 12709A, are estimated to be enrolled into the study. The exact number 
of enrolled patients will depend on the number and randomization rate of de novo and rollover patients. 
Approximately 40 psychiatric centres are planned for recruitment in approximately 10 countries worldwide.
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Target Patient Population
Main Inclusion Criteria
De novo patients
The patient has MDD, diagnosed according to Diagnostic and Statistical Manual of Mental Disorders, 5th 
edition (DSM-5TM) and confirmed by The Kiddie-Schedule for Affective Disorders and Schizophrenia for 
School-aged Children, Present and Lifetime version (K-SADS-PL). 
The patient has a CDRS-R total score ≥45 at the Screening and Baseline Visits.
The patient has a CGI-S ≥4 at the Screening and Baseline Visits.
The patient has a primary diagnosis of MDD, although co-morbid anxiety disorders will be permitted except 
Post Traumatic Stress Disorder (PTSD) and Obsessive-Compulsive Disorder (OCD).
The patient is aged ≥7 and <12 years at screening. Patients who turn 12 years during this study will be 
allowed to continue in the study.
Rollover patients from Study 12709A (enrolled to the open-label period)
The patient has completed Study 12709A (Visit 12, Completion Visit) immediately prior to enrolment into 
this study.
In the investigator’s opinion, the patient could benefit from participation in a study which includes continued 
treatment with vortioxetine.
The patient is a child aged ≥7 and <12 years at screening of Study 12709A. 
Rollover patients (remitters) from Study 12712A (randomized to the double-blind period)
The patient has received 8 to 12 weeks of open-label treatment with vortioxetine in Study 12712A and 
completed Visit 7 (Week 8), or Visit 8 (Week 10), or Visit 9 (Week 12) immediately prior to enrolment into 
this study.
In the investigator’s opinion, the patient could benefit from participation in a study which includes continued 
treatment with vortioxetine.
The patient is in remission at the last 2 visits in Study 12712A, in which the CDRS-R is assessed every 4 
weeks. Hence
a)If the patient rolls over at Visit 7 or Visit 8 (Week 8 or Week 10): the patient has a CDRS-R total score ≤28 
at Visit 5 (Week 4) and Visit 7 (Week 8) in Study 12712A
b)If the patient rolls over at Visit 9 (Week 12): the patient has a CDRS-R total score ≤28 at Visit 7 (Week 8) 
and Visit 9 (Week 12) in Study 12712A
The patient has been on a stable dose of vortioxetine for the past 4 weeks prior to rollover to this study.
The patient is a child aged ≥7 and <12 years at Baseline of Study 12712A.
Main Exclusion Criteria
The patient presents with, or has a history of, an Axis I (DSM-5TM) diagnosis of Bipolar Disorder, PTSD, 
OCD, Autism, Pervasive Developmental Disorder (PDD), or Schizophrenia or Schizoaffective Disorder.
The patient has a diagnosis of attention-deficit/hyperactivity disorder (ADHD) and is not maintained on a 
stable dose of a methylphenidate or amphetamine for a minimum of 4 weeks prior to the study treatment.
One of the parents or siblings of the patient has a history of Bipolar Disorder.
The patient has attempted suicide 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 
C-SSRS within the last 12 months).
The patient has a known intellectual disability (as suggested by an intelligence quotient [IQ] <70), or, clinical 
evidence or known social or school history indicative of intellectual disability.).
The patient has been treated with any antidepressant or anxiolytic medication within 2 weeks prior to Visit 2 
(only de novo patients).
The patient is unable to swallow capsules.
The patient has previously been treated with vortioxetine in a clinical study (only de novo patients).
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Investigational Medicinal Product, Reference Therapy, Doses and Mode of Administration
Open-label Period
Vortioxetine – 5, 10, 15, and 20 mg/day, tablets, orally
The treatment should be taken once daily, preferably at the same time each day.
Patients will receive a targeted dose of 10 mg/day vortioxetine, however the investigator has the possibility to 
adjust the dose in case of unsatisfactory response or in case of dose-limiting AEs. The patient will receive a 
lower initial dose (5 mg/day for 2 days) prior to receiving 10 mg/day. The dose can be up- or down-titrated 
with 5 mg/day. The patient should receive the same dose for 2 days before being up- or down-titrated to a new 
dose.
Double-blind Period
Vortioxetine – 5, 10, 15, and 20 mg/day, encapsulated tablets, orally
Placebo – encapsulated tablets, orally
The treatment should be taken once daily, preferably at the same time each day.
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Statistical Methodology
The following analysis sets will be used to analyse and present the data:
all-patients-enrolled set (APES) – all patients enrolled to the 12-week open-label, flexible-dose treatment 
period who took at least one dose of IMP
all-patients-randomized set (APRS) – all patients randomized to the 26-week double-blind treatment period 
full-analysis set (FAS) – all patients randomized to the 26-week double-blind treatment period who took at 
least one dose of double-blind IMP
The efficacy analyses will be based on the FAS.
Primary analysis: 
Primary efficacy analysis will compare the time to relapse (defined as either a total score ≥40 on the 
CDRS-R with a history of 2 weeks of clinical deterioration, or clinical deterioration as judged by the 
clinician) between Vortioxetine and placebo using a Cox regression model with exact adjustment for ties. A 
one-sided 5% level of significance will be used. Patients not relapsing before Week 26 will be censored at 
Week 26 and patients withdrawing due to other reasons than relapse will be censored at time of withdrawal. 
Sensitivity analysis of the primary endpoint: 
Primary analysis will be repeated ignoring relapses occurring during the first week, two weeks and four 
weeks of the double-blind period, respectively.
The number of relapses will be summarized according to relapse criteria: CDRS-R total score ≥40 with 
2 weeks of clinical deterioration, investigator’s judgement, or both.
Primary analysis will be repeated for the de novo patients and for the (pooled) 12709A patients and 12712A 
patients.
Analyses of secondary endpoints:
Relapse over 26 weeks will be analysed using logistic regression.
Secondary efficacy variables (CDRS-R, PQ-LES-Q, CGI-S, CGI-I) will, on an exploratory basis be 
analysed over the 26-week double-blind period by Mixed Model Repeated Measurements (MMRM) and 
analysis of covariance (ANCOVA) (observed cases [OC] and last observation carried forward [LOCF]).
The population pharmacokinetics (popPK) of vortioxetine in children will be analysed through non-linear 
mixed effect analysis and will be described in a separate popPK analysis plan.
Analyses of other endpoints: 
On an exploratory basis, potential use of psychotherapy in the double-blind period, severity of illness, 
gender, and age will be assessed as covariates or to generate subgroups for the Cox regression model.
Descriptive statistics will be used to compare patient populations and treatment outcome between the 
geographical regions.
The safety analyses will be based on the APES and the FAS.
Analyses of safety endpoints:
AEs, absolute and change from baseline in clinical safety laboratory tests (estradiol for girls, LH, FSH), 
Tanner staging, ECG, and effects on menstrual cycle, vital signs, height, weight, and ECG parameters will 
be summarized, and observed potentially clinically significant (PCS) safety laboratory test values will be 
flagged and summarized. GBI scores (using the 10-item mania subscale), and C-SSRS scores will be 
summarized using descriptive statistics. 
AEs and other safety endpoints will be reported separately for the 12-week open-label period and the 
26-week double-blind period.
Patient disposition and demographics will be summarized using descriptive statistics.
Testing Strategy
Not applicable
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Study 13546A – Clinical Study Protocol
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Sample Size Considerations
The calculation of power is based on a log-rank test for the time to relapse at a one-sided 5% level of 
significance using SAS® Proc Power. A sample size of 80 randomized patients (40 patients per treatment group) 
will provide at least 80% power to find a difference between vortioxetine and placebo as statistically 
significant, when expecting cumulative relapse rates at 0.42 and 0.69 over 26 weeks, respectively,
corresponding to a hazard-ratio of 2.15. 
It is anticipated that approximately 60% of de novo patients enrolled into the open-label period will qualify for 
the double-blind study period. One-hundred fifty (150) patients are estimated to be enrolled into the study 
(depending on number and randomization rate of de novo and rollover patients).
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Study 13546A – Clinical Study Protocol
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Panel 1
Study Design
* Patients in remission (CDRS total score ≤28) at the two last visits in the open-label treatment period / Study 12712A 
OR with an adequate clinical response (≥50% reduction in the CDRS-R total score compared to the baseline score and a 
CDRS-R total score ≤35) at the two last visits in the open-label treatment period
**Relapse: CDRS-R total score of ≥40 with a history of 2 weeks of clinical deterioration, or a clinical deterioration that in the 
investigator’s opinion warrants alteration of treatment to prevent full relapse
R
4 week 
safety
Follow -up
Up to 
15 days
Open label treatment
(12 weeks)
Vortioxetine 5-20 mg/day
Double-blind relapse prevention
(26 weeks)
Vortioxetine fixed dose (5-20 mg/day)
Relapse**
Flexible dose first 8 weeks Fixed dose
Screening
W0
Baseline
W8 W10 W12
W38
W42
Placebo
Remitted 
patients*only 
De novo
patients
Completers 
from 12709A
Remitters from 
12712A
Randomization
7-11 yrs
With MDD
CDRS-R ≥45
CGI-S ≥4 
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Study 13546A – Clinical Study Protocol
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Panel 2
Study Procedures and Assessments – Open-label Period for de novo Patients
and Rollover Patients from Study 12709A
Open-label Period
Visit Name
Screeninga 
only de novo
Baselineb
de novo
Baselinec
12709A rollover
Randomization
Withdrawald
Safety Follow-upe 
Visit Number
1
2
2
3
4
5
6
7
8
Day/End of Week
d-5/d-15
0
0
W1 W2
W4
W8
W10
W12
W16
Visit Windowf (days relative to 
nominal visit)
0
0
3
3
3
3
3
3
5
Screening and Baseline Procedures and Assessments
Signed Informed 
Assents/Consents 


Diagnosis (DSM-5TM) 

()g
K-SADS-PLh

()g
Disease-specific history

()g
Relevant history (social, medical, 
psychiatric, neurological)

()g
Demographics (age, sex, race)

()g 
Family psychiatric history

()g
Traumatic life events

()g
Inclusion/exclusion criteria 



Randomization criteria

History of stimulant medication 

()g 
Efficacy Assessments
CDRS-R 


()i







CGI-S 


()i







PQ-LES-Q (PRO)

()i



Pharmacokinetic Assessments
Blood sampling for vortioxetine 
quantification



Safety Assessments
Adverse events


()i







j
Blood and urine sampling for 
clinical safety laboratory tests
k
()i, l



Vital signs


()i







Weight and height

()i


ECG

()i



Examinations (physical and 
neurological)



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Study 13546A – Clinical Study Protocol
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Open-label Period
Visit Name
Screeninga 
only de novo
Baselineb
de novo
Baselinec
12709A rollover
Randomization
Withdrawald
Safety Follow-upe 
Visit Number
1
2
2
3
4
5
6
7
8
Day/End of Week
d-5/d-15
0
0
W1 W2
W4
W8
W10
W12
W16
Visit Windowf (days relative to 
nominal visit)
0
0
3
3
3
3
3
3
5
Tanner staging and menstrual 
cycle

√

C-SSRS


()i







GBI (Mania subscale) 


()i







Other Study Procedures and Assessments
IMP dispensed








Possible change in IMP dosem




IMP returned and IMP 
accountability







Recent and concomitant 
medication


()i







Pregnancy testn

()i


Drug and alcohol screeno
AE = adverse event; CDRS-R = Children depression rating scale revised version; CGI-S = Clinical 
Global Impression – Severity of Illness; C-SSRS = Columbia-Suicide Severity Rating Scale; 
ECG = electrocardiogram; eCRF = electronic case report form; GBI= General Behaviour Inventory; 
IMP = investigational medicinal product; K-SADS-PL = The Kiddie-Schedule for Affective Disorders 
and Schizophrenia for School-aged Children, Present and Lifetime version; PQ-LES-Q = Pediatric 
Quality of Life Enjoyment and Satisfaction Questionnaire – Patient rated; SAE = serious AE 
a
Screening visit will be performed only for de novo patients. Patients rolling over from Study 12709A will 
proceed directly to the Baseline Visit (see ‘Baseline Visit 12709A rollover’ column). The Informed 
Assent/Consent Form must be signed before any study-related activities take place.
b
Applicable only for De novo patients.
c
Applicable only for 12709A rollover patients. Assessments marked with () in this column will be used 
from 12709A study and therefore not repeated.
d
This visit should take place as soon as possible after the patient withdraws from the study. Any visit during 
the open-label treatment period can be converted into a Withdrawal Visit on the day of the visit.
e
Applicable for patients withdrawn prior or at Visit 8: Safety follow-up should be scheduled approximately 
30 days after the last dose of IMP. It can be a telephone contact, unless an SAE has occurred since the last 
visit or unless there was a clinically significant abnormal safety laboratory test value at the last visit. In 
such cases, safety follow-up(s) must be scheduled to allow for a medical examination and/or blood 
sampling. Further safety follow-up visits beyond 30 days may be needed as judged by the investigator (if 
further safety follow-up visits are performed, these must be recorded in the patient’s medical record, and 
not in the eCRF).
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Study 13546A – Clinical Study Protocol
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f
If the date of a visit does not conform to the schedule, subsequent visits should be planned to maintain the 
visit schedule relative to the Baseline Visit. Consider that the number of days between 2 visits must not 
exceed the number of days for which the patient has been dispensed IMP.
g
The data from the Screening Visit in the Study 12709A eCRF will be used.
h
The K-SADS-PL will be used to confirm diagnosis of MDD and to assess possible psychiatric co-
morbidities.
i
Values from all assessments and procedures (efficacy/safety, including blood/urine samples and use of 
concomitant medication) performed at the Completion Visit (Visit 12) in Study 12709A will be the 
Baseline Visit values in Study 13546A. 
j
Only for AEs ongoing at Withdrawal and new SAEs.
k
The hormones panel is to be collected at Visit 1 (estradiol in females only).
l
An extra tube of blood samples will be required for hormones at the Study 12709 Week 12 Visit.
m Between Week 2 and Week 8, the patient and/or parents /legal representative can request an unscheduled 
site visit to discuss their current dose. AEs will be collected and C-SSRS, GBI-mania and CGI-S will be 
done at the unscheduled visit.
n
If the patient is a female subject of childbearing potential (defined as females aged ≥10 years old and 
younger girls who, at the discretion of the investigator, are deemed to be of reproductive potential), a urine 
pregnancy test is to be performed at screening and randomization, and at the Withdrawal Visit.
o
It is not mandatory to screen for drugs and/or alcohol. However, it can be performed at any visit, at the 
discretion of the investigator.
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Study 13546A – Clinical Study Protocol
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Panel 3
Study Procedures and Assessments – Double-blind Period
Visit
Double-blind period
(Relapse-prevention)
Safety 
Follow-upb
Randomi
zationa
Completion or 
Withdrawal
Visit Number
8
9
10
11
12
13
14
15
16
17
18
End of Week (relative to 
Baseline)
12
13
14
16
18
22
26
30
34
38
42
End of Week (relative to 
Randomization)
0
1
2
4
6
10
14
18
22
26
30
Visit Windowc (days 
relative to nominal visit)
3
3
3
5
5
5
5

5
5
5
Randomisation Procedures and Assessments
Signed Informed 
Assent/Consent (rollover 
patients from 12712A only)

Inclusion criteria

Efficacy Assessments
CDRS-R
d









CGI-S
d









CGI-I





PQ-LES-Q (PRO)





Pharmacokinetic Assessments
Blood sampling for 
vortioxetine quantification 



Safety Assessments
Adverse events
e









f
Blood and urine sampling 
for clinical safety laboratory 
testsj
i


Vital signs
d







Weight and height
d


ECGs



Examinations (physical and 
neurological)
d


Menstrual cycle
d

Tanner staging
d

C-SSRS
d









GBI (mania subscale)






Other Study Procedures
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Study 13546A – Clinical Study Protocol
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CDRS-R = Children depression rating scale revised version; CGI-I = Clinical Global Impression – Global 
Improvement; CGI-S = Clinical Global Impression – Severity of Illness; C-SSRS = Columbia-Suicide Severity 
Rating Scale; eCRF = electronic case report form; ECG = electrocardiogram; GBI: General Behaviour 
Inventory; IMP = investigational medicinal product; K-SADS-PL = The Kiddie-Schedule for Affective 
Disorders and Schizophrenia for School-aged Children, Present and Lifetime version; PQ-LES-Q = Pediatric 
Quality of Life Enjoyment and Satisfaction Questionnaire – Patient rated; SAE = serious adverse event 
a
Patients from Study 12712A who are in remission after 8 to 12 weeks of open-label treatment in study 
12712A will enter directly into the Randomization Visit of this study.
b
This can be a telephone contact, unless an SAE has occurred since the last visit or unless there was a clinically 
significant abnormal safety laboratory test value at the last visit. In such cases, safety follow-up(s) must be 
scheduled to allow for a medical examination and/or blood sampling. Further safety follow-up visits beyond 
30 days may be needed as judged by the investigator (if further safety follow-up visits are performed, these 
must be recorded in the patient’s medical record, and not in the eCRF).
c
If the date of a patient visit does not conform to the study plan, subsequent visits should be planned to 
maintain the visit schedule relative to the Randomization Visit (Visit 8). Consider that the number of days 
between 2 visits must not exceed the number of days for which the patient has been dispensed IMP.
d
For 12712A-patients, last available values from assessments and procedures (efficacy/safety, and use of 
concomitant medication) performed at either Visit 7 (Week 8) and/or Visit 8 (Week 10), or Visit 9 (Week 12) 
in Study 12712A will be the Randomization Visit values for this study, when applicable. For patients who 
rollover at Visit 7 or Visit 8, weight, height, Tanner staging, menstrual cycle, and examinations should be 
done at the Randomization Visits.
e
For 12712A-patients, ongoing AEs and concomitant medication from study 12712A will be used for eCRF.
f
Only for AEs ongoing at Completion/Withdrawal and new SAEs
g
If the patient is a female subject of childbearing potential (defined as females aged ≥10 years old and younger 
girls who, at the discretion of the investigator, were deemed to be of reproductive potential), a urine 
pregnancy test is to be performed at randomization, Visit 13 (double-blind period Week 10) and at 
Completion/Withdrawal Visit. Additional pregnancy tests during the study will be performed according to 
local requirements. 
h
It is not mandatory to screen for drugs and/or alcohol. However, it can be performed at any visit, at the 
discretion of the investigator. 
i
Only for 12712A-patients who rollover into double-blind phase.
j
The hormones panel is to be collected at Visit 8 (for 12712A-patients) and Completion/Withdrawal (for all 
patients).
IMP dispensed









IMP returned and IMP 
accountability










Recent and concomitant 
medication
e









Pregnancy testg



Drug and alcohol screenh
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Study 13546A – Clinical Study Protocol
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Table of Contents
List of Panels...................................................................................................................................21
List of Abbreviations and Definitions of Terms.............................................................................22
1
Introduction............................................................................................................................25
1.1
Background...................................................................................................................25
1.1.1
Overview .......................................................................................................25
1.1.2
Nonclinical Data ............................................................................................25
1.1.3
Clinical Data..................................................................................................26
1.1.3.1
Pharmacokinetics............................................................................26
1.1.3.2
Efficacy..........................................................................................27
1.1.3.3
Safety.............................................................................................28
1.2
Rationale for the Study..................................................................................................29
1.3
COVID 19 Related Risk Assessment and Mitigation .....................................................29
2
Objectives and Endpoints.......................................................................................................29
3
Study Design...........................................................................................................................31
3.1
Overview of the Study Design.......................................................................................31
3.2
Rationale for the Study Design......................................................................................32
4
Ethics ......................................................................................................................................34
4.1
Ethical Rationale...........................................................................................................34
4.2
Informed Consent..........................................................................................................35
4.3
Personal Data Protection ...............................................................................................37
4.4
Ethics Committee(s) and Institutional Review Board(s).................................................37
4.5
Regulatory Approval/Notification Requirements ...........................................................37
5
Study Population ....................................................................................................................38
5.1
Number of Patients and Countries .................................................................................38
5.2
Patient Recruitment.......................................................................................................38
5.3
Selection Criteria ..........................................................................................................38
5.4
Randomization Criteria .................................................................................................42
5.5
Withdrawal Criteria.......................................................................................................43
6
Investigational Medicinal Products (IMPs)...........................................................................44
6.1
Treatment Regimen.......................................................................................................44
6.2
IMPs, Formulations, and Strengths................................................................................44
6.3
Manufacturing, Packaging, Labelling, and Storage of IMPs...........................................45
6.4
Method of Assigning Patients to Treatment ...................................................................45
6.5
IMP Accountability.......................................................................................................46
6.6
Unblinding Procedures..................................................................................................46
6.7
Post-study Access to IMP..............................................................................................46
7
Concomitant Medication........................................................................................................46
8
Study Visit Plan......................................................................................................................47
8.1
Overview ......................................................................................................................47
8.2
Screening Visit (Visit 1)................................................................................................47
8.2.1
Pre-screening .................................................................................................47
8.2.2
Patient Identification Card..............................................................................47
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8.2.3
Re-screening ..................................................................................................48
8.3
Baseline Visit Open-label Period (Visit 2).....................................................................48
8.4
Randomization Visit (Visit 8)........................................................................................49
8.5
Withdrawal Visit...........................................................................................................49
8.6
Safety Follow-up Visit ..................................................................................................50
8.7
End-of-study Definition ................................................................................................51
9
Assessments ............................................................................................................................51
9.1
Screening and Baseline Procedures and Assessments.....................................................52
9.1.1
Demographics and Baseline Characteristics....................................................52
9.1.2
Diagnostic Assessments .................................................................................52
9.1.3
The Kiddie-Schedule for Affective Disorders and Schizophrenia for 
School-aged Children, Present and Lifetime version (K-SADS-PL)................52
9.1.4
K-SADS-PL Rater Qualification and Certification..........................................53
9.1.5
Drug and Alcohol Screen................................................................................53
9.2
Efficacy Assessments....................................................................................................53
9.2.1
Clinical Outcome Assessments (COAs)..........................................................53
9.2.1.1
Use of COA Tools..........................................................................53
9.2.1.2
Children depression rating scale revised version (CDRS-R)............54
9.2.1.3
Clinical Global Impression Scales (CGI-S/I)...................................54
9.2.1.4
Rater Qualification .........................................................................54
9.2.2
Patient and/or Parent Reported Outcomes (PROs)...........................................55
9.2.2.1
Paediatric Quality of Life Enjoyment and Satisfaction 
Questionnaire (PQ- LES-Q)............................................................55
9.3
Pharmacokinetic Assessments.......................................................................................55
9.4
Safety Assessments.......................................................................................................56
9.4.1
Adverse Events ..............................................................................................56
9.4.2
Clinical Safety Laboratory Tests.....................................................................56
9.4.3
Vital Signs .....................................................................................................58
9.4.4
Height and Weight .........................................................................................58
9.4.5
Electrocardiograms (ECGs)............................................................................59
9.4.6
Physical and Neurological Examinations........................................................59
9.4.7
Tanner Staging...............................................................................................59
9.4.8
Menstrual Cycle.............................................................................................60
9.4.9
General Behaviour Inventory (GBI) 10-Item Mania Scale...............................60
9.4.10
Columbia-Suicide Severity Rating Scale (C-SSRS) ........................................60
9.4.10.1
Rater Qualification and Certification...............................................61
9.5
Order of Assessments....................................................................................................61
9.6
Total Volume of Blood Drawn and Destruction of Biological Material..........................62
9.7
Treatment Compliance ..................................................................................................62
10
Adverse Events .......................................................................................................................62
10.1
Definitions....................................................................................................................62
10.1.1
Adverse Event Definitions..............................................................................62
10.1.2
Adverse Event Assessment Definitions...........................................................63
10.2
Pregnancy .....................................................................................................................64
10.3
Recording Adverse Events ............................................................................................65
10.4
Reporting Serious Adverse Events (SAEs) ....................................................................65
10.5
Treatment and Follow-up of Adverse Events.................................................................66
10.6
Study Monitoring Committee........................................................................................66
10.6.1
Data Monitoring Committee (DMC)...............................................................66
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11
Data Handling and Record Keeping......................................................................................67
11.1
Data Collection .............................................................................................................67
11.1.1
Electronic Case Report Forms (eCRFs) ..........................................................67
11.1.2
Data Transfer for Rollover Patients (Studies 12709A and 12712A).................67
11.1.3
External Data From Study 12709A and Study 12712A ...................................67
11.1.4
Patient Binders eCRF.....................................................................................68
11.1.4.1
Use of Patient Binders ....................................................................68
11.1.4.2
Clinical Outcome Assessments (COAs)..........................................68
11.1.4.3
Serious Adverse Event Fallback Forms...........................................68
11.1.5
External Data .................................................................................................68
11.2
Retention of Study Documents at the Site......................................................................69
11.2.1
eCRF Data .....................................................................................................69
11.2.2
Other Study Documents..................................................................................69
12
Monitoring Procedures...........................................................................................................69
13
Audits and Inspections ...........................................................................................................70
14
Protocol Compliance ..............................................................................................................70
15
Study Termination..................................................................................................................71
16
Statistical Methodology..........................................................................................................71
16.1
Responsibilities.............................................................................................................71
16.2
Analysis Sets.................................................................................................................71
16.3
Descriptive Statistics.....................................................................................................71
16.4
Patient Disposition........................................................................................................72
16.5
Demographics and Baseline Characteristics...................................................................72
16.6
Recent and Concomitant Medication.............................................................................72
16.7
Exposure and Compliance.............................................................................................72
16.8
Efficacy Analyses .........................................................................................................73
16.8.1
General Efficacy Analysis Methodology.........................................................73
16.8.2
Primary Analysis of the Primary Endpoint......................................................73
16.8.3
Sensitivity Analyses of the Primary Endpoint .................................................73
16.8.4
Analysis of the Secondary Endpoint(s) ...........................................................73
16.8.5
Testing Strategy .............................................................................................74
16.8.6
Analysis of the Exploratory Endpoint(s).........................................................74
16.8.7
Pharmacokinetic Analyses..............................................................................74
16.8.8
Safety Analyses..............................................................................................75
16.8.9
Analysis of Adverse Events............................................................................75
16.8.10
Analysis of Other Safety Endpoints................................................................75
16.9
Interim Analyses...........................................................................................................75
16.10 Sample Size and Power.................................................................................................75
16.11 Statistical Analysis Plan ................................................................................................76
17
Clinical Study Report and Publications.................................................................................76
17.1
Data Ownership ............................................................................................................76
17.2
Clinical Study Report....................................................................................................76
17.3
Summary of Clinical Study Results ...............................................................................76
17.4
Publications ..................................................................................................................76
18
Indemnity and Insurance .......................................................................................................77
19
Finance....................................................................................................................................77
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19.1
Site Agreements............................................................................................................77
19.2
Financial Disclosure......................................................................................................77
19.3
Equipment.....................................................................................................................77
References .......................................................................................................................................78
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Appendices
Appendix I
Clinical Study Protocol Authentication and Authorization......................................81
Appendix II
Recent and Concomitant Medication Disallowed or Allowed with Restrictions......83
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List of Panels
Panel 1
Study Design.................................................................................................................10
Panel 2
Study Procedures and Assessments – Open-label Period for de novo Patients and 
Rollover Patients from Study 12709A ...........................................................................11
Panel 3
Study Procedures and Assessments – Double-blind Period ............................................14
Panel 4
Objectives and Endpoints..............................................................................................30
Panel 5
Clinical Safety Laboratory Tests....................................................................................57
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List of Abbreviations and Definitions of Terms
ADHD
attention-deficit/hyperactivity disorder
ALT
alanine aminotransferase
ANCOVA
analysis of covariance
APES
all-patients-enrolled
APRS
all-patients-randomized set
AST
aspartate aminotransferase
ATC
anatomical therapeutic chemical
AUC
Area under the curve
B
blood
BMI
body mass index
bpm
beats per minute
CDRS-R
Children Depression Rating Scale Revised Version
CGI-I
Clinical Global Impression – Global Improvement
CGI-S
Clinical Global Impression – Severity of Illness
CHMP
Committee for Medicinal Products for Human Use (European Union)
CI
confidence interval
Cmax
maximum observed concentration
COA
Clinical Outcome Assessments
COVID
Coronavirus disease
CBT
cognitive behavioural therapy 
CRA
clinical research associate
CRO
Contract Research Organisation
C-SSRS
Columbia-Suicide Severity Rating Scale 
CYP
cytochrome P450 isoenzyme
DMC
Data Monitoring Committee
DO
Doctor of osteopathy/osteopathic medicine
DSM-5TM
Diagnostic and Statistical Manual of Mental Disorders, 5th edition
ECG
electrocardiogram
eCRF
electronic case report form
eCOA
Electronic COA
EDTA
ethylenediamine tetra acetic acid
EMA
European Medicines Agency
EU
European Union
EudraCT
European Union Drug Regulating Authorities Clinical Trials
FAS
full-analysis set
FDA
Food and Drug Administration
FSH
follicle-stimulating hormone
GBI
General Behaviour Inventory
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HBsAg
hepatitis B surface antigen
hCG
human chorionic gonadotropin
HCV
hepatitis C virus
5-HT
serotonin
IB
Investigator’s Brochure
ICH
International Council for Harmonisation of Technical Requirements for 
Pharmaceuticals for Human Use
ICMJE
International Committee of Medical Journal Editors
IEC
Independent Ethics Committee
IMP
investigational medicinal product
IPT
interpersonal psychotherapy
IQ
intelligence quotient
IRB
institutional review board
IRT
interactive response technology
K-SADS-PL
The Kiddie-Schedule for Affective Disorders and Schizophrenia for School-aged 
Children, Present and Lifetime version
LH
luteinising hormone
LOCF
last observation carried forward
Lu
Lundbeck
MDD
major depressive disorder
MMRM
mixed model for repeated measurements
NOAEL
no-observed-adverse-effect level
OC
observed cases
OCD
Obsessive Compulsive Disorder
P
plasma
PCS
potentially clinically significant
PDD
Pervasive Developmental Disorder 
PIP
Paediatric Investigational Plan
PK
pharmacokinetic(s)
PKS
pharmacokinetic set
popPK
population pharmacokinetics 
PPS
per protocol set
PQ
specific ECG interval describing atrioventricular conduction 
PQ-LES-Q
Pediatric Quality of Life Enjoyment and Satisfaction Questionnaire
PR
specific ECG interval describing atrioventricular conduction 
PRO
patient-reported outcome
PROLCTN
prolactin
PTSD
Post Traumatic Stress Disorder
QP
qualified person
QRS
specific ECG interval describing ventricular depolarization
QT
specific ECG interval describing ventricular depolarization/repolarization
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QTc
heart rate corrected QT interval
QTcF
heart rate corrected QT interval using Fridericia’s correction formula
RR
specific ECG interval describing the ventricular depolarization/repolarization cycle
SAE
serious adverse event
SAS®
statistical software package from the SAS® Institute
SERT
serotonergic receptor activity and inhibition of the serotonin (5-HT) transporter
SOC
system organ class
SUSAR
suspected unexpected serious adverse reaction
TEAE
treatment-emergent adverse event
TMF
trial master file
TSH
thyroid stimulating hormone
U
urine
US
United States
Vss
volume of distribution 
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1
Introduction
1.1
Background
1.1.1
Overview
Mood disorders in children and adolescents are among the most debilitating illnesses, exerting 
a major impact on family and social functioning, school performance and an increased risk of 
recurrence, substance abuse, psychiatric comorbidity and suicidality.1,2,3,4
The prevalence of Major depressive disorder (MDD) is estimated to be approximately 2% in 
children and 4 to 8% in adolescents.3,4,5,6
Signs and symptoms of MDD are similar to the adult population, but depressive disorders 
meeting the diagnostic criteria are rarely present before the age of seven years.7,8 The clinical 
picture may differ according to age at presentation. Children may have mood liability, 
irritability, low frustration tolerance, somatic complaints, and/or social withdrawal instead of 
verbalising feelings of depression, whilst adolescents are more likely to complain of feelings 
of hopelessness/helplessness, lack of energy and to have a higher rate of suicidal thoughts.9,10
Although several acute treatment studies of antidepressants have been completed in the MDD 
patient population, only two antidepressants have shown replicate efficacy in two or more 
trials and have received regulatory approval for the treatment of MDD in paediatric patients. 
Fluoxetine is currently approved in both Europe and the US for the treatment of children and 
adolescents with MDD 11,12 and escitalopram is approved in the US for the treatment of 
adolescents with MDD.13,14 Thus, there is a critical need to broaden current pharmacological 
treatment options for this patient population.
The aim of this study is to evaluate the efficacy of vortioxetine versus placebo in preventing
relapse of depressive symptoms in children aged 7 to 11 years with a DSM-5TM diagnosis of 
MDD.
The following sections provide an overview of the nonclinical and clinical data currently 
available for vortioxetine. For further information, please refer to the current version of the 
Investigator’s Brochure (IB).15
1.1.2
Nonclinical Data
The mechanism of action of vortioxetine is thought to be related to its direct modulation of 
serotonergic receptor activity and inhibition of the serotonin (5-HT) transporter (SERT). 
Nonclinical data indicate that vortioxetine is a 5-HT3, 5-HT7, and 5-HT1D receptor 
antagonist, 5-HT1B receptor partial agonist, 5-HT1A receptor agonist and inhibitor of the 
SERT, leading to modulation of neurotransmission in several systems. This multimodal 
activity is considered to be responsible for the antidepressant and anxiolytic-like effects and 
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the improvement of cognitive function, learning and memory observed with vortioxetine in 
animal studies.16
Average exposures to vortioxetine and metabolites at the relevant human therapeutic doses are 
below the toxicity levels (NOAEL) determined in animals. In support of the paediatric 
program, 3 juvenile toxicity studies were completed. These studies concluded that no new or 
critical vortioxetine treatment-related findings were seen in juvenile rats compared to the 
repeat-dose toxicity and reproductive studies in adult rats.
1.1.3
Clinical Data
This relapse-prevention study is part of agreed European Medicines Agency (EMA) Paediatric 
Investigational Plan (PIP) to evaluate vortioxetine in the treatment of MDD in children and 
adolescents. The PIP includes a total of 6 studies:
Study 12708A that investigated pharmacokinetics (PK) and safety in children and 
adolescents 
2 short-term efficacy studies: Study 12709A in children and Study 12710A in adolescents 
2 open-label extension studies to Studies 12709A and 12710A: 12712A (6 months) and 
12712B (extension to 12712A; 18 months) 
Relapse-prevention study 13546A
The PK study, 2 short-term studies, and the 6- month extension study are also part of the 
paediatric programme for vortioxetine agreed with the US Food and Drug Administration 
(FDA). Of the 2 short-term efficacy and safety studies, Study 12710A in adolescents has been 
completed with a negative outcome, whereas Study 12709A in children is still ongoing. Of the 
2 open-label extension studies of 6 and 18 months’ duration that enrol completers from the 
short-term studies, Study 12712A (6-month extension) is ongoing and enrolling patients from 
12709A. Study 12712B which enrolled completers from Study 12712A has been completed. 
The data available from these studies are described in the following sections.
1.1.3.1
Pharmacokinetics
In adults, vortioxetine has shown to be a compound with slow absorption, large volume of 
distribution and medium clearance. Vortioxetine is slowly, but well absorbed after oral 
administration and the peak plasma concentration is reached within 7 to 11 hours. Following 
multiple dosing of 5, 10, or 20 mg/day, mean maximum observed concentration (Cmax) values 
of 9 to 33 ng/mL were observed. The absolute bioavailability is 75%. No effect of food on the 
pharmacokinetics was observed. The mean volume of distribution (Vss) is 2,600 L, indicating 
extensive extravascular distribution. Vortioxetine is highly bound to plasma proteins (98 to 
99%) and the binding appears to be independent of vortioxetine plasma concentrations. 
Vortioxetine is extensively metabolised in the liver, primarily through oxidation catalysed by 
CYP2D6 and to a minor extent CYP3A4/5 and CYP2C9, and subsequent glucuronic acid 
conjugation. No inhibitory or inducing effect of vortioxetine was observed in the drug-drug 
interaction studies for the CYP isozymes CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, 
CYP2C19, CYP2D6, CYP2E1, or CYP3A4/5. Vortioxetine is a poor P-gp substrate and 
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inhibitor. The major metabolite (Lu AA34443) of vortioxetine is pharmacologically inactive. 
The mean elimination half-life and oral clearance are 66 hours and 33 L/h, respectively. The 
pharmacokinetics is linear and time independent in the dose range studied (2.5 to 
60 mg/day).15
In the paediatric PK study (12708A), the pharmacokinetic properties of vortioxetine in the 
children and adolescent population after 14 days of dosing with 5, 10, 15 and 20 mg were 
investigated. Data showed that the exposures to vortioxetine and its metabolite Lu AA34443, 
in terms of Cmax and area under the curve (AUC), increased in a dose-proportional manner and 
were generally lower in the adolescent patients than in the children, but data suggests that the 
doses tested (5 to 20 mg/day vortioxetine) and the uptitration scheme employed in this study 
are appropriate for the paediatric population.
In the short-term efficacy study for adolescents (12710A), vortioxetine steady-state exposures 
in adolescents were similar to those previously reported in adults both for vortioxetine 10 mg 
and 20 mg. Regarding PK/PD, no apparent relationships could be found between the efficacy 
variables and plasma exposure of vortioxetine at the end of the double-blind period, which was 
in line with the primary analysis showing negative results for vortioxetine. Based on PK data, 
16% of the vortioxetine-treated patients (11% in the 10 mg group and 20% in the 20 mg 
group) and 14% of the vortioxetine and fluoxetine treated patients, could be regarded as 
non-compliant in this study.
1.1.3.2
Efficacy
Adults
Vortioxetine has been approved in the United States (US), European Union (EU) and a 
number of other countries for the treatment of MDD in the adult population. Broad efficacy on 
depressive symptoms has been proven in an extensive clinical development program. 
Vortioxetine was efficacious, safe, and well tolerated in adults and in the elderly with MDD in 
short-term treatment and long-term maintenance. This also includes proven effect of 
vortioxetine on cognitive dysfunction in adult patients with MDD, assessed using a range of 
objective neuropsychological tests.
Paediatrics
An 8-week, randomized, double-blind, placebo-controlled, active-reference, fixed-dose, study 
(Study 12710A) was conducted in adolescent patients with MDD aged 12 to 17 years. The 
study included a 4-week, single-blind, placebo lead-in period with standardized psychosocial 
intervention (N=777); only non-responders from the lead-in period were randomized (N=616). 
The study was concluded negative: similar improvements in depressive symptoms were 
observed over 8 weeks for vortioxetine and placebo-treated patients, with no statistically 
significant differences between vortioxetine and placebo on the primary endpoint (mean 
change from baseline to end-point [8 weeks] on the CDRS-R total score). The active reference 
(fluoxetine 20 mg/day) separated from placebo on the CDRS-R total score, however, a 
substantial placebo response was still observed. 
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In a similarly designed study in children with MDD aged 7 to 11 years (Study 12709A), an 
interim analysis was conducted based on data from 271 randomized patients to potentially 
terminate the study, if there was sufficient evidence of an effect of vortioxetine, or a clear lack 
thereof. As the results of the interim analysis met neither the efficacy nor the futility criterion, 
and no safety concerns have been raised, the study should continue as planned until the 
prespecified sample size of 539 patients has been reached. A review of unblinded efficacy data 
from the interim analysis by an independent data monitoring committee (DMC) indicated no 
concerns that would preclude continuation of studies of vortioxetine in children.
The efficacy data from the open-label extension studies (ongoing Study 12A and completed 
Study 12B) indicate continuous improvements on depressive symptoms in patients who 
continued to receive vortioxetine for up to 6 months or 24 months, respectively. 
1.1.3.3
Safety
Adults
The evaluation of the safety and tolerability of vortioxetine is based on data from a large 
clinical development programme and extensive post-approval experience (see IB15). Overall 
short- and long-term treatment with vortioxetine at the therapeutic doses (5 to 20 mg/day) was 
safe and well tolerated in adults and in the elderly. The incidence of nausea, the most common 
adverse event (AE), showed a trend towards a dose-response relationship. For vortioxetine, at 
the therapeutic doses, the incidences of AEs such as insomnia, somnolence, fatigue, and 
hyperhidrosis, were at placebo level, as was the incidence of sexual dysfunction. The changes 
in body weight, vital signs, electrocardiograms (ECGs) (including the QTc interval), and 
clinical safety laboratory tests (including liver and renal tests) were at placebo level for all 
therapeutic doses of vortioxetine. 
Paediatrics
The dose range of vortioxetine (5 to 20 mg/day) was chosen based on the knowledge from the 
clinical development programme in adult patients and the results of a paediatric 
pharmacokinetic and tolerability study (Study 12708A), which indicated that no dose 
adjustment was needed in the paediatric population. Hence, the doses known to be efficacious 
in the adult population (5 to 20 mg/day) and used in the paediatric development programme
are confirmed as well tolerated based on the current large paediatric database.
Study 12708A, 24 children and 24 adolescents (aged 7 to 17 years) with a depressive or 
anxiety disorder were treated with vortioxetine 5 to 20 mg/day. Based on the data from this 
study, no concerns were raised on the safety and tolerability profile of vortioxetine. 
Vortioxetine was safe and well tolerated following 14 days of dosing, as well as during an 
initial up-titration period and following 6 months of treatment. Overall, the tolerability profile 
in adolescents and children in this study was similar to that in adults with no new types of 
AEs.
Study 12710A, 308 adolescents (aged 12 to 17 years) with MDD were treated with 
vortioxetine 10 or 20 mg/day. In general, the adverse reaction profile of vortioxetine in 
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adolescents was similar to that in adults. The AEs with an incidence ≥5% in the vortioxetine 
groups were nausea, headache, vomiting, nasopharyngitis, diarrhoea, and dizziness. In 
particular, the incidences were higher in the vortioxetine groups than in the placebo group for 
nausea, headache, and vomiting. The mean changes from randomization in the clinical safety 
laboratory tests; vital signs; weight, body mass index (BMI), and height; and ECG parameters 
were small, comparable between treatment groups, and not clinically relevant.
Study 12712B, an open-label, flexible-dose, 18-month extension study to Study 12712A, (a 
6-month, open-label extension study), 94 children and adolescents (aged 7 to 17 years) with 
MDD were treated with vortioxetine 5 to 20 mg/day. None of the patients had a serious AE or 
an AE leading to withdrawal. Overall, the AE profile was similar in children and adolescents. 
The AEs with an incidence ≥5% were headache, nausea, nasopharyngitis, abdominal pain 
upper, hyperprolactinaemia, respiratory tract infection viral and vomiting. All the patients with 
hyperprolactinaemia were asymptomatic. Except for prolactin, the mean changes from 
baseline in all the other safety laboratory tests, vital signs, and ECG parameters were small 
and not clinically relevant.
Based on the completed paediatric studies, no new important risks have been identified in the 
paediatric population beyond those established for the adult population. In the paediatric 
patients, the safety and tolerability profile of vortioxetine after long-term use was comparable 
to that observed after short-term use. This conclusion is also supported by data emerging from 
the ongoing 6-month extension study 12712A that to date enrolled nearly 600 patients. For the 
ongoing, blinded study in children, continuous review of unblinded safety data by the DMC 
did not raise any safety concerns. Overall, there are no findings that would preclude 
continuation of studies of vortioxetine in children.
1.2
Rationale for the Study
This study is part of the agreed EMA PIP for vortioxetine with the purpose to investigate the 
antidepressant effect of vortioxetine in paediatric patients with MDD. The study is designed to 
evaluate maintenance of antidepressant effect in children aged 7 to 11 years who continue to 
receive vortioxetine compared with children switched to placebo after response to vortioxetine 
treatment.
1.3
COVID 19 Related Risk Assessment and Mitigation
Appropriate risk assessment has been performed and mitigations to be done in case of 
restrictions due to COVID-19 are described in detail in a separate “COVID-19 Mitigation 
Plan”.
2
Objectives and Endpoints
The study objectives and endpoints are summarized in Panel 4.
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Panel 4
Objectives and Endpoints
Objectives
Endpoints
Primary Objective
to evaluate the efficacy of vortioxetine in the 
prevention of relapse of major depressive 
episodes in paediatric patients with MDD
Depressive Symptoms
Primary endpoint:
time to relapse in the double-blind period
Secondary endpoint:
relapse rate in the double-blind period
Secondary Objectives
to evaluate efficacy of vortioxetine during 
continuation treatment of paediatric patients 
with MDD
to evaluate the efficacy of vortioxetine on:
clinical global impression
quality of life
to assess adherence to investigational 
medicinal product (IMP) through 
pharmacokinetic analysis 
Depressive Symptoms
Secondary endpoint:
change from baseline to Week 26 in the Children 
Depression Rating Scale Revised Version (CDRS-R) total 
score 
Global Clinical Impression
Secondary endpoints:
change from baseline to Week 26 in the Clinical Global 
Impression – Severity of Illness (CGI-S) score
Clinical Global Impression – Global Improvement (CGI-I) 
score at Week 26
Quality of life
• Secondary endpoint:
Change from baseline to Week 26 in Pediatric Quality of 
Life Enjoyment and Satisfaction Questionnaire 
(PQ-LES-Q) – Patient rated
Pharmacokinetics
Secondary endpoints:
plasma exposure to vortioxetine
population pharmacokinetic parameter values 
Safety Objectives
to evaluate long-term safety and tolerability of 
vortioxetine in paediatric patients with MDD
Safety Endpoints
adverse events
absolute values and changes from baseline in clinical safety 
laboratory test values (including estradiol [girls only], and 
luteinising hormone [LH], follicle-stimulating hormone 
[FSH]), vital signs, height, weight, Tanner staging, 
electrocardiogram (ECG) parameter values. Effects on 
menstrual cycle will be assessed.
potentially clinically significant clinical safety laboratory test 
values, vital signs, weight changes, and ECG parameter 
values
Columbia-Suicide Severity Rating Scale (C-SSRS) score
General Behaviour Inventory (GBI) using the 10-item mania 
subscale (parental version)
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3
Study Design
3.1
Overview of the Study Design
This study has been designed in accordance with the Declaration of Helsinki17 and will be 
conducted in compliance with the protocol, Good Clinical Practice,18 and applicable 
regulatory requirements.
This is an interventional, multi-national, multi-site, randomized, parallel-group, placebo-
controlled, relapse-prevention study in paediatric patients with MDD from 7 to 11 years of 
age. 
The study consists of a 12-week, open-label, flexible-dose treatment period with vortioxetine 
followed by a 26-week, randomized, double-blind, fixed-dose, placebo-controlled 
relapse-prevention period.
The study population will include de novo patients as well as rollover patients from other 
paediatric vortioxetine studies (Studies 12709A and 12712A), who, in the investigator’s 
opinion, could benefit from continued treatment with vortioxetine. To reach 80 randomized 
patients, approximately 150 patients recruited, either as de novo patients or rollover patients 
from Study 12709A, are estimated to be enrolled into the study.
De novo patients 
Patients meeting eligibility criteria for de novo patients will be enrolled in the 12-week,
open-label, flexible-dose treatment period.
Rollover patients from Study 12709A (enrolled to the open-label period)
Patients may participate in the present study after completion of the randomized, 8-week,
double-blind, placebo-controlled treatment period of Study 12709A. 
Eligible patients will be enrolled in the 12-week, open-label, flexible-dose treatment period.
The Baseline Visit of this study (Study 13546A) will take place at the same visit as Visit 12 
(Completion Visit) of Study 12709A. Participation in Study 12709A is considered 
completed when all assessments required at Visit 12 are completed.
Rollover patients (remitters) from Study 12712A (randomized to the double-blind period)
Patients who have received 8 to 12 weeks of treatment with vortioxetine in the open-label 
extension study 12712A may participate in the present study if they have remitted 
(CDRS-R total score ≤28) at the last 2 visits in Study 12712A prior to the rollover. In 
addition, the dose of vortioxetine must have been fixed for the last 4 weeks in 
Study 12712A prior to randomization in the present study.
Eligible patients will be randomized directly to the 26-week, double-blind treatment period.
An overview of the study is presented in Panel 1 (including the study periods) and the 
scheduled study procedures and assessments are summarized in Panel 2 and Panel 3.
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Open-label Period (for de novo patients and rollover patients from Study 12709A)
The duration of the open-label, flexible-dose treatment period will be 12 weeks.
The dosage of vortioxetine will be initiated at 5 mg/day for the first 2 days prior to 
receiving 10 mg/day.
The target dose is 10 mg/day, however, the investigator has the possibility to increase the 
dose to a maximum of 20 mg/day in case of unsatisfactory response or decrease the dose to 
5 mg/day in case of dose-limiting AEs. The dose can be up- or down-titrated with 
5 mg/day. The patient should receive the same dose for 2 days before being up- or down-
titrated to a new dose. Changes in dosing may occur at any visit during the first 8 weeks at 
the investigator's discretion. In addition, between Week 2 and Week 8, the patient and/or 
parent(s)/legal representative(s) can request an unscheduled visit to discuss their current 
dose. The maximum dose may not exceed 20 mg/day. The minimum dose is 5 mg/day.
From Week 8 and onwards the dose has to remain fixed.
Patients in remission (CDRS-R total score ≤28) at both Weeks 10 and 12 or with an 
adequate clinical response (defined as ≥50% reduction in the CDRS-R total score compared 
to the baseline score in this study [subtracted 17 to avoid flooring effect] and a CDRS-R 
total score ≤35) at both Weeks 10 and 12 will be randomized in the double-blind, placebo-
controlled, fixed-dose period. 
Patients who do not fulfil randomization criteria for remission or adequate response at 
Week 10 and/or Week 12 will be withdrawn from the study and will complete an early 
Withdrawal Visit. Non-remitters/non-responders who leave the study will be treated at the 
investigator’s discretion.
A Safety Follow-up Visit will be performed approximately 4 weeks after withdrawal from 
the open-label period.
Double-blind Period (for all patients)
Patients who fulfil the randomization criteria and do not meet any of the withdrawal criteria 
will be randomly assigned via a centralized randomization system to receive vortioxetine or 
placebo in a 1:1 ratio. Randomization will be stratified by patient inclusion sources (de 
novo patients, rollover patients from 12709A, or from 12712A).
Patients randomized to vortioxetine will continue on their final dose from the open-label 
period or the dose they had on their last visit in Study 12712A, as applicable. 
The duration of the double-blind period will be 26 weeks. 
Patients who relapse during the double-blind period must be withdrawn from the study. The 
criterion for a relapse is a CDRS-R total score of ≥40 with a history of 2 weeks of clinical 
deterioration, or a clinical deterioration that in the investigator’s opinion warrants alteration 
of treatment to prevent full relapse. 
A Safety Follow-up Visit will be performed 4 weeks after withdrawal or completion of the 
double-blind period. 
3.2
Rationale for the Study Design
This relapse-prevention study is part of the agreed EMA PIP to evaluate the PK, efficacy and 
safety of vortioxetine in the treatment of MDD in children and adolescents (section 1.1.3).
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Due to the character of the disorder, long-term studies are necessary to demonstrate that the 
short-term effect is maintained during an episode. This study will evaluate the antidepressant 
effect of vortioxetine in decreasing the rate of relapse using a randomised withdrawal design, 
which is the design of choice to establish maintenance of effect of long-term treatment within 
the episode.19 In this design, responders to an open-label course of the studied antidepressant 
are randomized to continue on the study drug or be switched to placebo and are observed for 
relapse over a defined period of time.
This study will enrol children 7 to 11 years of age. Adolescents will not be included in this 
study due to the negative results of the short-term efficacy and safety study in adolescents 
(Study 12710A).
Recruitment of young children with MDD into clinical studies is challenging for multiple 
reasons, including low prevalence of depression in this age group, difficulties in diagnosing 
MDD, reluctance to participate in a placebo-controlled study, and the burden on families 
associated with participation in a research study. To minimize the challenges associated with 
recruitment of de novo patients and to optimize the study design and feasibility, without 
compromising the validity or integrity of the study, children who complete 8 weeks of double-
blind treatment in the short-term study (12709A) and who could benefit from continued 
treatment with vortioxetine will be invited to participate in this study. The same approach was 
applied in a previous fluoxetine relapse-prevention study.20 In addition, patients who have 
received vortioxetine for 8 to 12 weeks in the open-label extension study (Study 12712A; 
6 months extension) and achieved stable remission may be enrolled. These patients will be 
randomized directly to the double-blind randomized treatment phase, as they have already 
stabilized on vortioxetine treatment. Inclusion of rollover patients who may have received 
vortioxetine for more than 12 weeks is supported by the results of an FDA review of 
relapse-prevention studies in adults which found no relationship between the length of the 
open-label phase and relapse rates in the placebo or drug arms.21
The duration of the double-blind treatment phase of 26 weeks is considered sufficient based on 
the experience from previous relapse-prevention studies in children22.
While acute studies in MDD tend to suffer from lack of sensitivity, placebo response appears 
to be of lesser concern in studies using this randomized withdrawal design which enrol only 
patients who tolerate and respond to a studied drug in the acute phase into the maintenance 
phase. Because it is “enriched” with responders/remitters, the differences between the two 
groups are typically larger than in the acute, parallel design studies. Virtually all 
antidepressants, irrespective of the class, that demonstrated efficacy in short-term studies have 
also demonstrated efficacy in relapse-prevention studies.
The dose range of vortioxetine (5 to 20 mg/day) was chosen based on the knowledge from the 
clinical development programme in adult patients and the results of a paediatric 
pharmacokinetic and tolerability study (Study 12708A), which indicated that no dose 
adjustment was needed in the paediatric population. Hence, the doses known to be efficacious 
in the adult population (5 to 20 mg/day) are used in the paediatric development programme 
and are confirmed as well tolerated based on the current large paediatric database. 
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4
Ethics
4.1
Ethical Rationale
Patients and their parent(s)/legal representative(s) will be fully informed about the study 
including the risks and benefits of his or her participation. The patient may withdraw from the 
study at any time, for any reason. Unscheduled visits can be made and immediate withdrawal 
is possible. Throughout the study, signs of suicidal risk will be assessed and patients at risk 
will be withdrawn.
The risks associated with the study are considered well controlled by cautionary measures in 
the study design, and well balanced with the potential benefits of the treatment. 
Vortioxetine is approved in 88 countries worldwide, including the US and EU, for the 
treatment of MDD in the adult population. As summarized in section 1.1.3, in the 3 completed 
paediatric studies, vortioxetine was safe and well-tolerated in paediatric patients with MDD
aged 7-17 years and the safety and tolerability profile of vortioxetine after long-term use was 
comparable to that observed after short-term use. Overall, based on the data from 3 completed 
paediatric studies and data available to date from the ongoing studies in children aged 
7-11 years, no new important risks have been identified in the paediatric population beyond 
those established for the adult population.
Vortioxetine did not separate from placebo in the short-term study in adolescents (12710A),
however, the results of the interim analysis in a similarly designed study in children found no 
evidence of futility. Furthermore, a review by an independent data monitoring committee
(DMC) of unblinded efficacy as well as continuous review of safety data from the children 
study (12709A) and the OLE 12712A data indicate no concerns that would preclude 
continuation of studies of vortioxetine in children.
The present study will permit the investigation of the efficacy - in particular maintenance of 
antidepressant effect - of a new potential treatment of MDD in children. The inclusion of a 
placebo group has major scientific importance in this evaluation to ensure adequate evaluation 
of efficacy. 
As stated in section 3.2 above, to address the challenges associated with recruitment of 
de novo patients and to minimize the number of patients exposed to IMP, the study will also
enrol rollover patients from Studies 12709A and 12712A.
The definition of relapse (CDRS-R score of ≥40 with a history of 2 weeks of clinical 
deterioration, or clinical deterioration as judged by the clinician) has been carefully considered 
and aligned with the previous study of fluoxetine 23, to avoid participants becoming too ill 
before declaring a relapse, but also to avoid counting minor worsening (which might improve 
spontaneously) as a sign of relapse. The patients will be asked to attend the investigational 
clinic at regular intervals to ensure an adequate follow-up. The visits will be performed either 
as a visit in an outpatient clinic or as a phone call. In order to minimize potential pain, distress, 
and fear, patients will be seen in facilities which will be appropriate for children; the study 
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personnel who interact with the patients will be experienced health care professionals 
(physicians with paediatric qualification, qualified paediatric nurses or psychologists); their 
education, training and experience will be documented. Age-appropriate explanations will be 
given to the child prior to any investigation or procedure, in order to decrease anxiety and 
anticipation of pain. Potentially painful procedures such as venepuncture will be minimized 
with the use of for example topical anaesthesia before venepuncture. Blood sampling will be 
limited to the minimum required for obtaining valid data for evaluation. The number of blood 
samples and visits has been carefully evaluated against the value for the overall objectives of 
the study.
Because the duration of the study (9 months) precludes withholding appropriate treatment for 
attention-deficit/hyperactivity disorder (ADHD), participants are allowed to be on stimulant 
treatment during the study if they have been on a stable dose for at least 4 weeks prior to study 
entry. The addition of stimulant treatment is not allowed during the study.
The selection criteria exclude the participation of patients at significant risk of suicide, and 
patients becoming at significant suicidal risk during the study will be withdrawn. Throughout 
the study, potential suicidal risk will be assessed by using the Columbia-Suicide Severity 
Rating Scale and by the investigator’s judgement. The GBI 10-item mania is included to 
screen for manic symptoms in children.
In accordance with Good Clinical Practice18, qualified medical personnel at Lundbeck and the 
contract research organisation (CRO) will be readily available to advise on study-related 
medical questions. Medical monitoring and safety surveillance will be performed throughout 
the study, according to Lundbeck standard procedures and Lundbeck will regularly monitor 
and re-examine the balance of risks and benefits of the full clinical study so that the health and 
wellbeing of the paediatric patients enrolled will be safeguarded.
The independent DMC for the paediatric vortioxetine programme will be continued 
throughout this study in order to review the safety and tolerability data (section 10.6). 
In accordance with Good Clinical Practice,18 the investigator will be responsible for all 
study˗related medical decisions.
4.2
Informed Consent
No study-related procedures, including any screening procedures, may be performed before 
the investigator has obtained written assent from the patient and written informed consent 
from his or her parent(s)/legal representative(s).
Changing (for example, discontinuing or down-tapering) a patient’s concomitant medications 
prior to the Screening Visit to ensure that the patient meets the selection criteria is a 
study-related activity and must not occur before the Informed Assent/Consent Forms have 
been signed.
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Minors are dependent on their parent(s)/legal representative(s) (typically their parent[s]) to 
assume responsibility for their participation in clinical studies.24
If the informed assent/consent process may be delegated, the requirements for the delegates 
must be documented prior to the start of the study. National laws must always be adhered to 
when allowing potential delegation. Any delegation must be documented in the site delegation 
log.
The investigator must identify vulnerable patients, that is, patients whose willingness to 
participate in this study might be unduly influenced by the expectation, regardless of whether 
it is justified, of benefits associated with participation, or of a retaliatory response from senior 
members of a hierarchy in case of refusal to participate. Patients thus identified must be 
excluded from participation in the study.
Prior to obtaining written informed assent/consent, the investigator or a designee must explain 
to the patients and their parent(s)/legal representative(s) the aims and methods of the study and 
any reasonably expected benefits and foreseeable risks or inconveniences to the patients.
The patients and their parent(s)/legal representative(s) must be informed:

that their participation in the study is voluntary and that they are free to withdraw from the 
study at any time without justifying their decision

of the possibility of withdrawing consent (section 8.5)

of their right to request a copy of their personal data from the study via the investigator

of their right to be informed by the investigator, after the study has been reported, about 
which treatment they received

of their right to receive information about the study results from the investigator on the 
patient’s own initiative; the results will be available approximately 1 year after the end of 
the study
The patients and their parent(s)/legal representative(s) must be informed that persons 
authorized by Lundbeck and authorized personnel from certain authorities (domestic, foreign, 
data protection agencies, or independent ethics committees (IECs)/institutional review boards 
(IRBs) may view their medical records. The patients and their parent(s)/legal representative(s) 
must also be informed that de-personalized copies of parts of their medical records may be 
requested by authorized personnel from certain authorities (domestic, foreign, data protection 
agencies, or IECs/IRBs) for verification of study procedures and/or data. The confidentiality 
of the patients will in all cases be respected.
The patients and their parent(s)/legal representative(s) must be given ample time and 
opportunity to enquire about details of the study prior to deciding whether to participate in the 
study.
It is the responsibility of the investigator to ensure that all questions about the study are 
answered to the satisfaction of the patients and their parent(s)/legal representative(s). Prior to 
allowing a patient to participate in the study, an Informed Assent/Consent Form must be 
signed and dated (including the time) by the patient and the patient’s parent(s)/legal 
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representative(s) and/or (co-)signed by an impartial witness (if applicable) and signed and 
dated by the investigator or a designee on the same day. If the patient and/or the patient’s 
parent(s)/legal representative(s) (if applicable) is/are able to understand the nature and 
potential consequences of the interventions and is/are able to give consent, but not in writing, 
an impartial witness, in addition to the informing physician, must sign the Informed Consent 
Form. The patients and their parent(s)/legal representative(s) (if applicable) must be given a 
copy of the written information (Patient Information Sheet) as well as a copy of the signed 
Informed Assent/Consent Form.
The consent procedures described above will only be implemented if allowed by local laws
and regulations and will only be initiated after approval by the relevant IECs/IRBs.
4.3
Personal Data Protection
The data collected in this study will be processed in accordance with the specifications 
outlined in the Danish Data Protection Act and the European Union legislation25 to ensure that 
requirements regarding personal data protection are met. If an external organization will 
process data on behalf of Lundbeck, a contractual procedure will be signed between Lundbeck 
and the external organization to ensure compliance with the above-mentioned legislation.
4.4
Ethics Committee(s) and Institutional Review Board(s) 
This study will be conducted only after Lundbeck has received confirmation that the 
regulatory authorities have approved or confirmed notification of the study and that written 
approval of the protocol has been granted by the appropriate IEC or IRB.
The investigator must not allow any patients to participate in the study before receiving 
confirmation from Lundbeck or the CRO that the required approvals and/or notifications have 
been received.
The IEC or IRB must be informed when specific types of protocol amendments have been 
made and written approval must be obtained before implementation of each amendment, if 
required by local law.
If applicable, interim reports on the study and reviews of its progress will be submitted to the 
IEC or IRB by the investigator at intervals stipulated in its guidelines.
4.5
Regulatory Approval/Notification Requirements
In accordance with local requirements, this study will be submitted to the regulatory 
authorities for approval or notification. The study will only be undertaken when Lundbeck has 
received written approval or confirmation of notification from the regulatory authorities.
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5
Study Population
5.1
Number of Patients and Countries
Planned countries and regions:
Patients from the European Union, Europe outside the European Union, North America and 
Latin America.
Planned number of patients:
to be screened (approximately): 170
to be enrolled (approximately): 150
to be randomized: 80
Planned number of:
study sites (approximately): 40
5.2
Patient Recruitment
Competitive patient recruitment between countries and sites will be used during the entire 
recruitment period to ensure that the required number of patients are randomized within the 
planned recruitment period.
The investigators will be notified immediately when the recruitment period comes to an end.
5.3
Selection Criteria
Patients will be recruited de novo (enrolled to the open-label period) as well among those who 
complete treatment in lead-in Study 12709A (enrolled to the open-label period) or remitters 
from Study 12712A (randomized to the double-blind period).
Patient selection is based on the inclusion and exclusion criteria listed below.
Patients who meet each of the inclusion criteria at the Screening Visit and Baseline (unless 
otherwise specified) and none of the exclusion criteria at the Screening Visit and Baseline 
(unless otherwise specified) are eligible to participate in this study. 
For patients rolling over from Studies 12709A or 12712A, their data from Studies 12709A and 
12712A - including Inclusion Criteria - will be used for this study (see also section 11.1.2).
Inclusion Criteria for de novo patients
1.
The patient is capable of communicating with the site personnel.
2.
The patient and/or the patient’s parent(s)/legal representative(s) are able to read and 
understand the Informed Assent/Consent Form.
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3.
The patient and the patient’s parent(s)/legal representative(s) have signed the Informed 
Assent/Consent Form.
4.
The patient and the patient’s parent(s)/legal representative(s) are willing and able to attend 
study appointments within the specified time windows.
5.
The patient is an outpatient consulting a clinician.
6.
The patient has a primary diagnosis of MDD according to DSM-5™ although co-morbid 
anxiety disorders will be permitted (except Post Traumatic Stress Disorder (PTSD) and 
Obsessive Compulsive Disorder (OCD)). The diagnoses will be confirmed using the 
K-SADS-PL.
7.
The patient has a CDRS-R total score ≥45 at the Screening and Baseline Visits.
8.
The patient has a CGI-S ≥4 at the Screening and Baseline Visits.
9.
The patient is boy or girl aged ≥7 and <12 years at screening. Patients who turn 12 years 
during this study will be allowed to continue in the study.
10. Contraception criterion, if applicable: The patient, if a girl who is sexually active and of 
childbearing potential (defined as girls aged ≥10 years and younger girls who, at the 
discretion of the investigator, are deemed to be of reproductive potential), must use 
adequate contraception from the Screening Visit until 30 days after the last dose of IMP.
11. The patient, if a girl aged ≥10 years, or if a younger girl who, at the discretion of the 
investigator, is deemed to be of reproductive potential, must have a confirmed negative 
urine pregnancy test at the Screening Visit.
12. Contraception criterion, if applicable: The patient, if a boy who is sexually active, must 
use adequate contraception from the Screening Visit until 30 days after the last dose of 
IMP.
Inclusion criteria for rollover patients from Studies 12709A and 12712A 
For rollover patients from Studies 12709A and 12712A:
1.
The patient and the patient’s parent(s)/legal representative(s) are able to read and 
understand the Informed Assent/Consent Form.
2.
The patient and the patient’s parent(s)/legal representative(s) have signed the Informed 
Assent/Consent Form.
3.
The patient and the patient’s parent(s)/legal representative(s) /are willing and able to 
attend study appointments within the specified time windows.
4.
Contraception criterion, if applicable: The patient, if a girl who is sexually active and of 
childbearing potential (defined as girls aged ≥10 years and younger girls who, at the 
discretion of the investigator, are deemed to be of reproductive potential), must use 
adequate contraception from the Screening Visit until 30 days after the last dose of IMP.
5.
The patient, if a girl aged ≥10 years, or if a younger girl who, at the discretion of the 
investigator, is deemed to be of reproductive potential, must have a confirmed negative 
urine pregnancy test at the Screening Visit.
6.
Contraception criterion, if applicable: The patient, if a boy who is sexually active, must 
use adequate contraception from the Screening Visit until 30 days after the last dose of 
IMP.
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For rollover patients from Study 12709A:
1.
The patient has completed Study 12709A (Visit 12, Completion Visit) immediately prior 
to enrolment into this study. 
2.
In the investigator’s opinion, the patient could benefit from participation in a study which 
includes continued treatment with vortioxetine.
3.
The patient is a child aged ≥7 and <12 years at Baseline of Study 12709A. 
For rollover patients from Study 12712A (randomized to the double-blind period):
1.
The patient has received 8 to 12 weeks of open-label treatment with vortioxetine in Study 
12712A and completed Visit 7 (Week 8), or Visit 8 (Week 10), or Visit 9 (Week 12) 
immediately prior to enrolment into this study
2.
In the investigator’s opinion, the patient could benefit from participation in a study which 
includes continued treatment with vortioxetine.
3.
The patient is in remission at the last 2 visits in Study 12712A, in which the CDRS-R is 
assessed every 4 weeks. Hence
a.
If the patient rolls over at Visit 7 or Visit 8 (Week 8 or Week 10): the patient 
has a CDRS-R total score ≤28 at Visit 5 (Week 4) and Visit 7 (Week 8) in 
Study 12712A
b. If the patient rolls over at Visit 9 (Week 12): the patient has a CDRS-R total 
score ≤28 at Visit 7 (Week 8) and Visit 9 (Week 12) in Study 12712A
4.
The patient has been on a stable dose of vortioxetine for the past 4 weeks prior to rollover 
to this study.
5.
The patient is a child aged ≥7 and <12 years at Baseline of Study 12712A.
Exclusion Criteria (de novo patients, rollover patients from Studies 12709A and 12712A)
1.
The patient has previously been enrolled in this study.
2.
The patient is a member of the study personnel or of their immediate families, or is a 
subordinate (or immediate family member of a subordinate) to any of the study personnel.
3.
The patient is pregnant or breastfeeding.
4.
The patient has a history of severe drug allergy or hypersensitivity, or known 
hypersensitivity or intolerance to any of the IMP(s) or its/their excipients.
5.
The patient has previously been treated with vortioxetine in a clinical study (applicable 
only to de novo patients). Patients who previously participated in 12709 study and were 
withdrawn prior to randomization may participate.
6.
The patient is under forced treatment. 
7.
The patient receives ongoing current psychotherapy that is planned to be intensified.
Interpersonal psychotherapy (IPT) or cognitive behavioural therapy (CBT) are not
allowed. 
8.
The patient has hereditary problems of fructose intolerance, glucose-galactose 
malabsorption, or sucrose-isomaltase insufficiency.
9.
The patient has any current psychiatric disorder (DSM-5TM criteria) different from MDD, 
established as the primary diagnosis, as assessed using The Kiddie-Schedule for Affective 
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Disorders and Schizophrenia for School-aged Children, Present and Lifetime version (K-
SADS-PL).
10. The patient suffers from intellectual disability, organic mental disorders, or mental 
disorders due to a general medical condition (DSM-5TM criteria).
11. The patient has a known intellectual disability (as suggested by a known intelligence 
quotient [IQ] <70), or, clinical evidence or known social or school history indicative of 
intellectual disability.
12. The patient has any other disorder for which the treatment takes priority over treatment of 
MDD or is likely to interfere with study treatment or impair treatment compliance.
13. 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.
14. The patient has a diagnosis of ADHD that requires a pharmacological treatment that 
cannot be maintained on a stable dose of an appropriate stimulant medication for a 
minimum of 4 weeks prior to the Baseline Visit.
15. The patient has a known first degree relative with a history of Bipolar Disorder.
16. The patient is unable to swallow capsules.
17. The patient has a history of cancer, other than basal cell or Stage 1 squamous cell 
carcinoma of the skin, that has not been in remission for >5 years prior to the first dose of 
IMP.
18. The patient has or has had one or more of the following conditions that is/are considered 
clinically relevant in the context of the study.

neurological disorder

other psychiatric disorder

cardiovascular disease

seizure disorder or encephalopathy

congestive heart failure

cardiac hypertrophy

arrhythmia
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bradycardia (heart rate <50 beats per minute [bpm])

respiratory disease

hepatic impairment or renal insufficiency

metabolic disorder

endocrinological disorder

gastrointestinal disorder

haematological disorder

infectious disorder

any clinically significant immunological condition

dermatological disorder

venereal disease
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
elevated intra-ocular pressure or is at risk of acute narrow-angle glaucoma
19. The patient takes or has taken recent or concomitant medication that is disallowed or 
allowed with restrictions (specified in Appendix II) or it is anticipated that the patient will 
require treatment with at least one of these medications during the study.
20. The patient has one or more clinically significant out-of-range vital signs at the Screening 
Visit (de novo patients, or at the last visit of Studies 12709A or 12712A for rollover 
patients).
21. The patient has one or more clinical laboratory test values outside the reference range, 
based on the blood and urine samples taken at the Screening Visit, that are of potential 
risk to the patient’s safety, or the patient has, at the Screening Visit (de novo patients, or at 
last visit of Studies12709A or 12712A for rollover patients):

a serum creatinine value >1.5 times the upper limit of the reference range

a serum total bilirubin value >1.5 times the upper limit of the reference range

a serum alanine aminotransferase (ALT) or aspartate aminotransferase (AST) value 
>2 times the upper limit of the reference range
22. The patient has a thyroid stimulating hormone (TSH) value outside the reference range.
Patients with thyroid disease may be enrolled in the study provided they are stable and 
euthyroid.
23. The patient has, at the Screening Visit (de novo patients, or at last visit of Studies 12709A 
or 12712A for rollover patients):

an abnormal ECG that is, in the investigator’s opinion, clinically significant

a QTcF interval >450 ms (based on the Fridericia correction where QTcF = QT/RR0.33)
24. The patient has a disease or takes medication that could, in the investigator’s opinion, 
interfere with the assessments of safety, tolerability, or efficacy, or interfere with the 
conduct or interpretation of the study.
25. The patient is, in the investigator’s opinion, unlikely to comply with the protocol or is 
unsuitable for any reason.
26. The patient has been treated with any antidepressant or anxiolytic medication within 
2 weeks prior to Visit 2 (only de novo patients).
27. The patient has attempted suicide 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 C-SSRS within the last 12 months).
5.4
Randomization Criteria
Randomization Criteria for de novo patients and rollover patients from Study 12709A
1.
The patients is in remission (CDRS-R total score ≤28) at both Weeks 10 and 12 or with 
an adequate clinical response (defined as ≥50% reduction in the CDRS-R total score 
compared to the baseline score in this study [subtracted 17 to avoid flooring effect] and a 
CDRS-R total score ≤35) at both Weeks 10 and 12.
2.
The patient has been on a stable dose of vortioxetine for the last 4 weeks prior to 
randomization.
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Randomization Criteria for rollover patients from Study 12712A
At the Randomization Visit, the inclusion/exclusion criteria will be checked and all patients 
included will be randomised (see inclusion criteria for rollover patients from Study 12712A in 
section 5.3).
5.5
Withdrawal Criteria
A patient must be withdrawn from the study if:
the patient and/or his or her parent(s)/legal representative(s) withdraw(s) his or her 
assent/consent (defined as a patient and/or his or her parent(s)/legal representative(s) who 
explicitly take back his or her assent/consent); section 8.5 states how the patient’s data will 
be handled
the patient has been randomized in error and has not taken IMP
the patient is lost to follow-up (defined as a patient who fails to comply with scheduled 
study visits or contact, who has not actively withdrawn from the study, and for whom no 
alternative contact information is available [this implies that at least two documented 
attempts have been made to contact the patient])
A patient must be withdrawn from treatment if:
the investigator considers it, for safety, lack of efficacy, and/or study compliance reasons, 
in the best interests of the patient that he or she be withdrawn from treatment
any site personnel break the randomization code for that patient
the patient becomes pregnant
the patient has a serum ALT or AST value >3 times the upper limit of the reference range 
and a serum total bilirubin value >2 times the upper limit of the reference range
patient has a serum ALT or AST value >5 times the upper limit of the reference range that 
is confirmed by testing <2 weeks later
the patient has a QTcF interval >500 ms; the decision to withdraw the patient may be 
postponed until a repeat ECG is taken, if it is taken within 24 hours
the patient attempts suicide 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 C-SSRS during the study) 
A patient may be withdrawn from the study if:
the patient and/or his or her parent(s)/legal representative (s) fails to comply with study 
procedures
the patient did not take IMP on the assigned dose level for 6 consecutive days
Patients who withdraw will not be replaced.
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6
Investigational Medicinal Products (IMPs)
6.1
Treatment Regimen
Open-label period:
The dosage of vortioxetine will be initiated at 5 mg/day for the first 2 days prior to receiving 
10 mg/day. The vortioxetine target dose is 10 mg/day, however the investigator has the 
possibility to increase the dose to a maximum of 20 mg/day in case of unsatisfactory response 
or decrease the dose to 5 mg/day in case of dose-limiting AEs. The dose can be up- or 
down-titrated with 5 mg/day. The patient should receive the same dose for 2 days before being 
up- or down-titrated to a new dose. Changes in dosing may occur at any visit during the first 8 
weeks at the investigator's discretion. From Week 8 onwards the dose has to remain fixed.
The tablets should be taken once daily, preferably at the same time each day. 
Double-blind period: 
Patients who fulfil the randomization criteria will be randomly assigned via a centralized 
randomization system to receive vortioxetine or placebo in a 1:1 ratio. Randomization will be 
stratified by patient inclusion sources (de novo patients, rollover patients from 12709A, or 
from 12712A).
Patients randomized to vortioxetine will continue on their final dose from the open-label 
period or the dose they had on their last visit in Study 12712A, as applicable.
The capsules should be taken once daily, preferably at the same time each day.
6.2
IMPs, Formulations, and Strengths
The IMPs supplied by Lundbeck in this study are:
Open-label period
Vortioxetine film-coated tablets 5 mg, orally
Vortioxetine film-coated tablets 10 mg, orally
Vortioxetine film-coated tablets 15 mg, orally
Vortioxetine film-coated tablets 20 mg, orally
Double-blind period
Encapsulated vortioxetine film-coated tablets 5 mg, orally 
Encapsulated vortioxetine film-coated tablets 10 mg, orally
Encapsulated vortioxetine film-coated tablets 15 mg, orally
Encapsulated vortioxetine film-coated tablets 20 mg, orally
Encapsulated placebo to vortioxetine film-coated tablets, orally
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The IMPs will be identical in appearance.
6.3
Manufacturing, Packaging, Labelling, and Storage of IMPs
The IMPs will be manufactured, packaged, labelled, released (by a qualified person [QP]), and 
distributed in accordance with the principles of Good Manufacturing Practice, under the 
responsibility of Lundbeck.
For the open-label period, the IMP will be provided in 1-week wallet cards, containing 
10 tablets of vortioxetine 5 mg, 10 mg, 15 mg or 20 mg, respectively. At the baseline visit 
(Visit 2), an up-titration wallet card containing 2 × 5 mg vortioxetine tablets and 8 × 10 mg 
vortioxetine tablets will be provided.
For the double-blind period, the IMP will be provided in 1-week wallet cards, containing 
10 capsules vortioxetine (5 mg, 10 mg, 15 mg or 20 mg) or placebo.
The wording on the labels will be in accordance with Good Manufacturing Practice regarding 
labelling and national and/or local regulatory requirements. If additional information is to be 
added when the IMP is dispensed to the patients, this will be clearly stated on the labels, and 
the investigator will be instructed to do so.
No manipulation, repackaging, or relabelling of IMP is permitted after QP release by 
Lundbeck, unless a repackaging/relabelling agreement exists, and the documentation is 
available to Clinical Supply, H. Lundbeck A/S, and, where necessary, new QP releases are 
made.
The IMPs will be identified using a unique medication number.
The IMPs must be stored in a safe and secure location, and in accordance with the storage 
conditions specified on the labels.
6.4
Method of Assigning Patients to Treatment
Interactive response technology (IRT) will be used in this study. The patient’s screening 
number from the lead-in studies will be used to identify the rollover patients in this study. De 
novo patients will be assigned a screening number by the IRT, and that number will be used to 
identify de novo patients throughout the study. When a patient is to be randomized, the 
investigator uses the IRT. The IRT allocates the patient to a treatment group during the call 
and assigns the patient a randomization number in accordance with the specifications from 
Biostatistics, H. Lundbeck A/S.
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6.5
IMP Accountability
IMP accountability is documented in the IRT.
The investigator and the pharmacist (if applicable) must agree to only dispense IMP to patients 
enrolled in the study. The investigator or the pharmacist (if applicable) must maintain an 
adequate record of the receipt and distribution of the IMPs. This record must be available for 
inspection at any time.
6.6
Unblinding Procedures
Pharmacovigilance, H. Lundbeck A/S, and the investigator or the pharmacist (if applicable), 
and the DMC will have access to the unblinded information for the double-blind treatment for 
each patient. Access to these details will be via IRT.
The IRT unblinding procedure is described in the IRT User Guide.
The investigator may only break the code for a patient if knowledge of the IMP is necessary to 
provide optimal treatment to the patient in an emergency. If possible, the investigator must 
consult the medical monitor before breaking the code. The investigator must record the date 
and reason for breaking the code on the IMP Code Break Form. If the emergency was an AE, 
it must be recorded on an Adverse Event Form. The medical monitor must be notified 
immediately. The IRT will capture the date and time of the code break call. Information on the 
allocated treatment will be provided during the call and by fax or email, depending on 
availability/preference. When the code is broken for a patient, the patient must be immediately 
withdrawn from the study. If this occurs during a visit, the investigator must complete the visit 
as a Withdrawal Visit; otherwise, the patient will be asked to attend a Withdrawal Visit.
6.7
Post-study Access to IMP
Post-study access to the IMPs will not be available. Patients in the study will have access to 
appropriate medical care after they complete or withdraw from the study.
7
Concomitant Medication
Concomitant medication is any medication other than the IMPs that are taken during the study, 
including the Screening Period up to Safety Follow-up.
The concomitant medications that are disallowed or allowed with restrictions during the study 
are summarized in Appendix II.
Details of all concomitant medication (prescription and over-the-counter) taken <3 months 
prior to the Screening Visit must be recorded in the electronic case report form (eCRF) at the 
first visit. Any changes (including reason for changes) in concomitant medication must be 
recorded at each subsequent visit. For any concomitant medication initiated or for which the 
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dose has changed due to a new disorder or worsening of a concurrent disorder, the disorder or 
worsening must be recorded as an adverse event.
Concomitant medication initiated after the last dose of IMP must only be recorded if 
associated with a SAE.
8
Study Visit Plan
8.1
Overview
An overview of the procedures and assessments to be conducted during the study and their 
timing is presented in Panel 2 and Panel 3. Further details are in chapter 9.
After completing or withdrawing from the study, the patient must be treated in accordance 
with usual clinical practice.
8.2
Screening Visit (Visit 1)
The Screening visit will be performed only for de novo patients. Patients rolling over from 
Study 12709A will proceed directly to the Baseline Visit.
The screening period begins when the first screening assessment is done, after written 
Informed Assent/Consent has been obtained. If there is a need for washout of disallowed 
medication, it should be completed before any Baseline (Visit 2) assessment is done and must 
comply with the required washout periods in Appendix II.
The Baseline visit should be scheduled 5 to 15 days after the Screening Visit. However, in 
exceptional cases, the visit interval between the Screening and Baseline Visits may be 
extended up to 30 days with consent from the Medical Monitor, provided the Medical Monitor 
accepts the rationale provided for the extension.
8.2.1
Pre-screening
Each site must record in a pre-screening log which patients attended the Screening Visit.
Preferably within 24 hours from the Screening Visit, a study-specific Pre-Enrolment Form 
needs to be completed for de novo patients by the site and transmitted to the CRO for their 
review. A confirmation that de novo patients can continue further with the study procedures is 
required before enrolment.
8.2.2
Patient Identification Card
Each patient will be provided with a patient identification card that states, at a minimum, the 
name of the IMP, the study number, the patient identification number, the investigator’s name, 
and an emergency telephone number providing 24-hour service.
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The patient identification card should be returned to the investigator upon completion of the 
patient’s participation in the study.
8.2.3
Re-screening
Re-screening is only allowed for de novo patients with a complete Screening Visit and who 
fail to attend the Baseline Visit within the planned window due to e.g., logistical constraints.
Only the sponsor’s medical expert (or the CRO’s medical monitor) may give permission to 
re-screen a patient.
Authorization for re-screening may only be granted by the CRO’s medical monitor after a 
thorough review of all data from the original Screening Visit.
At the new Screening Visit, the patient (and/or his or her parent(s)/legal representative(s) [if 
applicable] and/or the responsible caregiver) must sign new Informed Assent/Consent Forms
At the new Screening Visit, the patient will be assigned a new screening number. A re-
screened patient must have a complete new Screening Visit, and all the eligibility criteria must 
be re-assessed at the new Screening Visit.
The following information will also be recorded in the eCRF at the new Screening Visit:

that the patient has previously been screened for the study

that re-screening has been authorized by the CRO’s medical monitor

the screening number that was assigned to the patient at the original Screening Visit
If a patient is re-screened, no data from the original Screening Visit will be used.
A patient may only be re-screened once.
8.3
Baseline Visit Open-label Period (Visit 2)
De novo patients who continue to meet all inclusion criteria and none of the exclusion criteria 
(see section 5.3) will be enrolled into a 12-week open-label treatment period.
For patients rolling over from Study 12709A, the Baseline Visit will be performed the same 
day as the Week 12 (Completion) Visit of Study 12709A. The ICF must be signed before any 
Study 13546A-related activities take place. The eligibility criteria should be confirmed based 
on the evaluation of the latest data available in Study 12709A.
For 12709A patients, values from assessments and procedures (efficacy/safety, including 
blood/urine samples and use of concomitant medication) performed at the Completion Visit 
(Visit 12) in Study 12709A will be the Baseline Visit values in Study 13546A (detailed in 
Panel 2 and section 11.1.2). Please note that the hormones laboratory tests are specific for the 
13546A study and will have to be collected using a separate kit at the same time as collecting 
the blood samples required by the 12709A protocol. Assessments that are not part of the 
Completion visit in 12709A (that is, examinations, Tanner staging, and menstrual cycle) will 
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be performed as part of the 13546A Baseline Visit. Patients eligible for entering the open-label 
period will start IMP (vortioxetine) at the Baseline Visit. Patients will start with 5 mg/day as 
detailed in section 6.1.
The schedule of assessments during the open-label period is described in Panel 2.
8.4
Randomization Visit (Visit 8)
The double-blind period starts with the Randomization Visit (8) at Week 12. Patients who 
fulfil the randomization criteria (section 5.4) will be randomly assigned via a centralized 
randomization system to receive vortioxetine or placebo in a 1:1 ratio. 
Patients rolling over from Study 12712A need to fulfil inclusion/exclusion criteria detailed in 
sections 5.3. At the Randomization Visit, de novo patients and rollover patients from Study 
12709A undergo evaluation of randomization criteria, and evaluation of efficacy and safety 
assessments as per Panel 3. Patients who do not meet the randomization criteria will be 
withdrawn from the study and complete an early withdrawal visit.
For 12712A-patients, last available values from assessments and procedures (efficacy/safety, 
and use of concomitant medication) performed at either Visit 7 (Week 8) and/or Visit 8 (Week 
10), or Visit 9 (Week 12) in Study 12712A will be the Randomization Visit values for this 
study. For patients who rollover at Visit 7 or Visit 8, weight, height, Tanner staging, menstrual 
cycle, and examinations should be done at the Randomization Visits (detailed in Panel 3 and 
section 11.1.2).
The schedule of assessments during the Double-blind Period is described in Panel 3.
8.5
Withdrawal Visit
Open-label Period: Patients who withdraw from the study prior to Visit 8 will be asked to 
attend a Withdrawal Visit, if at all possible. The visit must be scheduled as soon as possible 
after withdrawal. Patients who withdraw from treatment will also be asked to attend a Safety 
Follow-up Visit.
Patients who do not fulfil randomization criteria for remission or adequate response at 
Week 10 and/or Week 12 will be withdrawn from the study and will complete an early 
Withdrawal Visit.
Double-blind Period: Patients who withdraw from the study prior to the Completion Visit after 
26 weeks of treatment in the double-blind period will be asked to attend a Withdrawal Visit, if 
at all possible. The visit must be scheduled as soon as possible after withdrawal. Patients who 
withdraw from the study will also be asked to attend a Withdrawal Visit (Visit 17, where both 
efficacy and safety are assessed).
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No new information will be collected from patients who withdraw from the study, except 
information collected in relation to the scheduled Withdrawal Visit or needed for the follow-
up of adverse events (section 10.5).
The reason for withdrawal must be recorded in the eCRF.
For a patient and/or the patient’s parent(s)/legal representative(s) who withdraw consent:
if the patient and/or the patient’s parent(s)/legal representative(s) withdraw consent during a 
visit and then agree(s) to it being the final visit, the investigator will complete the visit as a 
Withdrawal Visit and all the data collected up to and including that visit will be used
if the patient and/or the patient’s parent(s)/legal representative(s) withdraw(s) consent 
during a telephone conversation, the investigator will ask the patient if he or she will attend 
a Withdrawal Visit. If the patient:
agrees to attend a Withdrawal Visit, all the data collected up to and including that visit 
will be used
refuses to attend a Withdrawal Visit, the investigator should attempt to follow the 
patient’s safety and future treatment; any information collected will only be recorded in 
the patient’s medical records
if the patient and/or the patient’s patients/legal representative explicitly request(s) that the 
patient’s data collected from the time of withdrawal of consent onwards not be used, this 
will be respected
8.6
Safety Follow-up Visit
A safety follow-up is conducted to capture SAEs that occur during the Safety Follow-up 
Period as well as to follow-up on the outcome of adverse events ongoing at the end of the 
treatment period.
Safety follow-up for the open-label period is applicable for patients who are withdrawn or do 
not continue to the double-blind period: This can be a telephone contact, unless an SAE has 
occurred since the last visit or unless there was a clinically significant abnormal safety 
laboratory test value at the last visit. In such cases, safety follow-up(s) must be scheduled to 
allow for a medical examination and/or blood sampling. Further safety follow-up visits beyond 
30 days may be needed as judged by the investigator (if further safety follow-up visits are 
performed, these must be recorded in the patient’s medical record, and not in the eCRF).
Safety follow-up for the double-blind period: This visit should be scheduled approximately 
30 days after the last dose of IMP. This can be a telephone contact, unless an SAE has 
occurred since the last visit or unless there was a clinically significant abnormal safety 
laboratory test value at the last visit. In such cases, safety follow-up(s) must be scheduled to 
allow for a medical examination and/or blood sampling. Further safety follow-up visits beyond 
30 days may be needed as judged by the investigator (if further safety follow-up visits are 
performed, these must be recorded in the patient’s medical record, and not in the eCRF).
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For adverse events that were ongoing at the end of the treatment period and that resolved 
during the Safety Follow-up Period, the stop date must be recorded. For non-serious adverse 
events still ongoing at the safety follow-up, the Ongoing Adverse Event checkbox on the 
Adverse Event Form must be ticked. SAEs must be followed until resolution or the outcome is 
known.
Patients with a clinical safety laboratory test value that was out-of-range at the Completion/
Withdrawal Visit and judged clinically significant must be followed according to accepted 
medical standards for up to 30 days or until the value normalizes or stabilizes or a diagnosis or 
a reasonable explanation has been established. For these patients, safety follow-up visits must 
be scheduled to allow for a medical examination and/or blood sampling. The investigator must 
decide whether further safety follow-up visits are required after 30 days. If further safety 
follow-up visits are made, these must be documented in the patient’s medical record and not in 
the eCRF.
Patients who withdrew due to elevated AST or ALT values (see section 5.5) should be 
followed until the values normalize or stabilize or a diagnosis or a reasonable explanation has 
been established (see section 10.5).
The safety follow-up for patients who withdraw consent must be performed, if at all possible; 
any information collected will only be recorded in the patients’ medical records.
8.7
End-of-study Definition
The end of the study for an individual patient is defined as the last protocol-specified contact 
with that patient. The overall end of the study is defined as the last protocol-specified contact 
with the last patient ongoing in the study.
This study will be terminated if the result of the currently ongoing placebo-controlled, 
short-term study (12709A) in children is negative (that is, if vortioxetine fails to show a 
significant difference from placebo in acute treatment). In case of study termination, the 
participating patients will be treated at the discretion of the investigator in line with clinical 
practice.
9
Assessments
Timing and frequency of all assessments are specified in Panel 2 (open-label period) and 
Panel 3 (double-blind period).
Lundbeck reserves the right to use external quality oversight methods of all study assessment 
tools to ensure the validity of the diagnosis and the severity of the illness.
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9.1
Screening and Baseline Procedures and Assessments
9.1.1
Demographics and Baseline Characteristics
Prior to enrolling a patient in the study, the investigator must ascertain that the patient 
meets the selection criteria.
At the Screening Visit (concerns de novo patients only), the following will be recorded or 
assessed:
Relevant medical, social, psychiatric and neurological history including MDD history, time 
of diagnosis, treatment type and outcome (response and tolerability)
History of stimulant medication, if any
Demographics: age, sex, and race. In order to determine the exact age at any point in the 
study, full date of birth will be collected where permitted by local regulations.
Family psychiatric history
Traumatic life events
Height, weight
Puberty status (Tanner staging)
Menstrual cycle
9.1.2
Diagnostic Assessments
The K-SADS-PL will be used as screening assessment. The diagnosis of MDD (according 
to DSM-5™) will be established via a psychiatric evaluation. The K-SADS-PL will be used 
to confirm the diagnosis of MDD and to assess possible psychiatric co-morbidities.
The K-SADL-PL will be administered in local language. Only scales provided by Lundbeck
that have been validated in the language to which they have been translated will be used in
this study.
9.1.3
The Kiddie-Schedule for Affective Disorders and Schizophrenia for School-aged 
Children, Present and Lifetime version (K-SADS-PL).
The K-SADS-PL26 is a semi-structured diagnostic interview designed to assess current and 
past episodes of psychopathology in children and adolescents. The K-SADS-PL consists of 
interviews with the parent(s), the child, and information from other sources (for example, 
school report). The unstructured introductory interview establishes a rapport with the parent(s) 
and the child, the screening interview (comprising 82-items to survey key symptoms for 
current and past episodes of 20 different diagnostic areas) provides a diagnosis, and responses 
to skip-out criteria determine whether additional interviewing is necessary. If necessary, the 
additional interview consists of a maximum of five diagnostic supplements (affective 
disorders, psychotic disorders, anxiety disorders, behavioural disorders, and substance abuse, 
eating, and tic disorders). The K-SADS-PL items are scored using a 2-point or a 3-point scale 
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from 1 (no symptoms) to 3 (threshold levels of symptomatology). It takes approximately 180 
minutes to complete both K-SADS-PL interviews (parent(s) and child).
9.1.4
K-SADS-PL Rater Qualification and Certification
The K-SADS-PL should be administered by a rater who has adequate experience with 
paediatric patients with MDD. The rater should be a psychiatrist or doctor of osteopathy (DO) 
specialised in child and adolescent psychiatry, or a clinical paediatric (neuro-) psychologist 
involved in clinical practice.
Any exceptions must be discussed and approved by Lundbeck.
Only raters who have been certified in a study-specific Rater Certification Programme will be 
authorized to rate in this study. Documentation of training and certification will be delivered to 
the raters for archiving in the investigator trial master file (TMF). No patient may be rated 
before the documentation has been delivered.
New raters joining the study will be trained and certified locally using the same certification 
processes.
9.1.5
Drug and Alcohol Screen
It is not mandatory to screen for drugs and/or alcohol. However, it can be performed at any 
visit during the open-label and double-blind periods, at the discretion of the investigator. The 
blood and urine drug screen samples will be analysed at the central laboratory.
9.2
Efficacy Assessments
9.2.1
Clinical Outcome Assessments (COAs)
9.2.1.1
Use of COA Tools
The following clinician-rated electronic assessment tools will be used and accessed via a tablet 
provided by Signant Health, called a Rater Station:
CDRS-R – assessing depressive symptoms
CGI-S/I – assessing clinical global impression
Detailed instructions on how to administer the scales and how to score using the scales will be 
provided to the site in a Rater Station Site Manual.
The CDRS-R will be administered in the local language. Only scales provided by Lundbeck 
that have been validated in the language to which they have been translated will be used in this 
study.
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9.2.1.2
Children depression rating scale revised version (CDRS-R)
The CDRS-R27 is a clinician-rated scale to measure the severity of depression of children and 
adolescents. The CDRS-R is rated by a clinician following interviews with the child and 
parent(s) and consists of 17 items: 14 items rate verbal observations, and 3 items rate 
nonverbal observations (tempo of language, hypoactivity, and nonverbal expression of 
depressed affect). Items are rated for severity on a 7-point scale (1 to 7) for 14 items, and on a 
5-point scale (1 to 5) for 3 items (sleep disturbance, appetite disturbance, and listless speech). 
The total score ranges from 17 (normal) to 113 (severe depression). The CDRS-R can be 
administered by a clinician after a training session. It takes approximately 20 to 30 minutes to 
administer and rate the CDRS-R.
9.2.1.3
Clinical Global Impression Scales (CGI-S/I)
The CGI28 was developed to provide global measures of the severity of a patient’s clinical 
condition and improvement or worsening during clinical studies.
The clinician will use the scale to assess depressive symptoms.
The CGI consists of two clinician-rated subscales: severity of illness (CGI-S) and global 
improvement (CGI-I).
The 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).
The CGI-I provides the clinician’s impression of the patient’s improvement (or worsening). 
The clinician assesses the patient’s condition relative to Randomization (as the CGI-I only will 
be assessed in the Double-blind period) on a 7-point scale ranging from 1 (very much 
improved) to 7 (very much worse). In all cases, the assessment should be made independent of 
whether the rater believes the improvement is drug-related or not.
An experienced clinician can use the CGI after a short training session. It takes 1 to 2 minutes 
to score the CGI after a clinical interview.
9.2.1.4
Rater Qualification
The CDRS-R and CGI-S/I scales should only be administered by a rater who has adequate 
experience with paediatric patients with MDD and who has adequate experience in rating 
scales. The rater should be a psychiatrist or DO specialised in child and adolescent
psychiatry, or a clinical paediatric (neuro-) psychologist involved in clinical practice.
The CGI-S/I should be administered by the investigator responsible for the patient. The 
investigator must be a psychiatrist or DO specialised in child and adolescent psychiatry that 
has adequate experience with paediatric patients with MDD.
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Any exceptions must be discussed and approved by Lundbeck.
Only raters who have been certified in a study-specific Rater Certification Programme will 
be authorized to rate in this study. Documentation of training and certification will be 
delivered to the raters for archiving in the investigator TMF. No patient may be rated 
before the documentation has been delivered.
The individual scores from the primary scale rater qualification session will be used to 
document inter-rater reliability and filed in the sponsor TMF.
New raters joining the study will be trained and certified locally using the same 
certification processes. Rater training and certification will be conducted by Signant 
Health.
For each individual patient, the same certified rater should rate the patient. For unforeseen 
circumstances, certified back-up raters should be available throughout the study.
9.2.2
Patient and/or Parent Reported Outcomes (PROs)
The following electronic PRO will be completed by the patient on the Rater Station:
PQ-LES-Q29: designed to assess patient’s satisfaction with life
9.2.2.1
Paediatric Quality of Life Enjoyment and Satisfaction Questionnaire (PQ-
LES-Q)
The PQ-LES-Q29 is a patient-rated scale designed to assess satisfaction with life. It is an
adaptation of the Quality of Life Enjoyment and Satisfaction Questionnaire (Q-LES-Q), which
is used to measure quality of life in adults. The PQ-LES-Q consist of 15 items, item 1 to 14 
assess the degree of satisfaction experienced by patients in various areas of daily functioning 
and item 15 allows subjects to summarize their experience in a global rating.
Each item is rated on a 5-point scale from 1 (very poor) to 5 (very good). The total score range
of item 1 to 14 is 14 to 70, with higher scores indicating greater satisfaction. It takes 5 to 10
minutes to complete the scale.
The site staff should instruct patients on how to use the Rater Station. On-screen instructions 
on how to complete the scale will be available in the Rater Station.
9.3
Pharmacokinetic Assessments
Blood samples (1 mL) for IMP analysis will be collected in ethylenediamine tetra acetic acid 
(EDTA) tubes simultaneously with clinical safety lab samples. The blood sampling and 
handling procedures are described in the study-specific Laboratory Specification Manual.
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The blood samples will be analysed for vortioxetine using methods validated in accordance 
with the EMA Guideline on Bioanalytical Method Validation30 and the FDA Guidance for 
Industry.31
The bioanalysis of Lu AA21004 will be conducted by the contract laboratory PRA Health 
Sciences on behalf of Department of LC-MS Bioanalysis, H. Lundbeck A/S. A dedicated 
protocol for the bioanalytical study and a bioanalytical study report will be prepared by the 
contract laboratory.
9.4
Safety Assessments
9.4.1
Adverse Events
The patients will be asked a non-leading question (for example, “how do you feel?”, “how 
have you felt since your last visit?”) at each visit, starting at the Screening Visit. AEs 
(including worsening of concurrent disorders, new disorders, and pregnancies) either observed 
by the investigator or reported spontaneously by the patient will be recorded, and the 
investigator will assess the seriousness and the intensity of each AE and its relationship to the 
IMP. Results from relevant tests and examinations, such as clinical safety laboratory tests, 
vital signs, and ECGs, or their corresponding conditions will also be recorded as AEs if 
considered by the investigator to be clinically significant.
See chapter 10 for further information on AEs.
9.4.2
Clinical Safety Laboratory Tests
The clinical safety laboratory tests are listed in Panel 5.
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Panel 5
Clinical Safety Laboratory Tests
Haematology
Liverb
Serologyc
B-haemoglobin
B-erythrocyte count
B-total leucocyte count
B-neutrophilsa
B-eosinophilsa
B-basophilsa
B-lymphocytesa
B-monocytesa
B-thrombocyte count
S-total bilirubin
S-conjugated bilirubin
S-alkaline phosphatase
S-alanine aminotransferase
S-aspartate aminotransferase
S-gamma-glutamyl transferase
S-HBsAg
S-anti HCV
Infectionc
S-C-reactive protein
Electrolytesb
Kidneyb
Urined
S-sodium
S-potassium
S-calcium (total)
S-creatinine
S-urea nitrogen
U-protein (dipstick)
U-glucose (dipstick)
U-blood (dipstick)
Endocrine and Metabolicb
Lipidsb,e
Pregnancyf
S-albumin
S-estradiol [girls only]
S-luteinising hormone [LH]
S-follicle-stimulating hormone [FSH])
S-prolactin [PROLCTN]
S-glucosed
S-thyroid-stimulating hormonec
S-low density lipoprotein
S-high density lipoprotein
S-triglycerides
S-cholesterol (total)
U-hCG
B-hCG (confirmatory for 
positive urine test only)
B = blood; HBsAg = hepatitis B surface antigen; hCG = human chorionic gonadotropin; HCV = hepatitis C 
virus; P = plasma; S = serum; U = urine
a
Count and % of total leucocytes
b
Clinical chemistry
c
Performed at the Screening Visit only
d
Microscopic examination (leucocytes, erythrocytes, and casts) will be performed only if any of the urine 
evaluations are abnormal Fasting, when possible
e
Fasting, when possible
f
Performed at the Screening Visit only. Only for female patients aged ≥10 years or female patients at lower 
age judged by the investigator to be of childbearing potential
Blood samples for the clinical safety laboratory tests will be collected as outlined in Panel 2
and Panel 3.
The blood and urine drug screen samples will be analysed at the central laboratory. Urine drug 
screen requires an additional tube, but ethanol is part of the urine drug screen panel so will be 
optional as a check box on the requisition form without a need for another additional tube.
The additional urine samples will be collected and analysed at the site using dipsticks. If the
dipstick evaluation is positive or abnormal, further analysis will be performed at the central
laboratory.
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The investigator must review (initial and date) the results of the clinical safety laboratory tests 
as soon as possible after receipt of those results. Out-of-range values must be interpreted by 
the investigator as “not clinically significant” or “clinically significant” with a comment 
concerning the planned follow-up. Tests for clinically significant out-of-range values must be 
repeated, or an appropriate clinical follow-up must be arranged by the investigator and 
documented on the laboratory report, until the value has stabilized or until the value has 
returned to a clinically acceptable value (regardless of relationship to the IMP). A patient with 
a value that is out-of-range at the Completion Visit (Week 26 of double-blind period) or 
Withdrawal Visit and considered clinically significant must be followed in accordance with 
usual clinical practice for up to 30 days or until the value normalizes or stabilizes or a 
diagnosis or reasonable explanation has been established. Any out-of-range values followed 
after the last protocol-specified contact with the patient will be documented in the patient’s 
medical records.
Any out-of-range clinical safety laboratory test value considered clinically significant by the 
investigator must be recorded as an AE on an Adverse Event Form.
The central laboratory will be notified by the sponsor when the biological samples may be 
destroyed.
9.4.3
Vital Signs
The investigator may appoint a designee to measure vital signs, provided this is permitted 
according to local regulations and provided the investigator has trained the designee how to 
measure vital signs. The investigator must take responsibility for reviewing the findings.
Blood pressure and pulse rate will be measured using a standard digital meter with adequate 
cuff size after the patient has rested for at least 5 minutes in a supine position. The patient 
must then be instructed to change from a supine to a standing position in a manner that 
includes passing through a sitting position before assuming an upright position. Blood pressure
and pulse rate will be measured after the patient has been standing for at least 1 minute but no 
longer than 5 minutes.
Any out-of-range vital sign considered clinically significant by the investigator must be 
recorded as an AE on an Adverse Event Form.
9.4.4
Height and Weight
The patient’s height will be measured, without shoes.
The patients will be weighed wearing light clothing and no shoes. A similar amount of 
clothing must be worn on each occasion.
Any weight change considered clinically significant by the investigator must be recorded as an 
AE on an Adverse Event Form.
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9.4.5
Electrocardiograms (ECGs)
A standard 12-lead ECG will be recorded using digital ECG recording equipment provided to 
the investigator or, upon agreement, to an external cardiology centre. The ECGs will be 
transferred digitally to a central ECG laboratory for evaluation, where they will be reviewed 
by a paediatric cardiologist. The investigator will be provided with the results and a 
cardiologic interpretation of the ECG from the central ECG laboratory.
The results from the central ECG laboratory will include the RR, PR, QRS, QT, QTc, and 
QTcF intervals.
The investigator has the final decision on the interpretation of the ECG results. Any abnormal 
ECG result or out-of-range ECG parameter value considered clinically significant by the 
investigator must be recorded as an AE on an Adverse Event Form.
9.4.6
Physical and Neurological Examinations
The investigator may appoint a designee to be primarily responsible for performing the 
physical examinations, provided this is permitted according to local regulations. The 
investigator must take responsibility for reviewing the findings. Whenever possible, the same 
individual should perform all the physical examinations.
The physical examination must, at a minimum, include an examination of appearance, 
extremities, skin, head, neck, eyes, ears, nose, throat, lungs, chest, heart, abdomen, and 
musculoskeletal system and must be performed by a physician or physician assistant. If there 
is no physical examination at the Baseline Visit, the examination at the Screening Visit will be 
considered the baseline physical examination.
The neurological examination must be performed by a physician.
Any abnormal finding or out-of-range value considered clinically significant by the 
investigator must be recorded as an AE on an Adverse Event Form.
9.4.7
Tanner Staging
Tanner staging is a scale for assessing physical development and sexual maturity during onset 
and progress of puberty.
The scale includes 5 stages of pubertal changes (called Tanner stages) separate for males and 
for females.
For female the 5 stages of maturation are recognized by assessing pubic hair and breast 
development. For male the 5 stages of maturation are recognized by assessing pubic hair, 
growth of penis and testicles. Post-puberty is defined as a Tanner stage = 5 in both of observed 
criteria.
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The evaluation of Tanner stage will be performed by physician or trained nurse - they will be 
provided with figures depicting the somatic changes and tables describe these changes in 
words to facilitate the staging.
Tanner staging will be performed in conjunction with the physical examination according to 
the schedule displayed in Panel 2 and Panel 3.
9.4.8
Menstrual Cycle
The following will be recorded: 

Age of menarche 

The length of the menstrual cycle (number of days from the first day of menstruation to 
the day before the first day of the next menstrual period)

Menstrual cycle regularity
9.4.9
General Behaviour Inventory (GBI) 10-Item Mania Scale
The GBI 10-item mania scale32 is a parent- and subject-rated scale designed to screen for 
manic symptoms in children and adolescents. The ten items are rated on a 4-point scale 
from 0 (never or hardly ever) to 3 (very often or almost constantly). The total score ranges 
from 0 to 30, with higher scores indicating greater pathology. It takes approximately 
5 minutes to complete the GBI 10-item mania scale.
The parent-rated scale is validated and appropriate for the use in children and adolescents 
with psychiatric disorders.33 The subject-rated scale is validated only for patients in the age 
group 10 to 17 years.34 Therefore, only the parent-rated scale will be used in this study.
The GBI will be administered in the local language. Only scales provided by Lundbeck that 
have been validated in the language to which they have been translated will be used in this 
study.
The site staff should instruct patients and parents/caregivers on how to use the Rater Station, 
On-screen instructions on how to complete the scale will be available in the Rater Station.
9.4.10
Columbia-Suicide Severity Rating Scale (C-SSRS)
The C-SSRS35 is a semi-structured interview developed to systematically assess suicidal 
ideation and behaviour of patients participating in a clinical study. The C-SSRS has 
4 questions addressing suicidal behaviour, 5 questions addressing suicidal ideation, and 
sub-questions assessing the severity.
Different versions of the scale are available: in this study, the “Baseline Screening” version 
will be applied at the Screening Visit and the “Since last visit” version will be applied other 
visits including the C-SSRS.
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A version of the C-SSRS specifically developed for the use in children will be applied in the 
study population of children aged 7 to 11 years.
An experienced clinician can use the C-SSRS after a short training session. It takes 
approximately 5 minutes to administer and rate the C-SSRS.
The C-SSRS has 5 questions addressing suicidal ideation. If level 4 or 5 has been answered 
“yes”, a corresponding SAE should be reported.
If the electronic C-SSRS (eC-SSRS) system™is temporarily unavailable on the Rater Station,
a paper version of the C-SSRS (C-SSRS Fallback Form – Baseline/Screening Version) should 
be administered by the investigator. If the eC-SSRS is unavailable at the Screening Visit, the 
paper version should be used; however, the patient will have to return to the site to complete 
the eC-SSRS before he or she may be enrolled in the study. When a C-SSRS Fallback Form
has been used, it must be kept as a source document in the Patient Binder. Data from the 
C-SSRS Fallback Form will not be transcribed in the eCRF.
9.4.10.1
Rater Qualification and Certification
C-SSRS should only be administered by a rater who has adequate experience with paediatric 
patients and who has adequate experience in rating scales. The rater should be a psychiatrist or 
DO specialised in child and adolescent psychiatry, or a clinical paediatric (neuro-) 
psychologist involved in clinical practice. Any exceptions must be discussed with and 
approved by Lundbeck.
Only raters who have been certified through the scale author’s website will be authorized to
rate in this study. Documentation of training and certification will be delivered to the raters for 
archiving in the investigator TMF. No patient may be rated before the documentation has been 
delivered.
New raters joining the study will be trained and certified locally using the same certification 
process.
9.5
Order of Assessments
The scales should preferably be administered in the following order:
Screening Visit:
K-SADS-PL
CDRS-R
GBI
C-SSRS
CGI-S
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At visits other than the Screening Visit:
CDRS-R
PQ-LES-Q
GBI
C-SSRS
CGI-S, CGI-I
9.6
Total Volume of Blood Drawn and Destruction of Biological Material
The total volume of blood drawn during the study will be approximately 39.5 mL (20 mL in 
the open-label period and 19.5 ml in the double blind period) for de novo patients.
Additional blood samples may be required if the original blood samples are not viable or if 
re-testing is required.
9.7
Treatment Compliance
It is the responsibility of the investigator to account for all IMP (refer to IMP accountability 
section 6.5). The investigator or her/his designee must agree not to dispense any IMP to any 
person, except patient/parents included in the study and he/she/they must further agree only to 
use IMP in accordance with protocol.
In addition, measures of the blood concentration of vortioxetine will indicate whether patient 
has been overall compliant throughout the study.
10 Adverse Events
10.1
Definitions
10.1.1
Adverse Event Definitions36
Adverse event – is any untoward medical occurrence in a patient or clinical study patient 
administered a medicinal product and which does not necessarily have a causal relationship 
with this treatment.
An adverse event can therefore be any unfavourable and unintended sign (including clinically 
significant out-of-range values from relevant tests, such as clinical safety laboratory tests, vital 
signs, ECGs), symptom, or disease temporally associated with the use of a medicinal product, 
regardless of whether it is considered related to the medicinal product.
It is Lundbeck policy to collect and record all adverse events, including pre-treatment adverse 
events, that is, those that start after the patient has signed the Assent Form/Informed Consent 
Form and prior to the first dose of IMP.
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Serious adverse event (SAE) – is any adverse event that:
results in death
is life-threatening (this refers to an event in which the patient was at risk of death at the 
time of the event; it does not refer to an event that hypothetically might have caused death 
had it been more severe)
requires inpatient hospitalization or prolongation of existing hospitalization
results in persistent or significant disability/incapacity
is a congenital anomaly/birth defect
is medically important (this refers to an event that may not be immediately life-threatening
or result in death or hospitalization, but may jeopardize the patient or may require 
intervention to prevent any of the SAEs defined above)
Examples of medically important events are intensive treatment for allergic bronchospasm; 
blood dyscrasia or convulsions that do not result in hospitalization; or development of drug 
dependency or drug abuse.
Planned hospitalizations or surgical interventions for a condition that existed before the patient 
signed the Informed Assent/Consent Form and that did not change in intensity are not adverse 
events. Emergency room visits that do not result in admission to the hospital are not 
necessarily SAEs; however, they must be evaluated to determine whether they meet any of the 
SAE definitions (for example, life-threatening or other serious [medically important] event).
Non-serious adverse event – is any adverse event that does not meet the definition of an SAE.
If there is any doubt as to whether an AE meets the definition of an SAE, a conservative 
viewpoint must be taken, and the AE must be reported as an SAE.
Suspected unexpected serious adverse reaction (SUSAR) – is any AE that is assessed as 
serious, unexpected (its nature or intensity is not consistent with the current version of the 
Investigator’s Brochure for vortioxetine15 and related to a medicinal product by either the 
investigator or Lundbeck. 
Overdose – is a dose taken by a patient that exceeds the dose prescribed to that patient. Any 
overdose (and associated signs/symptoms) must, at a minimum, be recorded as a non-serious 
AE.
10.1.2
Adverse Event Assessment Definitions
Assessment of Intensity
The investigator must assess the intensity of the adverse event using the following definitions, 
and record it on the Adverse Event Form:
Mild – the adverse event causes minimal discomfort and does not interfere in a significant 
manner with the patient’s normal activities.
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Moderate – the adverse event is sufficiently uncomfortable to produce some impairment of 
the patient’s normal activities.
Severe – the adverse event is incapacitating, preventing the patient from participating in the 
patient’s normal activities.
Assessment of Causal Relationship
The investigator must assess the causal relationship between the adverse event and the IMP 
using the following definitions, and record it on the Adverse Event Form and the Serious 
Adverse Event Form (if applicable):
Probable – the adverse event has a strong temporal relationship to the IMP or recurs on 
rechallenge, and another aetiology is unlikely or significantly less likely.
Possible – the adverse event has a suggestive temporal relationship to the IMP, and an 
alternative aetiology is equally or less likely.
Not related – the adverse event has no temporal relationship to the IMP or is due to 
underlying/concurrent disorder or effect of another drug (that is, there is no causal 
relationship between the IMP and the adverse event).
An adverse event is considered causally related to the use of the IMP when the causality 
assessment is probable or possible. 
Assessment of Outcome
The investigator must assess the outcome of the adverse event using the following definitions, 
and record it on the Adverse Event Form and the Serious Adverse Event Form (if applicable):
Recovered – the patient has recovered completely, and no symptoms remain.
Recovering – the patient’s condition is improving, but symptoms still remain.
Recovered with sequelae – the patient has recovered, but some symptoms remain (for 
example, the patient had a stroke and is functioning normally, but has some motor 
impairment).
Not recovered – the patient’s condition has not improved and the symptoms are unchanged 
(for example, an atrial fibrillation has become chronic).
Death
10.2
Pregnancy
Although not necessarily considered an adverse event, a pregnancy in a patient in the study 
must be recorded on an Adverse Event Form, as well as on a Pregnancy Form (paper), even if 
no adverse event associated with the pregnancy has occurred. Pregnancies must be reported to 
Lundbeck using the same expedited reporting timelines as those for SAEs.
An uncomplicated pregnancy should not be reported as an SAE; hospitalization for a normal 
birth should not be reported as an SAE. If, however, the pregnancy is associated with an SAE, 
the appropriate serious criterion must be indicated on the Serious Adverse Event Form. 
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Examples of pregnancies to be reported as SAEs (medically important) are spontaneous 
abortions, stillbirths, and malformations.
The investigator must follow-up on the outcome of the pregnancy and report it on a Pregnancy 
Form (paper). The follow-up must include information on the neonate at least up until the age 
of 1 month.
10.3
Recording Adverse Events
Adverse events (including pre-treatment adverse events) must be recorded on an Adverse 
Event Form. The investigator must provide information on the adverse event, preferably with a 
diagnosis, or at least with signs and symptoms; start and stop dates (and start and stop time if 
the adverse event lasts less than 24 hours); intensity; causal relationship to the IMP; action 
taken; and outcome. If the adverse event is not related to the IMP, an alternative aetiology 
must be recorded, if available. If the adverse event is an overdose, the nature of the overdose 
must be stated (for example, medication error, accidental overdose, or intentional overdose). If 
the intensity changes during the course of the adverse event, this must be recorded on the AE 
Intensity Log.
If the adverse event is serious, this must be indicated on the Adverse Event Form. 
Furthermore, the investigator must fill out a Serious Adverse Event Form and report the SAE 
to Lundbeck immediately (within 24 hours) after becoming aware of it (see section 10.4).
If individual adverse events are later linked to a specific diagnosis, the diagnosis should be 
reported and linked to the previously reported adverse events.
10.4
Reporting Serious Adverse Events (SAEs)
The investigator must report SAEs to Lundbeck immediately (within 24 hours) after becoming 
aware of them by completing a Serious Adverse Event Form.
The initial Serious Adverse Event Form must contain as much information as possible and, if 
more information about the patient’s condition becomes available, the Serious Adverse Event 
Form must be updated with the additional information.
If the investigator cannot report the SAE in Rave®, then he or she must complete and sign the 
Serious Adverse Event Fallback Form and send it to:
For H. Lundbeck A/S studies:
Fax:
email:
Lundbeck will assume responsibility for reporting SAEs to the authorities in accordance with 
local requirements.
It is the investigator’s responsibility to be familiar with local requirements regarding reporting 
SAEs to the IEC or IRB and to act accordingly.
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Lundbeck will assume responsibility for reporting SUSARs to the authorities in accordance 
with local requirements. In those Member States of the European Union that have 
implemented the European Union Clinical Trials Directive37 and in Norway, Liechtenstein, 
and Iceland, that is, in the countries where unblinded expedited safety reporting is required, 
Lundbeck will also assume responsibility for reporting SUSARs to the IECs.
Lundbeck will assess the expectedness of SAEs and inform the investigator(s) about SUSARs 
in the blinded SUSAR listings.
10.5
Treatment and Follow-up of Adverse Events
Patients with adverse events must be treated in accordance with usual clinical practice at the 
discretion of the investigator.
The investigator must follow-up on non-serious adverse events until resolution or the Safety 
Follow-up Visit/Contact, whichever comes first. At the Safety Follow-up Visit/Contact, 
information on new SAEs, if any, and stop dates for previously reported adverse events must 
be recorded.
The investigator must follow-up on all SAEs until the patient has recovered, stabilized, or 
recovered with sequelae, and report to Lundbeck all relevant new information using the same 
procedures and timelines as those for the initial Serious Adverse Event Form.
SAEs that are spontaneously reported by a patient to the investigator after the Safety 
Follow-up Visit/Contact must be handled in the same manner as SAEs that occur during the 
study. These SAEs will be recorded in the Lundbeck safety database.
The investigator must follow-up on patients with a clinically significant out-of-range clinical 
safety laboratory test value at the Primary Outcome (Week 26 of double-blind period) or 
Withdrawal Visit in accordance with usual clinical practice be scheduled for a Safety 
Follow-up Visit to allow for a medical examination and/or blood sampling (see section 8.6). If 
further follow-up visits are made, these must be documented in the patient’s medical records 
and not in the eCRF.
Patients who withdraw due to an elevated AST or ALT value (see section 5.5) must be 
followed until the values normalize or stabilize or a diagnosis or a reasonable explanation has 
been established. Additional medical examinations (for example, ultrasound scanning and/or 
sampling for serology, conjugated bilirubin, prothrombin time) should be considered. A 
gastroenterology or hepatology consultation should also be considered.
10.6
Study Monitoring Committee
10.6.1
Data Monitoring Committee (DMC)
An independent Data Monitoring Committee (DMC) has been established to cover all the 
clinical studies in the paediatric vortioxetine programme. 
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The DMC is an independent, external committee which includes child and adolescent 
psychiatrists. The DMC review and evaluate safety data on an ongoing basis in addition to 
cumulative safety data. The DMC will have access to unblinded data and will provide 
recommendations on study continuation, modification or termination. Members of the DMC 
will not be involved in other study-related tasks. The DMC procedures are described in the 
Data Monitoring Committee Charter.
11 Data Handling and Record Keeping
11.1
Data Collection
11.1.1
Electronic Case Report Forms (eCRFs)
eCRFs will be used to collect all the data related to the study, except the external data 
described in section 11.1.5.
The eCRFs use third party software (Rave®) to capture data via an online system on a 
computer. When the investigator enters data in the eCRF (ideally during the visit or as soon as 
possible, <3 days thereafter), the data will be recorded electronically in a central database over 
encrypted lines, and all entries and modifications to the data will be logged in an audit trail. 
Access to the system will only be granted after appropriate and documented training. Written 
instructions for using the system will be provided along with the training.
Electronic signatures will be used where signatures are required on pages and/or visits. 
Automated data entry checks will be implemented where appropriate; other data will be 
reviewed and evaluated for accuracy by the sponsor and/or representatives from specify CRO. 
All entries, corrections, and changes must be made by the investigator or a delegate.
11.1.2
Data Transfer for Rollover Patients (Studies 12709A and 12712A)
Data available in the eCRF for Studies 12709A and 12712A will be transferred to the 
Study 13546A eCRF where possible, in accordance with Panel 2 and Panel 3. The data to be 
transferred from Studies 12709A and 12712A eCRF to the Study13546A eCRF will be 
specified in the eCRF Completion Guidelines.
11.1.3
External Data From Study 12709A and Study 12712A
All external data pertaining to the rollover visit assessments (as detailed in Panel 2 and 
Panel 3) will be transferred to the 13546A Study.
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11.1.4
Patient Binders eCRF
11.1.4.1
Use of Patient Binders
The Patient Binder contains different types of source documents, including paper versions of 
any COAs and PROs completed as a fall-back solution (see below). A ballpoint pen with 
waterproof ink must be used to enter information in the Patient Binder.
11.1.4.2
Clinical Outcome Assessments (COAs)
The Patient Binder contains the paper version of the following COA tool: K-SADS-PL, to be 
completed by the raters. The data will be transcribed to the Scoring Sheets in the eCRF by the 
investigator or a delegate; the raters must verify that all the entries are accurate and correct by 
signing and dating the relevant pages.
A paper version of any electronic clinical outcome assessments (eCOAs) (other than K-SADS-
PL) or ePRO will only be completed as a fall-back solution if the electronic Rater Station 
system is not available.
In case when paper scales are used, the patients and parents will be asked to complete the 
PROs in their local language. The responses may only be corrected by the patient/parent.
11.1.4.3
Serious Adverse Event Fallback Forms
Serious Adverse Event Fallback Forms must be used when the eCRF cannot be accessed.
11.1.5
External Data
All electronic data will be transferred using a secure method accepted by Lundbeck.
The clinical safety laboratory test data will be transferred by ICON laboratory.
The following electronic data will be transferred by ICON and kept in a secure designated 
storage area outside the eCRF:
PRO data
eCOA data
IMP quantification results
ECG results
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11.2
Retention of Study Documents at the Site
11.2.1
eCRF Data
If a site closes before the study has been completed, the investigator will continue to have 
read-only access to the eCRF until the study has been completed. After the study has been 
completed, all user access to the eCRF will be revoked. Renewed access to the eCRF will be 
given if corrections or updates to the database are required.
At the end of the study, the site will be provided with all data related to the site (including 
eCRF data, queries, and the audit trail) using a secure electronic medium; the secure storage of 
these data at the site is the responsibility of the investigator. When confirmation of receipt of 
the data has been received from all sites, all user access to the eCRF will be revoked. If, for 
some reason, the data are not readable for the full retention period (25 years or in accordance 
with national requirements, whichever is longer), the investigator may request that the data be 
re-sent.
11.2.2
Other Study Documents
The investigator must keep the investigator’s set of documents in the investigator TMF for at 
least 25 years after the Clinical Study Report has been approved or in accordance with national 
requirements, whichever is longer. Lundbeck will remind the investigator in writing of this 
obligation when the Clinical Study Report Synopsis is distributed to the site.
If off-site storage is used, a study-specific binder will remain at the site after the other 
study-specific documents have been shipped for off-site storage. This binder is considered part 
of the investigator TMF and must be kept in a secure place by the site for the required period 
of time. The binder must contain, at a minimum, the following documents: a copy of the 
Investigator TMF Index, a certified copy of the Patient Identification Code List, and a 
Retrieval Form.
When the required storage period has expired, the documents may be destroyed in accordance 
with regulations.
12 Monitoring Procedures
The monitoring strategy for the study foresees a risk-based monitoring approach, in line with 
the relevant FDA and EMA recommendations, and will be described in detail by the 
study-specific risk-based Monitoring Plan, including remote eCRF review and centralised 
monitoring of study data.
Prior to allowing patients to participate in the study, the investigator must sign a source data 
agreement that identifies the source documents (original documents, data, and records) at the 
site. The document will also list which data may be recorded directly on the eCRFs.
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If the investigator does not have a patient’s medical records, the investigator must attempt to 
obtain copies or a written summary of relevant medical records from the doctor who had 
treated the patient earlier and include the pertinent documentation in the patient’s medical 
records at the site. The investigator must obtain medical records documenting the patient’s 
lifetime MDD episodes and general medical history for the 3 months prior to the study.
During the study, the clinical research associate (CRA) will visit the site to ensure that the 
protocol is being adhered to and that all issues are being recorded, to perform source data 
verification, and to monitor IMP accountability. The visit intervals will depend on the outcome 
of the remote monitoring of the eCRFs, the site’s recruitment rate, and the compliance of the 
site to the protocol and Good Clinical Practice. In addition, the CRA will be available for 
discussions by telephone.
Source data verification requires that the CRA be given direct access to all the source 
documents. Direct access includes permission to examine and verify any records that are 
important for the evaluation of the study.
13 Audits and Inspections
Authorized personnel from Medical, Regulatory and Clinical Quality Assurance, 
H. Lundbeck A/S, and quality assurance personnel from business partners may audit the study 
at any time to assess compliance with the protocol and the principles of Good Clinical 
Practice and all other relevant regulations.
The investigator must be aware that representatives from regulatory authorities may also wish 
to inspect source data, such as medical records. The investigator must notify Lundbeck, 
without delay, of an announced inspection by a regulatory authority.
During audits and inspections, the investigator must permit direct access to all the source 
documents, including medical records and other documents pertinent to the study.
During audits and inspections, the auditors and inspectors may request relevant parts of 
medical records. No personal identification apart from the screening or randomization 
numbers will appear on these copies.
Patient data will not be disclosed to unauthorized third parties, and patient confidentiality will 
be respected at all times.
14 Protocol Compliance
Lundbeck has a “no-waiver” policy, which means that permission will not be given to deviate 
from the protocol.
If a deviation occurs, the investigator must inform the CRA and they must review, discuss, and 
document the implications of the deviation.
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15 Study Termination
Lundbeck or a pertinent regulatory authority may terminate the study or part of the study at 
any time. The reasons for such action may include, but are not limited to:
safety concerns
proven lack of efficacy of the IMP in the children’s study (12709A)
If the study is terminated or suspended, the investigator must promptly inform the patients and 
ensure appropriate therapy and follow-up. Furthermore, the investigator and/or sponsor must 
promptly inform the IEC or IRB and provide a detailed written explanation. The pertinent 
regulatory authorities must be informed in accordance with national regulations.
If the risk/benefit evaluation changes after the study is terminated, the new evaluation must be 
provided to the IEC or IRB if it will have an impact on the planned follow-up of the patients 
who participated in the study. If so, the actions needed to protect the patients must be 
described.
16 Statistical Methodology
16.1
Responsibilities
ICON Plc will perform the statistical analyses described below.
16.2
Analysis Sets
The following analysis sets will be used to analyse and present the data:
all-patients-enrolled (APES) – all-patients-enrolled to the 12-week open-label, flexible-
dose treatment period who took at least one dose of IMP
all-patients-randomized set (APRS) – all patients randomized to the 26-week double-blind 
treatment period 
full-analysis set (FAS) – all patients randomized to the 26-week double-blind treatment 
period who took at least one dose of double-blind IMP
The patients and data will be classified into the analysis sets according to these definitions at a 
Classification Meeting held after the study database has been released, but before the blind has 
been broken.
16.3
Descriptive Statistics
In general, summary statistics (n, arithmetic mean, standard deviation, median, lower and 
upper quartiles, minimum and maximum values) will be presented for continuous variables. 
Counts and, if relevant, percentages will be presented for categorical variables.
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16.4
Patient Disposition
Patient disposition will be summarized by treatment group and in total and will include the 
number of patients in the FAS who completed or withdrew from treatment and from study, as 
well as the number of patients in each analysis set (APES, APRS and FAS).
The disposition data will be summarized for the open-label period (split out by de novo
patients and rollover patients from Study 12709A), and the double-blind period separately.
The number of patients who completed or withdrew from the study will also be summarized 
per period.
The number of patients who withdrew from treatment and from study will be summarized by 
treatment group and primary reason for withdrawal as well as all reasons for withdrawal will 
be presented per period.
16.5
Demographics and Baseline Characteristics
Demographics (sex, age, and race), baseline characteristics (height, weight and BMI), baseline 
efficacy variables, and other disease characteristics will be summarized by treatment group 
and in total. Patient disposition and demographics will be summarized using descriptive 
statistics.
16.6
Recent and Concomitant Medication
Recent and concomitant medication will be summarized by anatomical therapeutic chemical 
(ATC) code and generic drug name by treatment group and in total.
16.7
Exposure and Compliance
Exposure and compliance will be calculated per patient and summarized by treatment group.
Exposure will be defined as the number of days between the date the last dose of IMP was 
taken and first dose of IMP was taken. Compliance will be defined as the number of days in
which a dose was taken related to the number of days the patient was expected to take IMP as 
per the protocol.
Exposure will be calculated for the open label period, the double-blind relapse period and in 
total.
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16.8
Efficacy Analyses
16.8.1
General Efficacy Analysis Methodology
All the statistical tests of the efficacy endpoints will be two-sided tests performed at the 5%
significance level and all confidence intervals (CIs) will be 95% CIs, unless otherwise
specified.
The efficacy analyses will be based on the FAS.
16.8.2
Primary Analysis of the Primary Endpoint
The primary efficacy analysis will compare the time to relapse in the double-blind period 
between vortioxetine and placebo treated patients. Relapse will be defined as either a total 
score ≥40 on the CDRS-R with a history of 2 weeks of clinical deterioration, or clinical 
deterioration as judged by the clinician and documented in the eCRF. 
The two treatment groups will be compared using a Cox regression model with exact 
adjustment for ties. 
The regression model will have treatment as fixed factor, CDRS-R Total Score at 
randomization as covariate, and separate baseline hazards for the stratification factor, i.e. the 
patient inclusion source (de novo patients, rollover patients from 12709A, or from 12712A). 
Further details will be given in the SAP.
A one-sided 5% level of significance will be used. Patients not relapsing before Week 26 will 
be censored at Week 26 and patients withdrawing due to other reasons than relapse will be 
censored at time of withdrawal. 
16.8.3
Sensitivity Analyses of the Primary Endpoint
The following sensitivity analyses will be performed:
1.
The primary analysis will be repeated ignoring relapses occurring during the first week, 
two weeks and four weeks of the double-blind period, respectively. 
2.
The number of relapses will be summarized according to relapse criteria: CDRS-R total 
score ≥40 with 2 weeks of clinical deterioration, investigator’s judgement, or both.
3.
Primary analysis will be repeated for the de novo patients and for the (pooled) 12709A 
patients and 12712A patients. 
16.8.4
Analysis of the Secondary Endpoint(s)
The number of relapses will be summarized according to relapse criteria (see section 16.8.2) 
and the relapse over the 26 weeks double-blind period will be analysed using logistic 
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regression, with treatment and inclusion source as fixed factors and CDRS-R Total Score at 
randomization as covariate.
Secondary efficacy variables (CDRS-R total score, PQ-LES-Q scores, CGI-S and CGI-I) will 
be analysed on an exploratory basis over the 26-week double-blind period by Mixed Model 
Repeated Measurements (MMRM) and analysis of covariance (ANCOVA). For the purpose of 
the analysis the change from baseline in CDRS-R total score, PQ-LES-Q scores, and in CGI-S 
score will be computed. In this respect, baseline will be defined as the start of the double-blind 
period.
For both the MMRM and the ANCOVA, the dependent variable will be the change from 
baseline in CDRS-R total score, change from baseline in PQ-LES-Q scores, change from 
baseline in CGI-S score and the absolute CGI-I score, respectively. In this respect, baseline 
will be defined as the start of the double-blind period.
The MMRM will have treatment, week and inclusion source as fixed factors and the baseline 
score will be added as a covariate. For CGI-I, the score at randomization for the CGI-S will be 
used as covariate. In addition, the interaction between treatment and week and between 
baseline score and week will be included and an unstructured covariance matrix will be 
applied. In this respect, baseline will be defined as the start of the double-blind period.
In the ANCOVA treatment and inclusion source will be included as a fixed factors and the 
respective baseline score will be included as a covariate. For CGI-I, the score at randomization 
for the CGI-S will be used as covariate.
Both the observed cases (OC) and last observation carried forward (LOCF) approach will be 
used.
16.8.5
Testing Strategy
This section is not applicable.
16.8.6
Analysis of the Exploratory Endpoint(s)
No formal exploratory endpoints have been defined.
On an exploratory basis, severity of illness, gender and age will be assessed as covariates or to 
generate subgroups for the Cox regression model as described in section 16.8.2.
In addition, descriptive statistics will be used to compare patient populations and treatment 
outcome between the geographical regions.
16.8.7
Pharmacokinetic Analyses
The pharmacokinetic analyses will be based on the pharmacokinetic set (PKS).
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The population pharmacokinetics (popPK) of vortioxetine in children will be analysed through 
non-linear mixed effect analysis and will be described in a separate popPK analysis plan. 
16.8.8
Safety Analyses
The safety analyses will be based on the APES and the FAS.
All safety endpoints will be reported for the 12-week open-label period and the 26-week 
double-blind period separately.
16.8.9
Analysis of Adverse Events
Adverse events will be classified according to the time of onset of the adverse event:
pre-treatment adverse event – an adverse event that starts on or after the date the patient 
signed the Informed Consent Form and prior to the date of first dose of IMP
treatment-emergent adverse event (TEAE) – an adverse event that starts or increases in 
intensity on or after the date of first dose of IMP
Adverse events, sorted by system organ class (SOC) and preferred term, will be summarized 
by treatment group.
Allocation of TEAEs to Study Periods
TEAEs may be allocated to study periods (these will be defined in the Statistical Analysis 
Plan).
16.8.10 Analysis of Other Safety Endpoints
Absolute and change from baseline in clinical safety laboratory tests (estradiol for girls, LH, 
FSH), Tanner staging, and effects on menstrual cycle, vital signs, height, weight, BMI and 
ECG parameters will be summarized by treatment group. Potentially clinically significant 
(PCS) safety laboratory test values will be flagged and summarized.
GBI scores (using the 10-item mania subscale), and C-SSRS scores will be summarized using 
descriptive statistics. 
16.9
Interim Analyses
No interim analysis is planned.
16.10 Sample Size and Power
The calculation of power is based on a log-rank test for the time to relapse at a one-sided 5% 
level of significance using SAS Proc Power. A sample size of 80 randomized patients 
(40 patients per treatment group) will provide at least 80% power to find a difference between 
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vortioxetine and placebo as statistically significant, when expecting cumulative relapse rates at 
0.42 and 0.69 over 26 weeks, respectively corresponding to a hazard-ratio of 2.15. The 
assumption of relapse rates (42% and 69% over 6 months for vortioxetine and placebo, 
respectively) is based on observed rates from a similarly designed relapse-prevention study of 
fluoxetine in paediatric patients with MDD who had an adequate response after 12 weeks of 
acute treatment.14
It is anticipated that approximately 60% of de novo patients enrolled into the open-label period 
will qualify for the double-blind study period. To achieve 80 randomized patients, 150 patients 
are estimated to be enrolled into the study (depending on number and randomization rate of de 
novo and rollover patients).
16.11 Statistical Analysis Plan
A Statistical Analysis Plan describing the handling of data issues and the planned statistical 
analyses in more detail will be prepared by ICON Plc.
The SAP will be finalised prior to the first subject enrolled in the study.
17 Clinical Study Report and Publications
17.1
Data Ownership
The data collected in this study are the property of Lundbeck.
17.2
Clinical Study Report
Upon completion of the study, a Clinical Study Report will be prepared by ICON.
17.3
Summary of Clinical Study Results
Upon completion of the study and when the study results are available, the patient has the right 
to be informed by the investigator about the overall study results.
17.4
Publications
The results of this study will be submitted for publication.
Lundbeck will submit results information to:

ClinicalTrials.gov

European Union Drug Regulating Authorities Clinical Trials (EudraCT)
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The primary publication based on this study must be published before any secondary 
publications. Authors of the primary publication must fulfil the criteria defined by the 
International Committee of Medical Journal Editors (ICMJE).38
18 Indemnity and Insurance
In the event of study-related injuries or deaths, insurance for the patients and indemnity of the 
investigators and those of their employees, servants, or agents whose participation in this study 
has been documented are provided. Insurance and liability will be in accordance with 
applicable laws and Good Clinical Practice.
19 Finance
19.1
Site Agreements
The financial agreements with each site are addressed in one or more documents. Both parties 
must sign the agreements before each site is initiated.
19.2
Financial Disclosure
All the investigators, including sub-investigators, and raters participating in the study must 
complete a Financial Disclosure Form.
19.3
Equipment
Equipment rented by ICON on behalf of Lundbeck that has been provided to the sites for use 
during the study must be returned at the end of the study.
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Questionnaire (PQ-LES-Q): reliability and validity. J Am Acad Child Adolesc Psychiatry. 2006;
45: 401-407.
30. European Medicines Agency (EMA). Committee for Medicinal Products for Human Use 
(CHMP). Guideline on bioanalytical method validation. EMEA/CHMP/EWP/192217/2009. 
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21 July 2011.
31. United States Food and Drug Administration (FDA). Guidance for Industry: Bioanalytical method 
validation. 2001.
32. Youngstrom EA, Van Meter A, Frazier TW, Youngstrom JK, Findling RL. Developing and 
validating short forms of the parent general behavior inventory mania and depression scales for 
rating youth mood symptoms. Journal of Clinical Child & Adolescent Psychology. 2020 Mar 
3;49(2):162-77.
33. Youngstrom EA, Van Meter A, Frazier TW, Youngstrom JK, Findling RL. Developing and 
validating short forms of the parent general behavior inventory mania and depression scales for 
rating youth mood symptoms. Journal of Clinical Child & Adolescent Psychology. 24 Jul 2018.
34. Findling RL, Youngstrom EA, Danielson CK, DelPorto‐Bedoya D, Papish‐David R, Townsend L, 
Calabrese JR. Clinical decision‐making using the General Behavior Inventory in juvenile 
bipolarity. Bipolar disorders. 2002 Feb;4(1):34-42.
35. Posner K, Oquendo MA, Gould M, Stanley B, Davies M. Columbia Classification Algorithm of 
Suicide Assessment (C-CASA): classification of suicidal events in the FDA’s pediatric suicidal 
risk analysis of antidepressants. Am J Psychiatry. 2007; 164(7): 1035-1043.
36. ICH. ICH Harmonised Tripartite Guideline E2A: Clinical safety data management: definitions and 
standards for expedited reporting. October 1994.
37. European Parliament and Council of the European Union. Directive 2001/20/EC: Approximation 
of the laws, regulations and administrative provisions of the Member States relating to the 
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reporting, editing, and publication of scholarly work in medical journals. [Internet] 
icmje.org/icmje-recommendations.pdf. December 2017.
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Appendix I
Clinical Study Protocol
Authentication and Authorization
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Clinical Study Protocol
Authentication and Authorization
Study title:
A double-blind, randomized, placebo-controlled, multicentre, relapse-prevention 
study of vortioxetine in paediatric patients aged 7 to 11 years with Major 
Depressive Disorder
Study No.:
13546A
Edition No.:
1.0
Date of edition:
7 January 2021
This document has been signed electronically. The signatories are listed below.
Authentication
I hereby confirm that I am of the opinion that the ethical and scientific basis of this study is sound.
International study manager:
Clinical research scientist:
Head of Biostatistics:
Head of GPS Medical Safety
Authorization
I hereby confirm that I am of the opinion that the ethical and scientific basis of this study is sound.
Head of Clinical Development -
Paediatrics
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Appendix II
Recent and Concomitant Medication
Disallowed or Allowed with Restrictions
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Recent and Concomitant Medication:
Disallowed or Allowed with Restrictions 
In the table below, recent and concomitant medications that are disallowed or allowed with 
restrictions with respect to their use prior to or during the study are listed.
Drug Class
Disallowed prior
to Baseline
Disallowed (X) During the Study for
Chronic
Use
Episodic
Use
Comments or Exceptions
Agents used for ADHD (non-
stimulant e.g. atomoxetine,
guanfacine, and clonidine)
2 weeks
X
X
Psychostimulants agents (e.g.
methylphenidate or amphetamine), are
allowed if the patient as a minimum has
had a 4-week stable dose period, prior to
the study treatment.
Anaesthetics
General
X
X
General anaesthetics are disallowed
during the study except in case of
emergency procedures requiring an-
aesthesia
Local
X
Analgesics
Narcotic
analgesics
X
X
NSAIDsa
X
Anorexics
2 weeks
X
X
Antiacne agents
2 weeks
X
X
Agents for topical use are allowed
Antibiotics
Only rifampicin is disallowed
Anticoagulants
X
X
Only low-molecular weight heparins
are allowed for episodic use
Anticonvulsants
2 weeks
X
X
Antidepressants
2 weeks (5 weeks
for fluoxetine)
X
X
Monoamine oxidase inhibitors (MAOs)
are contraindicated.
Antidiarrhoealagents
X
X
Only loperamide, bismuth and kaolin
preparations are allowed
Antihistamines
X
X
Only loratadine, desloratadine, cetiriz-
ine, levocetirizine, mizolastine and
fexofenadine are allowed
Antimigraine agents –
triptans, dopamine an-
tagonists
2 weeks
X
X
Antinauseants(including
dopamine antagonists)
2 weeks
X
X
Only phosphoric acid preparations,
bismuth and cola syrup are allowed
Antineoplastics
X
X
Antiobesity agents
X
X
Antiplatelettreatment (in-
cluding low dose aspirin)
X
X
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Drug Class
Disallowed
prior to Base-
line
Disallowed (X) During the Study for
Chronic
Use
Episodic
Use
Comments or Exceptions
Antipsychotics
6 weeks
(6 months
for depot)
X
X
Anxiolytics
2 weeks
X
X
Cough/cold agents
X
Preparations containing ephedrine,
pseudoephedrine and codeine are
allowed for episodic treatment for
a maximum of 1 week
Herbal remedies, which are
psychoactive (e.g. St.
John’s Wort, kava, vale-
rian, ginkgo biloba)
2 weeks
X
X
Hormones
X
X
Only thyroid hormone replace-
ment, contraceptives and proges-
terone replacement therapy are al-
Hypoglycaemic agents
X
Insuline
X
Mood stabilisers (includ-
ing lithium, valproate,
valpromide)
6 weeks
X
X
Muscle relaxant
2 weeks
X
X
Psychotropic agents not
otherwise specified (in-
cluding, tryptophan, and
dopamine agonists)
2 weeks
X
X
Sedatives/hypnoticsb
2 weeks
X
X
Only zolpidem, zopiclone or zaleplon
allowed, for severe insomnia, with a
maximum of 2 nights per week. Only
Melatonin is allowed with a maximum
of 3 nights per week. The patient is
not allowed to take any sleeping aid
the night before a study visit.
Systemic steroids
X
X
a
Both start and stop dates for each use are to be reported in the eCRF.
b
Both start and stop dates for each use are to be reported in the eCRF. Every tablet/capsule should be
reported for this type of medication from two weeks prior to Screening Visit, until Visit 17.
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