Conditions: Depressive Disorder, Major
Keywords: paediatric
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 683
Healthy volunteers: no

Brief summary:
Investigation of the efficacy and safety of a new potential treatment of Major depressive disorder (MDD) in paediatric participants (age 7 to 11 years).

Detailed description:

Arms:
arm 1: None arm 2: None arm 3: A decision has been taken to stop recruitment into this treatment arm. arm 4: None

Interventions: intervention 1: Vortioxetine 10 mg/day intervention 2: Vortioxetine 20 mg/day intervention 3: Fluoxetine 20mg/day intervention 4: Placebo
Intervention descriptions: intervention 1: 10 mg/day, encapsulated tablet, orally (with addition of lower initial dose levels).

Based on tolerability the dose may be reduced by 5 mg/day. No dose increase will be allowed intervention 2: 20 mg/day, encapsulated tablet, orally (with addition of lower initial dose levels).

Based on tolerability the dose may be reduced by 5 mg/day. No dose increase will be allowed intervention 3: 20 mg/day, encapsulated tablet, orally (with addition of lower initial dose levels).

Based on tolerability the dose may be reduced by 10 mg/day. No dose increase will be allowed intervention 4: Encapsulated tablet, orally

Protocol document:
Prot_000.pdf: 
 
ClinicalTrials.gov Identifier: NCT02709655 
H. Lundbeck A/S 
Confidential 
 
Electronic Signature Page 
Full Title 
Interventional, randomised, double-blind, placebo-controlled, active reference 
(fluoxetine), fixed-dose study of vortioxetine in paediatric patients aged 7 to 11 
years, with Major depressive disorder (MDD) 
 
 
 
Short Title 
12709A Protocol Edition 4.0 
 
 
 
Study Number 
12709A 
 
 
The following persons have electronically signed this document 
Server Date and Time 
Signed by 
22-Aug-2018 08:49:27 
 
Reason for Signature 
Correctness and Completeness 
 
22-Aug-2018 08:50:56 
 
Reason for Signature 
Clinical Approval 
 
22-Aug-2018 09:14:02 
 
Reason for Signature 
Biostatistic Approval 
 
22-Aug-2018 14:40:19 
 
Reason for Signature 
Clinical Safety Approval 
 
22-Aug-2018 14:49:27 
 
Reason for Signature 
Clinical Approval 
 
Reason for Signature 
 
Reason for Signature 
 
Reason for Signature 
 
Reason for Signature 
 
Reason for Signature 
 
 
 
Final: Version 1.0 
PLUTO ID: CLI_01105943 


H. Lundbeck A/S. 
Confidential 
Page 1 of 87 
LU Study Number: 12709A 
Pluto ID: CLI_01105943 
Status: Final 
Trial Site Number: Study Level 
Version: 1.0 
 
 
 
 
 
 
 
 
 
 
Clinical Study Protocol 
 
Interventional, randomised, double-blind, placebo- 
controlled, active reference (fluoxetine), fixed-dose study 
of vortioxetine in paediatric patients aged 7 to 11 years, 
with Major depressive disorder (MDD) 
 
 
Vortioxetine 
 
 
 
Study No.: 
12709A 
EudraCT No./IND: 
2008-005353-38/ 112581 
Sponsor: 
H. Lundbeck A/S (Lundbeck) 
2500 Valby (Copenhagen), Denmark 
 
Edition No.: 
4.0 (including PA03) 
(the version No. in the footer is the system version No.) 
Date of edition: 
21 August 2018 
Edition history: 
Edition 3.0 (including PA03), dated 18 January 2016 
Edition 2.0 (including PA01), 12 October 2015 
Edition 1.0 (original protocol), 14 August 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. 


H. Lundbeck A/S. 
Confidential 
Page 2 of 87 
LU Study Number: 12709A 
Pluto ID: CLI_01105943 
Status: Final 
Trial Site Number: Study Level 
Version: 1.0 
 
 
 
Synopsis – Study 12709A 
 
 
 
Sponsor 
H. Lundbeck A/S. 
Investigational Medicinal Product 
Vortioxetine 
EudraCT/IND No. 
2008-005353-38/ 112581 
Title of Study 
Interventional, randomised, double-blind, placebo-controlled, active reference (fluoxetine), fixed-dose study of 
vortioxetine in paediatric patients aged 7 to 11 years, with Major depressive disorder (MDD) 
Study Sites and Number of Patients Planned 
Approximately 100 sites are planned in approximately 15 countries worldwide (specialists, mainly outpatient 
clinics) with patients from the European Union, Europe outside the European Union, North America, and other 
geographical regions. 
Approximately 600 patients are planned for enrolment to the 4-week treatment with standardised brief 
psychosocial intervention (BPI) and placebo period (Phase A). At the end of Phase A, a total of 438 patients 
with incomplete improvement are planned to be randomised to the 8 week double-blind Phase B. 
Objectives 
• Primary objective: 
− to evaluate the efficacy of vortioxetine 10 mg/day and 20 mg/day versus placebo after 8 weeks of treatment 
on depressive symptoms in children with a DSM-5™ diagnosis of MDD. 
• Secondary objectives: 
− to evaluate the efficacy of vortioxetine 10 mg/day and 20 mg/day versus placebo during the 8 weeks of 
treatment on: 
• global clinical impression 
• functionality 
• health-related quality of life 
− to assess pharmacokinetics of vortioxetine in paediatric patients, aged 7 to 11 years using population 
pharmacokinetic approach 
• Exploratory objectives: 
− to explore the efficacy of vortioxetine 10 mg/day and 20 mg/day versus placebo on co-morbid symptoms 
• Safety objectives: 
− to evaluate the safety and tolerability of vortioxetine 10 mg/day and 20 mg/day versus placebo in children 
with a DSM-5™ diagnosis of MDD 


H. Lundbeck A/S. 
Confidential 
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LU Study Number: 12709A 
Pluto ID: CLI_01105943 
Status: Final 
Trial Site Number: Study Level 
Version: 1.0 
 
 
 
Study Methodology 
• This is an interventional, multi-national, multi-site, randomised, two-phase, single- and double-blind, parallel- 
group, placebo-controlled, active-reference (fluoxetine), fixed-dose study. 
• An interim analysis to potentially stop the study early for either efficacy or futility will be performed when at 
least 240 randomized patients have either completed or been withdrawn from the study. 
• If the study continues after the interim analysis, enrolment to the fluoxetine arm will be stopped and the study 
will continue as a 3-arm study. 
• The screening period will be 5 to 15 days followed by a 4-week single-blind period (Phase A) of treatment 
with standardised brief psychosocial intervention and single-blind (patients and parents) placebo. Patients 
who demonstrate an incomplete improvement of depressive symptoms at the end of Week 4 will be 
randomised to a double-blind, 8-week treatment period (Phase B) as follows: Prior to interim analysis (Study 
part 1), at least 240 patients will be randomized in a 1:1:1:1 ratio to vortioxetine 10 mg/day, vortioxetine 20 
mg/day, fluoxetine 20 mg/day, or placebo. If the study continues after interim analysis (Study part 2), patients 
will be randomized in a 1:1:1 ratio to vortioxetine 10 mg/day, vortioxetine 20 mg/day, or placebo. A total of 
438 patients are planned to be randomised to Phase B, provided that the study continues after the interim 
analysis. Patients and parents are blinded to the time point of randomisation to Phase B. There will be 2 
baselines in this study: Baseline A (Week 0) of the 4 week single-blind Phase A and Baseline B (week 4) of 
the 8 week double-blind Phase B. 
• Incomplete improvement in depressive symptoms is defined as patients demonstrating a <40% reduction from 
Baseline A on the Children depression rating scale revised version (CDRS-R), and with a (CDRS-R) ≥40 total 
score and confirmed by a Parent Global Assessment – Global Improvement (PGA) value of >2. 
• Randomisation will be done blinded at the end of Phase A (Week 4) using an Interactive Voice/Web 
Response system (IVRS/IWRS). 
• Patients participating in Phase B will be asked to come back to the study site for a safety follow up 4 weeks 
after early withdrawal or completion. This procedure will not apply for patients entering in an extension 
study. 
• Patients randomised to the 10 mg/day vortioxetine group will receive a lower initial dose (5 mg/day for 2 
days) prior to receiving 10 mg/day. Patients randomised to the 20 mg/day vortioxetine group will receive a 
lower initial dose (5 mg/day for 2 days followed by 10 mg/day for 2 days and 15 mg/day for 2 days) prior to 
receiving 20 mg/day. Patients randomised to the fluoxetine 20 mg/day group will receive a lower initial dose 
(10 mg/day for 6 days) prior to receiving 20 mg/day. 
• Based on tolerability the dose may be reduced at Week 8 (Visit 10 = Week 4 of Phase B). For patients 
randomised to vortioxetine the reduction will be by 5 mg/day and for fluoxetine 10 mg/day. No dose increase 
will be allowed. 
• Patients who do not fulfil the criteria of incomplete improvement in Phase A at Week 3 will be withdrawn 
from the study before Week 4. Patients who do not fulfil the criteria of incomplete improvement at week 4 
will be withdrawn from the study and not participate in the double-blind Phase B of the study. No specific 
study related follow-up is required for these patients. However as rescue procedure, they may receive up to 4 
outpatient visits to the study site for consultations over a two-month period. 
• Patients will receive 5 sessions of standardised brief psychosocial intervention at Week 1, 2, 3, 5 and 8. 
• Supportive psycho-educative material will be handed out to patients and families at the Screening Visit. 
• If the study is terminated early based on the results of interim analysis, patients ongoing in the study Phase B 
should complete the study according to the protocol. After completion of the phase B, these patients may be 
eligible to enter an open-label extension study. Patients ongoing in the study phase A at the early termination 
of the study will be offered treatment at the discretion of the investigator in line with clinical practice. As 
rescue procedure, they may receive up to 4 outpatient visits to the study site for consultations over a two- 
month period. 
• If the decision is to continue the study, patients ongoing in the study Phase B should complete their originally 
allocated treatment according to the protocol. Patients ongoing in the study phase A should complete this 
phase according to the protocol. Those eligible for the part B will be randomized according to the new 
randomization scheme, i.e., in a 1:1:1 ratio to vortioxetine 10 mg/day, vortioxetine 20 mg/day, or placebo, 
which will be implemented as soon as the decision to continue the study is taken. 


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LU Study Number: 12709A 
Pluto ID: CLI_01105943 
Status: Final 
Trial Site Number: Study Level 
Version: 1.0 
 
 
 
Study Methodology continued 
• The study design is presented in Panel 1 and the scheduled assessments are summarised in Panel 2. 
• Efficacy and safety measures will be assessed at relevant time points during the study summarised in Panel 2. 
Target Patient Population 
• The patient has Major depressive disorder (MDD), diagnosed according to DSM-5™. 
• The patient has a CDRS-R total score ≥45 at the Screening Visit and the Baseline A Visit (Week 0). 
• The patient has a Clinical Global Impression – Severity of Illness (CGI-S) score ≥4 at the Screening Visit and 
the Baseline A Visit (Week 0). 
• The patient is a boy or girl, aged ≥7 and <12 years at Screening Visit. 
Investigational Medicinal Products, Reference Therapy, Doses and Mode of Administration 
• Vortioxetine – 5 mg/day, encapsulated, orally 
• Vortioxetine – 10 mg/day, encapsulated, orally 
• Vortioxetine – 15 mg/day, encapsulated, orally 
• Vortioxetine – 20 mg/day, encapsulated, orally 
• Fluoxetine – 10 mg/day, encapsulated, orally 
• Fluoxetine – 20 mg/day, encapsulated, orally 
• Placebo – encapsulated, 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) 
− Patient and parent rated 
• General Behaviour Inventory (GBI), using the 10-item depression subscale 
− Parent rated 
• Parent Global Assessment – Global Improvement (PGA) 
• Assessment of Global Impression: 
− Investigator rated 
• Clinical Global Impression Scale – Global Improvement (CGI-I) 
• Clinical Global Impression Scale – Severity of Illness (CGI-S) 
• Assessment of functionality: 
− Investigator rated 
• Children’s Global Assessment Scale (CGAS) 
− Patient rated 
• The PedsQL Present Functioning Visual Analogue Scales (PedsQL VAS) 
• Assessment of health-related quality of life: 
− Patient rated 
• Paediatric Quality of Life Enjoyment and Satisfaction Questionnaire (PQ-LES-Q) 
Exploratory Assessments 
• Assessment of co-morbid symptoms: 
− Patient rated 
• Multidimensional Anxiety Scale for Children short version (MASC-10) 


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Pluto ID: CLI_01105943 
Status: Final 
Trial Site Number: Study Level 
Version: 1.0 
 
 
 
Safety Assessments 
• Adverse events (AEs) 
• Paediatric Adverse Event Rating Scale (PAERS) 
• Clinical safety laboratory tests 
• Vital signs 
• Weight/Height 
• Electrocardiograms (ECGs) 
• Physical examinations incl. Tanner scoring 
• Columbia Suicide Severity Rating Scale (C-SSRS) 
• General Behaviour Inventory (GBI), using the 10-item mania subscale 


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LU Study Number: 12709A 
Pluto ID: CLI_01105943 
Status: Final 
Trial Site Number: Study Level 
Version: 1.0 
 
 
 
Endpoints 
This section refers to the 8 week double-blind phase (Phase B) measuring changes from Baseline B Visit (Week 
4) after/during 8 weeks of treatment (Week 12 visit). Baseline refers to Baseline B Visit. 
Primary endpoints: 
− depressive symptoms: 
• change from Baseline B in the CDRS-R total score after 8 weeks of treatment 
• Secondary endpoints: 
− depressive symptoms: 
• change from Baseline B in the CDRS-R total score during the 8 weeks of treatment 
• CDRS-R response (defined as >50% reduction in the CDRS-R total score (subtracted 17 points) from 
Baseline B) during the 8 weeks treatment period. 
• remission over the 8 week treatment period (defined as CDRS-R ≤28), at each visit assessed 
• change from Baseline B in the General Behaviour Inventory (GBI), using the 10-item depression 
subscale, during the 8 weeks of treatment 
• score in the PGA during the 8 weeks treatment period 
− Global Clinical Impression: 
• change from Baseline B in the CGI-S score during the 8 weeks treatment period 
• score in the CGI-I during the 8 weeks treatment period 
• remission in the CGI-S score (defined as a CGI-S score of 1or 2) during the 8 week treatment period, at 
each visit assessed 
• response in the CGI-I score (defined as a CGI-I score of 1or 2) during the 8 week treatment period 
− functionality: 
• change from Baseline B in the CGAS score during the 8 weeks treatment period 
• change from Baseline B in the PedsQL VAS score during the 8 weeks treatment period 
− health-related quality of life: 
• change from Baseline B in the PQ-LES-Q scores during the 8 weeks treatment period 
− pharmacokinetics: 
• pharmacokinetic parameters for vortioxetine 
• Exploratory endpoint: 
− co-morbid symptoms: 
• change from Baseline B in the MASC-10 score during the 8 weeks treatment period 
• Safety endpoints during the 8 weeks treatment period: 
− adverse events (AEs) 
− tolerability will be assessed using the PAERS 
− absolute values and changes from Baseline B in clinical safety laboratory tests, vital signs, weight, height, 
and ECG parameters 
− potentially clinically significant clinical safety laboratory test values, vital signs, weight, and ECG 
parameter values 
− C-SSRS categorisation based on C-CASA definitions (1, 2, 3, 4, and 7) 
− GBI using the 10-item mania subscales (patient and parental versions) 


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LU Study Number: 12709A 
Pluto ID: CLI_01105943 
Status: Final 
Trial Site Number: Study Level 
Version: 1.0 
 
 
 
Statistical Methodology 
• The following analysis sets will be used to analyse and present the data: 
− all-patients-enrolled (APES) – all patients enrolled to the 4-week Single-blind period (Phase A) who 
received at least one dose of IMP 
− all-patients-randomised Phase B (APRS) – all patients randomised to the double-blind, 8-week treatment 
period (Phase B) 
− all-patients-treated set Phase B (APTS) – all patients randomised to the double-blind, 8-week treatment 
period (Phase B) who took at least one dose of double-blind IMP 
− full-analysis set Phase B (FAS) – all patients in the APTS who had a valid Baseline B assessment and at 
least one valid post-Baseline B assessment of the CDRS-R total score. 
− The efficacy analysis will be based on the FAS 
• Primary analysis: 
− For the primary endpoint (change from Baseline B in the CDRS-R total score to Week 8 in phase B (Week 
12)), comparisons of the pooled doses of vortioxetine 10 and 20 mg/day versus placebo will be made using 
Mixed Model Repeated Measurements (MMRM) with freely varying mean and covariance structure and 
with country as a fixed factor and Baseline B CDRS-R score as a covariate interacting with visit. Treatment 
(vortioxetine 10 mg/day, vortioxetine 20 mg/day, fluoxetine, and placebo) is included as a fixed factor 
interacting with visit. For the primary endpoint a contrast test with weights 0.5, 0.5, 0, and -1, respectively, 
to estimate the average effect of the pooled doses of vortioxetine against placebo, based on the LSMeans for 
the treatment by visit interaction at Week 8 in phase B (Week 12) will be used. This will be evaluated at a 
one-sided 2.5% significance level. 
• Key Secondary analyses: 
− Using the same model as in the primary analysis an evaluation of the separate comparisons of vortioxetine 
10 mg/day and vortioxetine 20 mg/day versus placebo will be made. These will be estimated based on 
LSMeans for the treatment by visit interaction at Week 8 in phase B (Week 12). Both of the comparisons 
will be evaluated at a one-sided 2.5% significance level. 
• Testing strategy for multiplicity controlled analyses: 
− Statistical significance can be claimed on the individual doses only if significance is claimed for the pooled 
vortioxetine doses. The multiplicity control for the primary and key secondary analyses is kept due to the 
closed testing principle. 
− To further account for the sequential approach, including one interim analysis with stopping rules for 
efficacy and futility, an error-spending approach based on Kim & DeMets method will be applied on the 
outcome from the MMRM model. 
• Sensitivity analyses of the primary endpoint: 
− The primary endpoint will also be analysed using an analysis of covariance (ANCOVA, OC and last 
observation carried forward [LOCF]) as sensitivity analysis. The Missing at Random assumption behind the 
MMRM model will be investigated. 
− A sensitivity analysis investigating the impact of the study methodological changes will be performed if the 
study is not stopped at interim analysis. This will be done by adding a factor to the primary analysis 
indicating whether the individual patient was enrolled prior to the change in study design or after. 
• Analyses of other efficacy endpoints: 
− For continuous endpoints, the same methodology as the primary analysis described for the primary endpoint 
will be used. In addition ANCOVA will be performed (OC and LOCF). 
− For dichotomous endpoints, such as response and remission, logistic regression with treatment as a factor 
and the baseline score as a covariate will be used. This will be done based on OC, LOCF and NRI. 
− The safety analyses will be based on the APES and the APTS. 
• Analyses of safety endpoints: 
− Adverse events, PAERS scores, clinical safety laboratory tests, vital signs, weight/BMI, ECG parameters, 
physical examinations, GBI scores (using the 10-item mania subscale), and C-SSRS scores will be 
summarised using descriptive statistics. Adverse events and other safety endpoints will be reported 
separately for Phase A and Phase B. 


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Pluto ID: CLI_01105943 
Status: Final 
Trial Site Number: Study Level 
Version: 1.0 
 
 
 
Statistical Methodology continued 
• A DMC will monitor safety data at regular intervals to be specified in the Data Monitoring Committee 
Charter. 
• Patient disposition and demographics will be summarised using descriptive statistics. 
• An interim analysis for both efficacy and futility is planned to be conducted when at least 240 have been 
randomized and completed the Week 12 visit or been withdrawn from the study. Interim analysis will be 
performed by an independent biostatistician as pre-specified in an interim statistical analysis plan and a 
charter. Only the decision to continue or terminate the study will be communicated to the Sponsor, without 
further details about the results. 
• To ensure that the study is sufficiently powered an estimate of the variability of the primary endpoint and the 
withdrawal rate will be derived. The analysis will be performed prior to the interim analysis and will be based 
on blinded and pooled data from all groups. Based on these estimates the power calculation will be updated 
and adequate actions will be taken if the study has lost power. 
• Patient disposition and demographics will be summarised using descriptive statistics. 
Pharmacokinetic Analysis 
Sparse PK samples (2) will be collected to measure vortioxetine and fluoxetine plasma concentration; however 
the population PK analysis will only be conducted for vortioxetine. Plasma concentrations of fluoxetine will be 
listed. 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 
To obtain a power of 85%, with a one-sided significance level of 2.5% and an expected effect size of 4 for each 
vortioxetine dose, and a standard deviation of 11 for the change from baseline for each dose, 102 patients need 
to be included in a non-sequential trial. To maintain the power at 85%, the sample size needs to be increased for 
the loss of power due to the sequential approach. As a result, then taking a drop-out rate of 15% in Phase B into 
account, 126 randomized patients per arm will be required. In total, 378 randomised patients are required in the 
final analysis if the study continues after the interim analysis, and in addition approximately 60 patients will be 
randomised to the fluoxetine group (Study part 1), which means a total of 438 randomised patients. 
More details are provided in the statistical analysis plan. 


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Trial Site Number: Study Level 
Version: 1.0 
 
 
 
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. 
As outlined in the EMA Assessment of the Paediatric Needs in psychiatry there is a therapeutic need in the 
paediatric population of depressed patients. 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. This study is part 
of the agreed EMA Paediatric Investigational Plan (PIP) for vortioxetine, and the US Paediatric Research 
Equity Act (PREA) with the purpose to investigate the anti-depressive effect of vortioxetine in MDD patients 
aged 7 to 11 years. It is the expectation that the investigation plan will provide positive efficacy data, with a 
favourable safety and tolerability profile, and therefore demonstrate 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 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 11 years) designed to guide the choice of doses to be used in 
the planned paediatric investigation plan. Hence the chosen doses of vortioxetine (10 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 the sole antidepressant approved both in children and adolescents for MDD in EU and US, 
fluoxetine has been selected as comparator to provide evidence of assay sensitivity. 
The presence of a high placebo response rate is known to be a confounding factor in antidepressant studies, 
particularly in those enrolling children and adolescents. The recent studies of duloxetine in the treatment of 
paediatric patients with MDD were failed as neither duloxetine nor the active control (fluoxetine, with known 
efficacy in children and adolescents with MDD), were statistically significantly different from placebo on the 
primary outcome measure. 
The present study is designed with the aim to lower the placebo response and includes a single-blind phase 
(Phase A) where patients who respond to standardised brief psychosocial intervention will not be eligible for 
entering the double-blind IMP treatment phase (Phase B). Furthermore patients and parents are blinded to the 
time point of randomisation to the double-blind phase in order to lower expectations. This study will permit the 
investigation of the efficacy and safety of a new potential treatment of MDD in paediatric patients and the 
inclusion of a placebo group has major scientific importance in this evaluation to ensure adequate evaluation of 
efficacy as well as distinguishing disease manifestations from adverse reactions of the compound. The choice of 
the double-blind 8 week study duration is based on previous experience with positive studies and European 
guidelines. 


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The patients will be asked to attend the investigational clinic at regular intervals to ensure an adequate follow- 
up. All visits will be performed on an outpatient basis at the clinic, other than the follow-up visit that can be 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 study participants 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 prior to any investigation or procedure, in order to decrease anxiety and anticipation of pain. Potentially 
painful procedures such as venipuncture will be minimized with the use of topical anaesthesia. 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, electrocardiogram and physical examination) and these will be evaluated by 
the investigator at each visit to ensure patient’s safety and wellbeing. 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. 
In accordance with Good Clinical Practice, qualified medical personnel at H. Lundbeck A/S will be readily 
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 H. Lundbeck A/S will 
regularly monitor and re-examine the balance of risk and benefit of the full clinical study so that the health and 
well-being of paediatric patients enrolled will be safeguarded. 
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 
judgement. 
An independent Data Monitoring Committee will be established in order to review the safety and tolerability 
data throughout the study. The same DMC will cover all the clinical studies in the paediatric vortioxetine 
program. 
Due to challenges with recruiting paediatric patients into clinical research, study design modifications have 
been made in agreement with the regulatory Authorities in Europe and US to reduce the size of the study. These 
modifications are considered ethically justified as they prevent unnecessary exposure of paediatric subjects to 
experimental treatments. 


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Panel 1 
Study Design 
 
Study part 1: 
Applicable prior to interim analysis 


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Study part 2: 
Applicable after interim analysis, if the study continues 
 
 


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Panel 2 
Study Procedures and Assessments 
 
Phase A 
Phase B 
Single-blind Treatment 
Period 
Double-blind Treatment 
Period 
Visit 
Scree- 
ning 
Base- 
line 
(Phase 
A) 
Base- 
line 
(Phase 
B) 
Com- 
pletion 
/With- 
drawala 
Safety 
Follow- 
upb 
Visit Number 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 11 
12 
13 
Day/End of Week 
d-5/d- 
15 
0 
W1 W2 W3 W4 W5 W6 W7 W8 W10 
W12 
W16 
Visit Windowc (days relative to 
nominal visit) 
± 2 ± 2 ± 2 
± 2 
± 2 ± 2 ± 2 ± 2 ± 2 
± 2 
± 2 
Screening/Baseline Procedures and Assessments 
Signed informed assents/consents 
√ 
Diagnosis (DSM-5™) 
√ 
K-SADS-PLd 
√ 
Disease-specific history 
√ 
Relevant history (social, medical, 
psychiatric, neurological) 
√ 
History of stimulant medication, 
if any 
√ 
Demographics (age, sex, race) 
√ 
Smoking, alcohol consumption 
√ 
Family psychiatric history 
√ 
Traumatic life events 
√ 
Pregnancy teste 
√ 
√f 
Inclusion/exclusion criteria 
√ 
√ 
Randomisation to Phase B 
√ 
BPI 
√ 
√ 
√ 
√ 
√ 
Efficacy Assessments 
CDRS-R 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
CGI-S 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
CGI-I 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
PGA (PRO)g 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
GBI (depression subscale ) 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√f 
CGAS 
√ 
√ 
√ 
√f 
PedsQL VAS (PRO) 
√ 
√ 
√ 
√f 
PQ-LES-Q (PRO) 
√ 
√ 
√ 
√f 


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Phase A 
Phase B 
Single-blind Treatment 
Period 
Double-blind Treatment 
Period 
Visit 
Scree- 
ning 
Base- 
line 
(Phase 
A) 
Base- 
line 
(Phase 
B) 
Com- 
pletion 
/With- 
drawala 
Safety 
Follow- 
upb 
Visit Number 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 11 
12 
13 
Day/End of Week 
d-5/d- 
15 
0 
W1 W2 W3 W4 W5 W6 W7 W8 W10 
W12 
W16 
Visit Windowc (days relative to 
nominal visit) 
± 2 ± 2 ± 2 
± 2 
± 2 ± 2 ± 2 ± 2 ± 2 
± 2 
± 2 
Exploratory Assessments 
MASC-10 (PRO) 
√ 
√ 
√ 
√f 
Vortioxetine and Fluoxetine Quantification 
Blood sampling vortioxetine and 
fluoxetine quantification 
√ 
√f 
Translational Medicine Assessmentsh 
Blood sampling for gene 
expression profiling 
√ 
√ 
√f 
Blood sampling for 
metabolomics/proteomics 
√ 
√ 
√f 
Blood sampling for 
pharmacogenetics (optional) 
√ 
Safety Assessments 
Adverse eventsi 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√j 
Blood and urine sampling for 
clinical safety laboratory tests 
√ 
√ 
√ 
√f 
Vital signs 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
ECGs 
√ 
√ 
√ 
√f 
Weight and height 
√ 
√ 
√ 
√f 
Examinations (physical and 
neurological) 
√ 
√f 
Tanner score 
√ 
PAERS 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√f 
C-SSRS 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
GBI (mania subscale) 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√f 
Other Study Procedures 
IMP dispensed 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
Possible change in IMP dose 
√k 
IMP returned and IMP 
accountability 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
Recent and concomitant 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 


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Status: Final 
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Phase A 
Phase B 
Single-blind Treatment 
Period 
Double-blind Treatment 
Period 
Visit 
Scree- 
ning 
Base- 
line 
(Phase 
A) 
Base- 
line 
(Phase 
B) 
Com- 
pletion 
/With- 
drawala 
Safety 
Follow- 
upb 
Visit Number 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
Day/End of Week 
d-5/d- 
15 
0 
W1 W2 W3 W4 W5 W6 W7 W8 W10 
W12 
W16 
Visit Windowc (days relative to 
nominal visit) 
± 2 ± 2 ± 2 
± 2 
± 2 ± 2 ± 2 ± 2 ± 2 
± 2 
± 2 
medication 
a. 
This visit should take place as soon as possible after the patient withdraws from the study. Any visit during 
Phase A, can be converted in to a withdrawal visit on the day of the visit. The BPI is optional if a visit 
during Phase A is converted into a withdrawal visit. 
b. 
This can be a telephone contact, unless an SAE has occurred since the last visit or there was a clinically 
significant abnormal safety laboratory test value at the last visit. In such cases, safety follow-up(s) must be 
scheduled to allow for a medical examination and/or blood sampling. Further safety follow-up visits 
beyond 30 days may be needed as judged by the investigator (if further safety follow-up visits are 
performed, these must be recorded in the patient’s medical record, and not in the eCRF). All enrolled 
patients should have a safety follow-up visit unless they continue into the extension study. 
c. 
If the date of a patient visit does not conform to the study plan, subsequent visits should be planned to 
maintain the visit schedule relative to randomisation/baselines. 
d. 
The Kiddie-Schedule for Affective Disorders and Schizophrenia for School-aged Children, Present and 
Lifetime version (K-SADS-PL) will be used to confirmed diagnosis of Major depressive disorder (MDD) 
and to assess possible psychiatric co-morbidities. 
e. 
If the patient is a female subject of childbearing potential (defined as females aged ≥10 year’s old and 
younger girls who, at the discretion of the investigator, were deemed to be of reproductive potential), a 
urine pregnancy test is to be performed at screening and if the patient has completed or withdrawn in Phase 
B. 
f. 
Should only be performed if the patient has completed or withdrawn in Phase B. 
g. 
The PGA assessment should be in reference to Baseline A. 
h. 
Samples will be collected at the designated time points. Any results of the Translational Medicine 
Assessments will not be available at the time of reporting and will consequently not be part of the actual 
report of the study. 
i. 
Pre-treatment adverse events (before IMP intake i.e. before Baseline B) must be recorded on the Adverse 
Event Form in the eCRF. Adverse events from open questioning in addition to all spontaneously reported 
adverse events must be recorded on the Adverse Event Form in the eCRF. If the adverse event is an SAE, 
the Serious Adverse Event Report Form must also be completed. For practical reasons, questioning for 
adverse events could follow vital sign assessments. In addition, the tolerability will also be assessed using 
the Paediatric Adverse Event Rating Scale (PAERS). Application of this scale should follow after the open, 
non-leading question for any adverse events. 
j. 
Only for adverse events on-going at Completion/Withdrawal and new SAEs. 
k. 
The vortioxetine dose may be down-titrated with 5mg/day based on poor tolerability, only one down- 
titration is allowed. No up-titration will be allowed. The fluoxetine dose may be down-titrated to 10 mg/day 
based on poor tolerability only one down-titration is allowed (Only applicable during Study part 1). No up- 
titration will be allowed. 


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Pluto ID: CLI_01105943 
Status: Final 
Trial Site Number: Study Level 
Version: 1.0 
 
 
 
Table of Contents 
Synopsis – Study 12709A ........................................................................................................................ 2 
List of Panels .......................................................................................................................................... 21 
List of Abbreviations and Definitions of Terms ................................................................................. 22 
1 
Introduction ................................................................................................................................ 25 
1.1 
Background ........................................................................................................................ 25 
1.1.1 
Overview ............................................................................................................ 25 
1.1.2 
Nonclinical Data .................................................................................................. 26 
1.1.3 
Clinical Data ....................................................................................................... 26 
1.1.3.1 
Pharmacokinetics .............................................................................. 26 
1.1.3.2 
Efficacy ............................................................................................ 27 
1.1.3.3 
Safety ............................................................................................... 27 
1.2 
Rationale for the Study ....................................................................................................... 28 
2 
Objectives .................................................................................................................................... 28 
3 
Study Design ............................................................................................................................... 29 
3.1 
Overview of the Study Design ........................................................................................... 29 
3.2 
Rationale for the Study Design ........................................................................................... 31 
4 
Ethics ........................................................................................................................................... 33 
4.1 
Ethical Rationale ................................................................................................................ 33 
4.2 
Informed Assent/Consent ................................................................................................... 35 
4.3 
Personal Data Protection .................................................................................................... 36 
4.4 
Independent Ethics Committees (IECs) and Institutional Review Boards (IRBs) .............. 36 
4.5 
Regulatory Approval/Notification Requirements ............................................................... 36 
5 
Study Population ........................................................................................................................ 37 
5.1 
Numbers of Patients and Sites ............................................................................................ 37 
5.2 
Patient Recruitment ............................................................................................................ 37 
5.3 
Selection Criteria ................................................................................................................ 37 
5.4 
Withdrawal Criteria ............................................................................................................ 40 
6 
Investigational Medicinal Products ........................................................................................... 41 
6.1 
Treatment Regimen ............................................................................................................ 41 
6.2 
IMPs, Formulations, and Strengths .................................................................................... 42 
6.3 
Manufacturing, Packaging, Labelling, and Storage of IMPs .............................................. 42 
6.4 
Method of Assigning Patients to Treatment ....................................................................... 43 
6.5 
IMP Accountability ............................................................................................................ 43 
6.6 
Unblinding Procedures ....................................................................................................... 43 
6.7 
Post-study Access to IMP................................................................................................... 44 
7 
Concomitant Medication ............................................................................................................ 44 
8 
Study Visit Plan .......................................................................................................................... 45 
8.1 
Overview ............................................................................................................................ 45 
8.2 
Screening Visit (Visit 1) ..................................................................................................... 45 
8.2.1 
Pre-screening ...................................................................................................... 45 
8.2.2 
Patient Identification Card .................................................................................. 45 


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8.2.3 
Re-screening ....................................................................................................... 45 
8.3 
Phase A (Visit 2 to 5) ......................................................................................................... 46 
8.4 
Phase B (Visit 6 to 12) ........................................................................................................ 46 
8.5 
Withdrawal Visit (Visit 12) ................................................................................................ 46 
8.6 
Safety Follow-up Visit/Contact (Visit 13) .......................................................................... 47 
8.7 
End-of-study Definition ..................................................................................................... 48 
9 
Brief Psychological intervention (BPI) ..................................................................................... 48 
10 
Assessments ................................................................................................................................. 48 
10.1 Screening and Baseline Procedures and Assessments ........................................................ 49 
10.1.1 
Demographics and Other Baseline Characteristics ............................................. 49 
10.1.2 
Diagnostic Assessments ...................................................................................... 49 
10.1.3 
The Kiddie-Schedule for Affective Disorders and Schizophrenia for 
School-aged Children, Present and Lifetime version (K-SADS-PL). ................. 49 
10.1.4 
K-SADS-PL Rater Qualification and Certification ............................................. 50 
10.2 Efficacy Assessments ......................................................................................................... 50 
10.2.1 
Clinician rated Scales ......................................................................................... 50 
10.2.1.1 
Use of Clinician-rated Scales ............................................................ 50 
10.2.1.2 
Children depression rating scale revised version (CDRS-R) ............ 50 
10.2.1.3 
Clinical Global Impression scales (CGI-S/I) .................................... 51 
10.2.1.4 
Children’s Global Assessment Scale (CGAS) .................................. 51 
10.2.1.5 
CDRS-R, CGI, CGAS Rater Qualification and Certification ............ 51 
10.2.2 
Patient and/or Parent Reported Outcomes (PROs) .............................................. 52 
10.2.2.1 
Use of PROs ..................................................................................... 52 
10.3 Blood Sampling for Vortioxetine and Fluoxetine Quantification ....................................... 53 
10.4 Safety Assessments ............................................................................................................ 54 
10.4.1 
Adverse Events .................................................................................................... 54 
10.4.2 
Clinical Safety Laboratory Tests ........................................................................ 54 
10.4.3 
Vital Signs .......................................................................................................... 56 
10.4.4 
Height and Weight .............................................................................................. 56 
10.4.5 
Electrocardiograms (ECGs) ................................................................................ 56 
10.4.6 
Physical and Neurological Examinations ............................................................. 57 
10.4.7 
Tanner evaluating ................................................................................................ 57 
10.4.8 
Assessment Tools ............................................................................................... 58 
10.4.9 
Paediatric Adverse Event Rating Scale (PAERS) ............................................... 58 
10.4.10 Columbia-Suicide Severity Rating Scale (C-SSRS) ........................................... 58 
10.4.11 General Behavior Inventory (GBI) 10-Item Mania Scale ................................... 59 
10.4.12 Rater Qualification and Certification .................................................................. 59 
10.5 Exploratory Assessments ................................................................................................... 59 
10.5.1 
Multidimensional Anxiety Scale for Children short version (MASC-10) ........... 59 
10.6 Exploratory Biomarker Assessments ................................................................................... 59 
10.6.1 
General Considerations ........................................................................................ 59 
10.6.2 
Blood Sampling for Gene Expression Profiling .................................................. 60 
10.6.3 
Blood Sampling for Metabolomic/Proteomic Biomarkers ................................... 60 
10.6.4 
Blood Sampling for Pharmacogenetics ............................................................... 61 
10.7 Order of Assessments ......................................................................................................... 61 
10.8 Total Volume of Blood Drawn and Destruction of Biological Material............................. 62 
10.9 Treatment Compliance ....................................................................................................... 62 
11 
Adverse Events ........................................................................................................................... 62 
11.1 Definitions .......................................................................................................................... 62 


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Status: Final 
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11.1.1 
Adverse Event Definitions .................................................................................. 62 
11.1.2 
Adverse Event Assessment Definitions .............................................................. 64 
11.2 Pregnancy ........................................................................................................................... 65 
11.3 Recording Adverse Events ................................................................................................. 65 
11.4 Reporting Serious Adverse Events ..................................................................................... 65 
11.5 Treatment and Follow-up of Adverse Events ..................................................................... 66 
12 
Data Handling and Record Keeping ......................................................................................... 67 
12.1 Data Collection ................................................................................................................... 67 
12.1.1 
Electronic Case Report Forms (eCRFs) .............................................................. 67 
12.1.2 
Patient Binders .................................................................................................... 67 
12.1.2.1 
Use of Patient Binders ...................................................................... 67 
12.1.2.2 
Rating Scales and Patient-reported Outcomes (PROs) ...................... 68 
12.1.2.3 
Serious Adverse Event Fallback Forms ............................................ 68 
12.1.3 
External Data ...................................................................................................... 68 
12.2 Retention of Study Documents at the Site .......................................................................... 68 
12.2.1 
eCRF Data .......................................................................................................... 68 
12.2.2 
Other Study Documents ...................................................................................... 69 
13 
Monitoring Procedures .............................................................................................................. 69 
14 
Audits and Inspections ................................................................................................................ 70 
15 
Protocol Compliance .................................................................................................................. 70 
16 
Study Termination...................................................................................................................... 70 
17 
Endpoints .................................................................................................................................... 71 
17.1 Primary Endpoints .............................................................................................................. 71 
17.2 Secondary Endpoints .......................................................................................................... 71 
17.3 Exploratory Endpoints ........................................................................................................ 72 
17.4 Safety Endpoints ................................................................................................................ 72 
18 
Statistical Methodology .............................................................................................................. 72 
18.1 Responsibilities .................................................................................................................. 72 
18.2 Analysis Sets ...................................................................................................................... 72 
18.3 Descriptive Statistics .......................................................................................................... 73 
18.4 Patient Disposition ............................................................................................................. 73 
18.5 Demographics and Other Baseline Characteristics ............................................................. 73 
18.6 Recent and Concomitant Medication ................................................................................. 73 
18.7 Exposure and Compliance ................................................................................................... 73 
18.8 Efficacy Analyses ............................................................................................................... 73 
18.8.1 
General Efficacy Analysis Methodology ............................................................ 73 
18.8.2 
Primary Analysis of the Primary Endpoint ......................................................... 74 
18.8.3 
Sensitivity Analyses of the Primary Endpoint .................................................... 74 
18.8.4 
Key Secondary Analyses .................................................................................... 74 
18.8.5 
Testing Strategy for multiplicity controlled analyses .......................................... 74 
18.8.6 
Analysis of the Secondary Endpoints ................................................................. 75 
18.8.7 
Analysis of the Exploratory Endpoints ............................................................... 75 
18.9 Pharmacokinetic Analyses ................................................................................................. 75 
18.10 Safety Analyses .................................................................................................................. 75 
18.10.1 Analysis of Adverse Events ................................................................................ 75 
18.10.2 Analysis of Other Safety Endpoints ..................................................................... 76 
18.11 Interim Analyses ................................................................................................................. 76 


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Trial Site Number: Study Level 
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18.12 Sample Size and Power ...................................................................................................... 76 
18.13 Statistical Analysis Plan ..................................................................................................... 77 
19 
Clinical Study Report and Publications .................................................................................... 77 
19.1 Clinical Study Report ......................................................................................................... 77 
19.2 Data Ownership .................................................................................................................. 77 
19.3 Publications ........................................................................................................................ 77 
20 
Indemnity and Insurance ........................................................................................................... 77 
21 
Finance ........................................................................................................................................ 78 
21.1 Site Agreement ................................................................................................................... 78 
21.2 Financial Disclosure ........................................................................................................... 78 
21.3 Equipment .......................................................................................................................... 78 
References.............................................................................................................................................. 79 


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LU Study Number: 12709A 
Pluto ID: CLI_01105943 
Status: Final 
Trial Site Number: Study Level 
Version: 1.0 
 
 
Appendices 
Appendix I 
Clinical Study Protocol Authentication and Authorisation ........................... 83 
Appendix II 
Recent and Concomitant Medication: Disallowed or Allowed with 
Restrictions ........................................................................................................ 85 


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Pluto ID: CLI_01105943 
Status: Final 
Trial Site Number: Study Level 
Version: 1.0 
 
 
List of Panels 
 
 
Panel 1 
Study Design ...................................................................................................................... 11 
Panel 2 
Study Procedures and Assessments .................................................................................... 13 
Panel 3 
Dose Titration Schedules ................................................................................................... 42 
Panel 4 
Clinical Safety Laboratory Tests ........................................................................................ 55 


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LU Study Number: 12709A 
Pluto ID: CLI_01105943 
Status: Final 
Trial Site Number: Study Level 
Version: 1.0 
 
 
 
List of Abbreviations and Definitions of Terms 
 
γGT 
γ-glutamyl transferase 
AIDS 
Acquired Immune Deficiency Syndrome 
ALT 
alanine aminotransferase 
ANCOVA 
analysis of covariance 
AP 
alkaline phosphatase 
APES 
All-patients-enrolled set 
APRS 
all-patients-randomised set 
APTS 
all-patients-treated set 
AST 
aspartate aminotransferase 
ATC 
anatomical therapeutic chemical 
BMI 
body mass index 
BP 
blood pressure 
BPI 
Brief Psychosocial Intervention 
bpm 
beats per minute 
BUN 
blood urea nitrogen 
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 
CHMP 
Committee for Medicinal Products for Human Use (European Union) 
Cmax 
maximum observed concentration 
CRA 
clinical research associate 
CRF 
case report form 
CRP 
C-reactive protein 
C-SSRS 
Columbia-Suicide Severity Rating Scale 
CYP 
cytochrome P450 isoenzyme 
DMC 
Data Monitoring Committee 
DO 
Doctor of osteopathic 
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 
FAS 
full-analysis set 
FDA 
United States Food and Drug Administration 
GAD 
Generalized Anxiety Disorder 


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Pluto ID: CLI_01105943 
Status: Final 
Trial Site Number: Study Level 
Version: 1.0 
 
 
 
GBI 
General Behaviour Inventory 
GPV 
Division of Global Pharmacovigilance, H. Lundbeck A/S 
HBsAg 
hepatitis B surface antigen 
hCG 
human chorionic gonadotropin 
HCV 
hepatitis C virus 
HDL 
high density lipoprotein 
HIV 
human immunodeficiency virus 
HR 
heart rate 
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 
INR 
international normalised ratio of prothrombin time 
IRB 
institutional review board 
IVRS 
interactive voice response system 
IWRS 
interactive web response system 
K-SADS_PL 
Kiddie-Schedule for Affective Disorders and Schizophrenia for School-aged 
Children, Present and Lifetime version 
LDH 
lactate dehydrogenase 
LDL 
low density lipoprotein 
LOCF 
last observation carried forward 
Lu 
Lundbeck 
MADRS 
Montgomery and Åsberg Depression Rating Scale 
MASC-10 
Multidimensional Anxiety Scale for Children short version 
MedDRA 
Medical Dictionary for Regulatory Activities 
MDD 
Major depression disorder 
MMRM 
mixed model for repeated measurements 
mRNA 
messenger ribonucleic acid 
NA 
not applicable 
NICE 
National Institute for Health and Care Excellence 
NOAEL 
no-observed-adverse-effect level 
OC 
observed cases 
OCD 
Obsessive Compulsory Disorder 
PCR 
polymerase chain reaction 
PCS 
potentially clinically significant 
PAERS 
Paediatric Adverse Event Rating Scale 
PedsQL VAS 
PedsQL Present Functioning Visual Analogue Scales 
PGA 
Parent Global Assessment – Global Improvement 


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Trial Site Number: Study Level 
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PIP 
Paediatric Investigational Plan 
PK 
pharmacokinetic(s) 
PQ-LES-Q 
Paediatric Quality of Life Enjoyment and Satisfaction Questionnaire 
PR 
specific ECG interval describing atrioventricular conduction 
PREA 
US Paediatric Research Equity Act 
PRO 
patient-reported outcome 
PTSD 
Post-traumatic Stress Disorder 
QP 
qualified person 
qPCR 
quantitative polymerase chain reaction 
QRS 
specific ECG interval describing ventricular depolarisation 
QT 
specific ECG interval describing ventricular depolarisation/repolarisation 
QTc 
heart-rate corrected QT interval 
RR 
specific ECG interval describing the ventricular depolarisation/repolarisation cycle 
SAE 
serious adverse event 
SCC 
Specialist Clinical Care 
SD 
standard deviation 
SERT 
serotonin (5-HT) transporter 
SmPC 
Summary of Product Characteristics 
SUSAR 
suspected unexpected serious adverse reaction 
t½ 
apparent elimination half-life 
TEAE 
treatment-emergent adverse event 
TMF 
trial master file 
TSH 
thyroid stimulating hormone 
WHO 
World Health Organization 


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Trial Site Number: Study Level 
Version: 1.0 
 
 
 
 
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 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.10,11 For this reason separate studies are to be conducted in children and 
adolescents.9 
The aim of this study is to evaluate the efficacy of vortioxetine 10 mg/day and 20 mg/day 
versus placebo after 8 weeks of treatment on depressive symptoms in children aged 7 to 11 
years with a DSM-5™ diagnosis of MDD. 
 
The following sections provide an overview of the nonclinical and clinical data currently 
available for vortioxetine. For further information please refer to the current version of the 
Investigator’s Brochure.12 
For information on the reference compound fluoxetine please refer to the Summary of Product 
Characteristics (SmPC)/Prescribing Information. 


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1.1.2 
Nonclinical Data 
 
The mechanism of action of vortioxetine is thought to be related to its direct modulation of 
serotonergic receptor activity and inhibition of the serotonin (5-HT) transporter (SERT). 
Nonclinical data indicate that vortioxetine is a 5-HT3, 5-HT7, and 5-HT1D receptor 
antagonist, 5-HT1B receptor partial agonist, 5-HT1A receptor agonist and inhibitor of the 
SERT, leading to modulation of neurotransmission in several systems. This multimodal 
activity is considered to be responsible for the antidepressant and anxiolytic-like effects and 
the improvement of cognitive function, learning and memory observed with vortioxetine in 
animal studies.13 
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).12 
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 


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children, but data suggests that the doses tested (5 to 20mg/day vortioxetine) and the up- 
titration scheme employed in this study are appropriate for the paediatric population. 
 
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 uncontrolled, 
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 and headache were the 
TEAEs with the overall highest incidence in this study, 11 (Nausea) and 12 (headache) 
patients. Nausea is also the most common TEAE in studies with adult patients, with an 


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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. 
 
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.14 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,15,16 and escitalopram in the treatment of 
adolescents with MDD.17,18 
Specific studies are necessary in the paediatric population and separate studies should 
generally be conducted in children and adolescents.19 This study is part of the agreed EMA 
Paediatric Investigational Plan (PIP) for vortioxetine and the US Pediatric Research Equity 
Act (PREA) with the purpose to investigate the antidepressive effect of vortioxetine in MDD 
patients aged 7 to 11 years. It is the expectation that the investigation plan will provide 
positive efficacy data, with a favourable safety and tolerability profile, and therefore 
demonstrate a positive benefit-risk ratio for the use of vortioxetine in the paediatric 
population. 
 
2 
Objectives 
• Primary objective: 
− to evaluate the efficacy of vortioxetine 10 mg/day and 20 mg/day versus placebo after 8 
weeks of treatment on depressive symptoms in children with a DSM-5™ diagnosis of 
MDD. 
• Secondary objectives: 
− to evaluate the efficacy of vortioxetine 10 mg/day and 20 mg/day versus placebo during 
the 8 weeks of treatment on: 
• global clinical impression 
• functionality 
• health-related quality of life 
− to assess pharmacokinetics of vortioxetine in paediatric patients, aged 7 to 11 years 
using population pharmacokinetic approach 
• Exploratory objectives: 
− to explore the efficacy of vortioxetine 10 mg/day and 20 mg/day versus placebo on co- 
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• Safety objectives: 
− to evaluate the safety and tolerability of vortioxetine 10 mg/day and 20 mg/day versus 
placebo in children with a DSM-5™ diagnosis of MDD 
 
3 
Study Design 
 
3.1 
Overview of the Study Design 
 
This study has been designed in accordance with the Declaration of Helsinki.20 
This is an interventional, multi-national, multi-site, randomised, two- phase, single- and 
double-blind, parallel-group, placebo-controlled, active reference (fluoxetine), fixed-dose 
study. 
 
The study was designed as a 4-arm study, with two doses of vortioxetine (10 and 20 mg), 
placebo, and fluoxetine (20 mg, included as an active reference). Due to recruitment 
difficulties, the study design was amended (Protocol Amendment PA3) focusing on the main 
objective of the study, as follows: 
 
An interim analysis to potentially stop the study early for either efficacy or futility will be 
performed when at least 240 randomized patients have either completed or been withdrawn 
from the study. If the study continues after the interim analysis, enrolment to the fluoxetine 
arm will be stopped and the study will continue as a 3-arm study. 
 
In addition, the testing strategy for the primary analysis is changed to allow reduction in 
sample size while maintaining the same statistical power. 
 
This study will be conducted in compliance with the protocol, Good Clinical Practice,21 and 
applicable regulatory requirements. 
 
An overview of the study is presented in Panel 1. 
 
The study will consist of a screening period of 5-15 days and will consist of two phases 
(Phase A and Phase B) after this screening period. 
 
Phase A is a single blind 4-weeks period where patients (and parents) are blinded and receive 
placebo + Brief Psychosocial Intervention (BPI). If not responding to BPI/placebo then 
patients are randomised into Phase B. 
 
Phase B is a double-blind 8-weeks period where patients and investigators are blinded. In this 
phase all patients continue to receive BPI in addition their randomized treatment, which can 
be either placebo, vortioxetine 10 mg, vortioxetine 20 mg, or fluoxetine 20 mg (fluoxetine 
only in the part 1 of the study, prior to interim analysis). 


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The patient is a boy or a girl, aged ≥7 and <12 at Screening Visit with a diagnosis of MDD 
according to DSM-5TM Criteria and a CDRS-R score ≥45 and a CGI-S score ≥4 at the 
Screening Visit and the Baseline A Visit (Week 0). 
 
Approximately 600 patients are planned for enrolment to the 4-week treatment with 
standardised brief psychosocial intervention and single-blind placebo period (Phase A). At the 
end of Phase A (Baseline B) patients with incomplete improvement are to be randomised to 
the 8 week double-blind Phase B as follows: 
 
Study part 1: Prior to the interim analysis, at least 240 patients will be randomized in a 1:1:1:1 
ratio to vortioxetine 10 mg, vortioxetine 20 mg, fluoxetine 20 mg, or placebo. 
 
Study part 2: If the study continues after interim analysis, patients will be randomized in a 
1:1:1 ratio to vortioxetine 10 mg, vortioxetine 20 mg, or placebo. 
 
In total, 438 patients will be randomised if the study continues after interim analysis, with 
approximately 126 patients in each of the vortioxetine and placebo groups, and approximately 
60 patients in the fluoxetine group. 
 
Incomplete improvement in depressive symptoms is defined as a <40% reduction from 
Baseline A on the Children depression rating scale revised version (CDRS-R), and with a 
(CDRS-R) ≥40 total score and confirmed by a Parent Global Assessment- Global 
Improvement (PGA) value of >2. 
 
Patients who do not fulfil the criteria of incomplete improvement in Phase A at Week 3 will 
be withdrawn from the study before Week 4. Patients who do not fulfil the criteria of 
incomplete improvement at week 4 will be withdrawn from the study and not participate in 
the double-blind Phase B of the study. No specific study related follow-up is required for 
these patients. However as rescue procedure, they may receive up to 4 outpatient visits to the 
study site for consultations over a two-month period. 
 
Patients will receive 5 sessions of standardised brief psychosocial intervention at Weeks 1, 2, 
3, 5 and 8. 
 
Interim analysis will be performed by an independent biostatistician as pre-specified in a 
charter. Only the decision to continue or terminate the study will be communicated to the 
Sponsor, without further details about the results. 
 
If the decision is to terminate the study early, patients ongoing in the study Phase B should 
complete the study according to the protocol. After completion of the phase B, these patients 
may be eligible to enter an open-label extension study. Patients ongoing in the study phase A 
at the early termination of the study will be offered treatment at the discretion of the 
investigator in line with clinical practice. As rescue procedure, they may receive up to 4 
outpatient visits to the study site for consultations over a two-month period. 
 
If the decision is to continue the study, patients ongoing in the study Phase B should complete 
their originally allocated treatment according to the protocol. Patients ongoing in the study 


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phase A should complete this phase according to the protocol. Those eligible for the part B 
will be randomized according to the new randomization scheme, i.e., in a 1:1:1 ratio to 
vortioxetine 10 mg/day, vortioxetine 20 mg/day, or placebo, which will be implemented as 
soon as the decision to continue the study is taken. 
 
An independent Data Monitoring Committee will be established in order to review the safety 
and tolerability data throughout the study. 
 
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 12709A is a randomised, two-phase single- and double-blind, fixed-dose 
study with the primary objective to evaluate the efficacy of vortioxetine 10 mg/day and 20 
mg/day versus placebo after 8 weeks of treatment on depressive symptoms in children with a 
DSM-5™ diagnosis of MDD. Secondary objectives are to evaluate the efficacy of 
vortioxetine 10 mg/day and 20 mg/day versus placebo during the 8 weeks of treatment on 
global clinical impression, functionality, health-related quality of life and to confirm the 
population pharmacokinetics of vortioxetine in paediatric patients, aged 7 to 11 years. In 
addition the efficacy of vortioxetine 10 mg/day and 20 mg/day versus placebo on co-morbid 
symptoms will be explored. 
 
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.22 The chosen doses of vortioxetine 
(10 and 20 mg/day) for this study is 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 11 years) designed to guide the choice of 
doses to be used in the planned paediatric investigation plan. 
 
The presence of a high placebo response rate is known to be a confounding factor in 
antidepressant studies, particularly in those enrolling children and adolescents. The recent 
studies of duloxetine in the treatment of paediatric patients with major depressive disorder 
(MDD) were failed as neither duloxetine nor the active control (fluoxetine, with known 
efficacy in children and adolescents with MDD), were statistically significantly different from 
placebo on the primary outcome measure.23,24 
The present study is designed with the aim to lower the placebo response and includes a 
single-blind phase (Phase A) where patients who respond to standardised brief psychosocial 
intervention and/or placebo will not be eligible for entering the double-blind IMP treatment 
Phase (Phase B). Furthermore patients and parents are blinded to the time point of 
randomisation to the double-blind phase in order to lower expectations. 


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The choice of the double-blind 8 week study duration is based on previous experience with 
positive studies and European guidelines.19 The 4-week single-blind period (Phase A) of 
treatment with standardised brief psychosocial intervention and single-blind (patients and 
parents) placebo run-in phase is in alignment with the new Guideline on clinical investigation 
of medicinal products in the treatment of depression19 and consistent with the NICE treatment 
guideline.25 Studies should include only patients with insufficient response to psychotherapy 
and all subjects should receive psychosocial interventions throughout the trials.19 For this 
reason patients who respond to placebo and or standardised brief psychosocial intervention 
received during the 4-week single blind period will not be included in the 8 week double blind 
treatment period. 
 
To standardise the psychosocial intervention, a brief psycho social intervention program (BPI) 
is developed for this study The BPI arises from the Specialist Clinical Care (SCC) programme 
and has its origins in the work of the ADAPT26 RCT team in order to implement high quality 
psychosocial intervention in the study. It is a pragmatic synthesis of clinical practice that 
results in good quality specialised psychosocial care for depressed children and adolescents. 
A detailed description of key elements of comprehensive BPI case management is provided in 
a manual that will be delivered to the site. 
 
The primary efficacy endpoint will be the CDRS-R total score, The CDRS-R 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 Parent Global Assessment- Global Improvement (PGA) is used as a secondary efficacy 
measure of the antidepressant effect symptoms and to confirm incomplete improvement in 
depressive symptoms. The PGA has been used receptively and successfully in studies in 
ADHD. The General Behavior Inventory 10-Item Depression Scale27 will also be used to 
assess depressive symptoms. The GBI 10- item version has been shown to discriminate 
between diagnostic groups using youth self-report.27, 28 The CGI-S and CGI-I are used for 
assessing disorder severity and improvement.29 
The Children’s Global Assessment Scale (CGAS) and the PedsQL Present Functioning Visual 
Analogue Scales (PedsQL™ VAS) will be used to assess functionality and the Paediatric 
Quality of Life Enjoyment and Satisfaction Questionnaire (PQ-LES-Q)30 will be used to 
assess health-related quality of life. Children and adolescents with MDD are at high risk of 
having severe difficulties in various domains of functioning and in quality of life.1,31 
Both the CGAS, PedsQL™ VAS and PQ-LES-Q are validated scales appropriate for use in 
children and adolescents with psychiatric disorders. 31,32 
The primary objective of this study is to demonstrate the superiority of vortioxetine versus 
placebo. In view of the recruitment difficulties experienced in the study, is it important to 
limit the size of the study while still ensuring that the main study objective can be addressed. 
The following modifications to the study design have been agreed with the regulatory 


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authorities in Europe (EMA/PDCO) and US FDA as a mean of optimising the ongoing 
paediatric vortioxetine studies to allow for their timely completion: 
 
• The testing strategy for the primary analysis is changed to a comparison of the pooled 
doses to placebo, to allow reduction in sample size while maintaining the same 
statistical power. The rationale for testing the pooled doses is that, under the design 
assumption of a similar effect for the vortioxetine doses, this strategy is more powerful 
than testing the doses separately and therefore allows for a smaller sample size (126 
patients per group as compared 150 patients per group). Importantly, the proposed 
testing strategy will still allow for subsequent multiplicity-controlled testing of each 
dose individually based on a closed testing procedure. 
 
• An interim analysis for efficacy or futility will be conducted based on the primary 
outcome data from at least 240 patients, to allow for early termination of the study if 
there is sufficient evidence of an effect of vortioxetine, or a clear lack thereof. If the 
results of the interim analysis meet neither the efficacy nor the futility criteria, the 
study will continue until the planned 438 patients have been randomized. 
 
• Recruitment to the fluoxetine group will stop after the interim analysis, if the study 
has to continue (Study part 2). Comparison to fluoxetine is not the primary objective 
and assay sensitivity can still be evaluated with reasonable precision based on the 
available data in the fluoxetine group. 
 
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 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 11 years) designed to guide the choice of doses to be used in 
the planned paediatric investigation plan. Hence the chosen doses of vortioxetine (10 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 the sole antidepressant 


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approved both in children and adolescents for MDD in EU and US, fluoxetine has been 
selected as comparator to provide evidence of assay sensitivity. 
 
This study will permit the investigation of the efficacy and safety of a new potential treatment 
of MDD in paediatric patients and the inclusion of a placebo group has major scientific 
importance in this evaluation to ensure adequate evaluation of efficacy as well as 
distinguishing disease manifestations from adverse reactions of the compound. The patients 
will be asked to attend the investigational clinic at regular intervals to ensure an adequate 
follow-up. All visits will be performed on an outpatient basis at the clinic, other than the 
follow-up visit that can be 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 prior to any investigation or procedure, in order to decrease anxiety and anticipation 
of pain. Potentially painful procedures such as venipuncture will be minimized with the use of 
topical anaesthesia. 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, 
electrocardiogram and physical examination) and these will be evaluated by the investigator 
at each visit to ensure the patient’s safety and wellbeing. 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. 
 
The key ethical dilemma in placebo-controlled studies lies in avoiding exposing children to 
unnecessary risk versus meeting the need for adequate information to guide clinical care. In 
view of this, as well as the challenges with recruiting paediatric patients into clinical research, 
study design modifications have been made in agreement with the Regulatory Authorities in 
Europe and US to reduce the size of the study. These modifications are considered ethically 
justified as they prevent unnecessary exposure of paediatric subjects to experimental 
treatments. In particular, implementation of an interim analysis ensures that the study is not 
continued unnecessarily, thereby avoiding that the enrolled children are put at unnecessary 
risk of receiving placebo or an inefficacious treatment. This may also enable children not 
participating in the study to get earlier access to the superior treatment. 
 
In accordance with Good Clinical Practice21 qualified medical personnel at Lundbeck or a 
delegate specify 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. 


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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 judgement. 
 
An independent Data Monitoring Committee will be established in order to review the safety 
and tolerability data throughout the study. The same DMC will cover all the clinical studies in 
the paediatric vortioxetine program. 
 
In accordance with Good Clinical Practice,21 the investigator will be responsible for all study- 
related medical decisions. 
 
4.2 
Informed Assent/Consent 
 
No study-related procedures, including any screening procedures, may be performed before 
the investigator has obtained written assent from the patient and written informed consent 
from his or her parents/legal representative. 
 
Changing (for example, discontinuing or down-tapering) a patient’s concomitant medications 
prior to the Screening Visit to ensure that the patient meets the selection criteria is a study- 
related activity and must not occur before the Informed Assents/Consents Forms have been 
signed. 
 
Minors are dependent on their legal representative(s) (typically their parent[s]) to assume 
responsibility for their participation in clinical studies.33 
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 assents/consents, the investigator or a designee must 
explain to the patients and their legal representatives the aims, methods, and potential hazards 
of the study and any discomfort it may entail. The patients and their legal representatives 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 must be informed of the possibility of withdrawing assents/consents 
(section 8.5). 
 
The patients and their legal representatives must be given ample time and opportunity to 
enquire about details of the study prior to deciding whether to participate in the study. 


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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 must be signed by his or her 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. 
 
The blood samples for exploratory biomarker analysis may be shared with academic or public 
institutions and companies; however, Lundbeck will retain full control of the samples and 
their use in accordance with the information in the Patient Information Sheet and a material 
transfer agreement. 
 
4.3 
Personal Data Protection 
 
The data collected in this study will be processed in accordance with the specifications 
outlined in the European Union legislation34 to ensure that requirements regarding personal 
data protection are met. If an external organization will process data on behalf of Lundbeck, a 
contractual procedure will be signed between Lundbeck and the external organization to 
ensure compliance with the above-mentioned legislation. 
 
4.4 
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 screen 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. 
 
4.5 
Regulatory Approval/Notification Requirements 
 
In accordance with local requirements, this study will be submitted to the regulatory 
authorities for approval or notification. The study will only be undertaken when Lundbeck has 
received written approval or confirmation of notification from the regulatory authorities. 


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5 
Study Population 
 
5.1 
Numbers of Patients and Sites 
 
Planned countries and regions: 
Patients from the European Union, Europe outside the European Union, North 
America and other geographical regions. 
 
Planned number of patients: 
 
to be screened (approximately): 
800 
to be enrolled (approximately): 
600 
to be randomised: 
438 
 
Planned number of: 
study sites (approximately): 
100 
 
5.2 
Patient Recruitment 
 
Competitive patient recruitment between countries and sites will be used during the entire 
recruitment period to ensure that the required numbers of patients are randomised within the 
planned recruitment period. 
 
The investigators will be notified immediately when the recruitment period comes to an end. 
 
5.3 
Selection Criteria 
 
Patient selection is based on the inclusion and exclusion criteria listed below. 
 
Patients who meet each of the inclusion criteria at the Screening Visit and Baseline A Visit 
and none of the exclusion criteria at the Screening Visit and Baseline A Visit are eligible to 
participate in this study. 
 
Patients with incomplete improvement of depressive symptoms in Phase A who meet the 
specific inclusion criteria at Baseline B (Week 4) visit are eligible to continue in Phase B of 
this study. 
 
Inclusion Criteria Phase A 
1. The patient is a boy or girl, aged ≥7 and <12years at screening (patients who turn 12 
years during the study will be allowed to continue in the study). 
2. The patient is capable of communicating with the site personnel. 
3. 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. 


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4. The patient has provided assent to participation and parent(s)/legal representative (s) 
signed the Informed Consent Form. 
5. The patient and parent(s)/ legal representative (s) is willing and able to attend study 
appointments within the specified time windows. 
6. The patient is an outpatient consulting a clinician. 
7. The patient has a primary diagnosis of MDD according to DSM-5™ although co-morbid 
anxiety disorders will be permitted (except Post Traumatic Stress Disorder (PTSD) and 
Obsessive Compulsive Disorder (OCD)). The diagnoses will be confirmed using the K- 
SADS-PL. 
8. The patient has a CDRS-R total score ≥45 at the Screening Visit and at the Baseline A 
Visit (Week 0). 
9. The patient has a CGI-S score ≥4 at the Screening Visit and at the Baseline A Visit 
(Week 0). 
10. Contraception criterion, if applicable: The patient, if a girl who is sexually active and 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), must use 
adequate contraception from the Screening Visit to 30 days following the last dose of 
IMP. 
11. Contraception criterion, if applicable: The patient, if a boy, who is sexually active, must 
use adequate contraception from the Screening Visit to 30 days following the last dose of 
IMP. 
12. The patient, if a girl aged ≥10 years old, or if a younger girl who, at the discretion of the 
investigator, was deemed to be of reproductive potential, must have a confirmed negative 
urine pregnancy test at the Screening Visit. 
 
Inclusion Criteria for participation in Phase B 
1. The patient has a CDRS-R total score ≥40 at the Week 3 visit and Week 4 visit. 
2. The patient has a decrease of the CDRS-R value (subtracted 17 to avoid flooring effect) 
compared to Baseline A < 40% at the Week 3 visit and Week 4 visit. 
3. The patient has a PGA value of >2 at the Week 3 visit and Week 4 visit. 
 
Exclusion Criteria 
1. The patient has previously been enrolled in this study. 
2. The patient has participated in a clinical study <30 days prior to the Screening Visit. 
3. 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. 
4. The patient has previously participated in a study with vortioxetine. 
5. The patient is under forced treatment. 
6. The patient is pregnant or breast-feeding. 
7. The patient receives on-going current psychotherapy that is planned to be intensified. 
Interpersonal psychotherapy (IPT) or cognitive behavioural therapy (CBT) are not 
allowed. 


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8. The patient has a history of severe drug allergy or hypersensitivity, or known 
hypersensitivity to any of the IMP(s) or their excipients. 
9. The patient has hereditary problems of fructose intolerance, glucose-galactose 
malabsorption, or sucrose-isomaltase insufficiency. 
10. The patient has any current psychiatric disorder (DSM-5™ criteria), established as the 
primary diagnosis, as assessed using The Kiddie-Schedule for Affective Disorders and 
Schizophrenia for School-aged Children, Present and Lifetime version (K-SADS-PL). 
11. The patient suffers from intellectual disability, organic mental disorders, or mental 
disorders due to a general medical condition (DSM-5™ criteria). 
12. The patient has a known intellectual disability (as suggested by a known IQ <70), or, 
clinical evidence or known social or school history indicative of intellectual disability. 
13. 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. 
14. 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. 
15. The patient has an attention-deficit/hyperactivity disorder (ADHD) that requires a 
pharmacological treatment that cannot be maintained on a stable dose of an appropriate 
stimulant medication for a minimum of 4 weeks prior to the Baseline A visit. 
16. The patient has a known first degree relative with a history of Bipolar Disorder. 
17. The patient is unable to swallow capsules. 
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 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 
− dermatological disorder 


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− 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 Screening Visit. 
22. The patient has one or more clinical laboratory test values outside the reference range, 
based on the blood and urine samples taken at the Screening Visit, that are of potential 
risk to the patient’s safety, or the patient has, at the Screening Visit: 
− 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. Patients with 
thyroid disease may be enrolled in the study provided they are stable and euthyroid. 
24. The patient has, at the Screening Visit: 
− 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 attempted suicide or is at significant risk of suicide (either in the opinion 
of the Investigator or defined as a “yes” to suicidal ideation questions 4 or 5 or answering 
“yes” to suicidal behaviour on the C-SSRS within the last 12 months). 
 
5.4 
Withdrawal Criteria 
A patient must be withdrawn from the study if: 
• the patient and/or his or her parent(s)/legal representative (s) withdraw(s) his or her 
assent/consent (defined as a patient and/or his or her parent(s)/legal representative (s) who 
explicitly take back his or her assent/consent); section 8.5 states how the patient’s data will 
be handled 
• the 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 
• the patient did not take IMP on the assigned dose level for 6 consecutive days 
• the patient has been randomised in error 
• any site personnel break the randomisation code for that patient 
• the patient becomes pregnant 
• the patient has a serum ALT or AST value >3 times the upper limit of the reference range 
and a serum total bilirubin value >2 times the upper limit of the reference range 


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• 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 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 screening period will be 5 to 15 days followed by a 4-week single-blind period (Phase A) 
of treatment with standardised brief psychosocial intervention and placebo. Patients who 
demonstrate an incomplete improvement of depressive symptoms at the end of Week 4 will 
be randomised to a double-blind, 8-week treatment period (Phase B) as follows: 
 
Study part 1: Prior to the interim analysis, at least 240 patients will be randomized in a 1:1:1:1 
ratio to vortioxetine 10 mg/day, vortioxetine 20 mg/day, fluoxetine 20 mg/day, or placebo. 
 
Study part 2: If the study continues after interim analysis, patients will be randomized in a 
1:1:1 ratio to vortioxetine 10 mg/day, vortioxetine 20 mg/day, or placebo. 
 
In total, 438 patients will be randomised if the study continues after interim analysis, with 
approximately 126 patients in each of the vortioxetine and placebo groups, and approximately 
60 patients in the fluoxetine group. 
 
Patients randomised to the 10 mg/day vortioxetine group will receive a lower initial dose (5 
mg/day for 2 days) prior to receiving 10 mg/day. Patients randomised to the 20 mg/day 
vortioxetine group will receive a lower initial dose (5 mg/day for 2 days followed by 10 
mg/day for 2 days and 15 mg/day for 2 days) prior to receiving 20 mg/day. Patients 
randomised to the fluoxetine 20 mg/day group will receive a lower initial dose (10 mg/day for 
6 days) prior to receiving 20 mg/day (Only applicable during Study part 1). 
 
Based on tolerability the dose may be reduced at Week 8 (Visit 10 = week 4 of Phase B). For 
patients randomised to vortioxetine the reduction will be by 5 mg/day and for fluoxetine 10 
mg/day (Only applicable during Study part 1). No dose increase will be allowed. 


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The dose titration schedules are presented in Panel 3. 
 
The capsule should be taken orally, once daily, preferably in the morning. 
 
Panel 3 
Dose Titration Schedules 
Study part 1: Applicable prior to interim analysis 
 
 
 
Visit 
Patients will take 1 capsule per day 
Treatment Group 
Vortioxetine 10 mg 
Vortioxetine 20 mg 
Fluoxetine 20 mg 
Placebo 
2-5 
Placebo 
Placebo 
Placebo 
Placebo 
6 
Up-titration 
Up-titration 
Up-titration 
Placebo 
7-9 
10 mg 
20 mg 
20 mg 
Placebo 
10-12 
10 mg or 5 mg* 
20 mg or 15 mg* 
20 mg or 10 mg* 
Placebo 
* Down-titration 
 
 
Study part 2: Applicable after interim analysis (if the study continues) 
 
 
 
 
Visit 
Patients will take 1 capsule per day 
Treatment Group 
 
 
 
 
 
 
* Down-titration 
 
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 encapsulated tablets 
• Fluoxetine – 10 mg and 20 mg encapsulated tablets or encapsulated capsules 
• Placebo – encapsulated tablets 
 
The IMPs will be identical in appearance. 
 
6.3 
Manufacturing, Packaging, Labelling, and Storage of IMPs 
 
The IMPs will be manufactured, packaged, labelled, released (by a qualified person [QP]), 
and distributed in accordance with the principles of Good Manufacturing Practice, under the 
responsibility of Lundbeck. 
Vortioxetine 10 mg 
Vortioxetine 20 mg 
Placebo 
2-5 
Placebo 
Placebo 
Placebo 
6 
Up-titration 
Up-titration 
Placebo 
7-9 
10 mg 
20 mg 
Placebo 
10-12 
10 mg or 5 mg* 
20 mg or 15 mg* 
Placebo 


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The IMP will be provided in 1-week wallet cards, containing 10 capsules. 
 
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 
 
An Interactive Voice Response System (IVRS/IWRS) will be used in this study. The patients 
will be assigned a screening number by the IVRS/IXRS system, and that number will be used 
to identify them throughout the study. 
 
When a patient is to be randomised, the investigator will contact the IVRS/IWRS. The 
IVRS/IWRS will allocate the patient to a treatment group during the call and assign the 
patient a randomisation number in accordance with the specifications from the Department of 
Biostatistics, H. Lundbeck A/S, and then follow up by fax, e-mail, or the web (depending on 
availability or preference at the site). 
 
6.5 
IMP Accountability 
 
The IMP(s) must be tracked at each site using two logs: 
• a site-specific log to track the complete inventory (that is, what is shipped between the site 
and Lundbeck) 
• a patient-specific log to track what is dispensed to and returned by the patient 
 
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(s). This record must be available 
for inspection at any time. 
 
6.6 
Unblinding Procedures 
 
GPV, and the investigator or the pharmacist (if applicable) will have access to the details of 
the double-blind treatment for each patient. Access to these details will be via IVRS/IWRS. 


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The IVRS/IWRS unblinding procedure is described in the IVRS User Guide. 
 
The investigator may only break the code if knowledge of the IMP is necessary to provide 
optimal treatment to the patient in an emergency situation. If possible, the investigator must 
consult the CRA before breaking the code. The investigator must record the date, time, and 
reason for breaking the code on the Completion/Withdrawal Form (this corresponds to the 
Completion/Withdrawal Visit, as the patient must be immediately withdrawn from the study) 
and sign the form. If the emergency situation was an adverse event, it must be recorded on an 
Adverse Event Form. The CRA must be notified immediately. 
 
The IVRS/IWRS will also capture the date and time of the code break call. Information on the 
allocated treatment will be provided during the call and by fax or e-mail, depending on 
availability/preference. 
 
6.7 
Post-study Access to IMP 
 
After completion of the study or withdrawal from the study, the patient must be treated in 
accordance with normal practice. 
 
No IMP will be provided by Lundbeck. 
 
7 
Concomitant Medication 
Concomitant medication is any medication other than the IMPs that are taken during the 
study, including the Screening Period. 
 
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 <3 months 
prior to the Screening Visit 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. 


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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. However, this will not apply for patients entering in an extension 
study. 
 
8.2 
Screening Visit (Visit 1) 
 
Screening Visit takes place between Day –5 and Day –15 prior to Baseline A. 
 
In exceptional cases, the visit interval between the Screening and Baseline Visits may be 
extended up to 30 days with consent from the Medical Monitor at Lundbeck, provided the 
Medical Monitor accepts the rationale provided for the extension. 
 
The screening period begins when the first screening assessment is done, after written 
Informed Assent/Consent has been obtained. If there is a need for washout of disallowed 
medication it should begin before any Baseline A assessment is done and must comply with 
the required washout periods in Appendix II. Baseline A assessment is described in Panel 2. 
 
8.2.1 
Pre-screening 
Each site must record in a pre-screening log which patients attended the Screening Visit. 
Preferably within 24 hours from the Screening Visit, a study-specific Pre-Enrolment Form 
needs to be completed by the site and transmitted to the Contract Research Organisation 
(CRO) for their review. A confirmation that the patient can continue further with the study 
procedures is required before randomization. 
 
8.2.2 
Patient Identification Card 
 
Each patient will be provided with a patient identification card that states, at a minimum, the 
name of the IMP, the study number, the patient identification number, the investigator’s 
name, and an emergency telephone number providing 24-hour service. 
 
The patient identification card should be returned to the investigator upon completion of the 
patient’s participation in the study. 
 
8.2.3 
Re-screening 
 
Re-screening is only allowed for patients with a complete Screening Visit and who fail to 
attend the Baseline A visit within the planned window due to e.g. logistical constraints. 


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Only the sponsor’s medical expert (or the CRO’s medical monitor) may give permission to re- 
screen a patient. 
 
Authorisation for re-screening may only be granted by the sponsor’s medical expert/CRO 
medical monitor after a thorough review of all data from the original Screening Visit. 
 
At the new Screening Visit, the patient (and/or his or her legal representative (if applicable) 
and the responsible caregiver) must sign new Informed Assent/Consent Forms. At the new 
Screening Visit, the patient will be assigned a new screening number. A re-screened patient 
must have a complete new Screening Visit, and all the eligibility criteria must be re-assessed 
at the new Screening Visit. 
 
The following information will also be recorded in the eCRF at the new Screening Visit: 
• that the patient has previously been screened for the study 
• that re-screening has been authorised by the sponsor’s medical expert or state who 
• the screening number that was assigned to the patient at the original Screening Visit 
If a patient is re-screened, no data from the original Screening Visit will be used. 
A patient may only be re-screened once. 
 
8.3 
Phase A (Visit 2 to 5) 
 
Phase A starts with Baseline A (Week 0) for the 4 week single-blind phase. 
 
Patients eligible for entering phase A will receive BPI at Week 1, 2 and 3 (visit 3, 4 and 5) 
and placebo. Patients who do not fulfil the criteria of incomplete improvement in Phase A at 
Week 3 will be withdrawn from the study before Week 4. Patients who do not fulfil the 
criteria of incomplete improvement at week 4 will be withdrawn from the study and not 
participate in the double-blind Phase B of the study. No specific study related follow-up is 
required for these patients. However, as rescue procedure, they may benefit from up to four 
outpatient visits to the study site for consultations over a two-month period. 
 
8.4 
Phase B (Visit 6 to 12) 
 
Phase B starts with Baseline B (Week 4) for the 8 week double-blind phase. 
 
The patients eligible for Phase B will be randomised at visit 6 (week 4) to one of the four 
treatment arms and receive BPI at Visit 7 and 10. 
 
8.5 
Withdrawal Visit (Visit 12) 
 
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. 


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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 11.5). 
The reason for withdrawal must be recorded on the Reason for Withdrawal Form. 
For a patient and/or his or her legal representative who withdraw assent/consent: 
• if the patient and/or his or her legal representative 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 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 
• if the patient and/or his or her legal representative explicitly request that his or her data 
collected from the time of withdrawal of assent/consent onwards not be used, this will be 
respected 
 
8.6 
Safety Follow-up Visit/Contact (Visit 13) 
 
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 on- 
going 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 on-going 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 on-going at the safety follow-up, the stop date must be recorded as “on-going”. 
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. 


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Patients who withdrew due to elevated AST or ALT values (see section 5.4) should be 
followed until the values normalise or stabilise or a diagnosis or a reasonable explanation has 
been established (see section 11.5). 
 
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. 
 
8.7 
End-of-study Definition 
 
The end of the study for an individual patient is defined as the last protocol-specified contact 
with that patient. The overall end of the study is defined as the last protocol-specified contact 
with the last patient on-going in the study. 
 
9 
Brief Psychological intervention (BPI) 
The patients will receive treatment with standardised brief psychosocial intervention during 
the study. The treatment will be spread across 5 sessions. There will be 3 sessions in Phase A 
(Weeks 1, 2 and 3), followed by 2 sessions in Phase B (Weeks 5 and 8). BPI for depression35 
is a comprehensive package of specialist care for children and adolescents with depression. It 
arises from the practise and formulation of a Specialist Clinical Care (SCC) programme and 
has its origins in the work of the ADAPT RCT26 team. It comprises: assessment, formulation, 
case management, achieving engagement with the young person and their parents, planning 
and delivery of treatment. It is structured around core clinical skills, key elements known to 
counter depressive tendencies, psycho-education & liaison and multi-systemic formulation 
(biological, psychological and social elements). A detailed description of key elements of BPI 
case management is provided in a manual that will be delivered to the site. The manual is 
intended as a guide to practice, not a session-by-session prescription. It is expected across the 
treatment period that due consideration is given to all elements described in the manual. The 
clinician is directed to use their clinical discretion to decide in which session to apply which 
element of BPI. Session length for BPI will be up to 30 minutes. The BPI session should be 
performed after assessment of efficacy scales. 
 
10 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 the severity of the illness. 


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10.1 
Screening and Baseline Procedures and Assessments 
 
10.1.1 Demographics and Other Baseline Characteristics 
 
Prior to enrolling a patient in the study, the investigator must ascertain that the patient meets 
the selection criteria. 
 
At the Screening Visit, the following will be recorded or assessed: 
• Relevant medical, social, psychiatric and neurological history including MDD history, 
time of diagnosis, treatment type and outcome (response and tolerability) 
• History of stimulant medication, if any 
• Demographics: age, sex, and race 
• Smoking, and alcohol consumption habits 
• Family psychiatric history 
• Traumatic life events 
• Height, weight 
• Puberty status (Tanner scoring) 
• Source of the recruitment: advertisement or other 
 
10.1.2 Diagnostic Assessments 
 
The K-SADS-PL will be used as screening assessment. The diagnosis of MDD (according to 
DSM-5™) will be established via a psychiatric evaluation. The K-SADS-PL will be used to 
confirm the diagnosis of MDD and to assess possible psychiatric co-morbidities. 
 
Detailed instruction 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 K-SADL-PL will be administered in local language. Only scales provided by Lundbeck 
that have been validated in the language to which they have been translated will be used in 
this study. 
 
10.1.3 The Kiddie-Schedule for Affective Disorders and Schizophrenia for School-aged 
Children, Present and Lifetime version (K-SADS-PL). 
 
The K-SADS-PL36 is a semi-structured diagnostic interview designed to assess current and 
past episodes of psychopathology in children and adolescents. The K-SADS-PL is interviews 
with the parent(s), the child, and information from other sources (for example, school report). 
The unstructured introductory interview establishes a rapport with the parent(s) and the child, 
the screening interview (comprising 82-items to survey key symptoms for current and past 
episodes of 20 different diagnostic areas) provides a diagnosis, and responses to skip-out 
criteria determine whether additional interviewing is necessary. If necessary, the additional 
interview consists of a maximum of five diagnostic supplements (affective disorders, 
psychotic disorders, anxiety disorders, behavioural disorders, and substance abuse, eating, and 


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tic disorders). The K-SADS-PL items are scored using a 2-point or a 3-point scale from 1 (no 
symptoms) to 3 (threshold levels of symptomatology). It takes approximately 180 minutes to 
complete both K-SADS-PL interviews (parent(s) and child). 
 
10.1.4 K-SADS-PL Rater Qualification and Certification 
 
The K-SADS-PL should be administered by a rater who has adequate experience with 
paediatric patients with MDD. The rater should be a psychiatrist or DO specialised in child 
and adolescent psychiatry, or a clinical paediatric (neuro-) psychologist involved in clinical 
practice. 
 
Any exceptions must be discussed and approved by Lundbeck. 
 
Only raters who have been certified in a study-specific Rater Certification Programme will be 
authorised to rate in this study. Documentation of training and certification will be delivered 
to the raters for archiving in the investigator trial master file (TMF). No patient may be rated 
before the documentation has been delivered. 
 
New raters joining the study will be trained and certified locally using the same certification 
processes. 
 
10.2 
Efficacy Assessments 
 
10.2.1 Clinician rated Scales 
 
10.2.1.1 
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. 
 
10.2.1.2 
Children depression rating scale revised version (CDRS-R) 
 
The CDRS-R37 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 


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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. 
 
10.2.1.3 
Clinical Global Impression scales (CGI-S/I) 
 
The CGI29 was developed to provide global measures of the severity of a patient’s clinical 
condition and improvement or worsening during clinical studies. 
 
The clinician will use the scale to assess depressive symptoms. 
 
The CGI consists of two clinician-rated subscales: severity of illness (CGI-S) and global 
improvement (CGI-I). 
 
The CGI-S provides the clinician’s impression of the patient’s current state of mental illness. 
The clinician uses his or her clinical experience of this patient population to rate the severity 
of the patient’s current mental illness on a 7-point scale ranging from 1 (Normal - not at all 
ill) to 7 (among the most extremely ill patients). 
 
The CGI-I provides the clinician’s impression of the patient’s improvement (or worsening). 
The clinician assesses the patient’s condition relative to Baseline A 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. 
 
10.2.1.4 
Children’s Global Assessment Scale (CGAS) 
 
The CGAS38 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. 
 
10.2.1.5 
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 
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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 certified in a study-specific Rater Certification Programme will be 
authorised to rate in this study. Documentation of training and certification will be delivered 
to the raters for archiving in the investigator trial master file (TMF). No patient may be rated 
before the documentation has been delivered. 
 
The individual scores from the primary scale rater qualification session will be used to 
document inter-rater reliability and filed in the sponsor TMF. 
 
New raters joining the study will be trained and certified locally using the same certification 
processes. Rater training and certification will be conducted by Scales vendor(s). 
 
For each individual patient, the same certified rater should rate the patient. For unforeseen 
circumstances, certified back-up raters should be available throughout the study. 
 
10.2.2 Patient and/or Parent Reported Outcomes (PROs) 
 
10.2.2.1 
Use of PROs 
 
The following PROs will be used: 
• GBI – assessing depressive symptoms 
• PGA – assessing depressive symptoms 
• PedsQL VAS – assessing functionality 
• PQ-LES-Q – assessing health-related quality of life 
The GBI, PGA, PedsQL VAS and PQ-LES-Q 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. 
 
10.2.2.1.1 General Behavior Inventory (GBI) 10-Item Depression Scale 
The GBI 10-item depression scale39 is a parent- and subject-rated scale designed to screen for 
depressive symptoms in children and adolescents. The ten depression items are rated on a 4- 
point scale from 0 (never or hardly ever) to 3 (very often or almost constantly). The total 
score ranges from 0 to 30, with higher scores indicating greater pathology. It takes 
approximately 5 minutes to complete the GBI 10-item depression scale. 
 
10.2.2.1.2 Parent Global Assessment – Global Improvement (PGA) 
 
The PGA40 is a parent- rated variation of the CGI-I to evaluate the severity of the child’s 
symptoms. The PGA reflects assessments of change from Baseline A symptoms using a 7 


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point scale ranging from 1 (very much improved) to 7 (very much worse). It takes 1 to 2 
minutes to score the PGA. 
 
10.2.2.1.3 The PedsQL Present Functioning Visual Analogue Scales (PedsQL™ VAS) 
 
The PedsQL™ VAS41 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. 
 
10.2.2.1.4 Paediatric Quality of Life Enjoyment and Satisfaction Questionnaire (PQ- 
LES-Q) 
 
The PQ-LES-Q42 is a patient-rated scale designed to assess satisfaction with life. It is an 
adaptation of the Quality of Life Enjoyment and Satisfaction Questionnaire (Q-LES-Q), 
which is used to measure quality of life in adults. The PQ LES Q consist of 15 items, item 1- 
14 assess the degree of satisfaction experienced by subjects in various areas of daily 
functioning and item 15 allows subjects to summarize their experience in a global rating. 
Each item is rated on a 5-point scale from 1 (very poor) to 5 (very good).The total score range 
of item 1-14 is 14 to 70, with higher scores indicating greater satisfaction. It takes 5 to 10 
minutes to complete the scale. 
 
10.3 
Blood Sampling for Vortioxetine and Fluoxetine 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 and fluoxetine using methods validated 
in accordance with the EMA Guideline on Bioanalytical Method Validation43 and the FDA 
Guidance for Industry.44 A bioanalytical protocol will be prepared by Lundbeck before the 
plasma samples are analysed. 
 
Selected samples will be subjected to incurred sample re-analysis (ISR) for fluoxetine as part 
of the in-study method validation of the applied bioanalytical method. PK results and ISR 
results will be clearly distinguished from each other in the bioanalytical study report that will 
be prepared by the Department of Bioanalysis, H. Lundbeck A/S. 


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10.4 
Safety Assessments 
 
10.4.1 Adverse Events 
 
The patients will be asked a non-leading question (for example, “how do you feel?”, “how 
have you felt since your last visit?”) at each visit, starting at the Screening Visit. 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 11 for further information on adverse events. 
 
10.4.2 Clinical Safety Laboratory Tests 
 
The clinical safety laboratory tests are listed in Panel 4. 


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Panel 4 
Clinical Safety Laboratory Tests 
 
Haematology 
B-haemoglobin 
B-erythrocyte count 
B-haematocrit 
B-total leucocyte count 
B-neutrophils (% of total leucocytes) 
B-eosinophils (% of total leucocytes) 
B-basophils (% of total leucocytes) 
B-lymphocytes (% of total leucocytes) 
B-monocytes (% of total leucocytes) 
B-thrombocyte count 
Lipidsa 
S-cholesterol (total) (non fasting) 
S-triglycerides (non fasting) 
S-low density lipoprotein (LDL) 
S-high density lipoprotein (HDL) 
Infectionc 
S-C-reactive protein (CRP) 
Urined 
U-protein (dipstick) 
U-glucose (dipstick) 
U-blood (dipstick) 
U-ketones (dipstick) 
Electrolytesa 
S-sodium 
S-potassium 
S-calcium (total) 
Pregnancye (women only) 
U-hCG 
B-hCG (confirmatory for 
positive urine test only) 
Endocrine and Metabolica 
S-albumin 
S-glucose (non fasting) 
S-TSHb 
Livera 
S-total bilirubin 
S-conjugated bilirubin 
S-alkaline phosphatase (AP) 
S-alanine aminotransferase (ALT) 
S-aspartate aminotransferase (AST) 
S-lactate dehydrogenase (LDH) 
S-γ-glutamyl transferase (γGT) 
Kidneya 
S-creatinine 
S-urea nitrogen (BUN) 
Serologyc 
S-HBsAg 
S-anti HCV 
B – blood; P – plasma; S – serum; U – urine 
a Clinical chemistry 
b Performed only at the Screening/washout visit in order to exclude patients with depression symptoms due to 
a thyroid dysfunction. 
c Performed at the Screening Visit only 
d Microscopic examination (leucocytes, erythrocytes, and casts) will be performed only if any of the urine 
evaluations are abnormal. 
e Performed at the Screening Visit only. Only for female patients aged ≥10 years or female patients at lower 
age judged by the investigator to be of childbearing potential. 
 
Blood samples for the clinical safety laboratory tests will be collected as outlined in Panel 2 
of the Clinical Study Synopsis. 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. 
 
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 


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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. 
 
10.4.3 Vital Signs 
 
Blood pressure 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 Report Form. 
 
10.4.4 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. 
 
10.4.5 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 eECGs 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. 


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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 the Adverse 
Event Report Form. 
 
10.4.6 Physical and Neurological Examinations 
The investigator may appoint a designee to be primarily responsible for performing the 
physical examinations provided this is permitted according to local regulations. The 
investigator must take responsibility for reviewing the findings. 
 
The physical examination must, at a minimum, include an examination of appearance, 
extremities, skin, head, neck, eyes, ears, nose, throat, lungs, chest, heart, abdomen and 
musculoskeletal system. The examination at the Screening Visit will be considered the 
baseline physical examination. 
 
The neurological examination must be performed by a physician. 
 
Abnormalities of clinical significance must be recorded as an adverse event on an Adverse 
Event Report Form. 
 
10.4.7 Tanner evaluating 
 
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 female the 5 stages of maturation are recognized by assessing pubic hair and breast 
development. For male the 5 stages of maturation are recognized by assessing pubic hair, 
growth of penis and testicles. Post-puberty is defined as a Tanner stage = 5 in both of 
observed criteria. 
 
The evaluation of Tanner stage will be performed by physician or trained nurse - they will be 
provided with figures depicting the somatic changes and tables describe these changes in 
words to facilitate the staging. 
 
Tanner staging will be performed at Screening Visit. 


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10.4.8 Assessment Tools 
 
The Paediatric Adverse Event Rating Scale (PAERS), The Columbia-Suicide Severity Rating 
Scale (C-SSRS) and GBI mania, will be used for evaluation of tolerability and safety. 
 
The PAERS, C-SSRS, and GBI will be administered in the local language. Only the scales 
provided for this Lundbeck study should be used. 
 
Detailed instructions on how to administer the scales and how to score using the scales will be 
provided to the sites in a Rater Station Site Manual. 
 
10.4.9 Paediatric Adverse Event Rating Scale (PAERS) 
 
The PAERS45 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 10.4). 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. 
 
10.4.10 Columbia-Suicide Severity Rating Scale (C-SSRS) 
 
The C-SSRS46 is a semi-structured interview developed to systematically assess suicidal 
ideation and behaviour of patients participating in a clinical study. The C-SSRS has 4 
questions addressing suicidal behaviour, 5 questions addressing suicidal ideation, and sub- 
questions assessing the severity. 
 
Different versions of the scale are available: in this study, the “Baseline Screening” version 
will be applied at the Screening Visit and the “Since last visit” version will be applied other 
visits including the C-SSRS. 
 
A version of the C-SSRS, specifically developed for the use in children, will be applied in the 
study population of children aged 7 to 11 years. 
 
An experienced clinician can use the C-SSRS after a short training session. It takes 
approximately 5 minutes to administer and rate the C-SSRS. 


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10.4.11 General Behavior Inventory (GBI) 10-Item Mania Scale 
 
The GBI 10-item mania scale47 is a parent- and subject-rated scale designed to screen for 
manic symptoms in children and adolescents. The 10 items are rated on a scale from 0 (never 
or hardly ever) to 3 (very often or almost constantly). The total score ranges from 0 to 30 
points, with high scores indicating greater pathology. It takes approximately 5 minutes to 
complete the GBI 10-item mania scale. 
 
10.4.12 Rater Qualification and Certification 
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 certified in a study-specific Rater Certification Programme will be 
authorised to rate in this study. Documentation of training and certification will be delivered 
to the raters for archiving in the investigator trial master file (TMF). No patient may be rated 
before the documentation has been delivered. 
 
New raters joining the study will be trained and certified locally using the same certification 
process. 
 
10.5 
Exploratory Assessments 
 
10.5.1 Multidimensional Anxiety Scale for Children short version (MASC-10) 
 
The MASC-1048 is designed to screen for anxiety in children, and is based on the 39-item 
MASC. The MASC-10 consists of 10 items assessing physiological symptoms, social anxiety, 
harm avoidance, and separation/panic. The anxiety symptoms are rated on a 4-point scale 
from 0 (never true about me) to 3 (often true about me). Total score ranges from 0 to 30, with 
higher scores indicating higher levels of anxiety. The MASC-10 takes approximately 5 
minutes to administer and score. 
 
10.6 
Exploratory Biomarker Assessments 
 
10.6.1 General Considerations 
 
Although the possible future exploratory biomarker analyses will help to increase our 
understanding of the aetiology of MDD and the molecular basis of the drug response, the 
efforts described in this protocol are strictly research based. Therefore, as the complex 
interactions between genes and disease are currently not characterised to a level that translates 
to a meaningful clinical advantage, individual results from the exploratory biomarker analyses 


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will not be given to the patients. For the same reasons, individual results will not be added to 
the patients’ medical records. 
 
The patients will have no direct benefit from the exploratory biomarker analyses. 
 
As blood sampling for the exploratory genomics, proteomics, and metabolomics is an integral 
part of the study, the main Patient Information Sheet covers these analyses. Conversely, blood 
sampling for the possible future genetic biomarker analysis is optional and a separate Patient 
Information Sheet covers this analysis. 
 
The blood samples for possible future exploratory biomarker analysis, or the data derived 
from these blood samples, may be shared with academic and public institutions and other 
companies. However, Lundbeck will retain full control of the samples and their use in 
accordance with the information in the Patient Information Sheet and a Material Transfer 
Agreement. Furthermore, the results based on the analysis of the samples may be pooled 
across studies to increase the statistical power of the analyses. 
 
A patient and/or his or her legal representative (if applicable) may, at any time and without 
stating a reason, specifically request the destruction of the patient’s exploratory biomarker 
sample, irrespective of his or her continued participation in the study. The investigator must 
send a written request on behalf of the patient to the international study manager. The 
investigator will receive written confirmation from Lundbeck when the sample has been 
destroyed. 
 
The blood samples for genomics, proteomics, and metabolomics will be single-coded using 
the patient’s screening number. The blood samples for genetic biomarker analysis will be 
double-coded as described in EMA’s position paper on pharmacogenetic terminology49 to 
ensure patient privacy protection. 
 
10.6.2 Blood Sampling for Gene Expression Profiling 
Blood samples for gene expression profiling will be collected in 2.5 mL PaxGene RNA tubes. 
The maximum volume of blood to be collected during the study for this purpose will be 
7.5 mL. 
 
The samples for gene expression profiling will be shipped to a Central Laboratory for sample 
storage. Sample preparation and analysis may be performed by a Contract Research 
Organisation (CRO) or by a bona fide research collaborator. 
 
10.6.3 Blood Sampling for Metabolomic/Proteomic Biomarkers 
 
Blood samples for metabolomic/proteomic biomarkers will be collected in 2 mL K2 EDTA 
tubes. 
 
The maximum volume of blood to be collected during the study for this purpose will be 6 mL. 


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The samples for metabolomic/proteomic biomarkers will be shipped to a Central Laboratory 
in the United States for sample storage. The analysis may be performed by a Contract 
Research Organisation (CRO) or by a bona fide research collaborator. 
 
10.6.4 Blood Sampling for Pharmacogenetics 
 
It is optional for the patient to donate a blood sample for exploratory pharmacogenetic 
analysis. 
 
A blood sample (2 mL) will be collected in K3 EDTA tube for subsequent DNA extraction. 
 
Blood tubes will be shipped on dry ice to the central laboratory, where DNA will be extracted 
and retained. DNA aliquots will be shipped to a Central Laboratory for storage. 
 
The genetic variants to be analysed may include single nucleotide polymorphisms (SNPs) and 
copy number variations (CNVs). The analytical methods may be polymerase chain reaction 
(PCR), qPCR (quantitative PCR), sequencing, or whole genome scans on microarrays. The 
analysis may be performed by a Contract Research Organisation (CRO) or by a bona fide 
research collaborator. 
 
10.7 
Order of Assessments 
 
The scales should preferably be administered in the following order: 
 
Screening Visit: 
• K-SADS-PL 
• CDRS-R 
• GBI 
• PAERS 
• C-SSRS 
• CGI-S 
 
At visits other than the Screening Visit: 
• CDRS-R 
• PGA 
• CGAS 
• PedsQL VAS, PQ-LES-Q, MASC-10 
• GBI 
• PAERS 
• C-SSRS 
• CGI-S, CGI-I 
 
The PAERS must be applied after the non-leading, open questions on any adverse events. 


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10.8 
Total Volume of Blood Drawn and Destruction of Biological Material 
 
The total volume of blood drawn from each patient will be approximately 47.5 mL during the 
study. 
 
Additional blood samples may be required if the original blood samples are not viable or if re- 
testing is required. 
 
All biological samples will be retained at the bioanalytical facility until the results have been 
reported. The samples will subsequently be destroyed by the responsible analytical laboratory. 
The bioanalytical lab will retain the samples until the bioanalytical report is final and no 
longer than 1 year from LPLV. The ISM/CRS will be notified that the samples are to be 
destroyed, and the documentation for sample destruction will be kept in the bioanalytical 
study file. 
 
The blood samples and any derived material for possible future exploratory pharmacogenetic 
analyses will be destroyed ≤15 years after the end of the study (see definition in section 8.7) 
by a Central Laboratory. 
 
The blood samples and any derived material for possible future exploratory gene expression 
profiling and metabolic or proteomic biomarker assessments will be destroyed ≤10 years after 
the end of the study (see definition in section 8.7) by a Central Laboratory. 
 
10.9 
Treatment Compliance 
 
It is the responsibility of the investigator to account for all IMP (ref to IMP accountability 
section 6.5). The investigator or her/his designee must agree not to dispense any IMP to any 
person, except patient/parents included in the study and he/she/they must further agree only to 
use IMP in accordance with protocol. 
 
In addition, measures of the blood concentration of vortioxetine and fluoxetine will indicate 
whether patient has been overall compliant throughout the study. 
 
11 Adverse Events 
 
11.1 
Definitions 
 
11.1.1 Adverse Event Definitions50 
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, 


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vital signs, ECGs), symptom, or disease temporally associated with the use of a medicinal 
product, regardless of whether it is considered related to the medicinal product. 
 
It is Lundbeck policy to collect and record all adverse events, including pre-treatment adverse 
events, that is, those that start after the patient has signed the Informed Assent Form and prior 
to the first dose of IMP. 
 
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 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 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 vortioxetine12 or the Summary of Product 
Characteristics (SmPC)/Prescribing Information for Fluoxetine), 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. 


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11.1.2 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. 
• 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. 
 
For pre-treatment adverse events, a causality assessment is not relevant. 
 
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 


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11.2 
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. 
 
11.3 
Recording Adverse Events 
 
Adverse events (including pre-treatment adverse events) must be recorded on an Adverse 
Event Form. The investigator must provide information on the adverse event, preferably with 
a diagnosis, or at least with signs and symptoms; start and stop dates (and start and stop time 
if the adverse event lasts less than 24 hours); intensity; causal relationship to 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. 
 
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 11.4). 
 
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. 
 
11.4 
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 
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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: 
Global Pharmacovigilance (GPV) 
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 Directive51 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 half-yearly, 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. 
 
11.5 
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. 
 
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 8.6). 


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Patients who withdraw due to elevated AST or ALT values (see section 5.4) 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. 
 
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. 
The same DMC will cover all the clinical studies in the paediatric vortioxetine program. 
 
12 Data Handling and Record Keeping 
 
12.1 
Data Collection 
 
12.1.1 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 12.1.3. 
 
The eCRFs use third party software (Rave®) to capture data via an online system on a 
computer. When the investigator enters data in the eCRF (ideally during the visit or as soon 
as possible [<3 days] thereafter), the data will be recorded electronically in a central database 
over encrypted lines, and all entries and modifications to the data will be logged in an audit 
trail. Access to the system will only be granted after appropriate and documented training. 
Written instructions for using the system will be provided along with the training. 
 
Electronic signatures will be used where signatures are required on pages and/or visits. 
Automated data entry checks will be implemented where appropriate; other data will be 
reviewed and evaluated for accuracy by the sponsor and/or representatives from ICON. All 
entries, corrections, and changes must be made by the investigator or a delegate. 
 
12.1.2 Patient Binders 
 
12.1.2.1 
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. 


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12.1.2.2 
Rating Scales and Patient-reported Outcomes (PROs) 
 
The patient binder contains paper version of the rating scale, K-SADS-PL and PRO, PedsQL- 
VAS. These will be completed by the rater(s) and the patient, respectively. The data will be 
transcribed to the Scoring Sheets in the eCRF by the investigator or a delegate. 
 
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 PROs in their local language. The patients’ 
responses may only be corrected by the patient. 
 
12.1.2.3 
Serious Adverse Event Fallback Forms 
 
Serious Adverse Event Fallback Forms must be used when the eCRF cannot be accessed. 
 
12.1.3 External Data 
 
All electronic data will be transferred using a secure method accepted by Lundbeck. 
 
The clinical safety and/or efficacy laboratory test results will be transferred by the central 
laboratory. The data will be loaded into the eCRF 
 
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 results of the IMP analysis will be transferred by Lundbeck Department of Bioanalysis 
• The ECG results will be transferred by the central ECG laboratory. 
 
12.2 
Retention of Study Documents at the Site 
 
12.2.1 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. 


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12.2.2 Other Study Documents 
 
The investigator must keep the investigator’s set of documents in the investigator TMF for at 
least 25 years after the Clinical Study Report has been approved or in accordance with 
national requirements, whichever is longer. Lundbeck will remind the investigator in writing 
of this obligation when the Clinical Study Report Synopsis is distributed to the site. 
 
If off-site storage is used, a study-specific binder will remain at the site after the other study- 
specific documents have been shipped for off-site storage. This binder is considered part of 
the investigator TMF and must be kept in a secure place by the site for the required period of 
time. The binder must contain, at a minimum, the following documents: a copy of the 
Investigator TMF Index, a certified copy of the Patient Identification Code List, and a 
Retrieval Form. 
 
When the required storage period has expired, the documents may be destroyed in accordance 
with regulations. 
 
13 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. 
 
If the investigator does not have a patient’s medical records, the investigator must attempt to 
obtain copies or a written summary of relevant medical records from the doctor who had 
treated the patient earlier and include the pertinent documentation in the patient’s medical 
records at the site. The investigator must attempt to obtain medical records documenting the 
patient’s lifetime MDD episodes and general medical history for the 3 months prior to the 
study. 
 
During the study, the 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. 
 
In this study a Risk Based Monitoring approach will be applied. 


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14 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 or randomisation 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. 
 
15 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. 
 
16 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 
• result of interim analysis (either efficacy or futility) 
 
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. 
 
17 Endpoints 
This section refers to the 8 week double-blind phase (Phase B) measuring changes from 
Baseline B (Week 4) after/during 8 weeks of treatment (Week 12 visit). Baseline refers to 
Baseline B. 
 
17.1 
Primary Endpoints 
 
• depressive symptoms: 
− change from Baseline B in the CDRS-R total score after 8 weeks of treatment 
 
17.2 
Secondary Endpoints 
 
• depressive symptoms: 
− change from Baseline B in the CDRS-R total score during the 8 weeks of treatment 
− CDRS-R response (defined as >50% reduction in the CDRS-R total score (subtracted 17 
points) from Baseline B) during the 8 weeks treatment period. 
− remission over the 8 week treatment period (defined as CDRS-R ≤28), at each visit 
assessed 
− change from Baseline B in the General Behaviour Inventory (GBI), using the 10-item 
depression subscale, during the 8 weeks of treatment 
score in the PGA during the 8 weeks treatment period 
 
• Global Clinical Impression: 
− change from Baseline B in the CGI-S score during the 8 weeks treatment period 
− score in the CGI-I during the 8 weeks treatment period 
− remission in the CGI-S score (defined as a CGI-S score of 1or 2) during the 8 week 
treatment period, at each visit assessed 
− response in the CGI-I score (defined as a CGI-I score of 1or 2) during the 8 week 
treatment period 
 
• functionality: 
− change from Baseline B in the CGAS score during the 8 weeks treatment period 
− change from Baseline B in the PedsQL VAS score during the 8 weeks treatment period 


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• health-related quality of life: 
− change from Baseline B in the PQ-LES-Q scores during the 8 weeks treatment period 
• pharmacokinetics: 
− pharmacokinetic parameters for vortioxetine and fluoxetine 
 
17.3 
Exploratory Endpoints 
 
• co-morbid symptoms: 
− change from Baseline B in the MASC-10 score during the 8 weeks treatment period 
 
17.4 
Safety Endpoints 
 
• adverse events (AEs) 
• tolerability will be assessed using the (PAERS) 
• absolute values and changes from baseline in clinical safety laboratory tests, vital signs, 
weight, height and ECG parameters 
• potentially clinically significant clinical safety laboratory test values, vital signs, weight, 
and ECG parameter values 
• C-SSRS categorisation based on C-CASA definitions (1, 2, 3, 4, and 7) 
• GBI using the 10-item mania subscales (patient and parental versions) 
 
18 Statistical Methodology 
 
18.1 
Responsibilities 
 
The Department of Biostatistics, H. Lundbeck A/S will perform the statistical analyses 
described below. An independent biostatistician will perform the interim analysis. 
 
18.2 
Analysis Sets 
• The following analysis sets will be used to analyse and present the data: 
− all-patients-enrolled (APES) – all patients enrolled to the 4-week Single-blind period 
(Phase A) who received at least one dose of IMP 
− all-patients-randomised Phase B (APRS) – all patients randomised to the double-blind, 
8-week treatment period (Phase B) 
− all-patients-treated set Phase B (APTS) – all patients randomised to the double-blind, 
8-week treatment period (Phase B) who took at least one dose of double-blind IMP 
full-analysis set Phase B (FAS) – all patients in the APTS who had a valid Baseline B 
assessment and at least one valid post-Baseline B assessment of the CDRS-R total score. 
• The patients and data will be classified according to these definitions at a Classification 
Meeting held after all the data have been entered in the study database and before the blind 


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has been broken. There will be two Classification Meetings. The first meeting will classify 
the patients for the interim analysis, and this classification will be kept at the second 
classification (after the end of the study). 
• The efficacy analysis will be based on the FAS. 
 
18.3 
Descriptive Statistics 
 
In general, summary statistics (n, arithmetic mean, standard deviation, median, lower and 
upper quartiles, minimum and maximum values) will be presented for continuous variables 
and counts and, if relevant, percentages will be presented for categorical variables. 
 
18.4 
Patient Disposition 
 
Patient disposition will be summarised by treatment group 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 (APES, APRS, APTS, and FAS). 
 
The number of patients who withdrew from treatment will be summarised by treatment group 
and primary reason for withdrawal as well as by treatment group and all reasons for 
withdrawal. 
 
Patient disposition and demographics will be summarised using descriptive statistics. 
 
18.5 
Demographics and Other Baseline Characteristics 
 
Demographics (sex, age, race), other baseline characteristics (height, weight and BMI), and 
baseline efficacy variables will be summarised by treatment group. 
 
18.6 
Recent and Concomitant Medication 
 
Recent and concomitant medication will be summarised by anatomical therapeutic chemical 
(ATC) code and generic drug name by treatment group. 
 
18.7 
Exposure and Compliance 
 
Exposure and compliance will be calculated per patient and summarised by treatment group. 
 
18.8 
Efficacy Analyses 
 
18.8.1 General Efficacy Analysis Methodology 
 
All the statistical tests of the efficacy endpoints will be two-sided tests performed at the 5% 
significance level and all confidence intervals (CIs) will be 95% CIs, unless otherwise 
specified. 


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18.8.2 Primary Analysis of the Primary Endpoint 
 
For the primary endpoint (change from Baseline B in the CDRS-R total score to Week 8 in 
phase B (Week 12)), comparisons of the pooled doses of vortioxetine 10 and 20 mg/day 
versus placebo will be made using Mixed Model Repeated Measurements (MMRM) with 
freely varying mean and covariance structure and with country as a fixed factor and Baseline 
B CDRS-R score as a covariate interacting with visit. Treatment (vortioxetine 10 mg/day, 
vortioxetine 20 mg/day, fluoxetine, and placebo) is included as a fixed factor interacting with 
visit. For the primary endpoint a contrast test with weights 0.5, 0.5, 0, and -1, respectively, to 
estimate the average effect of the pooled doses of vortioxetine against placebo, based on the 
LSMeans for the treatment by visit interaction at Week 8 in phase B (Week 12) will be used. 
This will be evaluated at a one-sided 2.5% significance level. 
 
18.8.3 Sensitivity Analyses of the Primary Endpoint 
 
The primary endpoint will also be analysed using an analysis of covariance (ANCOVA; OC 
and last observation carried forward [LOCF]) as sensitivity analysis. The Missing at Random 
assumption behind the MMRM model will be investigated. This sensitivity analysis will be 
performed with a) the same covariates and factors as the primary analysis and b) with age, 
weight and height as covariates as well. 
 
A sensitivity analysis investigating the impact of the study methodological changes will be 
performed if the study is not stopped at interim analysis. This will be done by adding a factor 
to the primary analysis indicating, whether the individual patient was enrolled prior to the 
change in study design or after. 
 
18.8.4 Key Secondary Analyses 
 
Using the same model as in the primary analysis an evaluation of the separate comparisons of 
vortioxetine 10 mg/day and vortioxetine 20 mg/day versus placebo will be made. These will 
be estimated based on LSMeans for the treatment by visit interaction at Week 8 in phase B 
(Week 12). Both of the comparisons will be evaluated at a one-sided 2.5% significance level. 
 
18.8.5 Testing Strategy for multiplicity controlled analyses 
Statistical significance can be claimed on the individual doses only if significance is claimed 
for the pooled vortioxetine doses. The multiplicity control for the primary and key secondary 
analyses is kept due to the closed testing principle. 
 
To further account for the sequential approach, including one interim analysis with stopping 
rules for efficacy and futility, an error-spending approach based on Kim & DeMets method 
will be applied on the outcome from the MMRM model.52 The precise procedure will be 
described in the Statistical Analysis Plan. 


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18.8.6 Analysis of the Secondary Endpoints 
 
For continuous endpoints, the same methodology as the primary analysis described for the 
primary endpoint will be used. In addition ANCOVA will be performed (OC and LOCF). 
 
For dichotomous endpoints, such as response and remission, logistic regression with 
treatment as a factor and the baseline score as a covariate will be used. This will be done 
based on OC, LOCF and NRI. 
 
18.8.7 Analysis of the Exploratory Endpoints 
For continuous endpoints, the same methodology as the primary analysis described for the 
primary endpoint will be used. In addition ANCOVA will be performed (OC and LOCF). 
 
18.9 
Pharmacokinetic Analyses 
 
Sparse sampling (2 time points) for vortioxetine and fluoxetine quantification will be 
performed but population PK will be applied for vortioxetine only. Plasma concentrations of 
fluoxetine will be listed. 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. 
 
18.10 Safety Analyses 
 
18.10.1 Analysis of Adverse Events 
Adverse events will be classified according to the time of onset of the adverse event: 
• pre-treatment adverse event – an adverse event that starts on or after the date the patient 
signed the Informed Consent Form and prior to the date of first dose of IMP 
• treatment-emergent adverse event (TEAE) – an adverse event that starts or increases in 
intensity on or after the date of first dose of IMP. 
 
Adverse events, sorted by system organ class (SOC) and preferred term, will be summarised 
by treatment group. 
 
The safety analyses will be based on the APES and the APTS. 
 
Adverse events will be summarised using descriptive statistics. Adverse events from Phase A 
will be reported separately as will adverse events and other safety endpoints from Phase B. 
 
Allocation of TEAEs to Treatment Periods 
 
TEAEs may be allocated into study periods (these will be defined in the Statistical Analysis 
Plan). 


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18.10.2 Analysis of Other Safety Endpoints 
 
The clinical safety laboratory test values, vital signs, and ECG parameters will be summarised 
by treatment group. Potentially clinically significant (PCS) values will be flagged and 
summarised. 
 
- Adverse events, PAERS scores, clinical safety laboratory tests, vital signs, weight/BMI, 
ECG parameters, physical examinations, GBI scores (using the 10-item mania subscale), and 
C-SSRS scores will be summarised using descriptive statistics. Adverse events and other 
safety endpoints will be reported separately for Phase A and Phase B 
 
18.11 Interim Analyses 
 
A DMC will monitor safety data in a blinded manner at regular intervals as specified in the 
DMC Charter. 
 
In addition, an interim analysis for efficacy and futility is planned to be performed. The 
interim analysis will take place when at least 240 patients (approximately 60 patients per 
treatment arm) have been randomised and have completed or been withdrawn from the study, 
and when the last patient has been randomised in study 12710A (the study in adolescents), 
whichever occurs latest. The details of interim analysis will be described in an Interim 
Analysis Plan. 
 
A sequential one-sided (also called asymmetric two-sided) testing strategy will be applied at a 
one-sided significance level of 2.5% and a power of 85%. Kim & deMets error spending 
function will be used for both the lower and upper boundaries. The model described in section 
18.8.2 will be used for the interim comparison of the pooled doses of vortioxetine versus 
placebo. 
 
The interim analysis will be performed by an independent statistical group. The Sponsor will 
only be informed about the decision to terminate or continue the study, as described in the 
Statistical Charter. If the decision is to terminate the study early, all patients ongoing in the 
study Phase B should complete the study according to the protocol. 
 
If the study continues after the interim analysis, the fluoxetine arm will be dropped. 
 
To ensure that the study is sufficiently powered an estimate of the variability of the primary 
endpoint and the withdrawal rate will be obtained. The analysis will be performed prior to the 
interim analysis and will be based on blinded and pooled data from all groups. Based on these 
estimates the power calculation will be updated and adequate actions will be taken if the study 
has lost power. 
 
18.12 Sample Size and Power 
 
To obtain a power of 85%, with a one-sided significance level of 2.5% and an expected effect 
size of 4 for each vortioxetine dose, and a standard deviation of 11 for the change from 
baseline for each dose, 102 patients need to be included in a non-sequential trial. 


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To maintain the power at 85%, the sample size needs to be increased for the loss of power due 
to the sequential approach. 
 
As a result, then taking a drop-out rate of 15% in Phase B into account, 126 randomized 
patients per arm will be required. 
 
In total, 378 randomised patients are required in the final analysis if the study continues after 
the interim analysis, and in addition approximately 60 patients will be randomised to the 
fluoxetine group (Study part 1), which means a total of 438 randomised patients. 
 
More details are provided in the statistical analysis plan. 
 
18.13 Statistical Analysis Plan 
 
An Interim Statistical Analysis Plan as well as 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, before the interim analysis. 
 
19 Clinical Study Report and Publications 
 
19.1 
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. 
 
19.2 
Data Ownership 
 
The data collected in this study are the property of Lundbeck. 
 
19.3 
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).53 
 
20 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 


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Version: 1.0 
 
 
 
study has been documented are provided. Insurance and liability will be in accordance with 
applicable laws and Good Clinical Practice. 
 
21 Finance 
 
21.1 
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. 
 
21.2 
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. 
 
21.3 
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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Version: 1.0 
 
 
 
References 
 
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31. Vitiello B, Rohde P, Silva S, Wells K, Casat C, Waslick B, et al. Functioning and Quality of Life 
in the Treatment for Adolescents With Depression Study (TADS). J Am Acad Child Adolesc 
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practice--substance and reliability as judged by intraclass correlations. Eur Child Adolesc 
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of natural persons with regard to the processing of personal data and on the free movement of 
such data, and repealing Directive 95/46/EC (General Data Protection Regulation). 27 April 2016. 
Official Journal of the European Union L119, 4 May 2016. 
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randomised controlled trial of cognitive behaviour therapy in adolescents with major depression 
treated by selective serotonin reuptake inhibitors. The ADAPT trial.Health Technol Assess. 2008 
May; 12(14):iii-iv, ix-60. 
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disorders and schizophrenia for school-age children-present and lifetime version (K-SADS-PL): 
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442-450. 
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assessment scale (CGAS). Arch Gen Psychiatry. 1983; 40: 1228-1231. 
39. Youngstrom EA, Zhao J, Mankoski R., Forbes RA, Marcus RM, Carson W, et al. Clinical 
significance of treatment effects with aripiprazole versus placebo in a study of manic or mixed 
episodes associated with pediatric bipolar I disorder Journal of Child & Adolescent 
Psychopharmacology 2013; 23: 72-79. 
40. Biederman J, Lopez FA, Boellner SW, Chandler MC. A randomized, double-blind, placebo- 
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45. 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. 
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Suicide Assessment (C-CASA): classification of suicidal events in the FDA’s pediatric suicidal 
risk analysis of antidepressants. Am J Psychiatry. 2007; 164(7): 1035-1043. 
47. Youngstrom EA, Frazier TW, Demeter C, Calabrese JR, Findling RL. Developing a 10-item 
mania scale from the Parent General Behavior Inventory for children and adolescents. J Clin 
Psychiatry 2008; 69: 831–839. 
48. March JS, Sullivan K, Parker J. Test-retest reliability of the multidimensional anxiety scale for 
children. Journal of Anxiety Disorders 1999; 13: 349-358. 
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Appendix I 
Clinical Study Protocol Authentication and Authorisation 


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Clinical Study Protocol 
Authentication and Authorisation 
 
 
Study title: 
Interventional, randomised, double-blind, placebo-controlled, active 
reference (fluoxetine), fixed-dose study of vortioxetine in paediatric patients 
aged 7 to 11 years, with Major Depressive Disorder (MDD) 
Study No.: 
12709A 
Edition No.: 
4.0 
Date of edition: 
21 August 2018 
 
 
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: 
 
Head of Med.Safety Psychiatry: 
 
 
 
Authorisation 
 
I hereby confirm that I am of the opinion that the ethical and scientific basis of this study is sound. 
 
 
Clinical Research - Paediatrics:  
 


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Version: 1.0 
 
 
 
 
 
 
 
 
 
 
 
 
 
Appendix II 
Recent and Concomitant Medication: 
Disallowed or Allowed with Restrictions 


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Version: 1.0 
 
 
 
Disallowed Recent and Concomitant Medication 
 
 
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 prior 
to Baseline A 
Visit 
Disallowed (X) During the Study for 
Chronic 
Use 
Episodic 
Use 
Comments or Exceptions 
Agents used for ADHD (non 
stimulant e.g. atomoxetine, 
guanfacine, and clonidine) 
2 weeks 
X 
X 
Psychostimulants agents (e.g. 
methylphenidate or amphetamine), are 
allowed if the patient as a minimum has 
had a 4-week stable dose period, prior 
to the study treatment. 
Anaesthetics 
General 
X 
X 
General anaesthetics are disallowed 
during the study except in case of 
emergency procedures requiring 
anaesthesia 
Local 
X 
Analgesics 
Narcotic 
analgesics 
X 
X 
NSAIDsa 
X 
Anorexics 
2 weeks 
X 
X 
Antiacne agents 
2 weeks 
X 
X 
Agents for topical use are allowed 
Antibiotics 
Only rifampicin is disallowed 
Anticoagulants 
X 
X 
Only low-molecular weight heparins 
are allowed for episodic use 
Anticonvulsants 
2 weeks 
X 
X 
Antidepressants 
2 weeks (5 weeks 
for fluoxetine) 
X 
X 
Monoamine oxidase inhibitors (MAOs) 
are contraindicated. 
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 
2 weeks 
X 
X 
Antinauseants (including 
dopamine antagonists) 
2 weeks 
X 
X 
Only phosphoric acid preparations, 
bismuth and cola syrup are allowed 
Antineoplastics 
X 
X 
Antiobesity agents 
X 
X 
Antiplatelet treatment 
(including low dose aspirin) 
X 
X 


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Drug Class 
Disallowed prior 
to Baseline A 
Visit 
Disallowed (X) During the Study for 
Chronic 
Use 
Episodic 
Use 
Comments or Exceptions 
Antipsychotics 
6 weeks 
(6 months for 
depot) 
X 
X 
Anxiolytics 
2 weeks 
X 
X 
Cough/cold agents 
X 
Preparations containing ephedrine, 
pseudoephedrine and codeine are 
allowed for episodic treatment for a 
maximum of 1 week 
Herbal remedies, which are 
psychoactive (e.g. St. John’s 
Wort, kava kava, valerian, 
ginkgo biloba) 
2 weeks 
X 
X 
Hormones 
X 
X 
Only thyroid hormone replacement, 
contraceptives and progesterone 
replacement therapy are allowed. 
Hypoglycaemic agents 
X 
Insuline 
X 
Mood stabilisers (including 
lithium, valproate, 
valpromide) 
6 weeks 
X 
X 
Muscle relaxant 
2 weeks 
X 
X 
Psychotropic agents not 
otherwise specified 
(including, tryptophan, and 
dopamine agonists) 
2 weeks 
X 
X 
Sedatives/hypnoticsb 
2 weeks 
X 
X 
Only zolpidem, zopiclone or zaleplon 
allowed, for severe insomnia, with a 
maximum of 2 nights per week. Only 
Melatonin is allowed with a maximum 
of 3 nights per week. The patient is not 
allowed to take any sleeping aid the 
night before a study visit. 
Systemic steroids 
X 
X 
A Both start and stop dates for each use are to be reported in the eCRF. 
B Both start and stop dates for each use are to be reported in the eCRF. Every tablet/capsule should be reported 
for this type of medication from two weeks prior to Screening Visit, until Visit 12. 

SAP_001.pdf: 
H. Lundbeck A/S
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Page 1 of 64
Statistical Analysis Plan
Interventional, randomised, double-blind, placebo-
controlled, active reference (fluoxetine), fixed-dose study 
of vortioxetine in paediatric patients aged 7 to 11 years, 
with Major depressive disorder (MDD)
Vortioxetine
Study No.:
12709A
Sponsor:
H. Lundbeck A/S (Lundbeck)
2500 Valby (Copenhagen), Denmark
SAP edition No.:
2.0
SAP edition date:
8 February 2022
Edition history:
Edition 1.0 (original SAP), 30 November 2015
(the version No. in the footer is the system version No.)
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.


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Table of Contents
List of Panels and Tables.......................................................................................................... 6
List of Abbreviations and Definitions of Terms....................................................................... 7
1
Objectives ......................................................................................................................... 9
1.1
Primary Objective................................................................................................... 9
1.2
Secondary Objectives.............................................................................................. 9
1.3
Exploratory Objective ............................................................................................. 9
1.4
Safety Objective(s).................................................................................................. 9
2
Study Design..................................................................................................................... 9
3
Endpoints........................................................................................................................ 12
3.1
Primary Endpoint.................................................................................................. 12
3.2
Secondary Endpoints............................................................................................. 12
3.3
Exploratory Endpoint............................................................................................ 13
3.4
Safety Endpoints................................................................................................... 13
4
Analysis Sets ................................................................................................................... 14
5
Descriptive Statistics....................................................................................................... 14
6
Patient Disposition.......................................................................................................... 15
6.1
Summary of Patient Disposition ............................................................................ 15
6.2
Withdrawal ........................................................................................................... 15
7
Demographics and Other Baseline Characteristics....................................................... 15
8
Recent and Concomitant Medication............................................................................. 16
9
Exposure and Compliance.............................................................................................. 16
10
Efficacy ........................................................................................................................... 18
10.1
General Efficacy Analysis Methodology ............................................................... 18
10.2
Interim Analysis.................................................................................................... 18
10.3
Testing Strategy .................................................................................................... 18
10.4
Analysis Methodology for the Primary Endpoint................................................... 19
10.4.1
Primary Analysis of the Primary Endpoint.............................................. 19
10.4.2
Rationale for Selected Analysis Method for the Primary Endpoint.......... 20
10.4.3
Model Assumptions for Analysis of the Primary Endpoint...................... 21
10.4.4
Sensitivity Analyses of the Primary Endpoint ......................................... 21
10.5
Analysis of the Secondary Endpoints..................................................................... 23
10.6
Analysis of the Exploratory Endpoint.................................................................... 24
11
Safety .............................................................................................................................. 25
11.1
Adverse Events ..................................................................................................... 25
11.1.1
General Methodology for Adverse Events .............................................. 25
11.1.2
Handling of Adverse Events................................................................... 25
11.1.2.1
Adverse Events Changing in Intensity or Seriousness ............. 25
11.1.2.2
Coding of Adverse Events ...................................................... 26
11.1.2.3
Assigning Treatment Emergent Status to Adverse Events 
Records .................................................................................. 26
11.1.2.4
Assigning Adverse Event Records to an Analysis Phase.......... 26


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11.1.3
All Adverse Events................................................................................. 26
11.1.4
Non-TEAE Records ............................................................................... 27
11.1.5
Treatment-emergent Adverse Events ...................................................... 27
11.1.6
Deaths.................................................................................................... 27
11.1.7
Serious Adverse Events.......................................................................... 27
11.1.8
Adverse Events Leading to Withdrawal.................................................. 27
11.1.9
Adverse Events Related to Tolerability................................................... 27
11.1.10
Adverse Events of Special Interest.......................................................... 28
11.2
General Methodology for Other Safety Data.......................................................... 28
11.3
Clinical Safety Laboratory Test Data..................................................................... 29
11.3.1
Data Presentation ................................................................................... 29
11.3.2
Urinalysis............................................................................................... 29
11.3.3
Potential Drug-induced Liver Injury (DILI)............................................ 29
11.3.4
Changes in Fasting and non-fasting Lipid and Glucose Concentrations... 30
11.4
Vital Signs, Height, and Weight ............................................................................ 30
11.4.1
Data Presentation ................................................................................... 30
11.5
ECGs .................................................................................................................... 31
11.5.1
Data Presentation ................................................................................... 31
11.6
Other Safety Endpoints ......................................................................................... 31
11.6.1
Columbia-Suicide Severity Rating Scale (C-SSRS) ................................ 31
11.6.2
Paediatric Adverse Event Rating Scale (PAERS).................................... 32
11.6.3
General Behavior Inventory (GBI) 10-Item Mania Scale......................... 33
12
Remote visits................................................................................................................... 33
13
Pharmacokinetic Analyses ............................................................................................. 33
14
Interim Analyses............................................................................................................. 33
15
Sample Size Considerations ........................................................................................... 33
16
Statistical Software......................................................................................................... 34
17
Changes to Analyses Specified in the Protocol and protocol amendments................... 34
18
Details on Data Handling ............................................................................................... 35
18.1
Derived Variables ................................................................................................. 35
18.1.1
Children depression rating scale revised version (CDRS-R).................... 35
18.1.2
Clinical Global Impression scales (CGI-S/I) ........................................... 36
18.1.3
Children’s Global Assessment Scale (CGAS)......................................... 36
18.1.4
General Behavior Inventory (GBI) 10-Item Depression Scale................. 36
18.1.5
Parent Global Assessment - Global Improvement (PGA)........................ 37
18.1.6
The PedsQL Present Functioning Visual Analogue Scales (PedsQL™ 
VAS)...................................................................................................... 37
18.1.7
Paediatric Quality of Life Enjoyment and Satisfaction Questionnaire (PQ-
LES-Q) .................................................................................................. 37
18.1.8
Multidimensional Anxiety Scale for Children short version (MASC-10). 37
18.1.9
Tanner evaluation................................................................................... 37
18.1.10
Paediatric Adverse Event Rating Scale (PAERS).................................... 38
18.1.11
General Behavior Inventory (GBI) 10-Item Mania Scale......................... 38
18.2
Identifying rows for analyses for rating scales and safety variables........................ 38
18.3
Handling of Missing or Incomplete Dates/Times ................................................... 40
18.3.1
IMP Start and Stop Dates by phase......................................................... 40
18.3.2
Medical Disorder Start and Stop Dates ................................................... 40


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18.3.3
Medication Start and Stop Dates............................................................. 40
18.3.4
Adverse Event Start Dates...................................................................... 40
18.4
Grouping of Small Countries................................................................................. 41
References ............................................................................................................................... 42


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Appendices
Appendix I
Statistical Analysis Plan  Authentication and Authorisation.............. 44
Appendix II
Study Flow Chart................................................................................. 46
Appendix III
Testing Strategy.................................................................................... 50
Appendix IV
SAS® Code............................................................................................. 52
Appendix V
PCS Criteria ......................................................................................... 61


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List of Panels and Tables
Panel 1
Study Design.........................................................................................................11
Panel 2
Secondary Efficacy Endpoints...............................................................................23
Panel 3
Insomnia related adverse events searches...............................................................28
Panel 4
C-SSRS Scores .....................................................................................................32
Panel 5
Assigning Period to Unscheduled Laboratory and ECG Assessments.....................35
Panel 6
Visit Windows Patients Withdrawn from Phase A.................................................39
Panel 7
Visit Windows Patients Withdrawn from Phase B .................................................39
Table 1
Lundbeck PCS Criteria for Clinical Safety Laboratory Tests..................................62
Table 2
Lundbeck PCS Criteria for ECG Parameters..........................................................64
Table 3
PCS Criteria for Vital Signs, Weight/BMI, and Waist Circumference....................64
Table 4
Normal ranges and PCS Criteria............................................................................64


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List of Abbreviations and Definitions of Terms
ALT
alanine aminotransferase 
ANCOVA
analysis of covariance
APES
All-patients-enrolled set
APRS
all-patients-randomised set
APTS
all-patients-treated set
AST
aspartate aminotransferase
ATC
anatomical therapeutic chemical
BMI
body mass index
BPI
Brief Psychosocial Intervention
BUN
blood urea nitrogen
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
CI
confidence interval
CRP
C-reactive protein
C-SSRS
Columbia-Suicide Severity Rating Scale
DSM-5™
Diagnostic and Statistical Manual of Mental Disorders, 5th edition
ECG
Electrocardiogram
eCRF
electronic case report form
FAS
full-analysis set
GBI
General Behavior Inventory
HDL
high density lipoprotein
HR
heart rate
IMP
investigational medicinal product
INR
international normalised ratio of prothrombin time
K-SADS-PL
Kiddie-Schedule for Affective Disorders and Schizofrenia for School-aged 
Children, Present and Lifetime version
LDH
lactate dehydrogenase
LDL
low density lipoprotein
LOCF
last observation carried forward
MAR
missing at random
MASC-10
Multidimensional Anxiety Scale for Children short version
MDD
Major depressive disorder
MedDRA
Medical Dictionary for Regulatory Activities 
MMRM
mixed model for repeated measurements
MNAR
missing not at random


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OC
observed cases
PAERS
Paediatric Adverse Event Rating Scale
PBO
placebo
PCS
potentially clinically significant
PedsQL
Pediatric Quality of Life Inventory
PGA
Parent Global Assessment – Global Improvement
PQ-LES-Q
Paediatric Quality of Life Enjoyment and Satisfaction Questionnaire
PRO
patient-reported outcome
PYE
patient years of exposure
QRS
specific ECG interval describing ventricular depolarisation
QT
specific ECG interval describing ventricular depolarisation/repolarisation
QTcB
heart-rate corrected QT interval using Bazett’s correction formula
QTcF
heart-rate corrected QT interval using Fridericia’s correction formula
REML
restricted maximum likelihood
SAE
serious adverse event
SAS
statistical software package from the SAS® Institute
SD
standard deviation
SOC
system organ class
TEAE
treatment-emergent adverse event


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1
Objectives
1.1
Primary Objective
To evaluate the efficacy of vortioxetine 10 mg/day and 20 mg/day versus placebo after 8 
weeks of treatment of depressive symptoms in children with a DSM-5™ diagnosis of Major 
depressive disorder (MDD).
1.2
Secondary Objectives
To evaluate the efficacy of vortioxetine 10 mg/day and 20 mg/day versus placebo during the 8 
weeks of treatment on:
• global clinical impression
• functionality 
• health-related quality of life
To assess pharmacokinetics of vortioxetine in paediatric patients, aged 7 to 11 years using 
population pharmacokinetic approach
1.3
Exploratory Objective
To explore the efficacy of vortioxetine 10 mg/day and 20 mg/day versus placebo on co-
morbid symptoms
1.4
Safety Objective(s)
To evaluate the safety and tolerability of vortioxetine 10 mg/day and 20 mg/day versus 
placebo in children with a DSM-5™ diagnosis of MDD
2
Study Design
This study has been designed in accordance with the Declaration of Helsinki.1
This is an interventional, multi-national, multi-site, randomised, two-period, single- and 
double-blind, parallel-group, placebo-controlled, active-reference (fluoxetine), fixed-dose 
study.
An overview of the study is presented in Panel 1.
The study was originally designed as a 4-arm study, with two doses of vortioxetine (10 and 20 
mg), placebo, and fluoxetine (20 mg, included as an active reference). Due to recruitment 
difficulties, the study design was amended (Protocol Amendment 3).


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An interim analysis to potentially stop the study early for either efficacy or futility was
performed when 271 randomized patients had either completed or been withdrawn from the 
study. An independent statistical group performed the interim efficacy analysis using the 
analyses for the primary hypothesis.
As the study continued after the interim analysis, enrolment to the fluoxetine arm was stopped 
and the study continued as a 3-arm study.
The study consists of a screening period of 5-15 days and consists of two Phases (Phase A 
and Phase B) after this screening period, and a safety follow-up period.
Phase A is a single-blind 4-weeks period where patients (and parents) are blinded and receive 
placebo + Brief Psychosocial Intervention (BPI). In case of incomplete improvement to 
BPI/placebo then patients are randomised into Phase B.
Phase B is a double-blind 8-weeks period where patients and investigators are blinded. In this 
Phase all patients continue to receive BPI and in addition either placebo, vortioxetine 10 mg, 
vortioxetine 20 mg, or fluoxetine 20 mg (NB: fluoxetine only prior to interim analysis).
The study includes male and female patients, aged ≥7 and <12 years at Screening Visit with a 
diagnosis of MDD according to DSM-5TM Criteria and a CDRS-R score ≥45 and a Clinical 
Global Impression – Severity of Illness (CGI-S) score ≥4 at the Screening Visit and the 
Baseline A Visit (Week 0).
Approximately 600 patients were planned for enrolment to the 4-week treatment with 
standardised brief psychosocial intervention (BPI) and placebo period (Phase A). At the end 
of Phase A, a total of 438 patients with incomplete improvement were planned to be 
randomised to the 8 week double-blind Phase B.  A blinded sample size re- assessment was 
performed prior to the interim analysis to ensure that the study was adequately powered, 
which resulted in an increase in sample size to 539 randomised patients (see Section 15).
Prior to interim analysis (Study part 1), patients were randomized in a 1:1:1:1 ratio to 
vortioxetine 10 mg/day, vortioxetine 20 mg/day, fluoxetine 20 mg/day, or placebo. After 
interim analysis (Study part 2), patients were randomized in a 1:1:1 ratio to vortioxetine 10 
mg/day, vortioxetine 20 mg/day, or placebo. 
Incomplete improvement in depressive symptoms is defined as a <40% reduction from 
Baseline A on the Children depression rating scale revised version (CDRS-R), and with a 
CDRS-R ≥40 total score and confirmed by a Parent Global Assessment- Global Improvement 
(PGA) value of >2.
Patients who do not fulfil the criteria of incomplete improvement in Phase A at Week 3 will 
be withdrawn from the study before Week 4. Patients who do not fulfil the criteria of 
incomplete improvement at week 4 will be withdrawn from the study and not participate in 
the double-blind Phase B of the study. No specific study related follow-up is required for
these patients. However, as rescue procedure, they may receive up to 4 outpatient visits to the 
study site for consultations over a two-month period. 


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Patients will receive 5 sessions of standardised BPI at Week 1, 2, 3, 5, and 8.
Patients randomised to the 10 mg/day vortioxetine group will receive a lower initial dose (5 
mg/day for 2 days) prior to receiving 10 mg/day. Patients randomised to the 20 mg/day 
vortioxetine group will receive a lower initial dose (5 mg/day for 2 days followed by 10 
mg/day for 2 days and 15 mg/day for 2 days) prior to receiving 20 mg/day. Patients 
randomised to the fluoxetine 20 mg/day group will receive a lower initial dose (10 mg/day for 
6 days) prior to receiving 20 mg/day.
Based on tolerability the dose may be reduced at Week 8 (Visit 10 = Week 4 of Phase B). For 
patients randomised to vortioxetine the reduction will be by 5 mg/day and for fluoxetine 10 
mg/day. No dose increase will be allowed.
An independent Data Monitoring Committee is established in order to review the safety and 
tolerability data throughout the study.
Panel 1
Study Design
Study part 1: 
Applicable prior to interim analysis 


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Study part 2: 
Applicable after interim analysis (from June 14th 2019)
3
Endpoints
3.1
Primary Endpoint
Depressive symptoms:
• change from Baseline B in the CDRS-R total score after 8 weeks of treatment  
3.2
Secondary Endpoints
Depressive symptoms:
• change from Baseline B in the CDRS-R total score during the 8 weeks of treatment 
• change from Baseline B in the CDRS-R sub scores Mood (4 items), Somatic (6 items), 
Subjective (4 items), and Behaviour (3 items) during the 8 weeks of treatment
• CDRS-R response (defined as ≥50% reduction (calculated as change from baseline divided 
by (baseline value-17)) in the CDRS-R total score from Baseline B) during the 8-week 
treatment period  
• remission over the 8-week treatment period (defined as CDRS-R ≤28), at each visit 
assessed


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• change from Baseline B in the General Behaviour Inventory (GBI) depression total score, 
using the 10-item depression subscale, assessed by parent (PGBI-10D) and child (CGBI-
10D), during the 8 weeks of treatment
• score in the PGA from one week after Baseline B during the 8-week treatment period
Global Clinical Impression:
• change from Baseline B in the CGI-S score during the 8-week treatment period 
• score in the Clinical Global Impression – Global Improvement (CGI-I) from one week 
after Baseline B during the 8-week treatment period 
• remission in the CGI-S score (defined as a CGI-S score of 1 or 2) during the 8 week 
treatment period, at each visit assessed
Functionality:
• change from Baseline B in the Children’s Global Assessment Scale (CGAS) score during 
the 8-week treatment period  
• change from Baseline B in the Pediatric Quality of Life Inventory (PedsQL) VAS score in 
each of the 6 domains during the 8-week treatment period
• change from Baseline B in the PedsQL average score over the 6 domains during the 8-
week treatment period
• change from Baseline B in the PedsQL emotional distress summary score during the 8-
week treatment period
Health-related quality of life:
• change from Baseline B in the Paediatric Quality of Life Enjoyment and Satisfaction 
Questionnaire (PQ-LES-Q) total score of item 1-14 during the 8 weeks treatment period
• change from Baseline B in the PQ-LES-Q overall evaluation score (item 15) during the 8-
week treatment period
Pharmacokinetics:
• pharmacokinetic parameters for vortioxetine and fluoxetine
All pharmacokinetic analyses will be addressed in a separate PK analysis plan.
3.3
Exploratory Endpoint
Depressive symptoms:
change from Baseline B in each CDRS-R item scores during the 8 weeks of treatment 
Co-morbid symptoms:
change from Baseline B in the Multidimensional Anxiety Scale for Children short version 
(MASC-10) total score during the 8-week treatment period
3.4
Safety Endpoints
adverse events (AEs)


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Paediatric Adverse Event Rating Scale (PAERS)
absolute values and changes from baseline in clinical safety laboratory tests, vital signs, 
weight, height and Electrocardiogram (ECG) parameters
potentially clinically significant clinical safety laboratory test values, vital signs, weight, 
and ECG parameter values
C-SSRS categorisation (suicidal ideation/suicidal behaviour)
change from Baseline B in the General Behaviour Inventory (GBI) mania total score, using 
the 10-item mania subscale, assessed by parent (PGBI-10M) and child (CGBI-10M) 
during the 8 weeks of treatment
4
Analysis Sets
The following analysis sets will be used to analyse and present the data:
All-patients-enrolled (APES) - all patients enrolled to the 4-week Single-blind period 
(Phase A)
all-patients-treated set Phase A (APTS_A) – all patients in APES who received at least 
one dose of investigational medicinal product (IMP)
all-patients-randomised set Phase B (APRS) – all patients randomised to the double-blind, 
8-week treatment period (Phase B)  
all-patients-treated set Phase B (APTS) – all patients randomised to the double-blind, 8-
week treatment period (Phase B) who took at least one dose of double-blind IMP 
full-analysis set Phase B (FAS) – all patients in the APTS who had a valid Baseline B 
assessment and at least one valid post-Baseline B assessment of the CDRS-R total score.
The patients and data will be classified into the analysis sets during a Classification Meeting
according to the definitions above after the study database has been released but before the 
blind has been broken for the final analysis. The classification of the patients in Study part 1 
should be kept at the final classification (after the end of the study).
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.
Unless otherwise specified, data listings will include site, study Phase, treatment group, 
patient screening number, sex, age, race, and baseline A weight.


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6
Patient Disposition
6.1
Summary of Patient Disposition
Patient disposition will be summarised by study Phase and by treatment group (in Phase B 
only) and include the number of patients in each analysis set defined in chapter 4, and the 
number of patients in Phase A (based on APES) and in Phase B (based on APRS) who 
completed or withdrew from the study.
6.2
Withdrawal
The number of patients who withdrew from study will be summarised in Phase A and by 
treatment group in Phase B. A summary of primary reason for withdrawal will be prepared for 
Phase A and summarised by treatment group in Phase B. A summary of all reasons for 
withdrawal will be prepared for Phase A and by treatment group in Phase B. 
In addition, as the study continued after the interim analysis, similar summaries will be 
created based on patients randomised before and after the drop of the fluoxetine arm, in order 
to check the potential introduction of bias in patient selection by implementing the major 
Protocol Amendment 3.
Patients who withdrew from study in each study Phase will be listed and the listings 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 from study for any reason will be presented by 
treatment group in Phase B. The time will be calculated from the date of first dose of IMP in 
the Phase B to the date of completion or withdrawal from study. Patients who completed the 
study Phase B will be regarded as censored.
All tables, graphs, and listings will be based on the APTS_A and APTS depending on the 
study Phase.
All tables and graphs will be repeated for the FAS for Phase B if relevant.
7
Demographics and Other Baseline Characteristics
Demographics (sex, age, and race), baseline characteristics (height, weight, and BMI), disease 
characteristics (MDE history: MDD history, including number of MDEs, year and duration of 
current episode, treatment type for MDD, and outcome/response and tolerability), Tanner 
score, and baseline efficacy variables, based on FAS, will be summarised in Phase A and by 
treatment group in Phase B using the relevant baselines. In addition, as the study continued
after the interim analysis, selected summaries will be created based on patients randomised 
before and after the drop of the fluoxetine arm, in order to check the potential introduction of 
bias in patient selection by implementing the major Protocol Amendment 3.


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The medical, neurological, psychiatric, and social histories as well as the concurrent medical, 
neurological, and psychiatric disorders will be coded using the Medical Dictionary for 
Regulatory Activities (MedDRA) and summarised.
A medical, neurological, or psychiatric history is a disorder that ended prior to the Screening 
Visit. A concurrent medical, neurological, or psychiatric disorder is a disorder that is ongoing 
at the Screening Visit.
Demographics, selected disease characteristics, and baseline characteristics will be 
summarised based on the APTS_A and the APTS depending on the study Phase.
8
Recent and Concomitant Medication
Recent and concomitant medication will be coded using the WHO Drug Dictionary 
(WHO-DDE).
For Phase A medications will be classified according to the start and stop time for the period 
and summarised by anatomical therapeutic chemical (ATC) code and generic drug name, and 
treatment group:
medication discontinued prior to first dose of IMP
concomitant medication continued after first dose of IMP
concomitant medication started at or after first dose of IMP and before first dose of IMP in 
Phase B
For Phase B medications will be classified according to the start and stop time for the period 
and summarised by ATC code, and generic drug name, and treatment group:
medication discontinued prior to first dose of IMP in Phase B for randomized patients
concomitant medication continued after first dose of IMP in Phase B
concomitant medication started at or after first dose of IMP in Phase B
The tables will be based on the APTS_A and APTS unless otherwise mentioned.
For assigning medications to an analysis phase, please see Data Handling Plan.
9
Exposure and Compliance
Exposure to IMP will be defined as:
date of last dose of IMP – date of first dose of IMP + 1
Exposure to IMP will be summarised by treatment group in Phase B using descriptive 
statistics, and 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.


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In addition, exposure to IMP will be categorised in intervals for Phase A (1 – 7 days, 8 – 14 
days, 15 - 21 days, 22 – days) and for Phase B (1 - 7 days, 8 – 14 days, 15 – 21 days, 22 – 28 
days, 29 - 42 days, 43-  days) and summarised by treatment group (only Phase B) in each 
study Phase. Missing values of exposure will not be imputed.
The number of patients who had at least one dose reduction due to poor tolerability will be 
summarised by treatment group.
Non-compliance 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 for an interval between two visits will be defined as:
{date of end of visit interval – date of beginning of visit interval + 1 – number of days 
of non-compliance in the visit interval} / {date of end of visit interval – date of 
beginning of visit interval + 1} × 100%
The visit interval will start on the day after the first visit of the interval and end on the day of 
the last visit, to reflect the interval in which compliance is captured.
Compliance with IMP for the entire study will be defined as the compliance for the interval 
between the Baseline A Visit and the Completion/Withdrawal Visit:
{date of Completion/Withdrawal Visit – date of Baseline A Visit + 1 – number of days 
of non-compliance between Baseline A Visit and Completion/Withdrawal Visit} / 
{date of Completion/Withdrawal Visit – date of Baseline A Visit + 1} × 100%
Compliance with IMP for Phase A will be defined as the compliance for the interval between 
the Baseline A Visit and the Baseline B Visit:
{date of Baseline B Visit – date of Baseline A Visit + 1 – number of days of non-
compliance between Baseline A Visit and Baseline B Visit} / {date of Baseline B Visit 
– date of Baseline A Visit + 1} × 100%
Compliance with IMP for Phase B will be defined as the compliance for the interval between 
the Baseline B Visit and the Completion/Withdrawal Visit:
{date of Completion/Withdrawal Visit – date of Baseline B Visit + 1 – number of days 
of non-compliance between Baseline B Visit and Completion/Withdrawal Visit} / 
{date of Completion/Withdrawal Visit – date of Baseline B Visit + 1} × 100%
Compliance with IMP will be categorised as “≤80% compliant” or “>80% compliant”. The 
number and percentage of patients in each category will be summarised in Phase A and by 
treatment group in Phase B, both by visit interval and for the entire study.
Exposure and compliance will be summarised based on the APTS_A for Phase A and APTS 
for Phase B, and repeated for the FAS for Phase B.


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10 Efficacy
10.1
General Efficacy Analysis Methodology
Unless otherwise specified, all the efficacy analyses will be based on the FAS, and all efficacy 
analyses will be done on both averaged and individual doses on vortioxetine.
As randomization to the fluoxetine arm has not been a possibility after the interim analyses, 
the number of fluoxetine patients in the final analyses will be substantially lower than for the 
placebo and vortioxetine patients. 
All the tables and graphs will be presented by treatment group in Phase B.
Unless otherwise stated, all the p-values will be based on two-sided tests; the confidence 
intervals (CIs) will be two-sided. P-values will be displayed with 4 decimal points in all 
relevant outputs.
For endpoints not included in multiplicity adjustment, nominal p-values will be presented 
together with nominal 95% CIs.
All efficacy assessments will be summarised using descriptive statistics by visit for Phase A 
based on the APTS_A and by treatment group in Phase B based on the APTS.
10.2
Interim Analysis
An interim analysis was conducted in July 2019.
The interim analysis was based on a sequential approach (see Interim Statistical Analysis 
Plan), including an interim analysis with binding stopping rules for efficacy and futility, and 
an error-spending approach based on Kim & DeMets method with rho=2 were applied on the 
outcome from the MMRM model.2
Details of the monitoring boundaries for the sequential approach used at the interim analysis 
are provided in the Interim Statistical Analysis Plan.
An overview of the analysis flow from interim to final analysis is shown in section 10.4.1 and 
the SAS programs to be used in Appendix IV.
10.3
Testing Strategy
The testing strategy is applied on the model in section 10.4.1 and is as follows with an overall 
significance level for the study of 2.5% one-sided:
Step 1: Test the average dose effects of the two vortioxetine doses against placebo at final 
analysis based on a one-sided test on the level obtained for the final analyses taking the alpha-


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spending for the interim into account. This new alpha-level will be calculated after 
unblinding.
Step 2: If significance is achieved in step 1, the two pairwise comparisons of the of the two 
vortioxetine doses (i.e., 10 mg/day or 20 mg/day) versus placebo will be performed separately 
based on a one-sided test on the same alpha-level as above.
The reason why both tests in step 2 can be performed without further multiplicity adjustment 
follows from a formal closed testing argument.
A formal descriptions of the closed testing principle can be seen in Appendix III.
10.4
Analysis Methodology for the Primary Endpoint
10.4.1
Primary Analysis of the Primary Endpoint
Change from Baseline B in the CDRS-R total in Phase B, will be analysed using a restricted 
maximum likelihood (REML)-based Mixed Model Repeated Measurements (MMRM) 
approach with freely varying mean and covariance structure and with country, treatment 
(vortioxetine 10 mg/day, vortioxetine 20 mg/day, fluoxetine, and placebo), and Week as fixed 
factors and Baseline B CDRS-R total score as a continuous covariate, the treatment-by-week 
interaction, and Baseline B CDRS-R-by-Week interaction. The Kenward-Roger 
approximation will be used to estimate denominator degrees of freedom. The analysis will be 
based on the missing-at-random (MAR) assumption and performed using all available 
observations (observed cases [OC] data) in Phase B.
The testing strategy is described in section 10.3, where the comparisons will be based on the 
least squares means for the treatment-by-visit interaction effect. The primary comparison will 
be the average effect with weights 0.5 and 0.5 of the two vortioxetine doses compared to 
placebo at Week 8 in Phase B based on the SAS LSMESTIMATE statement. The testing 
strategy also includes the comparisons of the individual vortioxetine doses to placebo.
The performed interim analysis is taken into account using the following stepwise approach:
The results from the interim analysis were used to update the interim-boundaries, based on the 
actual information fraction obtained at that time point. 
These updated interim-boundaries are then after unblinding combined with the results from 
the MMRM analysis to obtain the final alpha-level used in the evaluation of the primary 
analysis.
This final alpha-level will then also be used for analysing the two separate vortioxetine doses 
versus placebo.
The details of these steps can be seen in the SAS code for the primary analysis in Appendix 
IV.


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Both 95% CIs and (1-new alphalevel)*100% will be presented.
The country contributing the largest number of patients will be specified as reference group in 
the SAS CLASS statement country (ref=“XXX”), with XXX as the corresponding country 
code in order to ensure convergence. Should non-convergence appear despite this, the 
following sequence of steps will be used, continuing to the next step only if non-convergence 
persists:
1.
Grouped country will be used in the model instead of country (see section 18.4)
2.
Maximum likelihood (ML) method will be used instead of the restricted maximum 
likelihood (REML) method
3.
If non-convergence still persists, the sequence of steps (REML – ML) will be repeated 
with the following different covariance structures until convergence is reached:
a.
First-order Ante Dependence
b.
Heterogenous Toeplitz
c.
Heterogenous Compound Symmetry
d.
Compound Symmetry
10.4.2
Rationale for Selected Analysis Method for the Primary Endpoint
The MMRM analysis uses all available data measured repeatedly over time and allows for 
evaluation of the treatment-by-time interaction. The MMRM analysis provides an unbiased
estimate of the treatment effect under the assumption that missing data are MAR. The use of 
an analysis assuming missing not at random (MNAR) is more suitable as a sensitivity analysis 
to address the impact of clinically plausible deviations from MAR.3,4
Published data support the robustness of the MMRM analysis regarding protection against 
type I error and against bias, also in situations with a non-negligible proportion of missing 
data. Using extensive simulations, it has been demonstrated that the type I error is only 
affected to a limited extent and that the bias is small under the assumption that 1/3 of the 
missing data are missing-not-at-random, even when there is a severe imbalance between the 
treatment groups in the proportion of withdrawals.5
The chosen MMRM follows logically from the design of the study. The explanatory part of 
the model consists of the variables country, baseline CDRS-R score, visit and treatment. In 
this study stratification by site is done, and therefore including site as an explanatory variable 
is recommended in guidelines.6 In this case, country is used instead as the number of sites are 
very high. If needed, small countries may be grouped; the strategy for grouping countries is 
described in Section 18.4. The baseline CDRS-R total score is included in the model to 
account for any imbalances in the CDRS-R total score between treatment groups at baseline 
and because of the importance of baseline as a predictor of the endpoint. This is in accordance 
with the recommendations in guidelines.6 The baseline CDRS-R total score by-visit 
interaction is included in the model to allow for different dependence of the baseline CDRS-R 
score at different visits, and the treatment-by-visit interaction allows for estimation of the 
treatment effect at all visit, based on all available data.


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The unstructured covariance is feasible in this study because of the relative low number of 
visits, and allows for maximum flexibility in estimation. An unstructured modelling of time                          
and the treatment-by-time interaction provides an assumption-free approach, does not require 
estimation of an inordinate number of parameters, and can be depended upon to yield a useful 
result - attributes well suited to the primary analysis.7
In case of non-convergence the hierarchy of the chosen covariance structures was made so 
incremental model assumptions was added, meaning that the numbers of degrees of freedom 
was chosen as conservatively as possible.
10.4.3
Model Assumptions for Analysis of the Primary Endpoint
The assumption of normality will be investigated on an exploratory basis by inspection of a 
QQ-plot of the residuals.
The assumption of homoscedastic residuals will be investigated on an exploratory basis by 
inspection of a scatter-plot of the residuals versus the fitted values and by treatment group.
10.4.4
Sensitivity Analyses of the Primary Endpoint
Sensitivity analyses will be performed to evaluate how different assumptions affect the 
estimates of the treatment effect.
Sensitivity analysis using a pattern mixture model (PMM) for missing (valid) values, where it 
is assumed that the trajectory of patients with missing values in the vortioxetine groups is the 
same as that of the patients in the placebo group. The model will impute an outcome almost 
certainly worse than that assumed by MAR if vortioxetine is more efficacious than placebo.
Thus, this approach is likely to provide a conservative estimate of the treatment effect if there 
is a beneficial treatment effect for vortioxetine since it both penalises high withdrawal rates as 
well as higher withdrawal rates in the vortioxetine groups compared to placebo. Monotone 
missing values (missing values after last observed valid value) will be imputed using a 
sequential regression-based multiple imputation method, based on the imputation models 
established from the placebo group.8
The procedure for the PMM method will include the following steps:
1.
To prepare data for the PMM, non-monotone missing values (missing values before last 
valid observation), will be imputed using a Monte Carlo Markov Chain (MCMC) 
methodology assuming non-monotone missing values are missing at random. The 
imputation will be done by treatment group, and the model will include Baseline B 
CDRS-R total score and change from baseline B in CDRS-R total score at week 2, 4, 6, 
and 8 (Phase B). The SAS® procedure SAS®  PROC MI will be used, using 
seed=1952146, and 200 imputations (nimpute=200).
2.
Perform PMM on the monotone missing data created in step 1, where the monotone 
missing values are assumed to follow a MNAR pattern. The distribution for patients in 
the vortioxetine treatment groups at time t with last observation at time t-1, will be 
assumed to be equal to the conditional distribution for the placebo group with the 


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corresponding past. The regression model will include CDRS-R total score at Baseline B
and changes from Baseline B in CDRS-R total scores, by using SAS®  PROC MI using 
seed=195467 and the MONOTON REG () option.
3.
Assemble a dataset containing data for all patients, including the imputed data from time t 
to serve as predictors for the imputation of missing data at the next week
4.
Repeat steps 2) to 3) sequentially over all post-randomization visits at weeks (t+1, t+2, 
…)
5.
Each of the 200 complete datasets will be analysed using the same MMRM model as 
described in section 10.4.1.
6.
The estimated treatment effects for average effect of the two vortioxetine doses and the 
individual treatment groups obtained for the imputed datasets in step 5 will be combined 
to produce a unique point estimate and confidence interval using Rubin’s rule to form a 
unique point estimate and standard error (SE), taking into account the uncertainty of the 
imputation,9 using SAS® PROC MIANALYZE.
A sensitivity analysis of the primary endpoint will also be performed using an analysis of 
covariance (ANCOVA) model by visit using both the last observation carried forward 
(LOCF) and observed data (OC), including country and treatment (placebo, vortioxetine 10 
mg/day, vortioxetine 20 mg/day and fluoxetine 20 mg/day) as factors, and baseline B CDRS-
R Total Score as a continuous covariate. The mean difference between the averaged doses of
vortioxetine and placebo will be estimated from the model at Week 8 in Phase B (Study Week 
12). The estimates will be presented with p-values and 95% CIs.
The influence of other covariates such as age, sex, weight, height, and puberty as a covariate 
will be investigated with an ANCOVA with treatment and country as factors and baseline B 
score as a covariate and with both the use of appropriate interactions and main terms. The 
influence of quadratic terms of the covariates might be investigated similarly. All of this may 
lead to detailed subgroup analysis.
Evaluation of impact of potential non-compliance by PK concentration will be done (see the 
popPK plan for the study): after removing patients where PK indicates that they have not 
taken IMP, assessed through estimating oral clearance (CL/F; patients with CL/F values 
above 120 L/h are regarded as non-compliant) and/or plasma concentrations below lower 
quantification limit (LLOQ) ,an analysis based on an MMRM model similar to the one used 
in the primary analysis will be conducted.
If relevant, the potential impact of the major Protocol Amendment 3, will be investigated with 
an MMRM similar to the model for the primary analysis, where a factor will be added to the 
model indicating whether patients were randomised before or after the implementation of the 
amendment.
A supplementary analysis evaluating potential influential sites will be performed using the 
primary analysis model. Either via exclusion of sites or by site analysis as appropriate. 
The SAS code for the sensitivity analysis of the primary endpoint can be seen in Appendix 
IV.


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10.5
Analysis of the Secondary Endpoints
Panel 2
Secondary Efficacy Endpoints
Endpoint
Description
Type
Change from Baseline B in the CDRS-R score during the 
8 weeks of treatment
At each visit assessed after Baseline 
B
1
Change from Baseline B in the CDRS sub scores Mood, 
Somatic, Subjective, and Behaviour during the 8 weeks of 
treatment
At each visit assessed after Baseline 
B
1
CDRS-R response during the 8 weeks treatment period
At each visit assessed after Baseline 
B; defined as ≥50% reduction 
(calculated as change from baseline 
divided by (baseline-17)) in the 
CDRS-R total score from Baseline 
B) during the 8 weeks treatment 
period
2
Remission over the 8 week treatment period, at each visit 
assessed
defined as CDRS-R <28
2
Change from Baseline B in the GBI depression total 
score, both parent and child versions, using the 10-item 
depression subscale, during the 8 weeks of treatment
At each visit assessed after Baseline 
B
1
Change from Baseline B in the GBI mania total score, 
both parent and child versions, using the 10-item mania 
subscale, during the 8 weeks of treatment**
At each visit assessed after Baseline 
B
1
Score in PGA from two weeks after baseline B during the 
8 weeks treatment period
At each visit assessed after Baseline 
B
1
Change from Baseline B in the CGI-S score during the 8 
weeks treatment period
At each visit assessed after Baseline 
B
1
Score in the CGI-I from one week after Baseline B during 
the 8 weeks treatment period
At each visit assessed after Baseline 
B
1
Remission in the CGI-S score during the 8 weeks 
treatment period, at each visit assessed
At each visit assessed after Baseline 
B; defined as a CGI-S score of 1 or 2
2
Change from Baseline B in the CGAS score during the 8 
weeks treatment period
At each visit assessed after Baseline 
B
1
Change from Baseline B in the PedsQL VAS score in the 
6 domains during the 8 weeks treatment period
VAS score for each domain
separately at each visit assessed after
Baseline B
1
Change from Baseline B in the PedsQL average score 
over the 6 domains during the 8 weeks treatment period
At each visit assessed after Baseline
B
1


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Change from Baseline B in the PedsQL emotional distress
summary score during the 8 weeks treatment period
At each visit assessed after Baseline
B; defined as the average score of
domains anxiety, sadness, anger, and
worry
1
Change from Baseline B in the PQ-LES-Q total score 
during the 8 weeks treatment period
At each visit assessed after Baseline 
B
1
Change from Baseline B in the PQ-LES-Q overall
evaluation scores during the 8 weeks treatment period
At each visit assessed after Baseline
B
1
1 = continuous; 2 = binary;
**: this is a safety endpoint treated like an efficacy endpoint with a continuous outcome
Continuous secondary endpoints in Panel 2, type 1, will be analysed with an MMRM similar 
to the model specified for the primary endpoint with comparisons from the same model used 
for all time points. In addition, ANCOVA (OC and LOCF) will be performed per visit with 
treatment and country as factors and baseline B score as a covariate.
For analyses of the CGI-I score and PGA score, the CGI-I score and PGA score at Baseline B 
will be used as covariate.
For dichotomous outcomes, such as response and remission in Panel 2, type 2, the primary 
methodology for analysis at each week during Phase B (FAS, LOCF) will be logistic 
regression with treatment as factor and baseline B CDRS-R Total Score as a covariate, where 
the p-values and confidence intervals will be based on a Wald calculation. This will be 
supplemented by a similar analysis based on OC. In additional sensitivity analyses, patients 
having a missing value at the week analysed will be classified as a non-responder/non-
remitter (NRI), and the same logistic regression will be applied for both classifications.
For dichotomous outcomes the average effect of the two vortioxetine doses will be based on a 
SAS LSMESTIMATE statement using SAS PROC LOGISTIC.
All secondary analyses will present results for both the average effect of vortioxetine against 
placebo as well as the individual doses of vortioxetine and fluoxetine against placebo.
All comparisons will be presented with 95% CI and p-values.
10.6
Analysis of the Exploratory Endpoint
Comparisons between the averaged vortioxetine doses and placebo, as well as 10 and 20 
mg/day vortioxetine and placebo, for change from Baseline B in the CDRS-R item scores to 
week 8 in Phase B will be made using estimates from a MMRM model similar to the model 
specified for the primary endpoint.
Comparisons between the averaged vortioxetine doses and placebo, as well as 10 and 20 
mg/day vortioxetine and placebo, for change from Baseline B in the MASC-10 total score to 
week 8 in Phase B will be made using estimates from a MMRM model similar to the model 


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specified for the primary endpoint. In addition, ANCOVA (OC and LOCF) will be performed 
with treatment and country as factors and baseline score as a covariate.
11 Safety
11.1
Adverse Events
11.1.1
General Methodology for Adverse Events
Unless otherwise specified, tables, graphs, and listings will be based on the APTS_A and the 
APTS depending on the study Phase.
Tables by preferred term and tables by system organ class (SOC) and preferred term will be 
sorted in descending order by the percentage of patients in the highest dose group of 
vortioxetine and then by the percentage of patients in lowest dose group of vortioxetine then 
by the percentage of patients in the fluoxetine 20 mg/day group and the placebo group.
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. 
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 within each 
study Phase. Adverse events for which information on intensity is missing will be classified 
as severe.
Listings of adverse events will be sorted by patient, study Phase, site, treatment group, 
screening number, and adverse event start date and include preferred term, investigator term, 
adverse event start Phase and date, days since first dose of IMP in the study Phase, duration of 
the adverse event, action taken, causality, intensity, seriousness, and outcome. For adverse 
events that change in intensity, each intensity will be included.
11.1.2
Handling of Adverse Events
11.1.2.1
Adverse Events Changing in Intensity or Seriousness
In ADaM data, changes in intensity are included as additional records (rows) to the originally 
reported adverse event. For instance, an adverse event that changes from mild to moderate 
will have two records, one with intensity mild and one with intensity moderate.
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.


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11.1.2.2
Coding of Adverse Events
Adverse events will be coded using MedDRA version 21.0 or later.
11.1.2.3
Assigning Treatment Emergent Status to Adverse Events Records
Treatment Emergent status will be assigned to adverse event records based on the time of 
onset of the adverse event or worsening of the adverse event (increase in intensity compared 
to the preceding intensity or change from non-serious to serious) compared to first dose of 
IMP (for handling of change in intensity or seriousness are described in section 11.1.2.1, and 
handling of incomplete dates are described in section 18.3.4):
Treatment-emergent adverse event (TEAE) records -
All records for an adverse event that starts at or after the first dose of single-blind IMP 
The record for the first worsening and all records that follow the first worsening for an 
adverse event that starts before first single-blind IMP, and where the worsening occurs at 
or after the first IMP
Adverse event are considered causally related to the IMP when the causality assessment by 
the investigator is probable or possible.
For further details, see Data Handling Plan.
11.1.2.4
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 in which analysis phase an adverse event record is reported, and an adverse event 
may be reported in more than one analysis phase but only if it worsens. 
TEAE records will be assigned to an analysis phase according to handling of incomplete dates 
and are described in 18.3.4.
For further details, see Data Handling Plan.
11.1.3
All Adverse Events
All adverse events will be listed for the APES and for the APRS separately.
Overview of the PYE, numbers, and percentages of patients with TEAEs, serious adverse 
events (SAEs), adverse events leading to withdrawal, or who died will be provided based on 
the APTS_A and the APTS. For TEAEs, SAEs, and adverse events leading to withdrawal, the 
total number of events will be included.


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11.1.4
Non-TEAE Records
Non-TEAE adverse events (pre-treatment adverse events) will be summarised by preferred 
term based on the APES.
11.1.5
Treatment-emergent Adverse Events
The following summaries will be presented in Phase A and by treatment group in Phase B:
TEAEs by SOC and preferred term
TEAEs by preferred term
TEAEs with an incidence >=2% and >=5% in any treatment group by preferred term
causally related TEAEs by SOC and preferred term
TEAEs by intensity (mild/moderate/severe) and preferred term
causally related TEAEs by intensity and preferred term
11.1.6
Deaths
All adverse events for patients who died will be listed for the APES.
11.1.7
Serious Adverse Events
All SAE records will be listed for Phase A (APTS_A) and Phase B (APRS) separately. For 
patients not entering the planned extension study new SAEs will be collected during the 
safety/follow up visit and summarised.
Treatment-emergent SAE records will be summarised in Phase A and by treatment group in 
Phase B:
SOC and preferred term
preferred term
11.1.8
Adverse Events Leading to Withdrawal
All adverse events leading to withdrawal will be listed for Phase A (APTS_A) and Phase B 
(APRS) separately.
TEAEs leading to withdrawal will be summarised in Phase A and by treatment group in Phase 
B:
SOC and preferred term
preferred term
11.1.9
Adverse Events Related to Tolerability
Incidence and prevalence rates in every two-week interval during Phase B will be presented 
for nausea based on the APTS for events with complete start and stop dates.


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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 
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.
11.1.10
Adverse Events of Special Interest
Treatment-emergent nausea (preferred term), vomiting (preferred term) and insomnia (defined 
in Panel 3) will be summarised by treatment group in Phase B.
Panel 3
Insomnia related adverse events searches
Preferred term
Hyposomnia
Initial Insomnia
Insomnia
Middle Insomnia
Poor Quality Sleep
Sleep Disorder
Terminal Insomnia
Dyssomnia
11.2
General Methodology for Other Safety Data
Unless otherwise specified, tables, graphs, and listings will be based on the APTS_A and the 
APTS by treatment group.
Baseline will refer to either Baseline A or Baseline B depending on the study Phase.
The denominators for the summaries of a given variable will be based on the number of 
patients with non-missing values at a given visit or during the assessment period.
Descriptive statistics for the safety variables, both absolute values and changes from baseline
in Phase B, will be presented by visit and the last assessment. All available assessments will 
be included in the identification of the last assessment (scheduled, re-assessments, and 
unscheduled).
For variables for which potentially clinically significant (PCS) values are defined based on a 
relative change from baseline summary statistics for the relative change from baseline will be 
presented. For children (7-17 years of age) other PCS values for diastolic and systolic blood 
pressure have been used than those for adults.


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The number and percentage of patients with at least one PCS value at any post-baseline 
assessment time point will be summarised by variable. All available assessments will be 
included in the evaluation of PCS values (scheduled, re-assessments, and unscheduled).
For patients with post-baseline PCS values, listings will be provided including all available 
values for the variable, with flagging of PCS values and out-of-reference-range values.
The PCS definitions will be provided by H. Lundbeck and are stated in Appendix V.
11.3
Clinical Safety Laboratory Test Data
11.3.1
Data Presentation
All the clinical safety laboratory test values will be presented in conventional and/or Système 
International (SI) units.
Shift tables for all clinical lab parameters displaying shifts from normal to out-of-the-
reference range from Baseline B to withdrawal/completion will be provided by Phase B 
treatment and include the numbers and percentages of patients.
11.3.2
Urinalysis
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.
11.3.3
Potential Drug-induced Liver Injury (DILI)
Summaries will be presented by treatment group for Phase B.
Signals of DILI will be assessed according to the FDA guideline10 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
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


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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 in Phase B (ALT/AST, ALP, or BILI) will be 
listed, and the listing will include all available ALT, AST, BILI, and ALP, BILI,  GGT, and 
EOSEL 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 for Phase 
B. The criteria for the individual tests will be considered separately (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). The plot will include number of patients 
in each quadrant for each treatment group.
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 in Phase B. The test 
values will be normalised by the ULN (unit xULN) and the Y-axis will be on the log scale. 
All assessments at Visit 6 or in Phase B will be included, and the time will be days since first 
IMP in Phase B. Reference lines for the day of first-and last IMP in Phase B 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.
11.3.4
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 Baseline B to any visit in Phase B will be provided for 
each test and include the numbers and percentages of patients.
11.4
Vital Signs, Height, and Weight
11.4.1
Data Presentation
Descriptive statistics for the vital signs parameters in Phase A and Phase B will be presented 
by day and the last assessment in the Period.


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11.5
ECGs
11.5.1
Data Presentation
Shift tables displaying shifts from normal to out-of-the-reference range ECG findings from 
Baseline B to the Withdrawal/Completion Visit will be provided and include the numbers and 
percentages of patients.
11.6
Other Safety Endpoints
11.6.1
Columbia-Suicide Severity Rating Scale (C-SSRS)
The C-SSRS was assessed:
for lifetime (using the Baseline Version) – the C-SSRS assessment obtained at 
screening/baseline A that collects a lifetime recall
for the past 12 months (using the Baseline Version) – the C-SSRS assessment obtained at 
screening/baseline A that collects a recall of the past 12 months
at baseline (using the Since Last Visit Version) – the C-SSRS assessment obtained at 
baseline A that collects information for a pre-specified, limited period, for example, from 
screening to baseline
post-baseline A (using the Since Last Visit Version) – the C-SSRS assessments obtained 
after baseline A
Note, all assessments will be regarded as valid for C-SSRS (that is, the criteria that the 
assessment date-date of last IMP must be ≤7 days in Phase B will not be applied).
For lifetime, past 12 months, Baseline A, and Phase A and Phase B, patients will be counted 
as having No suicidal ideation or behavior (patients that answered no to all items in Panel 4), 
or for the most severe suicidal ideation or behavior (severity is given by the ascending order 
of the items in Panel 4). Number and percentage of patients in each category will be 
presented. In the tables, number and percentage of patients with any non-suicidal self-injury 
behavior will also be included. 
Lifetime, past 12 months, Baseline A will be presented for both APTS_A and APTS. Phase A 
and Phase B will be summarised for APTS_A, and APTS, respectively.


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Panel 4
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)
For patients with any post-baseline A suicidal behaviour (see Panel 4), listings will be 
prepared including all original C-SSRS items; C-SSRS scores related to suicidal behaviour 
will be flagged. The listing will be based on APES.
11.6.2
Paediatric Adverse Event Rating Scale (PAERS)
Note, all assessments will be regarded as valid for PAERS (that is, the criteria that assessment 
date-date of last IMP must be ≤7 days in Phase B 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 and all assessments will be assigned to an analysis phase, please see 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 the baseline (analysis value will be ‘Yes’ or ‘No’)
If a patient had a worsening of an item in a phase (Phase A or Phase B), all original 
assessments at the baseline (Baseline A for Phase A and Baseline B for Phase B) and in the 
phase will be listed.
For phase A, tables will be based on APTS_A, and listing will be based on APES.
For phase B, tables will be based on APTS, and listing will be based on APRS.


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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.
11.6.3
General Behavior Inventory (GBI) 10-Item Mania Scale
The GBI total score and change from baseline will be summarised by visit in Phase A and by 
visit and treatment group in Phase B.
12 Remote visits
Some patients may have remote visits, for example due to the COVID-19 virus, and primary 
efficacy analyses and safety tabulations will be done with respect to this subpopulation of 
patients (see Data Handling Plan).
Patients with remote visits will be summarized and listed.
13 Pharmacokinetic Analyses
A separate analysis plan for pharmacokinetic analyses will be prepared by the Department of 
Quantitative Pharmacology, H. Lundbeck A/S.
14 Interim Analyses
An interim analysis for efficacy and futility has been performed (see section 10.2).
BIOSTATA was contracted to perform the analyses for the Data Monitoring Committee
(DMC).
15 Sample Size Considerations
To obtain a power of 85%, with a one-sided significance level of 2.5% and an expected effect 
of 4 for each Vortioxetine dose, and a standard deviation of 11 for the change from baseline in 
CDRS-R for each dose, 102 patients needed to be included in a non-sequential trial.
To maintain the power at 85%, the sample size needed to be increased by a factor of 1.045
(see Blinded sample size re-assessment) to correct for the loss of power due to the sequential 
approach. This correction factor was obtained from R, and depends on the error spending 
function, its parameters, and the type I and type II errors.


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As a result, 102*1.045≈107 randomised patients per arm (vortioxetine 10 mg/day, 
vortioxetine 20 mg/day, placebo) were required in the final analysis. Taking a drop-out rate of 
15% in Phase B into account, 126 randomized patients per arm would be required.
In total, 378 randomized patients were required in the final analysis in addition to 68 patients 
was randomised to the fluoxetine group (Study part 1), which means a total of 446
randomised patients.
Per US FDA requirement, and as stipulated in the study protocol, a blinded sample size re-
assessment was performed prior to the interim analysis to ensure that the study is adequately 
powered. 
The SD estimate that appears to stabilize after approximately 160 patients (see Interim SAP) 
have been included. The mean value of the SDs observed after n=160 is 12.67 (with SDSD = 
0.1). The originally assumed SD for the study was 11. The observed withdrawal rate (WD) 
among the 271 patients was found to be 9.2 % since 246 patients provide data at Week 8. The 
originally assumed WD was 15%, thus, the observed withdrawal rate is less than originally 
assumed. With the updated SD and WD, the sample size of 480 patients for the fixed design 
was found to be insufficient to meet the target power. For a fixed design to have at least 85% 
power with and SD =12.67 and a withdrawal rate of 9.2%, n=150 patients would need to be 
randomised per group. 
In the sequential approach where an interim analysis were performed for 271 randomised 
patients (n=68) per group, the overall sample size was adjusted to n=157 per group. This 
gives a total sample size of 3*157+68 = 539 to be randomised as the decision at interim was 
to continue the study.  
16 Statistical Software
The statistical software used will be SAS® Version 9.4 or later.
17 Changes to Analyses Specified in the Protocol and protocol 
amendments
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
CDRS-R sub scores Mood, Somatic, Subjective, and Behaviour have been added as 
secondary endpoints
CDRS-R single items have been added as an exploratory endpoint
response in the CGI-I score (defined as a CGI-I score of 1 or 2) during the 8 week 
treatment period has been deleted
All previous major changes including interim analysis, average dose of vortioxetine versus 
placebo, and sample size re-assessment have been aligned with authorities.


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18 Details on Data Handling
Unless otherwise specified, the baseline value for Phase A will the latest value captured at or 
before Visit 2.
Unless otherwise specified, the baseline value for Phase B will be defined as the value at Visit 
6.
In the TFLs and CSR, Baseline A will be named Enrolment and Baseline B will be named 
Randomization.
Classification of adverse events into periods is defined in section 11.1.2.3.
For other data, assessments from unscheduled laboratory and ECG assessments will be 
assigned to an analysis phase according to Panel 5, while withdrawal visits and unscheduled 
scale assessments will be assigned to the study phase where assessment was performed (Phase 
A or Phase B). Scheduled visits will be assigned to an analysis phase based on the visit:
Screen (10 days) - Starts at the Screening Visit and continues up to, and including, Visit 2
Phase A (4 weeks) - Starts after Visit 2 and continues up to, and including, Visit 6
(including the withdrawal Visit for non-randomized patients)
Phase B (8 weeks) - Starts after Visit 6 and continues up to, and including, Visit 12 
Follow-Up Period - Starts after last Visit in Phase A (non-randomized patients) or Phase B 
(randomized patients)
In the TFLs and CSR, Phase A will be named Single-Blind Period, and Phase B will be 
named Double-Blind Period.
Panel 5
Assigning Period to Unscheduled Laboratory and ECG Assessments
Analysis
Period 
Assessment date ≤Visit 2
SCREEN
Visit 2<Assessment date ≤Visit 6    
Phase A
Assessment date>Visit 6 (randomized patients)
Phase B
18.1
Derived Variables
18.1.1
Children depression rating scale revised version (CDRS-R)
The CDRS-R is a clinician-rated scale to measure the severity of depression of children and 
adolescents. The CDRS-R consists of 17 items out of which 3 items rate nonverbal 
observations (listless speech, hypoactivity, and depressed affect). Fourteen items are rated on 
a 7-point scale from 1 to 7 and three items (sleep disturbance, appetite disturbance, and 
listless speech) are scored on a 5-point scale from 1 to 5. The total score ranges from 17 


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(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.
Four subscores11 are defined based on the CDRS-R:
Mood: sum of items 8, 11, 14, 15; score range 4 to 28
Somatic: sum of items 4, 5, 6, 7, 16, 17; score ranges from 6 to 36
Subjective: sum of items 9, 10, 12, 13; score ranges from 4 to 28
Behaviour: sum of items 1, 2, 3; score ranges from 3 to 21
18.1.2
Clinical Global Impression scales (CGI-S/I)
The CGI was developed to provide global measures of the severity of a patient’s clinical 
condition and improvement or worsening during clinical studies.
The clinician will use the scale to assess depressive symptoms. 
The CGI consists of two clinician-rated subscales: severity of illness (CGI-S) and global 
improvement (CGI-I). 
The CGI-S provides the clinician’s impression of the patient’s current state of mental illness. 
The clinician uses his or her clinical experience of this patient population to rate the severity 
of the patient’s current mental illness on a 7-point scale ranging from 1 (Normal - not at all 
ill) to 7 (among the most extremely ill patients).
The CGI-I provides the clinician’s impression of the patient’s improvement (or worsening). 
The clinician assesses the patient’s condition relative to baseline A 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.
18.1.3
Children’s Global Assessment Scale (CGAS)
The CGAS12 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 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.
18.1.4
General Behavior Inventory (GBI) 10-Item Depression Scale
The GBI 10-item depression scale13 is a parent- and subject-rated scale designed to screen for 
depressive symptoms in children and adolescents. The ten depression items are rated on a 4-
point scale from 0 (never or hardly ever) to 3 (very often or almost constantly). The total 


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score ranges from 0 to 30, with higher scores indicating greater pathology. It takes 
approximately 5 minutes to complete the GBI 10-item depression scale.
18.1.5
Parent Global Assessment - Global Improvement (PGA)
The PGA14 is a parent- rated variation of the CGI-I to evaluate the severity of the child’s 
symptoms. The PGA reflects assessments of change from baseline A symptoms using a 7 
point scale ranging from 1 (very much improved) to 7 (very much worse). It takes 1 to 2 
minutes to score the PGA.
18.1.6
The PedsQL Present Functioning Visual Analogue Scales (PedsQL™ VAS)
The PedsQL™ VAS15 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.
18.1.7
Paediatric Quality of Life Enjoyment and Satisfaction Questionnaire (PQ-
LES-Q)
The PQ-LES-Q16 is a patient-rated scale designed to assess satisfaction with life. It is an 
adaptation of the Quality of Life Enjoyment and Satisfaction Questionnaire (Q-LES-Q), 
which is used to measure quality of life in adults. The PQ LES Q consist of 15 items, item 1-
14 assess the degree of satisfaction experienced by subjects in various areas of daily 
functioning and item 15 allows subjects to summarise their experience in a global rating
(overall evaluation). Each item is rated on a 5-point scale from 1 (very poor) to 5 (very good).
The total score range of item 1-14 is 14 to 70, with higher scores indicating greater 
satisfaction. It takes 5 to 10 minutes to complete the scale.
18.1.8
Multidimensional Anxiety Scale for Children short version (MASC-10)
The MASC-1017 is designed to screen for anxiety in children, and is based on the 39-item 
MASC. The MASC-10 consists of 10 items assessing physiological symptoms, social anxiety, 
harm avoidance, and separation/panic. The anxiety symptoms are rated on a 4-point scale 
from 0 (never true about me) to 3 (often true about me). Total score ranges from 0 to 30, with 
higher scores indicating higher levels of anxiety. The MASC-10 takes approximately 5 
minutes to administer and score.
18.1.9
Tanner evaluation
Tanner staging is a scale for assessing physical development and sexual maturity during onset 
and progress of puberty.


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The scale includes five stages of pubertal changes (called Tanner stages) separate for males 
and for females.
For female the 5 stages of maturation are recognized by assessing pubic hair and breast 
development. For male the 5 stages of maturation are recognized by assessing pubic hair, 
growth of penis and testicles. Post-puberty is defined as a Tanner stage = 5 in both of 
observed criteria. 
The evaluation of Tanner stage will be performed by physician or trained nurse - they will be 
provided with figures depicting the somatic changes and tables describe these changes in 
words to facilitate the staging.
18.1.10
Paediatric Adverse Event Rating Scale (PAERS)
The PAERS18 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. 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.
18.1.11
General Behavior Inventory (GBI) 10-Item Mania Scale
The GBI 10-item mania scale19 is a parent- and subject-rated scale designed to screen for 
manic symptoms in children and adolescents. The 10 items are rated on a scale from 0 (never 
or hardly ever) to 3 (very often or almost constantly). The total score ranges from 0 to 30 
points, with high scores indicating greater pathology. It takes approximately 5 minutes to 
complete the GBI 10-item mania scale.
18.2
Identifying rows for analyses for rating scales and safety variables
For lab, ecg, vs, and scales except PAERS and C-SSRS, assessments (scheduled, re-
assessments, and unscheduled) in Phase B obtained more than 7 days after the last dose of 
IMP (assessment date – last dose date > 7) in the Phase or study will not be considered in 
descriptive statistics or statistical analyses but will be included in listings of safety variables 
(assessments≤7 days since last IMP will be referred to as valid). If the date of last dose is 


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Page 39 of 64
missing for a patient in Phase B, all assessments for the patient will be considered valid. Not 
valid assessments will be assigned analysis Day 8888 and analysis Week 888. 
For further details see Data Handling Plan.
Analysis day and week for assessments at scheduled visits (Withdrawal Visit not considered 
part of scheduled visits) will be the protocol (nominal) day and week:
Assessments at the Withdrawal Visit will be assigned to an analysis day in the phase from 
which the patient withdrew:
Patients withdrawn in Phase A:
Analysis day will be assigned according to Panel 6, based on days since Visit 2 
(assessment date-Visit 2 date) 
Patients withdrawn from Phase B:
Analysis day will be assigned according to Panel 7 based on days since Visit 6 
(assessment date-Visit 6 date) 
Panel 6
Visit Windows Patients Withdrawn from Phase A
CDRS-R 
PGA
GBI (depression) 
GBI (mania)
CGAS PedsQL VAS
PQ-LES-Q MASC-10
Weight
Laboratory 
ECG
CGI-S 
CGI-I 
PAERS
Vital 
Signs
Analysis
Phase
Target Day
based on 
assessment 
date-Visit 2
1 to 10
Phase A
7
1 to 17
1 to 21
11 to 17
Phase A
14
18 to 24
18 to 24
Phase A
21
>24
>21
>0
>24
Phase A
28 
Panel 7
Visit Windows Patients Withdrawn from Phase B
CDRS-R 
PGA
GBI (depression) 
GBI (mania)
CGAS PedsQL VAS
PQ-LES-Q MASC-10
Weight
Laboratory 
ECG
CGI-S 
CGI-I 
PAERS
Vital Signs
Analysis
Phase
Target Day
based on 
assessment 
date-Visit 6
1 to 10
Phase B
7
1 to 21
1 to 21
11 to 17
Phase B
14
18 to 24
Phase B
21
22 to 35
22 to 35
1 to 42
25 to 35
Phase B
28
36 to 49
36 to 49
36 to 49
Phase B
42
>49
>49
>42
>49
Phase B
56


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18.3
Handling of Missing or Incomplete Dates/Times
18.3.1
IMP Start and Stop Dates by phase
In derivation of data for adverse events and concomitant medications, a missing IMP start 
date in Phase A or Phase B will be imputed by:
Patients in APTS_A with a missing IMP start date in Phase A: Date of Visit 2 
Patients in APTS with a missing IMP start date in Phase B: Date of Visit 6
In evaluation of valid efficacy and safety assessments in Phase B (assessment is considered 
valid if assessment date-date of last IMP ≤7 days), a missing date of last IMP in Phase B will 
be imputed by the latest attended Visit in the study before the safety follow-up. 
Exposure for patients in APTS_A/APTS with missing IMP start or stop date will not be 
calculated.
Exposure for patients not in APTS_A/APTS will be set to 0.
18.3.2
Medical Disorder Start and Stop Dates
Incomplete dates will not be imputed. Classification of events into concurrent medical 
disorders or past disorders will be based on the reported ongoing status.
18.3.3
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 by phase. 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.
18.3.4
Adverse Event Start Dates
In order to classify the treatment emergent status and assign all adverse event records to an 
analysis, missing or incomplete start-or change in intensity dates will be imputed by phase.
Incomplete adverse start dates will be imputed before handling of incomplete dates for change 
in intensity-or seriousness.
Please see Data Handling Plan for further details.
Incomplete adverse event stop dates will not be imputed.


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Page 41 of 64
18.4
Grouping of Small Countries
Countries with few patients in the FAS will be grouped for potential use in case of the 
MMRM not converging. A country is considered small if it contained <4 patients in the FAS.
The final grouping of countries will be done in a blinded manner at the classification meeting 
and will be documented in the classification meeting minutes.


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Page 42 of 64
References
1.
World Medical Association (WMA). Declaration of Helsinki: Ethical principles for medical 
research involving human subjects. [Internet]
wma.net/en/30publications/10policies/b3/index.html
2.
Jennison C, Turnbull BW. Group Sequential Methods with Applications to Clinical Trials. Boca 
Raton, Florida: Chapman & Hall/CRC; 2000.
3.
Carpenter JR, Kenward M. Missing data in randomized controlled trials – A practical guide. 
21 November 2007.
4.
Shen S, Beunckens C, Mallinckrodt CH, Molenberghs G. A local influence sensitivity analysis 
for incomplete longitudinal depression data. J Biopharm Stat. 2006; 16: 365-384.
5.
Siddiqui O, Hung HMJ, O’Neill R. MMRM vs. LOCF: A comprehensive comparison based on 
simulation study and 25 NDA datasets. J Biopharm Stat. 2009; 19: 227-246.
6. 
Committee for Proprietary Medicinal Products (CPMP). Points to consider on adjustment for 
baseline covariates. 2003
7.
Mallinckrodt CH, Lane PW, Schnell D, Peng Y, Mancuso JP. Recommendations for the primary 
analysis of continuous endpoints in longitudinal clinical trials. Drug Information Journal. 2008; 
42: 303-319
8.
Little R, Yau L. Intent-to-treat analysis for longitudinal studies with drop-outs. Biometrics. 1996; 
52: 1324-1333.
9.
Rubin, DB. Multiple imputation for nonresponse in surveys. New York: Wiley; 1997.
10. United States Food and Drug Administration (FDA). Guidance for Industry: Drug-induced liver 
injury: Premarketing Clinical Evaluation. July 2009.
11. 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.
12. 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.
13. Youngstrom EA, Zhao J, Mankoski R., Forbes RA, Marcus RM, Carson W, et al. Clinical 
significance of treatment effects with aripiprazole versus placebo in a study of manic or mixed 
episodes associated with pediatric bipolar I disorder Journal of Child & Adolescent 
Psychopharmacology 2013; 23: 72-79.
14. Biederman J, Lopez FA, Boellner SW, Chandler MC. A randomized, double-blind, placebo-
controlled, parallel-group study of SLI381 (Adderall XR) in children with attention deficit/ 
hyperactivity disorder. Pediatrics 2002; 110: 258-266.
15. 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.


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16. Endicott J, Nee J, Yang R, Wohlberg C. Pediatric Quality of Life Enjoyment and Satisfaction 
Questionnaire (PQ-LES-Q): reliability and validity. J Am Acad Child Adolesc Psychiatry 2006; 
45: 401-407.
17. March JS, Sullivan K, Parker J. Test-retest reliability of the multidimensional anxiety scale for 
children. Journal of Anxiety Disorders 1999; 13: 349-358.
18. 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.
19. Youngstrom EA, Frazier TW, Demeter C, Calabrese JR, Findling RL. Developing a 10-item 
mania scale from the Parent General Behavior Inventory for children and adolescents. J Clin 
Psychiatry 2008; 69: 831–839.


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Study 12709A – Statistical Analysis Plan
Page 44 of 64
Appendix I
Statistical Analysis Plan 
Authentication and Authorisation


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Confidential
Study 12709A – Statistical Analysis Plan
Page 45 of 64
Statistical Analysis Plan
Authentication and Authorisation
Study title:
Interventional, randomised, double-blind, placebo-controlled, active 
reference (fluoxetine), fixed-dose study of vortioxetine in paediatric 
patients aged 7 to 11 years, with Major depressive disorder (MDD)
SAP date:
8 February 2022
This document has been signed electronically. The signatories are listed below.
Authentication
Authorisation


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Study 12709A – Statistical Analysis Plan
Page 46 of 64
Appendix II
Study Flow Chart


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Study 12709A – Statistical Analysis Plan
Page 47 of 64
Study Flow Chart
Phase A 
Phase B
Single-blind Treatment
Period    
Double-blind Treatment 
Period
Visit
Scree-
ning
Base-
line 
(Phase 
A)
Base-
line 
(Phase 
B)
Com-
pletion 
/With-
drawala
Safety 
Follow-
upb
Visit Number
1
2
3
4
5
6
7
8
9
10
11
12
13
Day/End of Week
d-5/d-
15
0
W1 W2 W3
W4
W5 W6 W7 W8 W10
W12
W16
Visit Windowc (days relative to 
nominal visit)
2 2 2
2
2 2 2 2 2
2
2
Screening/Baseline Procedures and Assessments
Signed informed assents/consents

Diagnosis (DSM-5™)

K-SADS-PLd

Disease-specific history

Relevant history (social, medical, 
psychiatric, neurological)

History of stimulant medication, 
if any

Demographics (age, sex, race)

Smoking, alcohol consumption

Family psychiatric history

Traumatic life events

Pregnancy teste

f
Inclusion/exclusion criteria


Randomisation to Phase B

BPI





Efficacy Assessments
CDRS-R









CGI-S












CGI-I










PGA (PRO)g







GBI (depression subscale )







f
CGAS



f
PedsQL VAS (PRO)



f
PQ-LES-Q (PRO)



f


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Study 12709A – Statistical Analysis Plan
Page 48 of 64
Phase A 
Phase B
Single-blind Treatment
Period    
Double-blind Treatment 
Period
Visit
Scree-
ning
Base-
line 
(Phase 
A)
Base-
line 
(Phase 
B)
Com-
pletion 
/With-
drawala
Safety 
Follow-
upb
Visit Number
1
2
3
4
5
6
7
8
9
10
11
12
13
Day/End of Week
d-5/d-
15
0
W1 W2 W3
W4
W5 W6 W7 W8 W10
W12
W16
Visit Windowc (days relative to 
nominal visit)
2 2 2
2
2 2 2 2 2
2
2
Exploratory Assessments
MASC-10 (PRO)



f
Vortioxetine and Fluoxetine Quantification
Blood sampling vortioxetine and 
fluoxetine quantification

f
Translational Medicine Assessmentsh
Blood sampling for gene 
expression profiling


f
Blood sampling for 
metabolomics/proteomics


f
Blood sampling for 
pharmacogenetics (optional)

Safety Assessments
Adverse eventsi












j
Blood and urine sampling for 
clinical safety laboratory tests 



f
Vital signs












ECGs



f
Weight and height



f
Examinations (physical and 
neurological)

f
Tanner score

PAERS 











f
C-SSRS












GBI (mania subscale)







f
Other Study Procedures
IMP dispensed










Possible change in IMP dose
k
IMP returned and IMP 
accountability 












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Study 12709A – Statistical Analysis Plan
Page 49 of 64
Phase A 
Phase B
Single-blind Treatment
Period    
Double-blind Treatment 
Period
Visit
Scree-
ning
Base-
line 
(Phase 
A)
Base-
line 
(Phase 
B)
Com-
pletion 
/With-
drawala
Safety 
Follow-
upb
Visit Number
1
2
3
4
5
6
7
8
9
10
11
12
13
Day/End of Week
d-5/d-
15
0
W1 W2 W3
W4
W5 W6 W7 W8 W10
W12
W16
Visit Windowc (days relative to 
nominal visit)
2 2 2
2
2 2 2 2 2
2
2
Recent and concomitant 
medication












a.
This visit should take place as soon as possible after the patient withdraws from the study. Any visit during 
Phase A, can be converted in to a withdrawal visit on the day of the visit. The BPI is optional if a visit 
during Phase A is converted into a withdrawal visit.
b.
This can be a telephone contact, unless an SAE has occurred since the last visit or there was a clinically 
significant abnormal safety laboratory test value at the last visit. In such cases, safety follow-up(s) must be 
scheduled to allow for a medical examination and/or blood sampling. Further safety follow-up visits 
beyond 30 days may be needed as judged by the investigator (if further safety follow-up visits are 
performed, these must be recorded in the patient’s medical record, and not in the eCRF). All enrolled 
patients should have a safety follow-up visit unless they continue into the extension study.
c.
If the date of a patient visit does not conform to the study plan, subsequent visits should be planned to 
maintain the visit schedule relative to randomisation/baselines. 
d.
The Kiddie-Schedule for Affective Disorders and Schizophrenia for School-aged Children, Present and 
Lifetime version (K-SADS-PL) will be used to confirmed diagnosis of Major depressive disorder (MDD) 
and to assess possible psychiatric co-morbidities.
e.
If the patient is a female subject of childbearing potential (defined as females aged ≥10 year’s old and 
younger girls who, at the discretion of the investigator, were deemed to be of reproductive potential), a
urine pregnancy test is to be performed at screening and if the patient has completed or withdrawn in Phase 
B.
f.
Should only be performed if the patient has completed or withdrawn in Phase B.
g.
The PGA assessment should be in reference to Baseline A. 
h.
Samples will be collected at the designated time points. Any results of the Translational Medicine 
Assessments will not be available at the time of reporting and will consequently not be part of the actual 
report of the study.       
i.
Pre-treatment adverse events (before IMP intake i.e. before Baseline B) must be recorded on the Adverse 
Event Form in the eCRF. Adverse events from open questioning in addition to all spontaneously reported 
adverse events must be recorded on the Adverse Event Form in the eCRF. If the adverse event is an SAE, 
the Serious Adverse Event Report Form must also be completed. For practical reasons, questioning for 
adverse events could follow vital sign assessments. In addition, the tolerability will also be assessed using 
the Paediatric Adverse Event Rating Scale (PAERS). Application of this scale should follow after the open, 
non-leading question for any adverse events.
j.
Only for adverse events on-going at Completion/Withdrawal and new SAEs.
k.
The vortioxetine dose may be down-titrated with 5mg/day based on poor tolerability, only one down-
titration is allowed. No up-titration will be allowed. The fluoxetine dose may be down-titrated to 10 mg/day 
based on poor tolerability only one down-titration is allowed (Only applicable during Study part 1). No up-
titration will be allowed.


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Confidential
Study 12709A – Statistical Analysis Plan
Page 50 of 64
Appendix III
Testing Strategy


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Testing strategy
The reason why both tests in step 2 can be performed at full significance level without further 
multiplicity adjustment follows from a formal closed testing argument.
A formal descriptions of the closed testing principle is as follows: 
“Suppose there are k hypotheses H1,..., Hk to be tested and the overall type I error rate is α. 
The closed testing principle allows the rejection of any one of these elementary hypotheses, 
say Hi, if all possible intersection hypotheses involving Hi can be rejected by using valid local 
level α tests. It controls the familywise error rate for all the k hypotheses at level α in the 
strong sense.”
In this study, there are 3 hypotheses that we want to multiplicity control for:
H1:  θL=0 (Low dose is in-efficacious)
H2:  θH =0 (High dose is in-efficacious)
H3:  0.5* θL + 0.5* θH =0 (The mean of the high and low dose is in-efficacious)
As described above Step 1 is to test H3 at full allocated alpha level. If this is rejected the 
procedure goes to Step 2 testing H1 and H2 also at full allocated alpha level. Following the 
closed testing principle this (Step 2) would require a test of the intersection hypothesis first. 
The intersection hypothesis H4 that needs to be tested is:
H4: H1∩H2: θL =0 ˄ θH =0 (Both doses are in-efficacious)
However, due to the testing strategy, it can be shown that H4 has already been tested:
Rejecting H3 in Step 1, gives that the average of the 2 comparisons is different from 0. 
Therefore, it is impossible for both comparisons θL and θH to be be zero simultaneously which 
means that H4 is rejected. So, rejection of H3 automatically leads to rejection of the 
intersection hypothesis H4, mathematically since it is contained in H3, H4⊆H3. The closed 
testing requirement concerning test of intersection hypotheses is therefore fulfilled and it is 
valid to test both H1 and H2 separately at full allocated alpha level.


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Appendix IV
SAS® Code


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SAS® Code
Implementation of MMRM for the primary analysis of the primary endpoint at the final 
stage
Interim analysis:
proc seqdesign
  altref=-4.0
  pss
  maxinfo=0.5865366
  boundaryscale= stdz;
  TwoSidedErrorSpending: design
  nstages=2
  method=errfuncpow(rho=2)
  boundarykey=alpha
  alt=lower
  stop=both(betaboundary=nonbinding)
  alpha=0.025
  info=cum(204 471 ); 
  samplesize
  model=twosamplemean(stddev= 12.67 weight=0.66666667 0.33333333);
  ods output Boundary=BOUNDARY(label="Interim: SEQDESIGN info used in 
SEQTEST");
run;
ods output LSMeans=CHG MMRM;
ods output lsmestimates=CHG MMRM_AvgVOR(drop=StmtNo);
ods output diffs=CHG MMRM Diff;
ods output estimates=CHG_MMRM_Diff_AvgVOR;
proc mixed data= adcdrsr int noclprint;
class USUBJID COUNTRY TRT02P NOMWEEK;
model  CHG = COUNTRY TRT02P*NOMWEEK BASE*NOMWEEK /s ddfm=kr;
repeated NOMWEEK /subject=USUBJID type=un;
lsmeans TRT02P*NOMWEEK/diffs;
lsmestimate trt02p*NOMWEEK 'Average effect of VOR at Week 8'
                      [ 1,3 4] [ 1,4 4] /divisor=2;
      
estimate 'Average VOR vs PBO at Week 8'
TRT02P*NOMWEEK 0 0 0 0
               0 0 0 -1


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               0 0 0 0.5
               0 0 0 0.5;
title2 "Primary analysis, including estimation of Average VOR effect and difference to PBO 
(FAS, MMRM)";
run;
***************************************************************;
%**START:
;
%**Prepare and print data with results from the MMRM-analysis
;
%**Data used for printing are saved in library Interim
;
%********************************************************************;
data CHG_MMRM(label="Interim: CHG CDRS-R Total Score (MMRM)");
length trt02p $20.;
set CHG MMRM_AvgVOR(in=vor) CHG_MMRM;
if vor then do;
TRT02P='Avg VOR’;
TRT02PN=2;
NOMWEEK=8;
end;
if TRT02P='FLU' then TRT02PN=1;
else if TRT02P='PBO' then TRT02PN=3;
else if TRT02P='VOR10' then TRT02PN=4;
if TRT02P='VOR20' then TRT02PN=5;
run;
proc sort data=CHG_MMRM;
by TRT02PN TRT02P NOMWEEK;
run;
data CHG MMRM Diff(drop=_NOMWEEK _TRT02P Effect label="Interim: CHG CDRS-
R Total Diff (MMRM)");
length trt02p $20.;
set CHG MMRM Diff AvgVOR(in=vor) 
CHG MMRM Diff(where=(((nomweek=_nomweek)) and (TRT02P="PBO" or 
TRT02P="PBO")));
if vor then do;
TRT02P='Avg VOR’;
NOMWEEK=8;
TRT02PN=2;
end;
if TRT02P='PBO' then do;
estimate=estimate*-1;
TRT02P=_TRT02P;
end;


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if TRT02P='FLU' then TRT02PN=1;
else if TRT02P='PBO' then TRT02PN=3;
else if TRT02P='VOR10' then TRT02PN=4;
if TRT02P='VOR20' then TRT02PN=5;
run;
proc sort data=CHG MMRM Diff;
by TRT02PN TRT02P NOMWEEK;
run;
title2 "Mean Change from Baseline B in CDRS-R Total Score at Week 8 (FAS, MMRM)";
proc print data=CHG MMRM noobs;
where NOMWEEK=8;
var TRT02P NOMWEEK Estimate StdErr DF Tvalue probt;
run;
title2 "Mean Difference in Change from Baseline B CDRS-R Total Score Compared to PBO
at Week 8 (FAS, MMRM)"; 
proc print data=CHG MMRM_Diff noobs;
where NOMWEEK=8;
var TRT02P NOMWEEK Estimate StdErr DF Tvalue probt;
run;
title2;
%********************************************************************;
%**END:
;
%**Prepare and print data with results from the MMRM-analysis
;
%********************************************************************;
%*************************************************************************
******;
%**Prepare data for Interim Analysis using SEQTEST (required variables added) ;
%*************************************************************************
******;
data CHG MMRM Diff AvgVOR(label="Interim: Data used in SEQTEST");
set CHG MMRM_Diff_AvgVOR;
_Scale_ = "MLE";
Stage = 1;
variable="Treat";
keep _Scale_ _Stage_ Estimate StdErr probt variable;
run;
%*************************************************************************
**************************;


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%** Run SEQTEST and print outcome (Action)
;
%** Note, input Z-statistic = Estimate/STDerr from nterim.CHG_MMRM_Diff becomes 'Es-
timate' in output;
%** Input are the derived boundaries generated by SEQDESIGN
    ;
%*************************************************************************
**************************;
ods graphics on;
proc seqtest Boundary=BOUNDARY
Parms(Testvar=treat)=CHG MMRM_Diff_AvgVOR
boundaryadj=errfuncpow(rho=2)
boundarykey=alpha
infoadj=prop;
ods output Test=InterimTest(label="Interim: Outcome of SEQTEST"); 
title2 "Analysis of Estimated Average VOR Versus Boundaries: Based on Z-statistic";
run;
title2 "Action";
footnote "Action: Continue=Study continue, Reject Null=Stop for Efficacy (Avg VOR supe-
rior to PBO), Accept Null=Stop for Futility (Avg VOR has no chance of reaching signifi-
cance)";
proc print data=InterimTest;
run;
title;
footnote;
ods graphics off;
final analyses:
ods output LSMeans=CHG_MMRM;
ods output lsmestimates=CHG MMRM_AvgVOR(drop=StmtNo);
ods output diffs=CHG MMRM Diff;
ods output estimates=CHG_MMRM_Diff_AvgVOR_fin;
proc mixed data=adcdrsr fin noclprint;
class USUBJID COUNTRY(ref="USA") TRT02P NOMWEEK;
model  CHG = COUNTRY TRT02P*NOMWEEK BASE*NOMWEEK /s ddfm=kr;
repeated NOMWEEK /subject=USUBJID type=un;


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lsmeans TRT02P*NOMWEEK/diffs;
lsmestimate trt02p*NOMWEEK 'Average effect of VOR at Week 8'
                      [ 1,3 4] [ 1,4 4] /divisor=2;
      
estimate 'Average VOR vs PBO at Week 8'
TRT02P*NOMWEEK 0 0 0 0
               0 0 0 -1
               0 0 0 0.5
               0 0 0 0.5;
title2 "Primary analysis, including estimation of Average VOR effect and difference to PBO 
(FAS, MMRM)";
run;
data finaltestdata;
   set CHG MMRM_Diff_AvgVOR_fin;
   Scale  = 'MLE';
   Stage = 2 ;
   variable="Treat";
   keep _Scale_ _Stage_ Estimate StdErr probt variable tValue;
run;
ods graphics on;
proc seqtest Boundary=InterimTest 
Parms(Testvar=treat)=finaltestdata
boundaryadj=errfuncpow(rho=2)
boundarykey=alpha
boundaryscale= stdz
errspend
infoadj=prop
cialpha=0.05
citype=twosided
order=stagewise;
ods output Test=finTest
               Design=finDesign;
run;
ods graphics off;
Implementation of MMRM for analysing continuous endpoints


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proc mixed noclprint data=xyz ic method=reml;
   
class usubjid country trt02p nomweek;
   model chg = base country nomweek  trt02p  trt02p * nomweek base* nomweek /s ddfm=kr;
   repeated nomweek /subject=usubjid type=un;
   lsmeans trt02p * nomweek/diff;
run;
Implementation of ANCOVA for analysing continuous endpoints
proc mixed data=xyz method=reml;
   class country trt02p  ;
   model chg=base country trt02p  / ddfm=kr;
   lsmeans actarm / diff=control("Placebo") cl alpha=0.05;
run;
Implementation of logistic regression for analysing dichotomous endpoints
proc logistic data=xyz;
   class trt02p / param=GLM;
   model y (event="1") = trt02p base/ clodds=wald alpha=0.05;
run;
Implementation of MNAR Sensitivity analysis for primary endpoint
The SAS code fragments described in this section are expected to form the basis of the 
MNAR sensitivity analyses. Below, we assume that:
•
anadat: the analysis dataset 
•
anadat_mono: the analysis dataset with non-monotone missing data being imputed using 
MCMC
•
score_5 to score_12: post-baseline CDRS-R total scores 
•
lastvis: the last visit at which data are observed
Imputation of non-monotone missing patterns using MCMC:


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PROC SORT DATA=anadat;
BY trt02p;
RUN;
PROC MI DATA=anadat OUT=anadat_mono nimpute=1000 SEED=xxxxx;
BY trt02p;
VAR country base score_5-score_12;
MCMC CHAIN=MULTIPLE IMPUTE=MONOTONE;
RUN;
The following SAS code will be used for the PMI at the ith visit, assuming the dataset 
impd_&i has been imputed before the ith visit. Once the missing data are imputed 
sequentially, the MMRM analysis can be performed and their results can be combined using 
PROC MIANALYZE.  
DATA anadat_PMI;
SET anadat_mono;
WHERE trt02p ="PBO";
RUN;
DATA imp_&i out_&i;
SET impd_&i;
IF trt02p ne “PBO” AND lastvis >= &i 
THEN OUTPUT out_&i;
ELSE OUTPUT imp_&i;
RUN;
PROC MI DATA=imp_&i OUT=imptd_&i NIMP=1 SEED=xxxx;
BY _imputation_;
VAR country base score_5-score_&i;
MONOTONE REG (score_&i = country base %DO _v=5 %TO %eval(&i-1);   
score_&v. %END;);
RUN;
DATA impd_%eval(&i+1);
SET out_&i imptd_&i;
RUN;
Assuming datain is the dataset with missing data imputed the analysis will proceed with:
PROC MIXED DATA= datain IC METHOD=REML;
BY _Imputation_;
CLASS usubjid trt02p country nomweek;
MODEL chg= country trt02p*nomweek base * nomweek /s DDFM=KR;
REPEAT nomweek / subject=usubjid type=UN;
LSMEAN trt02p*nomweek / diff cl alpha=0.05;
ODS OUTPUT diffs=dataout_d;


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ODS OUTPUT lsmeans=dataout_l;
RUN;
DATA dataout_d;
SET dataout_d;
WHERE nomweek=_nomweek and trt02p ne "PBO" and _trt02p = "PBO";
RUN;
PROC SORT data=dataout_l OUT=dataout_l NODUPKEY;
BY _Imputation_ trt02p nomweek;
RUN;
PROC SORT DATA=dataout_d; BY nomweek _Imputation_; run;
PROC SORT DATA=dataout_l; BY nomweek _Imputation_; run;
PROC MIANALYZE PARMS(classvar=full)=dataout_d;
CLASS trt02p;
MODELEFFECTS nomweek*trt02p;
ODS OUTPUT ParameterEstimates=dataout_d1;
BY visit;
RUN;


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Appendix V
PCS Criteria


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PCS Criteria
Table 1
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


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Table 2
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
HRMEAN 
QTCB
QTCF
beats/min
Msec
Msec
< 50 and de-
crease ≥15
< 300
< 300
≥ 120 and in-
crease ≥15
> 500 or in-
crease > 60
> 500 or in-
crease > 60
Increase/decrease is relative to the baseline value
Table 3
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, 
sitting/unknown
Systolic blood pressure, 
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 de-
crease ≥15
≤50 and de-
crease ≥15
≤ 90 and de-
crease ≥20
≤-30
decrease ≥2
increase ≥7% 
increase ≥7% 
increase ≥7%
≥ 120 and in-
crease ≥15
≥ 105 and in-
crease ≥ 15
≥180 and in-
crease ≥ 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 4
Normal ranges and PCS Criteria
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