Conditions: Depressive Disorder, Major
Keywords: adolescent children
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 662
Healthy volunteers: no

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

Detailed description:

Arms:
arm 1: Vortioxetine tablets for 26 weeks. Single dose of vortioxetine oral drops (only a subset of participants).

Interventions: intervention 1: Vortioxetine
Intervention descriptions: intervention 1: Target dose is 10 mg/day, however, the dose can be down- or uptitrated to 5, 15, or 20 mg/day.

Protocol document:
Prot_000.pdf: 
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Final: Version 
PLUTO ID: 
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1.0
CLI_00919715
Long-term, open-label, flexible-dose, extension study of vortioxetine in child and
adolescent patients with Major Depressive Disorder (MDD) from 7 to 18 years of
age.
12712A Protocol Edition 3.0
12712A
19-Jan-2017 06:54:38
Biostatistic Approval
19-Jan-2017 08:29:05
Correctness and Completeness
19-Jan-2017 09:08:30
Clinical Approval
19-Jan-2017 10:13:47
Clinical Approval
19-Jan-2017 11:08:29
Clinical Safety Approval
NCT02871297


H. Lundbeck A/S
Confidential
Page 1 of 67
Clinical Study Protocol
Long-term, open-label, flexible-dose, extension study of 
vortioxetine in child and adolescent patients with Major 
Depressive Disorder (MDD) from 7 to 18 years of age
Vortioxetine
Study No.:
12712A
EudraCT No./IND:
2008-005356-25 / 112581
Sponsor:
H. Lundbeck A/S (Lundbeck)
2500 Valby (Copenhagen), Denmark
Edition No.:
3.0 (including PA2)
(the version No. in the footer is the system version No.)
Date of edition:
16 January 2017
Edition history:
Edition 2.0, 18 January 2016 (including PA1)
Edition 1.0 (original protocol), 6 November 2015
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 authorisation 
from H. Lundbeck A/S.
LU Study Number: 
Trial Site Number: 
Pluto ID: 
Status: 
Version: 
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Study Level
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Page 2 of 67
Synopsis – Study 12712A
Sponsor
H. Lundbeck A/S 
Investigational Medicinal Product
Vortioxetine
EudraCT No./IND No.
2008-005356-25/ 112581
Title of Study
Long-term, open-label, flexible-dose, extension study of vortioxetine in child and adolescent patients with 
Major Depressive Disorder (MDD) from 7 to 18 years of age
Study Sites and Number of Patients Planned
Sites involved in studies 12709A and 12710A. Approximately 120 sites are planned in approximately 20
countries worldwide (specialists, mainly outpatient clinics)
Objectives
Primary objective:
to evaluate the long-term safety and tolerability of vortioxetine in child and adolescent patients with a 
DSM-5™/diagnosis of MDD
Secondary objectives:
to evaluate the long-term effectiveness of flexible doses of vortioxetine in a range of 5 mg/day to 20 mg/day 
on:
depressive symptoms
clinical global impression
cognitive function
functionality
Study Methodology
Interventional, multi-national, multi-site, open-label, flexible-dose, long-term extension study in child and 
adolescent patients with MDD who completed one of the double-blind, placebo-controlled, active-reference
studies 12709A and 12710A.
The Baseline Visit of this extension study hereafter referred to as Baseline Extension A, will be Visit 12 
(Completion Visit) of lead-in Study 12709A or 12710A.
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 adjust the dose in case of 
unsatisfactory response up to 20 mg or 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-titrated to a new 
dose. Changes in dosing may occur at any site visit during the treatment course at the investigator's discretion 
but the maximum dose may not exceed 20 mg/day.
The treatment period is 26 weeks. The total study duration per patient from Baseline Extension A to the end 
of follow-up will be approximately 30 weeks.
If possible, patients who withdraw are to be seen for a withdrawal visit as soon as possible and they will be 
contacted for a safety follow-up visit 4 weeks after withdrawal.
The study design is presented in Panel 1 and the scheduled assessments are summarised in Panel 2.
Investigators will not be informed about which treatment their patients received during the 12709A or 
12710A study at the time of enrolling them into this open-label extension study.
For ethical and equity reasons patients who turned 18 years during the lead-in study 12710A can be enrolled 
into this extension study.
LU Study Number: 
 
Trial Site Number: 
 
Pluto ID: 
 
 
Status: 
 
Version: 
 
 
 
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Study Level
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H. Lundbeck A/S
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Page 3 of 67
Target Patient Population
The patient is a male or female, child aged ≥7 and <12 years or adolescent aged ≥12 and ≤18 years at Baseline 
Extension A.
The patient must have completed Study 12709A or 12710A (Visit 12, Completion Visit) immediately prior to 
enrolment into this extension study.
The patient had a primary diagnosis of a Major Depressive Disorder (MDD) at entry in study 12709A or 
12710A, diagnosed according to DSM-5™.
The patient is indicated for long-term treatment with vortioxetine according to the clinical opinion of the 
investigator.
Investigational Medicinal Products, Doses and Mode of Administration
Vortioxetine – 5 mg/day, tablets, orally
Vortioxetine – 10 mg/day, tablets, orally
Vortioxetine – 15 mg/day, tablets, orally
Vortioxetine – 20 mg/day, tablets, orally
The treatment should be given once a day, preferably in the morning.
Efficacy Assessments
Assessment of depressive symptoms:
Investigator rated
Children Depression Rating Scale Revised version (CDRS-R)
Assessment of Global Impression:
Investigator rated 
Clinical Global Impression Scale – Severity of Illness (CGI-S) 
Clinical Global Impression Scale – Global Improvement (CGI-I) 
Assessment of cognitive function:
Parent rated (children aged 7-11 years at Baseline Extension A)
Behaviour Rating Inventory of Executive Function (BRIEF) – Global Executive Composite (overall 
summary score) – Subscales (initiate, working memory, plan/organize, organization of materials, 
monitor, inhibit, shift and emotional control)
BRIEF – Metacognition Index –  Subscales (initiate, working memory, plan/organize, self-monitor, 
organization of materials)
Patient rated (adolescents aged 12-18 years at Baseline Extension A)
Behaviour Rating Inventory of Executive Function – Adolescent version- (BRIEF-SR) – Global 
Executive Composite (overall summary score) – Subscales (working memory, plan/organize, 
organization of materials, task completion, monitor, inhibit, shift and emotional control)
BRIEF-SR – Metacognition Index –  Subscales (working memory, plan/organize, organization of 
materials and task completion)
Assessment of functionality:
Investigator rated
Children’s Global Assessment Scale (CGAS) 
Patient rated
The PedsQL Present Functioning Visual Analogue Scales (PedsQL VAS)
LU Study Number: 
 
Trial Site Number: 
 
Pluto ID: 
 
 
Status: 
 
Version: 
 
 
 
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Study Level
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Page 4 of 67
Safety Assessments
Adverse Events (AEs)
Paediatric Adverse Event Rating Scale (PAERS)
Clinical safety laboratory tests, including reproductive hormones
Vital signs
Menstrual cycle (age of menarche, the length of the menstrual cycle)
Weight/Height
Electrocardiograms (ECGs)
Physical examinations including Tanner scoring
Columbia Suicide Severity Rating Scale (C-SSRS)
Endpoints
Primary endpoint:
description of safety parameters, see safety endpoints below.
Secondary endpoints:
depressive symptoms:
change from Baseline Extension A to Week 26 in CDRS-R total score
time to first relapse (CDRS-R value of ≥40)
time to first loss of remission (CDRS-R >28)
Global Clinical Impression:
change from Baseline Extension A to Week 26 in CGI-S score
CGI-I score at Week 26. The assessment of the CGI-I should be in reference to Baseline A in the lead-in 
studies
cognitive function:  
Children (7-11 years)
change from Baseline Extension A to Week 26 in BRIEF using the Global Executive Composite score 
change from Baseline Extension A to Week 26 in BRIEF using the Metacognition Index
Adolescents (12-18 years)
change from Baseline Extension A to Week 26 in BRIEF-SR using the Global Executive Composite 
score 
change from Baseline Extension A to Week 26 in BRIEF-SR using the Metacognition Index
functionality:
change from Baseline Extension A to Week 26 in CGAS score
change from Baseline Extension A to Week 26 in PedsQL VAS score
Safety endpoints:
adverse events (AEs)
tolerability including assessment based on PAERS
Tanner score
absolute values and changes from Baseline Extension A in clinical safety laboratory tests, vital signs, 
weight, height, and ECG parameters
length of menstrual cycle 
potentially clinically significant clinical safety laboratory test values, vital signs, weight, and ECG 
parameter values relative to Baseline Extension A
C-SSRS categorisation based on C-CASA definitions (1, 2, 3, 4, and 7) 
LU Study Number: 
 
Trial Site Number: 
 
Pluto ID: 
 
 
Status: 
 
Version: 
 
 
 
12712A
Study Level
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Page 5 of 67
Statistical Methodology
The following analysis sets will be used to analyse and present the data:
all-patients-treated set (APTS) – all patients who took at least one dose of vortioxetine in the extension 
study.
full-analysis set (FAS) – all patients in the APTS with at least one valid post-Baseline Extension A 
assessment of the CDRS-R total score.
The safety analyses will be based on the APTS.
Descriptive statistics for all patients and by lead-in study and by treatment (n, arithmetic mean, standard 
deviation, median, minimum and maximum values) will be presented for continuous variables (values at each 
visit and, if relevant, changes from Baseline Extension A) and counts. If relevant, percentages will be 
presented for categorical variables.
Analyses of safety endpoints:
Adverse events, PAERS items, Tanner scores, clinical safety laboratory tests, vital signs, height, weight, 
BMI, and ECG parameters will be summarised, and observed potentially clinically significant (PCS) safety 
laboratory test values will be flagged and summarised. The length of menstrual cycle and C-SSRS scores 
will be summarised using descriptive statistics.
The change from baseline will be derived with respect both to baseline in the lead-in studies and baseline in 
extension Study 12712A. 
The primary objective will be addressed with an overall clinical evaluation of the safety results.
Adverse events occurring in the first two weeks of the study will be reported separately.
The efficacy analyses will be based on the FAS.
Analyses of efficacy endpoints:
Change from Baseline Extension A in CDRS-R, CGI-S, BRIEF, CGAS, and PedsQL VAS using 
descriptive statistics by lead-in study and by lead-in treatment.
CGI-I score at week 26 using descriptive statistics by lead-in study and by lead-in treatment.
Time to first relapse (CDRS-R value of ≥40) using Kaplan-Meier estimates. 
Time to first loss of remission (CDRS-R >28) using Kaplan-Meier estimates.
For exploratory use a random effects slope and intercept model on safety and efficacy parameters will be 
applied using Mixed Model Repeated Measurements (MMRM) to study long-term development in safety and 
efficacy parameters (e.g. weight and CDRS-R).
Summaries and analyses will be performed with respect to the Baseline in the lead-in studies.
No interim analyses for efficacy are planned. A DMC will monitor safety data at regular intervals to be 
specified in the Data Monitoring Committee Charter.
Pharmacokinetic Analysis
Sparse PK samples (2) will be collected to measure vortioxetine plasma concentration. The population PK of 
vortioxetine will be assessed by means of nonlinear mixed effect modelling and the results from the analysis 
will be reported in a separate population PK report.
Sample Size Considerations
No formal sample size calculation has been performed for the present study, which includes patients who have 
completed the studies 12709A or 12710A and are eligible for enrolment for this study. Sample size is based on 
an expected withdrawal of 15-20% of the 1200 patients randomised to the lead-in studies. A maximum of 85% 
of these lead-in completers are expected to accept to continue into this extension study. This gives 
approximately 850 patients.
LU Study Number: 
 
Trial Site Number: 
 
Pluto ID: 
 
 
Status: 
 
Version: 
 
 
 
12712A
Study Level
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Page 6 of 67
Ethical Rationale for Study and Study Design
In May 2014, WHO's "Health for the world’s adolescents" report reveals that “depression is the predominant 
cause of illness and disability for both boys and girls aged 10 to 19 years” and adds that the “top 3 causes of 
adolescent deaths globally are road traffic injuries, HIV/AIDS, and suicide. Worldwide, an estimated 1.3 
million adolescents died in 2012”. The prevalence of Major Depressive Disorder (MDD) is estimated to be 
approximately 2% in children and 4% to 8% in adolescents. 
Only one antidepressant, fluoxetine, is currently approved in Europe for the treatment of MDD in children and 
adolescents. In the US only fluoxetine is approved for use in children and fluoxetine and escitalopram for use in 
the adolescent population. Development of a new antidepressant will increase and strengthen the 
pharmacological treatment options for this patient population. This study is an extension study to Studies 
12709A and 12710A and part of the agreed EMA Paediatric Investigational Plan (PIP) and the US Pediatric 
Written Request (PWR) for vortioxetine with the purpose to investigate the long-term safety and tolerability of 
vortioxetine in paediatric patients aged 7-17 years. It is the expectation that this study will demonstrate a 
favourable safety and tolerability profile, and therefore a positive benefit-risk ratio for the use of vortioxetine in 
the paediatric population.
Vortioxetine is approved in the US, EU and a number of other countries for the treatment of MDE/MDD in the 
adult population. The evaluation of the safety and tolerability of vortioxetine is based on data from a large 
clinical development programme in adult and elderly patients. In the overall clinical development programme 
treatment with vortioxetine at the therapeutic doses (5-20 mg/day) was safe and well tolerated. The approved 
recommended dose range of 5-20 mg/day for adults was evaluated in a pharmacokinetic and tolerability study 
performed in the paediatric population (aged 7 to 17 years) designed to guide the choice of doses to be used in 
the planned paediatric programme. Hence the chosen doses of vortioxetine (5, 10, 15 and 20 mg/day) for this 
study is based on the results from the paediatric pharmacokinetic and tolerability study and the knowledge from 
the adult studies. 
As extrapolation of adult safety data is not considered appropriate for the paediatric population; a specific 
paediatric study is warranted to thoroughly address the long-term safety/tolerability of vortioxetine in the 
paediatric population. The 26-week treatment period is in alignment with treatment guidelines in EU and US 
that recommend continuation therapy with an antidepressant for at least 6 months in children and adolescents.
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 childcare; the 
study 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/adolescent prior to any 
investigation or procedure, in order to decrease anxiety and anticipation of pain. Potentially painful procedures 
such as venepuncture will be minimised with the use of 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.
The investigator plays an important role in protecting the safety of the patient. The assessment of potential 
burden and risk is defined specifically in the clinical study protocol (safety rating scales, recording of adverse 
events, clinical safety laboratory tests (blood biochemistry, haematology and urine analysis), vital signs (blood 
pressure and pulse rate), weight, height, electrocardiogram and physical examination) and these will be 
evaluated by the investigator at each visit to ensure the patients’ safety and well-being. If it does not remain in 
the patient’s best interest to stay in the study, the investigator will ensure that the patient is withdrawn. Patients 
that are withdrawn from the study and do not complete, will be treated according to normal clinical practice. 
In accordance with Good Clinical Practice, qualified medical personnel at Lundbeck will be available to advice
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 benefit of the full clinical study, so that the health and well-being of paediatric patients 
enrolled will be safeguarded. 
LU Study Number: 
 
Trial Site Number: 
 
Pluto ID: 
 
 
Status: 
 
Version: 
 
 
 
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Study Level
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Page 7 of 67
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 both by rating scale (Columbia-Suicide Severity Rating Scale) and by the investigator’s judgment. 
An independent Data Monitoring Committee will be established in order to review the safety and tolerability 
data throughout this study. The same DMC will cover all the clinical studies in the paediatric vortioxetine 
program.
LU Study Number: 
 
Trial Site Number: 
 
Pluto ID: 
 
 
Status: 
 
Version: 
 
 
 
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Panel 1
Study Design
LU Study Number: 
 
Trial Site Number: 
 
Pluto ID: 
 
 
Status: 
 
Version: 
 
 
 
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Panel 2
Study Procedures and Assessments
Visit
Base-
line 
Exten
sion 
A
Treatment Period
Com-
pletion 
/With-
drawala
Safety 
Follow-
upb
Visit Number
1
2
3
4c
5
6c
7
8c
9
10c
11
12c
13
14
End of Week
0
1
2
3
4
6
8
10
12
15
18
22
26
30
Visit Windowd (days 
relative to nominal 
visit)
0

2

2

2

2

2

2

2

2

2

5

5

5

5
Baseline Extension A Procedures and Assessments
Signed informed 
consent/assent

Inclusion/exclusion 
criteria

Efficacy Assessments
CDRS-R
e







CGI-S
e







CGI-If
e







BRIEF (7-11 years at 
Baseline Extension A)






BRIEF-SR (12-18
years at Baseline 
Extension A)






CGAS
e





PedsQL VAS (PRO)
e





Vortioxetine Quantification
Blood sampling 
vortioxetine 
quantification
e


Safety Assessments
Adverse events
g












h
Blood and urine 
sampling for clinical 
safety laboratory tests 
e,i


Vital signs
e







Weight and height
e


Menstrual cycle and 
Tanner score



ECGs
e


Examinations (physical
and  neurological)
e


PAERS 
e












C-SSRS
e












LU Study Number: 
 
Trial Site Number: 
 
Pluto ID: 
 
 
Status: 
 
Version: 
 
 
 
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Visit
Base-
line 
Exten
sion 
A
Treatment Period
Com-
pletion 
/With-
drawala
Safety 
Follow-
upb
Visit Number
1
2
3
4c
5
6c
7
8c
9
10c
11
12c
13
14
End of Week
0
1
2
3
4
6
8
10
12
15
18
22
26
30
Visit Windowd (days 
relative to nominal 
visit)
0

2

2

2

2

2

2

2

2

2

5

5

5

5
Other Study Procedures
IMP dispensed







Possible change in 
IMP dose






IMP returned and IMP 
accountability 







Recent and 
concomitant 
medication
g












Pregnancy testj
e


Drug and alcohol 
screene,k
a
This visit should take place as soon as possible after the patient withdraws from the 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/urine 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
A telephone contact. The patient and/or legal representative and/or the investigator can request an 
unscheduled site visit to discuss their current dose. During such an unscheduled site visit, the CDRS-R, CGI-
S, CGI-I, PAERS and C-SSRS must be performed.
d
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 Baseline Extension A.  The number of days between 2 visits must not 
exceed the number of days for which IMP is provided for in the drug kit.
e
Values from assessments and procedures conducted at Visit 12 (Completion Visit) of Study 12709A or 
12710A will be the Baseline Extension A Visit values for this study (12712A).
f
The assessment of the CGI-I should be in reference to Baseline A in the lead-in studies.
g
Ongoing adverse events and concomitant medications (at Completion Visit 12 in Study 12709A or 12710A) 
will be transcribed to the eCRF Adverse Event Form and Concomitant Medication Form.
h
Only for adverse events ongoing at Completion/Withdrawal and new SAEs.
i
The 12712A Hormones panel is to be collected using a separate study-specific kit 
j
Females >10 years of age or female patients at lower age judged by the investigator to be of childbearing 
potential. Additional pregnancy tests during the study will be performed according to local requirements. 
Females <11 years will be tested using a urine hCG test and females >11 years will be tested using a blood 
hCG test.
k
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.
LU Study Number: 
 
Trial Site Number: 
 
Pluto ID: 
 
 
Status: 
 
Version: 
 
 
 
12712A
Study Level
CLI_00919715
Final
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H. Lundbeck A/S
Confidential
Page 11 of 67
Table of Contents
Synopsis – Study 12712A.......................................................................................................................2
List of Panels.........................................................................................................................................15
List of Abbreviations and Definitions of Terms ................................................................................16
1
Introduction................................................................................................................................18
1.1
Background........................................................................................................................18
1.1.1
Overview............................................................................................................18
1.1.2
Nonclinical Data.................................................................................................18
1.1.3
Clinical Data.......................................................................................................19
1.1.3.1
Pharmacokinetics.............................................................................19
1.1.3.2
Efficacy............................................................................................20
1.1.3.3
Safety...............................................................................................20
1.2
Rationale for the Study......................................................................................................21
2
Objectives....................................................................................................................................21
3
Study Design...............................................................................................................................22
3.1
Overview of the Study Design...........................................................................................22
3.2
Rationale for the Study Design..........................................................................................23
4
Ethics...........................................................................................................................................24
4.1
Ethical Rationale................................................................................................................24
4.2
Informed Assent/Consent ..................................................................................................25
4.3
Personal Data Protection....................................................................................................26
4.4
Independent Ethics Committees (IECs) and Institutional Review Boards (IRBs) ............26
4.5
Regulatory Approval/Notification Requirements..............................................................27
5
Study Population........................................................................................................................27
5.1
Numbers of Patients and Sites ...........................................................................................27
5.2
Selection Criteria ...............................................................................................................27
5.3
Withdrawal Criteria ...........................................................................................................30
6
Investigational Medicinal Products..........................................................................................31
6.1
Treatment Regimen ...........................................................................................................31
6.2
IMPs, Formulations, and Strengths....................................................................................32
6.3
Manufacturing, Packaging, Labelling, and Storage of IMPs.............................................32
6.4
Method of Assigning Patients to Treatment ......................................................................32
6.5
IMP Accountability ...........................................................................................................32
6.6
Post-study Access to IMP..................................................................................................33
7
Concomitant Medication...........................................................................................................33
8
Study Visit Plan..........................................................................................................................33
8.1
Overview............................................................................................................................33
8.2
Baseline Extension A Visit (Visit 1)..................................................................................33
8.2.1
Patient Identification Card .................................................................................34
8.3
Visits 4, 6, 8, 10 and 12 .....................................................................................................34
8.4
Withdrawal Visit................................................................................................................34
8.5
Safety Follow-up Visit/Contact (Visit 14).........................................................................35
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8.6
End-of-study Definition.....................................................................................................35
9
Assessments ................................................................................................................................36
9.1
Baseline Extension A Procedures and Assessments..........................................................36
9.1.1
Demographics and Other Baseline Characteristics ............................................36
9.1.2
Drug and Alcohol Screen ...................................................................................36
9.2
Efficacy Assessments ........................................................................................................37
9.2.1
Clinician-rated Scales.........................................................................................37
9.2.1.1
Use of Clinician-rated Scales...........................................................37
9.2.1.2
Children Depression Rating Scale Revised Version (CDRS-R)......37
9.2.1.3
Clinical Global Impression scales (CGI-S/I) ...................................37
9.2.1.4
Children’s Global Assessment Scale (CGAS).................................38
9.2.1.5
CDRS-R, CGI, CGAS Rater Qualification and Certification..........38
9.2.2
Patient and/or Parent Reported Outcomes (PROs).............................................39
9.2.2.1
Use of PROs ....................................................................................39
9.2.2.1.1
Behavioural Rating Inventory of Executive 
Function® (BRIEF®).................................................39
9.2.2.1.2
PedsQL Present Functioning Visual Analogue 
Scales (PedsQL™ VAS) ............................................39
9.4
Safety Assessments............................................................................................................40
9.4.1
Adverse Events...................................................................................................40
9.4.2
Clinical Safety Laboratory Tests........................................................................40
9.4.3
Vital Signs..........................................................................................................42
9.4.4
Height and Weight .............................................................................................42
9.4.5
Menstrual Cycle .................................................................................................43
9.4.6
Tanner Staging ...................................................................................................43
9.4.7
Electrocardiograms (ECGs) ...............................................................................43
9.4.8
Physical and Neurological Examinations...........................................................43
9.4.9
Assessment Tools...............................................................................................44
9.4.10
Paediatric Adverse Event Rating Scale (PAERS)..............................................44
9.4.10.1
Columbia-Suicide Severity Rating Scale.........................................44
9.4.11
Rater Qualification and Certification .................................................................45
9.5
Order of Assessments ........................................................................................................45
9.6
Total Volume of Blood Drawn and Destruction of Biological Material ...........................45
9.7
Treatment Compliance.......................................................................................................46
10
Adverse Events...........................................................................................................................46
10.1
Definitions .........................................................................................................................46
10.1.1
Adverse Event Definitions .................................................................................46
10.1.2
Adverse Event Assessment Definitions .............................................................47
10.2
Pregnancy ..........................................................................................................................48
10.3
Recording Adverse Events ................................................................................................48
10.4
Reporting Serious Adverse Events ....................................................................................49
10.5
Treatment and Follow-up of Adverse Events....................................................................49
10.5.1
Data Monitoring Committee ..............................................................................50
11
Data Handling and Record Keeping ........................................................................................50
11.1
Data Collection..................................................................................................................50
11.1.1
Electronic Case Report Forms (eCRFs).............................................................50
11.1.2
Patient Binders ...................................................................................................51
11.1.2.1
Use of Patient Binders .....................................................................51
11.1.2.2
Rating Scales and Patient-reported Outcomes (PROs)....................51
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11.1.2.3
Serious Adverse Event Fallback Forms...........................................51
11.1.3
External Data......................................................................................................51
11.2
Retention of Study Documents at the Site.........................................................................52
11.2.1
eCRF Data..........................................................................................................52
11.2.2
Other Study Documents .....................................................................................52
12
Monitoring Procedures..............................................................................................................52
13
Audits and Inspections ..............................................................................................................53
14
Protocol Compliance..................................................................................................................53
15
Study Termination.....................................................................................................................53
16
Endpoints....................................................................................................................................54
16.1
Primary Endpoint...............................................................................................................54
16.2
Secondary Endpoints .........................................................................................................54
17
Statistical Methodology .............................................................................................................55
17.1
Responsibilities..................................................................................................................55
17.2
Analysis Sets......................................................................................................................55
17.3
Descriptive Statistics .........................................................................................................55
17.4
Patient Disposition.............................................................................................................56
17.5
Demographics and Other Baseline Characteristics............................................................56
17.6
Recent and Concomitant Medication.................................................................................56
17.7
Exposure and Compliance.................................................................................................56
17.8
Efficacy Analyses..............................................................................................................56
17.8.1
General Efficacy Analysis Methodology ...........................................................56
17.10 Safety Analyses .................................................................................................................57
17.10.1
Analysis of Adverse Events ...............................................................................57
17.10.2
Analyses of Safety Endpoints.............................................................................57
17.11 Interim Analyses................................................................................................................57
17.12 Sample Size and Power .....................................................................................................57
17.13 Statistical Analysis Plan ....................................................................................................58
18
Clinical Study Report and Publications...................................................................................58
18.1
Clinical Study Report ........................................................................................................58
18.2
Data Ownership .................................................................................................................58
18.3
Publications........................................................................................................................58
19
Indemnity and Insurance ..........................................................................................................58
20
Finance........................................................................................................................................58
20.1
Site Agreement ..................................................................................................................58
20.2
Financial Disclosure ..........................................................................................................59
20.3
Equipment..........................................................................................................................59
References.............................................................................................................................................60
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Appendices
Appendix I
Clinical Study Protocol Authentication and Authorisation..........................63
Appendix II
Recent and Concomitant Medication: Disallowed or Allowed with 
Restrictions .......................................................................................................65
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List of Panels
Panel 1
Study Design........................................................................................................................8
Panel 2
Study Procedures and Assessments.....................................................................................9
Panel 3
Dose Titration Schedules...................................................................................................31
Panel 4
Clinical Safety Laboratory Tests .......................................................................................41
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List of Abbreviations and Definitions of Terms
AIDS
Acquired Immune Deficiency Syndrome
ALT
alanine aminotransferase
APTS
all-patients-treated set
AST
aspartate aminotransferase
BPCA
Best Pharmaceuticals for Children Act
BRIEF
Behaviour Rating Inventory of Executive Function
BRIEF-SR
Behaviour Rating Inventory of Executive Function self-report
C-CASA
Columbia Classification Algorithm of Suicide Assessment
CDRS-R
Children Depression Rating Scale Revised Version
CGAS
Children’s Global Assessment Scale
CGI-I
Clinical Global Impression – Global Improvement
CGI-S
Clinical Global Impression – Severity of Illness
CRA
clinical research associate
C-SSRS
Columbia-Suicide Severity Rating Scale 
CYP
cytochrome P450 isoenzyme
DMC
Data Monitoring Committee
DO
doctor of osteopathic medicine
DSM-5™
Diagnostic and Statistical Manual of Mental Disorders, 5th edition
DSM-IV-TR™
Diagnostic and Statistical Manual of Mental Disorders, 4th edition, Text Revision
ECG
Electrocardiogram
eCRF
electronic case report form
EMA
European Medicines Agency
EudraCT
European Union Drug Regulating Authorities Clinical Trials
FDA
United States Food and Drug Administration
PV
Division of Pharmacovigilance, H. Lundbeck A/S
hCG
human chorionic gonadotropin
HIV
human immunodeficiency virus
IB
Investigator’s Brochure
ICH
International Conference on Harmonisation of Technical Requirements for 
Registration of Pharmaceuticals for Human Use
ICMJE
International Committee of Medical Journal Editors
IEC
independent ethics committee
IMP
investigational medicinal product
IND
Investigational New Drug Application
IRB
institutional review board
IVRS
interactive voice response system
IWRS
interactive web response system
Lu
Lundbeck
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MDD
major depressive disorder
NA
not applicable
PAERS
Paediatric Adverse Event Rating Scale
PedsQL™ VAS
PedsQL Present Functioning Visual Analogue Scales
PIP
Paediatric Investigational Plan
PK
pharmacokinetic(s)
PREA
US Paediatric Research Equity Act
PRO
patient-reported outcome
QP
qualified person
SAE
serious adverse event
SD
standard deviation
SERT
serotonin (5-HT) transporter
SUSAR
suspected unexpected serious adverse reaction
TEAE
treatment-emergent adverse event
TMF
trial master file
TSH
thyroid stimulating hormone
US PREA
US Paediatric Research Equity Act
WHO
World Health Organization
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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 In May 2014, 
WHO's Health for the world’s adolescents5 report reveals that depression is the predominant 
cause of illness and disability for both boys and girls aged 10 to 19 years and adds that the top 
3 causes of adolescent deaths globally are road traffic injuries, HIV/AIDS, and suicide. 
Worldwide, an estimated 1.3 million adolescents died in 2012. The prevalence of Major 
depressive disorder (MDD) is estimated to be approximately 2% in children and 4 to 8% in 
adolescents.3,4,6,7
Only one antidepressant, fluoxetine, is currently approved in Europe for the treatment of 
MDD in children and adolescents. In the US only fluoxetine is approved for children and 
fluoxetine and escitalopram for the adolescent population. Development of a new 
antidepressant will increase and strengthen the pharmacological treatment options for this 
patient population.
Signs and symptoms of MDD in children and adolescents are similar to the adult population, 
but depressive disorders meeting the diagnostic criteria rarely is present before the age of 
seven years.8,9 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 
than children to complain of feelings of hopelessness/helplessness, lack of energy and to have 
a higher rate of suicidal thoughts.1,10 As extrapolation of adult safety data is not considered 
appropriate for the paediatric population; a specific paediatric study is warranted to 
thoroughly address the long-term safety/tolerability of vortioxetine in the paediatric 
population. The 26-week treatment period is in alignment with treatment guidelines in EU and 
US that recommend continuation therapy with an antidepressant for at least 6 months in 
children and adolescents.1,9
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.11
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 
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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 
the improvement of cognitive function, learning and memory observed with vortioxetine in 
animal studies.12
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
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 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 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).11
In study 12708A, entitled An open-label study evaluating the pharmacokinetics and 
tolerability of Lu AA21004 in connection with multiple oral dosing of Lu AA21004 in child 
and adolescent patients with a DSM-IV-TRTM diagnosis of depressive or anxiety disorder, 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 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 up-
titration scheme employed in this study are appropriate for the paediatric population. 
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1.1.3.2
Efficacy
Vortioxetine has been approved in the US, 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.
To date, the efficacy of vortioxetine has not yet been investigated in children with MDD.
1.1.3.3
Safety
The evaluation of the safety and tolerability of vortioxetine is based on data from a large 
clinical development programme. In the completed Phase II to IV short- and long-term studies 
in adults, more than 8000 patients with MDD or Generalized Anxiety Disorder (GAD) 
received vortioxetine at doses of 1 to 20 mg/day, corresponding to an overall exposure >3200 
patient-years. Overall short- and long-term treatment with vortioxetine at the therapeutic 
doses (5-20 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 adverse events 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, 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. Abrupt discontinuation of vortioxetine 
after short, as well as after long-term treatment was well tolerated. Based on an 8-week 
vortioxetine study, the direct switch from ≥6-week treatment with selective serotonin reuptake 
inhibitor/serotonin-norepinephrine reuptake inhibitor (SSRI/SNRI) to vortioxetine was well 
tolerated. 
The tolerability of vortioxetine in multiple oral doses of 5 to 20 mg/day was also evaluated in 
an open label study among children and adolescent patients (aged 7 to 17 years) with a 
DSM-IV-TR™ diagnosis of depressive or anxiety disorder. The purpose of this, open-label 
study was to assess the safety, tolerability, and pharmacokinetics of vortioxetine in children 
and adolescents with depressive or anxiety disorder and to provide supportive information for 
its dose regimen in paediatric efficacy and safety studies. In total 24 children and 24 
adolescents received vortioxetine. Based on the data from this study, no concerns were raised 
on the safety and tolerability profile of vortioxetine among paediatric patients with depression 
or anxiety. Vortioxetine was safe and well tolerated following 14 days of dosing as well as 
during an initial up-titration period. Overall, the adverse event profile in adolescents and 
children appeared similar to that of the adult population. Nausea, headache and sedation were 
the TEAEs with the overall highest incidence in this study. Nausea is also the most common 
TEAE in studies with adult patients, with an incidence of approximately 20 to 30% following 
5 to 20 mg vortioxetine. Other common TEAEs were sedation, abdominal pain upper, fatigue, 
and vomiting. There was no apparent relationship between dose and the incidence of these 
adverse events. 
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1.2
Rationale for the Study
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
As outlined in the EMA Assessment of the Paediatric Needs in psychiatry there is a 
therapeutic need in the paediatric population of depressed patients.13 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 in 
the treatment of children and adolescents with MDD,14,15 and escitalopram in the treatment of 
adolescents with MDD.16,17
Specific studies are necessary in the paediatric population and separate studies should 
generally be conducted in children and adolescents.18 This study is an extension study to 
Studies 12709A and 12710A and part of the agreed EMA Paediatric Investigational Plan 
(PIP) and the US Pediatric Written Request (PWR) for vortioxetine with the purpose to 
investigate the long-term safety and tolerability of vortioxetine in paediatric patients aged 
7-17 years. It is the expectation that this study will demonstrate a favourable safety and 
tolerability profile, and therefore a positive benefit-risk ratio for the use of vortioxetine in the 
paediatric population.
2
Objectives
Primary Objective
• Primary objective:
to evaluate the long-term safety and tolerability of vortioxetine in child and adolescent 
patients with a DSM-5™/diagnosis of MDD
Secondary Objectives
• Secondary objectives:
to evaluate the long-term effectiveness of flexible doses of vortioxetine in a range of 5 
mg/day to 20 mg/day on:

depressive symptoms

clinical global impression

cognitive function

functionality
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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 Helsinki.19
This is an interventional, multi-national, multi-site, open-label, flexible-dose, long-term 
extension study in child and adolescent patients with MDD who completed one of the double-
blind, placebo-controlled, active-reference Studies 12709A and 12710A.
This study will be conducted in compliance with the protocol, Good Clinical Practice, 20 and 
applicable regulatory requirements.
An overview of the study is presented in Panel 1.
The Baseline Visit of this extension study, hereafter referred to as Baseline Extension A, will 
be Visit 12 (Completion Visit) of lead-in Study 12709A or 12710A.
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 adjust the dose in 
case of unsatisfactory response up to 20 mg or 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-titrated to a new dose. Changes in dosing may occur at any site visit
during the treatment course at the investigator's discretion but the maximum dose may not 
exceed 20 mg/day.
The treatment period is 26 weeks. The total study duration per patient from Baseline 
Extension A to the end of follow-up will be approximately 30 weeks.
If possible, patients who withdraw are to be seen for a withdrawal visit as soon as possible 
and they will be contacted for a safety follow-up visit 4 weeks after withdrawal.
Investigators will not be informed about which treatment their patients received during the 
12709A or 12710A study at the time of enrolling them into this open-label extension study.
For ethical and equity reasons patients who turned 18 years during the lead-in study 12710A 
can be enrolled into this extension study.
Approximately 850 patients at approximately 120 sites from 12709A and 12710A are planned 
for enrolment.
An independent Data Monitoring Committee will be established in order to review the safety 
and tolerability data throughout this study. The same DMC will cover all the clinical studies 
in the pediatric vortioxetine program. 
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An internal safety committee at H. Lundbeck A/S has been set up for vortioxetine, who will 
perform regular evaluations of blinded safety data.
3.2
Rationale for the Study Design
The proposed study 12712A is an interventional, open-label, flexible-dose, long-term 
extension study with the primary objective to evaluate the long-term safety and tolerability of 
vortioxetine in children and adolescents with a DSM-5™ diagnosis of MDD who completed 
studies 12709A or 12710A. Secondary objectives are to evaluate the long-term effectiveness
of flexible doses of vortioxetine in a range of 5 mg/day to 20 mg/day on depressive 
symptoms, clinical global impression, cognitive function and functionality.
In the overall adult clinical development programme, treatment with vortioxetine at the 
therapeutic doses (5-20 mg/day) was safe and well tolerated. It has been suggested that a 
failure to conduct and use information from appropriately designed preliminary 
pharmacokinetic and dose-finding studies has contributed to the failure of several large scale 
antidepressant studies in the paediatric MDD population.21 The chosen doses of vortioxetine 
for this study are based on the knowledge from the clinical development programme in adult 
patients and from the paediatric pharmacokinetic and tolerability study performed in the 
paediatric population (aged 7 to 17 years) designed to guide the choice of doses to be used in 
the planned paediatric investigation plan.
The primary efficacy endpoint will be the CDRS-R total score. The CDRS-R22 is the most 
widely used rating scale in clinical trials for assessing severity of depression and change in 
depressive symptoms in children and adolescents with depression. The CDRS-R is based on 
the adult Hamilton Depression Rating Scale. The Psychometric analyses provide evidence 
that the CDRS-R is a valid measure of severity and improvement of depressive symptoms in 
paediatric patients. A score of ≥40 is indicative of depression, whereas a score ≤28 is often 
used to define remission (minimal or no symptoms). 
The CGI-S and CGI-I will be used for assessing disorder severity and improvement.23
The Behaviour Rating Inventory of Executive Function (BRIEF)24 will be used to assess 
cognitive function for the children aged 7-11 years and the BRIEF-SR will be used for the 
adolescents aged 12-18 years. The BRIEF was designed to be used for a range of childhood 
disorders to assess executive function behaviors in the school and home environments. 
Children’s Global Assessment Scale (CGAS) and the PedsQL Present Functioning Visual 
Analogue Scales (PedsQL™ VAS) will be used to assess functionality. Children and 
adolescents with MDD are at high risk of having severe difficulties in various domains of 
functioning and in quality of life.1,25 Both the BRIEF, CGAS and PedsQL™ VAS are 
validated scales appropriate for use in children and adolescents with psychiatric 
disorders.24,25,26
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4
Ethics
4.1
Ethical Rationale
Patients 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 the US, EU and a number of other countries for the treatment of MDE/MDD in 
the adult population. The evaluation of the safety and tolerability of vortioxetine is based on 
data from a large clinical development programme in adult and elderly patients. In the overall 
clinical development programme treatment with vortioxetine at the therapeutic doses 
(5-20 mg/day) was safe and well tolerated. The approved recommended dose range of 
5-20 mg/day for adults was evaluated in a pharmacokinetic and tolerability study performed 
in the paediatric population (aged 7 to 17 years) designed to guide the choice of doses to be 
used in the planned paediatric programme. Hence the chosen doses of vortioxetine (5, 10, 15,
and 20 mg/day) for this study is based on the results from the paediatric pharmacokinetic and 
tolerability study and the knowledge from the adult studies. 
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 childcare. The study personnel who interact with the 
patients will be experienced health care professionals (physicians with paediatric 
qualification, qualified paediatric nurses or psychologists) and their education, training and 
experience will be documented. Age-appropriate explanations will be given to the 
child/adolescent prior to any investigation or procedure, in order to decrease anxiety and 
anticipation of pain. Potentially painful procedures such as venepuncture will be minimised 
with the use of 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.
The investigator plays an important role in protecting the safety of the patient. The assessment 
of potential burden and risk is defined specifically in the clinical study protocol (safety rating 
scales, recording of adverse events, clinical safety laboratory tests [blood biochemistry, 
haematology, reproductive hormones and urine analysis], vital signs [blood pressure and 
pulse rate], weight, electrocardiogram and physical examination) and these will be evaluated 
by the investigator at each visit to ensure study the patients’ safety and well-being. If it does 
not remain in the patient’s best interest to stay in the study, the investigator will ensure that 
the patient is excluded. If the patient is not completing the study, a treatment will be offered
to the patient at the discretion of the investigator in line with clinical practice. 
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In accordance with Good Clinical Practice,20 qualified medical personnel at Lundbeck or a 
delegate will be readily available to advise on study-related medical questions. Medical 
monitoring will be performed throughout the study. Safety data will be reviewed regularly by
the Lundbeck Vortioxetine Safety Committee to ensure that prompt action is taken, if needed, 
to maximise patient safety.
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 both by rating scale The Columbia-Suicide 
Severity Rating Scale and/or by the investigator’s judgment. 
An independent Data Monitoring Committee will be established in order to review the safety 
and tolerability data throughout this study. The same DMC will cover all the clinical studies 
in the pediatric vortioxetine program. 
In accordance with Good Clinical Practice,20 the investigator will be responsible for all study-
related medical decisions.
4.2
Informed Assent/Consent
No study-related procedures may be performed before the investigator has obtained written 
assent from the patient and written informed consent from his or her parents/legal 
representative, or written informed assent/consent from the patient (if applicable).
Minors are dependent on their legal representative(s) (typically their parent[s]) to assume 
responsibility for their participation in clinical studies.27
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/or their legal representatives (if applicable) the aims, methods, and 
potential hazards of the study and any discomfort it may entail. The patients and their legal 
representatives (if applicable) 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. The patients and their legal representatives (if applicable) must be informed of 
the possibility of withdrawing assent/consent (section 8.3).
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The patients and their legal representatives (if applicable) 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 legal representatives. Prior to including a 
patient in the study, an Informed Assent Form must be signed and dated by the patient and an 
Informed Consent Form signed by his or her parent and/or legal representative and signed and 
dated by the investigator or a designee. The patients and their legal representatives must
receive a copy of the written information (Patient Information Sheet) as well as a copy of the 
signed Informed Assent/Consent Forms.
The consent procedures described above will only be implemented if allowed by local law 
and regulations and will only be initiated after approval by the relevant ethics committees.
4.3
Personal Data Protection
In accordance with European Union Directive 95/46/EC,28 the data will be processed in 
accordance with the specifications outlined by the Danish Data Protection Agency to ensure 
that requirements regarding personal data protection are met. If an external organisation will 
process data on behalf of Lundbeck, a contractual procedure will be signed between 
Lundbeck and the external organisation to ensure compliance with the above-mentioned 
legislation.
If applicable, the participation of patients in this study will be reported to the appropriate local 
data protection agencies, in accordance with European Union Directive 95/46/EC and 
country-specific guidelines and laws.
4.4
Independent Ethics Committees (IECs) and Institutional Review Boards (IRBs)
This study will be conducted only after approval of the protocol has been granted by the 
appropriate IEC or IRB and a copy of the written approval has been received by Lundbeck.
The investigator must not include any patients before receiving written approval from the IEC 
or IRB.
The IEC or IRB must be informed when specific types of protocol amendments have been 
made and must be asked whether a re-evaluation of the ethical aspects of the study is 
necessary.
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.
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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.
5
Study Population
5.1
Numbers of Patients and Sites
Planned countries and regions:
A global study with patients from the US, EU and other geographic regions 
Planned number of patients:
to be enrolled (approximately):
850
Planned number of:
study sites (approximately):
120
5.2
Selection Criteria
Patients will be recruited among those who complete treatment in Study 12709A or 12710A. 
Patient selection is based on the inclusion and exclusion criteria listed below. 
Patients who meet each of the inclusion criteria and none of the exclusion criteria at the 
Baseline Extension A Visit of this extension study are eligible to participate in this study.  
However, the sponsor reserves the right to utilise quality oversight methods to determine 
appropriateness of patient enrolment into the study.  
Inclusion Criteria
1.
The patient is a male or female child aged ≥7 and <12 years or adolescent aged ≥12 and 
≤18 years at Baseline Extension A.
2.
For patients aged ≥7 and ≤17 years at the Baseline Extension A visit; the patient is able to 
understand the Informed Assent Form, and parent(s)/legal representative(s)/ are able to 
read and understand the Informed Consent Form. 
3.
For patients aged ≥7 and ≤17 years at the Baseline Extension A visit; The patient has 
provided a new assent to participation (signed the new informed assent form) and 
parent(s)/legal representative(s) signed the new Informed Consent Form which are 
separate from the informed assent/consent obtained from patient and parent(s)/legal 
representative(s) for Study 12709A or 12710A.
4.
For patients aged 18 at the Baseline Extension A visit; the patient is able to read and 
understand the Informed Consent Form. 
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5.
For patients who turned 18 years during the lead-in study 12710A; the patient has signed 
the Informed Consent Form.  
6.
The patient and parent(s)/ legal representative(s) are willing and able to attend study 
appointments within the specified time windows. For patients who turned 18 years during 
the lead-in study 12710A; the patient is willing and able to attend study appointments 
within the specified time windows.  
7.
The patient must have completed Study 12709A or 12710A (Visit 12, Completion Visit) 
immediately prior to enrolment into this extension study.
8.
The patient had a primary diagnosis of a Major Depressive Disorder (MDD) at entry in 
Study 12709A or 12710A, diagnosed according to DSM-5™.
9.
The patient is indicated for long-term treatment with vortioxetine according to the clinical 
opinion of the investigator.
10. The patient, if a female of childbearing potential (defined as girls aged ≥10 years old and 
younger girls who, at the discretion of the investigator, are deemed to be of reproductive 
potential) and sexually active, must:

use adequate, highly effective contraception (defined as those that result in a low fail-
ure rate [that is, <1% per year] when used consistently and correctly, for example, 
implants, injectables, combined oral contraceptives in combination with a double bar-
rier method, some intrauterine devices, sexual abstinence, vasectomised partner); this 
should be used from the Screening Visit of the lead in study 12709A or 12710A to 
30 days after the last dose of IMP.
11. The patient, if a male patient and sexually active, must:

use two methods of contraception in combination if his female partner is of childbear-
ing potential; this combination of contraceptive methods must be used from the 
Screening Visit of the lead in study 12709A or 12710A to 30 days after the last dose 
of IMP, OR

if applicable have been surgically sterilised prior to the Baseline Extension A Visit.
Exclusion Criteria
1.
The patient has been diagnosed with another psychiatric disorder (for example mania, 
bipolar disorder, schizophrenia or any psychotic disorder) during study 12709A or 
12710A.
2.
The patient has an attention-deficit/hyperactivity disorder (ADHD) that requires a 
pharmacological treatment other than a stimulant medication.
3.
The patient has, moderate or severe on-going adverse event, related to study medication 
in Study 12709A or 12710A considered a potential safety risk by the investigator.
4.
The patient has previously been enrolled in this study.
5.
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.
6.
The patient is under forced treatment.
7.
The patient is pregnant or breast-feeding.
8.
The patient has a history of severe drug allergy or hypersensitivity, or known 
hypersensitivity to any of the IMP(s) or their excipients.
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9.
The patient has hereditary problems of fructose intolerance, glucose-galactose 
malabsorption, or sucrose-isomaltase insufficiency.
10. The patient has a current diagnosis or history of substance dependence (excluding 
nicotine, and caffeine) or alcohol dependence (DSM-5™ criteria) <6 months prior to the 
Baseline Visit of the lead in study 12709A or 12710A.
11. The patient has reported current use of, or at the discretion of the investigator has tested 
positive for drugs of abuse (opiates, cocaine, amphetamines [including ecstasy], 
barbiturates, benzodiazepines, and cannabinoids) at the Baseline Extension A visit. If a 
patient tests positive for amphetamines due to his/her ADHD current treatment, as 
confirmed by a clinical interview, the patient is eligible for the study.
12. The patient suffers from intellectual disability, organic mental disorders, or mental 
disorders due to a general medical condition (DSM-5™ criteria). 
13. The patient has a known intellectual disability (as suggested by an IQ <70), or, clinical 
evidence or known social or school history indicative of intellectual disability.
14. 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.
15. 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.
16. The patient has a known first degree relative with a history of Bipolar Disorder.
17. The patient is unable to swallow tablets.
18. The patient has a history of cancer that has not been in remission for >5 years prior to the 
first dose of IMP.
19. The patient has or has had one or more of the following conditions diagnosed during 
Study 12709A or 12710A 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

bradycardia (pulse <50 bpm)

respiratory disease

hepatic impairment or renal insufficiency

metabolic disorder

endocrinological disorder

gastrointestinal disorder

haematological disorder

infectious disorder

any clinically significant immunological condition
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
dermatological disorder

congenital or juvenile glaucoma or is at risk of acute narrow-angle glaucoma
20. The patient takes or has taken disallowed recent or concomitant medication (specified in 
Appendix II or it is anticipated that the patient will require treatment with at least one of 
the disallowed concomitant medications during the study. 
21. The patient has clinically significant abnormal vital signs at the Completion Visit 
(Visit 12) of Study 12709A or 12710A and considered a potential safety risk by the 
investigator.
22. The patient has one or more clinical laboratory test values outside the reference range, 
based on the latest blood and urine sample results in the lead-in study, that are of 
potential risk to the patient’s safety, or the patient has, according to the latest blood 
sample:

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
23. The patient has an abnormal thyroid stimulating hormone (TSH) level based on the latest 
blood sample results in the lead-in study. Patients with thyroid disease may be enrolled in 
the study provided they are stable and euthyroid.
24. The patient has, at the Completion Visit (Visit 12) of Study 12709A or 12710A:

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)
25. 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.
26. The patient is, in the investigator’s opinion, unlikely to comply with the protocol or is 
unsuitable for any reason.
27. The patient has in the investigator’s clinical judgement  a significant risk of suicide OR 

answers “yes” to the C-SSRS suicidal ideation questions 4 or 5 OR 

answers “yes” to suicidal behaviour on the C-SSRS within the last 12 months)
28. The patient receives on-going current psychotherapy that is planned to be intensified.  
Interpersonal psychotherapy (IPT) or cognitive behavioural therapies (CBT) are not 
allowed.
5.3
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 8.4 states how the patient’s data will 
be handled
• 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
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• 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
• the 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 a patient may be 
postponed until a repeat ECG is taken, if it is taken within 24 hours 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])
• the patient and his or her parent(s)/legal representative(s) fails to comply with study 
procedures
• 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)
Patients who withdraw will not be replaced.
6
Investigational Medicinal Products
6.1
Treatment Regimen
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
adjust the dose in case of unsatisfactory response or 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-titrated to a new dose.
Changes in dosing may occur at any site visit during the treatment course at the investigator's 
discretion but the maximum dose may not exceed 20 mg/day. At telephone visits the patient 
and/or legal representative can request an unscheduled site visit to discuss their current dose.
The treatment period is 26 weeks. The total study duration per patient from Baseline 
Extension A to the end of follow-up will be approximately 30 weeks.
The tablets should be taken orally once daily, preferably in the morning.
Panel 3
Dose Titration Schedules
Visit
IMP
1
Up-titration
2-12
Maintenance*
*IMP dose may be changed
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6.2
IMPs, Formulations, and Strengths
The IMPs supplied by Lundbeck in this study are:
• Vortioxetine : 5 mg, 10 mg, 15 mg and 20 mg tablets.
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.
The IMPs will be provided in wallet cards.
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 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 the Department of Clinical Supply, H. Lundbeck A/S, and, where necessary, new 
QP releases are made.
The IMPs will be identified using a unique IMP 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
The patients’ screening numbers from the lead-in studies will be used to identify them in the 
extension study.
An interactive voice/web response system (IVRS/IWRS) will be used to dispense IMP to 
patients.
6.5
IMP Accountability
The IMP is tracked in IVRS.

IMP shipped to site (and returned)

IMP allocated to patients and returned by patient
Paper log

A patient-specific paper log for IMP tear off label to document the kit dispensed to 
patient at dispensing visits
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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 IMP (confirmation email 
from IVRS system). This record must be available for inspection at any time.
6.6
Post-study Access to IMP
Post-study access to the IMP 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 IMP that is taken during the study.
The concomitant medications that are disallowed or allowed with restrictions during the study 
are summarised in Appendix II.
Details of all concomitant medication (prescription and over-the-counter) taken at the time of 
the Final Visit in studies 12709A or 12710A must be recorded in the 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 dose has 
changed due to a new disorder or worsening of a concurrent disorder, the disorder must be 
recorded as an adverse event.
Concomitant medication initiated after the last dose of IMP must only be recorded if 
associated with an 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. 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
Baseline Extension A Visit (Visit 1)
The Baseline Extension A Visit (Visit 1) is the Final Visit (Visit 12) of study 12709A or 
12710A. Assessments are described in Panel 2.
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8.2.1
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.
The patient identification card should be returned to the investigator upon completion of the 
patient’s participation in the study.
8.3
Visits 4, 6, 8, 10 and 12
Visits 4, 6, 8, 10 and 12 are a telephone contacts where following assessments and 
procedures will be conducted - Adverse events, PAERS, C-SSRS, recent and concomitant 
medication. The patient and/or legal representative and/or the investigator can during the 
telephone contact request an unscheduled site visit to discuss their current dose. During such 
an unscheduled site visit, the CDRS-R, CGI-S, CGI-I, PAERS and C-SSRS must be 
performed.    
8.4
Withdrawal Visit
Patients who withdraw from the study prior to the Completion Visit will be asked to attend a 
Withdrawal Visit, if at all possible. The visit must be scheduled as soon as possible after 
withdrawal.
No new information will be collected from patients who withdraw, 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 on the Reason for Withdrawal Form.
For a patient and/or his or her legal representative (if applicable) who withdraw 
assent/consent:
• if the patient and/or his or her legal representative (if applicable) withdraw assent/consent 
during a visit and then agrees 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 this visit will be 
used
• if the patient and/or his or her legal representative (if applicable) withdraw assent/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 this 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 record
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• if the patient and/or his or her legal representative (if applicable) explicitly request that his 
or her data collected from the time of withdrawal of assent/consent onwards not be used, 
this will be respected
8.5
Safety Follow-up Visit/Contact (Visit 14)
The safety follow-up is conducted to capture serious adverse events (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. The safety follow-up may either be conducted as a visit to 
the site or as a telephone contact. The safety follow-up must be conducted approximately 30 
days after the last dose of IMP.
If any new SAEs have occurred since the last assessment at which the patient received IMP, 
the safety follow-up must, when possible, be a visit to the site.
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 stop date must be recorded as “ongoing”. 
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 or 
Withdrawal Visit and judged clinically significant must be followed according to accepted 
medical standards for up to 30 days or until the value normalises or stabilises 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 5.3) should be 
followed until the values normalise or stabilise or a diagnosis or a reasonable explanation has 
been established (see section 10.5).
The safety follow-up for patients who withdraw assent/consent must be performed, if at all 
possible; any information collected will be recorded in the patients’ medical records.
8.6
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.
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9
Assessments
Timing and frequency of all assessments are specified in Panel 2.
Lundbeck reserves the right to use external quality oversight methods of all study assessment 
tools to ensure the validity of the diagnosis and severity of illness.
9.1
Baseline Extension A Procedures and Assessments
9.1.1
Demographics and Other Baseline Characteristics
Prior to enrolling a patient in the study, the investigator must ascertain that the patient meets 
the selection criteria.
The following data from the Ongoing Logs in the lead-in study (12709A or 12710A) must be
entered by site staff into the eCRF’s of the Baseline Extension A.
• Ongoing Adverse Advents
• Ongoing Recent and concomitant medications
All other study related data can be found in the eCRFs of the lead-in studies.
Latest laboratory and ECG results available from the lead-in studies will be used for 
eligibility assessment.
9.1.2
Drug and Alcohol Screen
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.
If a patient tests positive for amphetamines due to his/her ADHD current treatment, as 
confirmed by a clinical interview, the patient can continue in the study. Patients may continue 
in the study if they have a positive blood alcohol result or have tested positive for opiates due 
to incidental use of codeine-containing medication, as assessed in a clinical interview, but 
only after consultation and approval by the medical monitor. Patients whose urine drug screen 
is positive for cocaine or other illicit drugs should be considered for withdrawal from the 
study after consultation and approval with the medical monitor.
Urine drug and blood alcohol screening kits will be supplied by a central laboratory.
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9.2
Efficacy Assessments
9.2.1
Clinician-rated Scales
9.2.1.1
Use of Clinician-rated Scales
The following assessment tools will be used:
• CDRS-R – assessing depressive symptoms
• CGI – assessing global impression
• CGAS – assessing functionality
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 and CGAS 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 CGI will be administered in English.
9.2.1.2
Children Depression Rating Scale Revised Version (CDRS-R) 
The CDRS-R22 is a clinician-rated scale to measure the severity of depression of children and 
adolescents. The CDRS-R consists of 17 items: 14 items rate verbal observations, and three 
items rate nonverbal observations (tempo of language, hypoactivity, and nonverbal expression 
of depressed affect). Depression symptoms are rated on a 5-point scale from 1 to 5 for the 
verbal observations, and a 7-point scale from 1 to 7 for the nonverbal observations. 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 CGI23 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).
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The CGI-I provides the clinician’s impression of the patient’s improvement (or worsening)
from Baseline A in the lead-in studies. The clinician assesses the patient’s condition relative 
to a baseline on a 7-point scale ranging from 1 (very much improved) to 7 (very much worse). 
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
Children’s Global Assessment Scale (CGAS)
The CGAS29 is a clinician-rated global scale to measure the lowest level of functioning for a 
child (4 to 16 years) during a specified time period. The CGAS contains behaviourally-
oriented descriptors at each anchor point that depict behaviours and life situations applicable 
to a child. The items range in value from 1 (most functionally impaired child) to 100 (the 
healthiest). A total score above 70 indicates normal function. The CGAS can be administered 
by a clinician after a training session. It takes approximately 2 minutes to administer CGAS.
9.2.1.5
CDRS-R, CGI, CGAS Rater Qualification and Certification
The CDRS-R, CGI and CGAS 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 should be administered by the investigator responsible for the patient. The 
investigator must be psychiatrists or DO specialised in child and adolescent psychiatry that 
has adequate experience with paediatric patients with MDD. 
Any exceptions must be discussed and approved by Lundbeck. 
Only raters who have been already trained and certified in Study 12709A or Study 12710A 
are allowed to rate the patients in Study 12712A. The certificate(s) issued during Study 
12709A or Study 12710A cover the extension study and no additional certificate will be 
issued.
New raters joining Study 12712A will be trained and certified using the same certification 
processes as in Study 12709A and Study 12710A. Documentation of training and certification 
will be delivered to the raters for arching in the investigator trial master file (TMF). No 
patient may be rated before the documentation has been delivered.
For each individual patient, the same certified rater should rate the patient, and preferably the 
same as in Study 12709A or Study 12710A study. For unforeseen circumstances, certified 
back-up raters should be available throughout the study.
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9.2.2
Patient and/or Parent Reported Outcomes (PROs)
9.2.2.1
Use of PROs
The following PRO will be used:
• BRIEF – Assessing cognitive function
• PedsQL VAS – assessing functionality
9.2.2.1.1
Behavioural Rating Inventory of Executive Function® (BRIEF®)
The BRIEF30 is a patient and carer-rated scale designed to measure executive function 
behaviour in children and adolescents in an everyday environment. We use BRIEF (parent 
form) for the children aged 7 to 11 years and BRIEF-SR (self-report) for the adolescents aged 
12 to 18 years. Both versions of the BRIEF contain 86 items. Items are rated on a 3-point 
scale, from N (never) to O (often).  These items cover 8 non-overlapping clinical scales: 3 
scales in the Behavioural Regulation Index (inhibit, shift and emotional control), and 5 scales 
in the Metacognition Index (initiate, working memory, plan/organize, organisation of 
materials, and monitor).  The clinical scales also provide the Global Executive Composite 
score, which represents the child’s overall executive function behaviour. There are 2 validity 
scales: negativity and inconsistency. It takes approximately 30 minutes to complete and score 
the BRIEF.
9.2.2.1.2
PedsQL Present Functioning Visual Analogue Scales (PedsQL™ VAS)
The PedsQL™ VAS31 is designed to measure at-that-moment functioning in children and 
adolescents. The PedsQL VAS consists of 6 domains: anxiety, sadness, anger, worry, fatigue 
and pain using visual analogue scales. The functionality for each domain is measured on a 10 
cm line with a happy face at one end and a sad face at the other. The patients are asked to 
mark on the line how they feel. The total score is the average of all 6 items, and the emotional 
distress summary score is the mean of the anxiety, sadness, anger, and worry items. It takes 2 
to 5 minutes to administer and rate the PedsQL VAS.
9.3
Blood Sampling for Vortioxetine Quantification
Blood samples (2 x 1 mL) for IMP analysis will be collected in EDTA tubes simultaneously 
with clinical safety lab samples. The blood sampling and handling procedures are described in 
the study-specific Laboratory Specification Manual.
The blood samples will be analysed for vortioxetine using a method validated in accordance 
with the EMA Guideline on Bioanalytical Method Validation32 and the FDA Guidance for 
Industry.33 A bioanalytical protocol will be prepared by Lundbeck before the plasma samples 
are analysed.
The results of the bioassay will be given will be given in the bioanalytical study report that 
will be prepared by the Department of Bioanalysis, H. Lundbeck A/S.
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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 Baseline Extension A Visit. 
Adverse events (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 the adverse 
event 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 adverse events if considered by the investigator to be clinically 
significant.
See chapter 10 for further information on adverse events.
9.4.2
Clinical Safety Laboratory Tests
The clinical safety laboratory tests are listed in Panel 4.
Results of safety laboratory tests for Visit 12 (Completion Visit) of the lead-in studies 
12709A or 12710A will be transcribed to Visit 1 (Baseline Extension A) of 12712A study 
(i.e. these tests should not be collected at Visit 1).  However, the Hormones laboratory tests 
are specific for the 12712A study and will be collected at the 12712A Visit 1 using a separate 
kit.
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Panel 4
Clinical Safety Laboratory Tests
Haematology
Electrolytesa
Urineb
B-haemoglobin
S-sodium
U-protein (dipstick)
B-erythrocyte count
S-potassium
U-glucose (dipstick)
B-haematocrit
S-calcium (total)
U-blood (dipstick)
B-total leucocyte count
Endocrine and Metabolica
U-ketones (dipstick)
B-neutrophils (% of total leucocytes)
S-albumin
Pregnancyd (women only)
B-eosinophils (% of total leucocytes)
S-glucose (non fasting)
U-hCG
B-basophils (% of total leucocytes)
Kidneya
B-hCG
B-lymphocytes (% of total leucocytes)
S-creatinine
Urine Drug Screene
B-monocytes (% of total leucocytes)
S-urea nitrogen (BUN)  
U-amphetamines (incl. 
methamphetamine)
B-thrombocyte count
Hormones 
U-barbiturates
Livera
S-estradiol (girls)
U-benzodiazepines
S-total bilirubin
S-total testosterone  (boys)
U-cannabinoids
S-conjugated bilirubin
S-LH
U-cocaine
S-alkaline phosphatase (AP)
S-FSH
U-opiates
S-alanine aminotransferase (ALT)
S-LHRH
U-phencyclidine
S-aspartate aminotransferase (AST)
S-prolactin
Blood Alcohol Screene
S-lactate dehydrogenase (LDH)
S-TSHc
B-ethanol
S-γ-glutamyl transferase (γGT)
Infection
Lipidsa
S-C-reactive protein (CRP)
S-cholesterol (total) (non fasting)
Serologyc
S-triglycerides (non fasting)
B-HBsAg
S-low density lipoprotein (LDL)
B-anti HCV
S-high density lipoprotein (HDL)
B – blood; P – plasma; S – serum; U – urine 
a.
Clinical chemistry
b.
Microscopic examination (leucocytes, erythrocytes, and casts) will be performed only if any of the 
urine evaluations are abnormal.
c.
TSH and hepatitis B and C panels are optional and may be performed at the investigator’s discretion if 
there is clinical justification.
d.
Females >10 years of age or female patients at lower age judged by the investigator to be of 
childbearing potential. Additional pregnancy tests during the study will be performed according to 
local requirements. Females under 11 years will be tested with a urine hCG test and females over 11 
years will be tested with using a blood hCG test.
e.
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. 
Blood samples for the clinical safety laboratory tests will be collected as outlined in Panel 2.
The blood sampling and handling procedures are described in the study-specific Laboratory 
Specification Manual.
The blood and urine drug screen samples will be analysed at the central laboratory.
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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.
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 stabilised or until the value has 
returned to a clinically acceptable value (regardless of relationship to IMP). Any value that is 
out-of-range at the Completion or Withdrawal Visit and judged clinically significant must be 
followed according to accepted medical standards for up to 30 days or until the value 
normalises or stabilises 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 record.
Clinically significant out-of-range values must be recorded as an adverse event 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
Blood pressure (BP) and pulse rate will be measured using a standard digital meter 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.
Vital signs should be assessed prior to blood sampling.
Abnormalities of clinical significance must be recorded as an adverse event on an Adverse 
Event Form.
9.4.4
Height and Weight
Height will be measured with a stadiometer, without shoes.
Patients will be weighed wearing light clothing and no shoes. A similar amount of clothing 
must be worn on each occasion.
Abnormalities of clinical significance must be recorded as an adverse event on an Adverse 
Event Form.
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9.4.5
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
9.4.6
Tanner Staging
Tanner staging is a scale for assessing physical development and sexual maturity during onset 
and progress of puberty.
The scale includes five stages of pubertal changes (called Tanner stages) separate for males 
and for females.
For females, the 5 stages of maturation are recognized by assessing pubic hair and breast 
development. For males, 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. 
The evaluation of Tanner stage will be performed by a physician or trained nurse; they will be 
provided with figures depicting the somatic changes and tables describing these changes in 
words to facilitate the staging.
9.4.7
Electrocardiograms (ECGs)
A standard 12-lead electronic ECG (eECG) will be performed 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, and the 
results from the central ECG laboratory will include the RR, PR, QRS, QT, and QTc 
intervals.
The investigator will, during the study be provided with the results and a cardiological 
interpretation of the ECG performed by a paediatric cardiologist from the central ECG 
laboratory.
The investigator has the final decision on the clinical significance of the ECG evaluation.
Abnormalities of clinical significance must be recorded as an adverse event on an Adverse 
Event Form.
9.4.8
Physical and Neurological 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 
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musculoskeletal system. 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.
The neurological examination must be performed by a physician.
Abnormalities of clinical significance must be recorded as an adverse event on an Adverse 
Event Form.
9.4.9
Assessment Tools
9.4.10
Paediatric Adverse Event Rating Scale (PAERS)
The PAERS34 is a clinician-rated scale designed and validated to assess adverse events 
occurring in paediatric patients who are treated with psychotropic medication in clinical 
studies.  
The PAERS consists of 45 items: 43 specific signs and symptoms and two to be specified. 
Each item specifies if the adverse event was present recently, if it was resolved (No, Yes), 
related to drug (No, Study drug, Other drug, Drug-drug interaction), its severity (Mild, 
Moderate, Severe, Extreme) and if it impaired function (No, Yes).
The PAERS can be administered by a clinician after a short training session. It takes 
approximately 10 minutes to administer and score the PAERS.
The PAERS must be applied after the non-leading, open questions on any adverse events (see 
section 9.4.1). As this recording of adverse events should precede the use of the PAERS, the 
numbers of adverse events captured by these two methods potentially differ.
9.4.10.1
Columbia-Suicide Severity Rating Scale
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. 
In this study, the “Since last visit” version will be applied. 
An age-appropriate version of the C-SSRS will be used.
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.
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9.4.11
Rater Qualification and Certification
The PAERS and 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 already trained and certified in Study 12709A or  Study 12710A 
are allowed to rate the patients in Study 12712A. The certificate(s) issued during Study 
12709A or Study 12710A cover the extension study and no additional certificate will be 
issued.
New raters joining Study 12712A will be trained and certified using the same certification 
processes as in Study 12709A and Study 12710A. Documentation of training and certification 
will be delivered to the raters for arching in the investigator trial master file (TMF). No 
patient may be rated before the documentation has been delivered.
For each individual patient, the same certified rater should rate the patient, and preferably the 
same as in Study 12709A or Study 12710A study. For unforeseen circumstances, certified 
back-up raters should be available throughout the study.
An electronic version of the PAERS and C-SSRS will be used in this study.
9.5
Order of Assessments
The scales should preferably be administered in the following order:
• CDRS-R
• CGAS
• BRIEF (7-11 years), BRIEF-SR (12-18 years), PedsQL VAS (PRO)
• PAERS
• C-SSRS
• CGI-S, CGI-I
The PAERS must be applied after the non-leading, open questions on any adverse events.
9.6
Total Volume of Blood Drawn and Destruction of Biological Material
The volume of blood drawn from each patient will be approximately 13 ml at the required
study visits. 
Safety blood test drawn at the Visit 12 of the lead-in Study 12709A or 12710A will be used as 
the safety blood test for Baseline Extension A Visit (excluding the additional Hormones panel 
of approximately 5 ml).  Hence, the total volume of the blood drawn for the entire study is 
approximately 31 ml.
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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.
10 Adverse Events
10.1
Definitions
10.1.1
Adverse Event Definitions36
Adverse event – is any untoward medical occurrence in a 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.
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 hospitalisation or prolongation of existing hospitalisation
• 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 hospitalisation, but may jeopardise 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 hospitalisation; or development of drug 
dependency or drug abuse.
Planned hospitalisations 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 
SAEs. Emergency room visits that do not result in admission to the hospital are not 
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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).
The C-SSRS has 5 questions addressing suicidal ideation. If level 4 or 5 has been answered 
“yes”, a corresponding SAE should be reported.
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 adverse event meets the definition of an SAE, a 
conservative viewpoint must be taken, and the adverse event must be reported as an SAE.
Suspected unexpected serious adverse reaction (SUSAR) – is any adverse event that is 
assessed as serious, unexpected (its nature or intensity is not consistent with the current 
version of the Investigator’s Brochure for vortioxetine),11 and related to an investigational 
product by either the investigator or the sponsor.  
Overdose – is a dose taken by a patient that exceeds the dose prescribed to that patient. Any 
overdose (and associated symptoms) must, at a minimum, be recorded as a non-serious 
adverse event.
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.
• 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 his 
or her normal activities.
Assessment of Causality
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.
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• Not related – the adverse event has no temporal relationship to the IMP or is due to 
underlying/concurrent illness 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 considered an SAE. If, however, the pregnancy is 
associated with an SAE, the appropriate serious criterion (for example, hospitalisation) must 
be indicated on the Serious Adverse Event Form. 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 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 IMP; action taken; and outcome. 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.
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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 (section 10.4).
Adverse events, including clinically significant out-of-range clinical safety laboratory test
values and findings from for example, ECGs, must be recorded individually, except when 
considered manifestations of the same medical condition or disease state; in such cases, they 
must be recorded under a single diagnosis.
10.4
Reporting Serious Adverse Events
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 report 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:
Pharmacovigilance (PV)
Fax: 
e-mail: 
Lundbeck will assume responsibility for reporting SAEs to the authorities in accordance with 
local regulations.
It is the investigator’s responsibility to be familiar with local requirements regarding reporting 
SAEs to the IEC or IRB and to act accordingly.
Lundbeck will assume responsibility for reporting SUSARs to the authorities in accordance 
with local regulations. 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 ethics committees.
Lundbeck will assess the expectedness of SAEs and inform the investigator(s) about 
SUSARs, at a minimum, in the 6-monthly, blinded SUSAR listings. CIOMS-I reports for 
SUSARS are not normally distributed to investigators in those countries where SUSAR 
listings are sufficient. However, if the CIOMS-I reports are required (for example, by the 
local EC/IRB/REB), they will be sent to the investigator.
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.
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Non-serious adverse events must be followed up until resolution or the safety follow-up 
assessment, whichever comes first. At the safety follow-up, information on new SAEs, if any, 
and stop dates for previously reported adverse events must be recorded.
It is the responsibility of the investigator to follow up on all SAEs until the patient has 
recovered, stabilised, or recovered with sequelae, and to report to Lundbeck all relevant new 
information using the same procedures and timelines as those for the initial report. Relevant 
information includes discharge summaries, autopsy reports, and medical consultations.
SAEs that are spontaneously reported by a patient to the investigator after the safety follow-
up assessment must be handled in the same manner as SAEs that occur during the study. 
These SAEs will be captured in the GPV database.
Patients with clinically significant out-of-range clinical safety laboratory test values at the 
Completion or Withdrawal Visit must be followed in accordance with usual clinical practice 
and be scheduled for a Safety Follow-up Visit to allow for a medical examination and/or 
blood sampling (see section 8.5).
Patients who withdraw due to elevated AST or ALT values (see section 5.3) must be followed 
until the values normalise or stabilise or a diagnosis or a reasonable explanation has been 
established. Additional medical examinations (for example, ultrasound scanning and/or 
sampling for serology, conjugated bilirubin, INR) should be considered. A gastroenterology 
or hepatology consultation should also be considered.
10.5.1
Data Monitoring Committee
The Data Monitoring Committee (DMC) includes child and adolescent psychiatrists. The 
DMC ensures that the ethical principles are observed and monitors the safety of the patients. 
The DMC will be informed to what extent the data and analyses provided to them have been 
quality controlled. Members of the DMC will not be involved in other study-related tasks. 
The details of 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 11.1.3.
The eCRFs use third party software (Rave®) to capture data via an on-line system on a 
computer. Data related to the study 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. 
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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 CRA. All entries, corrections, and changes must 
be made by the investigator or a delegate.
11.1.2
Patient Binders
11.1.2.1
Use of Patient Binders
Lundbeck will provide a Patient Binder for each patient.  The Patient Binder contains
different types of source documents, organised by visit and type. A ballpoint pen with 
waterproof ink must be used to enter information in the Patient Binder.
11.1.2.2
Rating Scales and Patient-reported Outcomes (PROs)
The Patient Binder contains paper versions of the rating scales and PROs. The rater(s) must 
verify that all the entries in the Scale Section are accurate and correct by signing and dating 
the relevant pages.
The patients will be asked to complete the PRO in their local language. The patient’s
responses may only be corrected by the patient.
11.1.2.3
Serious Adverse Event Fallback Forms
Serious Adverse Event Fallback Forms must be used when the eCRF cannot be accessed.
11.1.3
External Data
All electronic data will be transferred using a secure method accepted by Lundbeck.
The clinical safety laboratory test results will be transferred by the central laboratory.
The electronic data received from the following vendors will be kept in a secure designated 
storage area outside the eCRF:
• In case of any electronic Assessment(s) /PRO(s) the results will be transferred by 
designated vendor.
• The ECG results will be transferred by the central ECG laboratory.
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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. If a site closes after the study has been completed, the 
investigator will no longer have read access to the eCRF. Instead, each site will be provided 
with a CD-ROM containing the data related to the site (including eCRF data, queries, and the 
audit trail). As a CD-ROM is not considered a durable medium and may therefore not be 
readable for the full retention period (for example, 15 years [if required by the applicable 
regulatory requirements]), it is possible for the investigator to request a new CD-ROM with 
the data related to the site.
11.2.2
Other Study Documents
The investigator must keep the investigator’s set of documents in the investigator TMF for at 
least 15 years after the Clinical Study Report has been approved or in accordance with 
national requirements, whichever is longer.
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.
Lundbeck will notify the investigator in writing when the required storage period has expired 
and when the documents may be destroyed according to regulations.
12 Monitoring Procedures
Prior to including patients 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.
During the study, the 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, analyse, and verify any records and 
reports that are important for the evaluation of the study.
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In this study a Risk Based Monitoring approach will be applied.
13 Audits and Inspections
Authorised personnel from Global Clinical Quality Assurance at Lundbeck 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 patients must be informed that authorised personnel from Lundbeck may wish to review
their medical records. The investigator must be aware and the patients must be informed 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 copy relevant parts of medical 
records. No personal identification apart from the screening number will appear on these 
copies.
Patient data will not be disclosed to unauthorised third parties, and patient confidentiality will 
be maintained 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 deviations occur, the investigator must inform the CRA and they must review, discuss, and 
document the implications of the deviation.
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 other studies
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 
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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 analysis changes after the termination of the study, 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 Endpoints
16.1
Primary Endpoint
Safety:
• adverse events (AEs)
• tolerability including assessment based on PAERS
• Tanner score
• absolute values and changes from Baseline Extension A in clinical safety laboratory tests, 
vital signs, weight, height, and ECG parameters
• length of menstrual cycle
• potentially clinically significant clinical safety laboratory test values, vital signs, weight, 
and ECG parameter values relative to Baseline Extension A
• C-SSRS categorisation based on C-CASA definitions (1, 2, 3, 4, and 7)
16.2
Secondary Endpoints
Depressive symptoms:
• change from Baseline Extension A to Week 26 in CDRS-R total score
• time to first relapse (CDRS-R value of ≥40)
• time to first loss of remission (CDRS-R >28)
Global Clinical Impression:
• change from Baseline Extension A to Week 26 in CGI-S score
• CGI-I score at Week 26. The assessment of the CGI-I should be in reference to Baseline A 
in the lead-in studies.
Cognitive function:
Children (7-11 years)
• change from Baseline Extension A to Week 26 in BRIEF using the Global Executive 
Composite score 
• change from Baseline Extension A to Week 26 in BRIEF using the Metacognition Index 
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Adolescents (12-18 years)
• change from Baseline Extension A to Week 26 in BRIEF-SR using the Global Executive 
Composite score 
• change from Baseline Extension A to Week 26 in BRIEF-SR using the Metacognition 
Index
Functionality:
• change from Baseline Extension A to Week 26 in CGAS score
• change from Baseline Extension A to Week 26 in PedsQL VAS
17 Statistical Methodology
17.1
Responsibilities
The Department of Biostatistics, H. Lundbeck A/S will perform the statistical analyses 
described below.
17.2
Analysis Sets
The following analysis sets will be used to analyse and present the data:
• all-patients-treated set (APTS) – all patients who took at least one dose of vortioxetine in 
the extension study.
• full-analysis set (FAS) –all patients in the APTS with at least one valid post-Baseline 
Extension A assessment of the CDRS-R total score.
The safety analyses will be based on the APTS.
The efficacy analyses will be based on the FAS.
17.3
Descriptive Statistics
In general, summary statistics (n, arithmetic mean, standard deviation, median, minimum and 
maximum values) will be presented for continuous variables and counts and, if relevant,
percentages will be presented for categorical variables.
The data will be summarised for all patients, and by lead-in study and by lead-in treatment 
(lead-in Study 12709A and Study 12710A).
For some variables summaries will include data from the lead-in study. 
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17.4
Patient Disposition
Patient disposition will be summarised and include the number of patients who completed and 
the number of patients who withdrew from treatment, as well as the number of patients in 
each analysis set (APTS and FAS).
The number of patients who withdrew from treatment will be summarised by primary reason 
for withdrawal as well as by all reasons for withdrawal.
17.5
Demographics and Other Baseline Characteristics
Demographics (sex, age, race), other baseline (Baseline Extension A) characteristics (height, 
weight, BMI) for the extension study, and baseline efficacy variables for the extension study 
will be summarised.
17.6
Recent and Concomitant Medication
Recent and concomitant medication will be summarised by anatomical therapeutic chemical 
(ATC) code and generic drug name.
17.7
Exposure and Compliance
Exposure and compliance will be calculated per patient and summarised.
17.8
Efficacy Analyses
17.8.1
General Efficacy Analysis Methodology
Change from Baseline Extension A in CDRS-R, CGI-S, BRIEF, CGAS, and PedsQL VAS 
using descriptive statistics by lead-in study and by lead-in treatment.
CGI-I score at Week 26 using descriptive statistics by lead-in study and by lead-in treatment.
Time to first loss of remission and time to first relapse will be analysed using Kaplan-Meier 
estimates.
For exploratory use a random effects slope and intercept model will be applied using Mixed 
Model Repeated Measurements (MMRM) to study long-term development in efficacy 
parameters such as CDRS-R.
17.9
Pharmacokinetic Analyses
Sparse sampling (2 time points) for vortioxetine quantification will be performed. The 
population PK of vortioxetine will be assessed by means of nonlinear mixed effect modelling 
and the results from the analysis will be reported in a separate population PK report.
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17.10 Safety Analyses
17.10.1 Analysis of Adverse Events
Adverse events will be classified according to the time of onset of the adverse event:
• lead-in adverse event – an adverse event ongoing from lead-in study 12709A or study 
12710A and prior to the date of first dose of IMP in study 12712A
• treatment-emergent adverse event (TEAE) – an adverse event that starts or increases in 
intensity on or after the date of first dose of IMP in study 12712A. 
Adverse events, sorted by system organ class (SOC) and preferred term, will be summarised.
TEAEs may be allocated into study periods (these will be defined in the Statistical Analysis 
Plan).
The primary objective will be addressed with an overall clinical evaluation of the safety 
results.
17.10.2 Analyses of Safety Endpoints
Adverse events, PAERS items, Tanner scores, clinical safety laboratory tests, vital signs, 
height, weight, BMI, and ECG parameters will be summarised, and observed potentially 
clinically significant (PCS) safety laboratory test values will be flagged and summarised. 
Length of menstrual cycle and C-SSRS scores will be summarised using descriptive statistics.
For variables that are heavily dependent on sex and age (such as Tanner and menstrual cycle 
length) further exploratory descriptions will be made.
Analyses will be performed with respect to the baseline in lead-in study 12709A or 12710A 
and Baseline Extension A. 
For exploratory use a random effects slope and intercept model will be applied using Mixed 
Model Repeated Measurements (MMRM) to study long-term development in safety 
parameters such as weight.
17.11 Interim Analyses
No interim analyses for efficacy are planned. A DMC will monitor safety data at regular 
intervals to be specified in the Data Monitoring Committee Charter.
17.12 Sample Size and Power
No formal sample size calculation has been performed for the present study, which includes 
patients who have completed the studies 12709A or 12710A and are eligible for enrolment for 
this study. Sample size is based on an expected withdrawal of 15-20% of the 1200 patients 
randomised to the lead-in studies. A maximum of 85% of these lead-in completers are 
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expected to accept to continue into this extension study. This gives approximately 850 
patients.
17.13 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 the Department of Biostatistics, H. Lundbeck A/S.
18 Clinical Study Report and Publications
18.1
Clinical Study Report
Upon completion of the study, a Clinical Study Report will be prepared by the Department of 
Medical Writing, H. Lundbeck A/S.
18.2
Data Ownership
The data collected in this study are the property of H. Lundbeck A/S.
18.3
Publications
The results of this study will be submitted for publication.
The primary publication based on this study must be published before any secondary 
publications are submitted for publication.
Authors of the primary publication must fulfil the criteria defined by the International 
Committee of Medical Journal Editors (ICMJE).38
19 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.
20 Finance
20.1
Site Agreement
The financial agreements for the site are addressed in one or more documents.  Both parties 
must sign the agreements before the site is initiated.
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20.2
Financial Disclosure
All the investigators, including sub-investigators, and raters participating in the study must 
complete a Financial Disclosure Form in order to comply with the United States Food and 
Drug Administration (FDA) Financial Disclosure requirements.
20.3
Equipment
Equipment owned or rented by Lundbeck that has been provided to the site for use during the 
study must be returned at the end of the study.
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of scholarly work in medical journals. August 2013. 
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Appendix I
Clinical Study Protocol Authentication and Authorisation
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Clinical Study Protocol
Authentication and Authorisation
Study title:
Long-term, open-label, flexible-dose, extension study of vortioxetine in child
and adolescent patients with Major Depressive Disorder (MDD) from 7 to 18
years of age
Study No.:
12712A
Edition No.:
3.0
Date of edition:
16 January 2017
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, Biostatistics:
Divisional Director, GPV:
Authorisation
I hereby confirm that I am of the opinion that the ethical and scientific basis of this study is sound.
Director,
Clinical Research  - Paediatrics:
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Study Level
CLI_00919715
Final
1.0


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Page 65 of 67
Appendix II
Recent and Concomitant Medication:
Disallowed or Allowed with Restrictions
LU Study Number: 
 
Trial Site Number: 
 
Pluto ID: 
 
 
Status: 
 
Version: 
 
 
 
12712A
Study Level
CLI_00919715
Final
1.0


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Page 66 of 67
Recent and Concomitant Medication:
Disallowed or Allowed with Restrictions 
In the table below disallowed recent and concomitant medications are listed, including any 
restrictions with respect to their use prior to and during the study.
Drug Class
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)
X
X
Psychostimulant agents (e.g. methylphenidate 
and amphetamine), are allowed. 
Anaesthetics
General
X
X
General anaesthetics are disallowed during the 
study except in case of emergency procedures 
requiring anaesthesia
Local
X
Analgesics
Narcotic 
analgesics
X
X
NSAIDsa
X
Anorexics
X
X
Antiacne agents
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
X
X
Antidepressants
X
X
Monoamine oxidase inhibitors (MAOs) are 
contraindicated. 
Antidiarrhoeal agents
X
X
Only loperamide, bismuth and kaolin 
preparations are allowed 
Antihistamines
X
X
Only loratadine, desloratadine, cetirizine, 
levocetirizine, mizolastine and fexofenadine are 
allowed
Antimigraine agents – triptans, 
dopamine antagonists
X
X
Antinauseants (including dopamine 
antagonists)
X
X
Only phosphoric acid preparations, bismuth and 
cola syrup are allowed 
Antineoplastics
X
X
Antiobesity agents
X
X
Antiplatelet treatment (including 
low dose aspirin)
X
X
Antipsychotics
X
X
Anxiolytics
X
X
LU Study Number: 
 
Trial Site Number: 
 
Pluto ID: 
 
 
Status: 
 
Version: 
 
 
 
12712A
Study Level
CLI_00919715
Final
1.0


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Page 67 of 67
Drug Class
Disallowed (X) During the Study for
Chronic 
Use
Episodic 
Use
Comments or Exceptions
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 kava, valerian, ginkgo biloba)
X
X
Hormones
X
X
Only thyroid hormone replacement, 
contraceptives and progesterone replacement 
therapy are allowed.
Hypoglycaemic agents 
X
Insulin
X
Mood stabilisers (including lithium, 
valproate, valpromide)
X
X
Muscle relaxant
X
X
Psychotropic agents not otherwise 
specified (including,  tryptophan, 
and dopamine agonists)
X
X
Sedatives/hypnoticsb
X
X
Zolpidem, zopiclone or zaleplon allowed, for 
severe insomnia, with a maximum of 2 nights 
per week. 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 the Baseline Extension A Visit until Visit 13.
LU Study Number: 
 
Trial Site Number: 
 
Pluto ID: 
 
 
Status: 
 
Version: 
 
 
 
12712A
Study Level
CLI_00919715
Final
1.0

SAP_001.pdf: 
H. Lundbeck A/S
Confidential
Study 12712A – Statistical Analysis Plan
Page 1 of 39
Statistical Analysis Plan
Long-term, open-label, flexible-dose, extension study of 
vortioxetine in child and adolescent patients with Major 
Depressive Disorder (MDD) from 7 to 18 years of age
Vortioxetine
Study No.:
12712A
Sponsor:
H. Lundbeck A/S (Lundbeck)
2500 Valby (Copenhagen), Denmark
SAP date:
2 May 2022
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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Study 12712A – Statistical Analysis Plan
Page 2 of 39
Table of Contents
List of Abbreviations and Definitions of Terms...............................................................................6
1
Objectives .................................................................................................................................7
1.1
Primary Objective...........................................................................................................7
1.2
Secondary Objectives......................................................................................................7
2
Study Design.............................................................................................................................7
3
Endpoints..................................................................................................................................8
3.1
Primary Endpoint............................................................................................................8
3.2
Secondary Endpoints.......................................................................................................9
4
Analysis Sets .............................................................................................................................9
5
Descriptive Statistics...............................................................................................................10
6
Patient Disposition..................................................................................................................10
6.1
Summary of Patient Disposition ....................................................................................10
6.2
Withdrawals..................................................................................................................10
7
Demographics and Baseline Characteristics..........................................................................11
8
Recent and Concomitant Medication.....................................................................................11
9
Exposure and Compliance......................................................................................................11
10
Efficacy ...................................................................................................................................12
10.1
Overview of Planned Efficacy Analyses........................................................................12
10.2
General Efficacy Analysis Methodology .......................................................................13
10.3
Analysis Methodology for the Secondary Endpoints......................................................13
10.3.1
Analysis of the Secondary Endpoints..............................................................13
11
Palatability and Acceptability................................................................................................13
12
Safety ......................................................................................................................................14
12.1
Adverse Events .............................................................................................................14
12.1.1
General Methodology for Adverse Events ......................................................14
12.1.2
Handling of Adverse Events...........................................................................15
12.1.2.1
Adverse Events Changing in Intensity or Seriousness .....................15
12.1.2.2
Coding of Adverse Events ..............................................................15
12.1.2.3
Classification of Adverse Events.....................................................15
12.1.2.4
Assigning Adverse Event Records to an Analysis Phase..................15
12.1.3
Summary of All Adverse Events.....................................................................15
12.1.4
Lead-in Adverse Events..................................................................................16
12.1.5
Summary of Treatment-emergent Adverse Events ..........................................16
12.1.6
Deaths............................................................................................................16
12.1.7
Serious Adverse Events..................................................................................16
12.1.8
Adverse Events Leading to Withdrawal..........................................................16
12.1.9
Adverse Events Related to Tolerability...........................................................16
12.1.10
Adverse Events of Special Interest..................................................................17
12.2
General Methodology for Other Safety Data..................................................................19
12.3
Clinical Safety Laboratory Test Data.............................................................................19
12.3.1
Data Presentation ...........................................................................................19


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Study 12712A – Statistical Analysis Plan
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12.3.2
Urine analysis.................................................................................................19
12.3.3
Potential Drug-induced Liver Injury (DILI)....................................................19
12.3.4
Changes in Fasting and non-fasting Lipid and Glucose Concentrations...........20
12.4
Vital Signs and Weight..................................................................................................20
12.5
ECGs ............................................................................................................................21
12.6
Other Safety Endpoints .................................................................................................21
12.6.1
Columbia-Suicide Severity Rating Scale (C-SSRS) Scores .............................21
12.6.2
Paediatric Adverse Event Rating Scale (PAERS)............................................22
12.6.3
Tanner Evaluation ..........................................................................................22
12.6.4
Menstrual Cycle.............................................................................................23
12.6.5
Remote Visits.................................................................................................23
13
Pharmacokinetic/Pharmacodynamic Analyses......................................................................23
14
Interim Analyses.....................................................................................................................23
15
Sample Size Considerations ...................................................................................................23
16
Statistical Software.................................................................................................................23
17
Changes to Analyses Specified in the Protocol ......................................................................24
18
Details on Data Handling .......................................................................................................24
18.1
Definition of Baseline and Period..................................................................................24
18.2
Derived Variables .........................................................................................................24
18.2.1
Behavioural Rating Inventory of Executive Function® (BRIEF®)..................24
18.3
Missing items on Rating Scales .....................................................................................25
18.4
Identifying rows for analysis .........................................................................................26
18.5
Handling Missing or Incomplete Dates/Times ...............................................................26
18.5.1
IMP Start and Stop Dates ...............................................................................26
18.5.2
Withdrawal Date ............................................................................................26
18.5.3
Medication Start and Stop Dates.....................................................................26
18.5.4
Adverse Event Start and Stop Dates................................................................26
References .......................................................................................................................................27


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Study 12712A – Statistical Analysis Plan
Page 4 of 39
Appendices
Appendix I
Statistical Analysis Plan Authentication and Authorization ....................................28
Appendix II
Study Flow Chart...................................................................................................30
Appendix III
SAS® Code...........................................................................................................34
Appendix IV
PCS Criteria ..........................................................................................................36


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Study 12712A – Statistical Analysis Plan
Page 5 of 39
List of Panels and Tables
Panel 1
Study Design...................................................................................................................8
Panel 2
Overview of Planned Efficacy Analyses........................................................................12
Panel 3
Palatability and acceptability.........................................................................................14
Panel 4
Insomnia related adverse events searches.......................................................................17
Panel 5
Sexual dysfunction related adverse events searches .......................................................18
Panel 6       C-SSRS Scores .............................................................................................................21
Panel 7    
Clinical Scales of BRIEF...............................................................................................25
Panel 8
Maximum Number of Missing Items on Rating Scales ..................................................25
Table 1 
Study procedures and Assessments................................................................................31
Table 2
Lundbeck PCS Criteria for Clinical Safety Laboratory Tests..........................................37
Table 3
Lundbeck PCS Criteria for ECG Parameters..................................................................38
Table 4
PCS Criteria for Vital Signs, Weight/BMI, and Waist Circumference............................39
Table 5 
PCS Criteria for Vital Signs (Continued).......................................................................39


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Study 12712A – Statistical Analysis Plan
Page 6 of 39
List of Abbreviations and Definitions of Terms
ANCOVA
analysis of covariance
APTS
all-patients-treated set
CI
confidence interval
DMC
Data Monitoring Committee
DSM
Diagnostic and Statistical Manual of Mental Disorders
eCRF
electronic case report form
FAS
full-analysis set
IMP
investigational medicinal product
LOCF
last observation carried forward
MDD
Major Depressive Disorder
MedDRA
Medical Dictionary for Regulatory Activities 
MMRM
mixed model for repeated measurements
OC
OLEXA
observed case(s)
baseline extension A
PCS
potentially clinically significant
PYE
patient years of exposure
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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Study 12712A – Statistical Analysis Plan
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1
Objectives
1.1
Primary Objective
• Primary objective:
to evaluate the long-term safety and tolerability of vortioxetine in child and adolescent 
patients with a DSM-5™/diagnosis of MDD
1.2
Secondary Objectives
• Secondary objectives:
to evaluate the long-term effectiveness of flexible doses of vortioxetine in a range of 5 
mg/day to 20 mg/day on:
depressive symptoms
clinical global impression
cognitive function
functionality
to evaluate the palatability and acceptability of vortioxetine oral drops
2
Study Design
This is an interventional, multi-national, multi-site, open-label, flexible-dose, long-term 
extension study in child and adolescent patients with MDD who completed one of the double-
blind, placebo-controlled, active-reference studies 12709A and 12710A.
The Baseline Visit, hereafter referred to as OLEXA, of this extension study, will be Visit 12 
(Completion Visit) of lead-in Study 12709A or 12710A, see section 18.1.
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 
adjust the dose in case of unsatisfactory response up to 20 mg or 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-titrated to a new dose. Changes in dosing 
may occur at any site visit during the treatment course at the investigator's discretion but the 
maximum dose may not exceed 20 mg/day. 
For subset of patients participating in the palatability assessment (patients enrolled in Bulgaria, 
Estonia, Germany, Latvia, Mexico, Poland, Russia, Serbia, Ukraine, and Colombia),
palatability and acceptability of vortioxetine oral drops will be assessed after intake of a 
single dose (5-20 mg) corresponding to the patient’s current vortioxetine dose (instead of their 
vortioxetine tablet on that day). The assessment can be done at any visit to the clinic from 
Week 4 to Week 18 (i.e., at Visits 5, 7, 9, or 11).


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Study 12712A – Statistical Analysis Plan
Page 8 of 39
The treatment period is 26 weeks. The total study duration per patient from OLEXA to the 
end of follow-up will be approximately 30 weeks.
If possible, patients who withdraw are to be seen for a withdrawal visit as soon as possible 
and they will be contacted for a safety follow-up visit 4 weeks after withdrawal.
The study design is presented in Panel 1.
Panel 1
Study Design
3
Endpoints
3.1
Primary Endpoint
Safety and tolerability:
• adverse events (AEs)
• PAERS assesment
• Tanner score
• absolute values and changes from OLEXA in clinical safety laboratory tests, vital signs, 
height, weight and ECG parameters
• length of menstrual cycle


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Study 12712A – Statistical Analysis Plan
Page 9 of 39
• potentially clinically significant clinical safety laboratory test values, vital signs, weight, 
and ECG parameter values relative to OLEXA
• C-SSRS categorisation
3.2
Secondary Endpoints
Depressive symptoms:
• change from OLEXA to Week 26 in CDRS-R total score
Global Clinical Impression:
• change from OLEXA to Week 26 in CGI-S score
• CGI-I score at Week 26. The assessment of the CGI-I should be in reference to Baseline A 
in the lead-in studies. The Baseline A lies 12 weeks prior to OLEXA.
Cognitive function:
Children (7-11 years)
• change from OLEXA to Week 26 in BRIEF using the Global Executive Composite score 
• change from OLEXA to Week 26 in BRIEF using the Metacognition Index 
Adolescents (12-18 years)
• change from OLEXA to Week 26 in BRIEF-SR using the Global Executive Composite 
score 
• change from OLEXA to Week 26 in BRIEF-SR using the Metacognition Index
Functionality:
• change from OLEXA to Week 26 in CGAS score
• change from OLEXA to Week 26 in PedsQL VAS
Palatability and acceptability:
• absolute value of palatability and acceptability item scores
4
Analysis Sets
The following analysis sets will be used to analyse and present the data:
• all-patients-treated set (APTS) – all patients who took at least one dose of vortioxetine in 
12712A.
• full-analysis set (FAS) –all patients in the APTS with valid OLEXA assessment and at 
least one valid post-OLEXA assessment of the CDRS-R total score.
The safety analyses will be based on the APTS. The efficacy analyses will be based on the 
FAS.


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Study 12712A – Statistical Analysis Plan
Page 10 of 39
The patients and data will be classified into the analysis sets according to the definitions 
above after the study database has been released.
5
Descriptive Statistics
Unless otherwise specified, summary statistics (n, arithmetic mean, standard deviation [SD], 
median, lower and upper quartiles, minimum and maximum values) will be presented for 
continuous variables, and counts and, if relevant, percentages will be presented for categorical 
variables.
Furthermore, and unless otherwise specified, the data will be summarised for all patients, and 
by lead-in study and by lead-in treatment, respectively.
Lastly, and unless otherwise specified, data listings will include site, lead-in study, patient 
number, sex, age, race, and weight at OLEXA.
6
Patient Disposition
6.1
Summary of Patient Disposition
Patient disposition will be summarized for all patients and by lead-in studies, and will include 
the number of patients in each analysis set defined in chapter 4, and the number of patients in 
the APTS who completed or withdrew from study.
6.2
Withdrawals
The number of patients who withdrew will be summarized for all patients, by lead-in studies
and by lead-in treatment, respectively, and by primary reason for withdrawal and all reasons 
for withdrawal.
Patients who withdrew will be listed and the listing will include the number of days in the 
study until withdrawal, the number of days on IMP, the primary reason for withdrawal and all 
reasons for withdrawal.
Kaplan-Meier plots of time to withdrawal will be presented for all patients, by lead-in studies
and by lead-in treatment, respectively. The time will be calculated from the date of first dose 
of IMP in the current trial to the date of completion or withdrawal. Patients who completed 
study will be regarded as censored.
All tables, graphs, and listings will be based on the APTS.


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Study 12712A – Statistical Analysis Plan
Page 11 of 39
7
Demographics and Baseline Characteristics
Demographics (sex, age, race); baseline (OLEXA) characteristics (height, weight, BMI and 
Tanner score); and baseline efficacy variables will be summarized for all patients and by lead-
in study and by lead-in treatment when applicable.
Demographics and baseline characteristics will be summarized based on the APTS, and 
baseline efficacy variables will be summarized based on the FAS.
8
Recent and Concomitant Medication
Recent and concomitant medication will be coded using the WHO Drug Dictionary
(WHO-DDE).
Medications will be classified according to the start and stop time and summarized by 
anatomical therapeutic chemical (ATC) code, generic drug name, for all patients and by lead-
in study and by lead-in treatment, respectively:
• concomitant medication continued from lead-in studies
• concomitant medication started at or after Visit 1 of study 12712A
The tables will be based on the APTS.
9
Exposure and Compliance
Exposure (days) to IMP will be calculated as:
• Date of last dose of IMP – Date of first dose of IMP in study 12712A + 1
Exposure to IMP will be summarized for all patients and by lead-in study and by lead-in 
treatment using descriptive statistics, and, 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.
In addition, exposure to IMP will be categorized in intervals (1 – 14 days, 15 – 35 days, 36 –
70 days, 71 – 105 days, 106 – 140 days, 141 – 182 days and >182 – days) and summarized by 
lead-in study and by lead-in treatment. Missing values of exposure will not be imputed.
Non-compliant days are days on which no IMP has been taken, less than the full dose of IMP 
has been taken, or more than the full dose of IMP has been taken.
Compliance (%) with IMP will be calculated as:
• (date of Completion/Withdrawal Visit – date of Visit 1 – number of days of non-
compliance)/ (date of Completion/Withdrawal Visit – date of Visit 1) × 100%


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Study 12712A – Statistical Analysis Plan
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where the number of non-compliant days is defined as the sum of all non-compliant days in 
the treatment period.
Compliance with IMP will be categorized as “≤80% compliant” or “>80% compliant”. The 
number and percentage of patients in each category will be summarized by lead-in study and 
lead-in treatment, respectively, by visit interval and for the entire study.
The mean and modal dose of IMP will be calculated for each patient and summarised (mean, 
median, and lower and upper quartiles for the mean and counts for the modal dose). IMP dose 
level at the completion or withdrawal of the study will be summarized. Number and 
percentage of patients who reached highest and lowest dose level will be summarised. In 
addition, number and percentage of patients with each dose level will be summarised by visit. 
Number of patients who exposed to oral drops will be summarized.
Exposure and compliance will be summarized based on the APTS.
10 Efficacy
10.1
Overview of Planned Efficacy Analyses
An overview of all planned efficacy analyses is provided in Panel 2. 
Panel 2
Overview of Planned Efficacy Analyses
Endpoints
Description
Type
Depressive 
Symptoms
Change from OLEXA to week 26 in 
CDRS-R1 total score
1
Remission
Defined as CDRS-R ≤ 28
2
Relapse
Defined as CDRS-R value ≥ 40
2
Global Clinical 
Impression
Change from OLEXA to week 26 in 
CGI-S score
1
CGI-I score at week 26
In reference to Baseline A in the 
lead-in study
1
Cognitive Function
Change from OLEXA to week 26 in 
BRIEF (parent) using Global Executive 
Composite Score
For children (aged 7-11 years at 
OLEXA), 72 items are included in 
GEC
1
Change from OLEXA to week 26 in 
BRIEF (parent) using Metacognition 
Index Score
For children (aged 7-11 years at 
OLEXA), 44 items are included in 
MI
1
Change from OLEXA to week 26 in 
BRIEF-SR using Global Executive 
Composite Score
For adolescents (aged 12-18 years
at OLEXA), 80 items are included 
in GEC
1
Change from OLEXA to week 26 in 
BRIEF-SR using Metacognition Index
Score
For adolescents (aged 12-18 years
at OLEXA), 42 items are included
in MI
1


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Study 12712A – Statistical Analysis Plan
Page 13 of 39
Functionality
Change from OLEXA to week 26 in 
CGAS2 score
1
Change from OLEXA to week 26 in 
PedsQL3 VAS score
1
1 = continuous; 2 = binary
10.2
General Efficacy Analysis Methodology
Unless otherwise specified, all the efficacy analyses will be based on the FAS.
All the tables and graphs will be presented for all patients and by lead-in studies and by lead-
in treatments, respectively.
Analysis of the endpoints subjected to inferential statistical methods will be presented with 
95% CIs. 
10.3
Analysis Methodology for the Secondary Endpoints
10.3.1
Analysis of the Secondary Endpoints
Absolute values and change from OLEXA in the continuous efficacy variables, except CGI-I, 
will be summarized descriptively. Absolute values of CGI-I will be summarized. 
CDRS-R remission and relapse during treatment period will be summarized descriptively by 
visit.
For the continuous efficacy variables CDRS-R and CGI-S, change from OLEXA will be 
analyzed using a restricted maximum likelihood (REML)-based Mixed Model Repeated 
Measurements (MMRM) approach, using all available observations until completion or 
withdrawal.
The model will include country, lead-in study interacting with week as factors, and baseline 
score interacting with week as covariate. An unstructured covariance structure will be used to 
model the within-patient errors and the Kenward-Roger approximation will be used to 
estimate denominator degrees of freedom.
For the CDRS-R total score the primary analyses will be also presented by lead-in study by 
lead-in treatment.
In addition, ANCOVA models will be fitted for CDRS-R and CGI-S, including country and 
lead-in study as factors and baseline score as a covariate, the analysis will be conducted by 
visit, based on OC and LOCF.
11 Palatability and Acceptability
Palatability and acceptability assessments were performed in 10 countries only.


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Study 12712A – Statistical Analysis Plan
Page 14 of 39
Each assessment contains 7 questions, 4 on palatability and 3 on acceptability. Palatability 
assessment includes taste, mouthfeel, aftertaste and smell, based on 5-points hedonic scales. 
Acceptability assessment includes acceptability of the taste, ease of use and willingness to 
take the drops every day, based on 3-points scales.
Palatability and acceptability item scores will be summarized using descriptive statistics.
The oral drops were considered acceptable if the mean hedonic scores were ≤3 for each aspect 
of palatability (taste, aftertaste, smell and mouthfeel), and <60% of participants responded 
“no” to each of the 3 questions regarding acceptability.
Panel 3
Palatability and acceptability
Endpoint
Description
Type
Palatability and 
acceptability
Absolute value of palatability
1
Absolute value of acceptability item 
scores
1
1 = continuous; 2 = binary
12 Safety
12.1
Adverse Events
12.1.1
General Methodology for Adverse Events
Unless otherwise specified, tables, graphs, and listings will be based on the APTS.
All the tables will be presented for all patients and by lead-in study and by lead-in treatment, 
respectively, unless otherwise specified.
Tables by preferred term and tables by system organ class (SOC) and preferred term will be 
sorted in descending order by the overall percentage of patients.
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 events. For sex-specific 
preferred terms, the denominator in the % calculations will be the number of patients of that 
sex. Sex-specific preferred terms will be marked in the summaries.
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, lead-in study, lead-in treatment, patient 
number, and adverse event start date, and include preferred term, investigator term, adverse 


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Study 12712A – Statistical Analysis Plan
Page 15 of 39
event start date, days since first dose of IMP, duration of the adverse event, date of death, 
action taken, causality, intensity, seriousness, and outcome. For adverse events that change in 
intensity, each intensity will be included.
12.1.2
Handling of Adverse Events
12.1.2.1
Adverse Events Changing in Intensity or Seriousness
In ADaM data, changes in intensity are included as additional records (rows) to the originally 
reported adverse events. 
If an adverse event changes from non-serious to serious, in addition to the originally reported 
adverse event start date, the start date for the seriousness is reported. In ADaM data, adverse 
events that change from non-serious to serious will be included as two records, one with 
seriousness non-serious and one with seriousness serious.
12.1.2.2
Coding of Adverse Events
Adverse events will be coded using MedDRA, Version 22 or later.
12.1.2.3
Classification of Adverse Events
Adverse events will be classified according to the time of onset of the adverse events:
• Lead-in adverse event – an adverse event starts before visit 1 in 12712A and ongoing from 
(= with start date in) lead-in study 12709A or 12710A
• treatment-emergent adverse event – an adverse event that starts or increases in intensity/or 
seriousness at or after visit 1 of study 12712A
An adverse event is considered causally related to the use of the IMP when the causality 
assessment by the investigator is probable or possible.
12.1.2.4
Assigning Adverse Event Records to an Analysis Phase
All records for an adverse event will be assigned to an analysis phase. The analysis phase will 
determine how an adverse event record is reported, and an adverse event may be reported in 
more than one analysis phase insofar as it worsens.
For further details, see Data Handling Plan.
12.1.3
Summary of All Adverse Events
All adverse events will be listed, including a flag for TEAE.
An overview of the PYE, numbers, and percentages of patients with TEAE, serious adverse 
events (SAEs), or adverse events leading to withdraw, and of patients who died will be 


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Study 12712A – Statistical Analysis Plan
Page 16 of 39
provided for APTS. For TEAE, SAEs, and adverse events leading to withdrawal, the total 
number of events will be included.
12.1.4
Lead-in Adverse Events
Lead-in adverse events will be summarized by preferred term.
12.1.5
Summary of Treatment-emergent Adverse Events
The following summaries will be provided for the APTS:
• TEAE by SOC and preferred term
• TEAE by preferred term
• TEAE with an incidence > 2% and 5% by preferred term
• Causally related TEAE by SOC and preferred term
• TEAE by intensity (mild/moderate/severe), and preferred term
• Causally related TEAE by intensity and preferred term
12.1.6
Deaths
All the adverse events in patients who died will be listed.
12.1.7
Serious Adverse Events
All the SAEs will be listed.
Treatment-emergent SAEs for the APTS will be summarized by:
• SOC and preferred term
• Preferred term
12.1.8
Adverse Events Leading to Withdrawal
All the adverse events leading to withdrawal will be listed.
TEAE leading to withdrawal will be summarized by:
• SOC and preferred term
• preferred term
12.1.9
Adverse Events Related to Tolerability
Incidence and prevalence rates in every four-week interval will be presented for nausea based 
on the APTS for events with complete start and stop dates.
Incidence will be defined as the number of patients with a new event in the specified time 
interval. The denominator in each interval will be the number of patients without the event at 


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the start of the interval plus the number of patients with an ongoing event at the start of the 
interval for which the event stops before the end of the interval.
Prevalence will be defined as the number of patients with the event at the start of the interval 
or who have the event during the interval. The denominator will be the number of patients at 
the start of the interval.
12.1.10 Adverse Events of Special Interest
Treatment-emergent nausea (preferred term), vomiting (preferred term), insomnia (defined 
below), and sexual dysfunction (defined below) will be summarised. TEAE related to the 
musculoskeletal SOC will be summarized.
Insomnia related adverse events and sexual dysfunction related adverse events are defined in 
Panel 4 and Panel 5.
Panel 4
Insomnia related adverse events searches
Preferred term
Hyposomnia
Initial Insomnia
Insomnia
Middle Insomnia
Poor Quality Sleep
Sleep Disorder
Terminal Insomnia
Dyssomnia


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Panel 5
Sexual dysfunction related adverse events searches
Preferred Term
Anorgasmia
Genital hypoaesthesia
Kluver-Bucy syndrome
Ejaculation delayed
Persistent genital arousal disorder
Libido increased
Ejaculation failure
Adrenal androgen deficiency
Luteinising hormone deficiency
Female orgasmic disorder
Adrenal androgen excess
Masochism
Female sexual arousal disorder
Adrenogenital syndrome
Mauriac syndrome
Libido decreased
Albright's disease
Nocturnal emission
Loss of libido
Compulsive sexual behaviour
Painful ejaculation
Male orgasmic disorder
Delayed puberty
Painful erection
Orgasm abnormal
Erection increased
Paraphilia
Orgasmic sensation decreased
Excessive masturbation
Precocious puberty
Premature ejaculation
Excessive sexual fantasies
Priapism
Vulvovaginal dryness
Exhibitionism
Primary ciliary dyskinesia
Disturbance in sexual arousal
Fertility increased
Primary hypogonadism
Dyspareunia
Fetishism
Pseudoprecocious puberty
Ejaculation disorder
Follicle stimulating hormone 
deficiency
Psychosexual disorder
Erectile dysfunction
Frotteurism
Pubertal failure
Female sexual dysfunction
Gender dysphoria
Retrograde ejaculation
Genito-pelvic pain/penetration 
disorder
HAIR-AN syndrome
Sadism
Inadequate lubrication
Hyperandrogenism
Spontaneous ejaculation
Libido disorder
Hypergonadism
Spontaneous penile erection
Male sexual dysfunction
Hyperoestrogenism
Transvestism
Organic erectile dysfunction
Hyperprogesteronism
Voyeurism
Psychogenic erectile dysfunction
Hypersexuality
Paedophilia
Sexual aversion disorder
Hypogonadism
Post-sterilisation regret
Sexual dysfunction
Hypoprogesteronism
Sexual inhibition
Incomplete precocious puberty
The second and third column represent the preferred terms that has been added based on a post-marketing 
request by EMA.


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12.2
General Methodology for Other Safety Data
Unless otherwise specified, tables, graphs, and listings will be based on the APTS, and the 
tables will be presented for all patients and by lead-in study and by lead-in treatment.
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 change from baselines
(baseline at randomisation in lead-in study and OLEXA), will be presented by visit and for 
the last assessment. All available post-OLEXA assessments will be included in the 
identification of the last assessment.
The number and percentage of patients with at least one 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 definition will be provided by H. Lundbeck and are stated in Appendix IV.
12.3
Clinical Safety Laboratory Test Data
12.3.1
Data Presentation
The clinical safety laboratory test values will be presented in conventional and/or Système 
International (SI) units.
12.3.2
Urine analysis
For urine dipsticks, for which the results are categorical values (for example, negative, trace, 
1+, 2+), the number and percentage of patients will be summarised for each test by visit. 
The microscopy results will be listed for patients with findings by assessment time point.
12.3.3
Potential Drug-induced Liver Injury (DILI)
Signals of DILI will be assessed according to the FDA guideline4 using the following criteria:
• alanine aminotransferase (ALT) or AST >2-, >3-, 5-, 10-, or 20ULN
• total bilirubin (BILI) >2ULN
• alkaline phosphatase (ALP) >1.5ULN


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• ALT or AST >3ULN and BILI >1.5or >2ULN
In addition, assessment time points for patients for whom Hy’s Law is potentially fulfilled 
will also be flagged in the listing (pHYL):
• ALT or AST >3×ULN AND
• BILI >2xULN AND
• ALP<2xULN
In the summaries, each patient should be counted only once using the maximum assessment, 
or the most severe for the combined criteria. 
Patients fulfilling any of the individual criteria (ALT/AST, ALP, or BILI) will be listed, and 
the listing will include all available ALT, AST, BILI, and ALP, BILI, EOSLE, and GGT 
values (absolute and normalised), sorted by assessment date in ascending order. 
Evaluation of potential Drug-Induced Serious Hepatotoxicity (eDISH) will also be done by 
plots. Scatter plots of maximum ALT/AST versus maximum BILI will be presented. The 
criteria for the individual tests will be considered separately (that this means that the 
maximum of ALT/AST and the maximum BILI may not occur at the same assessment 
timepoint). The values will be normalised by the ULN (unit xULN) and the X-and Y-axes 
will be on the log scale. The plot will include a reference line for ALT/AST values >3xULN, 
and a reference line for BILI values>2xULN. Four quadrants are defined by the reference 
lines, where the right upper quadrant being the most specific indicator for a drug’s potential 
for causing serious liver injury (Hy’s law quadrant).
Subject line plots with values-by-time for ALT, AST, ALP, BILI, GGT and EOSLE (overlaid 
in the same plot) will be generated for patients with ALT/AST > 3xULN. The test values will 
be normalised by the ULN (unit xULN) and the Y-axis will be on the log scale. All 
assessments will be included, and the time will be days since first IMP. Reference lines for 
the day of first-and last IMP will be included. If there is more than one assessment at the same 
time point for a test, the maximum value will be used.
For further details, see Data Handling Plan.
12.3.4
Changes in Fasting and non-fasting Lipid and Glucose Concentrations
Shift tables displaying the change in classification for fasting and non-fasting lipids and 
fasting and non-fasting glucose from OLEXA to any post-baseline visit will be provided for 
each test and include the numbers and percentages of patients.
12.4
Vital Signs and Weight
Descriptive statistics for the vital sign parameters will be presented by visit and the last 
assessment in the Period.


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12.5
ECGs
Shift tables displaying shifts from normal to abnormal ECG findings from OLEXA to the 
Withdrawal/Completion Visit will be provided and include the numbers and percentages of 
patients.
12.6
Other Safety Endpoints
12.6.1
Columbia-Suicide Severity Rating Scale (C-SSRS) Scores
The C-SSRS was assessed after OLEXA using the Since Last Visit Version
The numbers and percentages of patients with suicide-related events based on the C-SSRS 
will be summarized for each category of suicidal ideation (items 1-5) and suicidal behaviour 
(items 6-10). The most severe score (Panel 6) 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 1 to 5 
(related to suicidal ideation) and answered ‘no’ to items 6 to 10 (related to suicidal 
behavour)
Panel 6       C-SSRS Scores
C-SSRS Score
Related to:
1
Wish to be dead
Suicidal ideation
2
Non-specific active suicidal thoughts
3
Active suicidal ideation with any methods (not plan) without intent to act
4
Active suicidal ideation with some intent to act, without specific plan
5
Active suicidal ideation with specific plan and intent
6
Preparatory acts or behaviour
Suicidal behaviour
7
Aborted attempt
8
Interrupted attempt
9
Non-fatal suicide attempt
10
Completed suicide (only applicable for the post-baseline assessments)
In the C-SSRS, non-suicidal self-injurious behaviour is captured as a different behaviour; 
patients may have reported non-suicidal self-injurious behaviour in addition to suicidal 
ideation/behaviour. Positive responses to non-suicidal self-injurious behaviour will be 
summarised separately. 
For patients with any post-baseline suicidal behaviour (C-SSRS scores of 6 to 10), listings 
will be prepared including all C-SSRS scores; C-SSRS scores related to suicidal behavior will 
be flagged.


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All assessments will be regarded as valid for C-SSRS. 
Missing C-SSRS scores will not be imputed.
12.6.2
Paediatric Adverse Event Rating Scale (PAERS)
Note, all assessments will be regarded as valid for PAERS5 (that is, the criteria that 
assessment date-date of last IMP must be ≤7 days will not be applied).
For each item, a severity score will be derived where the analysis value is defined as:
• If Recently Present=No, the analysis value will be Absent. 
Otherwise, the analysis value will be the reported Severity (Mild, Moderate, Severe, or 
Extreme)
The assessments for the PAERS will be prepared according to the description in the Data 
Handling Plan. For each item 1 to 43, the following parameters will be derived for each 
analysis phase following a baseline (all assessments within a phase will be included in the 
evaluation):
• Worst severity score:
Worst severity score of the item (analysis value will be the worst severity)
• Worsening of severity score compared to baseline:
Worsening of the item compared to OLEXA (analysis value will be ‘Yes’ or ‘No’)
If a patient had a worsening of an item, all original assessments at the OLEXA will be listed.
Also graphical presentations of the PAERS will be done.
Item 44 and 45 will only be listed, based on APES.
For further details, see Data Handling Plan.
12.6.3
Tanner Evaluation
Tanner staging is a scale for assessing physical development and sexual maturity during onset 
and progress of puberty. The scale includes five stages of pubertal changes (called Tanner 
stages) separate for males and for females.
For females, the 5 stages of maturation are recognized by assessing pubic hair and breast 
development. For males, 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. 
Shift tables for the Tanner evaluation displaying shifts from OLEXA to withdrawal/ 
completion will be provided by sex, lead-in treatment and lead-in study, and include the 
numbers and percentages of patients.


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12.6.4
Menstrual Cycle
Age of menarche, length of the menstrual cycle and menstrual cycle regularity will be 
summarized for girls by lead-in study and lead-in treatment.
12.6.5
Remote Visits
Patients with remote visits will be listed.
13 Pharmacokinetic/Pharmacodynamic Analyses
A separate analysis plan for pharmacokinetic/pharmacodynamic analyses will be prepared by 
Quantitative Pharmacology, H. Lundbeck A/S.
14 Interim Analyses
No interim analyses for efficacy are planned. 
An independent Data Monitoring Committee was established in order to review the safety and 
tolerability data throughout the study. The same Data Monitoring Committee (DMC) will 
cover all the clinical studies in the paediatric vortioxetine program. DMC includes child and 
adolescent psychiatrists. The DMC ensures that the ethical principles are observed and 
monitors the safety of the patients. The DMC will be informed to what extent the data and 
analyses provided to them have been quality controlled. Members of the DMC will not be 
involved in other study-related tasks. The details of the DMC procedures are described in the 
Data Monitoring Committee Charter.
A CRO is contracted to perform the analyses for the DMC.
15 Sample Size Considerations
No sample size calculation has been performed for the present study, which just includes 
patients who have completed the studies 12709A or 12710A and are eligible for enrolment for 
this study.
It is expected that some 15-20% of the 1200 patients randomised to the lead-in studies will 
drop out these and that a maximum of 85% of these “lead-in completers” are expected to 
accept to continue into this extension study. This gives approximately 850 patients.
16 Statistical Software
The statistical software used will be SAS®, Version 9.4 or later.


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17 Changes to Analyses Specified in the Protocol
The following changes have been made as compared to the latest version of the protocol:
• C-SSRS categorisation has been updated and will no longer include C-CASA.
• Treatment emergent adverse events (TEAE) in 12712A is defined as an adverse event that 
starts or increases in intensity or seriousness after visit 1 of study 12712A.
• The analyses regarding time to first relapse and time to first loss of remission have been 
removed
• The analysis of random slope and intercept has been removed
18 Details on Data Handling
18.1
Definition of Baseline and Period
OLEXA will be Visit 1 in 12712A for assessments not included in 12709A or 12710A. For 
assessments included study in 12709A or 12710A, Visit 12 in either 12709A or 12710A will 
otherwise serve as OLEXA.
No baseline in 12712A is defined for the C-SSRS.
18.2
Derived Variables
18.2.1
Behavioural Rating Inventory of Executive Function® (BRIEF®)
BRIEF6 (parent) form was used for children aged 7-11 and contains 86 items, the BRIEF-SR 
(self-reported) form was used for adolescents aged 12-18 and contains 80 items. Items are 
rated on a 3-point scale, with 1 corresponding to Never, 2 corresponding to Sometimes, and 3 
corresponding to Often. These items cover 8 non-overlapping clinical scales (Panel 7). For 
BRIEF (parent) form, only the first 72 items will be included in the clinical scales.
The clinical scales combine to form two Indexes, the Behavioural Regulation Index (BRI) and 
the Metacognition Index (MI), and one composite summary score, the Global Executive 
Composite (GEC), which is a summary score that incorporates all eight clinical scales.
For BRIEF (parent), the Metacognition Index (MI) is comprised of Initiate, Working 
Memory, Plan/Organize, Organization of Materials, and Monitor scales. For BRIEF-SR, the 
Metacognition Index (MI) is comprised of Working Memory, Plan/Organize, Organization of 
Materials, and Task Completion.
For each clinical scale, the scale raw score is calculated as the sum of its item scores, and then 
converted to T-score based on the conversion table. The index (BRI and MI) scores are 
calculated as the sum of the corresponding scale T-scores, and, was converted to index T-


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scores based on the conversion table. GEC score was then calculated as the sum of the index 
scores and converted to T scores based on the conversion Table. 
If the total number of missing items that contribute to the calculation of total score (GEC) is 
greater than 14, then the total score will not be calculated. Similarly, if more than two items 
that contribute to the calculation of a scale score are missing, then the scale score should not 
be calculated for that scale. Otherwise, missing responses for one or two items that contribute 
to a scale score should be assigned a score of 1 when calculating the scale score.
If a patient used a wrong form at some visit, data from this visit would be excluded from the 
analysis. If a patient used a wrong form at the baseline visit, this patient will be excluded from 
the analysis of BRIEF scales.
Panel 7    Clinical Scales of BRIEF
BRIEF (Parent)
BRIEF-SR
Clinical Scales
Number of items
Clinical Scales
Number of items
Inhibit
10
Inhibit
13
Shift
8
Shift
10
Emotional Control
10
Emotional Control
10
Initiate
8
Monitor
5
Working Memory
10
Working Memory
12
Plan/ Organize
12
Plan/ Organize
13
Organization of Materials
6
Organization of Materials
7
Monitor
8
Task Completion
10
18.3
Missing items on Rating Scales
The general rule when single-item scores are missing is that the total score will be calculated 
as the expected sum of items given non-missingness using SAS function CEIL: [(sum of non-
missing items) × (total number of items) / (number of non-missing items)].
If more than 20% of the items for a rating scale or subscale are missing, the total score or 
subscore will be set to missing. Since most rating scales will be done as an Electronic clinical 
outcome assessment (eCOA) the number of missing items should be very limited.
The application of the above rules can be found in Panel 8.
Panel 8
Maximum Number of Missing Items on Rating Scales
Variable
Description
Maximum Number of 
Missing Items
CDRS-R TOT
CDRS-R total score
3
PEDSQL VAS TOT
PEDSQL VAS total score
1
BRIEFa
Global Executive Composite
14
BRIEF - SR
Global Executive Composite
14
a BRIEF SCALES: refer to section 18.2.1


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18.4
Identifying rows for analysis
Assessments at Withdrawal Visits will be assigned to a target day according to Data Handling 
Plan. Unscheduled scale assessments will be windowed in the corresponding way as 
withdrawal assessments but after any assessments from Withdrawal Visits has been 
windowed. 
Before protocol amendment (PA2), CDRS-R was only assessed at week 0, 12 and 26, 
however, the same visit window will be applied.
Analysis day will then be mapped based on target day. Analysis week will be analysis day/7.
18.5
Handling Missing or Incomplete Dates/Times
18.5.1
IMP Start and Stop Dates
In evaluation of valid efficacy and safety assessments (assessment is considered valid if 
assessment date-date of last IMP ≤7 days), a missing date of last IMP will be imputed by the 
latest attended Visit in the study before the safety follow-up.  
Exposure with missing IMP start or stop date will not be calculated.  
18.5.2
Withdrawal Date
For withdrawn patients with a missing Withdrawal Visit, the date of the last attended visit will 
be used in the calculation of time to withdrawal from study.
18.5.3
Medication Start and Stop Dates
In order to assign all medications to an analysis start-and stop phase, missing or incomplete 
start-or stop dates will be imputed. Ongoing medications at the end of a study will not be 
assigned a stop phase in that study. 
No duration will be calculated for medications with imputed start-or stop date, or for ongoing 
medications.
For further details, see Data Handling Plan. 
18.5.4
Adverse Event Start and Stop Dates
Incomplete adverse start dates will be imputed before handling of incomplete dates for change 
in intensity or seriousness.
For further details, see Data Handling Plan. 


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References
1
Poznanski EO, Grossman JA, Buchsbaum Y, Banegas M, Freeman L, Gibbons R. Preliminary 
studies of the reliability and validity of the children’s depression rating scale. Journal of the 
American Academy of Child Psychiatry 1984; 23, 2:191-197.
2
Shaffer D, Gould MS, Brasic J, Ambrosini P, Fisher P, Bird H, et al. A children’s global 
assessment scale (CGAS). Arch Gen Psychiatry 1983; 40: 1228-1231.
3
Sherman SA, Eisen S, Burwinkle TM, Varni JW. The PedsQL™ present functioning visual 
analogue scales: preliminary reliability and validity. Health and Quality of Life Outcomes 2006; 
4: 75.
4
United States Food and Drug Administration (US FDA). Guidance for Industry: Drug-induced 
liver injury: premarketing clinical evaluation. July 2009.
5
March J, Karayal O, Chrisman A. CAPTN:  The Pediatric Adverse Event Rating Scale. Paper 
presented at: Scientific Proceedings of the 2007 Annual Meeting of the American Academy of 
Child and Adolescent Psychiatry; October 23 to 28, 2007; Edited by Novins DK, DeYoung. 
Boston, MA; 2007; 241
6
Gioia GA, Isquith PK, Steven GC, Guy SC and Kenworthy L. Behavior Rating Inventory of 
Executive Function, Professional Manual; version 2000.


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Appendix I
Statistical Analysis Plan
Authentication and Authorization


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Statistical Analysis Plan
Authentication and Authorization
Study title:
Long-term, open-label, flexible-dose, extension study of vortioxetine in child and 
adolescent patients with Major Depressive Disorder (MDD) from 7 to 18 years of 
age
Study No.:
12712A
SAP date:
2 May 2022
This document has been signed electronically. The signatories are listed below.
Authentication
Authorization


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Appendix II
Study Flow Chart






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Females <11 years will be tested using a urine hCG test and females >11 years will be tested using a blood 
hCG test.
k
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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Appendix III
SAS® Code


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SAS® Code
MMRM for analysing continuous endpoints
proc mixed noclprint data=xyz ic method=reml;
class usubjid country week lead-in _study;
model y=baseline country week lead-in_study*week baseline*week / s ddfm=kr;
repeated week/subject=usubjid type=un;
run;


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Appendix IV
PCS Criteria


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PCS Criteria
Table 2
Lundbeck PCS Criteria for Clinical Safety Laboratory Tests
Laboratory Test
CDISC Term
Unit
PCS LOW
PCS HIGH
Haematology / Coagulation
B-haemoglobin
B-erythrocytes (red cell count)
B-haematocrit (packed cell volume) 
B-MCV (mean cell volume)
B-total leucocyte (white cell count)
B-neutrophils/leucocytes 
B-eosinophils/leucocytes 
B-basophils/leucocytes
B-lymphocytes/leucocytes
B-monocytes/leucocytes
B-thrombocytes (platelet count) 
P-INR (prothrombin ratio)
B-prothrombin time
HGB 
RBC 
HCT
MCV 
WBC 
NEUTLE 
EOSLE 
BASOLE 
LYMLE 
MONOLE 
PLAT
INR 
PT
g/dL
x 10E12/L 
V/V
fL
x 10E9/L
%
%
%
%
%
x 10E9/L 
Ratio
Sec
≤9.5 (women);
≤11.5 (men)
≤3.5 (women);
≤3.8 (men)
≤0.32 (women);
≤0.37 (men)
≤0.8 x LLN
≤2.8
≤20
≤10
≤75
≥ 16.5 (women);
≥18.5 (men)
≥6.0 (women);
≥7.0 (men)
≥0.50 (women);
≥0.55 (men)
≥1.2 x ULN
≥16
≥85
≥10
≥10
≥75
≥15
≥600
≥2.0
≥18
Liver
S-aspartate aminotransferase
S-alanine aminotransferase
S-bilirubin
S-bilirubin, direct
S-bilirubin, indirect
S-alkaline phosphatase
S-gamma glutamyl transferase
S-alpha-glutathione S-transferase
(alpha-GST)
AST 
ALT 
BILI 
BILDIR 
BILIND 
ALP 
GGT 
GSTAL
IU/L 
IU/L
µmol/L
µmol/L
µmol/L 
IU/L 
IU/L
µg/L
≥3 × ULN
≥3 × ULN
≥34
≥12
≥22
≥3 × ULN
≥200
≥20
Kidney
S-creatinine
B-urea nitrogen (BUN) 
S-uric acid (urate)
CREAT 
BUN 
URATE
µmol/L
mmol/L
µmol/L
≥1.5 x ULN
≥11
≥ 510 (women);
≥ 630 (men)
Electrolytes
S-sodium (natrium)
S-potassium (kalium) 
S-calcium
S-chloride
S-magnesium
S-phosphate (phosphorus, (inorganic) 
S-bicarbonate
SODIUM 
K
CA
CL MG 
PHOS 
BICARB
mmol/L 
mmol/L 
mmol/L 
mmol/L 
mmol/L 
mmol/L 
mmol/L
≤ 125
≤3.0
≤1.8
≤90
≤0.6
≤0.65
≤12
≥ 155
≥6.0
≥3.0
≥117
≥1.3
≥1.95
≥38


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Endocrine / Metabolic
B-glucose, non-fasting/unknown
B-glucose, fasting
S-glucose, non-fasting/unknown
S-glucose, fasting
B-glycosylated haemoglobin, fasting
S-prolactin
S-thyrotropin/TSH
S-protein (total) 
S-albumin
GLUC 
GLUC 
GLUC 
GLUC 
HBA1C 
PROLCTN 
TSH
PROT 
ALB
mmol/L 
mmol/L 
mmol/L 
mmol/L
% 
mIU/L 
mIU/L
g/L
g/L
≤3.4
≤3.0
≤3.9
≤3.5
≤0.3
≤45
≤27
≥9.4
≥6.0
≥11.1
≥7.0
≥6.5
≥1350
≥5.5
≥95
Lipids
S-cholesteroltotal, non-fasting/unknown
S-cholesterol total, fasting
S-triglycerides, non-fasting/unknown
S-triglycerides, fasting
S-LDL cholesterol,non-fasting/unknown
S-LDL cholesterol, fasting
S-HDL cholesterol,non-fasting/unknown
S-HDL cholesterol, fasting
CHOL 
CHOL 
TRIG 
TRIG 
LDL 
LDL 
HDL 
HDL
mmol/L 
mmol/L 
mmol/L 
mmol/L 
mmol/L 
mmol/L 
mmol/L 
mmol/L
≤0.8
≤0.9
≥7.8
≥6.2
≥5.65
≥4.2
≥5.3
≥4.9
Cardiac / Skeletal/Muscle
S-creatine kinase (total)
S-creatine kinase MB isoenzyme
S-lactate dehydrogenase (total) 
S-troponin I
S-troponin T
CK
CKMB 
CKMBCK
LDH 
TROPONI 
TROPONT
IU/L
µg/L
%
IU/L
µg/L
µg/L
≥400 (women);
≥750 (men)
≥8.5 or
≥3.5% of total CK
≥ 750
≥1.5
≥0.4
Infection
S-C-reactive protein
S-globulin (total)
CRP 
GLOBUL
mg/L
g/L
≤15
≥25
≥55
Urine
Urinary pH
PH
≤4
≥9
S=serum; B=whole blood; U=urine
Table 3
Lundbeck PCS Criteria for ECG Parameters
ECG Parameter
CDISC Term
Unit
PCS LOW
PCS HIGH
Absolute Time Interval
PR interval 
QRS interval 
QT interval
PRMEAN 
QRSDUR 
QTMEAN
Msec 
Msec 
Msec
≥260
≥ 150
≥500
Derived Time Interval
Heart rate
QTcB interval
QTcF interval
RR interval
HRMEAN
QTCB
QTCF
RR
beats/min
Msec
Msec
Mses
< 50 and decrease
≥15
< 300
< 300
<500
≥ 120 and increase
≥15
> 500 or increase >
60
> 500 or increase >
60
>1200
Increase/decrease is relative to the baseline value


H. Lundbeck A/S
Confidential
Study 12712A – Statistical Analysis Plan
Page 39 of 39
Table 4
PCS Criteria for Vital Signs, Weight/BMI, and Waist Circumference
Parameter
CDISC Term
Unit
PCS LOW
PCS HIGH
Waist circumference
Weight
Body Mass Index
Pulse rate, supine/sitting/unknown
Diastolic blood pressure, 
supine/sitting/unknown
Systolic blood pressure, 
supine/sitting/unknown
Orthostatic systolic blood pressurea
Orthostatic pulse ratea
Temperatureb
WSTCIR 
WEIGHT 
BMI
PULSE 
DIABP 
SYSBP
OBP 
OPR
TEMP
Cm
Kg
kg/m2
beats/min 
mmHg 
mmHg
mmHg 
beats/min
oC
decrease ≥7% 
decrease ≥7% 
decrease ≥7%
< 50 and decrease
≥15
≤50 and decrease
≥15
≤ 90 and decrease
≥20
≤-30
decrease ≥2
increase ≥7% 
increase ≥7% 
increase ≥7%
≥ 120 and increase
≥15
≥ 105 and increase
≥ 15
≥180 and increase
≥ 20
≥20
≥38.3 and increase
≥2
Increase/decrease is relative to the baseline value
aFor definition of orthostatic blood pressure and pulse rate, see text after Table 3
bNote, the diurnal variation may affect the temperature. Morning temperature is lower
Table 5
PCS Criteria for Vital Signs (Continued)
Normal Range (mm Hg)
PCS High (mm Hg)
PCS Low (mm Hg)
Systolic blood pressure, 
supine
7-9 years: 80-115
10-12 years: 85-120
13-17 years: 90-130
≥ 18 years: 110-140
≥ 140 and increase ≥ 20
≥ 140 and increase ≥ 20
≥ 140 and increase ≥ 20
≥ 180 and increase ≥ 20
≤ 90 and decrease ≥ 20
Diastolic blood pressure, 
supine
7-9 years: 40-75
10-12 years: 40-80
13-17 years: 40-80
≥ 18 years: 51-85
≥ 90 and increase ≥ 15
≥ 90 and increase ≥ 15
≥ 90 and increase ≥ 15
≥ 105 and increase ≥ 15
≤ 50 and decrease ≥ 15