Conditions: Major Depressive Disorder
Keywords: Drug therapy
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 1106
Healthy volunteers: no

Brief summary:
The purpose of this study is to evaluate the efficacy of vortioxetine (5, 10, and 20 mg) versus placebo during the first 28 weeks of the 32-week double-blind treatment period in the prevention of relapse in participants with MDD who responded to acute treatment with vortioxetine 10 mg.

Detailed description:
The drug being tested in this study is called vortioxetine. Vortioxetine is being tested for the prevention of relapse in adults with major depressive disorder (MDD) who respond to daily treatment with vortioxetine. This study will look at relapse rates of MDD in people who take vortioxetine.

The study will enroll approximately 1100 participants. All participants will receive vortioxetine 10 mg open-label for the first 16 weeks of the study. Participants who meet the appropriate MDD response criteria from the Week 8 Visit through Week 16 Visit will be eligible for randomization into the double-blind treatment period. Participants will be randomly assigned (by chance, like flipping a coin) to one of the four treatment groups-which will remain undisclosed to the patient and study doctor during the study (unless there is an urgent medical need):

* Vortioxetine 5 mg
* Vortioxetine 10 mg
* Vortioxetine 20 mg
* Placebo (dummy inactive pill) - this is a capsule that looks like the study drug but has no active ingredient

All participants will be asked to take one capsule at the same time each day throughout the study.

This multi-center trial will be conducted in the United States. The overall time to participate in this study is up to 55 weeks. Participants will make 19 visits to the clinic, and will be contacted by telephone 4 weeks after last dose of study drug for a follow-up assessment.

Arms:
arm 1: Vortioxetine 10 mg, capsules, orally, once, daily (QD) up to 8 weeks. Participants who achieved response (defined as a ≥50% reduction in Montgomery Asberg Depression Rating Scale (MADRS) total score from Baseline) continued to receive vortioxetine 10 mg, capsules, orally, QD for up to Week 16 (stabilization period) in the Open-label Period. arm 2: Following Open-label Period, participants who achieved remission criteria (defined as MADRS total score ≤12 at Weeks 14 and 16) were randomized to receive vortioxetine placebo-matching capsules, orally, QD from Week 17 up to Week 44 in the Double-blind Period. arm 3: Following Open-label Period, participants who achieved remission criteria (defined as MADRS total score ≤12 at Weeks 14 and 16) were randomized to receive vortioxetine 5 mg, capsules, orally, QD from Week 17 up to Week 44 in the Double-blind Period. arm 4: Following Open-label Period, participants who achieved remission criteria (defined as MADRS total score ≤12 at Weeks 14 and 16) were randomized to receive vortioxetine 10 mg, capsules, orally, QD from Week 17 up to Week 44 in the Double-blind Period. arm 5: Following Open-label Period, participants who achieved remission criteria (defined as MADRS total score ≤12 at Weeks 14 and 16) were randomized to receive vortioxetine 20 mg, capsules, orally, QD from Week 17 up to Week 44 in the Double-blind Period.

Interventions: intervention 1: Vortioxetine intervention 2: Placebo
Intervention descriptions: intervention 1: Vortioxetine capsules intervention 2: Vortioxetine placebo-matching capsules

Protocol document:
Prot_001.pdf: 



Title: A Randomized, Double-Blind, Placebo-Controlled, Phase 4, Relapse Prevention Study 
Evaluating the Efficacy and Safety of Vortioxetine (5, 10 and 20 mg) in Adults With Major 
Depressive Disorder
NCT Number: NCT02371980
Protocol Approve Date: 25 September 2015
Certain information within this protocol has been redacted (ie, specific content is masked irreversibly from 
view with a black/blue bar) to protect either personally identifiable information (PPD) or company 
confidential information (CCI). 
This may include, but is not limited to, redaction of the following: 
Named persons or organizations associated with the study.
Proprietary information, such as scales or coding systems, which are considered confidential 
information under prior agreements with license holder.
Other information as needed to protect confidentiality of Takeda or partners, personal information, or 
to otherwise protect the integrity of the clinical study.


PROTOCOL AMENDMENT
A Randomized, Double-Blind, Placebo-Controlled, Phase 4, Relapse Prevention Study
Evaluating the Efficacy and Safety of Vortioxetine (5, 10 and 20 mg) in Adults With Major 
Depressive Disorder
Vortioxetine, 5, 10, and 20 mg, Relapse Prevention Study in Adults with 
Major Depressive Disorder
Sponsor:
Takeda Development Center Americas, Inc.
One Takeda Parkway
Deerfield, IL 60015
Study Number:
LuAA21004_402
IND Number:
76,307
EudraCT Number:
N/A
Compound:
Vortioxetine
Date:
25 September 2015
Amendment Number: 
01
Date
Amendment Number
Region
23 October 2014
25 September 2015
Initial Protocol
Amendment 01
North America (United States)
North America (United States)
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1.0
ADMINISTRATIVE INFORMATION 
1.1
Contacts 
A separate contact information list will be provided to each site.
Takeda sponsored investigators per individual country requirements will be provided with 
emergency medical contact information cards to be carried by each subject.
General advice on protocol procedures should be obtained through the monitor assigned to the 
study site. Information on service providers is given in Section 3.1 and relevant guidelines 
provided to the site.
Contact Type/Role
North America (United States) Contact
Serious adverse event and pregnancy reporting
Medical Monitor
(medical advice on protocol and compound)
Responsible Medical Officer 
(carries overall responsibility for the conduct of the 
study)
Property of Takeda: For non-commercial u
l u
he applicable Terms of Use
witith h 
assigned
ssigne
ant guide
t guid
ted Sta
ted S
he
PPD


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1.2
Approval 
REPRESENTATIVES OF TAKEDA 
This study will be conducted with the highest respect for the individual participants in accordance 
with the requirements of this clinical study protocol and also in accordance with the following:
!
The ethical principles that have their origin in the Declaration of Helsinki.
!
International Conference on Harmonisation E6 Good Clinical Practice: Consolidated 
Guideline.
!
All applicable laws and regulations, including, without limitation, data privacy laws, clinical 
trial disclosure laws, and regulations.
SIGNATURES
The signature of the responsible Takeda medical officer (and other signatories, as applicable) can 
be found on the signature page.
Electronic Signatures may be found on the last page of this document.
Property of Taked
d subject to the applicable Terms of Use
rdance
rdance
wing:
wing:
solidated
lidat
ta privac
ta priva
other sig
other s
thihis doc
s do
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INVESTIGATOR AGREEMENT 
I confirm that I have read and that I understand this protocol, the Investigator’s Brochure, and/or 
package insert, and any other product information provided by the sponsor. I agree to conduct this 
study in accordance with the requirements of this protocol and also to protect the rights, safety, 
privacy, and well-being of study subjects in accordance with the following:

The ethical principles that have their origin in the Declaration of Helsinki.

International Conference on Harmonisation, E6 Good Clinical Practice: Consolidated 
Guideline.

All applicable laws and regulations, including, without limitation, data privacy laws and 
regulations.

Regulatory requirements for reporting serious adverse events defined in Section 10.2 of this 
protocol.

Terms outlined in the Clinical Study Site Agreement.

Appendix B – Responsibilities of the Investigator.
I further authorize that my personal information may be processed and transferred in accordance 
with the uses contemplated in Appendix D of this protocol.
Signature of Investigator
Date
Investigator Name (print or type)
Investigator’s Title
Location of Facility (City, State/Provence)
Location of Facility (Country)
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1.3
Protocol Amendment No. 1 Summary of Changes 
This document describes the changes in reference to the Protocol Incorporating Amendment No. 1.
The primary purpose of this amendment is to update the protocol regarding exclusion criteria #12 
and the addition of exclusion criteria #24, the addition of using Clinical Trial Subject Database, 
and the addition of PK and RNA blood sampling for any open-label withdrawal visit. Other minor 
changes in procedures are proposed. Minor grammatical and editorial changes are included for 
clarification purposes only. Full details on changes of text are given in Appendix F. The following 
is a summary of the changes made in the amendment:
1. Clarification of exclusion criteria #12 for unstable illnesses.
Justification: To exclude subjects with fibromyalgia, obstructive sleep apnea, chronic pain 
diagnosis, and morbid obesity due to the potential impact on assessment of the primary 
endpoint.
2. Addition of exclusion criteria #24 excluding subjects who are treatment- resistant.
Justification: To clarify the exclusion of those subjects who are considered to be 
treatment-resistant as defined by not responding to adequate monotherapy treatments of at 
least 6 weeks duration or only responding to combination or augmentation therapy.
3. Addition of utililizing Clinical Trial Subject Database (CTSdatabase).
Justification: To include the use of a subject registry to help reduce subjects from enrolling into 
multiple clinical trials simultaneously by identifying duplicate subjects before enrollment.
4. Addition of PK and RNA blood sampling for any open-label withdrawal visit.
Justification: To clarify the PK and RNA blood sample procedure for subjects who withdraw 
during the open-label period.
5. Clarification for rater qualifications for Clinical Global Improvement (CGI).
Justification: To allow for flexibility for a competent rater who is not a physician (MD) or 
doctor of osteopathy (DO) to qualify to rate this scale with sponsor approval.
6. Addition of a Relapse Checklist to be completed at Visits 18 to 48.
Justification: To provide a tool for sites to use to evaluate potential indicators of relapse for 
each subject at each visit post baseline during the double blind-period.
7. Correction of serious adverse event (SAE) language.
Justification: This wording was changed to be consistent with ICH and other guidance
documentation.
8. Correction of inconsistencies within the original protocol.
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TABLE OF CONTENTS
1.0
ADMINISTRATIVE INFORMATION ...........................................................................2
1.1
Contacts.....................................................................................................................2
1.2
Approval....................................................................................................................3
1.3
Protocol Amendment No. 1 Summary of Changes .....................................................5
2.0
STUDY SUMMARY ....................................................................................................12
3.0
STUDY REFERENCE INFORMATION ......................................................................17
3.1
Study-Related Responsibilities.................................................................................17
3.2
Principal Investigator...............................................................................................17
3.3
List of Abbreviations ...............................................................................................18
3.4
Corporate Identification...........................................................................................19
4.0
INTRODUCTION.........................................................................................................20
4.1
Background .............................................................................................................20
4.2
Rationale for the Proposed Study.............................................................................21
5.0
STUDY OBJECTIVES AND ENDPOINTS..................................................................22
5.1
Objectives................................................................................................................22
5.1.1
Primary Objective ..............................................................................................22
5.1.2
Secondary Objective ..........................................................................................22
5.1.3
Safety Objective.................................................................................................22
5.1.4
Additional Objectives.........................................................................................22
5.2
Endpoints.................................................................................................................22
5.2.1
Primary Endpoint...............................................................................................22
5.2.2
Secondary Endpoints..........................................................................................22
5.2.3
Safety Assessments............................................................................................23
5.2.4
Additional Endpoints .........................................................................................23
6.0
STUDY DESIGN AND DESCRIPTION.......................................................................24
6.1
Study Design ...........................................................................................................24
6.2
Justification for Study Design, Dose, and Endpoints ................................................26
6.2.1
Study Design......................................................................................................26
6.2.2
Dose ..................................................................................................................26
6.2.3
Endpoints...........................................................................................................26
6.3
Premature Termination or Suspension of Study or Investigational Site.....................26
6.3.1
Criteria for Premature Termination or Suspension of the Study..........................26
6.3.2
Criteria for Premature Termination or Suspension of Investigational Sites .........27
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6.3.3
Procedures for Premature Termination or Suspension of the Study or the 
Participation of Investigational Site(s)................................................................27
7.0
SELECTION AND DISCONTINUATION/WITHDRAWAL OF SUBJECTS..............28
7.1
Inclusion Criteria .....................................................................................................28
7.2
Exclusion Criteria ....................................................................................................28
7.3
Randomization Criteria............................................................................................31
7.4
Excluded Medications, Procedures, and Treatments.................................................31
7.5
Criteria for Discontinuation or Withdrawal of a Subject...........................................33
7.6
Additional Guidance for Withdrawal Criteria...........................................................35
7.7
Procedures for Discontinuation or Withdrawal of a Subject......................................35
8.0
CLINICAL TRIAL MATERIAL MANAGEMENT ......................................................36
8.1
Study Medication and Materials...............................................................................36
8.1.1
Dosage Form, Manufacturing, Packaging, and Labeling.....................................36
8.1.1.1 Investigational drug......................................................................................36
8.1.1.2 Sponsor-Supplied Drug ................................................................................36
8.1.2
Storage...............................................................................................................37
8.1.3
Dose and Regimen .............................................................................................37
8.1.4
Overdose............................................................................................................38
8.2
Investigational Drug Assignment and Dispensing Procedures ..................................38
8.3
Randomization Code Creation and Storage..............................................................39
8.4
Investigational Drug Blind Maintenance ..................................................................39
8.5
Unblinding Procedure..............................................................................................39
8.6
Accountability and Destruction of Sponsor-Supplied Drugs.....................................40
9.0
STUDY PLAN ..............................................................................................................42
9.1
Study Procedures.....................................................................................................42
9.1.1
Informed Consent Procedure..............................................................................42
9.1.1.1 Pharmacogenomic Informed Consent Procedure...........................................42
9.1.1.2 Clinical Trial Subject Database (CTSdatabase) Authorization ......................42
9.1.2
CTSdatabase and Subject Database Authorization..............................................42
9.1.3
Demographics, Medical History, and Medication History Procedure..................42
9.1.4
Physical Examination Procedure ........................................................................43
9.1.5
Weight, Height...................................................................................................43
9.1.6
Vital Sign Procedure..........................................................................................43
9.1.7
Diagnostic Assessment.......................................................................................43
9.1.7.1 MINI International Neuropsychiatric Interview ............................................43
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9.1.7.2 Subject-completed Diagnostic Validation.....................................................44
9.1.8
Primary Efficacy Measurements.........................................................................44
9.1.9
Psychiatric/Neurological Rating Scales ..............................................................44
9.1.9.1 Order of Psychiatric/Neurological Rating Scales/Assessments......................45
9.1.10 Documentation of Concomitant Medications......................................................45
9.1.11 Documentation of Concurrent Medical Conditions.............................................46
9.1.12 Procedures for Clinical Laboratory Samples.......................................................46
9.1.13 Contraception and Pregnancy Avoidance Procedure...........................................47
9.1.14 Pregnancy ..........................................................................................................48
9.1.15 ECG Procedure..................................................................................................49
9.1.16 Pharmacogenomic Sample Collection ................................................................49
9.1.17 Pharmacokinetic Sample Collection and Analysis ..............................................50
9.1.17.1
Collection of Plasma for Pharmacokinetic Sampling...............................50
9.1.17.2
Bioanalytical Methods............................................................................51
9.1.18 Documentation of Screen Failure .......................................................................51
9.1.19 Documentation of Re-Screening.........................................................................51
9.1.20 Documentation of Study Entrance......................................................................51
9.1.21 Rater Qualification and Certification Process .....................................................51
9.1.21.1
Prior to Study Start.................................................................................52
9.1.21.2
Report Training Certification..................................................................52
9.1.21.3
Site Changes to Rater Personnel during the Study...................................53
9.1.22 Rater Monitoring................................................................................................53
9.2
Monitoring Subject Treatment Compliance..............................................................53
9.3
Schedule of Observations and Procedures................................................................53
9.3.1
Screening Visit 1 (Days -21 to -5)......................................................................54
9.3.2
Study Entrance into Open-Label Treatment; Baseline I, Visit 2 (Day 0) .............55
9.3.3
Open-Label Treatment Visits 3-9, Weeks 2, 4, 6, 8, 10, 12, and 14 (± 3 days) ....55
9.3.4
Withdrawal Visit from Open-label Treatment (± 3 days)....................................56
9.3.5
Baseline II Randomization, Visit 10, Week 16 (± 3 days)...................................57
9.3.6
Double-Blind Treatment, Visits 11 and 12, Week 18 (± 3 days) and Week 20 (± 
5 days) ...............................................................................................................58
9.3.7
Double-Blind Treatment Subject Well Being Calls Weeks 22, 26, 30, 34, 38, 
42, and 46 ..........................................................................................................58
9.3.8
Double-Blind Treatment Visits 13-18, Weeks 24, 28, 32, 36, 40, and 44 (± 5 
days)..................................................................................................................58
9.3.9
Completion/Withdrawal from Double-Blind, Visit19, Week 48 (± 5 days).........59
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9.3.10 Safety Follow-up Phone Call..............................................................................60
9.3.11 Post-Study Care .................................................................................................60
9.4
Biological Sample Retention and Destruction ..........................................................60
10.0
PRETREATMENT EVENTS AND ADVERSE EVENTS ............................................61
10.1
Definitions...............................................................................................................61
10.1.1 PTEs..................................................................................................................61
10.1.2 AEs....................................................................................................................61
10.1.3 Additional Points to Consider for PTEs and AEs................................................61
10.1.4 SAEs..................................................................................................................63
10.1.5 Special Interest AEs...........................................................................................64
10.1.5.1
Skin and Allergic Type Reactions...........................................................65
10.1.5.2
Liver Injury ............................................................................................65
10.1.5.3
Overdose ................................................................................................65
10.1.6 Severity of PTEs and AEs..................................................................................66
10.1.7 Causality of AEs ................................................................................................66
10.1.8 Relationship to Study Procedures.......................................................................66
10.1.9 Start Date...........................................................................................................66
10.1.10
Stop Date .....................................................................................................66
10.1.11
Frequency ....................................................................................................66
10.1.12
Action Concerning Study Medication...........................................................66
10.1.13
Outcome.......................................................................................................67
10.2
Procedures...............................................................................................................67
10.2.1 Collection and Reporting of AEs........................................................................67
10.2.1.1
PTE and AE Collection Period ...............................................................67
10.2.1.2
PTE and AE Reporting ...........................................................................68
10.2.1.3
Special Interest AE Reporting.................................................................68
10.2.2 Collection and Reporting of SAEs......................................................................68
10.3
Follow-up of SAEs ..................................................................................................69
10.3.1 Safety Reporting to Investigators, IRBs, and Regulatory Authorities..................69
11.0
STUDY-SPECIFIC COMMITTEES .............................................................................70
12.0
DATA HANDLING AND RECORDKEEPING............................................................71
12.1
CRFs (Electronic)....................................................................................................71
12.2
Record Retention .....................................................................................................71
13.0
STATISTICAL METHODS..........................................................................................73
13.1
Statistical and Analytical Plans ................................................................................73
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13.1.1 Analysis Sets......................................................................................................73
13.1.2 Analysis of Demographics and Other Baseline Characteristics ...........................73
13.1.3 Efficacy Analysis...............................................................................................74
13.1.4 Pharmacokinetic Analysis ..................................................................................75
13.1.5 Safety Analysis ..................................................................................................75
13.2
Interim Analysis and Criteria for Early Termination ................................................75
13.3
Determination of Sample Size..................................................................................75
14.0
QUALITY CONTROL AND QUALITY ASSURANCE...............................................76
14.1
Study-Site Monitoring Visits ...................................................................................76
14.2
Protocol Deviations..................................................................................................76
14.3
Quality Assurance Audits and Regulatory Agency Inspections ................................76
15.0
ETHICAL ASPECTS OF THE STUDY........................................................................77
15.1
IRB and/or IEC Approval ........................................................................................77
15.2
Subject Information, Informed Consent, and Subject Authorization .........................78
15.3
Subject Confidentiality ............................................................................................79
15.4
Publication, Disclosure, and Clinical Trial Registration Policy.................................79
15.4.1 Publication and Disclosure.................................................................................79
15.4.2 Clinical Trial Registration..................................................................................80
15.4.3 Clinical Trial Results Disclosure ........................................................................80
15.5
Insurance and Compensation for Injury....................................................................80
16.0
REFERENCES..............................................................................................................81
LIST OF IN-TEXT TABLES
Table 7.a
Excluded Medications and Treatments...............................................................31
Table 8.a
Dose and Regimen .............................................................................................38
Table 9.a
Clinical Laboratory Tests...................................................................................46
Table 10.a
Takeda Medically Significant AE List................................................................64
LIST OF IN-TEXT FIGURES
Figure 6.a
Schematic of Study Design ................................................................................25
LIST OF APPENDICES
Appendix A
Schedule of Study Procedures............................................................................83
Appendix B
Responsibilities of the Investigator.....................................................................87
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Appendix C
Elements of the Subject Informed Consent.........................................................89
Appendix D
Investigator Consent to Use of Personal Information..........................................92
Appendix E
Collection, Shipment, and Storage of Pharmacogenomic and Collection, 
Storage, and Shipment of PK Samples ...............................................................93
Appendix F
Detailed Description of Amendments to Text.....................................................96
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2.0
STUDY SUMMARY
Name of Sponsor(s):
Takeda Development Center Americas, Inc.
Compound:
Vortioxetine
Title of Protocol: A Randomized, Double-Blind, 
Placebo-Controlled, Phase 4, Relapse Prevention Study 
Evaluating the Efficacy and Safety of Vortioxetine (5, 10 
and 20 mg) in Adults With Major Depressive Disorder
IND No.: 76,307
EudraCT No.:
N/A
Study Number: LuAA21004_402
Phase: 4
Study Design:
This study is a randomized, double-blind, placebo-controlled, phase 4 study to evaluate 3 fixed doses (5, 10, and 20 
mg oral tablets) of vortioxetine once daily in the prevention of relapse in adult subjects with major depressive disorder 
(MDD) who have responded to acute treatment with vortioxetine.
This study is comprised of a 16-week open-label treatment period followed by a 32-week double-blind randomized 
treatment periods. This study will enroll approximately 1100 subjects into the open label in order to target 
approximately 600 subjects into the double-blind treatment phases and will be conducted at approximately 60 sites in 
the United States.
Eligible subjects are men and women between the ages of 18 and 75, inclusive, meeting the diagnostic criteria from the 
Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision (DSM-IV-TR) for recurrent 
MDD, who have had at least 2 major depressive episodes prior to the current episode, with a current episode of 
between 8 weeks and 18 months duration from screening, and a Montgomery-Asberg Depression Rating Scale 
(MADRS) total score of ≥26. At Baseline I (open-label baseline),eligible subjects will be enrolled into the 16-week 
open-label treatment period and will receive 10 mg vortioxetine. 
Subjects who are in response (defined as a ≥50% reduction in MADRS total score from Baseline I) at Week 8 will 
continue for an additional 8 weeks of treatment (Stabilization period) and will continue to receive 10 mg vortioxetine. 
Subjects must continue to meet response criteria as assessed at every study visit during the Stabilization period. In 
addition, subjects must meet remission criteria (defined as ≤12 MADRS total score) at weeks 14 and 16 to be eligible 
for randomization into the double-blind treatment period. Subjects who do not meet the response and/or remission 
criteria will be withdrawn from the study and will complete an early withdrawal visit.
At Baseline II (double-blind randomization), subjects who have met the randomization criteria (response and 
remission as described above) and have not met any other withdrawal criteria will be randomized in a ratio of 
1:1:1:1 of the following 4 treatment groups for 32 weeks of double-blind treatment: vortioxetine 5 mg; vortioxetine 10 
mg; vortioxetine 20 mg; and placebo.
Subjects will be seen twice the first month and then once monthly during the remainder of the 32-week double-blind 
treatment period. Subject well-being calls will be made every 2 weeks after Week 20, in between scheduled subject 
visits. 
Subjects will be considered as “relapsed” and withdrawn from the study if the following criteria are met: MADRS 
22, or lack of efficacy as determined by the investigator. In addition, investigator judgment should be used to 
determine unsatisfactory treatment response indicative of relapse to depression, such as subject hospitalization for 
depression, medication prescribed for MDD, electroconvulsive therapy, suicide attempt, etc. 
Primary Objectives:
To determine the efficacy of vortioxetine (5, 10, and 20 mg) versus placebo during the first 28 weeks of the 32-week
double-blind treatment period in the prevention of relapse in subjects with MDD who responded to acute treatment 
with vortioxetine 10 mg.
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Secondary Objective:
To determine the overall efficacy of vortioxetine versus placebo during continuation treatment of subjects with MDD.
Safety Objective:
To evaluate long-term safety and tolerability of vortioxetine versus placebo in subjects with MDD.
Additional Objectives:

To assess the effect of long-term treatment with vortioxetine and placebo on suicidal ideation and behavior.

Determine the pharmacokinetic parameters of vortioxetine using a population pharmacokinetic approach.

Samples for pharmacogenomics will be collected and stored for possible exploratory investigation of drug 
response or disease. Pharmacogenomics analyses may be conducted to explore relationships of gene 
polymorphisms with drug responses, as indicated by the findings.
Subject Population: Male or female subjects with recurrent MDD aged 18-75 years, inclusive.
Number of Subjects:
Estimated total in the open-label lead-in phase in order to 
meet the target for the double-blind phase: Approximately 
1100 subjects
Estimated total in the double-blind phase: 
Approximately 600 subjects
Per treatment group in the double-blind phase: 150 subjects
Number of Sites: 
Approximately 60 sites in United States
Dose Level(s):
5 mg vortioxetine
10 mg vortioxetine
20 mg vortioxetine
Placebo
Route of Administration:
Oral
Duration of Treatment:
Up to 48 weeks
Period of Evaluation:
Up to 55 weeks
Main Criteria for Inclusion:

The subject suffers from recurrent MDD as the primary diagnosis according to DSM-IV-TR criteria 
(classification code 296.3x), and the current episode is confirmed by the Mini International Neuropsychiatric 
Interview (MINI), hereafter referred to as MINI.

The reported duration of the current episode is ≥8 weeks and ≤18months.

The subject had at least 2 other major depressive episodes (MDE) before the current episode. 

The subject has a MADRS total score ≥26 at the Screening and Baseline I Visits.

The subject is a man or woman aged 18 to 75 years, inclusive.
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Main Criteria for Exclusion:.

The subject has participated in 2 or more clinical studies in the year prior to Screening, or has participated in a 
clinical trial for a psychiatric condition that is exclusionary per this protocol.

The subject is an immediate family member, study site employee, or is in a dependent relationship with a study 
site employee who is involved in conduct of this study (eg, spouse, parent, child, sibling) or may consent under 
duress. 

The subject has one or more of the following:
a)
Any current psychiatric disorder which is the primary focus of treatment other than MDD as defined in the 
DSM-IV-TR, and assessed by the MINI.
b)
Current or history of: manic or hypomanic episode, schizophrenia or any other psychotic disorder, including 
schizoaffective disorder, major depression with psychotic features, bipolar depression with psychotic 
features, obsessive compulsive disorder (OCD), mental retardation, organic mental disorders, or mental 
disorders due to a general medical condition as defined in the DSM-IV-TR.
c)
Current diagnosis or history of alcohol or other substance abuse or dependence (excluding nicotine or 
caffeine) as defined in the DSM-IV-TR that has not been in full and sustained remission for at least 3 months 
from the day of screening (Subject must also have negative urine drug screen at Screening and Baseline I.)
d)
Presence or history of a clinically significant neurological disorder (including epilepsy) as determined by the 
investigator.
e)
Neurodegenerative disorder (Alzheimer disease, Parkinson disease, multiple sclerosis, Huntington disease, 
etc).
f)
Any Axis II disorder as defined by DSM-IV-TR that might compromise the study.

The current depressive symptoms of the subject are considered by the investigator to have been resistant to 2 
adequate antidepressant treatments of at least 6 weeks duration each.

The subject has a history of lack of response to previous adequate treatment with vortioxetine for any MDD 
episode with adequate treatment considered to be known dose of vortioxetine in the approved recommended dose 
range for at least 6 weeks duration.

The subject has received electroconvulsive therapy, vagal nerve stimulation, or repetitive transcranial magnetic 
stimulation within 6 months prior to Screening.

The subject has started receiving formal cognitive or behavioral therapy, systematic psychotherapy within 30 
days from screening or plans to initiate such therapy during the study (supportive therapy, marital therapy and 
bereavement counseling are allowed).

The subject has a significant risk of suicide according to the investigator’s clinical judgment or has a score ≥5 on 
item 10 (suicidal thoughts) of the MADRS or has made a suicide attempt in the previous 6 months.

The subject has a clinically significant unstable illness, for example hepatic impairment or renal insufficiency, or 
a cardiovascular, pulmonary, gastrointestinal, endocrine, neurological, rheumatologic, immunologic, 
hematological, infectious, dermatological disorder or metabolic disturbance.

The subject has a known history of or currently has increased intraocular pressure or is at risk of acute 
narrow-angle glaucoma.

The subject has a disease or takes medication that, in the opinion of the investigator, could interfere with the 
assessments of safety, tolerability, or efficacy.
Randomization Criteria:

The subject is in response from the Week 8 Visit through Week 16 Visit (response defined as a ≥50% reduction in 
MADRS total score from Baseline I).
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
The subject is in remission (MADRS total score ≤12) at the Week 14 and Week 16 visits.

The subject has not met any other withdrawal criteria, such as major protocol violation.
Main Criteria for Evaluation and Analyses:
Primary Endpoint:
The primary endpoint is time from randomization to relapse during the first 28 weeks of the 32-week double-blind 
treatment period with relapse defined as depression (MADRS 22), or lack of efficacy as determined by the 
investigator.
Secondary Endpoints:

Change from double-blind baseline in MADRS total score at all time points assessed.

Change from double-blind baseline in Clinical Global Impression Scale-Severity of Illness Scale (CGI-S) score at 
all time points assessed.

Clinical Global Impression Scale-Global Improvement Scale (CGI-I) score at all time points assessed.

Time from randomization to relapse during the entire 32-week double-blind treatment period with relapse defined 
as depression (MADRS ≥22), or lack of efficacy as determined by the investigator.
Safety Assessments:
Safety and tolerability of vortioxetine will also be evaluated using the following general assessments:

Adverse events (AEs).

Laboratory values.

Vital signs.

Weight.

Electrocardiograms (ECGs).
Additional Endpoints:

The time from randomization to withdrawal for any reason during 28 weeks of double-blind treatment.

Columbia-Suicide Severity Rating Scale (C-SSRS) summary data at all time points assessed.

Estimate individual exposure parameters of vortioxetine, including area under the plasma concentration-time 
curve from time 0 to time tau (AUCτ), average serum concentration (Cav), maximum observed plasma 
concentration (Cmax).
Statistical Considerations:
Primary Efficacy Analysis:
The primary efficacy variable will be the time from randomization to relapse during the first 28 weeks of the 32-week
double-blind treatment (date of relapse – date of randomization +1), with relapse defined as depression (MADRS 
22), or lack of efficacy as determined by the investigator. Primary analysis will be based on a Cox model with an 
exact method to handle ties (based on the full analysis set [FAS]), with treatment as the factor and baseline MADRS 
total score as the covariate of the Cox model.
Secondary Efficacy Analysis:
Change from double-blind Baseline II in MADRS total score will be analyzed using a mixed model for repeated 
measurements (MMRM) analysis with treatment, center, week, treatment-by-week interaction, baseline MADRS total 
score-by-week as fixed effects, and a completely unstructured covariance matrix. Change in MADRS total score will 
also be analyzed using analysis of covariance (ANCOVA), with treatment and center as fixed factors, Baseline II 
MADRS total score as covariate, and using the last-observation-carried forward (LOCF) technique and observed case 
(OC) methods. Comparisons between the different doses of vortioxetine and placebo will be performed over all the 
assessment points. 
CGI-I scores and change from Baseline II in the CGI-S will be analyzed by study visit using both MMRM and 
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ANCOVA similar to the ones described above for the change of MADRS total score.
Time from randomization to relapse of MDD occurring during the entire 32-week double-blind treatment period will 
be analyzed using a Cox model similar to the one described above for the primary variable.
Controlling Type I Error
To control the type I error of the study, comparison between each dose of vortioxetine and placebo will be tested in the 
sequential order of 20 mg vs placebo, 10 mg vs placebo, and 5 mg vs placebo at significance level 0.05; as soon as a 
dose is non-significant from placebo at 0.05, the testing procedure stops for all subsequent dose(s).
Safety Analysis
The safety data will be summarized for the open-label period and double-blind period separately.
Adverse Events
Adverse events will be reported throughout the study. The definition of treatment-emergent adverse events will be 
provided in the statistical analysis plan (SAP). Adverse events will be coded using the Medical Dictionary for 
Regulatory Activities (MedDRA) and will be summarized by system organ class and preferred term. Adverse events 
that were reported more than once by a subject during the same period will be counted only once for that subject and at 
period of the maximum severity.
Clinical Evaluations
Absolute values and changes from Screening/Baseline I in clinical safety laboratory tests, vital signs, ECG parameters, 
and weight/body mass index will be summarized for each treatment group using descriptive techniques. Values 
outside normal ranges and potentially clinically significant values will be flagged and tabulated.
Sample Size Justification: Assuming a cumulative relapse rate at 28 weeks of 15% for the vortioxetine group versus 
30% for the placebo group, a total of 600 subjects (150 per treatment group) will provide 85% power to find a 
statistically significant difference between each dose of vortioxetine and placebo at a 5% significance level.
It is anticipated that approximately 55% of the patients enrolled into the open-label period will qualify for the 
double-blind study phase. Therefore, a total of about 1100 patients will need to be enrolled into the open-label period 
of the study. However, if the number of subjects who relapsed during the double-blind treatment period is much less 
than expected, sample size adjustment will be considered. In addition, as the required number of subjects enrolled into 
the open-label period is dependent upon the number randomized into the double-blind, the number enrolled may be 
more or less than the estimated 1100.
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3.0
STUDY REFERENCE INFORMATION
3.1
Study-Related Responsibilities 
The sponsor will perform all study-related activities with the exception of those identified in the 
Study-Related Responsibilities template. The identified vendors in the template for specific 
study-related activities will perform these activities in full or in partnership with the sponsor.
3.2
Principal Investigator
Takeda will select a Signatory Coordinating Investigator from the investigators who participate in 
the study. Selection criteria for this investigator will include significant knowledge of the study 
protocol, the study medication, their expertise in the therapeutic area and the conduct of clinical 
research as well as study participation. The Signatory Coordinating Investigator will be required to 
review and sign the clinical study report and by doing so agrees that it accurately describes the 
results of the study.
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3.3
List of Abbreviations
AE
adverse event
ALT
Alanine aminotransferase
ANCOVA
analysis of covariance
APA
American Psychiatric Association
AST
aspartate aminotransferase
AUCτ
area under the plasma concentration-time curve from time 0 to time tau
bpm
beats per minute
Cav
average serum concentration
CGI-I
Clinical Global Impression Scale – Global Improvement Scale
CGI-S
Clinical Global Impression Scale – Severity of Illness Scale
Cmax
maximum observed plasma/blood/serum concentration
CRO
contract research organization
C-SSRS
Columbia-Suicide Severity Rating Scale
CTSdatabase
Clinical Trial Subject Database (CTSdatabase)
DNA
deoxyribonucleic acid
DO
doctor of osteopathy
DRESS
drug reaction with eosinophilia and systemic symptoms
DSM-IV-TR
Diagnostic & Statistical Manual of Mental Disorders, 4th Edition - Text Revision
DVD
digital versatile disc
DvX
diagnostic validation
ECG
electrocardiogram
eCRF
electronic case report form
FAS
full analysis set
FDA
Food and Drug Administration
GCP
Good Clinical Practice
GGT
-glutamyl transferase
HbA1c
glycosylated hemoglobin
HBsAg
hepatitis B surface antigen
hCG
human chorionic gonadotropin
HCV
hepatitis C virus
HIV
human immunodeficiency virus
ICH
International Conference on Harmonisation
ID
identification
IEC
independent ethics committee
INR
international normalized ratio
IR
immediate release
IRB
institutional review board
IWRS
interactive web response system
K2EDTA
potassium ethylenediaminetetraacetic acid
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LFT
liver function tests
LOCF
last observation carried forward
MADRS
Montgomery-Asberg Depression Rating Scale
MDD
major depressive disorder
MDE
major depressive episodes
MedDRA
Medical Dictionary for Regulatory Activities
MINI
Mini International Neuropsychiatric Interview
MMRM
mixed model for repeated measures
NONMEM
nonlinear mixed effect modeling
OC
observed case
OCD
obsessive compulsive disorder
OE
over encapsulation
PI
principal investigator
PK
Pharmacokinetic(s)
PPS
per protocol set
PTE
pretreatment event
QD
once daily
OE
overencapsulation
QTc
corrected QT interval
RNA
ribonucleic acid
SAE
serious adverse event
SAP
statistical analysis plan
SIGMA
Structured Interview Guide for the MADRS
SJS
Stevens-Johnson syndrome
SUSAR
suspected unexpected serious adverse reaction
TEN
toxic epidermal necrolysis
TSH
thyroid stimulating hormone
ULN
upper limit of normal
WHO
World Health Organization
3.4
Corporate Identification 
TDC Americas
Takeda Development Center Americas, Inc.
TDC
TDC Japan, TDC Asia, TDC Europe and/or TDC Americas, as applicable
Takeda
TDC Japan, TDC Asia, TDC Europe and/or TDC Americas, as applicable
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4.0
INTRODUCTION
4.1
Background
The prevalence of major depressive disorder (MDD) in the United States is 8.3%, based on a 
recent World Health Organization (WHO) World Mental Health survey [1]. Furthermore, the 
burden is likely to grow over the coming years. According to the WHO, depression alone accounts 
for 4.3% of the global burden of disease and is among the largest single causes of disability 
worldwide (11 % of all years lived with disability globally), particularly for women [2].
Depression poses an economic burden both on the patients, their families and friends, and on 
society. The ability of the depressed patients or their caregivers to work and make productive 
contributions to the economy is reduced, whereas the utilization of treatment and support services 
is increased. The economic consequences of these health losses are significant: a recent study 
estimated that the cumulative global impact of mental disorders in terms of lost economic output 
will amount to US$ 16.3 million between 2011 and 2030 [2]. 
Depression is recurrent in 75% to 80% of patients, becomes chronic (that is, lasts 2 years or longer) 
in 15% to 20% of depressed patients [3,4], and can lead to substantial impairments in an 
individual’s ability to take care of his/her everyday responsibilities. Furthermore, depression may 
lead to suicide, and of those patients who are treated for depression, approximately 15% commit 
suicide [5]. 
The risk of relapse of recurrence, chronicity (as measured by the duration of episodes) and 
treatment resistance increases with each new episode. Thus, treatment to full remission and 
continue treatment to prevent relapse and recurrence are both major priorities for management of 
recurrent MDD [6].
Clinical practice guidelines, such as those provided by the American Psychiatric Association 
(APA), recommend that patients who respond to acute-phase therapy with antidepressant 
medications receive at least 6 months of continuation therapy to prevent relapse [7].
Vortioxetine (LuAA21004) is an antidepressant agent approved in 2013 in the United States and 
the European Union for treatment of MDD. It differs from preexisting antidepressants in that it 
combines 2 pharmacological modes of action: direct modulation of receptor activity and inhibition 
of the serotonin transporter. Vortioxetine is an antagonist at 5-HT3, 5-HT7, and 5-HT1D receptors, 
an agonist at 5-HT1A receptors, a partial agonist at 5-HT1B receptors, and an inhibitor of the 5-HT 
transporter [8,9].
During the clinical development program, the efficacy, safety and tolerability of vortioxetine in 
MDD subjects was evaluated at doses from 1 to 20 mg/day in short-term efficacy studies of 6-8 
weeks duration and long-term safety studies up to 52 weeks duration. Vortioxetine was safe and 
well-tolerated across the dose range. The efficacy of vortioxetine in the treatment of MDD was 
established in six 6-8 week randomized, double-blind, placebo-controlled, fixed-dose studies 
(including one study in the elderly). Efficacy was established at doses of 5, 10, 15 and 20 mg with 
the recommended starting dose being 10 mg/day [10].
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The long-term efficacy and maintenance of effect of vortioxetine treatment at doses of 5 and 
10 mg/day has been previously established in subjects with MDD [11]. The aim of this study is to 
evaluate the efficacy of vortioxetine at 5 and 10 mg/day as well as the highest approved dose of 
vortioxetine 20 mg/day in the prevention of relapse in patients with MDD.
4.2
Rationale for the Proposed Study
MDD is a long-term illness for many patients and maintenance therapy is recommended to prevent 
relapse in patients with recurrent depression. This study is being conducted to evaluate the 
long-term maintenance of subjects treated with vortioxetine in the prevention of relapse. 
Vortioxetine doses of 5, 10, and 20 mg are being explored in this randomized withdrawal study. 
The primary endpoint will be assessed during the first 28 weeks of the 32-week double-blind 
treatment period to allow sufficient time to detect a difference in the time to relapse between 
vortioxetine and placebo.
Blood samples for pharmacogenomic assessment are being collected in this study. 
Pharmacogenomic analysis may be conducted to investigate the contribution of genetic variance 
on drug response, eg, its efficacy and safety. Participation of study subjects in pharmacogenomic 
sample collection is optional.
As pharmacogenomics is an evolving science, currently many genes and their function are not yet 
fully understood. Future data may suggest a role of some of these genes in drug response, which 
may lead to additional hypothesis-generating exploratory research on banked samples.
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5.0
STUDY OBJECTIVES AND ENDPOINTS
5.1
Objectives
5.1.1
Primary Objective
The primary objective is to evaluate the efficacy of vortioxetine (5, 10, and 20 mg) versus placebo
during the first 28 weeks of the 32-week double-blind treatment period in the prevention of relapse 
in subjects with (MDD) who responded to acute treatment with vortioxetine 10 mg.
5.1.2
Secondary Objective 
To evaluate the overall efficacy of vortioxetine versus placebo during continuation treatment of 
subjects with MDD
5.1.3
Safety Objective
To evaluate long-term safety and tolerability of vortioxetine versus placebo in subjects with MDD
5.1.4
Additional Objectives 

To assess the effect of long-term treatment with vortioxetine and placebo on suicidal ideation 
and behavior.

Determine the pharmacokinetic (PK) parameters of vortioxetine using a population 
pharmacokinetic approach.

Samples for pharmacogenomics will be collected and stored for possible exploratory 
investigation of drug response or disease. Pharmacogenomics analyses may be conducted to 
explore gene polymorphism relationships with drug responses, as indicated by the findings.
5.2
Endpoints
5.2.1
Primary Endpoint
The primary endpoint is time from randomization to relapse during the first 28 weeks of the 
32-week double-blind treatment with relapse defined as depression Montgomery-Asberg 
Depression Rating Scale (MADRS 22), or lack of efficacy as determined by the investigator.
5.2.2
Secondary Endpoints

Change from double-blind baseline in MADRS total score at all time points assessed.

Change from double-blind baseline in Clinical Global Impression Scale – Severity of Illness 
(CGI-S) score at all time points assessed.

Clinical Global Impression Scale – Global Improvement Scale (CGI-I) score at all time points 
assessed.
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
Time from randomization to relapse during the entire 32-week double-blind treatment period 
with relapse defined as depression (MADRS ≥22), or lack of efficacy as determined by the 
investigator.
5.2.3
Safety Assessments
Safety and tolerability of vortioxetine will also be evaluated using the following general 
assessments:

Adverse events (AEs).

Laboratory values.

Vital signs.

Weight.

Electrocardiograms (ECGs).
5.2.4
Additional Endpoints

The time from randomization to withdrawal for any reason during 28 weeks of double-blind 
treatment.

Columbia-Suicide Severity Rating Scale (C-SSRS) summary data at all time points assessed.

Estimate individual exposure parameters of vortioxetine, including area under the plasma 
concentration-time curve from time 0 to time tau (AUCτ), average serum concentration (Cav), 
maximum observed plasma concentration (Cmax).
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6.0
STUDY DESIGN AND DESCRIPTION
6.1
Study Design
This study is a randomized, double-blind, placebo-controlled, Phase 4 study to evaluate 3 fixed 
doses (5, 10, and 20 mg oral tablets) of vortioxetine once daily in the prevention of relapse in adult 
subjects with MDD who have responded to acute treatment with vortioxetine.
This study is comprised of a 16-week open-label treatment period followed by a 32-week 
double-blind randomized treatment periods. This study will enroll approximately 1100 subjects 
into the open-label phase in order to target approximately 600 subjects into the double-blind 
treatment phases and will be conducted at approximately 60 sites in the United States.
Men and women between the ages of 18 and 75, inclusive, meeting the diagnostic criteria from the 
Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision 
(DSM-IV-TR) for recurrent MDD, who have had at least 2 major depressive episodes (MDEs) 
prior to the current episode, with a current episode of between 8 weeks and 18 months duration 
from screening, a MADRS total score of ≥26, and who sign the informed consent form will be 
further assessed for study eligibility at a screening visit. At Baseline I, subjects who continue to 
meet all inclusion criteria and none of the exclusion criteria will be enrolled into a 16-week 
open-label treatment period. During the open-label period all subjects will receive 10 mg 
vortioxetine. Subjects will take their first dose of study medication the morning after their Baseline 
I visit. During the open-label treatment period, subjects will be seen every 2 weeks until 
randomization (Baseline II). 
Subjects who are in response (defined as a ≥50% reduction in MADRS total score from Baseline I) 
at Week 8 will continue for an additional 8 weeks of treatment (Stabilization period) and will 
continue to receive 10 mg vortioxetine. Subjects must continue to meet response criteria as 
assessed at every study visit during the Stabilization period. In addition, subjects must meet 
remission criteria (defined as ≤12 MADRS total score) at weeks 14 and 16 to be eligible for 
randomization into the double-blind treatment period. Subjects who do not meet the response 
and/or remission criteria will be withdrawn from the study and will complete an early withdrawal 
visit. Subjects are to remain on 10 mg throughout the open-label period. If a subject requires a 
dose-adjustment, they should be withdrawn from study.
At Baseline II, subjects who have met the randomization criteria (response and remission as 
described above) and have not met any other withdrawal criteria will be randomized in a ratio of 
1:1:1:1 of the following 4 treatment groups for 32 weeks of double-blind treatment: vortioxetine 
5 mg; vortioxetine 10 mg; vortioxetine 20 mg; and placebo.
Subjects will be seen twice the first month and then once monthly during the remainder of the 
32-week double-blind treatment period. Subject well-being calls will be made every 2 weeks after 
Week 20, in between scheduled subject visits. 
Subjects will be considered as “relapsed” and withdrawn from the study if the following criteria 
are met: MADRS 22, or lack of efficacy as determined by the investigator. In addition, 
investigator judgment should be used to determine unsatisfactory treatment response indicative of 
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relapse to depression, such as subject hospitalization for depression, medication prescribed for 
MDD, electroconvulsive therapy, suicide attempt, etc.
A safety follow-up phone call will be made 30 days after completion of double-blind treatment. 
Subjects (either in open-label or double-blind) who discontinue or who are withdrawn prior to 
study completion will come to the site for an early withdrawal visit as soon as possible and will be 
contacted for a safety follow-up 30 days after the last dose of study medication. 
NOTE: The investigators will be requested to make a note of the approximate date of relapse 
within the period since last visit rather than specify the visit at which relapse was detected. If 
necessary, subjects that are suspected of relapse or impending relapse (eg, clinically relevant 
worsening of depression symptoms) should come to the study site as soon as possible to be 
assessed.
A schematic of the study design is included as Figure 6.a. A schedule of assessments is listed in 
Appendix A.
Figure 6.a
Schematic of Study Design
*Defined as 50% reduction in MADRS total score. Subjects must remain in response throughout stabilization 
period.
VOR = vortioxetine, pd. = period
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6.2
Justification for Study Design, Dose, and Endpoints
6.2.1
Study Design
Due to the character of the disorder, long-term studies are necessary to demonstrate that the 
short-term effect is maintained during an episode. As recommended in Food and Drug 
Administration (FDA) Guidance for Industry [12], a randomized withdrawal study is the most 
appropriate design to utilize in order to evaluate the maintenance of treatment effect.
6.2.2
Dose
The previously conducted long-term relapse prevention study evaluated vortioxetine at 5 and 
10 mg/day [11]. As the approved dose range is 5 to 20 mg, this study will evaluate doses of 
vortioxetine at 5 and 10 mg/day as well as the highest dose of vortioxetine 20 mg/day.
6.2.3
Endpoints
The MADRS was selected for evaluation of the efficacy endpoints. The MADRS is a 
well-established tool for assessing the severity of depression symptoms [13,14].
The CGI-S, and CGI-I are used as secondary efficacy measures, since these scales are also 
frequently used to assess clinical response [15].
Adequate measures have been taken regarding the methodology of this study to assess suicidal 
risk. The selection criteria exclude the participation of subjects at significant risk for suicide.
Throughout the study, signs of suicidal risk will be assessed both by rating scale assessment and by 
investigator’s clinical judgment. Subjects will be withdrawn from the study in case of such risk.
Furthermore, subjects will be screened for the history of suicidal behavior.
In order to more accurately and systematically assess the potential relationship between 
antidepressant agents and suicidality, the C-SSRS will be implemented in this study [16,17].
6.3
Premature Termination or Suspension of Study or Investigational Site
6.3.1
Criteria for Premature Termination or Suspension of the Study
The study will be completed as planned unless one or more of the following criteria are satisfied 
that require temporary suspension or early termination of the study.

New information or other evaluation regarding the safety or efficacy of the study medication
that indicates a change in the known risk/benefit profile for the product, such that the risk
/benefit is no longer acceptable for subjects participating in the study.

Significant violation of Good Clinical Practice (GCP) that compromises the ability to achieve 
the primary study objectives or compromises subject safety.
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6.3.2
Criteria for Premature Termination or Suspension of Investigational Sites
A study site may be terminated prematurely or suspended if the site (including the investigator) is 
found in significant violation of GCP, protocol, or contractual agreement, is unable to ensure 
adequate performance of the study, or as otherwise permitted by the contractual agreement.
6.3.3
Procedures for Premature Termination or Suspension of the Study or the 
Participation of Investigational Site(s)
In the event that the sponsor, an institutional review board (IRB)/independent ethics committee 
(IEC) or regulatory authority elects to terminate or suspend the study or the participation of an 
investigational site, a study-specific procedure for early termination or suspension will be 
provided by the sponsor; the procedure will be followed by applicable investigational sites during 
the course of termination or study suspension.
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7.0
SELECTION AND DISCONTINUATION/WITHDRAWAL OF SUBJECTS
All entry criteria, including test results, need to be confirmed prior to enrollment or first dose of 
study medication.
7.1
Inclusion Criteria
Subject eligibility is determined according to the following criteria prior to entry into the study: 
1. In the opinion of the investigator, the subject is capable of understanding and complying with 
protocol requirements.
2. The subject or, when applicable, the subject’s legally acceptable representative signs and dates 
a written, informed consent form and any required privacy authorization prior to the initiation 
of any study procedures. 
3. The subject suffers from recurrent MDD as the primary diagnosis according to DSM-IV-TR 
criteria (classification code 296.3x), and the current episode is confirmed by the Mini 
International Neuropsychiatric Interview (MINI).
4. The reported duration of the current episode is ≥8 weeks and ≤18months.
5. The subject had at least 2 other MDEs before the current episode. 
6. The subject has a MADRS total score ≥26 at the Screening and Baseline I visits.
7. The subject is a man or woman aged 18 to 75 years, inclusive.
8. A female subject of childbearing potential who is sexually active with a nonsterilized male 
partner agrees to routinely use adequate contraception from signing of the informed consent 
throughout the duration of the study and for 30 days after the last dose.
*Definitions and acceptable methods of contraception are defined in 
Section 9.1.13 Contraception and Pregnancy Avoidance Procedure and 
reporting responsibilities are defined in Section 9.1.14 Pregnancy.
7.2
Exclusion Criteria
Any subject who meets any of the following criteria will not qualify for entry into the study: 
1. The subject has received any investigational compound within 30 days prior to screening or 
5 half-lives prior to screening, whichever is longer.
2. The subject has previously or is currently participating in this study.
3. The subject has participated in 2 or more clinical studies in the year prior to screening, or has 
participated in a clinical trial for a psychiatric condition that is exclusionary per this protocol.
4. The subject is an immediate family member, study site employee, or is in a dependent 
relationship with a study site employee who is involved in conduct of this study (eg, spouse, 
parent, child, sibling) or may consent under duress. 
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5. The subject has one or more of the following:
a) Any current psychiatric disorder which is the primary focus of treatment other than MDD
as defined in the DSM-IV-TR, and assessed by the MINI.
b) Current or history of: manic or hypomanic episode, schizophrenia or any other psychotic 
disorder, including schizoaffective disorder, major depression with psychotic features, 
bipolar depression with psychotic features, obsessive compulsive disorder (OCD), mental 
retardation, organic mental disorders, or mental disorders due to a general medical 
condition as defined in the DSM-IV-TR.
c) Current diagnosis or history of alcohol or other substance abuse or dependence (excluding 
nicotine or caffeine) as defined in the DSM-IV-TR that has not been in full and sustained 
remission for at least 3 months from the day of screening (Subject must also have negative 
urine drug screen at Screening and Baseline I.)
d) Presence or history of a clinically significant neurological disorder (including epilepsy) as 
determined by the investigator.
e) Neurodegenerative disorder (Alzheimer disease, Parkinson disease, multiple sclerosis, 
Huntington disease, etc).
f)
Any Axis II disorder as defined by DSM-IV-TR that might compromise the study.
6. The current depressive symptoms of the subject are considered by the investigator to have been 
resistant to 2 adequate antidepressant treatments of at least 6 weeks duration each.
7. The subject has a history of lack of response to previous adequate treatment with vortioxetine 
for any MDD episode with adequate treatment considered to be known dose of vortioxetine in 
the approved recommended dose range for at least 6 weeks duration.
8. The subject has received electroconvulsive therapy, vagal nerve stimulation, or repetitive 
transcranial magnetic stimulation within 6 months prior to Screening.
9. The subject has started receiving formal cognitive or behavioral therapy, systematic 
psychotherapy within 30 days from screening or plans to initiate such therapy during the study 
(supportive therapy, marital therapy and bereavement counseling are allowed).
10. The subject has a significant risk of suicide according to the investigator’s clinical judgment or 
has a score 5 on item 10 (suicidal thoughts) of the MADRS or has made a suicide attempt in 
the previous 6 months.
11. The subject is required to take excluded medications or it is anticipated that the subject will 
require treatment with at least 1 of the disallowed concomitant medications during the study.
12. The subject has a clinically significant unstable illness, for example hepatic impairment or 
renal insufficiency, or a cardiovascular, pulmonary, gastrointestinal, endocrine, neurological, 
rheumatologic, immunologic, hematological, infectious, dermatological disorder or metabolic 
disturbance.
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NOTE: For the purposes of this protocol fibromyalgia, obstructive sleep apnea, chronic 
pain diagnosis, and morbid obesity (BMI of > 40) are considered unstable due to the 
potential impact on assessment of the primary endpoint.
13. The subject has a known history of or currently has increased intraocular pressure or is at risk 
of acute narrow-angle glaucoma.
14. The subject has 1 or more laboratory value outside the normal range, based on the blood or 
urine samples taken at the Screening Visit, that are considered by the investigator to be 
clinically significant; or the subject has any of the following values at the Screening Visit:
a) A serum creatinine value >1.5 times the upper limits of normal (ULN).
b) A serum total bilirubin value >1.5 xULN.
c) A serum alanine aminotransferase (ALT) or aspartate aminotransferase (AST) value 
>2 xULN.
15. The subject has glycosylated hemoglobin (HbA1C)≥7% at screening and no prior diagnosis of 
diabetes and/or treatment for diabetes. NOTE: Subjects with known stable diabetes are not 
excluded.
16. The subject has a thyroid stimulating hormone (TSH) value outside the normal range at the 
Screening Visit that is deemed clinically significant by the investigator. NOTE: Free T4 will be 
checked if TSH is out of range. If free T4 is abnormal the subject will be excluded.
17. The subject has clinically significant abnormal vital signs as determined by the investigator.
18. The subject has an abnormal ECG as determined by the central reader and confirmed as 
clinically significant by the investigator.
19. The subject is positive for Hepatitis B surface antigen (HBsAg), anti-hepatitis C virus (HCV) 
antibodies, or has a history of human immunodeficiency virus (HIV) infection.
20. The subject has a disease or takes medication that, in the opinion of the investigator, could 
interfere with the assessments of safety, tolerability, or efficacy.
21. The subject, in the opinion of the investigator, is unlikely to comply with the clinical study 
protocol or is unsuitable for any reason.
22. The subject has a history of hypersensitivity or allergies to vortioxetine.
23. If female, the subject is pregnant or lactating or intending to become pregnant before, during, 
or within 1 month after participating in this study; or intending to donate ova during such time 
period.
24. The subject is considered to be treatment resistant, eg, the subject has not responded to 
adequate monotherapy treatments of at least 6 weeks’ duration, or has only responded to 
combination or augmentation therapy.
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7.3
Randomization Criteria
1. The subject is in response from the Week 8 Visit through Week 16 Visit (response defined as a 
≥50% reduction in MADRS total score from Baseline I).
2. The subject is in remission (MADRS total score ≤12) at the Weeks 14 and 16 visits.
3. The subject has not met any other withdrawal criteria, such as major protocol violation.
7.4
Excluded Medications, Procedures, and Treatments
Use of any investigational medications will be prohibited within 30 days prior to Screening or 5 
half-lives prior to Screening, whichever is longer.
Subjects must be instructed not to take any medications including over-the-counter products, 
without first consulting with the investigator.
Table 7.a provides a list of excluded medications. Items with an ‘X’ indicate restrictions on either 
chronic use, or episodic use. Drug classes without an ‘X’ in these columns indicate no restrictions.
Table 7.a
Excluded Medications and Treatments
Drug Class
Disallowed Prior to 
Baseline I unless 
otherwise noted
Disallowed (X) During the Study 
[sections without (X) indicate no restriction]
Chronic 
Use
Episodic 
Use
Comments or Exceptions
Any investigational drug
<30 days before 
Screening or 5 half-lives 
– whichever is longer
X
X
Analgesics
Narcotic 
analgesics
X
X
Episodic use of opiates is allowed 
provided the subject has a valid 
prescription. 
NSAIDs 
X
Cox-2 selective 
inhibitors
Acetaminophen
Anorexics
2 weeks
X
X
Antacids
Antiacne agents
Antianginal agents
Antiarrhythmics of 1C class
Quinidine NOT allowed
Antibiotics
Rifampin NOT allowed
Antithrombic agents (including low 
dose aspirin) and anticoagulants
X
X
Low-molecular weight heparins 
are allowed for acute use
Anticonvulsants 
2 weeks 
X
X
Antidepressants (including MAOIs and 
RIMAs)
2 weeks (5 weeks for 
fluoxetine)
X
X
Antidiarrheal agents
Footnotes are on last table page
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Table 7.a
Excluded Medications and Treatments (continued)
Drug Class
Disallowed Prior to 
Baseline I unless 
otherwise noted
Disallowed (X) During the Study 
[sections without (X) indicate no restriction]
Chronic 
Use
Episodic 
Use
Comments or Exceptions
Antifungal agents 
Antihistamines
X
X
Only loratadine, desloratadine, 
cetirizine, levocetirizine, 
mizolastine and fexofenadine are 
allowed
Antihypertensives
Anti-impotence agents
Antimigraine agents – Triptans, 
Dopamine antagonists
2 weeks
X
X
.
Antinauseants, antiemetics (including 
dopamine antagonists)
2 weeks 
X
X
Only phosphoric acid and bismuth 
preparations are allowed
Antineoplastics
X
X
Antiobesity agents
2 weeks
X
X
Antipsoriatic agents
Antimalarial 
Antipsychotics
2 weeks (6 months for 
depot)
X
X
Antiviral agents
Anxiolytics (including 
benzodiazepines)
2 weeks 
X
X
Cough/cold agents 
X
Allowed for episodic treatment for 
a maximum of 1 week 
Diuretics
Herbal remedies, which are 
psychoactive (eg, St. Johns Wort, 
kava kava, valerian, ginkgo biloba, 
melatonin)
2 weeks
X
X
H2 Blockers
Proton pump inhibitors
Hormones
X
X
Thyroid hormone replacement, 
parathyroid hormone, and its 
recombinant form (Forteo), 
contraceptives (oral, patch, 
injectables and implants), 
estrogen and progesterone 
replacement therapy as well as 
benign prostatic hyperplasia 
treatment are allowed
Hypoglycemic agents 
X
Hypolipidemics
Footnotes are on last table page.
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Table 7.a
Excluded Medications and Treatments (continued)
Drug Class
Disallowed Prior to 
Baseline I unless 
otherwise noted
Disallowed (X) During the Study 
[sections without (X) indicate no restriction]
Chronic 
Use
Episodic 
Use
Comments or Exceptions
Insulin
X
Laxatives
Mood stabilizers 
2 weeks
X
X
Psychotropic agents not otherwise 
specified (including stimulants, 
tryptophan, melatonin and dopamine 
agonists)
2 weeks 
X
X
Sedatives/hypnotics 
2 weeks 
(see comments)
X
From 2 weeks to Baseline I to the 
end of the study, only zolpidem, 
eszopiclone/zopiclone, zaleplon, 
ramelteon allowed, with a 
maximum of 2 nights per week, 
and not the night before a study 
visit
Steroids:
Systemic
2 weeks 
X
X
Injectable steroids are also not 
allowed. 
Topical
Inhalant
Vaccines
COX-2=cyclooxygenase-2, MAOI=monoamine oxidase inhibitor, NSAID =nonsteroidal anti-inflammatory drug, 
RIMA=reversible inhibitor of monoamine oxidase type A, H2 Blockers=H2 receptor antagonists (acid reducers)
7.5
Criteria for Discontinuation or Withdrawal of a Subject
The primary reason for discontinuation or withdrawal of the subject from the study or study 
medication should be recorded in the electronic case report form (eCRF) using the following 
categories. For screen failure subjects, refer to Section 9.1.18.
Applies to either Open-Label or Double-Blind Periods of Study.
1. Pretreatment event (PTE) or AE. The subject has experienced a PTE or AE that requires early 
termination because continued participation imposes an unacceptable risk to the subject’s 
health or the subject is unwilling to continue because of the PTE or AE.

Liver Function Test (LFT) Abnormalities
Study medication should be discontinued immediately with appropriate clinical follow-up 
(including repeat laboratory tests, until a subject’s laboratory profile has returned to 
normal/baseline status, see Section 9.1.12), if the following circumstances occur at any 
time during study medication treatment:
–
ALT or AST >8 × ULN, or
–
ALT or AST >5 × ULN and persists for more than 2 weeks, or
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–
ALT or AST >3 × ULN in conjunction with elevated total bilirubin >2 × ULN or 
international normalized ratio (INR) >1.5, or
–
ALT or AST >3 × ULN with appearance of fatigue, nausea, vomiting, right upper 
quadrant pain or tenderness, fever, rash and/or eosinophilia (>5%).
2. Significant protocol deviation. The discovery after the first dose of study medication that the 
subject failed to meet protocol entry criteria or did not adhere to protocol requirements, and 
continued participation poses an unacceptable risk to the subject’s health.
3. Noncompliance with study drug. This includes subjects who did not take the study medication 
for 6 of more consecutive days or are less than 70% compliant between visits. NOTE: if 
noncompliance occurred during the Double-Blind phase and was preceded by a relapse to 
depression, then the main reason for withdrawal should be “relapse”.
4. Lost to follow-up. The subject did not return to the clinic and attempts to contact the subject 
were unsuccessful. Attempts to contact the subject must be documented.
5. Voluntary withdrawal. The subject (or subject’s legally acceptable representative) wishes to 
withdraw from the study. The reason for withdrawal, if provided, should be recorded in the 
eCRF.
Note: All attempts should be made to determine the underlying reason for the withdrawal and, 
where possible, the primary underlying reason should be recorded (ie, withdrawal due to an 
AE or for relapse) should not be recorded in this category.
6. Study termination. The sponsor, IRB, IEC, or regulatory agency terminates the study.
7. Pregnancy. The subject is found to be pregnant. 
Note: If the subject is found to be pregnant, the subject must be withdrawn immediately. The 
procedure is described in Section 9.1.14.
9. Other.
Note: The specific reasons should be recorded in the “specify” field of the eCRF.
Applies to Open-label Period ONLY:
1. Lack of efficacy. The investigator has determined that the subject is not benefiting from 
investigational treatment; and, continued participation would pose an unacceptable risk to the 
subject. 
2. Subject did not meet randomization criteria (response or remission criteria as specified in 
Section 7.3).
Applies to Double-Blind Period ONLY:
1. Relapse.
a) MADRS 22.
b) Lack of efficacy that is indicative of relapse per Investigator judgment.
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c) Other unsatisfactory treatment response indicative of relapse as determined by Investigator 
(eg, subject hospitalization for depression, medication prescribed for MDD, 
electroconvulsive therapy, suicide attempt, etc.)
Note: A Relapse Checklist will be used by sites to evaluate potential indicators of relapse for 
each subject at each visit post baseline during the double blind-period.
7.6
Additional Guidance for Withdrawal Criteria
Throughout the study, signs of suicidal risk will be assessed by both the C-SSRS and MADRS 
assessment and the investigator’s clinical judgment. If the subject has a significant risk of suicide 
according to the investigator or has a score of ≥5 on item 10 (suicide ideation) of the MADRS, the 
subject should be withdrawn from study. Significant risk of suicide would likely be indicative of 
relapse or pending relapse. This should be taken into consideration as reason for withdrawal in the 
Double-Blind Period.
7.7
Procedures for Discontinuation or Withdrawal of a Subject
The Investigator may discontinue a subject’s study participation at any time during the study when 
the subject meets the study termination criteria described in Section 7.5. In addition, a subject may 
discontinue his or her participation without giving a reason at any time during the study. Should a 
subject’s participation be discontinued, the primary criterion for termination must be recorded by 
the investigator. In addition, efforts should be made to perform all procedures scheduled for the 
Withdrawal Visit. Discontinued or withdrawn subjects will not be replaced. 
Note: All procedures for the Withdrawal Visit should be performed regardless of the reason for 
withdrawal, with the exception of subjects who refuse any further contact.
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8.0
CLINICAL TRIAL MATERIAL MANAGEMENT
This section contains information regarding all medication and materials provided directly by the 
sponsor, and/or sourced by other means, that are required by the study protocol, including 
important sections describing the management of clinical trial material.
8.1
Study Medication and Materials
8.1.1
Dosage Form, Manufacturing, Packaging, and Labeling
In this protocol, the term study medication refers to all or any of the drugs defined below.

Commercial vortioxetine (Brintellix) tablets in encapsulated strengths of 5, 10, and 20 mg

Matching placebo capsules.
Vortioxetine 5, 10, and 20 mg tablets are manufactured by Takeda or H. Lundbeck A/S, Valby, 
Denmark. Overencapsulation (OE) of vortioxetine tablets and the manufacture of the placebo 
capsules using Swedish-Orange capsules with lactose monohydrate filler is by Almac Clinical 
Services, Souderton, PA USA
The study medication will be packaged in bottles with child resistant closures. Each bottle contains 
14 daily doses plus 4 extra capsules for a total of 18 capsules per bottle. The daily dose is 1 capsule 
by oral administration.
OE vortioxetine 10 mg bottles will be labeled and dispensed as open labeled for the initial acute 
treatment phase. OE vortioxetine 5, 10, 20 mg and placebo bottles will be labeled and dispensed as 
double-blind for the relapse prevention treatment phase. Each label will contain pertinent study 
information.
8.1.1.1
Investigational drug
Vortioxetine is a novel compound developed by Takeda and H. Lundbeck A/S as an antidepressant 
and treatment for MDD. Vortioxetine belongs to a new chemical class of psychotropics, the 
bis-aryl-sulfayl amines, which possess unique properties compared with currently known 
psychotropics. This new class of compounds is structurally different from all currently known 
psychotropics.
Vortioxetine is commercially formulated as immediate release (IR) tablets intended for oral 
administration. The study medication is film-coated tablets containing hydrobromide salt of 
LuAA21004. The tablets contain Lu AA21004-HBr corresponding to 5, 10, and 20 mg of 
LuAA21004 base. Well known excipients are used to manufacture the tablet cores.
8.1.1.2
Sponsor-Supplied Drug
Sponsor-supplied drugs referenced in other sections of the protocol include the following:

Commercial vortioxetine tablets in encapsulated strengths of 5, 10, and 20 mg.

Matching placebo capsules.
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8.1.2
Storage
Study medication should be stored at 25ºC (77ºF) excursions permitted to 15 ºC to 30ºC (59 ºF
-86ºF).
Investigational drug, OE vortioxetine 5, 10, and 20 mg and matching placebo must be kept in an 
appropriate, limited-access, secure place until it is used or returned to the sponsor or designee for 
destruction. Investigational drug, OE vortioxetine 5, 10, and 20 mg and matching placebo must be 
stored under the conditions specified on the label, and remain in the original container until 
dispensed. A daily temperature log of the drug storage area must be maintained every working day.
8.1.3
Dose and Regimen
The investigator or designee should contact the interactive web response system (IWRS) to 
register each subject at the initial screening visit. At each applicable study visit (Visits 2-18), the 
investigator or designee should contact the IWRS to receive the appropriate investigational 
medication assignment for dispensation. The IWRS will provide the medication identification (ID) 
number for each bottle dispensed at each study visit. The medication ID number assigned should 
be recorded in the source document and eCRF.
Each subject who qualifies following the initial screening visit will enter the 16-week open-label 
acute treatment phase and will be dispensed OE vortioxetine 10 mg. 
Subjects will be instructed to take 1 capsule per day, orally, at the same time of day, preferably in 
the morning, or as directed. The first dose is to be taken the day after the study medication has been 
dispensed to the subject. Study medication can be taken with or without food. The subject should 
be advised to be consistent in the dosing time throughout the duration of the trial.
Subjects who qualify for randomization into the double-blind treatment period at week 16 (Visit 
10) will be randomly assigned to 1 of 4 treatment groups: Vortioxetine 5, 10, 20 mg or placebo
through the IWRS and will be dispensed the blinded study medication. 
Subjects who complete the 16 week open-label acute treatment phase and the 32 week 
double-blind relapse prevention phase will receive a total of 24 bottles of study medication. 
The investigator or designee will instruct the subject on the dosing procedures and investigational 
medication storage requirements. Subjects should return their unused investigational medication at 
each study visit to allow the opportunity for the investigator or designee to evaluate subjects’ 
compliance with the dosing instructions
Table 8.a describes the daily dose and tablet count that will be provided to each group. 
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Table 8.a
Dose and Regimen
Treatment 
Group
Dose
Treatment Description
Active
Placebo
Open-label
10 mg Vortioxetine 
QD
1 capsule containing one 10 
mg vortioxetine tablet 
0 placebo capsules
A
Placebo QD
0 active tablets/capsules
1 placebo capsule
B
5 mg Vortioxetine
QD
1 capsule containing one 5 mg 
vortioxeting tablet
0 placebo capsules
C
10 mg Vortioxetine 
QD
1 capsule containing one 10 
mg vortioxetine tablet
0 placebo capsules
D
QD = once daily
20 mg Vortioxetine 
QD
1 capsule containing one 20 
mg vortioxetine tablet
0 placebo capsules
8.1.4
Overdose
An overdose is defined as a known deliberate or accidental administration of investigational drug, 
to or by a study subject, at a dose above that which is assigned to that individual subject according 
to the study protocol.
All cases of overdose (with or without associated AEs) will be documented on an Overdose page 
of the eCRF, in order to capture this important safety information consistently in the database. 
Cases of overdose without manifested signs or symptoms are not considered AEs. AEs associated 
with an overdose will be documented on AE CRF(s) according to Section 10.0, Pretreatment 
Events and Adverse Events.
Serious adverse events (SAEs) associated with overdose should be reported according to the 
procedure outlined in Section 10.2.2, Collection and Reporting of SAEs.
In the event of drug overdose, general symptomatic and supportive measures should be used, along 
with immediate gastric lavage where appropriate. Intravenous fluids should be administered as 
needed. As in all cases of drug overdose, respiration, pulse, blood pressure, and other appropriate 
signs should be monitored and general supportive measure employed. 
As with the management of all overdoses, the possibility of multiple drug ingestion should be 
considered. The physician may contact a poison control center for current information on the 
management of overdose.
8.2
Investigational Drug Assignment and Dispensing Procedures
The investigator or investigator’s designee will access the IWRS at Screening to obtain the subject 
study number. The investigator or the investigator’s designee will utilize the IWRS to enroll the 
subject into the open-label acute treatment at the Baseline 1 visit should they qualify, where 
subjects will be dispensed OE vortioxetine 10 mg. The investigator or investigator’s designee will 
access the IWRS to randomize the subject into the study should they meet the eligibility 
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requirements. Subjects will be assigned in a 1:1:1:1 ratio to one of the 4 treatment arms of 
Vortioxetine 5, 10, or 20 mg or placebo. Subject randomization across treatments will be balanced 
at the site level. 
During each IWRS contact, the investigator or designee will provide the necessary 
subject-identifying information, including the subject number assigned at screening. The 
medication ID number(s) of the investigational drug necessary to support the visit schedule to be 
dispensed will then be provided by the IWRS. If sponsor-supplied drug is lost or damaged, the site 
can request a replacement from the IWRS (refer to IWRS manual provided separately.) The 
medication ID number(s) will be entered onto the eCRF. At subsequent drug-dispensing visits, the 
investigator or designee will again contact the IWRS to request additional investigational drug for 
a subject. The medication ID number of the investigational drug to be dispensed will be provided 
by the IWRS. The medication ID number will be entered onto the eCRF. 
Subjects should be instructed for the following:

The sponsor-supplied drug is to remain in original container until time of dosing

The subject should take only one tablet per day as instructed. If the dose is missed in the 
morning, it is acceptable to take the dose later in the same day. If the subject misses a dose, 
he/she should not take twice the dosing the next day. 

To store their sponsor-supplied drug according to the label and to keep out of the reach of 
children.

Subjects are to return their sponsor-supplied drug at each visit.
8.3
Randomization Code Creation and Storage 
Takeda randomization personnel or designee will generate the randomization schedule for the 
study; an IWRS will be used in a centralized fashion for subject randomization and study 
medication assignments.
All randomization information will be stored in a secured area, accessible only by authorized 
personnel.
8.4
Investigational Drug Blind Maintenance 
The investigational drug blind will be maintained using the IWRS. The principal investigator (PI)
at each study site will receive instructions for obtaining the medication assignment through the 
IWRS. During regularly scheduled monitoring visits, a study monitor from the sponsor or a 
designee will perform an inventory of double-blind study medication unassigned and assigned 
treatment bottles. All assigned/unassigned treatment bottles will be reconciled and returned to the 
sponsor or a designee before study closure.
8.5
Unblinding Procedure 
The investigational drug blind shall not be broken by the investigator unless information 
concerning the investigational drug is necessary for the medical treatment of the subject. If 
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possible, the sponsor/designee should be notified before the investigational drug blind is broken. If 
a medical emergency requiring unblinding occurs, the investigator (or designee) at the site will 
contact the sponsor or designee (see medical monitor contact information listed in Section 1.1) to 
assess the necessity to break the investigational drug blind.
For unblinding a subject, the investigational drug blind can be obtained by accessing the IWRS. 
The sponsor/designee must be notified immediately if the study medication blind is broken. The 
date, time, and reason the blind was broken must be recorded in the source documents and on the 
appropriate eCRF.
If any site personnel is unblinded, investigational drug must be stopped immediately and the 
subject must be withdrawn from the study. The reason for withdrawal should be recorded as 
“Protocol Deviation”.
8.6
Accountability and Destruction of Sponsor-Supplied Drugs
Drug supplies will be counted and reconciled at the site before being returned to the sponsor or 
designee.
The investigator or designee must ensure that the sponsor-supplied drug is used in accordance with 
the protocol and is dispensed only to subjects enrolled in the study. To document appropriate use 
of sponsor-supplied drug (Vortioxetine 5, 10, 20 mg and placebo), the investigator or designee 
must maintain records of all sponsor-supplied drug delivery to the site, site inventory, dispensation 
and use by each subject, and return to the sponsor or designee.
Upon receipt of sponsor-supplied drug, the investigator or designee must verify the contents of the 
shipments against the packing list. The verifier should ensure that the quantity is correct, and the 
medication is in good condition. If quantity and conditions are acceptable, investigator or designee 
should acknowledge the receipt of the shipment by recording in IWRS. If there are any 
discrepancies between the packing list versus the actual product received, Takeda must be 
contacted to resolve the issue. The packing list should be filed in the investigator’s essential 
document file.
The investigator or designee must maintain 100% accountability for all sponsor-supplied drugs
received and dispensed during his or her entire participation in the study. Proper drug 
accountability includes, but is not limited to:

Frequently verifying that actual inventory matches documented inventory.

Verifying that the log is completed for the drug lot (or Medication ID number) used to prepare 
each dose.

Verifying that all containers used are documented accurately on the log.

Verifying that required fields are completed accurately and legibly.
If any dispensing errors or discrepancies are discovered, the sponsor must be notified immediately.
The IWRS will include all required information as a separate entry for each subject to whom 
sponsor-supplied drug is dispensed.
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The investigator or designee must record the current inventory of all sponsor-supplied drugs 
(Vortioxetine 5, 10, 20 mg and placebo) on a sponsor-approved drug accountability log/IWRS. 
The following information will be recorded at a minimum: protocol number and title, name of 
investigator, site identifier and number, description of sponsor-supplied drugs, date and amount 
dispensed including initials of the person dispensing the drug, and the date and amount returned to 
the site by the subject, including the initials of the person receiving the sponsor-supplied drug. The 
log should include all required information as a separate entry for each subject to whom 
sponsor-supplied drug is dispensed. 
All study drug that was not returned to the site by a subject must be investigated by the site and 
appropriately documented on the drug accountability log/IWRS.
Prior to site closure or at appropriate intervals, a representative from the sponsor or its designee 
will perform sponsor-supplied drug accountability and reconciliation before sponsor-supplied 
drugs are returned to the sponsor or its designee for destruction. The investigator or designee will 
retain a copy of the documentation regarding sponsor-supplied drug accountability, return, and/or 
destruction, and originals will be sent to the sponsor or designee.
The investigator will be notified of any expiry date or retest date extension of sponsor-supplied 
drug during the study conduct. On expiry date notification from the sponsor or designee, the site 
must complete all instructions outlined in the notification, including segregation of expired 
sponsor-supplied drug for return to the sponsor or its designee for destruction.
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9.0
STUDY PLAN
9.1
Study Procedures
The following sections describe the study procedures and data to be collected. For each procedure, 
subjects are to be assessed by the same investigator or site personnel whenever possible. The 
Schedule of Study Procedures is located in Appendix A.
9.1.1
Informed Consent Procedure
The requirements of the informed consent are described in Section 15.2.
Informed consent must be obtained prior to the subject entering into the study, and before any 
protocol-directed procedures are performed.
A unique subject identification number (subject number) will be assigned to each subject at the 
time that informed consent is obtained; this subject number will be used throughout the study.
9.1.1.1
Pharmacogenomic Informed Consent Procedure
A separate informed consent form pertaining to storage of the sample must be obtained prior to 
collecting a blood sample for pharmacogenomic research for this study. The provision of consent 
to collect and analyze the pharmacogenomic sample is independent of consent to the other aspects 
of the study.
9.1.1.2
Clinical Trial Subject Database (CTSdatabase) Authorization
A separate subject authorization will be obtained at the Screening Visit that will allow sites to enter 
specific subject information into CTSdatabase, a clinical trial registry. 
9.1.2
CTSdatabase and Subject Database Authorization
Clinical trial registries, such as CTSdatabase, seek to reduce subjects from enrolling into multiple 
clinical trials by identifying duplicates before enrollment. At the time of providing the informed 
consent for the study, the Investigator or designee will explain the IRB-approved Subject Database 
Authorization to the subject and witness the signature.
During screen, site staff that have received training and login information access 
www.ctsdatabase.com and enter the subject study ID and authorized subject identifiers. An 
immediate report detailing matches is generated and should be printed for source documentation. 
The report will specify either (1) no matches found, (2) a match was found with a subject 
participating in another study within 30 days or (3) the subject matches with a subject who has 
pre-screened at another site.
9.1.3
Demographics, Medical History, and Medication History Procedure
Demographic information to be obtained will include date of birth, sex, Hispanic ethnicity, race as 
described by the subject, and smoking status of the subject at Screening. 
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Medical history to be obtained will include determining whether the subject has any significant 
conditions or diseases relevant to the disease under study that stopped at or prior to signing of 
informed consent. Ongoing conditions are considered concurrent medical conditions (see 
Section 9.1.11).
Medication history information to be obtained includes any medication relevant to eligibility 
criteria and efficacy/safety evaluation stopped at or within 90 days prior to signing of informed 
consent.
9.1.4
Physical Examination Procedure
A baseline physical examination (defined as the assessment prior to first dose of investigational 
drug) will consist of the following body systems: (1) eyes; (2) ears, nose, throat; (3) cardiovascular 
system; (4) respiratory system; (5) gastrointestinal system; (6) dermatologic system; 
(7) extremities; (8) musculoskeletal system; (9) nervous system; (10) lymph nodes; and (11) other.
Genitourinary examination will not be required. 
All subsequent physical examinations should assess clinically significant changes from the 
assessment prior to first dose examination.
9.1.5
Weight, Height
A subject should have weight and height measured while wearing indoor clothing and with shoes 
off. The Takeda standard for collecting height is centimeters without decimal places and for 
weight it is kilograms (kg) with 1 decimal place. 
9.1.6
Vital Sign Procedure
Vital signs will include body temperature (oral or tympanic), pulse (beats per minute [bpm]), and 
sitting blood pressure (taken after 5 minutes in the sitting position).
When vital signs are scheduled at the same time as blood draws, the blood draw will take priority 
and vital signs will be obtained before or after the scheduled blood draw.
9.1.7
Diagnostic Assessment
Axis I disorders will be diagnosed according to DSM-IV-TR criteria. The assessment of MDE will 
be standardized by using the MINI. The MINI will also be used to evaluate the presence of 
comorbid psychiatric disorders in order to assess the appropriateness of the subject for inclusion.
9.1.7.1
MINI International Neuropsychiatric Interview 
The MINI is a short structured diagnostic interview developed jointly by psychiatrists and 
clinicians in the United States and Europe for DSM-IV and International Classification of Diseases 
10th Revision psychiatric disorders. With an administration time of approximately 15 minutes, it 
was designed to meet the need for a short but accurate structured psychiatric interview for
multicenter clinical trials and epidemiology studies. It is to be used as a first step in outcome 
tracking in nonresearch clinical settings. Validation and reliability studies have been done 
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comparing the MINI to the Structured Clinical Interview for DSM-IV, Patient Edition and the 
Composite International Diagnostic Interview. The results of these studies showed that the MINI 
has acceptably high validation and reliability scores, but can be administered in a much shorter 
period of time (mean 18.7±11.6 minutes, median 15 minutes) than the above referenced
instruments. The clinician responsible for the subject must administer the MINI [18-20].
9.1.7.2
Subject-completed Diagnostic Validation
Subjects will complete a computer-administered Diagnostic Validation (DvX) assessment at the 
Screening Visit prior to the rater-administered MINI, on a laptop or tablet provided to the site. The 
DxV will collect data about the subjects’ history relative to lifelong history of MDD. The subject’s 
diagnostic information based on the responses to the computerized interview will be reviewed by 
the rater vendor’s clinician, and any uncertainty raised by the subject’s responses on the diagnostic 
interview will be discussed with the Investigator/site clinician in order to establish confidence in 
the diagnosis. Subjects for whom diagnostic agreement between the Investigator/site clinician and 
the rater vendor clinician cannot be reached, may not be appropriate for study participation.
9.1.8
Primary Efficacy Measurements
The following assessments will be performed during the open-label and double-blind treatment 
periods, unless otherwise indicated:

Prompted MADRS/Structured Interview Guide for the MADRS (SIGMA).

CGI-S.

CGI-I (CGI-I will be assessed during the open-label period; and at Baseline II and 
Completion/Withdrawal during the double-blind period).
9.1.9
Psychiatric/Neurological Rating Scales
MADRS
The MADRS is a depression rating scale consisting of 10 items, each rated 0 to 6. The 10 items 
represent the core symptoms of depressive illness. The rating should be based on a clinical 
interview with the subject, moving from broadly phrased questions about symptoms to more 
detailed ones, which allow a precise rating of severity, covering the last 7 days. Nine of the items 
are based upon subject report, and 1 is based on the observation of the subjects. The Prompted 
Assessment does prompt the rater to ask the subject questions in assessing this item (apparent 
sadness). The clinician, who conducts the rating, must decide whether the rating for each item lies 
on the defined scale steps (0, 2, 4, 6) or between them (1, 3, 5). Decrease in the total score or on 
individual items indicates improvement [13].
The MADRS will be assessed by the rater utilizing the laptop/tablet provided to the site in a 
prompted assessment fashion. The Prompted Assessment incorporates questions and decision 
trees in a semi-structured format. Based on the responses entered into the laptop/tablet by the rater, 
the computer will determine once enough information has been collected to accurately score each 
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item. Raters are encouraged to ask additional questions as needed in order to score each item. The 
scores are recorded into the laptop/tablet and serve as the source for the study.
SIGMA
Sites may choose, in addition to the Prompted Assessment, to utilize the SIGMA to assist in 
assessing the MADRS; however, this is not required. The SIGMA was created to standardize the 
administration of the MADRS and ensure comprehensive coverage of MADRS items through the 
use of structured questions. The SIGMA questions were developed to obtain the information 
needed to assess each of the items’ anchor points. In the SIGMA, the original MADRS appears on 
the right-hand side of the page and the structured interview guide questions appear on the left [14]. 
If a site chooses to use the SIGMA it must be used for all visits for an individual subject.
Clinical Global Impression Scales
The CGI scales [15] consist of 2 subscales: the CGI-S and the CGI-I.
The CGI-S assesses the clinician’s impression of the subject’s current mental illness state. The 
clinician should use his/her total clinical experience with this patient population and rate the 
current severity of the subject’s mental illness on a 7-point scale.
The CGI-I assesses the subject’s improvement (or worsening). The clinician is required to assess 
the subject’s condition relative to Baseline I (baseline at start of treatment) on a 7-point scale. In all 
cases, the assessment should be made independent of whether the rater believes the 
improvement/worsening is drug-related or not.
The rater will enter their CGI-S and CGI-I scores directly on the laptop/tablet provided to the site. 
When these scores are recorded in the laptop/tablet, they will serve as the source for the study.
9.1.9.1
Order of Psychiatric/Neurological Rating Scales/Assessments
Sites should make every attempt to complete the assessments in the following order:
Diagnostic Validation (DvX) (Screening only).
MINI (Screening only).
MADRS via Prompted Assessment.
C-SSRS. 
CGI-S.
9.1.10 Documentation of Concomitant Medications
Concomitant medication is any drug given in addition to the study medication. These may be 
prescribed by a physician or obtained by the subject over the counter. Concomitant medication is 
not provided by Takeda. At each study visit, subjects will be asked whether they have taken any 
medication other than the study medication (used from signing of informed consent through the 
end of the study), and all medication including vitamin supplements, over-the-counter 
medications, and oral herbal preparations, must be recorded in the eCRF.
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9.1.11 Documentation of Concurrent Medical Conditions
Concurrent medical conditions are those significant ongoing conditions or diseases that are present 
at signing of informed consent. This includes clinically significant laboratory, ECG or physical 
examination abnormalities noted at screening or Baseline I examination. The condition (ie, 
diagnosis) should be described.
9.1.12 Procedures for Clinical Laboratory Samples 
Laboratory samples will be taken at the time points stipulated in the Schedule of Study Procedures; 
samples will be collected in accordance with acceptable laboratory procedures. The maximum 
volume of blood at any single visit is approximately 29 mL, and the approximate total volume of 
blood for the study is 186 mL. Details of these procedures and required safety monitoring will be 
given in the laboratory manual. Appendix E describes procedures for specimen handling.
Table 9.a
Clinical Laboratory Tests
Hematology
Serum Chemistry 
Urinalysis
RBC
WBC
Hemoglobin
Hematocrit
Platelets
Neutrophils
Eosinophils
Basophils
Lymphocytes
Monocytes
HbA1c(a)
ALT
Albumin
Alkaline phosphatase
AST 
Total protein
Creatinine
Blood urea nitrogen
Creatine kinase
GGT
Potassium
Sodium
Total bilirubin
Direct bilirubin (b)
Calcium
Glucose (fasting or nonfasting) (c)
Lipids (fasting or nonfasting) (c)
Cholesterol total
Triglycerides
High-density lipoprotein
Low-density lipoprotein
Specific gravity
pH (dipstick)
Glucose (dipstick)
Protein (dipstick)
Occult blood (dipstick)
Microscopic battery: 
(WBC, RBC, epithelial 
cells, casts) (d)
Other:
Serum
Urine 
HBsAg (a)
HCV (a)
TSH, free thyroxine (e)
Drug screen including: amphetamines, barbiturates, 
benzodiazepines, cannabinoids, cocaine, sedatives, 
narcotics, opiates, and alcohol (f).
Female subjects of childbearing potential
Female subjects of childbearing potential
hCG for pregnancy
hCG for pregnancy
Footnotes are on last table page.
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GGT=-glutamyl transferase, hCG=human chorionic gonadotropin, RBC-red blood cells, WBC=white blood cells.
(a) To be done at Screening only.
(b) Assess only if total bilirubin ≥2 mg/dL. 
(c) Fasting labs will be performed at Baseline I, Baseline II/Randomization or Withdrawal from open-label, and 
Completion/Withdrawal of double-blind. 
(d) Microscopic examination of sediment will be performed only if the dipstick results are positive 
(e) TSH assessed at screening in order to exclude subjects with clinically significant thyroid dysfunction 
(hyperthyroidism or hypothyroidism), which may mimic symptoms of depression and anxiety. If TSH value is outside 
the normal range, a free T4 will be obtained. 
(f) To be done at Screening, Baseline I, and Baseline II/Randomization and at any time per Investigator discretion.
The central laboratory will perform laboratory tests for hematology, serum chemistries, and 
urinalysis. The results of laboratory tests will be returned to the investigator, who will be 
responsible for filing and reviewing these results together with the data in the eCRF. The 
investigator is responsible for recording the interpretation of clinical significance of any abnormal 
laboratory results in the eCRF. The investigator will maintain a copy of the laboratory 
accreditation and the reference ranges for the laboratory used.
If subjects experience ALT or AST >3 ×ULN, follow-up laboratory tests (at a minimum, serum 
alkaline phosphatase, ALT, AST, total bilirubin, GGT, and INR) should be performed within a 
maximum of 7 days and preferably within 48-72 hours after the abnormality was noted.
(Please refer to Section 7.5 for discontinuation criteria, and Section 10.1.5.2 for the appropriate 
guidance on Reporting of Abnormal Liver Function Tests in relation to ALT or AST >3 ×ULN in 
conjunction with total bilirubin >2 ×ULN.)
If the ALT or AST remains elevated >3 ×ULN on these 2 consecutive occasions the investigator 
must contact the Medical Monitor for consideration of additional testing, close monitoring, 
possible discontinuation of study medication, discussion of the relevant subject details and 
possible alternative etiologies. The abnormality should be recorded as an AE (please refer to 
Section 10.2.1.3 Reporting of Abnormal Liver Function Tests for reporting requirements).
9.1.13 Contraception and Pregnancy Avoidance Procedure
From signing of informed consent, throughout the duration of the study, and for 30 days after last 
dose of study medication, female subjects of childbearing potential* who are sexually active with a 
nonsterilized male partner** must use adequate contraception. In addition they must be advised 
not to donate ova during this period.
*Females NOT of childbearing potential are defined as those who have been surgically sterilized 
(hysterectomy, bilateral oophorectomy or tubal ligation) or who are postmenopausal (eg, defined 
as at least 2 years since last regular menses).
**Sterilized males should be at least 1 year postvasectomy and have confirmed that they have 
obtained documentation of the absence of sperm in the ejaculate.
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An acceptable method of contraception is defined as one that has no higher than a 1% failure rate. 
In this study, where medications and devices containing hormones are included, the only 
acceptable methods of contraception are:
Barrier methods (each time the 
subject has intercourse):
Intrauterine devices 
(IUDs):
Hormonal contraceptives:

Male condom PLUS spermicide.

Cap (plus spermicidal cream or 
jelly) PLUS male condom and 
spermicide.

Diaphragm (plus spermicidal 
cream or jelly) PLUS male 
condom and spermicide.

Copper T PLUS condom 
or spermicide.

Progesterone T PLUS 
condom or spermicide.

Implants.

Hormone shot/injection.

Combined pill.

Minipill.

Patch.

Vaginal ring PLUS male 
condom and spermicide.
Subjects will be provided with information on acceptable methods of contraception as part of the 
subject informed consent process and will be asked to sign a consent form stating that they 
understand the requirements for avoidance of pregnancy and donation of ova during the course of 
the study.
During the course of the study, regular urine hCG pregnancy tests will be performed only for 
women of childbearing potential and subjects will receive continued guidance with respect to the 
avoidance of pregnancy as part of the study procedures (Appendix A).
In addition to a negative serum hCG pregnancy test at Screening, subjects also must have a 
negative urine hCG pregnancy test at the Baseline 1 Visit prior to receiving any dose of study 
medication.
9.1.14 Pregnancy
If any subject is found to be pregnant during the study she should be withdrawn and any 
sponsor-supplied drug (vortioxetine or placebo) should be immediately discontinued.
If the pregnancy occurs during administration of active study medication, eg, after Baseline l Visit 
or within 30 days of the last dose of active study medication, the pregnancy should be reported 
immediately, using a pregnancy notification form, to the contact listed in Section 1.0.
Should the pregnancy occur during or after administration of blinded drug, the investigator must 
inform the subject of their right to receive treatment information. If the subject chooses to receive 
unblinded treatment information, the individual blind should be broken by the investigator. 
Subjects randomized to placebo need not be followed.
If the female subject agrees to the primary care physician being informed, the investigator should 
notify the primary care physician that the subject was participating in a clinical study at the time 
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she became pregnant and provide details of treatment the subject received (blinded or unblinded, 
as applicable).
All pregnancies in subjects on active study drug including comparator will be followed up to final 
outcome, using the pregnancy form. Pregnancies will remain blinded to the study team. The 
outcome, including any premature termination, must be reported to the sponsor. An evaluation 
after the birth of the child will also be conducted.
9.1.15 ECG Procedure 
A standard 12-lead ECG will be recorded. The following parameters will be recorded 
electronically by a central reader from the subject’s ECG trace: heart rate, RR interval, PR interval, 
QT interval, QRS interval and corrected QT interval (QTc). The central reader will interpret the 
ECG using 1 of the following categories: within normal limits or abnormal. If interpreted as 
abnormal, the investigator will assess the findings as either abnormal clinically significant, or 
abnormal not clinically significant. The interpretation of the ECG will be recorded in the source 
documents and in the eCRF. ECG traces recorded on thermal paper will be photocopied to avoid 
degradation of trace over time. Requirements for the ECG equipment and procedure for collecting 
and transferring information to the central reader will be provided in the site manual. 
9.1.16
Pharmacogenomic Sample Collection
When sampling of whole blood for pharmacogenomic analysis occurs, every subject must sign 
informed consent/be consented in order to participate in the pharmacogenomic sample analysis.
Two 3-mL whole blood sample for deoxyribonucleic acid (DNA) isolation will be collected before 
dosing on Day 0 from each subject in the study, into plastic potassium ethylenediamine tetraacetic 
acid (K2EDTA) spray-coated tubes, and stored under frozen conditions.
Two whole blood samples (2.5 mL per sample) will be collected at each time point at predose on 
Day 0, Week 8 (Visit 6), Week 16 (Visit 10) and Week 48 (Completion/Early Termination) for 
ribonucleic acid (RNA) pharmacogenomic analysis from each subject in the study, into a PaxGene 
TM tube. For subjects who withdraw during the open-label treatment period, a blood sample will be 
collected at study termination, regardless of the treatment duration. 
DNA forms the basis for the genes that make the body produce proteins such as enzymes, drug 
transporters or drug targets, and may be evaluated for the genetic contribution how the drug is 
broken down, or how the drug affects the body. This is called a “Pharmacogenomics research 
study.” Specific purposes of this study include:

Identifying genetic reasons why certain people respond differently to vortioxetine.

Finding out more information about how vortioxetine works.

Generating information needed for research, development, and regulatory approval of tests to 
predict response to vortioxetine.

Identifying variations in genes related to the biological target of vortioxetine.
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This information may be used, for example, to develop a better understanding of the safety and 
efficacy of vortioxetine and other study medications, and for improving the efficiency, design and 
study methods of future research studies.
If necessary and feasible, a second aliquot of blood may be taken if isolation of DNA from the first 
sample was not successful or possible.
Each pharmacogenomic sample for a study subject should be identifiable on the requisition form 
with a 7-digit subject ID (the 4-digit site number plus the 3-digit subject number).
The pharmacogenomic samples will be shipped to PPD for initial study storage and then to 
Covance Central Lab for long term storage.
A portion of the DNA sample may be analyzed for the presence of, eg, allelic variants in drug
metabolizing enzymes, drug transporters, or putative drug targets. 
The samples will be stored for no longer than 15 years after completion of the study or vortioxetine 
is no longer actively pursued by Takeda or its collaborators. No samples will be stored for longer 
than permitted by the applicable law and samples will be destroyed upon notification from Takeda.
“Stored samples” are defined as samples that are key-coded (the samples are stripped of all 
personal identifying information but a key links the samples to the clinical data collected from the 
sample donor) and are used in the analysis of investigational drug or related drugs.
Detailed instructions for the handling and shipping of samples are provided in Appendix E.
9.1.17 Pharmacokinetic Sample Collection and Analysis 
9.1.17.1 Collection of Plasma for Pharmacokinetic Sampling
All subjects will participate in plasma sampling collection. The subject(s) will have 2 blood 
samples to be collected at Week 8 (Visit 6) and Week 16 (Visit 10). The sample should be 
collected prior to randomization at Week 16 (Visit 10). For subjects who withdraw during the 
open-label treatment period, blood samples will be collected at study termination, regardless of the 
treatment duration. Following randomization on Week 16 (Visit 10), 2 additional blood samples 
from each subject will be collected at Week 32 (Visit 15) and Week 48 (Completion/Early 
Termination). The blood samples for pharmacokinetic analysis will be collected at the same time 
points as the blood sample for clinical laboratory tests. At Visits 10, 15 and Completion sites are 
encouraged to schedule the blood draw to occur after the subject has taken his/her study 
medication that day. The plasma samples will be analyzed for plasma concentration of 
vortioxetine (LuAA21004) by validated method. The approximate blood collection is 6 mL per 
scheduled time point.
For all participating subjects, the exact date and time of the plasma sample collection and the two
last doses taken prior to the plasma sampling will be documented in the source documents and
captured in the eCRFs. Please refer to Appendix E for instructions for the collection, handling and
shipping of plasma samples for pharmacokinetic analysis. Placebo samples will not be analyzed by 
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the bioanalytical laboratory, and the bioanalytical laboratory will be unblinded to select those 
patients receiving placebo.
9.1.17.2 Bioanalytical Methods
Plasma concentrations of vortioxetine will be measured by high-performance liquid 
chromatography with tandem mass spectrometry. 
9.1.18 Documentation of Screen Failure
Investigators must account for all subjects who sign informed consent.
If the subject is found to be not eligible at this screening or Baseline I visit, the investigator should 
complete the eCRF. The IWRS should be contacted as a notification of screen failure.
The primary reason for screen failure is recorded in the eCRF using the following categories:

PTE/AE.

Did not meet inclusion criteria or did meet exclusion criteria (specify reason)

Significant protocol deviation.

Lost to follow-up.

Voluntary withdrawal (specify reason).

Study termination.

Other (specify reason).
Subject numbers assigned to subjects who fail screening should not be reused.
9.1.19 Documentation of Re-Screening
Re-screening of subjects who do not meet eligibility requirements is not allowed. If the PI believes 
in the appropriateness of the subject for the study and considers a re-screen, permission for this 
must be obtained from Medical Monitor. Re-screening at the investigator’s discretion without 
prior approval from the medical monitor is not permitted. 
9.1.20 Documentation of Study Entrance
Only subjects who meet all of the inclusion criteria and none of the exclusion criteria are eligible 
for entrance into the treatment phase.
If the subject is found to be not eligible for treatment phase, the investigator should record the 
primary reason for failure on the applicable eCRF.
9.1.21 Rater Qualification and Certification Process
In order to ensure collection of quality data from scales administered by raters, raters assigned to 
this study will be required to fulfill qualification and certification requirements. Furthermore, the 
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study will include additional steps related to monitoring the quality of rater activity which is 
described in Section 9.1.22. 
The rater academic degree and experience required will be defined and collected for each rater by 
completion of a questionnaire. Raters must be qualified by this process prior to completing any 
training or attending the Investigator Meeting. Raters meeting qualification criteria must also 
complete the certification process on the MADRS. 
All raters will be required to successfully fulfill the full scope of rater training requirements for any 
scale they will be administering prior to rating any subjects in this study. Raters who successfully 
meet all requirements will be approved for participation in the study by Takeda and/or its designee 
before enrollment may commence at sites. Raters who do not meet all the qualification and 
training requirements may be prohibited from participating as raters on this study. Takeda and/or 
its designee may revoke a rater’s certification during the study. 
The training materials and requirements may be adjusted or modified as needed throughout the course 
of the study. 
9.1.21.1 Prior to Study Start
Rater Qualifications
Each site will be required to identify and provide skilled raters who meet appropriate prespecified 
qualifications. Takeda and/or its designee will make the final decision regarding whether the site 
assigned raters are acceptable to participate in the study.
Note: The investigator responsible for the subject must be the only one to rate the subject using the 
CGI. The investigator is defined as a clinician with suitable training and experience as deemed by 
the sponsor.
Submission of Experience Details:
Raters will be required to complete and submit experience details and curriculum vitae (if 
applicable) to the rater vendor in a timely manner. Once the rater’s experience level is reviewed 
and deemed adequate then study assigned raters will be approved to participate in the rater 
certification process.
9.1.21.2 Report Training Certification
Formal rater training and certification will be conducted at the Investigator Meeting, For those 
raters who need to be trained outside of the Investigator Meeting, the training will be conducted 
via web portal or digital versatile disc (DVD). Rater training curriculum will be comprised of some 
or all of the following elements:

Training presentation for the protocol instruments capturing background and study 
conventions related to administration and interview skills for protocol related scales and 
placebo response training.

Viewing and scoring of videotaped MADRS interviews.
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
Interview skills training and assessment.
Training and/or certification is required in order for a rater to rate the scales in the study. Raters 
that meet a predefined MADRS scoring and interview skills proficiency threshold will be issued 
MADRS certification. Raters that do not meet the threshold will be subject to additional training 
and an individual assessment by a clinician from the rater training vendor. MADRS certification 
and secondary scale qualification documents for each rater will be provided to sites and 
maintained by the rater training vendor throughout the study.
Enrollment at the site may not commence until the respective site rater has been informed that they 
have met the necessary certification requirements. Raters who receive an unacceptable rating will 
be required to complete additional training in conjunction with the Takeda designated rater 
training vendor.
9.1.21.3 Site Changes to Rater Personnel during the Study
If a site rater changes during the course of the study, the newly appointed rater must be approved 
by Takeda for participation and must complete all training and certification requirements 
satisfactorily before the rater can begin participation on any study related activities.
9.1.22 Rater Monitoring
Computerized scores will be generated during the Prompted Assessments for the MADRS and 
CGI. The computerized scores are utilized as post-interview quality control by the rater vendor, 
but the rater assigned scores entered into the computer are the outcome scores documented. Rater 
assigned scores are not changed based on the outcome of the Prompted Assessment computerized 
scores, but are used for ongoing quality control and to increase the precision and validity of 
clinician ratings.
Additional scale data will be monitored for consistency and quality control throughout the trial. 
Further instructional activities or advisement will occur and may be requested for certain sites if 
necessary.
9.2
Monitoring Subject Treatment Compliance
Subjects will be required to bring study medication containers/unused medications to each 
dispensing site visit regardless of whether or not the study medication container is empty. 
If a subject is persistently noncompliant with the study medication (eg, 6 or more consecutive 
doses missed in any given week; less than 70% compliant between visits), it may be appropriate to 
withdraw the subject from the study. All subjects should be reinstructed about the dosing 
requirement during study contacts. The authorized study personnel conducting the re-education 
must document the process in the subject source records.
9.3
Schedule of Observations and Procedures
The schedule for all study-related procedures for all evaluations is shown in Appendix A.
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Assessments should be completed at the designated visit/time point(s).
9.3.1
Screening Visit 1 (Days -21 to -5)
Subjects will be screened within 21 to 5 days prior to Baseline I (Day 0). Subjects will be screened 
in accordance with predefined inclusion and exclusion criteria as described in Section 7.0. See 
Section 9.1.18 for procedures for documenting screening failures.
Sites will complete a pre-enrollment form for subjects who meet the screening requirements. The 
form will be submitted to the contract research organization (CRO) for medical monitor review 
and confirmation of certain inclusion/exclusion criteria. The sponsor reserves the right to utilize 
external quality oversight methods to ensure the validity of diagnosis, severity of illness, and other 
factors in determining appropriateness of subject selection.
Procedures to be completed at Screening Visit 1 include:

Informed consent.

CTSdatabase Authorization.

Demographics, medical history, and medication history.

Pretreatment event assessment.

Concurrent medical conditions.

Relevant psychiatric and social history.

Diagnostic validation.

MINI.

Vital signs.

Weight, height.

Physical examination.

Concomitant medications.

Screening clinical laboratory tests, urine drug screen, serum hCG pregnancy test.

ECG procedure.

Pregnancy avoidance counseling.

C-SSRS.

Prompted MADRS.

Assess inclusion/exclusion criteria/eligibility verification.

Access IWRS to obtain subject number.
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9.3.2
Study Entrance into Open-Label Treatment; Baseline I, Visit 2 (Day 0)
Study entrance will take place on Day 0. The following procedures will be performed and 
documented during Baseline I:
If the subject has satisfied all of the inclusion criteria and none of the exclusion criteria for 
enrollment into Open-Label Treatment, the subject should be enrolled using the IWRS as 
described in Section 8.2. Subjects will be instructed on when to take the first dose of 
investigational drug as described in Section 8.1.3. The procedure for documenting Screening 
failures is provided in Section 9.1.18.

Concurrent medical conditions.

Assess inclusion/exclusion criteria.

Pretreatment event assessment.

Vital signs.

Weight.

Physical examination.

Concomitant medications.

Clinical laboratory tests, urine drug screen, urine pregnancy test.

ECG procedure.

Pregnancy avoidance counseling.

C-SSRS.

MADRS.

CGI-S.

Pharmacogenomic sample (DNA and RNA).

Access IWRS for medication ID.

Dispense study medication.
9.3.3
Open-Label Treatment Visits 3-9, Weeks 2, 4, 6, 8, 10, 12, and 14 (± 3 days)

Vital signs.

Weight (week 8 only).

Concomitant medication.

Clinical laboratory test (week 8 only).

Urine pregnancy test.
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
Pregnancy avoidance counseling.

C-SSRS.

Adverse events assessment.

MADRS.

CGI-S.

CGI-I.

Stabilization criteria (Weeks 8, 10, 12, and 14).

PK sampling for study medication (week 8 only).

Pharmacogenomic sampling RNA (Week 8 only).

Access IWRS for medication ID.

Dispense study medication.

Study medication return/accountability/compliance.
9.3.4
Withdrawal Visit from Open-label Treatment (± 3 days)
This visit will be performed for any subject that does not meet response or remission criteria 
during open-label period or has met other withdrawal criteria outlined in Section7.5. The 
following procedures will be performed and documented.

Vital signs.

Weight.

Physical examination.

Concomitant medication.

Clinical laboratory test, serum hCG pregnancy test.

PK sampling for study medication.

Pharmacogenomic sampling RNA.

ECG.

Pregnancy avoidance counseling.

C-SSRS.

Adverse events assessment.

MADRS.

CGI-S.
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
CGI-I.

Access IWRS for subject status.

Study medication return/accountability/compliance.
9.3.5
Baseline II Randomization, Visit 10, Week 16 (± 3 days)
At baseline II subjects who have met the randomization criteria (response and remission) and have 
not met any withdrawal criteria will be randomized in the double-blind treatment.

Stabilization criteria.

Randomization criteria.

Vital signs.

Weight.

Physical examination.

Concomitant medication.

Clinical laboratory test.

Urine drug test. 

ECG.

Serum hCG pregnancy test.

Pregnancy avoidance counseling.

C-SSRS.

Adverse events assessment.

MADRS.

CGI-S.

CGI-I.

PK sampling for study medication.

Pharmacogenomic sample (RNA only).

Access IWRS for medication ID.

Dispense study medication.

Study medication return/accountability/compliance.
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9.3.6
Double-Blind Treatment, Visits 11 and 12, Week 18 (± 3 days) and Week 20 (± 5 
days)

Vital signs.

Weight (week 18 only).

Physical examination (week 18 only).

Concomitant medication.

Clinical laboratory test (week 18 only).

Urine pregnancy test.

Pregnancy avoidance counseling.

C-SSRS.

Adverse events assessment.

Relapse Checklist.

MADRS.

CGI-S.

Access IWRS for medication ID.

Dispense study medication.

Study medication return/accountability/compliance.
9.3.7
Double-Blind Treatment Subject Well Being Calls Weeks 22, 26, 30, 34, 38, 42, and 
46
Subjects will be called to check on status and reminded about study visits, study medication 
compliance, assess adverse events, and assess for any relapse.
9.3.8
Double-Blind Treatment Visits 13-18, Weeks 24, 28, 32, 36, 40, and 44 (± 5 days)

Vital signs.

Weight (weeks 24, 32, and 40 only).

Physical examination (week 32 only).

Concomitant medication.

Clinical laboratory test (week 32 only).

ECG (week 32 only).

Urine pregnancy test.
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
Pregnancy avoidance counseling.

C-SSRS.

Adverse events assessment.

Relapse Checklist.

MADRS.

CGI-S.

PK sampling for study medication (week 32 only).

Access IWRS for medication ID.

Dispense study medication.

Study medication return/accountability/compliance.
9.3.9
Completion/Withdrawal from Double-Blind, Visit19, Week 48 (± 5 days)
The Final Visit will be performed on week 48 for a completed subject or at the withdrawal visit for 
a subject who withdrawals from the study early. This visit will be performed for any subject who 
relapses during double-blind period or has met other withdrawal criteria outlined in Section7.5. 
The following procedures will be performed and documented:

Vital signs.

Weight.

Physical examination.

Concomitant medication.

Clinical laboratory test.

ECG.

Serum hCG pregnancy test.

Pregnancy avoidance counseling.

C-SSRS.

Adverse events assessment.

Relapse Checklist.

MADRS.

CGI-S.

CGI-I.

PK sampling for study medication.
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
Pharmacogenomic sampling (RNA only).

Access IWRS for subject status.

Study medication return/accountability/compliance.
For all subjects receiving study medication, the investigator must complete the End of Study eCRF 
page.
9.3.10 Safety Follow-up Phone Call 
A safety follow-up phone call will be made 30 days (+ 5 days) after withdrawal from either open 
label or double-blind treatment or after completion of study. The following procedures will be 
performed:

Concomitant medications.

AE assessment.
9.3.11 Post-Study Care
The study medication will not be available upon completion of the subject’s participation in the 
study. The subject should be returned to the care of a physician and standard therapies as required.
9.4
Biological Sample Retention and Destruction
The pharmacogenomic samples will be preserved and retained at Covance Central Lab for up to 
but not longer than 15 years or as required by applicable law. The sponsor has put into place a 
system to protect the subjects’ personal information to ensure optimal confidentiality and defined 
standard processes for sample and data collection, storage, analysis, and destruction.
The samples will be sent to a central laboratory that processes the blood sample and serves as a 
secure storage facility. The samples will be initially stored at PPD Central Labs prior to being 
transferred to Covance Central Lab. The sponsor and researchers working with the sponsor will 
have access to the samples collected and any test results. All samples collected during the study
will be stored securely with limited access and the sponsor will require anyone who works with the 
samples to agree to hold the research information and any results in confidence.
The sample will be labeled with a unique sample identifier similar to labeling in the main study but 
using a code that is different from the code attached to the health information and other clinical test 
results collected in the study. The sample and data are linked to personal health information with 
code numbers. This link means that the subject may be identified but only indirectly. The code 
numbers will be kept secure by or on behalf of the Sponsor.
Subjects who consented and provided a pharmacogenomic sample for DNA and RNA analysis can 
withdraw their consent and request disposal of a stored sample at any time. Notify sponsor of 
consent withdrawal.
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10.0
PRETREATMENT EVENTS AND ADVERSE EVENTS
10.1
Definitions
10.1.1 PTEs
A PTE is defined as any untoward medical occurrence in a clinical investigation subject who has 
signed informed consent to participate in a study but prior to administration of any study 
medication; it does not necessarily have to have a causal relationship with study participation.
10.1.2 AEs
An AE is defined as any untoward medical occurrence in a clinical investigation subject 
administered a drug; it does not necessarily have to have a causal relationship with this treatment.
An AE can therefore be any unfavorable and unintended sign (eg, a clinically significant abnormal 
laboratory finding), symptom, or disease temporally associated with the use of a drug whether or 
not it is considered related to the drug.
10.1.3 Additional Points to Consider for PTEs and AEs
An untoward finding generally may:

Indicate a new diagnosis or unexpected worsening of a pre-existing condition. (Intermittent 
events for pre-existing conditions underlying disease should not be considered PTEs or AEs.)

Necessitate therapeutic intervention.

Require an invasive diagnostic procedure.

Require discontinuation or a change in dose of study medication or a concomitant medication.

Be considered unfavorable by the investigator for any reason.

PTEs/AEs caused by a study procedure (eg, a bruise after blood draw) should be recorded as a 
PTE/AE.
Diagnoses versus signs and symptoms:

Each event should be recorded to represent a single diagnosis. Accompanying signs (including 
abnormal laboratory values or ECG findings) or symptoms should NOT be recorded as 
additional AEs. If a diagnosis is unknown, sign(s) or symptom(s) should be recorded 
appropriately as a PTE(s) or as an AE(s).
Laboratory values and ECG findings:

Changes in laboratory values or ECG parameters are only considered to be PTEs or AEs if they 
are judged to be clinically significant (ie, if some action or intervention is required or if the 
investigator judges the change to be beyond the range of normal physiologic fluctuation). A 
laboratory re-test and/or continued monitoring of an abnormal value are not considered an 
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intervention. In addition, repeated or additional noninvasive testing for verification, evaluation 
or monitoring of an abnormality is not considered an intervention.

If abnormal laboratory values or ECG findings are the result of pathology for which there is an 
overall diagnosis (eg, increased creatinine in renal failure), the diagnosis only should be 
reported appropriately as a PTE or as an AE.
Pre-existing conditions:

Pre-existing conditions (present at the time of signing of informed consent) are considered 
concurrent medical conditions and should NOT be recorded as PTEs or AEs. Baseline 
evaluations (eg, laboratory tests, ECG, X-rays etc.) should NOT be recorded as PTEs unless 
related to study procedures. However, if the subject experiences a worsening or complication 
of such a concurrent condition, the worsening or complication should be recorded 
appropriately as a PTE (worsening or complication occurs before start of study medication) or 
an AE (worsening or complication occurs after start of study medication). Investigators should 
ensure that the event term recorded captures the change in the condition (eg, “worsening 
of…”).

If a subject has a pre-existing episodic condition (eg, asthma, epilepsy) any occurrence of an 
episode should only be captured as a PTE/AE if the episodes become more frequent, serious or 
severe in nature, that is, investigators should ensure that the AE term recorded captures the 
change in the condition from Baseline (eg “worsening of…”).

If a subject has a degenerative concurrent condition (eg, cataracts, rheumatoid arthritis), 
worsening of the condition should only be captured as a PTE/AE if occurring to a greater 
extent to that which would be expected. Again, investigators should ensure that the AE term 
recorded captures the change in the condition (eg, “worsening of…”).
Worsening of PTEs or AEs:

If the subject experiences a worsening or complication of a PTE after starting administration of 
the study medication, the worsening or complication should be recorded appropriately as an 
AE. Investigators should ensure that the AE term recorded captures the change in the condition 
(eg, “worsening of…”).

If the subject experiences a worsening or complication of an AE after any change in study 
medication, the worsening or complication should be recorded as a new AE. Investigators 
should ensure that the AE term recorded captures the change in the condition (eg, “worsening 
of…”).
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Changes in severity of AEs /Serious PTEs:

If the subject experiences changes in severity of an AE/serious PTE, the event should be 
captured once with the maximum severity recorded.
Preplanned surgeries or procedures:

Preplanned procedures (surgeries or therapies) that were scheduled prior to signing of 
informed consent are not considered PTEs or AEs. However, if a preplanned procedure is 
performed early (eg, as an emergency) due to a worsening of the pre-existing condition, the
worsening of the condition should be captured appropriately as a PTE or an AE. Complications 
resulting from any planned surgery should be reported as AEs.
Elective surgeries or procedures:

Elective procedures performed where there is no change in the subject’s medical condition 
should not be recorded as PTEs or AEs, but should be documented in the subject’s source 
documents. Complications resulting from an elective surgery should be reported as AEs.
Insufficient clinical response (lack of efficacy):

Insufficient clinical response, efficacy, or pharmacologic action, should NOT be recorded as 
an AE. The investigator must make the distinction between exacerbation of pre-existing illness 
and lack of therapeutic efficacy. Note that lack of efficacy during double-blind treatment 
should be recorded as a relapse.
Suicidality events:

A completed suicide is always an SAE based on its fatal outcome. Additionally, for the 
purpose of this development program, active suicidal behaviors such as “suicidal intention 
with a definite plan” and “suicide attempt” will also be collected as SAEs. Unless the event 
meets other serious criteria, suicidal thoughts or suicidal ideations that do not include a definite 
plan or action will be collected as nonserious AEs in accordance with the standard AE 
reporting requirements (eg, if a pre-existing suicidal ideation recorded on the screening 
C-SSRS got worse during the study, it should be reported as an AE). A subject presenting with 
self-mutilation or other types of self-injury should be questioned by the investigator to clarify 
if the action was suicidal in intent. If the event was suicidal in intent, the investigator should 
include suicidal behavior as part of the verbatim term on the eCRF, that is, “slit wrists/suicidal 
behavior”. Such an event will be collected as an SAE. Acts of self-mutilation or self-injury 
without suicidal intention, for example, self-imposed cigarette burns, will be collected as 
nonserious AEs.
10.1.4 SAEs
An SAE is defined as any untoward medical occurrence that at any dose:
1. Results in DEATH.
1.
Is LIFE THREATENING.
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
The term “life threatening” refers to an event in which the subject was at risk of death at the 
time of the event; it does not refer to an event that hypothetically might have caused death 
if it were more severe.
2.
Requires inpatient HOSPITALIZATION or prolongation of existing hospitalization.
3.
Results in persistent or significant DISABILITY/INCAPACITY.
4.
Is a CONGENITAL ANOMALY/BIRTH DEFECT.
5.
Is an IMPORTANT MEDICAL EVENT that satisfies any of the following:

May require intervention to prevent items 1 through 5 above.

May expose the subject to danger, even though the event is not immediately life 
threatening or fatal or does not result in hospitalization.

Includes any event or synonym described in the Takeda Medically Significant AE List 
(Table 10.a).
Table 10.a
Takeda Medically Significant AE List 
Term
Acute respiratory failure/acute respiratory distress 
syndrome
Hepatic necrosis
Torsade de pointes / ventricular fibrillation / ventricular 
tachycardia
Acute liver failure
Anaphylactic shock
Malignant hypertension
Acute renal failure
Convulsive seizure
Pulmonary hypertension
Agranulocytosis
Pulmonary fibrosis 
Aplastic anemia
Confirmed or suspected endotoxin shock
Toxic epidermal necrolysis/Stevens-Johnson syndrome Confirmed or suspected transmission of infectious agent by a 
medicinal product
Neuroleptic malignant syndrome / malignant hyperthermia
Spontaneous abortion / stillbirth and fetal death
PTEs that fulfill 1 or more of the serious criteria above are also to be considered SAEs and should 
be reported and followed up in the same manner (see Sections 10.2.2 and 10.3).
10.1.5 Special Interest AEs 
A Special Interest Adverse Event (serious or non-serious) is one of scientific and medical concern 
specific to the compound or program, for which ongoing monitoring and rapid communication by 
the investigator to Takeda may be appropriate. Such events may require further investigation in 
order to characterize and understand them and would be described in protocols and instructions 
provided for investigators as to how and when they should be reported to Takeda.
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10.1.5.1 Skin and Allergic Type Reactions
Any subject who develops rash should undergo assessment to characterize the nature and location
of the rash. Subjects should be adequately examined for any clinical features that might suggest a
developing drug reaction with eosinophilia and systemic symptoms (DRESS), a developing toxic 
epidermal necrolysis (TEN) or Stevens-Johnson syndrome (SJS). For example, all subjects who 
develop rash should undergo a physical examination and be monitored for the appearance of any of 
the following features (and findings should be recorded):
a) Involvement of mucous membranes or conjunctiva.
b) The development of skin pain.
c) Urticaria, blistering, other skin lesions.
d) Any evidence of angioedema.
If there are subjects with symptoms of systemic reaction (eg, generalized rash), or signs of a severe 
rash (such as those outlined above) or if clinically appropriate then the following laboratory 
parameters should also be conducted and monitored accordingly: complete blood count with 
differentials, liver and renal functions tests, and urinalysis.
Any subjects showing symptoms or signs outlined above or if clinically indicated should also be 
assessed by a dermatologist and undergo an adequate diagnostic work-up (to assess for developing
DRESS, TEN, or SJS).
Finally, consider taking photographs of rashes and, when appropriate, obtain skin biopsies.
For all cases of rash where an alternative causality is not known a skin or allergy type reaction 
eCRF form should be completed within 1 business day of the investigator’s awareness of the 
event. If the alternative causality has been identified, then no skin or allergy type reaction eCRF 
should be completed.
10.1.5.2 Liver Injury
Management of liver toxicity AEs is described in Section 7.5 of the protocol. If ALT or AST
>3×ULN, laboratory tests should be repeated within a maximum of 7 days, and preferably within 
48 to 72 hours. If the ALT or AST remains elevated >3×ULN on these 2 consecutive occasions, 
and this observation cannot be explained by concomitant disease or another alternative causality, 
the abnormality should be recorded on an AE page. The investigator must contact the Medical 
Monitor for consideration of immediate discontinuation of study medication, discussion of the 
relevant subject details and possible alternative causalities.
For events that meet the criteria described in Section 7.5 of the protocol a liver injury eCRF form 
should be completed within 1 business day of the investigator’s awareness of the event.
10.1.5.3 Overdose
Management of an overdose is described in Section 8.1.4 of this protocol. All cases of overdose
(with or without associated AEs) will be documented as AEs. For events that meet the criteria of an
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overdose, an overdose eCRF form should be completed within 1 business day of the investigator’s
awareness of the event.
10.1.6 Severity of PTEs and AEs
The different categories of intensity (severity) are characterized as follows:
Mild:
The event is transient and easily tolerated by the subject.
Moderate:
The event causes the subject discomfort and interrupts the subject’s usual activities.
Severe:
The event causes considerable interference with the subject’s usual activities.
10.1.7 Causality of AEs
The relationship of each AE to study medication(s) will be assessed using the following 
categories:
Related:
An AE that follows a reasonable temporal sequence from administration of a drug (including the 
course after withdrawal of the drug), or for which possible involvement of the drug cannot be 
ruled out, although factors other than the drug, such as underlying diseases, complications, 
concomitant drugs and concurrent treatments, may also be responsible.
Not Related:
An AE that does not follow a reasonable temporal sequence from administration of a drug and/or 
that can reasonably be explained by other factors, such as underlying diseases, complications, 
concomitant drugs and concurrent treatments.
10.1.8 Relationship to Study Procedures
Relationship (causality) to study procedures should be determined for all PTEs and AEs.
The relationship should be assessed as Related if the investigator considers that there is reasonable 
possibility that an event is due to a study procedure. Otherwise, the relationship should be assessed 
as Not Related. 
10.1.9 Start Date
The start date of the AE/PTE is the date that the first signs/symptoms were noted by the subject 
and/or physician.
10.1.10
Stop Date 
The stop date of the AE/PTE is the date at which the subject recovered, the event resolved but with 
sequelae or the subject died.
10.1.11
Frequency 
Episodic AEs/PTE (eg, vomiting) or those which occur repeatedly over a period of consecutive 
days are intermittent. All other events are continuous.
10.1.12
Action Concerning Study Medication

Drug withdrawn – a study medication is stopped due to the particular AE.
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
Dose not changed – the particular AE did not require stopping a study medication.

Unknown – only to be used if it has not been possible to determine what action has been taken.

Not Applicable – a study medication was stopped for a reason other than the particular AE eg,
the study has been terminated, the subject died, dosing with study medication was already 
stopped before the onset of the AE.

Dose Interrupted – the dose was interrupted due to the particular AE.
10.1.13
Outcome

Recovered/Resolved – Subject returned to first assessment status with respect to the AE/PTE.

Recovering/Resolving – the intensity is lowered by one or more stages: the diagnosis or 
signs/symptoms has almost disappeared; the abnormal laboratory value improved, but has not
returned to the normal range or to baseline; the subject died from a cause other than the 
particular AE/PTE with the condition remaining “recovering/resolving”.

Not recovered/not resolved – there is no change in the diagnosis, signs or symptoms; the 
intensity of the diagnosis, signs/ symptoms or laboratory value on the last day of the observed 
study period has got worse than when it started; is an irreversible congenital anomaly; the 
subject died from another cause with the particular AE/PTE state remaining “Not 
recovered/not resolved”.

Resolved with sequelae – the subject recovered from an acute AE/PTE but was left with 
permanent/significant impairment (eg, recovered from a cardiovascular accident but with 
some persisting paresis.

Fatal – the AEs/PTEs which are considered as the cause of death. 

Unknown – the course of the AE/PTE cannot be followed up due to hospital change or 
residence change at the end of the subject’s participation in the study.
10.2
Procedures
10.2.1 Collection and Reporting of AEs
10.2.1.1 PTE and AE Collection Period
Collection of PTEs will commence from the time the subject signs the informed consent to 
participate in the study and continue until the subject is first administered study medication
(Baseline l Visit) or until screen failure. For subjects who discontinue prior to study medication
administration, PTEs are collected until the subject discontinues study participation.
Collection of AEs will commence from the time that the subject is first administered study 
medication (Baseline l Visit). Routine collection of AEs will continue for 30 days post the last 
dose of study medication.
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10.2.1.2 PTE and AE Reporting
At each study visit, the investigator will assess whether any subjective AEs have occurred. A 
neutral question, such as “How have you been feeling since your last visit?” may be asked. 
Subjects may report AEs occurring at any other time during the study. Subjects experiencing a 
serious PTE must be monitored until the symptoms subside and any clinically relevant changes in 
laboratory values have returned to baseline or there is a satisfactory explanation for the change. 
Non-serious PTEs, related or unrelated to the study procedure, need not to be followed-up for the 
purposes of the protocol.
All subjects experiencing AEs, whether considered associated with the use of the study medication
or not, must be monitored until the symptoms subside and any clinically relevant changes in 
laboratory values have returned to baseline or until there is a satisfactory explanation for the 
changes observed. All PTEs and AEs will be documented in the PTE/AE page of the eCRF, 
whether or not the investigator concludes that the event is related to the drug treatment. The 
following information will be documented for each event:
1.
Event term.
2.
Start and stop date.
3.
Severity.
4.
Investigator’s opinion of the causal relationship between the event and administration of 
study medication(s) (related or not related) (not completed for PTEs).
5.
Investigator’s opinion of the causal relationship to study procedure(s), including the details 
of the suspected procedure.
6.
Action concerning study medication (not applicable for PTEs).
7.
Outcome of event.
8.
Seriousness.
10.2.1.3 Special Interest AE Reporting
If the subject experiences a skin rash or allergic type event as described above, liver injury, or 
overdose during the treatment period or the safety follow-up period based on the criteria outlined 
in Section 10.1.5 the event should be reported on a specific eCRF form within 1 business day of the 
investigator’s awareness. Any relevant supporting documentation (ie, photographs, additional 
diagnostic testing, consultation reports) must be submitted to the sponsor. The special interest AEs 
have to be recorded as AEs in the eCRF. 
10.2.2 Collection and Reporting of SAEs
When an SAE occurs through the AE collection period it should be reported according to the 
following procedure:
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A Takeda SAE form must be completed, in English, and signed by the investigator immediately or 
within 24 hours of first onset or notification of the event. The information should be completed as 
fully as possible but contain, at a minimum:

A short description of the event and the reason why the event is categorized as serious.

Subject identification number.

Investigator’s name.

Name of the study medication(s)

Causality assessment.
The SAE form should be transmitted within 24 hours to the attention of the contact listed in 
Section 1.1.
Any SAE spontaneously reported to the investigator following the AE collection period should be 
reported to the sponsor if considered related to study participation.
Reporting of Serious PTEs will follow the procedure described for SAEs.
10.3
Follow-up of SAEs
If information not available at the time of the first report becomes available at a later date, the 
eCRF report should be updated with the additional information within 24 hours of receipt. Copies 
of any relevant data from the hospital record (eg, ECGs, laboratory tests, discharge summary, 
postmortem results) should be sent to the addressee, if requested.
All SAEs should be followed up until resolution or permanent outcome of the event. The timelines 
and procedure for follow-up reports are the same as those for the initial report.
10.3.1 Safety Reporting to Investigators, IRBs, and Regulatory Authorities
The sponsor will be responsible for reporting all suspected unexpected serious adverse reactions 
(SUSARs) and any other applicable SAEs to regulatory authorities, investigators and IRBs as 
applicable, in accordance with national regulations in the country where the study is conducted. 
Relative to the first awareness of the event by/or further provision to the sponsor or sponsor’s 
designee, SUSARs will be submitted to the regulatory authorities as expedited reports within 7 
days for fatal and life-threatening events and 15 days for other serious events, unless otherwise 
required by national regulations. The sponsor will also prepare an expedited report for other safety 
issues where these might materially alter the current benefit-risk assessment of an investigational 
medicinal product or that would be sufficient to consider changes in the investigational medicinal 
products administration or in the overall conduct of the trial. The investigational site also will 
forward a copy of all expedited reports to his or her local IRB, if one is used.
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11.0
STUDY-SPECIFIC COMMITTEES
No steering committee, data safety monitoring committee, or clinical endpoint committee will be 
used in this study.
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12.0
DATA HANDLING AND RECORDKEEPING
The full details of procedures for data handling will be documented in the Data Management Plan. 
AEs, PTEs, medical history, and concurrent conditions will be coded using the Medical Dictionary 
for Regulatory Activities (MedDRA). Drugs will be coded using the WHO Drug Dictionary.
12.1
CRFs (Electronic)
Completed eCRFs are required for each subject who signs an informed consent.
The sponsor or its designee will supply investigative sites with access to eCRFs. The sponsor will 
make arrangements to train appropriate site staff in the use of the eCRF. These forms are used to 
transmit the information collected in the performance of this study to the sponsor and regulatory 
authorities. Subject eCRFs must be completed in English. Data are transcribed directly onto 
eCRFs.
After completion of the entry process, computer logic checks will be run to identify items, such as 
inconsistent dates, missing data, and questionable values. Queries may be issued by Takeda 
personnel (or designees) and will be answered by the site. 
Corrections are recorded in an audit trail that captures the old information, the new information, 
identification of the person making the correction, the date the correction was made, and the reason 
for change. Reasons for significant corrections should additionally be included.
The principal investigator must review the eCRFs for completeness and accuracy and must sign 
and date the appropriate eCRFs as indicated. Furthermore, the investigator must retain full 
responsibility for the accuracy and authenticity of all data entered on the eCRFs.
After the lock of the clinical study database, any change of, modification of or addition to the data 
on the eCRFs should be made by the investigator with use of change and modification records of 
the eCRFs provided by the sponsor. The principal investigator must review the data change for 
completeness and accuracy, and must sign.
Subject eCRFs will be reviewed for completeness and acceptability at the study site during 
periodic visits by study monitors. The sponsor or its designee will be permitted to review the 
subject’s medical and hospital records pertinent to the study to ensure accuracy of the eCRFs. The 
completed eCRFs are the sole property of the sponsor and should not be made available in any 
form to third parties, except for authorized representatives of appropriate governmental health or 
regulatory authorities, without written permission of the sponsor.
12.2
Record Retention
The investigator agrees to keep the records stipulated in Section 12.1 and those documents that 
include (but are not limited to) the study-specific documents, the identification log of all 
participating subjects, medical records, temporary media such as thermal sensitive paper, source 
worksheets, all original signed and dated informed consent forms, subject authorization forms 
regarding the use of personal health information (if separate from the informed consent forms), 
electronic copy of eCRFs, including the audit trail, and detailed records of drug disposition to 
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enable evaluations or audits from regulatory authorities, the sponsor or its designees. Any source 
documentation printed on degradable thermal sensitive paper should be photocopied by the site 
and filed with the original in the subject’s chart to ensure long term legibility. Furthermore, 
International Conference on Harmonisation (ICH) E6 Section 4.9.5 requires the investigator to 
retain documents until at least 2 years after the last approval of a marketing application in an ICH 
region and until there are no pending or contemplated marketing applications in an ICH region or 
at least 2 years have elapsed since the formal discontinuation of clinical development of the 
investigational product. In addition, ICH E6 Section 4.9.5 states that the study records should be 
retained until an amount of time specified by applicable regulatory requirements or for a time 
specified in the Clinical Study Site Agreement between the investigator and sponsor.
Refer to the Clinical Study Site Agreement for the sponsor’s requirements on record retention. The 
investigator should contact and receive written approval from the sponsor before disposing of any 
such documents.
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13.0
STATISTICAL METHODS
13.1
Statistical and Analytical Plans
A statistical analysis plan (SAP) will be prepared and finalized prior to unblinding of subject’s 
treatment assignment/database lock. This document will provide further details regarding the 
definition of analysis variables and analysis methodology to address all study objectives.
A blinded data review will be conducted prior to unblinding of subject’s treatment 
assignment/database lock. This review will assess the accuracy and completeness of the study 
database, subject evaluability, and appropriateness of the planned statistical methods.
13.1.1 Analysis Sets
The full analysis set (FAS) will include all subjects who were randomized to the double-blind 
treatment period and received at least 1 dose of double-blind study drug after randomization. In 
FAS efficacy summaries, subjects will be analyzed by the treatment to which they were 
randomized.
A per protocol set (PPS) will include all FAS subjects who had no major protocol violations. 
Subjects to be excluded from the PPS, whether due to protocol violations or noncompliance to the 
dosing schedule, will be identified in the minutes of the subject evaluability assessment performed 
prior to unblinding.
The safety set will include all subjects who were enrolled into the study and received at least 1 dose 
of study medication. In safety summaries, subjects will be analyzed according to the treatment 
they received. In the event that a subject receives more than 1 treatment, the actual treatment will 
be defined as the 1 that is used most frequently. If the 2 most common treatments are used with 
equal frequency, then the randomized treatment will be used as the actual treatment.
13.1.2 Analysis of Demographics and Other Baseline Characteristics
Baseline characteristics will be listed and summarized for demographics (gender, age, race, and 
body mass index), physical examination including assessment of menopausal status and medical 
history including psychiatric history.
Baseline values for efficacy and safety parameters in both open-label and double-blind treatment 
periods will be in the standard tables summarizing data per visit; however, baseline efficacy data 
will also be presented separately based on all subjects randomized.
For continuous variables, comparability of treatment groups will be assessed using an analysis of 
variance with treatment and center as factors. For discrete variables, comparability will be 
assessed using the Cochran-Mantel-Haenszel general association test, stratified by center. The 
p-values will be displayed as descriptive statistics of comparability.
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13.1.3 Efficacy Analysis
Primary Efficacy Analysis
The primary efficacy variable will be the time from randomization to relapse during the first 
28 weeks of the 32-week double-blind treatment with relapse defined as depression (MADRS 
22), or lack of efficacy as determined by the investigator (date of relapse – date of randomization 
+1). Primary analysis will be based on a Cox model with an exact method to handle ties (based on 
the FAS), with treatment as the factor and baseline MADRS total score as the covariate of the Cox 
model.
Secondary Efficacy Analyses
Change from double-blind Baseline II in MADRS total score will be analyzed using a mixed 
model for repeated measurements (MMRM) analysis with treatment, center, week, 
treatment-by-week interaction, baseline MADRS total score-by-week interaction as fixed effects, 
and a completely unstructured covariance matrix. Change in MADRS total score will also be 
analyzed using analysis of covariance (ANCOVA), with treatment and center as fixed factors, 
Baseline II MADRS total score as covariate, and using the last-observation-carried forward 
(LOCF) technique and observed case (OC) methods. Comparisons between the different doses of 
vortioxetine and placebo will be performed over all the assessment points. Ninety-five percent 
confidence intervals will be presented together with the estimated p-value and the ANCOVA tests 
will be 2-sided.
CGI-I scores and change from Baseline II in the CGI-S will be analyzed by study visit using both 
MMRM and ANCOVA similar to the ones described above for the change of MADRS total score.
Time from randomization to relapse of MDD occurring during the entire 32-week double-blind 
treatment period will be analyzed using a Cox model similar to the one described above for the 
primary variable. 
Controlling Type I Error
To control the type I error of the study, comparison between each dose of vortioxetine and placebo 
will be tested in the sequential order of 20 mg vs placebo, 10 mg vs placebo, and 5 mg vs placebo 
at significance level 0.05; as soon as a dose is non-significant from placebo at 0.05, the testing 
procedure stops for all subsequent dose(s).
Additional Analyses
The time from randomization to withdrawal for any reason during 28 weeks of double-blind 
treatment, will be analyzed using a Cox model similar to the one described above for the primary 
variable. 
C-SSRS will be summarized at all time points for each treatment group using descriptive 
techniques.
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13.1.4 Pharmacokinetic Analysis 
The population pharmacokinetics of vortioxetine will be assessed by means of nonlinear mixed 
effect modeling (NONMEM). Individual exposure parameters (eg, AUCτ, Cav, Cmax) will be 
estimated and their correlation with relevant pharmacodynamic parameters will be explored 
(efficacy and tolerability/safety) if necessary. A separate population pharmacokinetics analysis 
plan and report will be generated for the analysis.
Plasma concentrations of vortioxetine will be summarized by treatment and visits.
13.1.5 Safety Analysis
The safety data will be summarized for the open-label period and double-blind period separately.
Adverse Events
Adverse events will be reported throughout the study. The definition of treatment-emergent 
adverse events will be provided in the SAP. Adverse events will be coded using the MedDRA and 
will be summarized by system organ class and preferred term. Adverse events that were reported 
more than once by a subject during the same period will be counted only once for that subject and 
at period of the maximum severity.
Clinical Evaluations
Absolute values and changes from Baselines I and II in clinical safety laboratory tests, vital signs, 
ECG parameters, and weight/body mass index will be summarized for each treatment group using 
descriptive techniques. Values outside normal ranges and potentially clinically significant values 
will be flagged and tabulated.
13.2
Interim Analysis and Criteria for Early Termination
No interim analysis is planned. No early termination of the study is planned based on the number 
of relapses observed, all randomized subjects will be followed for 32 weeks of double-blind study.
13.3
Determination of Sample Size
Assuming a cumulative relapse rate at 28 weeks of 15% for the vortioxetine group versus 30% for 
the placebo group, a total of 600 subjects (150 per treatment group) will provide 85% power to find 
a statistically significant difference between each dose of vortioxetine and placebo at a 5% 
significance level.
It is anticipated that approximately 55% of the patients enrolled into the open-label period will 
qualify for the double-blind study phase. Therefore, a total of about 1100 patients will need to be 
enrolled into the open-label period of the study. However, if the number of subjects who relapsed 
during the double-blind treatment period is much less than expected, sample size adjustment will 
be considered. In addition, as the required number of subjects enrolled into the open-label period is 
dependent upon the number randomized into the double-blind, the number enrolled may be more 
or less than the estimated 1100.
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14.0
QUALITY CONTROL AND QUALITY ASSURANCE
14.1
Study-Site Monitoring Visits
Monitoring visits to the study site will be made periodically during the study to ensure that all 
aspects of the protocol are followed. Source documents will be reviewed for verification of data 
recorded on the eCRFs. Source documents are defined as original documents, data, and records. 
The investigator and institution guarantee access to source documents by the sponsor or its 
designee (CRO) and by the IRB or IEC.
All aspects of the study and its documentation will be subject to review by the sponsor or designee 
(as long as blinding is not jeopardized), including but not limited to the Investigator’s Binder, 
study medication, subject medical records, informed consent documentation, documentation of 
subject authorization to use personal health information (if separate from the informed consent 
forms), and review of eCRFs and associated source documents. It is important that the investigator 
and other study personnel are available during the monitoring visits and that sufficient time is 
devoted to the process.
14.2
Protocol Deviations
The investigator should not deviate from the protocol, except where necessary to eliminate an 
immediate hazard to study subjects. Should other unexpected circumstances arise that will require 
deviation from protocol-specified procedures, the investigator should consult with the sponsor or 
designee (and IRB or IEC, as required) to determine the appropriate course of action. There will be 
no exemptions (a prospectively approved deviation) from the inclusion or exclusion criteria.
The site should document all protocol deviations in the subject’s source documents. In the event of 
a significant deviation, the site should notify the sponsor or its designee (and IRB or EC, as 
required). Significant deviations include, but are not limited to, those that involve fraud or 
misconduct, increase the health risk to the subject, or confound interpretation of primary study 
assessment. A Protocol Deviation Form should be completed by the site and signed by the sponsor 
or designee for any significant deviation from the protocol.
14.3
Quality Assurance Audits and Regulatory Agency Inspections
The study site also may be subject to quality assurance audits by the sponsor or designees. In this 
circumstance, the sponsor-designated auditor will contact the site in advance to arrange an 
auditing visit. The auditor may ask to visit the facilities where laboratory samples are collected, 
where the medication is stored and prepared, and any other facility used during the study. In 
addition, there is the possibility that this study may be inspected by regulatory agencies, including 
those of foreign governments (eg, the FDA, the United Kingdom Medicines and Healthcare 
products Regulatory Agency, the Pharmaceuticals and Medical Devices Agency of Japan). If the 
study site is contacted for an inspection by a regulatory body, the sponsor should be notified 
immediately. The investigator and institution guarantee access for quality assurance auditors to all 
study documents as described in Section 14.1.
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15.0
ETHICAL ASPECTS OF THE STUDY
This study will be conducted with the highest respect for the individual participants (ie, subjects) 
according to the protocol, the ethical principles that have their origin in the Declaration of 
Helsinki, and the ICH Harmonised Tripartite Guideline for GCP. Each investigator will conduct 
the study according to applicable local or regional regulatory requirements and align his or her 
conduct in accordance with the “Responsibilities of the Investigator” that are listed in Appendix B. 
The principles of Helsinki are addressed through the protocol and through appendices containing 
requirements for informed consent and investigator responsibilities.
15.1
IRB and/or IEC Approval
IRBs and IECs must be constituted according to the applicable state and federal/local requirements 
of each participating region. The sponsor or designee will require documentation noting all names 
and titles of members who make up the respective IRB or IEC. If any member of the IRB or IEC 
has direct participation in this study, written notification regarding his or her abstinence from 
voting must also be obtained. Those Americas sites unwilling to provide names and titles of all 
members due to privacy and conflict of interest concerns should instead provide a Federal Wide 
Assurance Number or comparable number assigned by the Department of Health and Human 
Services.
The sponsor or designee will supply relevant documents for submission to the respective IRB or 
IEC for the protocol’s review and approval. This protocol, the Investigator’s Brochure, a copy of 
the informed consent form, and, if applicable, subject recruitment materials and/or advertisements 
and other documents required by all applicable laws and regulations, must be submitted to a 
central or local IRB or IEC for approval. The IRB’s or IEC’s written approval of the protocol and 
subject informed consent must be obtained and submitted to the sponsor or designee before 
commencement of the study (ie, before shipment of the sponsor-supplied drug or study specific 
screening activity). The IRB or IEC approval must refer to the study by exact protocol title, 
number, and version date; identify versions of other documents (eg, informed consent form) 
reviewed; and state the approval date. The sponsor will ship drug/notify site once the sponsor has 
confirmed the adequacy of site regulatory documentation and, when applicable, the sponsor has 
received permission from competent authority to begin the trial. Until the site receives notification 
no protocol activities, including screening may occur.
Sites must adhere to all requirements stipulated by their respective IRB or IEC. This may include 
notification to the IRB or IEC regarding protocol amendments, updates to the informed consent 
form, recruitment materials intended for viewing by subjects, local safety reporting requirements, 
reports and updates regarding the ongoing review of the study at intervals specified by the 
respective IRB or IEC, and submission of the investigator’s final status report to IRB or IEC. All 
IRB and IEC approvals and relevant documentation for these items must be provided to the 
sponsor or its designee.
Subject incentives should not exert undue influence for participation. Payments to subjects must 
be approved by the IRB or IEC and sponsor.
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15.2
Subject Information, Informed Consent, and Subject Authorization
Written consent documents will embody the elements of informed consent as described in the 
Declaration of Helsinki and the ICH Guidelines for GCP and will be in accordance with all 
applicable laws and regulations. The informed consent form, subject authorization form (if 
applicable), and subject information sheet (if applicable) describe the planned and permitted uses, 
transfers, and disclosures of the subject’s personal and personal health information for purposes of 
conducting the study. The informed consent form and the subject information sheet (if applicable) 
further explain the nature of the study, its objectives, and potential risks and benefits, as well as the 
date informed consent is given. The informed consent form will detail the requirements of the 
participant and the fact that he or she is free to withdraw at any time without giving a reason and 
without prejudice to his or her further medical care.
The investigator is responsible for the preparation, content, and IRB or IEC approval of the 
informed consent form and if applicable, the subject authorization form. The informed consent 
form, subject authorization form (if applicable), and subject information sheet (if applicable) must 
be approved by both the IRB or IEC and the sponsor prior to use.
The informed consent form, subject authorization form (if applicable), and subject information 
sheet (if applicable) must be written in a language fully comprehensible to the prospective subject. 
It is the responsibility of the investigator to explain the detailed elements of the informed consent 
form, subject authorization form (if applicable), and subject information sheet (if applicable) to the 
subject. Information should be given in both oral and written form whenever possible and in the 
manner deemed appropriate by the IRB or IEC. In the event the subject is not capable of rendering 
adequate written informed consent, then the subject’s legally acceptable representative may 
provide such consent for the subject in accordance with applicable laws and regulations.
The subject, or the subject’s legally acceptable representative, must be given ample opportunity to: 
(1) inquire about details of the study and (2) decide whether or not to participate in the study. If the 
subject, or the subject’s legally acceptable representative, determines he or she will participate in 
the study, then the informed consent form and subject authorization form (if applicable) must be 
signed and dated by the subject, or the subject’s legally acceptable representative, at the time of 
consent and prior to the subject entering into the study. The subject or the subject’s legally 
acceptable representative should be instructed to sign using their legal names, not nicknames, 
using blue or black ballpoint ink. The investigator must also sign and date the informed consent 
form and subject authorization (if applicable) at the time of consent and prior to subject entering 
into the study; however, the sponsor may allow a designee of the investigator to sign to the extent 
permitted by applicable law.
Once signed, the original informed consent form, subject authorization form (if applicable), and 
subject information sheet (if applicable) will be stored in the investigator’s site file. The 
investigator must document the date the subject signs the informed consent in the subject’s 
medical record. Copies of the signed informed consent form, the signed subject authorization form 
(if applicable), and subject information sheet (if applicable) shall be given to the subject.
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All revised informed consent forms must be reviewed and signed by relevant subjects or the 
relevant subject’s legally acceptable representative in the same manner as the original informed 
consent. The date the revised consent was obtained should be recorded in the subject’s medical 
record, and the subject should receive a copy of the revised informed consent form.
15.3
Subject Confidentiality
The sponsor and designees affirm and uphold the principle of the subject’s right to protection 
against invasion of privacy. Throughout this study, a subject’s source data will only be linked to 
the sponsor’s clinical study database or documentation via a unique identification number. As 
permitted by all applicable laws and regulations, limited subject attributes, such as sex, age, or date 
of birth, and subject initials may be used to verify the subject and accuracy of the subject’s unique 
identification number.
To comply with ICH Guidelines for GCP and to verify compliance with this protocol, the sponsor 
requires the investigator to permit its monitor or designee’s monitor, representatives from any 
regulatory authority (eg, FDA, Medicines and Healthcare products Regulatory Agency, 
Pharmaceuticals and Medical Devices Agency), the sponsor’s designated auditors, and the
appropriate IRBs and IECs to review the subject’s original medical records (source data or 
documents), including, but not limited to, laboratory test result reports, ECG reports, admission 
and discharge summaries for hospital admissions occurring during a subject’s study participation, 
and autopsy reports. Access to a subject’s original medical records requires the specific 
authorization of the subject as part of the informed consent process (see Section 15.2).
Copies of any subject source documents that are provided to the sponsor must have certain 
personally identifiable information removed (ie, subject name, address, and other identifier fields 
not collected on the subject’s eCRF).
15.4
Publication, Disclosure, and Clinical Trial Registration Policy
15.4.1 Publication and Disclosure
The investigator is obliged to provide the sponsor with complete test results and all data derived by 
the investigator from the study. During and after the study, only the sponsor may make study 
information available to other study investigators or to regulatory agencies, except as required by 
law or regulation. Except as otherwise allowable in the clinical study site agreement, any public 
disclosure (including publicly accessible websites) related to the protocol or study results, other 
than study recruitment materials and/or advertisements, is the sole responsibility of the sponsor.
The sponsor may publish any data and information from the study (including data and information 
generated by the investigator) without the consent of the investigator. Manuscript authorship for 
any peer-reviewed publication will appropriately reflect contributions to the production and 
review of the document. All publications and presentations must be prepared in accordance with 
this section and the Clinical Study Site Agreement. In the event of any discrepancy between the 
protocol and the Clinical Study Site Agreement, the Clinical Study Site Agreement will prevail.
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15.4.2 Clinical Trial Registration
In order to ensure that information on clinical trials reaches the public in a timely manner and to 
comply with applicable laws, regulations and guidance, Takeda will, at a minimum register 
interventional clinical trials it sponsors anywhere in the world on ClinicalTrials.gov or other 
publicly accessible websites before start of study, as defined in Takeda Policy/Standard. Takeda 
contact information, along with investigator’s city, state (for Americas investigators), country, and 
recruiting status will be registered and available for public viewing. 
For some registries, Takeda will assist callers in locating trial sites closest to their homes by 
providing the investigator name, address, and phone number to the callers requesting trial 
information. Once subjects receive investigator contact information, they may call the site 
requesting enrollment into the trial. The investigative sites are encouraged to handle the trial 
inquiries according to their established subject screening process. If the caller asks additional 
questions beyond the topic of trial enrollment, they should be referred to the sponsor.
Any investigator who objects to Takeda providing this information to callers must provide Takeda 
with a written notice requesting that their information not be listed on the registry site. 
15.4.3 Clinical Trial Results Disclosure
Takeda will post the results of clinical trials on ClinicalTrials.gov or other publicly accessible 
websites, as required by Takeda Policy/Standard, applicable laws and/or regulations.
15.5
Insurance and Compensation for Injury
Each subject in the study must be insured in accordance with the regulations applicable to the site 
where the subject is participating. If a local underwriter is required, then the sponsor or sponsor’s 
designee will obtain clinical study insurance against the risk of injury to clinical study subjects. 
Refer to the Clinical Study Site Agreement regarding the sponsor’s policy on subject 
compensation and treatment for injury. If the investigator has questions regarding this policy, he or 
she should contact the sponsor or sponsor’s designee.
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16.0
REFERENCES
1.
Kessler RC, Birnbaum HG, Shahly V, Bromet E, Hwang I, McLaughlin KA, et al. Age 
differences in the prevalence and co-morbidity of DSM-IV major depressive episodes: 
results from the WHO World Mental Health Survey Initiative. Depress Anxiety 
2010;27(4):351-64.
2.
World Health Organization. Mental Health Action Plan 2013-2020. Published 2013. 
Accessed 08 October 2014. Available at: 
http://apps.who.int/iris/bitstream/10665/89966/1/9789241506021_eng.pdf?ua=1.
3.
Angst J. How recurrent and predictable is depressive disorder? In: Montgomery S, 
Rouillon F, editors. Long-Term Treatment of Depression; Perspectives in Psychiatry. 
Chichester, UK: John Wiley & Sons Ltd.; 1992:Vol. 3, p. 1-13.
4.
Montgomery SA. Why do we need new and better antidepressants? Int Clin 
Psychopharmacol 2006;21 (Suppl 1):S1-S10.
5.
Paykel ES, Brugha T, Fryers T. Size and burden of depressive disorders in Europe. Eur 
Neuropsychopharmacol 2005;15(4):411-23.
6.
Thase ME. Preventing relapse and recurrence of depression: a brief review of therapeutic 
options. CNS Spectr 2006;11(12 Suppl 15):12-21.
7.
American Psychiatric Association. Practice guideline for the treatment of patients with 
major depressive disorder (revision). Am J Psychiatry 2000;157(4 Suppl):1-45.
8.
Bang-Andersen B, Ruhland T, Jorgensen M, Smith G, Frederiksen K, Jensen KG, et al. 
Discovery of 1-[2-(2,4-dimethylphenylsulfanyl)phenyl]piperazine (Lu AA21004): a novel 
multimodal compound for the treatment of major depressive disorder. J Med Chem 
2011;54(9):3206-21.
9.
Westrich L, Pehrson A, Zhong H, Nielsen SM, Frederickson K, Stensbol TB, et al. In vitro 
and in vivo effects of the multimodal and antidepressant vortioxetine (Lu AA21004) at 
human and rat targets. Int J Psychiatry Clin Pract 2012;16((Suppl 1)):47. Abstract No. P 
71.
10.
Brintellix (vortioxetine) Tablets. Package Insert. Deerfield, IL: Takeda Pharmaceuticals 
America, Inc. and Lundbeck, July 2014.
11.
Boulenger JP, Loft H, Florea I. A randomized clinical study of Lu AA21004 in the 
prevention of relapse in patients with major depressive disorder. J Psychopharmacol 
2012;26(11):1408-16.
12.
Guidance for Industry: E 10 Choice of Control Group and Related Issues in Clinical Trials. 
US Dept of Health and Human Services, Food and Drug Administration, Center for Drug 
Evaluation and Research (CDER), Center for Biologics Evaluation and Research (CBER). 
May 2001.
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13.
Montgomery SA, Åsberg M. A new depression scale designed to be sensitive to change. Br 
J Psychiatry 1979;134:382-9.
14.
Williams JB, Kobak KA. Development and reliability of a structured interview guide for 
the Montgomery Asberg Depression Rating Scale (SIGMA). Br J Psychiatry 
2008;192(1):52-8.
15.
Guy W. Clinical Global Impression (CGI), ECDEU Version. In: ECDEU Assessment 
Manual for Psychopharmacology. Revised ed. Rockville, MD: U.S. Dept. of Health, 
Education, and Welfare; 1976; DHEW publication no. (ADM) 76-338, p. 218-22.
16.
Posner K, Oquendo MA, Gould M, Stanley B, Davies M. Columbia Classification 
Algorithm of Suicide Assessment (C-CASA): classification of suicidal events in the FDA's 
pediatric suicidal risk analysis of antidepressants. Am J Psychiatry 2007;164(7):1035-43.
17.
Posner K, Melvin GA, Stanley B, Oquendo MA, Gould M. Factors in the assessment of 
suicidality in youth. CNS Spectr 2007;12(2):156-62.
18.
Lecrubier Y, Sheehan DV, Weiller E, Amorim P, Bonora I, Sheehan KH, et al. The 
Mini-International Neuropsychiatric Interview (MINI). A short diagnostic structured 
interview: reliability and validity according to the CIDI. European Psychiat 
1997(12):224-31.
19.
Sheehan DV, Lecrubier Y, Sheehan KH, Janavs J, Weiller E, Keskiner A, et al. The 
validity of the Mini International Neuropsychiatric Interview (MINI) according to the 
SCID-P and its reliability. Eur Psychiatry 1997;12:232-41.
20.
Sheehan DV, Lecrubier Y, Sheehan KH, Amorim P, Janavs J, Weiller E, et al. The 
Mini-International Neuropsychiatric Interview (M.I.N.I.): the development and validation 
of a structured diagnostic psychiatric interview for DSM-IV and ICD-10. J Clin Psychiatry 
1998;59 Suppl 20:22-33;quiz 4-57.
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CONFIDENTIAL
Appendix A
Schedule of Study Procedures
Screening
Baseline I
Open-Label Treatment
Baseline II/
Random-
ization(a)
Withdrawal 
(b) 
Follow-up 
call
Study Day/End of Week:
Day 0
2
4
6
8
10
12
14
16
Visit Windows (Days relative to 
Baseline I)
Days -21 to -5
0
±3
±3
±3
±3
±3
±3
±3
±3
±3
±5
Visit Number:
1
2
3
4
5
6
7
8
9
10
Screening/Baseline Procedures and Assessments
Informed consent
X
CTSdatabase
X(c)
Demographics, medical history, 
height
X
Concurrent medical conditions
X
X (d)
Relevant psychiatric and social history
X
Diagnostic Validation
X
MINI 
X
Diagnosis (DSM-IV-TR)
X
Medication history
X
Inclusion/exclusion criteria
X
X (d)
Eligibility verification
X
Stabilization criteria (e)
X
X
X
X
X
Randomization criteria
X
Safety Assessments
PTE assessment (f)
X
X
Vital signs 
X
X
X
X
X
X
X
X
X
X
X
Body weight
X
X
X
X
X
Physical examination
X
X
X
X
Concomitant medications
X
X
X
X
X
X
X
X
X
X
X
X (g)
Clinical laboratory tests (h)
X
X
X
X
X
Urine drug screening
X
X
X
ECG
X
X
X
X
Pregnancy test (hCG) (i)
X
X
X
X
X
X
X
X
X
X
X
Pregnancy avoidance counseling 
X
X
X
X
X
X
X
X
X
X
X
C-SSRS 
X
X
X
X
X
X
X
X
X
X
X
AE assessment
X
X
X
X
X
X
X
X
X
X (j)
Footnotes are on last table page.
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CONFIDENTIAL
Appendix A
Schedule of Study Procedures (continued)
Screening
Baseline I
Open-Label Treatment
Baseline II/
Random-
ization(a)
Withdrawal 
(b) 
Follow-up 
call
Study Day/End of Week:
Day 0
2
4
6
8
10
12
14
16
Visit Windows (Days relative to 
Baseline I)
Days -21 to 
-5
0
±3
±3
±3
±3
±3
±3
±3
±3
±3
±5
Visit Number:
1
2
3
4
5
6
7
8
9
10
Efficacy Assessments
MADRS (SIGMA if site chooses to 
use)
X
X
X
X
X
X
X
X
X
X
X
CGI-S
X
X
X
X
X
X
X
X
X
X
CGI-I
X
X
X
X
X
X
X
X
X
Other Blood Sampling
PK sampling for study medication
X
X
X
Pharmacogenomic sampling (h)
X
X
X
X
Clinical Supplies
Call IWRS for Subject 
ID/Medication ID/subject status
X
X
X
X
X
X
X
X
X
X
X
Dispense study medication
X (k)
X
X
X
X
X
X
X
X
Study medication return/ 
accountability/compliance
X
X
X
X
X
X
X
X
X
(a) Subjects who meet all randomization criteria please follow schedule of procedures for week 16 on schedule of study procedures for double-blind treatment period.
(b) All subjects who withdraw early, except those who withdraw their consent and refuse further contact, are to attend a withdrawal visit as soon as possible.
(c) Obtain subject authorization, enter subject into the CTS database.
(d) Update at Baseline I. 
(e) Subjects must meet response criteria from Week 8 through Week 16 and remission criteria at Weeks 14 and 16.
(f) Pretreatment event assessment occurs from the date of Screening up to the first dose of study medication. 
(g)Assess post-treatment adverse events, ongoing adverse events and/or serious adverse events, and record all ongoing medications for subjects who withdraw early.
(h) Fasting labs must be performed at Baseline I and Baseline II (randomization). 
(i) Serum hCG for female subject of childbearing potential at Screening, Baseline II (randomization) and Withdrawal. Urine stick pregnancy tests to be done at all other visits.
(j) Two whole blood samples (3 mL per sample) will be collected predose on Day 0 for DNA isolation. Two whole blood samples (2.5 mL per sample) will be collected for RNA 
isolation at each time point at predose on Day 0 and weeks 8, and 16 and any early withdrawal visit during open-label. The sample for pharmacogenomics may be drawn at the earliest 
visit after Baseline I, if missed at visit 2 (Baseline I). Pharmacogenomics sample collection is optional for subjects. A separate Informed Consent Form will be obtained.
(k) The subjects will be instructed to take the first dose of study medication on the morning after enrollment (Baseline I).
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CONFIDENTIAL
Appendix A
Schedule of Study Procedures (continued)
Baseline II/ 
Random-
ization
Double-Blind Treatment (a)
Completion/ 
Withdrawal (b)
Follow-up 
call
End of Week:
16
18
20
24
28
32
36
40
44
48
52
Visit Windows (Days relative to 
Baseline II)
+3
±3
±5
±5
±5
±5
±5
±5
±5
±5
±5
Visit Number:
10
11
12
13
14
15
16
17
18
19
Baseline II Procedures and Assessments
Randomization criteria
X (c)
Safety Assessments
Vital signs 
X
X
X
X
X
X
X
X
X
X
Body weight
X
X
X
X
X
X
Physical examination
X
X
X
X
Concomitant medications
X
X
X
X
X
X
X
X
X
X
X(d)
Clinical laboratory tests (e)
X
X
X
X
Urine drug screening
X
ECG
X
X
X
Pregnancy test (hCG) (f)
X
X
X
X
X
X
X
X
X
X
Pregnancy avoidance counseling 
X
X
X
X
X
X
X
X
X
X
C-SSRS 
X
X
X
X
X
X
X
X
X
X
AE assessment
X
X
X
X
X
X
X
X
X
X
X(d)
Relapse Checklist
X
X
X
X
X
X
X
X
X
Efficacy Asssessments
MADRS (SIGMA if site chooses to 
use)
X
X
X
X
X
X
X
X
X
X
CGI-S
X
X
X
X
X
X
X
X
X
X
CGI-I
X
X
Other Blood Sampling
PK sampling for study medication 
(g)
X
X
X
Pharmacogenonic sampling (h)
X
X
Clinical Supplies
Call IWRS for Subject 
ID/Medication ID/subject status
X
X
X
X
X
X
X
X
X
X
Footnotes are on last table page.
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CONFIDENTIAL
Appendix A
Schedule of Study Procedures (continued)
Baseline 
II/ 
Random-
ization
Double-Blind Treatment (a)
Completion/ 
Withdrawal (b)
Follow-up 
call
End of Week:
16
18
20
24
28
32
36
40
44
48
52
Visit Windows (Days relative 
to Baseline II)
+3
±3
±5
±5
±5
±5
±5
±5
±5
±5
±5
Visit Number:
10
11
12
13
14
15
16
17
18
19
Dispense study medication
X (i)
X
X
X
X
X
X
X
X
Study medication return/ 
accountability/compliance
X
X
X
X
X
X
X
X
X
X
(a) Subject well-being phone calls should be made every 2 weeks post Week 20 through week 46.
(b)All subjects who withdraw early, except those who withdraw their consent and refuse further contact, are to attend a withdrawal visit as soon as possible.
(c) Confirm stabilization criteria of response and remission are met and there are no major protocol violations.
(d)Assess post-treatment adverse events, ongoing adverse events and/or serious adverse events, and record all ongoing medications for subjects who withdraw early.
(e) Fasting labs to be performed at Baseline II/ Randomization and Completion/Withdrawal. 
(f) Serum hCG for female subject of childbearing potential at Baseline II/Randomization and Completion/Withdrawal. Urine stick pregnancy tests to be done at all other visits.
(g) PK sampling must be taken prior to first dose of double-blind study medication.
(h) Only samples for RNA to be collected at Week 16 and Week 48 for those subjects who consented to pharmacogenomic sampling. 
(i) The subjects will be instructed to take the first dose of study medication on the morning after randomization.
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Appendix B
Responsibilities of the Investigator
Clinical research studies sponsored by the sponsor are subject to ICH GCP and all the applicable 
local laws and regulations. The responsibilities imposed on investigators by the FDA are 
summarized in the “Statement of Investigator” (Form FDA 1572), which must be completed and 
signed before the investigator may participate in this study. 
The investigator agrees to assume the following responsibilities by signing a Form FDA 1572:
1. Conduct the study in accordance with the protocol.
2. Personally conduct or supervise the staff who will assist in the protocol.
3. Ensure that study related procedures, including study specific (non routine/non standard panel) 
screening assessments are NOT performed on potential subjects, prior to the receipt of written 
approval from relevant governing bodies/authorities.
4. Ensure that all colleagues and employees assisting in the conduct of the study are informed of 
these obligations.
5. Secure prior approval of the study and any changes by an appropriate IRB/IEC that conform to 
21 CFR Part 56, ICH, and local regulatory requirements.
6. Ensure that the IRB/IEC will be responsible for initial review, continuing review, and approval 
of the protocol. Promptly report to the IRB/IEC all changes in research activity and all 
anticipated risks to subjects. Make at least yearly reports on the progress of the study to the 
IRB/IEC, and issue a final report within 3 months of study completion.
7. Ensure that requirements for informed consent, as outlined in 21 CFR Part 50, ICH and local 
regulations, are met.
8. Obtain valid informed consent from each subject who participates in the study, and document 
the date of consent in the subject’s medical chart. Valid informed consent is the most current 
version approved by the IRB/IEC. Each informed consent form should contain a subject 
authorization section that describes the uses and disclosures of a subject’s personal 
information (including personal health information) that will take place in connection with the 
study. If an informed consent form does not include such a subject authorization, then the 
investigator must obtain a separate subject authorization form from each subject or the 
subject’s legally acceptable representative.
9. Prepare and maintain adequate case histories of all persons entered into the study, including 
eCRFs, hospital records, laboratory results, etc, and maintain these data for a minimum of 
2 years following notification by the sponsor that all investigations have been discontinued or 
that the regulatory authority has approved the marketing application. The investigator should 
contact and receive written approval from the sponsor before disposing of any such 
documents.
10. Allow possible inspection and copying by the regulatory authority of GCP-specified essential 
documents.
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11. Maintain current records of the receipt, administration, and disposition of sponsor-supplied
drugs, and return all unused sponsor-supplied drugs to the sponsor.
12. Report adverse reactions to the sponsor promptly. In the event of an SAE, notify the sponsor 
within 24 hours.
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Appendix C
Elements of the Subject Informed Consent 
In seeking informed consent, the following information shall be provided to each subject:
1. A statement that the study involves research.
2. An explanation of the purposes of the research.
3. The expected duration of the subject’s participation.
4. A description of the procedures to be followed, including invasive procedures.
5. The identification of any procedures that are experimental.
6. The estimated number of subjects involved in the study.
7. A description of the subject’s responsibilities.
8. A description of the conduct of the study.
9. A statement describing the treatment(s) and the probability for random assignment to each 
treatment.
10. A description of the possible side effects of the treatment that the subject may receive.
11. A description of any reasonably foreseeable risks or discomforts to the subject and, when 
applicable, to an embryo, fetus, or nursing infant.
12. A description of any benefits to the subject or to others that reasonably may be expected from 
the research. When there is no intended clinical benefit to the subject, the subject should be 
made aware of this.
13. Disclosures of appropriate alternative procedures or courses of treatment, if any, that might be 
advantageous to the subject and their important potential risks and benefits.
14. A statement describing the extent to which confidentiality of records identifying the subject 
will be maintained, and a note of the possibility that regulatory agencies, auditor(s), IRB/IEC, 
and the monitor may inspect the records. By signing a written informed consent form, the 
subject or the subject’s legally acceptable representative is authorizing such access.
15. For research involving more than minimal risk, an explanation as to whether any compensation 
and an explanation as to whether any medical treatments are available if injury occurs and, if 
so, what they consist of or where further information may be obtained.
16. The anticipated prorated payment(s), if any, to the subject for participating in the study.
17. The anticipated expenses, if any, to the subject for participating in the study.
18. An explanation of whom to contact for answers to pertinent questions about the research 
(investigator), subject’s rights, and IRB/IEC and whom to contact in the event of a 
research-related injury to the subject.
19. A statement that participation is voluntary, that refusal to participate will involve no penalty or 
loss of benefits to which the subject otherwise is entitled, and that the subject may discontinue 
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participation at any time without penalty or loss of benefits to which the subject is otherwise 
entitled.
20. The consequences of a subject’s decision to withdraw from the research and procedures for 
orderly termination of participation by the subject.
21. A statement that the subject or the subject’s legally acceptable representative will be informed 
in a timely manner if information becomes available that may be relevant to the subject’s 
willingness to continue participation in the study.
22. A statement that results of pharmacogenomic analysis will not be disclosed to an individual, 
unless prevailing laws require the sponsor to do so.
23. The foreseeable circumstances or reasons under which the subject’s participation in the study 
may be terminated.
24. A written subject authorization (either contained within the informed consent form or provided 
as a separate document) describing to the subject the contemplated and permissible uses and 
disclosures of the subject’s personal information (including personal health information) for 
purposes of conducting the study. The subject authorization must contain the following 
statements regarding the uses and disclosures of the subject’s personal information:
a) that personal information (including personal health information) may be processed by or 
transferred to other parties in other countries for clinical research and safety reporting 
purposes, including, without limitation, to the following: (1) Takeda, its affiliates, and 
licensing partners; (2) business partners assisting Takeda, its affiliates, and licensing 
partners; (3) regulatory agencies and other health authorities; and (4) IRBs/IECs;
b) it is possible that personal information (including personal health information) may be 
processed and transferred to countries that do not have data protection laws that offer 
subjects the same level of protection as the data protection laws within this country; 
however, Takeda will make every effort to keep your personal information confidential, 
and your name will not be disclosed outside the clinic unless required by law;
c) that personal information (including personal health information) may be added to 
Takeda’s research databases for purposes of developing a better understanding of the 
safety and effectiveness of the study medication(s), studying other therapies for patients, 
developing a better understanding of disease, and improving the efficiency of future 
clinical studies;
d) that subjects agree not to restrict the use and disclosure of their personal information 
(including personal health information) upon withdrawal from the study to the extent that 
the restricted use or disclosure of such information may impact the scientific integrity of 
the research; and
e) that the subject’s identity will remain confidential in the event that study results are 
published.
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25. Female subjects of childbearing potential (eg, nonsterilized, premenopausal female subjects) 
who are sexually active must use adequate contraception (as defined in the informed consent) 
from Screening throughout the duration of the study. Regular pregnancy tests will be 
performed throughout the study for all female subjects of childbearing potential. If a subject is 
found to be pregnant during study, study medication will be discontinued and the investigator 
will offer the subject the choice to receive unblinded treatment information.
26. Male subjects must use adequate contraception (as defined in the informed consent) from 
Screening throughout the duration of the study. If the partner or wife of the subject is found to 
be pregnant during the study, the investigator will offer the subject the choice to receive 
unblinded treatment information.
27. A statement that clinical trial information from this trial will be publicly disclosed in a publicly 
accessible website, such as ClinicalTrials.gov.
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Appendix D
Investigator Consent to Use of Personal Information
Takeda will collect and retain personal information of investigator, including his or her name, 
address, and other personally identifiable information. In addition, investigator’s personal 
information may be transferred to other parties located in countries throughout the world (eg, the 
United Kingdom, United States, and Japan), including the following:

Takeda, its affiliates, and licensing partners.

Business partners assisting Takeda, its affiliates, and licensing partners.

Regulatory agencies and other health authorities.

IRBs and IECs.
Investigator’s personal information may be retained, processed, and transferred by Takeda and 
these other parties for research purposes including the following:

Assessment of the suitability of investigator for the study and/or other clinical studies.

Management, monitoring, inspection, and audit of the study.

Analysis, review, and verification of the study results.

Safety reporting and pharmacovigilance relating to the study.

Preparation and submission of regulatory filings, correspondence, and communications to 
regulatory agencies relating to the study.

Preparation and submission of regulatory filings, correspondence, and communications to 
regulatory agencies relating to other medications used in other clinical studies that may contain 
the same chemical compound present in the study medication.

Inspections and investigations by regulatory authorities relating to the study.

Self-inspection and internal audit within Takeda, its affiliates, and licensing partners.

Archiving and audit of study records.

Posting investigator site contact information, study details and results on publicly accessible 
clinical trial registries, databases, and websites.
Investigator’s personal information may be transferred to other countries that do not have data 
protection laws that offer the same level of protection as data protection laws in investigator’s own 
country.
Investigator acknowledges and consents to the use of his or her personal information by Takeda 
and other parties for the purposes described above.
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Appendix E
Collection, Shipment, and Storage of Pharmacogenomic and Collection, 
Storage, and Shipment of PK Samples
Collection, Shipment, and Storage of Pharmacogenomic Samples 
Sample Collection
Two 3-mL whole blood sample for DNA isolation will be collected from each subject at the 
earliest study visit after randomization into a plastic tube spray coated with 
potassium ethylenediamine-tetraacetic acid (K2EDTA).
Two whole blood samples (2.5 mL per sample) will be collected at each time point at predose on 
Day 0 and week 8, week 16 and week 48/Early Termination visit for RNA pharmacogenomic 
analysis from each subject in the study, into a PaxGene TM tube. For subjects who withdraw during 
the open-label treatment period, a blood sample will be collected at study termination, regardless 
of the treatment duration.
Sample Shipment
Ship samples only on Monday, Tuesday, or Wednesday, and at least 2 days prior to a national 
holiday, to minimize the possibility of samples in transit over a weekend or holiday. The 
laboratory must confirm arrival of the shipped samples.
For instructions on shipping and packing follow the laboratory manual and shipping instructions 
provided by the central laboratory.
Before shipping, ensure the sample tubes are tightly sealed.
PPD will do the initial study period storage of the DNA and RNA samples. The samples will be 
shipped to Covance Laboratories for long term storage. Covance will store the DNA and RNA 
samples in a secure storage space with adequate measures to protect confidentiality. The samples 
will be retained while research on vortioxetine continues for 15 years or as required by applicable 
law.
Samples should be shipped as per conditions detailed in the lab manual.
The storage provider has validated procedures in place for transport, delivery, retention, retrieval, 
and destruction of the specimens, and will appropriately retain the specimens for up to but not 
longer than 15 years as required by applicable law. 
Collection, Storage, and Shipment of Pharmacokinetic Samples
Instructions for processing of plasma samples for pharmacokinetic analysis of vortioxetine
1.
Collect 6 mL of venous blood into a chilled Becton-Dickinson Vacutainer containing
K2EDTA.
2.
Gently invert the Vacutainer several times to mix the additive with the collected blood prior 
to centrifugation and place immediately on ice.
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Study No. LuAA21004_402
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3.
Centrifuge the Vacutainers for 10 minutes at approximately 1100 to 1300 RCF at 
approximately 4°C in a refrigerated centrifuge. Note: if using a collection device other than 
Becton-Dickinson refer to manufacturer’s instruction for proper centrifugation force and 
time.
4.
Immediately following centrifugation, gently remove plasma from the packed cells. To 
ensure a more homogeneous sample, all plasma should first be transferred into 1 aliquot. 
From there, split the plasma evenly between the 2 aliquots. A minimum of 1.0 mL needs to 
be obtained for each sample. Labeling may include protocol number LuAA21004_402, 
matrix (ie, plasma), analyte (vortioxetine), Subject ID (XXXX-XXX), nominal day and time, 
and either “SET 1” (for original sample) or “SET 2” (for duplicate sample).
5.
Cap the labeled storage tubes and freeze the plasma samples immediately at approximately 
-20°C or lower. No more than 60 minutes will elapse between blood collection and freezing 
the plasma sample.
6.
Keep samples frozen at approximately -20°C or lower until shipment to the central 
laboratory. SET 1 samples will be shipped first on dry ice, followed by shipment of duplicate 
SET 2 samples after SET 1 samples have been received by the central laboratory.
Shipping of plasma for vortioxetine 
1.
Biological samples (plasma) should be shipped on dry ice to prevent thawing during transit. 
Samples should be shipped only on Monday, Tuesday, or Wednesday, and at least 2 days 
prior to a national holiday, in order to minimize the possibility of samples in transit over a 
weekend or holiday. If duplicate samples are to be shipped, send SET 1 samples and await 
confirmation of arrival before shipping the duplicate SET 2 samples.
2.
Before shipping, make sure the sample tubes are tightly sealed. Separate each subject’s 
samples as follows:
3.
Separate the duplicate SET 2 samples from the SET 1 samples.
4.
Place SET 1 samples for each subject into a self-sealing bag (eg, Ziploc) containing 
additional absorbent material.
5.
Using a permanent marker, write the subject ID, sample matrix (ie, plasma), analyte 
(vortioxetine), number of samples, and “SET 1” on each self-sealing bag.
6.
Place the bags of individual subject’s samples into a larger plastic bag so that samples are 
double bagged. Duplicate SET 2 samples should be returned to the freezer for storage. 
Repeat steps 3 through 6 above when preparing duplicate samples for shipment, except 
self-sealing bags should be marked “SET 2”.
7.
An inventory of individual samples should accompany each shipment and should include the 
Sponsor’s name (Takeda), study drug (Vortioxetine), protocol number (Lu AA21004_402), 
investigator’s name, sample type (ie, plasma), subject ID, nominal collection day and time, 
and intended sample storage conditions. When duplicate SET 2 samples are being shipped, 
make a copy of the original SET 1 sample inventory and mark as “SET 2”. Place the 
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Study No. LuAA21004_402
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inventory paperwork into a large self-sealing bag. SET 1 samples will be shipped first on dry 
ice, followed by shipment of duplicate SET 2 samples after SET 1 samples have been 
received by the central laboratory.
8.
For sample packing, use dry ice generously (eg, 20 to 25 pounds per day of transit) to 
safeguard against longer than expected shipping times and delays. Use newspaper or other 
material to insulate the double-bagged samples from direct contact with the dry ice. Place the 
sample bundles into a polystyrene (eg, Styrofoam) container (or other suitable container) and 
fill the excess space with dry ice slabs or ice pellets (preferably the latter). Make a note of the 
estimated weight of the dry ice used per shipping container.
9.
Place the inventory paperwork (in a large self-sealing bag) on top of the dry ice in the 
polystyrene container. Place the lid on the polystyrene container and seal completely with 
strapping tape. Place the polystyrene container in a cardboard shipping carton and seal 
securely with strapping tape.
10.
Mark the outside of shipping carton(s) with a tally number (1 of 5, 2 of 5, etc). 
11.
Affix an address label to each shipping carton. Use the preprinted air waybills provided by 
the central lab. 
12.
Obtain the air waybill number and a receipt of shipment from the carrier.
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Appendix F
Detailed Description of Amendments to Text
This document describes changes in reference to Protocol Incorporating Amendment No. 01
Page 2, Section 1.1 Contacts 
Existing Text
Revised Text
Rationale for Amendment
Change in Medical Monitor at 
.
Page 3, Section 1.2 Approval
Existing Text
Revised Text
Change in signatory.
Page 3, Section 1.2 Approval
Existing Text
Revised Text
Rationale for Amendment
Change in signatory.
Propert
f 
: For no
rcial use only and subject to the applicable Terms of Use
y.
on 1.2 A
on 1.2
Fo
Text
xt
Revise
Rev
PPD
PPD
CCI
PPD
PPD
PPD
PPD


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Page 18, Section 3.3 List of Abbreviations
Existing Text
No text
Revised Text
Added CTSdatabase to abbreviations. Clinical Trial Subject Database (CTSdatabase)
Rationale for Amendment
Adding vendor to the LuAA21004_402 study.
Page 18, Section 3.3 List of Abbreviations
Existing Text
HBsAG
Revised Text
HBsAg
Rationale for Amendment
Correction
Page 18, Section 3.3 List of Abbreviations
Existing Text
EDTA ethylenediaminetetraacetic acid
Revised Text
K2EDTA potassium ethylenediaminetetraacetic acid
Rationale for Amendment
Standard Takeda abbreviation.
Page 29, Section 7.2 Exclusion Criteria 
Existing Text
12. The subject has a clinically significant unstable illness, for example hepatic impairment or 
renal insufficiency, or a cardiovascular, pulmonary, gastrointestinal, endocrine, neurological, 
rheumatologic, immunologic, hematological, infectious, dermatological disorder or metabolic 
disturbance
Revised Text
12. The subject has a clinically significant unstable illness, for example hepatic impairment or 
renal insufficiency, or a cardiovascular, pulmonary, gastrointestinal, endocrine, neurological, 
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rheumatologic, immunologic, hematological, infectious, dermatological disorder or metabolic 
disturbance
NOTE: For the purposes of this protocol fibromyalgia, obstructive sleep apnea, chronic pain 
diagnosis, and morbid obesity (BMI of > 40) are considered unstable due to the potential 
impact on assessment of the primary endpoint
Rationale for Amendment
Added clarification for unstable illnesses.
Page 30, Section 7.2 Exclusion Criteria
Existing Text
None
Revised Text
24. The subject is considered to be treatment resistant, eg, the subject has not responded to 
adequate monotherapy treatments of at least 6 weeks duration, or has only responded to 
combination or augmentation therapy
Rationale for Amendment
Provide parameters for excluding treatment resistant subjects.
Page 35, Section Criteria for Discontinuation or Withdrawal of a Subject
Existing Text
None
Revised Text
Note: A Relapse Checklist will be used by sites to evaluate potential indicators of relapse for 
each subject at each visit post baseline during the double blind-period.
Rationale for Amendment
Clarification of Relapse Checklist to be used by sites.
Page 41, Section 8.6 Accountability and Destruction of Sponsor-Supplied Drugs 
Existing Text
The investigator or designee must record the current inventory of all sponsor-supplied drugs 
(Vortioxetine 5, 10, 20 mg and placebo) on a sponsor-approved drug accountability log
All study drug that was not returned to the site by a subject must be investigated by the site and 
appropriately documented on the drug accountability log.
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Revised Text
The investigator or designee must record the current inventory of all sponsor-supplied drugs 
(Vortioxetine 5, 10, 20 mg and placebo) on a sponsor-approved drug accountability log/IWRS.
All study drug that was not returned to the site by a subject must be investigated by the site and 
appropriately documented on the drug accountability log/IWRS.
Rationale for Amendment
IWRS will capture all drug accountability for this study.
Page 42, Section 9.1.1.2 Clinical Trial Subject Database (CTSdatabase) Authorization
Existing Text
None
Revised Text
A separate subject authorization will be obtained at the Screening Visit that will allow sites 
to enter specific subject information into CTSdatabase, a clinical trial registry.
Rationale for Amendment
Subject authorization is needed for CTSdatabase to be able to use the subject’s information.
Page 42, Section 9.1.2 CTSdatabase and Subject Database Authorization
Existing Text
None
Revised Text
Clinical trial registries, such as CTSdatabase, seek to reduce subjects from enrolling into 
multiple clinical trials by identifying duplicates before enrollment. At the time of providing 
the informed consent for the study, the Investigator or designee will explain the 
IRB-approved Subject Database Authorization to the subject and witness the signature.
During screen, site staff that have received training and login information access 
www.ctsdatabase.com and enter the subject study ID and authorized subject identifiers. An 
immediate report detailing matches is generated and should be printed for source 
documentation. The report will specify either (1) no matches found, (2) a match was found 
with a subject participating in another study within 30 days or (3) the subject matches with a 
subject who has pre-screened at another site.
Rationale for Amendment
Adding vendor CTSdatabase to help reduce the potential for subjects to participate in multiple 
trials simultaneously.
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Page 43, Section 9.1.6 Vital Sign Procedure
Existing Text
When vital signs are scheduled at the same time as blood draws, the blood draw will take priority 
and vital signs will be obtained within 0.5 hour before or after the scheduled blood draw
Revised Text
When vital signs are scheduled at the same time as blood draws, the blood draw will take 
priority and vital signs will be obtained before or after the scheduled blood draw.
Rationale for Amendment
Clarification on when to take vital signs.
Page 44, Section 9.1.8 Primary Efficacy Measurements
Existing Text
MADRS
Revised Text
Prompted MADRS
Rationale for Amendment
Clarification.
Page 46, Section Table 9.a Clinical Laboratory Tests
Existing Text
(Please refer to Section 7.5 for discontinuation criteria, and Section 10.2.2 for the appropriate 
guidance on Reporting of Abnormal Liver Function Tests in relation to ALT or AST >3 ×ULN in 
conjunction with total bilirubin >2 ×ULN.)
The abnormality should be recorded as an AE (please refer to Section 10.2.2 Reporting of 
Abnormal Liver Function Tests for reporting requirements).
Revised Text
(Please refer to Section 7.5 for discontinuation criteria, and Section 10.1.5.2 for the appropriate 
guidance on Reporting of Abnormal Liver Function Tests in relation to ALT or AST >3 ×ULN in 
conjunction with total bilirubin >2 ×ULN.)
The abnormality should be recorded as an AE (please refer to Section 10.2.1.3 Reporting of 
Abnormal Liver Function Tests for reporting requirements).
Rationale for Amendment
Correct reference sections added.
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Page 49, Section 9.1.16 Pharmacogenomic Sample Collection
Existing Text
Two 3-mL whole blood sample for deoxyribonucleic acid (DNA) isolation will be collected before 
dosing on Day 1 from each subject in the study, into plastic K2 ethylenediaminetetraacetic acid 
(EDTA) spray-coated tubes, and stored under frozen conditions.
Two whole blood samples (2.5 mL per sample) will be collected at each time point at predose on 
Day 1, Week 8, Week 16 and Week 48 for ribonucleic acid (RNA) pharmacogenomic analysis from 
each subject in the study, into a PaxGene TM tube.
Revised Text
Two 3-mL whole blood sample for deoxyribonucleic acid (DNA) isolation will be collected before 
dosing on Day 0 from each subject in the study, into plastic potassium ethylenediaminetetraacetic 
acid (K2EDTA) spray-coated tubes, and stored under frozen conditions.
Two whole blood samples (2.5 mL per sample) will be collected at each time point at predose on 
Day 0, Week 8 (Visit 6), Week 16 (Visit 10) and Week 48 (Completion/Early Termination) for 
ribonucleic acid (RNA) pharmacogenomic analysis from each subject in the study, into a PaxGene 
TM tube. For subjects who withdraw during the open-label treatment period, a blood sample 
will be collected at study termination, regardless of the treatment duration.
Rationale for Amendment
Corrected day 1 to accurately reflect day 0. Added visit numbers for consistency. Added blood 
sample for any early withdrawal visit during open-label. Corrected abbreviation.
Page 50, Section 9.1.17.1 Collection of Plasma for Pharmacokinetic Sampling
Existing Text
None
Revised Text
For subjects who withdraw during the open-label treatment period, blood samples will be 
collected at study termination, regardless of the treatment duration.
Rationale for Amendment
Added blood sample for any early withdrawal visit during open-label.
Page 50, Section 9.1.17.1 Collection of Plasma for Pharmacokinetic Sampling
Existing Text
Following randomization on week 16, 2 additional blood samples from each subject will be 
collected at Week 32 (Visit 15) and Week 48 (Completion)/Early Termination.
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Revised Text
Following randomization on Week 16 (Visit 10), 2 additional blood samples from each subject 
will be collected at Week 32 (Visit 15) and Week 48 (Completion)/Early Termination.
Rationale for Amendment
Capitalized week. Added visit number for consistency.
Page 52, Section 9.1.21.1 Prior to Study Start
Existing Text
NOTE: The investigator (MD or DO ie, a physician) responsible for the subject must be the only 
one to rate the subject using the CGI-S.
Revised Text
Note: The investigator responsible for the subject must be the only one to rate the subject 
using the CGI. The investigator is defined as a clinician with suitable training and 
experience as deemed by the sponsor.
Rationale for Amendment
Clarified definition of rater qualification for CGI.
Page 54, Section 9.3.1 Screening Visit 1 (Days -21 to -5)
Existing Text
Sites will complete a pre-randomization form for subjects who meet the screening requirements.
Revised Text
Sites will complete a pre-enrollment form for subjects who meet the screening requirements.
Rationale for Amendment
Changed to reflect that this form is completed prior to enrollment.
Page 54, Section 9.3.1 Screening Visit 1 (Days -21 to -5)
Existing Text
None
Revised Text
CTSdatabase Authorization
Rationale for Amendment
Added procedure to obtain authorization from subject for CTSdatabase.
Page 54, Section 9.3.1 Screening Visit 1 (Days -21 to -5)
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Existing Text
MADRS
Revised Text
Prompted MADRS
Rationale for Amendment
Clarification.
Page 55, Section 9.3.2 Study Entrance into Open-Label Treatment; Baseline I, Visit 2 
(Day 0)
Existing Text
Subjects will be instructed on when to take the first dose of investigational drug as described in 
Section 6.1.
Revised Text
Subjects will be instructed on when to take the first dose of investigational drug as described in 
Section 8.1.3.
Rationale for Amendment
Correct reference section added.
Page 56, Section 9.3.4 Withdrawal Visit from Open-label Treatment (± 3 days)
Existing Text
This visit will be performed for any subject that does not meet response or remission criteria 
during open-label period or has met other withdrawal criteria outlined in Section 7.7.
Revised Text
This visit will be performed for any subject that does not meet response or remission criteria 
during open-label period or has met other withdrawal criteria outlined in Section 7.5.
Rationale for Amendment
Correct reference section added.
Page 56, Section 9.3.4 Withdrawal Visit from Open-label Treatment (± 3 days) 
Existing Text
None
Revised Text

PK sampling for study medication 

Pharmacogenomic sampling RNA 
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Rationale for Amendment
Added blood samples for PK and RNA for any open-label treatment withdrawal.
Pages 58-59, Sections 9.3.6, 9.3.8 and 9.3.9
Existing Text
None
Revised Text
Relapse Checklist
Rationale for Amendment
Added to ensure that sites are completing the Relapse Checklist at each double-blind treatment 
visit.
Page 58, Section 9.3.7 Double-Blind Treatment Subject Well Being Calls Weeks 22, 26, 30, 
34, 38, 42, and 46
Existing Text
Double-Blind Treatment Subject Well Being Calls Weeks 22, 26, 30, 34, 38, and 42
Revised Text 
Double-Blind Treatment Subject Well Being Calls Weeks 22, 26, 30, 34, 38, 42, and 46
Rationale for Amendment
Added week 46 for consistency with protocol.
Page 59, Section 9.3.9 Completion/Withdrawal from Double-Blind, Visit19, Week 48 (± 5 
days)
Existing Text
This visit will be performed for any subject who relapses during double-blind period or has met 
other withdrawal criteria outlined in Section 7.7.
Revised Text 
This visit will be performed for any subject who relapses during double-blind period or has met 
other withdrawal criteria outlined in Section7.5
Rationale for Amendment
Correct reference section added.
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Page 64, Section 10.1.4 SAEs
Existing Text
Leads to a CONGENITAL ANOMALY/BIRTH DEFECT
Revised Text
Is a CONGENITAL ANOMALY/BIRTH DEFECT
Rationale for Amendment
Required change per Takeda template.
Page 83, Section Appendix A Schedule of Study Procedures
Existing Text
None
Revised Text 
CTSdatabase added at Screening Visit 
PK sampling for study medications added at withdrawal visit
Pharmacogenomic sampling added at withdrawal visit
Rationale for Amendment
Subject authorization needed for CTSdatabase.
Decision to obtain PK and RNA sample at any open-label withdrawal visit.
Page 83-86, Section Appendix A Schedule of Study Procedures
Existing Text
(a) All subjects who withdraw early, except those who withdraw their consent and refuse further contact, are to attend a withdrawal 
visit as soon as possible. 
(b) Update at Baseline I. 
(c) Subjects must meet response criteria from Week 8 through Week 16 and remission criteria at Weeks 14 and 16.
(d) Pretreatment event assessment occurs from the date of Screening up to the first dose of study medication. 
(e) Assess post-treatment adverse events, ongoing adverse events and/or serious adverse events, and record all ongoing medications 
for subjects who withdraw early.
(f) Fasting labs must be performed at Baseline I and Baseline II (randomization). 
(g) Serum hCG for female subject of childbearing potential at Screening, Baseline II (randomization) and Withdrawal. Urine stick 
pregnancy tests to be done at all other visits.
(h) The sample for pharmacogenomics may be drawn at the earliest visit after Baseline I, if missed at visit 2 (Baseline I). 
Pharmacogenomics sample collection is optional for subjects. A separate Informed Consent Form will be obtained. Only RNA 
pharmacogenomic sample collected on Week 8 and Week 16 visit.
(i) The subjects will be instructed to take the first dose of study medication on the morning after enrollment (Baseline I).
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Revised Text 
(a) Subjects who meet all randomization criteria please follow schedule of procedures for week 16 on schedule of study 
procedures for double-blind treatment period.
(b) All subjects who withdraw early, except those who withdraw their consent and refuse further contact, are to attend a withdrawal 
visit as soon as possible.
(c) Obtain subject authorization, enter subject into the CTS database.
(d) Update at Baseline I. 
(e) Subjects must meet response criteria from Week 8 through Week 16 and remission criteria at Weeks 14 and 16.
(f) Pretreatment event assessment occurs from the date of Screening up to the first dose of study medication. 
(g) Assess post-treatment adverse events, ongoing adverse events and/or serious adverse events, and record all ongoing medications 
for subjects who withdraw early.
(h) Fasting labs must be performed at Baseline I and Baseline II (randomization). 
(i) Serum hCG for female subject of childbearing potential at Screening, Baseline II (randomization) and Withdrawal. Urine stick 
pregnancy tests to be done at all other visits.
(j) Two whole blood samples (3 mL per sample) will be collected predose on Day 0 for DNA isolation. Two whole blood 
samples (2.5 mL per sample) will be collected for RNA isolation at each time point at predose on Day 0 and weeks 8, and 16
and any early withdrawal visit during open-label. The sample for pharmacogenomics may be drawn at the earliest.
(k) The subjects will be instructed to take the first dose of study medication on the morning after enrollment (Baseline I).
Rationale for Amendment
Clarification for procedures at week 16 for subjects who are randomized.
Addition of subject authorization for CTSdatabase.
Clarification for PGx blood draws during the open-label period.
Page 86, Section Appendix A Schedule of Study Procedures
Existing Text
None
Revised Text 
Relapse Checklist added at visits 18-48
Rationale for Amendment
Added to ensure sites are completing checklist at these visits.
Page 86, Section Appendix A Schedule of Study Procedures
Existing Text
(a) Subject well-being phone calls should be made every 2 weeks post Week 20.
Revised Text 
(a) Subject well-being phone calls should be made every 2 weeks post Week 20 through Week 46
Rationale for Amendment
Consistency with the protocol.
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Page 86, Section Appendix A Schedule of Study Procedures
Existing Text
(g) PK sampling must be taken prior to first dose of double-blind study medication. If subject is not 
randomized, PK sample should still be drawn. Collect only one PK sample at Week 16 draw
Revised Text 
(g) PK sampling must be taken prior to first dose of double-blind study medication.
Rationale for Amendment
Deleted part of footnote instructions for consistency with schedule of procedures for open-label 
treatment period.
Page 93, Section Collection, Shipment, and Storage of Pharmacogenomic and Collection, 
Storage, and Shipment of PK Samples
Existing Text
None
Revised Text 
For subjects who withdraw during the open-label treatment period, a blood sample will be 
collected at study termination, regardless of the treatment duration
Rationale for Amendment
Added PK sample for any early withdrawal visit during open-label treatment.
Page 94, Section Collection, Shipment, and Storage of Pharmacogenomic and Collection, 
Storage, and Shipment of PK Samples
Existing Text
A minimum of 1.0 mL needs to be obtained for each sample. Labeling may include protocol 
number Lu AA21004_402, matrix (ie, plasma), analyte (vortioxetine), enrollment number, 
nominal day and time, and either “SET 1” (for original sample) or “SET 2” (for duplicate 
sample).
Revised Text 
A minimum of 1.0 mL needs to be obtained for each sample. Labeling may include protocol 
number Lu AA21004_402, matrix (ie, plasma), analyte (vortioxetine), Subject ID (XXXX-XXX),
nominal day and time, and either “SET 1” (for original sample) or “SET 2” (for duplicate sample).
Rationale for Amendment
Clarification of enrollment number as the Subject ID.
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Study No. LuAA21004_402
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Page 94, Section Collection, Shipment, and Storage of Pharmacogenomic and Collection, 
Storage, and Shipment of PK Samples
Existing Text
Keep samples frozen at approximately -20°C or lower until shipment to the analytical laboratory. 
SET 1 samples will be shipped first on dry ice, followed by shipment of duplicate SET 2 samples 
after SET 1 samples have been received by the analytical laboratory
SET 1 samples will be shipped first on dry ice, followed by shipment of duplicate SET 2 samples 
after SET 1 samples have been received by the analytical laboratory.
Revised Text
Keep samples frozen at approximately -20°C or lower until shipment to the central laboratory. 
SET 1 samples will be shipped first on dry ice, followed by shipment of duplicate SET 2 samples 
after SET 1 samples have been received by the central laboratory
SET 1 samples will be shipped first on dry ice, followed by shipment of duplicate SET 2 samples 
after SET 1 samples have been received by the central laboratory
Rationale for Amendment
Corrected to show analytical lab as the central lab.
Page 94, Section Collection, Shipment, and Storage of Pharmacogenomic and Collection, 
Storage, and Shipment of PK Samples
Existing Text
Using a permanent marker, write the 4-digit subject number, sample matrix (ie, plasma, urine), 
analyte (vortioxetine), number of samples, and “SET 1” on each self-sealing bag
An inventory of individual samples should accompany each shipment and should include the 
Sponsor’s name (Takeda), study drug (Vortioxetine), protocol number (Lu AA21004_402), 
investigator’s name, sample type (ie, plasma), 4-digit enrollment number, nominal collection day 
and time, and intended sample storage conditions.
Revised Text 
Using a permanent marker, write the subject ID, sample matrix (ie, plasma), analyte 
(vortioxetine), number of samples, and “SET 1” on each self-sealing bag
An inventory of individual samples should accompany each shipment and should include the 
Sponsor’s name (Takeda), study drug (Vortioxetine), protocol number (Lu AA21004_402), 
investigator’s name, sample type (ie, plasma), subject ID, nominal collection day and time, and 
intended sample storage conditions.
Rationale for Amendment
Corrected to indicates subject ID and removed urine as a sample.
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Study No. LuAA21004_402
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Page 95, Section Collection, Shipment, and Storage of Pharmacogenomic and Collection, 
Storage, and Shipment of PK Samples
Existing Text
Affix an address label to each shipping carton.
Revised Text 
Affix an address label to each shipping carton. Use the preprinted air waybills provided by the 
central lab
Rationale for Amendment
Instructions for sites to use preprinted air waybills.
Page 95, Section Collection, Shipment, and Storage of Pharmacogenomic and Collection, 
Storage, and Shipment of PK Samples
Existing Text
Obtain the airway bill number and a receipt of shipment from the carrier
Revised Text
Obtain the air waybill number and a receipt of shipment from the carrier
Rationale for Amendment
Minor typo.
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SAP_000.pdf: 


Other information as needed to protect confidentiality of Takeda or partners, personal
information, or to otherwise protect the integrity of the clinical study.
Title: A Randomized, Double-Blind, Placebo-Controlled, Phase 4, Relapse Prevention Study 
Evaluating the Efficacy and Safety of Vortioxetine (5, 10 and 20 mg) in Adults With Major 
Depressive Disorder
NCT Number: NCT02371980
SAP Approve Date: 12 June 2019
Certain information within this Statistical Analysis Plan has been redacted (ie, specific content is masked 
irreversibly from view with a black/blue bar) to protect either personally identifiable (PPD) information 
or company confidential information (CCI). 
This may include, but is not limited to, redaction of the following: 
Named persons or organizations associated with the study.
Proprietary information, such as scales or coding systems, which are considered confidential 
information under prior agreements with license holder.


STATISTICAL ANALYSIS PLAN
STUDY NUMBER: Lu AA21004_402
A Randomized, Double-Blind, Placebo-Controlled, Phase 4, Relapse 
Prevention Study Evaluating the Efficacy and Safety of Vortioxetine (5, 
10 and 20 mg) in Adults With Major Depressive Disorder 
Vortioxetine, 5, 10, and 20 mg, Relapse Prevention Study in Adults with
Major Depressive Disorder
PHASE 4
Version: Final
Date: 12 June 2019
Prepared by:
Based on:
Protocol Version: Amendment 1
Protocol Date: 25 September 2015
Prope y of Takeda:
ommercial use only and subject to the applicable Terms of Use
Phase 4
hase 4
y of Vo
of V
ressive 
essiv
vention 
vention
Disorde
Disord
SE 
SE 4
Versi
Version
o
Date
Date:
on:n:
Pro
Pr
PPD


Lu AA21004_402
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Statistical Analysis Plan, Final
12 June 2019
2.0
TABLE OF CONTENTS
1.0
TITLE PAGE ..................................................................................................................1
2.0
TABLE OF CONTENTS.................................................................................................2
3.0
OBJECTIVES .................................................................................................................6
3.1
Primary Objective......................................................................................................6
3.2
Secondary Objective..................................................................................................6
3.3
Safety Objective ........................................................................................................6
3.4
Additional Objectives ................................................................................................6
3.5
Study Design .............................................................................................................6
4.0
ANALYSIS ENDPOINTS...............................................................................................9
4.1
Primary Endpoint.......................................................................................................9
4.2
Secondary Endpoints .................................................................................................9
4.3
Safety Assessments....................................................................................................9
4.4
Additional Endpoints .................................................................................................9
5.0
DETERMINATION OF SAMPLE SIZE.......................................................................10
6.0
METHODS OF ANALYSIS AND PRESENTATION...................................................11
6.1
General Considerations............................................................................................11
6.1.1
Statistical Software ............................................................................................11
6.1.2
Summary Statistics and Precision.......................................................................11
6.1.3
Definition of Study Day and Study Visit Windows.............................................11
6.1.4
Grouping of Centers...........................................................................................14
6.2
Major Protocol Violations........................................................................................14
6.3
Analysis Sets ...........................................................................................................14
6.4
Disposition of Subjects ............................................................................................15
6.5
Demographic and Baseline Characteristics...............................................................15
6.6
Medical History and Concurrent Medical Conditions...............................................16
6.7
Medication History and Concomitant Medications...................................................17
6.8
Study Drug Exposure and Compliance.....................................................................18
6.9
Primary, Secondary and Additional Analyses...........................................................18
6.9.1
Overview of Primary, Secondary and Additional Variables................................18
6.9.2
Missing Items on Rating Scales..........................................................................20
6.9.3
Analysis of Primary Variable .............................................................................20
6.9.4
Analysis of Secondary Variables........................................................................21
6.9.5
Analysis of Additional Variables........................................................................22
6.9.6
Controlling Type I Error ....................................................................................23
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Statistical Analysis Plan, Final
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6.10
Pharmacokinetic Analysis........................................................................................23
6.11
Pharmacogenomic Analyses ....................................................................................23
6.12
Safety Analysis........................................................................................................23
6.12.1 Adverse Events ..................................................................................................24
6.12.2 Clinical Laboratory Evaluations .........................................................................26
6.12.3 Liver Function Tests ..........................................................................................27
6.12.4 Vital Signs and Weight ......................................................................................27
6.12.5 Physical Examinations .......................................................................................27
6.12.6 12-Lead ECGs ...................................................................................................27
6.12.7 Pregnancy Test...................................................................................................28
6.13
Interim Analysis ......................................................................................................28
6.14
Changes in the Statistical Analysis Plan From the Protocol Analysis Plan................28
7.0
REFERENCES..............................................................................................................29
LIST OF IN-TEXT TABLES
Table 6.a
Visit Windows Open Label Period .....................................................................12
Table 6.b
Visit Windows Double-Blind Period..................................................................13
Table 6.c
Primary, Secondary and Additional Variables ....................................................20
LIST OF IN-TEXT FIGURES
Figure 3.a
Schematic of Study Design ..................................................................................8
LIST OF APPENDICES
Appendix A
Schedule of Study Procedures............................................................................30
Appendix B
Criteria for Identification of Potentially Clinically Significant Laboratory 
Values................................................................................................................34
Appendix C
Criteria for Identification of Potentially Clinically Significant Vital Signs..........36
Appendix D
Criteria for Identification of Potentially Clinically Significant 12-Lead ECG 
Parameters .........................................................................................................37
Appendix E
Relapse Events Prediction for Possible Sample Size Adjustment........................38
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Statistical Analysis Plan, Final
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LIST OF ABBREVIATIONS
AE
adverse event
AESI
adverse of special interest
ALT
alanine aminotransferase
ANCOVA
analysis of covariance
ANOVA
analysis of variance
AST
aspartate aminotransferase
AUC0-τ
area under the plasma concentration-time curve from time 0 to the end of the dosing interval (τ)
BMI
body mass index
BUN
blood urea nitrogen
C-SSRS
Columbia-Suicide Severity Rating Scale
Cavg
average plasma concentration at steady state
CGI
Clinical Global Impression Scale
CGI-I
Clinical Global Impression Scale-Global Improvement Scale
CGI-S
Clinical Global Impression Scale-Severity of Illness Scale
CI
confidence interval
Cmax
maximum plasma concentration at steady state
DSM-IV-TR
Diagnostic and Statistical Manual of Mental Disorders, 4th Edition, Text Revision
ECG
electrocardiogram
eCRF
electronic case report form
FAS
full analysis set
HAM-A
Hamilton Anxiety Scale
HDL
high density lipoprotein
ICH
International Conference on Harmonization
IMP
investigational medical product
LDL
low density lipoprotein
LLN
lower limit of normal
LOCF
last observation carried forward
LS
least squares
MADRS
Montgomery Åsberg Depression Rating Scale
MAR
missing at random
MDD
major depressive disorder
MedDRA
Medical Dictionary for Regulatory Activities
NONMEM
nonlinear mixed effect modeling
OC
observed case
PCS
potentially clinically significant
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Statistical Analysis Plan, Final
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PE
physical examination
PK
pharmacokinetic
PPS
per protocol set
QD
once daily
RBC
red blood cell
SAE
serious adverse event
SAP
statistical analysis plan
SD
standard deviation
SDS
Sheehan Disability Scale
SE
standard error
SI
Systeme International
SOC
system organ class
TEAE
treatment-emergent adverse event
TDC Americas
Takeda Development Center Americas, Inc.
ULN
upper limit of normal
WBC
white blood cell
WHO
World Health Organization
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Statistical Analysis Plan, Final
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3.0
OBJECTIVES
3.1
Primary Objective
The primary objective is to evaluate the efficacy of vortioxetine (5, 10, and 20 mg) versus 
placebo during the first 28 weeks of the 32-week double-blind treatment period in the prevention 
of relapse in subjects with MDD who responded to acute treatment with vortioxetine 10 mg.
3.2
Secondary Objective
To evaluate the overall efficacy of vortioxetine versus placebo during continuation treatment of 
subjects with MDD.
3.3
Safety Objective
To evaluate long-term safety and tolerability of vortioxetine versus placebo in subjects with 
MDD.
3.4
Additional Objectives

To assess the effect of long-term treatment with vortioxetine and placebo on suicidal ideation 
and behavior.

Determine the pharmacokinetic (PK) parameters of vortioxetine using a population 
pharmacokinetic approach.

Samples for pharmacogenomics will be collected and stored for possible exploratory 
investigation of drug response or disease. Pharmacogenomics analyses may be conducted to 
explore gene polymorphism relationships with drug responses, as indicated by the findings.
3.5
Study Design
This study is a randomized, double-blind, placebo-controlled, Phase 4 study to evaluate 3 fixed 
doses (5, 10, and 20 mg oral tablets) of vortioxetine once daily in the prevention of relapse in 
adult subjects with MDD who have responded to acute treatment with vortioxetine.
This study is comprised of a 16-week open-label treatment period followed by a 32-week 
double-blind randomized treatment periods. This study will enroll approximately 1100 subjects 
into the open-label phase in order to target approximately 600 subjects to be enrolled into the 
double-blind treatment phase and will be conducted at approximately 60 sites in the United 
States.
Men and women between the ages of 18 and 75, inclusive, meeting the diagnostic criteria from 
the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision (DSM-
IV-TR) for recurrent MDD, who have had at least 2 major depressive episodes (MDEs) prior to 
the current episode, with a current episode of between 8 weeks and 18 months duration from 
screening, a MADRS total score of ≥26, and who sign the informed consent form will be further 
assessed for study eligibility at a screening visit. At Baseline I, subjects who continue to meet all 
inclusion criteria and none of the exclusion criteria will be enrolled into a 16-week open-label 
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Statistical Analysis Plan, Final
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treatment period. During the open-label period all subjects will receive 10 mg vortioxetine. 
Subjects will take their first dose of study medication the morning after their Baseline I visit. 
During the open-label treatment period, subjects will be seen every 2 weeks until randomization 
(Baseline II).
Subjects who are in response (defined as a ≥50% reduction in MADRS total score from Baseline
I) at Week 8 will continue for an additional 8 weeks of treatment (Stabilization period) and will 
continue to receive 10 mg vortioxetine. Subjects must continue to meet response criteria as 
assessed at every study visit during the Stabilization period. In addition, subjects must meet 
remission criteria (defined as ≤12 MADRS total score) at weeks 14 and 16 to be eligible for 
randomization into the double-blind treatment period. Subjects who do not meet the response 
and/or remission criteria will be withdrawn from the study and will complete an early withdrawal 
visit. Subjects are to remain on 10 mg throughout the open-label period. If a subject requires a 
dose-adjustment, they should be withdrawn from study.
At Baseline II, subjects who have met the randomization criteria (response and remission as 
described above) and have not met any other withdrawal criteria will be randomized in a ratio of 
1:1:1:1 of the following 4 treatment groups for 32 weeks of double-blind treatment: vortioxetine 
5 mg; vortioxetine 10 mg; vortioxetine 20 mg; and placebo.
Subjects will be seen twice the first month and then once monthly during the remainder of the 
32-week double-blind treatment period. Subject well-being calls will be made every 2 weeks 
after Week 20, in between scheduled subject visits. 
Subjects will be considered as “relapsed” and withdrawn from the study if the following criteria 
are met: MADRS 22, or lack of efficacy as determined by the investigator. In addition, 
investigator judgment should be used to determine unsatisfactory treatment response indicative 
of relapse to depression, such as subject hospitalization for depression, medication prescribed for 
MDD, electroconvulsive therapy, suicide attempt, etc.
A safety follow-up phone call will be made 30 days after completion of double-blind treatment. 
Subjects (either in open-label or double-blind) who discontinue or who are withdrawn prior to 
study completion will come to the site for an early withdrawal visit as soon as possible and will 
be contacted for a safety follow-up 30 days after the last dose of study medication. 
NOTE: The investigators will be requested to make a note of the approximate date of relapse 
within the period since last visit rather than specify the visit at which relapse was detected. If 
necessary, subjects that are suspected of relapse or impending relapse (eg, clinically relevant 
worsening of depression symptoms) should come to the study site as soon as possible to be 
assessed.
A schematic of the study design is included as Figure 3.a. A schedule of assessments is listed in 
the protocol.
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Statistical Analysis Plan, Final
12 June 2019
CONFIDENTIAL
Figure 3.a
Schematic of Study Design
*Defined as 50% reduction in MADRS total score. Subjects must remain in response throughout stabilization period.
VOR = vortioxetine, pd. = period
VOR 20 mg/day
Responders*
Endpoint 
W44
Response 
pd. 8 weeks
Stabilization 
pd. 8 weeks
VOR 10 mg/day
W0
W16
W48
W52
Safety
follow-up
Baseline I
Baseline II
Open-label 
Acute treatment
(16 weeks)
Double-blind 
Relapse prevention
(32 weeks/endpoint:28 weeks)
Remitters only:
MADRS total score 12 at Wk 
14 and Wk 16 are eligible
MADRS 
26
Placebo
Relapse:
MADRS 22 or 
lack of efficacy
VOR 5 mg/day
W1
W8
VOR 10 mg/day
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Statistical Analysis Plan, Final
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4.0
ANALYSIS ENDPOINTS
4.1
Primary Endpoint
The primary endpoint is the time from randomization to relapse during the first 28 weeks of the 
32-week double-blind treatment with relapse defined as depression Montgomery-Asberg 
Depression Rating Scale (MADRS 22), or lack of efficacy as determined by the investigator.
4.2
Secondary Endpoints

Change from double-blind baseline (ie, Baseline II) in MADRS total score at all time points 
assessed.

Change from double-blind baseline in Clinical Global Impression Scale – Severity of Illness 
(CGI-S) score at all time points assessed.

Clinical Global Impression Scale – Global Improvement Scale (CGI-I) score at all time 
points assessed.

Time from randomization to relapse during the entire 32-week double-blind treatment period 
with relapse defined as depression (MADRS ≥22), or lack of efficacy as determined by the 
investigator.
4.3
Safety Assessments
Safety and tolerability of vortioxetine will also be evaluated using the following general 
assessments:

Adverse events (AEs).

Laboratory values.

Vital signs.

Weight.

Electrocardiograms (ECGs).
4.4
Additional Endpoints

The time from randomization to withdrawal for any reason during 28 weeks of double-blind 
treatment.

Columbia-Suicide Severity Rating Scale (C-SSRS) summary data at all time points assessed.

Estimate individual exposure parameters of vortioxetine, including area under the plasma 
concentration-time curve from time 0 to time tau (AUC0-τ), average serum concentration
(Cavg), maximum observed plasma concentration (Cmax).
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Statistical Analysis Plan, Final
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5.0
DETERMINATION OF SAMPLE SIZE
Assuming a cumulative relapse rate at 28 weeks of 15% for the vortioxetine group versus 30% 
for the placebo group, a total of 600 subjects (150 per treatment group) will provide 85% power 
to find a statistically significant difference between each dose of vortioxetine and placebo at a 
5% significance level (ie, alpha=0.05). The total number of relapse events required in the 
placebo and three vortioxetine groups is about 110.
It is anticipated that approximately 55% of the patients enrolled into the open-label period will 
qualify for the double-blind study phase. Therefore, a total of about 1100 patients will need to be 
enrolled into the open-label period of the study. 
If the number of subjects who relapsed during the double-blind treatment period is much less 
than expected, sample size adjustment will be considered. After approximately 75% of planned 
subjects (825) are enrolled into the open-label period of the study, the total number of relapse 
events, the numbers of subjects who have completed or are still in the double-blind treatment 
period, and the numbers of subjects in the open-label phase will be used to predict the final total 
number of relapse events. If the predicted total number of relapse events is far smaller than 110, 
with the planned 1100 enrolled subjects, more subjects will be enrolled in the study. All of these 
evaluations will be done while maintaining the study blind. The details for these analyses are in 
Appendix E.
As the number of randomized subjects, and ultimately the number of relapse subjects, are partly 
dependent on the number enrolled in the open label period, the final number enrolled may be 
more than the estimated 1100.
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Statistical Analysis Plan, Final
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6.0
METHODS OF ANALYSIS AND PRESENTATION
6.1
General Considerations
6.1.1
Statistical Software
Statistical analysis will be performed using the SAS System®, Version 9.4 or greater, on a 
Windows platform.
6.1.2
Summary Statistics and Precision
All tabulations of analysis results will include summaries for the following treatment groups: 
placebo, vortioxetine 5 mg QD, vortioxetine 10 mg QD, and vortioxetine 20 mg QD.
All confidence intervals, statistical tests, and resulting p-values will be reported as nominal 
2-sided and will be assessed at the 5% significance level. No adjustments will be made for 
multiplicity aside from those for the primary efficacy analyses (see section 6.9.5).
For continuous variables, descriptive statistics will include the number of subjects (n), mean, SD 
or standard error (SE), as appropriate, minimum, median, and maximum. The number of decimal 
places displayed for each statistic will be determined as follows:

Mean and median: 1 more than the number of decimal places allotted in the electronic case 
report form (eCRF) except for the CGI scales, where 2 decimal places will be reported.

SD and SE: 2 more than the number of decimal places allotted in the eCRF.

Minimum and maximum: equal to the number of decimal places allotted in the eCRF.

Confidence intervals will be presented using the same number of decimal places as the 
parameters (eg, mean).
For categorical data, frequency counts and percentages will be presented. Percentages will be 
reported to 1 decimal place.
The data summaries will be accompanied by individual subject data listings sorted by treatment, 
study center and subject identifier. All data available from eCRFs will be listed. The actual day 
relative to the start of treatment will be determined and included in the listings.
Derived analysis datasets will be produced from raw data and laboratory data. This allows for 
convenient reviewing of the data as well as any necessary supplemental analyses. All data from 
the raw datasets will be included in the derived datasets. Derived dataset specifications will be 
developed to include the names and definitions of derived variables in the derived SAS datasets.
6.1.3
Definition of Study Day and Study Visit Windows
Visit windowing will not be used for the primary efficacy analysis and other time-to-event 
analyses in this study. For other analyses, a windowing convention will be used to determine the 
analysis value for a given study visit that applies to observed data.
In general, Study Day -1 corresponds to the date of the Baseline I or II visit. Other study days are 
defined relative to Study Day 1, the date of first study drug dose in the open label period or 
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Statistical Analysis Plan, Final
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double blind period. Relative day is calculated as (date of interest – date of first dose +1) for 
study days on or after the date of first dose and as (date of interest – date of first dose) for study 
days prior to the first dose date.
For each visit, a window will be defined such that the lower and upper bounds of each window is 
generally the midpoint between 2 consecutive study visits. The visit windows and applicable 
study day ranges are presented below in Table 6.a and Table 6.b.
Table 6.a
Visit Windows Open Label Period
Nominal Visit 
Week
Nominal 
Visit Day
MADRS, CGI-S, CGI-I, 
C-SSRS, Vital signs
Lab, Weight, PK
PE, Lipids 
fasted, ECG
Baseline I
-1 (a)
≤1 (b)
≤1 (b)
≤1
2
14
2 – 21
4
28
22 – 35
6
42
36 – 49
8
56
50 – 63
2 – 94
10
70
64 – 77
12
84
78 – 91
14
98
92 – 105
16
112
≥106
≥95
≥2
(a) Baseline I day has been defined as Day -1 in keeping with Clinical Data Interchange Consortium standards. 
There is no Day 0.
(b) No baseline assessment for CGI-I or pharmacokinetic (PK) sampling. For others, last non-missing value prior to 
the first dose of study drug is defined as the Baseline.
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Statistical Analysis Plan, Final
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Table 6.b
Visit Windows Double-Blind Period
Nominal 
Visit Week
Nominal 
Visit 
Day
MADRS, CGI-S, 
C-SSRS, Vital signs
Weight
Lab, PE
ECG, PK 
CGI-I
Baseline
II/Week 16
-1 (a)
≤1
≤1
≤1 
≤1
≤1
16+2=18
14
2 – 21
2 – 35
2 – 63
16+4=20
28
22 – 42
16+8=24
56
43 – 70
36 – 84
16+12=28
84
71 – 98
16+16=32
112
99 – 126
85 – 140
64 – 168
2 – 168
16+20=36
140
127 – 154
16+24=40
168
155 – 182
141 – 196
16+28=44
196
183-210
16+32=48
224
≥211
≥197
≥169
≥169
≥2
(a) Baseline II day has been defined as Day -1 in keeping with Clinical Data Interchange Consortium standards. 
There is no Day 0. The first dose in this table is the first dose in the double-blind study medication. Baseline value is 
the last non-missing observation prior to the first dose of the double-blind study medication.
More than 1 result for a parameter may be obtained in a visit window. In such an event, the result 
with the date closest to the scheduled visit day will be used. In the event of 2 observations 
equidistant to the scheduled visit day, the later of the observations will be used. Double-blind 
treatment Period Last Visit values will be defined irrespective of falling in a particular window. 
Hence, the windowed Week 48 value may be different than the Last Visit value.
In general, the baseline value, Baseline I or Baseline II, for a variable is defined as the last 
observation prior to the first dose of open-label or double-blind study medication (visit date ≤ 
first dose date) respectively, including the screening value, if necessary.
Adverse events that start more than 30 days after the last dose of study medication (start date –
last dose date >30) will be listed, but excluded from the summaries and analyses. For efficacy 
and other safety data, data that are obtained more than 7 days after the last dose of study 
medication (visit date – last dose date >7) will be listed, but excluded from summaries and 
analyses.
If the date of the first open-label dose is missing, then the date of the first dose dispensed + 1 day 
will be used. If the date of the last open-label dose is missing and the subject is not randomized 
into double-blind period, then the earlier of the 2 dates will be used for the last open-label dose 
date for analysis and summary purpose: the early termination visit date or the last open-label 
drug dispense date +7 days. If the date of the last open-label dose is missing and the subject is 
randomized into double-blind period, then the date of first double-blind dose – 1 day will be 
used.
If the date of last double-blind dose is missing, then the earlier of the following 2 dates will be
used for the last dose date for analysis and summary purpose: the final visit (Week 48) /early 
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Statistical Analysis Plan, Final
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termination visit date or the last double-blind drug dispense date +7 days. If the date of the first 
double-blind dose is missing, then the first dose dispensed date + 1 day will be used for analysis 
and summary purposes.
The study window convention will not be applied to the eCRF data listings. The data listings for 
eCRF data will display the raw data as collected and entered in the eCRF. For MADRS, CGI-I, 
and CGI-S, windowed visits will also be shown on the listings.
6.1.4
Grouping of Centers
Before unblinding the data, centers will be pooled with geographically similar centers to 
minimize artifacts in the statistical analyses from imbalances in subject counts within the centers.
The pooling of the centers will be reviewed and approved by the clinical team for agreement, and 
is then used in the appropriate analyses once the database is locked and unblinded.
6.2 Major Protocol Violations
All subjects with major protocol violations will be identified in the minutes of the subject 
evaluability assessment performed prior to unblinding, and will be listed by study center and 
subject number.
Subjects with the following major protocol violations will be excluded from the per protocol set 
(PPS) defined in Section 6.3:

No evaluable baseline MADRS assessment.

No evaluable post-baseline assessment of MADRS.

Low study drug compliance (<70%) or missed study drug for 6 consecutive days.

Double-blind study medication exposure less than 14 days (last dose date – first dose date 
+1 <14).

Subjects switch treatment during study.
Other major protocol violations will be identified by the study team prior to unblinding.
6.3 Analysis Sets
The safety set for open-label period will include all subjects who received at least 1 dose of 
open-label study medication. The safety set for double-blind period will include all subjects who 
were randomized and received at least 1 dose of double-blind study medication. In safety 
summaries for the double-blind period, subjects will be analyzed according to the treatment they 
received. In the event that a subject inadvertently took capsules from more than 1 drug dose 
level, the actual treatment will be defined as the one taken most frequently. If the most common 
treatments were taken with equal frequency, the randomized treatment will be used as the actual 
treatment.
The full analysis set (FAS) will include all subjects who were randomized in the double-blind 
period and received at least 1 dose of double-blind study drug. FAS subjects with a non-missing 
baseline and at least one valid post-baseline value for an efficacy endpoint will be included in the 
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appropriate summaries and analyses. In FAS summaries, subjects will be analyzed by the 
treatment to which they were randomized.
The PPS will include all FAS subjects who had no major protocol violations. If more than 5% of 
the total subjects in the FAS have major protocol violations, analyses based on the PPS will be 
performed for the primary efficacy variable only.
The PK analysis set for open-label period will include all subjects who received at least 1 dose of 
open-label study medication and have at least 1 measurable open-label post-dose plasma 
concentration. The PK analysis set for double-blind period will include all subjects who received 
at least 1 dose of double-blind study medication and have at least 1 measurable double-blind 
post-dose plasma concentration. 
6.4 Disposition of Subjects
Disposition for all enrolled subjects in the open-label period will be summarized. In addition, 
disposition for subjects who were randomized in the double blind treatment period will be 
summarized by treatment group and overall. The categories will include all subjects who were 
enrolled, subjects who were not treated, subjects who were randomized, subjects who 
discontinued from the study categorized by reason, subjects who discontinued treatment 
categorized by reason, and subjects who completed the study. The discontinuation reasons in the 
open-label period include pretreatment event or adverse event, significant protocol deviation, lost 
to follow-up, lack of efficacy, non-compliance with study drug, voluntary withdrawal, study 
termination, pregnancy, randomization criteria unmet, and other. The discontinuation reasons in 
the double-blind period include pretreatment event/adverse event, significant protocol deviation, 
lost to follow-up, lack of efficacy, relapse, non-compliance with study drug, voluntary 
withdrawal, study termination, pregnancy, randomization criteria unmet, and other. A listing will 
be presented to describe study period, treatment received during the period, date of first dose, 
date of last dose, date of completion or early withdrawal and the reason for early discontinuation. 
A summary of inclusion/exclusion criteria and responses for subjects with violations will also be 
provided.
6.5 Demographic and Baseline Characteristics
For subjects who were enrolled in the open-label period and took at least one dose of open-label 
drug, demographic and baseline I characteristics including gender, age, race, ethnicity, height, 
weight, body mass index (BMI), smoking habits, physical examination, and medical history 
including the number of prior episodes and the duration of current episode will be listed and 
summarized overall for Baseline I. For subjects who were randomized to the double-blind 
period, gender, age, race, ethnicity, height, weight, body mass index (BMI), smoking habits, 
physical examination, and medication history including the number of prior episodes and the 
duration of the current episode, will be summarized for Baseline II by treatment groups and 
overall based on double-blind safety set and the FAS, separately. Baseline I demographic and 
characteristics will also be summarizing for subjects who were enrolled in the open-label period 
but failed randomization.
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Baseline values for efficacy parameters (MADRS and CGI-S) will be summarized in both open-
label and double-blind treatment periods. CGI-I Baseline II values will be summarized in double-
blind treatment period. Baseline I and Baseline II efficacy data will be presented for all enrolled 
subjects in open-label period and summarized by treatment group and overall based on all 
randomized subjects and the FAS, separately. Baseline I efficacy parameters will also be 
summarized for subjects who were enrolled in open-label period but failed randomization.
Height and weight values will be presented in metric units (cm and kg, respectively). BMI is 
calculated as [weight (kg)/height (m) 2], using the weight collected prior to the first dose of the
open-label or double-blind period.
Race is classified into Caucasian, Black, Asian, American Indian or Alaska Native, Native 
Hawaiian or Other Pacific Islander. In addition, ethnicity (Hispanic or Latino) is also captured.
For continuous variables, the number of non-missing values and the mean, median, SD, 
minimum and maximum will be tabulated by treatment group and overall. For the categorical 
variables, the count and percentages of each possible value will be tabulated by treatment group 
and overall.
All individual demographic and baseline data will be listed by treatment, study center, and 
subject number.
6.6 Medical History and Concurrent Medical Conditions
Medical history refers to the significant conditions/diseases that stopped at or prior to Screening 
(time of informed consent). Concurrent medical conditions are those significant ongoing 
conditions/diseases present at Screening (time of informed consent).
For partially missing end dates, the following will be conducted:

Day missing: the minimum between last day of the month and date of transfer will be used to 
impute the end date.

Month and day missing: the minimum between last day of the year and date of transfer will 
be used to impute the end date.
Medical history and concurrent medical conditions will be coded using the Medical Dictionary 
for Regulatory Activities (MedDRA) version 18.0 or higher and will be summarized by 
treatment group and overall using system organ class (SOC) and preferred term (PT). The table 
will include number and percentages of subjects. SOC will be sorted in alphabetical order and 
the PT will be sorted in decreasing frequency based on the total number of subjects. A subject 
will only be counted once within a particular class even if he/she has multiple 
conditions/symptoms. Summaries will be based on all enrolled subjects in open-label period and 
all randomized subjects in double-blind period. Concurrent medical conditions in the double-
blind period include significant ongoing conditions or diseases present at the time of informed 
consent.
All medical history and concurrent medical condition data will be listed by treatment, study 
center and subject number. The listing will contain subject identifier, whether there was any 
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significant medical history or concurrent condition, including system organ class, preferred term 
and details of the medical history or condition.
6.7 Medication History and Concomitant Medications
The medication history and concomitant medications are defined as follows:

Medication history refers to the medication that the study subjects stopped taking within 
90 days prior to signing of informed consent.

Concomitant medication is defined as medication that the study subjects continued taking or 
took from Screening through end of study:
–
Concomitant medication that started and stopped prior to baseline I (ie, stop date ≥ first 
screening visit date, and stop date ≤ first dose date).
–
Concomitant medication that started prior to Baseline I and was ongoing in the open-
label period (ie, start date < first dose date, and stop date ≥ first dose date).
–
Concomitant medication that was ongoing in the double-blind period for the randomized 
patients (ie, start date ≤ last double-blind dose date, and stop date>first double-blind dose 
date).
–
Concomitant medication taken during the study (ie, start date ≤ last dose date, and stop 
date ≥first dose date.
–
If start date and stop date are missing, medication will be assumed to occur both prior and 
concomitantly.
For missing dates of concomitant medication, the following will be conducted:

Missing start date:
–
Day missing: the first day of the month will be used for the start date.
–
Month and day missing: January 1 of that year will be used for the start date.
–
Year, month and day all missing: If date of birth is available, use the date of birth as the 
start date. If date of birth is not available, estimate date of birth using the screening date 
and age, and use the estimated date of birth as the start date.

Missing end date:
–
Day missing: the last day of the month will be used for the end date. If the imputed end 
date is before the start date, keep the end date same as the start date.
–
Month and day missing: December 31 of that year will be used for the end date.
–
Year, month and day all missing: December 31 of the last dose year will be used for the 
end date. If the imputed end date is before the start date, keep the end date same as the 
start date.
Medication history and concomitant medications will be coded using the 01MAR2015E version 
of the World Health Organization (WHO) Drug Dictionary and summarized by giving the 
number and percentage of subjects by preferred term within each therapeutic class, with 
therapeutic class and medications in each class sorted in alphabetical order. The total number of 
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subjects with medications will also be summarized overall for open-label period, by treatment 
groups and overall for the double-blind period. If a subject reports taking 2 drugs belonging to 
the same class, he/she will only be counted once within that class. Summaries of medication 
history and concomitant medication will be based on all subjects in the open-label period and 
randomized subjects for the double-blind period.
All prior and concomitant medications will be listed by treatment, study center and subject 
number. The listings will contain subject identifier, WHO Drug preferred term and reported 
term, dose, unit, route, frequency, the indication for which the medication was being taken, start 
date, stop date, and whether the medication was ongoing.
6.8 Study Drug Exposure and Compliance
The summary of study drug exposure and compliance will be based on the safety set. Duration of 
exposure to study medication is defined as (date of last dose – date of first dose +1). Since study 
medication for the same subject in the open-label and double-blind periods may be different, the 
summary will be provided separately. Date of last dose is defined as the last dose in the treatment 
period.
Treatment duration will be summarized by duration category in days (open-label period: 1 to 13 
days, 14 to 27 days, 28 to 41 days, 42 to 55 days, 56 to 69 days, 70 to 83 days, 84 to 97 days, 98 
to 111 days, and ≥112 days; double-blind period: 1 to 13 days, 14 to 27 days, 28 to 55 days, 56 
to 83 days, 84 to 111 days, 112 to 195 days, and ≥196 days) and the number of subjects in the 
double-blind duration category by treatment group. Treatment duration (weeks) will also be 
summarized using descriptive statistics (n, mean, SD, median, minimum, and maximum).
Percent of study drug compliance is defined as {(number of capsules dispensed – number of 
capsules returned)/(date of last dose – date of first dose +1)}x100%. If a value for the number of 
returned capsules is missing or the return date is missing, then 100% compliance will be assigned 
for each day up to the number of capsules dispensed or up to the date of return whichever is 
earlier.
For each treatment group, study medication compliance will be summarized by compliance 
category (<80%, 80 to 120%, and ≥120%) and the number of subjects in each compliance 
category. Study medication compliance will also be summarized as a continuous variable using 
descriptive statistics (n, mean, SD, median, minimum, and maximum) for each treatment group.
All study drug administration and accountability data will be listed by treatment, study site, and 
subject number. The following variables will be listed: subject identifier, visit number, first and 
last dose dates, medication identification number, date dispensed and returned, number of 
capsules dispensed and returned, and percent compliance.
6.9
Primary, Secondary and Additional Analyses
6.9.1
Overview of Primary, Secondary and Additional Variables
The analyses and summaries will be based on the FAS.
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Relapse is defined as either:

a MADRS total score of 22 or more or

lack of efficacy as determined by the investigator

other unsatisfactory treatment response judged by the investigator.
The ‘Time to Relapse’ is in general defined as:
Date of Relapse – Date of Randomization (Visit 10) + 1
The date of relapse will normally be equal to the date of study drug discontinuation in the 
double-blind treatment period. If the date of study drug discontinuation is missing, date of last 
contact from study visit discontinuation will be used. 
The time to relapse will be analysed using two different conventions:
Relapse Convention 1: Within 28 Weeks (primary):
This convention essentially only considers data during the first 28 weeks of the 32-week double-
blind treatment, i.e., data up to week 44.
All withdrawals (relapses or other reasons) occurring after Visit 18/Week 44 will be regarded as 
censored observations and will be assigned the date of Visit 18 as censoring time. 
Patients who did not relapse and withdrew before or at Visit 18 will be considered as non-relapse 
and will receive the date of study drug withdrawal as censoring time. If the date of study drug 
withdrawal is missing, the date of last contact will be used as censoring time.
The variables associated with these conventions will be defined as below,
Status_1:
“0” indicating “Censoring”; “1” indicating “Relapse”
T_Relapse_1: Time to Censoring or Relapse.
These variables will be the basis for the primary analysis of efficacy.
Relapse Convention 2: Complete double-blind period (Secondary):
All relapses occurring in the entire 32-week double-blind period will be considered. All 
withdrawals who did not relapse will be considered as non-relapse and will receive the date of 
study drug withdrawal as censoring time. If the date of study drug withdrawal is missing, the 
date of last contact will be used as censoring time.
The variables associated with these conventions will be defined as below,
Status_2:
“0” indicating “Censoring”; “1” indicating “Relapse”
T_Relapse_2: Time to Censoring or Relapse.
These variables will be the basis for secondary analysis of efficacy.
The primary, secondary and additional variables for this study are presented in Table 6.c.
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Table 6.c
Primary, Secondary and Additional Variables
Parameter
Description
Variable 
Type (a)
T_Relapse_1
Time to Relapse within 28 Weeks
4
T_Relapse_2
Time to Relapse within 32 Weeks
4
MADRS
MADRS total score
1
CGI-S
CGI severity
2
CGI-I
CGI improvement
2
T_withdrawal
Time to withdrawal for any reason within 28 Weeks
4
C-SSRS
C-SSRS response
2
(a) 1 = continuous; 2 = categorical; 3 = binary; 4 = time to event.
6.9.2
Missing Items on Rating Scales
The general rule when individual items are missing from a multiple-item assessment is as 
follows: the total score will be calculated using a SAS function CEIL, as CEIL[(sum of 
nonmissing items)×(total number of items)/(number of nonmissing items)]. If more than 20% of 
the items are missing, the total score will be set to missing. The MADRS total score will be set to 
missing if the number of missing items is at least 3. The resulting calculated total scores will be 
used in all analyses.
6.9.3
Analysis of Primary Variable
The time from randomization to relapse during the first 28 weeks of the 32-week double-blind 
treatment will be the primary variable. Primary analysis will compare the efficacy of vortioxetine 
(5, 10, and 20 mg) versus placebo based on a Cox proportional hazards model using an exact 
method to handle ties, with treatment as the factor and baseline MADRS total score as the 
covariate of the Cox model.
The SAS code for the time-to-relapse analysis will be as follows:
proc phreg;
–
class treat;
–
model T_Relapse_1*status_1(0) = treat baseline/ ties=exact;
Here, baseline is the MADRS score at the double-blind baseline (Baseline II). The analysis will 
be supplemented with plots of Kaplan-Meier estimates of relapse. The tests will be 2-sided 
comparing each of the 3 doses of vortioxetine to placebo. Ninety-five percent confidence 
intervals will be presented together with the estimated p-values.
In order to support the results of the primary analyses, a number of sensitivity analyses will be 
performed including the one described in the secondary analyses. In addition, since covariate 
adjustment in the Cox regression model requires stronger model assumptions, the covariate 
baseline MADRS total score will be excluded and only the treatment factor will be kept as the 
independent variable in the Cox model of the primary analysis. The standard log-rank test and 
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the accelerated failure time models will be also performed. Various distribution will be studied in 
the parametric models e.g. Weibull, log-normal and log-logistic. Sensitivity analyses, using the 
same methodology as for the primary analysis, will be performed where patients with relapses 
occurring within the first 14 days of the double-blind period are excluded (considered to have 
rebound instead of relapse) and where AE withdrawal is counted as relapse event, respectively. 
The primary analyses (Cox model) will be also be repeated based on the PPS.
Some covariates including pooled center, race, Baseline I and II MADRS scores, sex, baseline 
weight, BMI, and age with interaction terms may also be added to the Cox model of the primary 
efficacy analysis for exploratory analyses. 
For the primary efficacy variable, subgroup analyses by:

age (≤median, >median).

sex (female, male).

race (white, non-white).

Baseline II MADRS (≤ median, > median).
and other variables, if necessary, will be performed if each of the subgroups contains at least 
20% of the total subjects in the study. The treatment groups will be compared within each 
subgroup. Additional exploratory analyses examining subgroup effect and treatment by subgroup 
interaction may be performed.
6.9.4
Analysis of Secondary Variables
Change from double-blind Baseline II in MADRS total score will be analyzed using a mixed 
effects model for repeated measurements (MMRM) analysis with treatment, week, baseline 
MADRS total score, treatment-by-week interaction as fixed effects, center as random effect, and 
a completely unstructured covariance matrix. Study visits with at least 50% of the subjects have 
non-missing values will be included. Comparisons between the different doses of vortioxetine 
and placebo will be performed over all the assessment points. 
The SAS code for the MMRM analysis will be as follows:
Proc mixed data=all;
–
class week treat center subject;
–
model Change = treat center week baseline week*treat /solution;
–
repeated week/subject=subject type=UN;
–
random center;
–
lsmeans week*treat / cl pdiff.
Here, baseline is the MADRS score at baseline II, change is the change in MADRS score from 
baseline II, and week is to be recounted from baseline II.
Change from Baseline II in the CGI-S will be analyzed by study visit (including all visits for 
which at least 50% of the subjects have non-missing values) using MMRM similar to the model 
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described above for the change of MADRS total score. It should also be noted that the above 
longitudinal analyses (MMRM) on MADRS score change and CGI-S may be biased due to the 
unknown dropout pattern among the treatment groups. 
Observed CGI-I scores will be summarized by treatment group for each visit.
Time from randomization to relapse of MDD occurring during the entire 32-week double-blind 
treatment period will be analyzed using a Cox model similar to the one described in 6.9.2 for the 
primary variable. It may also be considered a sensitivity analysis of the primary variable.
All statistical tests will be 2-sided and at the 5% level of significance. Ninety-five percent 
confidence intervals will be presented together with the estimated p-values.
6.9.5
Analysis of Additional Variables
The time from randomization to withdrawal for any reason during 28 weeks of double-blind 
treatment, will be analyzed using a Cox model similar to the one described in 6.9.2 for the 
primary variable. 
The following summaries will be presented for C-SSRS scale:

Descriptive statistics by study visit.

Number of subjects with positive reports at baseline and during treatment.

A shift-table to demonstrate changes in C-SSRS scores from baseline during treatment.
A subject with a positive report at baseline if the subject reported any of the following suicidal 
ideation or behavior:

Active suicidal ideation with some intent to act, without specific plan.

Active suicidal ideation with specific plan and intent.

Any actual suicide attempt.

Any interrupted suicide attempt.

Any aborted suicide attempt.

Any preparatory acts or behavior.
A subject with a positive report during treatment if the subject reported any of the following 
suicidal ideation or behavior:

Active suicidal ideation with some intent to act, without specific plan.

Active suicidal ideation with specific plan and intent.

Any actual suicide attempt.

Any interrupted suicide attempt.

Any aborted suicide attempt.

Any preparatory acts or behavior.

Completed suicide.
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6.9.6
Controlling Type I Error
To control the type I error for the primary efficacy endpoint, comparison between each dose of 
vortioxetine and placebo will be tested in the sequential order of 20 mg vs placebo, 10 mg vs 
placebo, and 5 mg vs placebo at significance level 0.05; as soon as a dose is non-significant from 
placebo at 0.05, the testing procedure stops for all subsequent dose(s).
6.10
Pharmacokinetic Analysis
The plasma concentration will be listed for each subject and summarized by each time point for 
each treatment group in both open-label and double-blind period (N, mean, SD, median, 
minimum, and maximum).
The population pharmacokinetics of vortioxetine and its metabolites will be assessed by means 
of nonlinear mixed effect modeling (NONMEM). Individual exposure parameters (eg, AUC0-τ, 
Cavg, Cmax) maybe estimated and their correlation with relevant pharmacodynamic parameters 
may be explored (effect and tolerability/safety). A separate population pharmacokinetics plan 
and report will be written.
6.11
Pharmacogenomic Analyses
No pharmacogenomic analyses will be performed.
6.12
Safety Analysis
The safety data will be summarized for the open-label period and double-blind period separately.
Safety summaries will be based on the safety set. Conventions for the definition of baseline 
values and visit windowing are given in Section 6.1.3. Missing safety data will not be imputed.
Safety summaries will include descriptive statistics for values, changes, and incidence of events 
for all treatment groups combined in addition to summary by treatment group.
For adverse events with completely or partially missing date, the following will be conducted:

Missing AE start dates:
–
Day missing: 
•
If the month and year are the same as those in the first dose date, the first dose date 
will be used to impute the start date.
•
If the month and year are after the first dose date, the first of the month will be used 
to impute the start date.
–
Month and day missing:
•
If the year is the same as the year of the first dose, the first dose date will be used to 
impute the start date.
•
If the year is after the year of the first dose, set the start date as January 1.
–
Year, month, day all missing: the first dose date will be used to impute the start date.
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
Missing AE stop dates:
–
Day missing: the last day of the month will be used to impute the end date. If the imputed 
end date is before the AE start date, keep the end date same as the start date. If the subject 
died, use the date of death to impute the end date.
–
Month and day missing: If the year is the same as or before the year of the last dose, set 
the end date as December 31. If the year is after the year of the last dose, set the end date 
as January 1.
–
Year, month, day all missing: Impute the end date as December 31 of the last dose year. 
If the imputed end date is before the AE start date, keep the end date same as the start 
date. If the subject died, use the date of death to impute the end date.
6.12.1 Adverse Events
All adverse events will be coded using MedDRA version 18.0 or higher. In this dictionary, each 
verbatim term is coded to a lower level term, and then mapped to a preferred MedDRA term, 
which is then mapped to an SOC. All adverse events will be included in the data listings, but 
only treatment-emergent adverse events will be included in the summary tables.
A treatment-emergent adverse event (TEAE) is defined as an adverse event with an onset that 
occurs after receiving study drug (AE start date ≥ first dose date) and within 30 days after 
receiving the last dose of study drug (AE start date – last dose date ≤30). The first dose date and 
last dose date for the open label period and double blind period may be defined differently based 
on the summary table in the two treatment periods. A TEAE may also be a pretreatment adverse 
event or a concurrent medical condition diagnosed prior to the date of first dose of study drug 
that increases in severity after the start of dosing. Adverse events data with onset occurring more 
than 30 days after last dose of study drug (AE start date – last dose date >30) will be listed, but 
not included in the summary tables. Adverse events with missing onset dates will be summarized 
regardless of severity and relationship to study medication.
Serious adverse events (SAEs) with onset that occurs after receiving study drug (AE start date 
≥first dose date) and within 30 days after receiving the last dose of study drug (AE start 
date - last dose date ≤30) will be summarized.
In the high-level adverse event summary tables, TEAEs will be summarized regardless of 
intensity and relationship to study drug. Within each subject, multiple reports of events that map 
to a common MedDRA term will be counted only once.
At the adverse event level, the summary tables will present the number of subjects reporting each 
of these MedDRA events, ie, the number of subjects reporting 1 or more events that map to the 
given MedDRA term.
At the SOC level, the summary tables will present the number of subjects reporting 1 or more 
events that map to the given SOC. That is, the number of subjects reported at the SOC level will 
be less than or equal to the sum of the subject counts across all adverse events within that SOC.
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In selected summaries (TEAEs overview, and TEAEs by SOC and preferred term), adverse 
events will be summarized by the number of events reported in addition to the number and 
percentage of subjects with events.
For the summary of TEAEs by SOC, preferred term and maximum intensity, if a subject 
experiences more than 1 episode of a particular coded adverse event, the subject will be counted 
only once within period by the maximum intensity of the episode (preferred term). Similarly, if a 
subject has more than 1 adverse event within an SOC, the subject will be counted only once by 
the maximum intensity in that SOC. Adverse events with missing severity will be classified as 
having the highest severity.
TEAEs classified in the eCRF as possibly or probably related to the study medication will also 
be summarized by preferred term and SOC. If a subject experiences more than 1 episode of a 
particular coded adverse event, the subject will be counted only once by the most related report 
for the preferred term. Similarly, if a subject has more than 1 adverse event within an SOC, the 
subject will be counted only once by the most related report in that SOC. Adverse events with 
missing relationship will be classified as having the highest relationship to study drug.
The following summaries will be presented separately for the open-label period and double-blind 
period:

Overview of TEAEs during the study - number and percentage of subjects, number of events.

TEAEs by SOC and preferred term - number and percentage of subjects, number of events.

TEAEs by SOC and preferred term by sex (male and female) - number and percentage of 
subjects, number of events.

TEAEs by SOC and preferred term by age group (≤median, >median) - number and 
percentage of subjects, number of events.

TEAEs by SOC - number and percentage of subjects.

TEAEs by preferred term - number and percentage of subjects.

Most frequent (at least 5% in any treatment group) TEAEs by preferred term - number and 
percentage of subjects.

Most frequent (at least 5% in any treatment group) non-serious TEAEs by preferred term -
number and percentage of subjects.

Intensity of TEAEs by SOC and preferred term - number and percentage of subjects.

Drug-related TEAEs by SOC and preferred term - number and percentage of subjects, 
number of events.

TEAEs leading to study discontinuation by SOC and preferred term - number and percentage 
of subjects, number of events.

Treatment-emergent SAEs by SOC and preferred term - number and percentage of subjects, 
number of events.
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SOCs will be sorted by alphabetical order. Within an SOC, adverse events will be sorted in 
descending order of total number of subjects with the preferred term among all the treatment 
groups.
For treatment emergent nausea, the following summaries will be presented additionally for open-
label period and double-blind period:

Duration of nausea during study.

Time to first nausea.
Figures for point prevalence of nausea (occurring during the double-blind period – core phase) 
relative to number of subjects at risk for female, male, and overall will be presented.
All adverse events will be listed by treatment, study center, subject number, and onset date of the 
adverse event. The listing will contain: subject identifier, age, sex, body weight, race, adverse 
event (preferred term and reported term), SOC, onset date, end date or whether the event was 
ongoing, duration, frequency, intensity (mild, moderate or severe), action taken concerning study 
drug (change in concomitant medication, change in IMP, or subject withdrawal), causality to 
study drug (not related, possibly related, or probably related), the outcome (recovered, 
recovering, not recovered, recovered with sequelae, or death), whether the adverse event was an 
SAE and whether the event was an adverse event of special interest (AESI).
Special listings for TEAEs leading to study discontinuation, SAEs, deaths, duration of nausea 
during the study, and AEs of special interest will also be presented.
6.12.2 Clinical Laboratory Evaluations
The following clinical laboratory parameters will be summarized:

Serum chemistry including blood urea nitrogen (BUN), sodium, alkaline phosphatase, 
potassium, calcium, creatinine, glucose, alanine aminotransferase (ALT), aspartate 
aminotransferase (AST), total bilirubin, albumin, creatine kinase, total protein and GGT

Lipids including cholesterol total, triglycerides, high-density lipoprotein (HDL), and 
low-density lipoprotein (LDL).

Hematology including white blood cell count (WBC), red blood cell count (RBC), 
hemoglobin, hematocrit, platelets, neutrophils, eosinophils, basophils, lymphocytes, and 
monocytes.

Urinalysis including pH, protein, glucose, occult blood and specific gravity.
For each laboratory parameter, the following will be displayed for each scheduled time point
(each visit and end of study).

Summary statistics (n, mean, SD, median, minimum, and maximum) by treatment group and 
overall for the actual values and change from Baseline values.

Shift tables for the change from Baseline to each post-baseline time point will be presented. 
For these tables each subject will be categorized as low, normal, or high for the baseline 
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Statistical Analysis Plan, Final
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value, and low, normal, or high for each post-Baseline time point, according to the central 
laboratory reference ranges. The number of subjects in each of the combinations of shifts will 
be presented.
Potentially clinically significant (PCS) laboratory values, as defined in Appendix B, will be 
summarized by treatment group and overall. The number and percentage of subjects with PCS 
values observed post-Baseline in each of the applicable laboratory parameters will be presented.
A listing of all laboratory data will be provided. Laboratory data outside of the normal reference 
range will be flagged on the listing along with values meeting PCS criteria. The listing will also 
include the age (at consent) and sex of the subject. Listings of PCS laboratory values will also be 
presented. Thyroid stimulating hormone, Free T4 (c), γ-Glutamyl transferase, and direct bilirubin 
will not be summarized but will be listed.
When lab values are recorded in the form of “<x” or “>y”, “x” will be used for “<x” and “y” will 
be used for “>y” in the summary tables. However, these values will be displayed as is when the 
individual subject data listings are presented.
Summaries and listings of laboratory data will be presented, as appropriate, in System 
International (SI) and conventional units.
6.12.3 Liver Function Tests
Liver function tests will be summarized by visit. Number and percentage of subjects who meet 
liver function test criteria will be summarized by treatment.
6.12.4 Vital Signs and Weight
Vital signs and weight at scheduled visits and their changes from Baseline will be summarized 
overall for the open-label period and summarized for each treatment group and overall using 
descriptive statistics by visit and end of study for the double blind period, separately. The 
number and percentage of subjects with at least one post-Baseline PCS vital sign value during 
the double-blind treatment period will be presented for each variable over all visits. A listing of 
PCS vital signs values will also be presented.
The criteria for identification of PCS vital signs values are given in Appendix C.
6.12.5 Physical Examinations
All physical examination findings will be listed by treatment, study center and subject number. 
The following variables will be listed: subject identifier, age, sex, study visit, visit date, whether 
there was any clinically significant findings.
6.12.6 12-Lead ECGs
ECG variables at scheduled visits and their changes from Baseline will be summarized for each 
treatment group and overall using descriptive statistics by study visit and end of study. A shift 
table for the investigator’s ECG interpretation will provide the number of subjects in each of the 
appropriate categories (Normal, Abnormal but not clinically significant, or Abnormal and 
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Statistical Analysis Plan, Final
12 June 2019
clinically significant) at the scheduled visit relative to the Baseline status. The number and 
percentage of subjects with at least one post-Baseline PCS ECG value during the double-blind 
treatment period will be presented for each variable over all visits. A listing of PCS ECG values 
will also be presented.
The criteria for identification of PCS ECG values are given in Appendix D.
6.12.7 Pregnancy Test
For females, pregnancy test results will be listed by treatment, study center, and subject number.
6.13
Interim Analysis
A blinded summary of ongoing data will be conducted when approximately 75% of the planned 
subjects are enrolled. See Appendix E for details about these calculations that will be used to 
verify the numbers of subjects to be enrolled.
6.14
Changes in the Statistical Analysis Plan From the Protocol Analysis Plan
Analysis of covariance (ANCOVA) model (using LOCF and OC) for MADRS, CGI-S and CGI-I 
won’t be performed.
Comparability of treatment groups using analysis of variance for continuous variables and using 
Cochran-Mantel-Haenszel test for discrete variables for demographics and baseline 
characteristics won’t be performed.
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Statistical Analysis Plan, Final
12 June 2019
7.0
REFERENCES
1. A Randomized, Double-Blind, Placebo-Controlled, Phase 4, Relapse Prevention Study 
Evaluating the Efficacy and Safety of Vortioxetine (5, 10 and 20 mg) in Adults With Major 
Depressive Disorder. Takeda Global Research & Development Centre Inc., Protocol 
No. Lu AA21004_402 Incorporating Amendment No.1, dated 25 September 2015.
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Statistical Analysis Plan, Final
12 June 2019
CONFIDENTIAL
Appendix A
Schedule of Study Procedures
Screening
Baseline I
Open-Label Treatment
Baseline II/
Random-
ization(a)
Withdrawal
(b)
Follow-up
Phone call
Study Day/End of Week:
Day 0
2
4
6
8
10
12
14
16
Visit Windows (Days relative to
Baseline I)
Days -21 to -5
0
±3
±3
±3
±3
±3
±3
±3
±3
±3
±5
Visit Number:
1
2
3
4
5
6
7
8
9
10
Screening/Baseline Procedures and Assessments
Informed consent
X
CTSdatabase
X(c)
Demographics, medical history,
height
X
Concurrent medical conditions
X
X (d)
Relevant psychiatric and social history
X
Diagnostic Validation
X
MINI
X
Diagnosis (DSM-IV-TR)
X
Medication history
X
Inclusion/exclusion criteria
X
X (d)
Eligibility verification
X
Stabilization criteria (e)
X
X
X
X
X
Randomization criteria
X
Safety Assessments
PTE assessment (f)
X
X
Vital signs
X
X
X
X
X
X
X
X
X
X
X
Body weight
X
X
X
X
X
Physical examination
X
X
X
X
Concomitant medications
X
X
X
X
X
X
X
X
X
X
X
X (g)
Clinical laboratory tests (h)
X
X
X
X
X
Urine drug screening
X
X
X
ECG
X
X
X
X
Pregnancy test (hCG) (i)
X
X
X
X
X
X
X
X
X
X
X
Pregnancy avoidance counseling
X
X
X
X
X
X
X
X
X
X
X
C-SSRS
X
X
X
X
X
X
X
X
X
X
X
AE assessment
X
X
X
X
X
X
X
X
X
X (j)
Footnotes are on last table page.
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Statistical Analysis Plan, Final
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CONFIDENTIAL
Appendix A
Schedule of Study Procedures (continued)
Screening
Baseline I
Open-Label Treatment
Baseline II/
Random-
ization(a)
Withdrawal
(b)
Follow-up
Phone Call
Study Day/End of Week:
Day 0
2
4
6
8
10
12
14
16
Visit Windows (Days relative to
Baseline I)
Days -21 to
-5
0
±3
±3
±3
±3
±3
±3
±3
±3
±3
±5
Visit Number:
1
2
3
4
5
6
7
8
9
10
Efficacy Assessments
MADRS (SIGMA if site chooses to
use)
X
X
X
X
X
X
X
X
X
X
X
CGI-S
X
X
X
X
X
X
X
X
X
X
CGI-I
X
X
X
X
X
X
X
X
X
Other Blood Sampling
PK sampling for study medication
X
X
X
Pharmacogenomic sampling (h)
X
X
X
X
Clinical Supplies
Call IWRS for Subject ID/Medication
ID/subject status
X
X
X
X
X
X
X
X
X
X
X
Dispense study medication
X (k)
X
X
X
X
X
X
X
X
Study medication return/
accountability/compliance
X
X
X
X
X
X
X
X
X
(a) Subjects who meet all randomization criteria please follow schedule of procedures for week 16 on schedule of study procedures for double-blind treatment period.
(b) All subjects who withdraw early, except those who withdraw their consent and refuse further contact, are to attend a withdrawal visit as soon as possible.
(c) Obtain subject authorization, enter subject into the CTS database.
(d) Update at Baseline I.
(e) Subjects must meet response criteria from Week 8 through Week 16 and remission criteria at Weeks 14 and 16.
(f) Pretreatment event assessment occurs from the date of Screening up to the first dose of study medication.
(g) Assess post-treatment adverse events, ongoing adverse events and/or serious adverse events, and record all ongoing medications for subjects who withdraw early.
(h) Fasting labs must be performed at Baseline I and Baseline II (randomization).
(i) Serum hCG for female subject of childbearing potential at Screening, Baseline II (randomization) and Withdrawal. Urine stick pregnancy tests to be done at all other visits.
(j) Two whole blood samples (3 mL per sample) will be collected predose on Day 0 for DNA isolation. Two whole blood samples (2.5 mL per sample) will be collected for RNA 
isolation at each time point at predose on Day 0 and weeks 8, and 16 and any early withdrawal visit during open-label. The sample for pharmacogenomics may be drawn at the 
earliest visit after Baseline I, if missed at visit 2 (Baseline I). Pharmacogenomics sample collection is optional for subjects. A separate Informed Consent Form will be obtained.
(k) The subjects will be instructed to take the first dose of study medication on the morning after enrollment (Baseline I).
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Statistical Analysis Plan, Final
12 June 2019
CONFIDENTIAL
Appendix A
Schedule of Study Procedures (continued)
Baseline II/
Random-
ization
Double-Blind Treatment (a)
Completion/
Withdrawal (b)
Follow-up Phone 
Call
End of Week:
16
18
20
24
28
32
36
40
44
48
52
Visit Windows (Days relative to
Baseline II)
+3
±3
±5
±5
±5
±5
±5
±5
±5
±5
±5
Visit Number:
10
11
12
13
14
15
16
17
18
19
Baseline II Procedures and Assessments
Randomization criteria
X (c)
Safety Assessments
Vital signs
X
X
X
X
X
X
X
X
X
X
Body weight
X
X
X
X
X
X
Physical examination
X
X
X
X
Concomitant medications
X
X
X
X
X
X
X
X
X
X
X(d)
Clinical laboratory tests (e)
X
X
X
X
Urine drug screening
X
ECG
X
X
X
Pregnancy test (hCG) (f)
X
X
X
X
X
X
X
X
X
X
Pregnancy avoidance counseling
X
X
X
X
X
X
X
X
X
X
C-SSRS
X
X
X
X
X
X
X
X
X
X
AE assessment
X
X
X
X
X
X
X
X
X
X
X(d)
Relapse Checklist
X
X
X
X
X
X
X
X
X
Efficacy Asssessments
MADRS (SIGMA if site chooses to
use)
X
X
X
X
X
X
X
X
X
X
CGI-S
X
X
X
X
X
X
X
X
X
X
CGI-I
X
X
Other Blood Sampling
PK sampling for study medication
(g)
X
X
X
Pharmacogenonic sampling (h)
X
X
Clinical Supplies
Call IWRS for Subject
ID/Medication ID/subject status
X
X
X
X
X
X
X
X
X
X
Footnotes are on last table page.
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Statistical Analysis Plan, Final
12 June 2019
CONFIDENTIAL
Appendix A
Schedule of Study Procedures (continued)
Baseline II/
Random-
ization
Double-Blind Treatment (a)
Completion/
Withdrawal (b)
Follow-up 
Phone Call
End of Week:
16
18
20
24
28
32
36
40
44
48
52
Visit Windows (Days relative to 
Baseline II)
+3
±3
±5
±5
±5
±5
±5
±5
±5
±5
±5
Visit Number:
10
11
12
13
14
15
16
17
18
19
Dispense study medication
X (i)
X
X
X
X
X
X
X
X
Study medication return/
accountability/compliance
X
X
X
X
X
X
X
X
X
X
(a) Subject well-being phone calls should be made every 2 weeks post Week 20 through week 46.
(b) All subjects who withdraw early, except those who withdraw their consent and refuse further contact, are to attend a withdrawal visit as soon as possible.
(c) Confirm stabilization criteria of response and remission are met and there are no major protocol violations.
(d) Assess post-treatment adverse events, ongoing adverse events and/or serious adverse events, and record all ongoing medications for subjects who withdraw early.
(e) Fasting labs to be performed at Baseline II/ Randomization and Completion/Withdrawal.
(f) Serum hCG for female subject of childbearing potential at Baseline II/Randomization and Completion/Withdrawal. Urine stick pregnancy tests to be done at all other visits.
(g) PK sampling must be taken prior to first dose of double-blind study medication.
(h) Only samples for RNA to be collected at Week 16 and Week 48 for those subjects who consented to pharmacogenomic sampling.
(i) The subjects will be instructed to take the first dose of study medication on the morning after randomization.
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Statistical Analysis Plan, Final
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Appendix B
Criteria for Identification of Potentially Clinically Significant Laboratory 
Values
Parameter
Unit Type
Unit (a)
PCS Definition
Hematology
Hemoglobin
SI
g/L
Low: 0.9LLN
conventional
g/dL
Low: 0.9LLN
Erythrocytes (red cell count [RBC])
SI
10^12/L
High: 1.1ULN, Low: 0.9LLN
conventional
10^12/L
High: 1.1ULN, Low: 0.9LLN
Hematocrit (packed cell volume)
SI
Fraction of 1.00
Low: 0.9LLN
conventional
%
Low: 0.9LLN
Total leucocytes (white cell count 
[WBC])
SI
10^9/L
High: 16, Low: 2.8
conventional
10^9/L
High: 16, Low: 2.8
Neutrophils
SI
10^9/L
High: ≥15, Low: 1.4
conventional
10^9/L
High: ≥15, Low: 1.4
Lymphocytes
SI
10^9/L
High: 7.0, Low: 0.6
conventional
10^9/L
High: 7.0, Low: 0.6
Monocytes
SI
10^9/L
High: 2.5
conventional
10^9/L
High: 2.5
Eosinophils
SI
10^9/L
High: 0.6
conventional
10^9/L
High: 0.6
Basophils
SI
10^9/L
High: 0.6
conventional
10^9/L
High: 0.6
Thrombocytes (platelet count)
SI
10^9/L
High: 700, Low: 75
conventional
10^9/L
High: 700, Low: 75
Blood Chemistry
Total bilirubin
SI
mol/L
High: 34.2
conventional
mg/dL
High: 2.0
Alkaline phosphatase
both
U/L
High: 3ULN
Aspartate aminotransferase (AST)
both
U/L
High: 3ULN
Alanine aminotransferase (ALT)
both
U/L
High: 3ULN
Albumin
SI
g/L
Low: 25
conventional
g/dL
Low: 2.5
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Statistical Analysis Plan, Final
12 June 2019
Appendix B Criteria for Identification of Potentially Clinically Significant Laboratory 
Values (continued)
Parameter
Unit Type
Unit (a)
PCS Definition
Sodium
SI
mmol/L
High: 155, Low: 125
conventional
mEq/L
High: 155, Low: 125
Potassium
SI
mmol/L
High: 5.5, Low: 3.0
conventional
mEq/L
High: 5.5, Low: 3.0
Calcium (total)
SI
mmol/L
High: 3.0, Low: 1.75
conventional
mg/dL
High: 12.0, Low: 7.0
Creatinine
SI
mol/L
High: 175
conventional
mg/dL
High: 2.0
Creatine phosphokinase (CPK)
both
U/L
High: 2ULN
Glucose (non-fasting)
SI
mmol/L
High: 13.9, Low: 2.8
conventional
mg/dL
High: 250, Low: 50
Cholesterol (total)
SI
mmol/L
High: 7.8
conventional
mg/dL
High: 302
Triglycerides
SI
mmol/L
High: 3.40
conventional
mg/dL
High: 301
High density lipoproteins (HDL) 
cholesterol
SI
mmol/L
Low: <0.9
conventional
mg/dL
Low: <35
Low density lipoproteins (LDL) 
cholesterol
SI
mmol/L
High: 5.0
conventional
mg/dL
High: 193
Total protein
SI
g/L
High: >1.2ULN, Low: <0.8LLN
conventional
g/dL
High: >1.2ULN, Low: <0.8LLN
Blood Urea Nitrogen
SI
mmol/L
High: >10.7
conventional
mg/dL
High: >30
γ-Glutamyl Transferase
both
U/L
High: >3ULN
Urinalysis
Glucose
N/A
Protein
N/A
Occult Blood
N/A
Pregnancy
N/A
(a) Systeme International (SI) units, conventional units and conversion factors were obtained from Laposata, 
Michael. SI Unit Conversion Guide. Boston: NEJM Books, 1992.
LLN=lower limit of normal range; N/A=not applicable; PCS=potentially clinically significant; ULN=upper limit of 
normal range.
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Statistical Analysis Plan, Final
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Appendix C
Criteria for Identification of Potentially Clinically Significant Vital Signs
Parameter
Unit
PCS Definition (a)
Systolic BP
mmHg
≥180 mmHg and an increase of ≥20 mmHg or 
≤90 mmHg and a decrease of ≥20 mmHg
Diastolic BP
mmHg
≥105 mmHg and an increase of ≥15 mmHg or 
≤50 mmHg and a decrease of ≥15 mmHg
Pulse
bpm
≥120 bpm and an increase of ≥15 bpm or 
≤50 bpm and a decrease of ≥15 bpm
Body Temperature
oC
Low: <35.6
High: >37.7
oF
Low: <96.1
High: >99.9
Weight
kg
Change of 7% body weight
BP=Blood pressure.
(a) PCS criteria are applied to postbaseline values and changes relative to Baseline values, as appropriate.
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Statistical Analysis Plan, Final
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Appendix D
Criteria for Identification of Potentially Clinically Significant 12-Lead ECG 
Parameters
Parameter
Unit
PCS Definition (a)
Heart rate
beats per minute
(≤50 bpm and Change ≤-15 bpm) or
(≥120 bpm and Change ≥15 bpm)
RR
msec
(<500 msec and Change ≤-200 msec) or
(>1200 msec and Change ≥200 msec)
PR
msec
<120 msec or ≥250 msec
QRS
msec
<40 msec or >150 msec
QT
msec
<280 msec or >500 msec
QTcB
msec
<340 msec or >500 msec or 
Change <-60 msec or Change >60 msec
QTcF
msec
<340 msec or >500 msec or 
Change <-60 msec or Change >60 msec
(a) PCS criteria are applied to postbaseline values and changes relative to Baseline values, as appropriate.
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Statistical Analysis Plan, Final
12 June 2019
Appendix E
Relapse Events Prediction for Possible Sample Size Adjustment
Proper
f Use
CCI


Lu AA21004_402
Page 39 of 39
Statistical Analysis Plan, Final
12 June 2019
Property of Takeda: For non-commercial use 
f Use
CCI


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