Conditions: Major Depressive Disorder
Keywords: Drug Therapy
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 123
Healthy volunteers: no

Brief summary:
The purpose of this study is to determine the effectiveness of treatment with vortioxetine on participant goal achievement after a change in antidepressant medication for the treatment of major depressive disorder (MDD).

Detailed description:
The drug being tested in this study is called Vortioxetine. Vortioxetine is being tested to treat depression in people who have major depressive disorder. This study will look at effectiveness of treatment with vortioxetine in participant's goal achievement for the treatment of major depressive disorder.

The study enrolled 123 patients. Participants will receive:

• Vortioxetine 10 to 20 mg

All participants will be asked to take one tablet at the same time each day throughout the study. The participants will receive a starting dose of 10 mg. The dose may be up-titrated to 20 mg. The dose may then be decreased by 5 mg based on participant's response and tolerability to higher dose as judged by the Investigator.

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

Arms:
arm 1: Vortioxetine 10 mg, tablets, orally, once daily followed by a dose adjustment to a maximum of 20 mg, tablets, orally, once daily up to 12 weeks. The dose may be decreased by 5 mg based on participant's response and tolerability as judged by the investigator.

Interventions: intervention 1: Vortioxetine
Intervention descriptions: intervention 1: Vortioxetine tablet

Protocol document:
Prot_001.pdf: 
This may include, but is not limited to, redaction of the following: 


•
Title: An Open-Label, Single-Arm, Multicenter, Prospective, Phase 4, Interventional, Flexible 
Dose Study to Evaluate the Effectiveness of Vortioxetine on Goal Achievement After a Change 
in Antidepressant Medication for the Treatment of Subjects With Major Depressive Disorder
NCT Number: NCT02972632
Protocol Approve Date: 18 August 2017
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 or company confidential information. 
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.


1.0 TITLE PAGE
TAKEDA PHARMACEUTICALS
PROTOCOL AMENDMENT
An Open-Label, Single-Arm, Multicenter, Prospective, Phase 4, Interventional, Flexible 
Dose Study to Evaluate the Effectiveness of Vortioxetine on Goal Achievement After a 
Change in Antidepressant Medication for the Treatment of Subjects With Major Depressive 
Disorder
Goal Achievement After a Change to Vortioxetine in Adults With Major Depressive 
Disorder 
Sponsor:
Takeda Development Center Americas, Inc.
One Takeda Parkway
Deerfield, IL 60015
Study Number:
Vortioxetine-4003
IND Number:
76,307
EudraCT Number:
N/A
Compound:
Vortioxetine
Date:
18 August 2017
Version/Amendment 
Number:
1
Amendment History: 
Date
Amendment Number
Amendment Type 
Region
30 August 2016
Initial version
Not applicable
Global
18 August 2017
01
Substantial
Global
CONFIDENTIAL PROPERTY OF TAKEDA
This document is a confidential communication of Takeda. Acceptance of this document constitutes the agreement by 
the recipient that no information contained herein will be published or disclosed without written authorization from 
Takeda except to the extent necessary to obtain informed consent from those persons to whom the drug may be 
administered. Furthermore, the information is only meant for review and compliance by the recipient, his or her staff, 
and applicable institutional review committee and regulatory agencies to enable conduct of the study.


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1.0
ADMINISTRATIVE INFORMATION
1.1
Contacts
A separate contact information list will be provided to each site.
Takeda Development Center (TDC) 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
US Contact
Serious adverse event and pregnancy 
reporting
Medical Monitor
(medical advice on protocol and study 
drug)
Responsible Medical Officer 
(carries overall responsibility for the 
conduct of the study)
Personal Protected Data


Personal Protected Data


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1.3
Protocol Amendment #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 responsible medical 
officer contact, clarify Exclusion Criteria #4, 
, add assessment of GAS 
approach, and revise interim analysis criteria. Other minor changes in procedures are proposed. 
Minor grammatical and editorial changes are included for clarification purposes only. Full details 
regarding the text changes are given in Appendix E, including detailed rationale. The following is 
a summary of the changes made in the amendment:

Updated responsible medical officer and protocol signatories.
–
Justification: Change in personnel.

Clarified Exclusion Criteria #4.
–
Justification: The intent of this criteria is to exclude subjects who currently have significant 
risk of suicide (according to the investigator’s clinical judgment), or made an actual suicide 
attempt in the previous 6 months prior to Screening, or within the same time frame have 
had active suicidal ideation with some intent to act (item 4 of CSSRS) or have had active 
suicidal ideation with specific plan and intent to act (item 5 of CSSRS). A lifetime “yes” 
answer to items 4 and 5 will not exclude the subject, but a “yes” answer to past 6 months 
for items 4 and 5 is exclusionary.

Added assessment of Clinician and subject satisfaction with the GAS approach as a method for 
establishing treatment goals, evaluating progress towards treatment goals, and improving 
communication between clinicians and patients.
–
Justification: To assess the GAS approach in clinical practice and to guide future GAS 
work.

.
–

Clarified Interim Analysis criteria.
–
Justification: Analysis will be conducted once 60 subjects have completed, but enrollment 
will not be stopped. 

Correction of inconsistencies within the original protocol.
Company Confidential 
Information
Company Confidential 
Information
Company Confidential Information


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CONFIDENTIAL
INVESTIGATOR AGREEMENT 
I confirm that I have read and that I understand this protocol, the Investigator’s Brochure, 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 Council for Harmonisation, E6(R2) 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 study site agreement.

Responsibilities of the Investigator. (Appendix B)
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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TABLE OF CONTENTS
1.0
ADMINISTRATIVE INFORMATION ...........................................................................2
1.1
Contacts.....................................................................................................................2
1.2
Approval....................................................................................................................3
1.3
Protocol Amendment #1 Summary of Changes ..........................................................4
2.0
STUDY SUMMARY ....................................................................................................11
3.0
STUDY REFERENCE INFORMATION ......................................................................16
3.1
Study-Related Responsibilities.................................................................................16
3.2
Principal Investigator/Coordinating Investigator ......................................................16
3.3
List of Abbreviations ...............................................................................................17
3.4
Corporate Identification...........................................................................................18
4.0
INTRODUCTION.........................................................................................................19
4.1
Background .............................................................................................................19
4.1.1
Vortioxetine.......................................................................................................19
4.1.1.1 Nonclinical Background...............................................................................19
4.1.1.2 Clinical Background.....................................................................................19
4.2
Rationale for the Proposed Study.............................................................................20
5.0
STUDY OBJECTIVES AND ENDPOINTS..................................................................21
5.1
Objectives................................................................................................................21
5.1.1
Primary Objective ..............................................................................................21
5.1.2
Secondary Objectives.........................................................................................21
5.1.3
Additional Objectives.........................................................................................21
5.2
Endpoints.................................................................................................................21
5.2.1
Primary Endpoint...............................................................................................21
5.2.2
Secondary Endpoints..........................................................................................21
5.2.3
Additional Endpoints .........................................................................................22
5.3
Safety Assessments..................................................................................................22
6.0
STUDY DESIGN AND DESCRIPTION.......................................................................23
6.1
Study Design ...........................................................................................................23
6.2
Justification for Study Design, Dose, and Endpoints ................................................25
6.2.1
Study Design......................................................................................................25
6.2.2
Dose ..................................................................................................................25
6.2.3
Endpoints...........................................................................................................26
6.3
Premature Termination or Suspension of Study or Study Site...................................26


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6.3.1
Criteria for Premature Termination or Suspension of the Study..........................26
6.3.2
Criteria for Premature Termination or Suspension of Study Sites .......................26
6.3.3
Procedures for Premature Termination or Suspension of the Study or the 
Participation of Study Site(s)..............................................................................26
7.0
SELECTION AND DISCONTINUATION/WITHDRAWAL OF SUBJECTS..............27
7.1
Inclusion Criteria .....................................................................................................27
7.2
Exclusion Criteria ....................................................................................................27
7.3
Excluded Medications..............................................................................................29
7.4
Criteria for Discontinuation or Withdrawal of a Subject...........................................31
7.5
Procedures for Discontinuation or Withdrawal of a Subject......................................32
8.0
CLINICAL STUDY MATERIAL MANAGEMENT.....................................................33
8.1
Study Drug and Materials ........................................................................................33
8.1.1
Dosage Form, Manufacturing, Packaging, and Labeling.....................................33
8.1.1.1 Study drug....................................................................................................33
8.1.1.2 Sponsor-Supplied Drug ................................................................................33
8.1.2
Storage...............................................................................................................33
8.1.3
Dose and Regimen .............................................................................................34
8.1.4
Overdose............................................................................................................34
8.2
Study Drug Assignment and Dispensing Procedures ................................................34
8.3
Accountability and Destruction of Sponsor-Supplied Drugs.....................................35
9.0
STUDY PLAN ..............................................................................................................37
9.1
Study Procedures.....................................................................................................37
9.1.1
Informed Consent Procedure..............................................................................37
9.1.1.1 Pharmacogenomic Informed Consent Procedure...........................................37
9.1.2
Demographics, Medical History, Medication History, and Disease History 
Procedure...........................................................................................................37
9.1.3
Weight and Height .............................................................................................37
9.1.4
Vital Sign Procedure..........................................................................................38
9.1.5
Documentation of Concomitant Medications......................................................38
9.1.6
Documentation of Concurrent Medical Conditions.............................................38
9.1.7
Effectiveness Patient Reported Outcomes and Health Economic Outcome 
Research (HEOR) Assessments..........................................................................38
9.1.7.1 GAS.............................................................................................................38
9.1.7.2 PHQ-9..........................................................................................................39
9.1.7.3 PDQ-D.........................................................................................................39


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9.1.7.4 Clinical Global Impression Scales ................................................................39
9.1.7.5
...........................................................................................................40
9.1.7.6
.....................................................................................................40
9.1.7.7 C-SSRS........................................................................................................40
9.1.7.8 Q-LES-Q......................................................................................................40
9.1.7.9 WHO-5 ........................................................................................................41
9.1.7.10
...................................................................................................41
9.1.7.11
...................................................................................................41
9.1.7.12
Order of Assessments .............................................................................41
9.1.8
Procedures for Clinical Laboratory Samples.......................................................41
9.1.9
Contraception and Pregnancy Avoidance Procedure...........................................43
9.1.9.1 Definitions and Procedures for Contraception and Pregnancy Avoidance .....43
9.1.10 Pregnancy ..........................................................................................................45
9.1.11 PGx Sample Collection......................................................................................46
9.1.12 Documentation of Screen Failure .......................................................................46
9.1.13 Documentation of Study Entrance......................................................................47
9.2
Monitoring Subject Treatment Compliance..............................................................47
9.3
Schedule of Observations and Procedures................................................................47
9.3.1
Screening Visit 1 (Days -21 to -1)......................................................................47
9.3.2
Study Entrance/Baseline Visit 2 (Day 1) ............................................................48
9.3.3
Open-Label Treatment Visits 3 and 5: Week 2 (Day 15), and Week 6 (Day 43) .48
9.3.4
Telephone Visit 4 and 6: Week 4 (Day 29) and Week 9 (Day 64).......................48
9.3.5
Final Visit or Early Termination.........................................................................48
9.3.6
Unscheduled Visit..............................................................................................48
9.3.7
Safety Follow-up Phone Call (Week 16 or Early Termination)...........................49
9.3.8
Poststudy Care ...................................................................................................49
9.4
PGx Sample Retention and Destruction ...................................................................49
10.0
PRETREATMENT EVENTS AND ADVERSE EVENTS ............................................50
10.1
Definitions...............................................................................................................50
10.1.1 PTEs..................................................................................................................50
10.1.2 AEs....................................................................................................................50
10.1.3 Additional Points to Consider for PTEs and AEs................................................50
10.1.4 SAEs..................................................................................................................52
10.1.5 AEs of Special Interest.......................................................................................53
10.1.5.1
Skin and Allergic Type Reactions...........................................................53
Compa
ny 
Confide
ntial 
Informat
ion
Company 
Confidential 
Information
Company 
Confidenti
al 
Informatio
n
Company 
Confidenti
al 
Informatio
n


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10.1.5.2
Liver Injury ............................................................................................54
10.1.5.3
Overdose ................................................................................................54
10.1.6 Intensity of PTEs and AEs .................................................................................54
10.1.7 Causality of AEs ................................................................................................55
10.1.8 Relationship to Study Procedures.......................................................................55
10.1.9 Start Date...........................................................................................................55
10.1.10
Stop Date .....................................................................................................55
10.1.11
Frequency ....................................................................................................55
10.1.12
Action Concerning Study Drug ....................................................................55
10.1.13
Outcome.......................................................................................................56
10.2
Procedures...............................................................................................................56
10.2.1 Collection and Reporting of AEs........................................................................56
10.2.1.1
PTE and AE Collection Period ...............................................................56
10.2.1.2
PTE and AE Reporting ...........................................................................56
10.2.1.3
AEs of Special Interest ...........................................................................57
10.2.2 Collection and Reporting of SAEs......................................................................58
10.2.3 Reporting of Abnormal LFTs.............................................................................58
10.3
Follow-up of SAEs ..................................................................................................59
10.3.1 Safety Reporting to Investigators, IRBs or IECs, and Regulatory Authorities.....59
11.0
STUDY-SPECIFIC COMMITTEES .............................................................................60
12.0
DATA HANDLING AND RECORDKEEPING............................................................61
12.1
eCRFs......................................................................................................................61
12.2
Record Retention .....................................................................................................61
13.0
STATISTICAL METHODS..........................................................................................63
13.1
Statistical and Analytical Plans ................................................................................63
13.1.1 Analysis Sets......................................................................................................63
13.1.2 Analysis of Demographics and Other Baseline Characteristics ...........................63
13.1.3 Effectiveness Analysis .......................................................................................63
13.1.4 Safety Analysis ..................................................................................................64
13.2
Interim Analysis and Criteria for Early Termination ................................................64
13.3
Determination of Sample Size..................................................................................64
14.0
QUALITY CONTROL AND QUALITY ASSURANCE...............................................65
14.1
Study-Site Monitoring Visits ...................................................................................65
14.2
Protocol Deviations..................................................................................................65
14.3
Quality Assurance Audits and Regulatory Agency Inspections ................................66


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15.0
ETHICAL ASPECTS OF THE STUDY........................................................................67
15.1
IRB and/or IEC Approval ........................................................................................67
15.2
Subject Information, Informed Consent, and Subject Authorization .........................68
15.3
Subject Confidentiality ............................................................................................69
15.4
Publication, Disclosure, and Clinical Trial Registration Policy.................................69
15.4.1 Publication and Disclosure.................................................................................69
15.4.2 Clinical Trial Registration..................................................................................70
15.4.3 Clinical Trial Results Disclosure ........................................................................70
15.5
Insurance and Compensation for Injury....................................................................70
16.0
REFERENCES..............................................................................................................71
LIST OF IN-TEXT TABLES
Table 7.a
Excluded Medications and Treatments ...............................................................30
Table 9.a
Clinical Laboratory Tests...................................................................................42
Table 10.a
Takeda Medically Significant AE List................................................................53
LIST OF IN-TEXT FIGURES
Figure 6.a
Schematic of Study Design ................................................................................25
LIST OF APPENDICES
Appendix A
Schedule of Study Procedures............................................................................74
Appendix B
Responsibilities of the Investigator.....................................................................77
Appendix C
Elements of the Subject Informed Consent.........................................................79
Appendix D
Investigator Consent to Use of Personal Information..........................................82
Appendix E
Detailed Description of Amendments to Text.....................................................83


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2.0
STUDY SUMMARY
Name of Sponsor:
Takeda Development Center Americas, Inc.
Compound:
Vortioxetine
Title of Protocol: An Open-Label, Single-Arm, 
Multicenter, Prospective, Phase 4, Interventional, Flexible 
Dose Study to Evaluate the Effectiveness of Vortioxetine on 
Goal Achievement After a Change in Antidepressant 
Medication for the Treatment of Subjects With Major 
Depressive Disorder
IND No.: 76,307
EudraCT No.:
Not applicable
Study Number: Vortioxetine-4003
Phase: 4
Study Design:
This study is a nonrandomized, open-label, single-arm, multicenter, prospective, phase 4, interventional, flexible-dose 
study to determine the effectiveness of treatment with vortioxetine (per Trintellix United States [US] package insert) 
on subject goal achievement after a change in antidepressant medication for the treatment of major depressive disorder 
(MDD).
Potential subjects with MDD who are changing from another antidepressant to vortioxetine per routine care will be 
eligible to enroll. Subjects will determine treatment goals with their clinicians utilizing the Goal Attainment Scale 
(GAS) Methodology adapted for an MDD population. The subject and clinician will work to establish 3 goals at 
Baseline. One goal will be determined based on the subject’s self-defined objectives. Two goals will be selected from 
the following predefined categories representing MDD residual symptoms, antidepressant side effects, and common 
reasons for changing antidepressant medication, including but not limited to: 
MDD Domains
Psychological
Motivation
Emotional
Physical/ 
Functional
Cognition
Predefined Goal 
Categories:
Depressed 
mood Anxious 
mood
Lack of 
motivation
Low self 
esteem 
Anhedonia
Fatigue
Insomnia 
Muscle tension 
Sexual 
dysfunction
Weight gain
Problems 
concentrating
Short-term memory 
problems
Difficulty staying 
focused 
Difficulty paying 
attention
Problems thinking 
clearly
This study is comprised of up to a 3-week Screening Period, followed by a 12-week Treatment Period and a 4-week 
Safety Follow-up Period. Study visits will occur at Baseline (Day 1), and Weeks 2, 4 (Telephone), 6, 9 (Telephone), 
and 12. This study will enroll approximately 120 subjects and will be conducted at approximately 25 sites in the 
United States. The investigator or the investigator’s designee will access the Interactive Response Technology (IxRT) 
at Screening to obtain the subject study number. At the Baseline Visit, if the subject has satisfied all of the inclusion 
criteria and none of the exclusion criteria for enrollment, the subject will be enrolled using the IxRT. Subjects will be 
instructed on when to take the first dose of study drug. The dosing (both initial and adjustments) will be determined by 
the investigator or designee as per routine clinical practice and per approved Trintellix labeling.
Subjects who discontinue or who are withdrawn prior to study completion will come to the site for an Early 
Termination Visit as soon as possible and will be contacted for a Safety Follow-up 4 weeks after the last dose of study 
medication. 
A futility analysis may be performed at an interim analysis after approximately 60 subjects have completed the study.


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Primary Objective:
To determine the effectiveness of treatment with vortioxetine on subject goal achievement after a change in
antidepressant medication for the treatment of MDD.
Secondary Objectives:
To determine the effectiveness of treatment with vortioxetine on depressive symptoms/outcomes, clinical global 
impression, cognitive impairment, and quality of life in subjects with MDD.
Exploratory/Additional Objectives:

To determine the effectiveness of treatment with vortioxetine on cognitive performance and functionality in 
subjects with MDD.

To determine the effectiveness of treatment with vortioxetine on work performance in subjects with MDD.

To determine the effectiveness of treatment with vortioxetine on general health status and well being in subjects 
with MDD.

To assess health care utilization and the safety and tolerability of vortioxetine in subjects with MDD.
Safety Assessments
Safety and tolerability of vortioxetine will also be evaluated using the following general assessments:

Adverse events (AEs).

AEs leading to discontinuation.

Weight.

Columbia-Suicide Severity Rating Scale (C-SSRS). 
Subject Population: Men and women between the ages of 18 and 65 years, inclusive, with a primary diagnosis of 
MDD, who have previously been treated within 6 weeks of Screening or are currently being treated for a major 
depressive episode (MDE) with an approved antidepressant for 6 weeks or longer at an adequate dose. The change in 
antidepressant medication will be based on the investigator’s judgment in collaboration with the subject’s level of 
dissatisfaction with their current or recent antidepressant treatment (ie, residual mood symptoms, intolerable side 
effects). Subjects currently on an antidepressant at Screening will be discontinued in a manner that is consistent with 
labeling recommendations and conventional medical practice. Enrollment caps may be implemented throughout the 
course of the study based on the patient reported outcome (ie, Patient Health Questionnaire-9 [PHQ-9] and Perceived 
Deficits Questionnaire-Depression [PDQ-D]) scores at Baseline.
Number of Subjects:
Approximately 120 subjects
Number of Sites: 
Estimated total: approximately 25 sites in the United 
States
Dose Levels:
Vortioxetine 5, 10, or 20 mg once daily as per Trintellix US 
Package Insert
Route of Administration:
Oral
Duration of Treatment:
12-week Treatment Period 
Period of Evaluation:
Up to 19 weeks including a 3-week Screening Period 
(maximum of 21 days), a 12-week Treatment Period 
and 4-week Safety Follow-up Period


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Main Criteria for Inclusion:
1.
Subject is a man or woman between 18 to 65 years, inclusive, and able to read and understand English.
2.
Subject suffers from MDD as the primary psychiatric diagnosis. 
3.
Subject has been or is currently being treated with an approved antidepressant (monotherapy) for 6 weeks or 
longer at an adequate therapeutic dose as per investigator judgment.
4.
The antidepressant treatment must be ongoing or have been discontinued within 6 weeks of Screening. Subjects 
currently on an antidepressant at Screening will be discontinued in a manner that is consistent with labeling 
recommendations and conventional medical practice.
5.
Subject is considered appropriate for a change in antidepressant medication based on investigator judgment in 
collaboration with the subject.
6.
Subject has scores on PHQ-9 ≥5 and Clinical Global Impression Scale-Severity (CGI-S) ≥4 at Screening.
7.
In the opinion of the investigator, the subject is capable of understanding and complying with protocol 
requirements.
8.
The subject signs and dates a written, informed consent form and any required privacy authorization prior to the 
initiation of any study procedures. 
9.
A female subject of childbearing potential who is sexually active 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 of 
study drug.
Main Criteria for Exclusion:
Any subject who meets any of the following criteria will not qualify for entry into the study: 
1.
Subject has any current psychiatric disorder other than MDD (except nonprimary concurrent anxiety), other 
illness or condition which may compromise the study in the opinion of the investigator.
2.
The subject has discontinued prior antidepressant treatment greater than 6 weeks prior to Screening.
3.
Subject is considered to be at imminent risk for hospitalization due to severe depression in the opinion of the 
investigator. Recent hospitalization due to MDD within 3 months prior to Screening is also exclusionary.
4.
The subject has a significant risk of suicide according to the investigator’s clinical judgment or has made an actual 
suicide attempt in the previous 6 months prior to Screening or scores “yes” on Items 4 or 5 in the past 6 months on 
the Suicidal Ideation section of the C-SSRS. 
5.
The subject is considered to be treatment resistant, defined as patients with MDD who have not responded to 2 or 
more different antidepressants monotherapy studies of adequate dose and duration (6 weeks or longer) in their 
current episode. History of only responding to either combination or augmentation therapy in previous MDEs is 
also considered evidence of treatment resistant depression. 
6.
The subject has received any investigational compound within 30 days prior to Screening or 5 half-lives prior to 
Screening, whichever is longer.
7.
The subject has previously or is currently participating in this study or another vortioxetine or LuAA21004 study. 
8.
The subject has participated in 2 or more interventional clinical studies in the year prior to Screening, or has 
participated in a clinical study for a psychiatric condition that is exclusionary per this protocol.
9.
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). 
10. The subject has 1 or more of the following:
a)
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, mental retardation, organic mental disorders, or mental disorders 
due to a general medical condition as defined in The Diagnostic and Statistical Manual of Mental Disorders, 


Vortioxetine
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Fifth Edition as determined by the investigator.
b)
Current diagnosis or history of alcohol or other substance abuse or dependence (excluding nicotine or 
caffeine). The subject must have a negative urine drug screen at Screening and Baseline, this includes 
benzodiazepines and opiates (including oxycodone) for which there is no prescription.
c)
Presence or history of a clinically significant neurological disorder (including epilepsy) as determined by the 
investigator.
d)
Neurodegenerative disorder (Alzheimer disease, Parkinson disease, multiple sclerosis, Huntington disease, 
etc).
11. The subject has received vortioxetine previously, or the subject has a history of hypersensitivity or allergies to 
vortioxetine or any of its components.
12. Subjects receiving or who have started receiving formal cognitive or behavioral therapy, systematic 
psychotherapy within 30 days from screening or plan to initiate such therapy during the study (marital therapy, 
and bereavement counseling are allowed). 
13. The subject is receiving excluded medications or it is anticipated that the subject will require treatment with at 
least 1 of the disallowed concomitant medications during the study.
14. The subject has a clinically significant unstable illness as determined by the investigator.
15. The subject has a known history of acute narrow-angle glaucoma or is at risk of acute narrow-angle glaucoma.
16. The subject has a known unstable thyroid disorder or a thyroid-stimulating hormone value outside the normal 
range based on medical history that is deemed clinically significant by the investigator. 
17. The subject has clinically significant abnormal vital signs as determined by the investigator.
18. The subject has active hepatitis B or a known history of hepatitis C virus.
19. The subject has a known history of human immunodeficiency virus infection.
20. The subject has a history of gastric bypass.
21. The subject has a disease or takes medication that, in the opinion of the investigator, could interfere with the 
assessments of safety, tolerability, or effectiveness.
22. 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.
Main Criteria for Evaluation and Analyses:

Primary endpoint: Proportion of subjects who achieve their identified goals as demonstrated by an outcome 
GAS Score of >50 at Week 12.

Secondary endpoints:
–
Mean change from Baseline in total GAS Score at Week 6 and Week 12.
–
Change from Baseline in depression severity as measured by the PHQ-9 Score at Week 6 and 12. 
–
Change from Baseline in perceived cognitive deficits and cognitive function as measured by the PDQ-D at 
Weeks 6 and 12. 
–
Change from Baseline in Quality of Life Enjoyment and Satisfaction Scale (Q-LES-Q) Score at Week 12.
–
Change from Baseline in 5-item World Health Organization Well-Being Index (WHO-5) Score at Week 12. 
–
Change from Baseline in CGI-S at Week 12. 
–
Clinical Global Impression Scale-Improvement (CGI-I) Score at Week 12.


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
Exploratory/Additional:
Safety Assessments
Safety and tolerability of vortioxetine will also be evaluated using the following general assessments:

AEs.

AEs leading to discontinuation.

Weight.

C-SSRS. 
Statistical Considerations:
Primary Effectiveness Analysis:

The primary effectiveness variable will be the proportion of subjects who changed to treatment with vortioxetine 
who achieve their identified goals at Week 12 (ie, GAS Score ≥50). The GAS yields a norm-based score 
(standardized to a mean of 50, SD of 10) at Baseline and for each follow-up; the change from score at Baseline 
will be summarized. The responder rate at Week 12 and the change in total GAS Score at each follow-up will be 
assessed by the 95% CI. Similar analyses will be done for other endpoints.
Secondary Effectiveness Analysis:
A paired t-test will be applied to the change from Baseline for the GAS Score. For the secondary endpoints of 
outcomes measures on PHQ-9, PDQ-D, Q-LES-Q Score, WHO-5 Score, and CGI-S total scores and changes from 
Baseline will be summarized by each time point of Baseline and Week 12 with paired t-tests. Tests of significance will 
be 2-tailed with alpha level at 0.05. CGI-I Scores will be summarized at Week 12 using descriptive statistics.
Additional analyses: 
Safety Analysis:
The safety data will be summarized. AEs will be reported throughout the study. The definition of treatment-emergent 
AEs will be provided in the statistical analysis plan. AEs will be coded using the Medical Dictionary for Regulatory 
Activities and will be summarized by system organ class and preferred term. AEs 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.
Sample Size Justification:
As no formal hypothesis testing is performed for the primary endpoint, the purpose of sample size estimation is to 
determine the adequate sample size needed to provide a precise estimate for the response rate (GAS Score ≥50) with 
95% CIs. Conservatively estimating that 50% of subjects will be responders (GAS ≥50) and that 100 subjects will 
complete the study, CIs will be ±0.098 around the point estimate (proportion of responders).
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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. The vendors identified in the template for specific study-related 
activities will perform these activities in full or in partnership with the sponsor.
3.2
Principal Investigator/Coordinating 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 drug, 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
5-HT
serotonin
AE
adverse event
ALT
alanine aminotransferase
AST
aspartate aminotransferase
CGI-I
Clinical Global Impression Scale-Improvement
CGI-S
Clinical Global Impression Scale-Severity
CRO
contract research organization
C-SSRS
Columbia-Suicide Severity Rating Scale
DRESS
drug reaction with eosinophilia and systemic symptoms
DSM-5
Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition
ECG
electrocardiogram
eCRF
electronic case report form
FAS
full analysis set
FSH
follicle-stimulating hormone
GAS
Goal Attainment Scale
GCP
Good Clinical Practice
hCG
human chorionic gonadotropin
ICH
International Council for Harmonisation
ID
identification
IEC
independent ethics committee
INR
international normalized ratio
IRB
institutional review board
IxRT
Interactive Response Technology
LFT
liver function tests
MDD
major depressive disorder
MDE
major depressive episode
MedDRA
Medical Dictionary for Regulatory Activities
PGx
pharmacogenomics
PDQ-D
Perceived Deficits Questionnaire-Depression
PHQ-9
Patient Health Questionnaire-9
PPS
per protocol set
PTE
pretreatment event
Q-LES-Q 
Quality of Life and Enjoyment and Satisfaction Questionnaire
QD
once daily
SAE
serious adverse event
SJS
Stevens-Johnson syndrome
Comp
any 
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ential 
Inform
ation
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STAR*D
Sequenced Treatment Alternatives to Relieve Depression
SUSAR
suspected unexpected serious adverse reaction
TEN
toxic epidermal necrolysis
UDS
urine drug screen
ULN
upper limit of normal
US
United States
WAIS-IV
Wechsler Adult Intelligence Scale Fourth Edition
WHO
World Health Organization
WHO-5
5-item World Health Organization Well-Being Index
3.4
Corporate Identification 
TDC Japan
Takeda Development Center Japan
TDC Asia
Takeda Development Center Asia, Pte Ltd
TDC Europe
Takeda Development Centre Europe Ltd.
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
According to the World Health Organization (WHO), depression 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) [1]. Specifically in the United States, the prevalence of major 
depressive disorder (MDD) is currently 8.3%, with expectations that prevalence will increase over 
the coming years [2]. 
The economic consequences of MDD are significant. The ability of depressed patients or their 
caregivers to work and make productive contributions to the economy is reduced, while the use of 
treatment and support services is increased. 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 [1].
Depression is recurrent in 75% to 80% of patients and becomes chronic (lasts 2 years or longer) in 
15% to 20% of depressed patients [3,4]. Furthermore, depression can lead to substantial 
impairments in an individual’s ability to take care of his/her everyday responsibilities and 
approximately 15% of depressed patients commit suicide [5]. Unfortunately, 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 continued treatment to 
prevent relapse and recurrence are both major priorities for management of recurrent MDD [6,7].
4.1.1
Vortioxetine
Vortioxetine 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]. The following sections briefly review the results from nonclinical 
and clinical studies of vortioxetine.
4.1.1.1
Nonclinical Background
Preclinical studies concluded that vortioxetine had a difference pharmacological profile than other 
selective serotonin reuptake inhibitors) and serotonin noradrenaline reuptake inhibitors. Key 
pharmacological differences include its interaction with 5-HT targets which modulates multiple 
neurotransmitter systems, the reversal of cognitive deficits in various animal models, and its 
effects in depression models [10]. 
4.1.1.2
Clinical Background
During the clinical development program, the efficacy, safety, and tolerability of vortioxetine in
MDD subjects was evaluated at doses from 1 to 20 mg once daily (QD) in short-term efficacy 


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studies of 6 to 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 6- to 8-week randomized, double-blind, placebo-controlled, fixed-dose 
studies (including 1 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 [11].
4.2
Rationale for the Proposed Study
After unsuccessful treatment with initial antidepressant monotherapy treatment of adequate dose 
and duration, clinical practice guidelines for the treatment of MDD recommend changing the 
antidepressant. This treatment change may be necessary when patients respond poorly to 
antidepressant medication or exhibit intolerable side effects. 
Data from clinical studies regarding switching antidepressant medication rates is minimal and the 
rationale for the switch varies across studies [12]. Claims databases have shown switching rates for 
antidepressants have ranged from 2.78% to 13.7% [13,14]. The results of switching, in particular, 
multiple switching can lead to suboptimal outcomes for patients. Results of the Sequenced 
Treatment Alternatives to Relieve Depression (STAR*D) study showed that as the number of 
switches increased the burden of illness, including relapse rates, also increased. Relapse may 
trigger a pharmacologic switch [15]. Switching antidepressant agents has been shown to increase 
treatment costs and can be burdensome to the patient, so it is important to get the patient to the 
optimal treatment as early as possible in the therapeutic pathway [16]. 
A process used in the mental health arena to assess and capture the patient’s experience regarding 
whether or not treatment is successful is Goal Attainment Scaling; however, this approach has not 
been widely used in assessing the treatment of depression or in clinical research. Goal Attainment 
Scaling was first developed by Thomas Kiresuk and Robert Sherman in response to the wide 
variety of evaluation models regarding mental illness and treatment [17]. Goal Attainment Scaling 
has long been used in clinical care and program assessment to evaluate patient progress and ensure 
alignment between clinician and patient on treatment objectives [17]. Through a structured 
interview and goal setting between clinician and patient, the Goal Attainment Scaling process 
captures meaningful aspects of a person’s progress throughout the course of treatment that are 
challenging to assess using available standardized measures. The aim of this study is to 
demonstrate that the process of Goal Attainment Scaling in MDD in conjunction with a change in 
antidepressant treatment to vortioxetine is effective in achieving outcomes that matter to patients, 
improves quality of life and is an effective strategy to treat MDD when the current or recent
antidepressant is not adequate.


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5.0
STUDY OBJECTIVES AND ENDPOINTS
5.1
Objectives
5.1.1
Primary Objective 
To determine the effectiveness of treatment with vortioxetine on subject goal achievement after a 
change in antidepressant medication for the treatment of MDD.
5.1.2
Secondary Objectives 
To determine the effectiveness of treatment with vortioxetine on depressive symptoms/outcomes, 
clinical global impression, cognitive impairment, and quality of life in subjects with MDD.
5.1.3
Additional Objectives 

To determine the effectiveness of treatment with vortioxetine on cognitive performance and 
functionality in subjects with MDD.

To determine the effectiveness of treatment with vortioxetine on work performance in subjects 
with MDD.

To determine the effectiveness of treatment with vortioxetine on general health status and well 
being in subjects with MDD.

To assess health care utilization and the safety and tolerability of vortioxetine in subjects with 
MDD.
5.2
Endpoints
5.2.1
Primary Endpoint
The primary endpoint is to estimate the proportion of subjects who achieve their identified goals as 
demonstrated by an outcome Goal Attainment Scale (GAS) Score of >50 at Week 12.
5.2.2
Secondary Endpoints 
The secondary endpoints are:

Mean change from Baseline in total GAS Score at Week 6 and Week 12.

Change from Baseline in depression severity as measured by the Patient Health Questionnaire 
(PHQ-9) Score at Weeks 6 and 12.

Change from Baseline in perceived cognitive deficits and cognitive function as measured by 
the Perceived Deficits Questionnaire-Depression (PDQ-D) at Weeks 6 and 12.

Change from Baseline in Quality of Life Enjoyment and Satisfaction Scale (Q-LES-Q) Score 
at Week 12.


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
Change from Baseline in 5-item World Health Organization Well-Being Index (WHO-5) 
Score at Week 12.

Change from Baseline in Clinical Global Impression Scale Severity (CGI-S) at Week 12.

Clinical Global Impression Scale-Improvement (CGI-I) Score at Week 12.
5.2.3
Additional Endpoints 
The exploratory/additional endpoints include:
5.3
Safety Assessments
Safety and tolerability of vortioxetine will also be evaluated using the following general
assessments:

Adverse events (AEs).

AEs leading to discontinuation.

Weight.

Columbia-Suicide Severity Rating Scale (C-SSRS). 
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6.0
STUDY DESIGN AND DESCRIPTION
6.1
Study Design
This study is an open-label, single-arm, multicenter, prospective, phase 4, interventional, 
flexible-dose study (as per the Trintellix US package insert) to determine the effectiveness of 
treatment with vortioxetine on subject goal achievement after a change in antidepressant
medication for the treatment of MDD.
This study is comprised of a 3-week Screening Period (maximum 21 days), to be followed by a 
12-week Treatment Period and a 4-week Safety Follow-up Period. Study visits will occur at 
Baseline (Day 1), and Weeks 2, 4 (Telephone), 6, 9 (Telephone), and 12. This study will enroll 
approximately 120 subjects and will be conducted at approximately 25 sites in the United States. 
This study will enroll men and women between the ages of 18 and 65, inclusive, with a primary 
diagnosis of MDD, who have previously been treated within 6 weeks of Screening or are currently 
being treated for a major depressive episode (MDE) with an approved antidepressant for 6 weeks 
or longer at an adequate dose. Subjects who are dissatisfied with their current or recent 
antidepressant and are interested in a change in antidepressant treatment will be eligible for 
Screening.
The change in antidepressant medication will be based on the investigator’s judgment in 
collaboration with the subject’s level of dissatisfaction with their current or recent antidepressant 
treatment (ie, residual mood symptoms, intolerable side effects). Subjects also need to be eligible 
per the Trintellix United States (US) package insert and sign and date a written, informed consent 
form and any required privacy authorization prior to the initiation of any study procedures.
The investigator or the investigator’s designee will access the Interactive Response Technology 
(IxRT) at Screening to obtain the subject study number. At the Baseline Visit, if the subject has 
satisfied all of the inclusion criteria and none of the exclusion criteria for enrollment, the subject 
will be enrolled using the IxRT. Subjects will be instructed on when to take the first dose of study 
drug. The dosing (both initial and adjustments) will be determined by investigator or designee as 
per routine clinical practice and per approved Trintellix labeling. Subjects will determine 
treatment goals with their clinicians using the GAS adapted for an MDD population. The subject 
and clinician will work to establish 3 goals at Baseline. One goal will be determined based on the 
subject’s self-defined objectives. Two goals will be selected from the following predefined 
categories representing MDD residual symptoms, antidepressant side effects, and common 
reasons for a change in antidepressant medication, including but not limited to: 


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MDD Domains
Psychological
Motivation
Emotional
Physical/ 
Functional
Cognition
Predefined goal 
categories:
-Depressed mood 
-Anxious mood
-Lack of 
motivation
-Low self 
esteem
-Anhedonia
-Fatigue
-Insomnia 
-Muscle 
tension 
-Sexual 
dysfunction
-Weight gain
-Problems 
concentrating
-Short term memory 
problems
-Difficulty staying 
focused 
-Difficulty paying 
attention
-Problems thinking 
clearly
A prepopulated list of categories will be provided in the structured guidance for goal assessment, 
including behavioral examples describing goals and observable benchmarks to help clinicians set 
the appropriate goals with subjects. Goals will be set at Baseline/Visit 1. Progress will be evaluated 
at the Week 6 visit. At the Final Visit the goals will be assessed based on levels of achievement on
a 5-point scale. Investigators will be trained on goal setting/goal assessment and monitored for 
ability in key domains of goal setting (eg, attainability of goals, use of observable objectives and 
benchmarks, equidistance of scaling, general level of difficulty, goal differentiation, and overall 
quality).
A safety follow-up phone call will be made 4 weeks after completion of the 12 weeks of treatment. 
Subjects who discontinue or who are withdrawn prior to study completion will come to the site for 
an Early Termination Visit as soon as possible and will be contacted for a safety follow-up 4 weeks 
after the last dose of study medication. 
Enrollment caps may be implemented throughout the course of the study based on the patient 
reported outcome (ie, PHQ-9 and PDQ-D) scores at Baseline.
A futility analysis may be performed at an interim analysis after approximately 60 subjects have 
completed the study.


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Figure 6.a
Schematic of Study Design
(a) Recommended starting dosage is 10 mg/day as ideal dosage. Dosage may be decreased to 5 mg/day at discretion of 
the investigator or designee.
(b) If all screening activities are completed and the subject meets the eligibility criteria the Screening and Baseline 
Visits can be combined into 1 visit.
(c) Subjects currently on an antidepressant at Screening will be discontinued in a manner that is consistent with 
labeling recommendations and conventional medical practice prior to Baseline.
6.2
Justification for Study Design, Dose, and Endpoints
6.2.1
Study Design
Clinical practice guidelines for the treatment of MDD suggest changing the antidepressant after 
unsuccessful treatment with the initial antidepressant. An open-label, single-arm, multicenter, 
prospective, phase 4, interventional, flexible-dose study was chosen because this type of study 
design is designed to better understand if vortioxetine is effective in achieving outcomes that 
matter to subjects, improves quality of life, and is an effective strategy to treat MDD when current 
antidepressant is not adequate. The single-arm design allows each subject to serve as their own 
“control” in comparing baseline assessments with those performed at Week 12.
6.2.2
Dose
In the current study, dosing (both initial and adjustments) will be determined by the treating 
physician as per routine clinical practice. The recommended starting dose is 10 mg administered 
orally once daily without regard to meals as per the Trintellix US Package Insert. Dosage should 
then be increased to 20 mg/day, as tolerated, because higher doses demonstrated better treatment 
effects in studies conducted in the United States. The effectiveness and safety of doses above 
20 mg/day have not been evaluated in controlled clinical studies. A dose decrease down to 
5 mg/day may be considered for subjects who do not tolerate higher doses. The dose can be 
reduced/increased/interrupted due to a particular AE.


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6.2.3
Endpoints
The GAS, adapted for MDD, is being used in this study. As this is an adaptation of an existing 
instrument, the results will provide novel outcome data for the goal attainment literature. 
Therefore, secondary endpoint assessments with validated instruments will provide additional 
confirmation of the effectiveness of vortioxetine in treating MDD when current antidepressant 
treatment is not adequate. 
The following outcome measures will be used for secondary and exploratory endpoints as they are 
frequently used to assess clinical response: PHQ-9, PDQ-D, Q-LES-Q, WHO-5, CGI-S, CGI-I, 
and
 
. 
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 (C-SSRS) 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.
6.3
Premature Termination or Suspension of Study or Study Site
6.3.1
Criteria for Premature Termination or Suspension of the Study
The study will be completed as planned unless 1 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 effectiveness of vortioxetine that 
indicates a change in the known risk/benefit profile for the product, such that the risk 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.

Study meets predefined rule for futility.
6.3.2
Criteria for Premature Termination or Suspension of Study 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 Study 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 a study 
site, a study-specific procedure for early termination or suspension will be provided by the 
sponsor; the procedure will be followed by applicable study 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.
7.1
Inclusion Criteria
Subject eligibility is determined according to the following criteria prior to entry into the study: 
1. Subject is a man or woman, aged 18 to 65 years, inclusive, and able to read and understand 
English.
2. Subject suffers from MDD as the primary psychiatric diagnosis.
3. Subject has been or is currently being treated with an approved antidepressant (monotherapy)
for 6 weeks or longer at an adequate therapeutic dose. Subjects currently on an antidepressant 
at Screening will be discontinued in a manner that is consistent with labeling recommendations 
and conventional medical practice.
4. The subject’s antidepressant treatment must be on-going at time of Screening, or have been 
discontinued within the 6 weeks prior to Screening.
5. Subject is considered appropriate for a change in antidepressant medication based on 
investigator judgment in collaboration with the subject.
6. Subject has scores on PHQ-9 ≥5 and CGI-S ≥4.
7. A female subject of childbearing potential who is sexually active 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 of study drug.
8. In the opinion of the investigator, the subject is capable of understanding and complying with 
protocol requirements.
9. The subject signs and dates a written, informed consent form and any required privacy 
authorization prior to the initiation of any study procedures. 
*Definitions and acceptable methods of contraception and Contraception and 
Pregnancy Avoidance Procedure are defined in Section 9.1.9.Pregnancy reporting 
responsibilities are defined in Section 9.1.10.
7.2
Exclusion Criteria
Any subject who meets any of the following criteria will not qualify for entry into the study: 
1. Subject has any current psychiatric disorder other than MDD (except nonprimary concurrent 
anxiety), other illness or condition which may compromise the study in the opinion of the 
investigator.
2. Subject has discontinued prior antidepressant treatment greater than 6 weeks from Screening.


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3. Subject is considered to be at imminent risk for hospitalization due to severe depression in the 
opinion of the investigator. Recent hospitalization due to MDD within 3 months prior to 
Screening is exclusionary also.
4. The subject has a significant risk of suicide according to the investigator’s clinical judgment or 
has made an actual suicide attempt in the previous 6 months prior to Screening or scores “yes” 
on items 4 or 5 in the past 6 months on the Suicidal Ideation section of the C-SSRS. 
5. The subject is considered to be treatment resistant, defined as patients with MDD who have not 
responded to 2 or more separate different antidepressant monotherapy trials of adequate dose 
and duration (6 weeks or longer) in their current episode. History of only responding to 
combination or augmentation therapy in previous MDEs is also considered evidence of 
treatment resistant depression. 
6. The subject has received any investigational compound within 30 days prior to Screening or 
5 half-lives prior to Screening, whichever is longer.
7. The subject has previously or is currently participating in this study or another vortioxetine or 
LuAA21004 study. 
8. The subject has participated in 2 or more interventional clinical studies in the year prior to 
Screening, or has participated in a clinical study for a psychiatric condition that is exclusionary 
per this protocol.
9. 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). 
10. The subject has 1 or more of the following:
a) 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, mental 
retardation, organic mental disorders, or mental disorders due to a general medical 
condition as defined in Diagnostic and Statistical Manual of Mental Disorders (DSM-5) as 
determined by the investigator.
b) Current diagnosis or history of alcohol or other substance abuse or dependence (excluding 
nicotine or caffeine). The subjects must have a negative urine drug screen (UDS) at 
Screening and Baseline, this includes benzodiazepines and opiates (including oxycodone) 
for which there is no prescription (see Table 9.a).
c) Presence or history of a clinically significant neurological disorder (including epilepsy) as 
determined by the investigator.
d) Neurodegenerative disorder (Alzheimer disease, Parkinson disease, multiple sclerosis, 
Huntington disease, etc).


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11. The subject has received vortioxetine previously, or the subject has a history of 
hypersensitivity or allergies to vortioxetine or any of its components.
12. Subjects receiving or who have started receiving formal cognitive or behavioral therapy, 
systematic psychotherapy within 30 days from Screening or plan to initiate such therapy 
during the study (marital therapy, and bereavement counseling are allowed). 
13. The subject is receiving excluded medications (see Section 7.3) or it is anticipated that the 
subject will require treatment with 1 or more of the disallowed concomitant medications 
during the study.
14. The subject has a clinically significant unstable illness as determined by the investigator.
15. The subject has a known history of acute narrow-angle glaucoma or is at risk of acute 
narrow-angle glaucoma.
16. The subject has a known unstable thyroid disorder or a thyroid-stimulating hormone value 
outside the normal range based on medical history that is deemed clinically significant by the 
investigator. 
17. The subject has clinically significant abnormal vital signs as determined by the investigator.
18. The subject has active hepatitis B or a known history of hepatitis C virus.
19. The subject has a known history of human immunodeficiency virus infection.
20. The subject has a history of gastric bypass.
21. The subject has a disease or takes medication that, in the opinion of the investigator, could 
interfere with the assessments of safety, tolerability, or effectiveness.
22. 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.
7.3
Excluded Medications
A list of excluded medications and treatments is provided in Table 7.a. Use of any investigational 
medications will be prohibited within 4 weeks 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.


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Table 7.a
Excluded Medications and Treatments
Drug Class
Disallowed (X) During the Study 
[sections without (X) indicate no restriction]
Chronic Use
Episodic Use
Comments or Exceptions
Any investigational drug
X
X
Analgesics
Narcotic analgesics
X
X
Episodic use of opiates is allowed provided 
the subject has a valid prescription. 
NSAIDs 
X
Chronic use disallowed during the study
Antiarrhythmics (Class Ia, III, and Ic (including 
flecainide and propafenone)
Quinidine NOT allowed
Antibiotics
Rifampin NOT allowed
Antithrombotic agents (including low dose 
aspirin) and anticoagulants
X
X
Anticonvulsants 
X
X
Anticonvulsants not allowed within 6 weeks 
prior to Screening. 
Antidepressants 
X
X
Lifetime use of MAOIs and RIMAs is 
excluded
Antimigraine agents – triptans, dopamine 
antagonists
X
Antinauseants, antiemetics (including dopamine 
antagonists)
X
Only phosphoric acid and bismuth 
preparations are allowed
Antineoplastics
X
X
Antiobesity agents
X
X
Antiobesity agents excluded within 24 
weeks prior to Screening.
Antipsychotics
X
X
Low dose allowed for sleep
Anxiolytics (including benzodiazepines)
X
Episodic use is allowed in the context of the 
current MDE as long the primary diagnosis 
continues to be MDD and not an anxiety 
disorder.
Cough/cold agents 
X
This includes among others: 
dextromethorphan, phenylephrine, 
pseudoephedrine, low dose doxylamine 
contained in cough & cold agents
Dextromethorphan frequent intermittent use 
should be monitored carefully
Herbal remedies, which are psychoactive (eg, St. 
Johns Wort, kava kava, valerian, ginkgo biloba, 
melatonin)
X
X
Mood stabilizers
X
X
Lifetime use is excluded
Muscle relaxants, centrally acting agents
X
X
Sedatives/hypnotics 
X
Episodic use is allowed in the context of the 
current MDE. 
Psychotropic agents not otherwise specified 
(including psychostimulants, tryptophan, 
melatonin and dopamine agonists)
X
X
Not allowed within 6 weeks prior to 
Screening.
MAOI=monoamine oxidase inhibitor, NSAID=nonsteroidal anti-inflammatory drug, RIMA=reversible inhibitor of monoamine 
oxidase A.


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7.4
Criteria for Discontinuation or Withdrawal of a Subject
The primary reason for discontinuation or withdrawal of the subject from the study or study drug
should be recorded in the case report form (eCRF) using the following categories. For screen 
failure subjects, refer to Section 9.1.12.
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 drug 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), if the following circumstances occur at any time during study drug 
treatment:
– Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) >8× upper limit 
of normal (ULN), or
– ALT or AST >5×ULN and persists for more than 2 weeks, or
– 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 drug 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. 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 in the subject’s source 
documents.
4. 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. The specific reasons for discontinuation from study drug will be collected for both the 
subject and as determined by the investigator.
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 should not be recorded in the “voluntary withdrawal” category). Similarly, lack of 
effectiveness should not be recorded in the “voluntary withdrawal” category.
5. Study termination. The sponsor, IRB, IEC, or regulatory agency terminates the study.


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6. 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 9.1.10.
7. Lack of effectiveness. The investigator has determined that the subject is not benefiting from 
study treatment; and, continued participation would pose an unacceptable risk to the subject.
7.5
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 7.4. 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 
Early Termination Visit. Discontinued or withdrawn subjects will not be replaced.


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8.0
CLINICAL STUDY MATERIAL MANAGEMENT
This section contains information regarding all medications 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 study material.
8.1
Study Drug and Materials
8.1.1
Dosage Form, Manufacturing, Packaging, and Labeling
In this protocol, the term study drug refers to all or any of the drugs defined below.

Commercial vortioxetine tablets in strengths of 5, 10, and 20 mg.
Vortioxetine 5, 10, and 20 mg tablets are manufactured by Takeda or H. Lundbeck A/S, Valby,
Denmark. 
8.1.1.1
Study drug
Vortioxetine is a compound developed by Takeda and H. Lundbeck A/S as an antidepressant and 
treatment for MDD. Vortioxetine was approved in September 2013 and commercialized in the 
United States in January 2014. Vortioxetine belongs to a new chemical class of psychotropics, the 
bis-arylsulfonyl amines, which possess unique properties compared with currently known 
psychotropics. This class of compounds is structurally different from all currently known 
psychotropics.
Vortioxetine is commercially formulated as immediate-release tablets intended for oral 
administration. 
The study drug will be packaged in high-density polyethylene bottle with child resistant closures. 
Each bottle contains 28 daily doses plus 7 extra tablets for a total of 35 tablets per bottle to be 
dispensed at the visits indicated in the Schedule of the Study Procedures (Appendix A). The 
subjects will be required to take 1 tablet orally, at the same time of day, preferably in the morning, 
or as directed. The study drug will be labeled with a single label and dispensed as open-label for 
the 12-week treatment phase. The study drug will be identifiable by a unique identification (ID) 
number that will be assigned by an IxRT. Each bottle will be labeled with pertinent study 
information.
8.1.1.2
Sponsor-Supplied Drug
Sponsor-supplied drugs referenced in other sections of the protocol include the following: 
Commercial vortioxetine tablets in strengths of 5, 10, and 20 mg.
8.1.2
Storage
Study medication should be stored at 25°C (77°F); excursions permitted to 15°C-30°C 
(59°F-86○F). 


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Vortioxetine 5, 10, and 20 mg must be kept in an appropriate, limited-access, secure place until it 
is used or returned to the sponsor or designee for destruction. Vortioxetine 5, 10, and 20 mg 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 dosing (both initial and adjustments) will be determined by the investigator or designee as per 
routine clinical practice and per approved labeling.
8.1.4
Overdose
An overdose is defined as a known deliberate or accidental administration of study drug, to or by a 
study subject, at a dose above that which is assigned to that individual subject according to the 
treating physician per routine standard of care.
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. AEs 
associated with an overdose will be documented on AE eCRF(s) according to Section 10.0.
Serious adverse events (SAEs) associated with overdose should be reported according to the 
procedure outlined in Section 10.2.2.
In the event of deliberate or accidental 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 measures 
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 drug overdose. 
8.2
Study Drug Assignment and Dispensing Procedures
Subjects will be assigned to begin the study drug with the recommended starting dose of
10 mg/day administered orally once daily without regard to meals. Based on the discretion of the 
investigator or designee, dosage should then be increased to 20 mg/day, as tolerated, because 
higher doses demonstrated better treatment effects in trials conducted in the United States. A dose
decrease down to 5 mg/day may be considered for subjects who do not tolerate higher doses. The 
investigator (or designee) may increase or decrease the dosage at any time. Dose adjustments 
should occur during regularly scheduled visits, or subjects should return for an unscheduled visit.
The investigator or the investigator’s designee will access the IxRT at Screening to obtain the 
subject study number. The investigator or the investigator’s designee will utilize the IxRT to enroll
the subject into the study. During this contact, the investigator or designee will provide the 
necessary subject-identifying information, including the subject number assigned at Screening. 


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The medication ID number of the sponsor-supplied drug to be dispensed will then be provided by 
the IxRT. If sponsor-supplied drug (vortioxetine) is lost or damaged, the site can request a 
replacement from IxRT (refer to IxRT manual provided separately). At subsequent 
drug-dispensing visits, the investigator or designee will again access IxRT to request additional 
sponsor-supplied drug for a subject. The medication ID number of the study drug to be dispensed 
will be provided by the IxRT. 
8.3
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 QD), 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 IxRT. 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/job 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 IxRT will include all required information as a separate entry for each subject to whom 
sponsor-supplied drug is dispensed.
The investigator or designee must record the current inventory of all sponsor-supplied drug 
(vortioxetine) on a sponsor-approved drug accountability log. 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, expiry and/or retest date, date and amount 


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dispensed including initials, seal, or signature of the person dispensing the drug, and the date and 
amount returned to the site by the subject, including the initials, seal, or signature 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. 
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.
In the event of expiry date extension of sponsor-supplied drug already at the study site, 
sponsor-supplied drugs may be relabeled with the new expiry date at that site. In such cases, 
Takeda or its designee will prepare additional labels, certificates of analyses, and all necessary 
documentation for completion of the procedure at the sites. The on-site pharmacist (site designee) 
will immediately return unused study drugs to the sponsor.


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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/that informed consent is explained. This subject number 
will be used throughout the study.
9.1.1.1
Pharmacogenomic Informed Consent Procedure
A separate informed consent form pertaining to collection, storage, and analysis of the sample 
must be obtained prior to collecting a blood sample for pharmacogenomic (PGx) research for this 
study. The provision of consent to collect and analyze the PGx sample is independent of consent to 
the other aspects of the study.
9.1.2
Demographics, Medical History, Medication History, and Disease History Procedure
Demographic information to be obtained will include date of birth, sex, Hispanic ethnicity, race as 
described by the subject, height, weight, and smoking status of the subject at Screening. 
Medical and psychiatric history to be obtained will include determining whether the subject has 
any significant conditions or diseases relevant to the disease under study that resolved at or prior to 
signing of informed consent, specifically psychiatric and MDD history as well as previous 
treatments related to psychiatric and MDD history. Ongoing conditions are considered concurrent 
medical conditions (see Section 9.1.6). Additionally, the factors for determining a 
change/discontinuation from the prior antidepressant as assessed by the subject and by the 
investigator will be collected.
Medication history information to be obtained includes any medication relevant to eligibility 
criteria and effectiveness/safety evaluation stopped at or within 12 weeks prior to signing of 
informed consent.
9.1.3
Weight and Height 
A subject should have weight measured while wearing indoor clothing and with shoes off during 
Screening, Baseline, and Week 12. Height, measured at Screening only, is recorded in centimeters 
without decimal places. Weight is collected in kilograms with 1 decimal place. 


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9.1.4
Vital Sign Procedure
Vital signs will include blood pressure, pulse, and temperature will be performed during the
Screening Visit.
9.1.5
Documentation of Concomitant Medications
Concomitant medication is any drug given in addition to the sponsor-supplied drug. A 
concomitant medication may be prescribed by a physician or obtained by the subject over the 
counter. Concomitant medication is not provided by the sponsor. At each study visit, subjects will 
be asked whether they have taken any medication other than the sponsor-supplied drug (used from 
signing of informed consent through the Safety Follow-up Visit), and all medication including 
vitamin supplements, over-the-counter medications, and oral herbal preparations, must be 
recorded in the eCRF.
9.1.6
Documentation of Concurrent Medical Conditions
Concurrent medical conditions are those significant ongoing conditions or diseases that are present 
at the time of signing the informed consent. This includes clinically significant laboratory or 
physical examination abnormalities noted at Screening/Baseline examination, according to the 
judgment of the investigator. The condition (ie, diagnosis) should be described.
9.1.7
Effectiveness Patient Reported Outcomes and Health Economic Outcome Research 
(HEOR) Assessments
The following assessments will be conducted during the Treatment Period of the study, unless 
otherwise indicated.
9.1.7.1
GAS
The GAS [17,18] is a tool to measure the progress each subject has towards achieving their 
individualized goals. While the outcome measure is unique to each subject, standardized scoring is 
applied to allow for statistical analysis. 
The GAS allows for 1 of 2 types of goals to be set:
1. Subject defined goals, allow a “subject’s chief complaint” approach taken towards establishing 
the goal, with no specific limitations set for the type or focus of the goal, beyond requiring that 
it meets the basic standards of measurability, equidistance, and difficulty.
2. Domain-Defined goals are more structured in nature, presenting the subject with an array of 
broadly defined domains and more specific subdomains. After selecting an appropriate domain 
and (where applicable) subdomain, the clinician will work with the subject to establish a 
specific goal that fits within the selected category.
For GAS, a total of 3 goals will be selected, 1 subject defined and 2 from pre-defined domain 
categories. A 5-point rating scale will then be applied to each of the 3 goals. A semistructured 
interview will be conducted with each subject to conduct goal-setting at the outset of the study. 


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Another evaluation will take place at Week 6 and Week 12/End of Study visits or at Early 
Termination Visit (as applicable) to determine the level of progress at that time, with assignment 
of appropriate scores. It takes subjects approximately 45 minutes to complete the GAS. 
9.1.7.2
PHQ-9
The PHQ-9 [19] will be used as a secondary efficacy measure of depression severity. This is a 
well-established patient reported outcome tool for assessment of change in depressive symptoms 
and is a sensitive measure of depression severity. 
The PHQ-9 consists of a 9-item scale originally developed for primary care settings, with 1 item 
corresponding to each of the 9 MDE symptom criteria for depression in DSM, asking if they have 
bothered the patient over the last 2 weeks. Each question is rated on a scale from 0 (not at all) to 3 
(nearly every day). If any problems are answered 1 or higher, a final question on how difficult 
those problems made it to do work, take care of things at home, or get along with other people is 
completed, rated from not difficult at all to extremely difficult. The 9 questions are summed to a 
total score ranging from 0 to 27 with higher scores reflecting greater severity. It takes 
approximately 5 minutes to complete the PHQ-9. 
9.1.7.3
PDQ-D
The PDQ-D [20], a validated version of the original PDQ specifically modified to depressed 
patients, will be used to evaluate self-reported cognitive complaints in patients with MDD. The 
PDQ was originally developed to assess cognitive complaints in patients with multiple sclerosis. 
However, it does address cognitive aspects highly relevant for depression, including attention and 
concentration, retrospective memory, prospective memory, and planning and organization. It takes 
approximately 10 minutes to complete the PDQ-D. 
9.1.7.4
Clinical Global Impression Scales
The CGI was developed to provide global measures of the severity of a patients clinical condition 
during clinical studies. The CGI scales consist of 2 subscales: the CGI-S and the CGI-I [21].
CGI-S and CGI-I raters will be required to have suitable experience and training (as deemed by 
sponsor) to be eligible to rate subjects within the study. The total time to score the CGI is 
approximately 1 to 2 minutes after the clinical interview.
CGI-S
The CGI-S is a clinician rated scale designed to assess global severity of illness and change in the 
clinical condition over time. The CGI-S provides the clinician’s impression of the patient’s current 
state of mental illness. The clinician uses his or her clinical experience of this patient population to 
rate the severity of the patient’s current mental illness on a 7-point scale ranging from 1 (normal -
not at all ill) to 7 (among the most extremely ill patients). 


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CGI-I
The CGI-I assesses the subject’s improvement (or worsening). The clinician is required to assess 
the subject’s condition relative to Baseline (Randomization/Day 1) 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. 
9.1.7.5
 
9.1.7.6
9.1.7.7
C-SSRS
The C-SSRS [25] Baseline/Screening will be administered at Screening and the Since-Last-Visit 
C-SSRS will be administered at all other time points. The C-SSRS was developed by researchers 
at Columbia University as a tool to help systematically assess suicidal ideation and behavior in 
subjects during participation in a clinical trial of centrally acting drugs. The C-SSRS is composed 
of 3 questions addressing suicidal behavior and 5 questions addressing suicidal ideation, with 
subquestions assessing severity. The tool is administered via an interview with the subject. If 
possible, the same interviewer should be used throughout the study for the same subject. It takes 
approximately 10 minutes to complete the C-SSRS.
9.1.7.8
Q-LES-Q
The Q-LES-Q [26] is a scale designed to allow researchers to assess the degree of a subject’s 
quality of life in various areas of daily living. Ninety-one of the 93 items are assembled into 
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8 categories: physical health/activities, feelings, work, household duties, school/course work, 
leisure time activities, social relations, and general activities. Items are scored on a 5-point scale, 
from 1 (not at all or never) to 5 (frequently or all the time), to indicate the degree of enjoyment or 
satisfaction experienced. Higher scores indicate greater enjoyment/satisfaction. Typically a 
self-report measure, this scale will be read to the subject by a member of the site staff and verbatim 
answers recorded to ensure all data points are captured. It takes approximately 40 to 45 minutes to 
complete the Q-LES-Q.
9.1.7.9
WHO-5
The WHO-5 [27,28] is a short, self-administered questionnaire covering 5 positively worded 
items, related to positive mood (good spirits, relaxation), vitality (being active and waking up fresh 
and rested), and general interests (being interested in things). Administering the WHO-5 takes 2 to 
3 minutes to complete.
9.1.7.10
 
9.1.7.11
9.1.7.12 Order of Assessments
The order of assessments is not defined, it is recommended that the WHO-5 and the CGI-I/CGI-S, 
as applicable, are done after the completion of all other assessments.
9.1.8
Procedures for Clinical Laboratory Samples
All samples will be collected in accordance with acceptable laboratory procedures. The maximum 
volume of blood at any single visit is approximately 19 mL, and the approximate total volume of 
blood for the study is 46 mL. Details of these procedures and required safety monitoring will be 
given in the laboratory manual.
Table 9.a lists the tests that will be obtained for each laboratory specimen.
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Table 9.a
Clinical Laboratory Tests
Hematology
Limited Serum Chemistry
RBC
WBC
Hemoglobin
Hematocrit
Platelets
Neutrophils
Eosinophils
Basophils
Lymphocytes
Monocytes
ALT
Albumin
Alkaline phosphatase
AST
Total bilirubin
Direct bilirubin
Other:
Serum
Urine
Female subjects :
hCG (a,c)
Female subjects only: 
hCG (b)
All subjects: Urine drug and alcohol screen including: 
amphetamines (including methamphetamine), barbiturates, 
benzodiazepines, cannabinoids, cocaine, opiates, methadone 
and phencyclidine (d)
hCG=human chorionic gonadotropin, RBC=red blood cell, WBC=white blood cell.
(a) Urine hCG pregnancy tests will be performed at Screening and for all other visits during the Treatment Period for 
women of childbearing potential only.
(b) Urine hCG must be negative at Visit 2 prior to enrollment. 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 1 year since last regular menses with a follicle-stimulating hormone 
[FSH]>40 IU/L or at least 5 years since last regular menses, confirmed before any study medication is implemented). 
(c) Serum hCG pregnancy tests will be performed at Baseline and End of Study/Early Termination visits on all 
females. For combined Screening and Baseline Visits, there will be 1 urine and 1 serum hCG. Subjects (women of 
childbearing potential) may be enrolled with a negative urine hCG; however if the serum hCG is positive the subject 
must be withdrawn from study drug immediately and withdrawn from the study as soon as possible.
(d) The subject must have a negative UDS. This includes benzodiazepines and opiates for which there is no 
prescription (including oxycodone) at Screening and Baseline performed locally by the site.
Urine drug screen test kits will be supplied by the sponsor for UDS testing at the clinic. Urine for 
drug screening will not be sent to the central laboratory for testing. The central laboratory will 
perform laboratory tests for serum pregnancy, hematology and limited serum chemistries. Local 
UDS and urine pregnancy screening results must be confirmed prior to conducting the Baseline 
Visit. Serum pregnancy collected at Baseline should be sent to the central laboratory. In the case of 
a combined Screening and Baseline Visit the UDS and the urine pregnancy test will be done once 
in the clinic and a serum pregnancy test will be sent to the central laboratory. The results of central 
laboratory tests will be returned to the investigator, who is responsible for reviewing and filing 
these results.
If subjects experience ALT or AST >3 ×ULN, follow-up laboratory tests (at a minimum, serum 
alkaline phosphatase, ALT, AST, total bilirubin, gamma-glutamyl transferase, and INR) should be 
performed within a maximum of 7 days and preferably within 48 to72 hours after the abnormality 


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was noted. (Refer to Section 7.4 and Section 10.2.3 for the appropriate guidance on reporting 
abnormal liver function tests.)
If 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 sponsor-supplied drug. discussion of the relevant subject details and possible 
alternative etiologies. The abnormality should be recorded as an AE (please refer to 
Section 10.2.3).
9.1.9
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 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 1 year since last regular menses with a FSH>40 IU/L or at least 5 years since last regular 
menses, confirmed before any study medication is implemented).
9.1.9.1
Definitions and Procedures for Contraception and Pregnancy Avoidance
The following definitions apply for contraception and pregnancy avoidance procedures.
* A woman is considered a woman of childbearing potential, ie, fertile, following menarche and 
until becoming postmenopausal unless permanently sterile. Permanent sterilization methods 
include hysterectomy, and bilateral oophorectomy. A postmenopausal state is defined as no 
menses for 12 months without an alternative medical cause. A high FSH level in the 
postmenopausal range (FSH>40 IU/L) may be used to confirm a postmenopausal state in younger 
women (eg, those <45 years old) or women who are not using hormonal contraception or 
hormonal replacement therapy. However, in the absence of 12 months of amenorrhea, a single 
FSH measurement is insufficient.
The following procedures apply for contraception and pregnancy avoidance.
1. Highly effective methods of contraception are defined as “those, alone or in combination, that 
result in a low failure rate (ie, less than 1% failure rate per year when used consistently and 
correctly)”. In this study, where medications and devices containing hormones are included, 
the only acceptable methods of contraception are:

Nonhormonal methods: 
–
IUD. 
–
Bilateral tubal occlusion. 


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–
Vasectomized partner (provided that partner is the sole sexual partner of the trial 
participant and that the vasectomized partner has received medical assessment of the 
surgical success). 
–
True sexual abstinence, only if this is in line with the preferred and usual lifestyle of 
the subject. True abstinence is defined as refraining from heterosexual intercourse 
during the entire period of the study, from 1 month prior to the first dose, throughout 
the duration of the study, and for 30 days after completion of the study.

Hormonal Methods. (Vortioxetine has been shown not to interact with hormonal 
contraceptives.)
–
Combined (estrogen and progestogen) hormonal contraception associated with 
inhibition of ovulation initiated at least 3 months prior to the first dose of study drug 
OR combined with a barrier method (male condom, female condom or diaphragm) if 
for shorter duration until she has been on contraceptive for 3 months:

Oral.

Intravaginal (eg, ring).

Transdermal.
–
Progestogen-only hormonal contraception associated with inhibition of ovulation 
initiated at least 3 months prior to the first dose of study drug OR combined with a 
barrier method (male condom, female condom or diaphragm) if shorter till she has been 
on contraceptive for 3 months:

Oral.

Injectable.

Implantable.
2. Effective methods of contraception (there may be a higher than 1% failure rate) are: 

Double-barrier method (contraceptive sponge, diaphragm or cervical cap with spermicidal 
jellies or creams PLUS male condom).

Progestogen only hormonal contraception, where inhibition of ovulation is not the primary 
mode of action PLUS condom with or without spermicide.
3. Unacceptable methods of contraception are:

Periodic abstinence (eg, calendar, ovulation, symptothermal, postovulation methods).

Spermicides only.

Withdrawal.

No method at all.


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
Use of female and male condoms together.

Cap/diaphragm/sponge without spermicide and without condom.
4. Subjects will be provided with information on highly effective/effective 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, 
donation of ova donation during the course of the study.
5. During the course of the study, regular urine hCG pregnancy tests will be performed only for 
women of childbearing potential. Women of childbearing potential will receive continued 
guidance with respect to the avoidance of pregnancy and ova donation as part of the study 
procedures. Such guidance should include a reminder of the following:
a) Contraceptive requirements of the study.
b) Reasons for use of barrier methods (ie, condom).
c) Assessment of subject compliance through questions such as:
i. Have you used the contraception consistently and correctly since the last visit?
ii. Have you forgotten to use contraception since the last visit?
iii. Are your menses late? (even in women with irregular or infrequent menstrual cycles a 
pregnancy test must be performed if the answer is “yes”).
iv. Is there a chance you could be pregnant?
6. In addition to a negative urine hCG pregnancy test at Screening, Female subjects of 
childbearing potential must also have confirmed menses in the month before first dosing (no 
delayed menses), a negative urine hCG pregnancy test prior to receiving any dose of study 
medication (as close as possible and prior to first dose of study medication, preferably on the 
same day).
9.1.10 Pregnancy
If any subject is found to be pregnant during the study she should be withdrawn and any
sponsor-supplied drug should be immediately discontinued. 
If the pregnancy occurs during administration of active study medication, eg, after Visit 2 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 1.1.
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. 
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 
she became pregnant and provide details of treatment the subject received.


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All reported pregnancies will be followed up to final outcome, using the pregnancy form. The 
outcome, including any premature termination, must be reported to the sponsor. An evaluation 
after the birth of the child will also be conducted.
9.1.11 PGx Sample Collection 
When sampling of whole blood for PGx analysis occurs, every subject must sign informed 
consent/be consented in order to participate in the PGx sample analysis.
Two 3-mL whole blood samples for DNA isolation will be collected at the Baseline Visit before 
dosing from each subject in the study, into plastic K2EDTA spray-coated tubes, and stored under 
frozen conditions.
Two whole blood samples (2.5 mL per sample) for RNA isolation will be collected at the Baseline 
Visit before dosing and at the Week 12/Early Termination (Visit 6) into PAXgene tubes, and 
stored under frozen conditions.
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.
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.
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.
Detailed instructions for the handling and shipping of samples are provided in the Laboratory 
Manual.
9.1.12 Documentation of Screen Failure
Investigators must account for all subjects who sign informed consent.


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If the subject is withdrawn at screening, the investigator should complete the eCRF. The IxRT
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 identification numbers assigned to subjects who fail screening should not be reused.
9.1.13 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.
9.2
Monitoring Subject Treatment Compliance
Subjects will be required to bring study medication containers/unused study medication to each 
dispensing site visit. All supplies used to administer study drug to the subject will be recorded on 
the eCRFs.
If a subject is persistently noncompliant with study drug (eg, less than 70% compliant or greater 
than 125% 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 discussion 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. 
Assessments should be completed at the designated visit/time point(s).
9.3.1
Screening Visit 1 (Days -21 to -1) 
Subjects will may be screened within 21 days prior to Baseline. Procedures to be completed during 
the Screening Visit are detailed in Appendix A. Subjects will be screened in accordance with 
predefined inclusion and exclusion criteria as described in Section 7.0. See Section 9.1.12 for 


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procedures for documenting screening failures. IxRT will be accessed for the subject screening 
number. The factors for determining a change/discontinuation from the prior antidepressant as 
assessed by the subject and by the investigator will be collected. The Screening and Baseline Visits 
may be combined if determined appropriate per the investigator. Any procedure that is to be 
performed at both visits should only be conducted once for a combined visit. 
9.3.2
Study Entrance/Baseline Visit 2 (Day 1)
Study enrollment will take place on Day 1 (Baseline, Visit 2). Procedures to be completed during 
the Baseline Visit are detailed in Appendix A.
If the subject has satisfied all of the inclusion criteria and none of the exclusion criteria for 
enrollment, the subject should be enrolled and study drug should be dispensed using the IxRT, as 
described in Section 8.2. Subjects will be instructed on when to take the first dose of study drug. 
The procedure for documenting Screening failures is provided in Section 9.1.12. The factors for 
determining a change/discontinuation from the prior antidepressant as assessed by the subject and 
by the investigator will be collected.
9.3.3
Open-Label Treatment Visits 3 and 5: Week 2 (Day 15), and Week 6 (Day 43)
The Subjects will return to the study site for their Week 2 (Visit 3) and Week 6 (Visit 5) Visits. 
Subjects will be instructed to return their bottle of study drug dispensed at the previous visit for 
drug accountability. Procedures to be completed during Visits 3 and 5 are detailed in Appendix A.
9.3.4
Telephone Visit 4 and 6: Week 4 (Day 29) and Week 9 (Day 64) 
A telephone visit will occur at Visit 4 (Week 4) and 6 (Week 9). Procedures to be completed 
during Visits 4 and 6 are detailed in Appendix A.
9.3.5
Final Visit or Early Termination
The Final Visit will be performed at Visit 7 (Week 12) or at Early Termination Visit. For all 
subjects receiving study drug, the investigator must complete the End of Study eCRF page. 
Procedures to be completed during Final Visit/Early Termination Visit are detailed in Appendix A.
For subjects who permanently discontinue study drug early, all Final Visit/Early Termination 
assessments detailed in Appendix A should be performed in close proximity to, or at the time of, 
study drug discontinuation. 
At the End of Study Visit the Clinician and subject satisfaction with the antidepressant treatment 
will be collected. In addition, Clinician and subject satisfaction with the GAS approach as a 
method for establishing treatment goals, evaluating progress towards treatment goals, and 
improving communication between clinicians and patients will be collected.
9.3.6
Unscheduled Visit
Unscheduled visits may occur at any time after the Week 2 visit.


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Subjects may return to the study center for unscheduled visits as needed. Unscheduled study visits 
can be performed when the subject has a study related issue in between regular study visits. The 
following procedures should be performed during this visit:

Concomitant medications.

AE assessment.

Other procedures, including dose adjustments, as deemed appropriate by the investigator.
9.3.7
Safety Follow-up Phone Call (Week 16 or Early Termination)
A safety follow-up phone call will be made 28 days (±7 days) after withdrawal from the study or 
after completion of the study. A concomitant medication and AE assessment will be completed.
9.3.8
Poststudy Care
Sponsor-supplied drug 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
PGx Sample Retention and Destruction 
In this study, specimens for genome/gene analysis will be collected as described in Section 9.1.11. 
The genetic material will be preserved, retained, and initially stored at PPD Central Laboratory 
and then preserved and retained for long-term storage at Covance Central Laboratory 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 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 PGx sample for DNA and RNA analysis can withdraw 
their consent and request disposal of a stored sample at any time. Sponsor must be notified of the 
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 drug; 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 value), 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 or 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 drug 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 eCRF page.
Diagnoses vs signs and symptoms:

Each event should be recorded to represent a single diagnosis. Accompanying signs (including 
abnormal laboratory values or electrocardiogram [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 findings 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 


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laboratory or ECG re-test and/or continued monitoring of an abnormal value or finding are not 
considered an 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) should NOT be recorded as PTEs unless 
related to study procedures. However, if the subject experiences a worsening or complication 
of such a concurrent medical condition, the worsening or complication should be recorded 
appropriately as a PTE (worsening or complication occurs before start of study drug) or an AE 
(worsening or complication occurs after start of study drug). 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 concurrent medical condition (eg, asthma, epilepsy) any 
occurrence of an episode should only be captured as a PTE/AE if the condition becomes more 
frequent, serious, or severe in nature. 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 medical condition (eg, cataracts, rheumatoid 
arthritis), worsening of the condition should only be recorded as a PTE/AE if occurring to a 
greater extent to that which would be expected. 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 the start of study drug, 
the worsening or complication should be recorded as an AE. Investigators should ensure that 
the AE term recorded captures the change in the PTE (eg, “worsening of…”).

If the subject experiences a worsening or complication of an AE after any change in study 
drug, 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…”).
Changes in intensity of AEs /Serious PTEs:

If the subject experiences changes in intensity of an AE/serious PTE, the event should be 
captured once with the maximum intensity recorded.
Preplanned procedures (surgeries or interventions):

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 


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worsening of the condition should be recorded 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 effectiveness):

Insufficient clinical response, effectiveness, 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 effectiveness.
Overdose:

Cases of overdose with any medication without manifested side effects are NOT considered 
PTEs or AEs, but instead will be documented on an Overdose page of the eCRF. Any 
manifested side effects will be considered PTEs or AEs and will be recorded on the AE page of 
the eCRF.
10.1.4 SAEs
An SAE is defined as any untoward medical occurrence that at any dose:
1. Results in DEATH.
2. Is LIFE THREATENING.

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.
3. Requires inpatient HOSPITALIZATION or prolongation of existing hospitalization.
4. Results in persistent or significant DISABILITY/INCAPACITY.
5. Is a CONGENITAL ANOMALY/BIRTH DEFECT.
6. 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).


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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
Note: Terms identified on the Medically Significant AE List represent the broad medical concepts to be considered as 
“Important Medical Events” satisfying SAE reporting requirements. 
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 AEs of Special Interest
AEs of special interest are to be reported and followed up in the same manner of other AEs (see 
Section 10.2.2).
An AE of Special Interest (serious or nonserious) 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. The reporting of specific AE of Special Interest are described 
in the following sections. 
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.


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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 7.4 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 drug, discussion of the relevant 
subject details and possible alternative causalities.
If a subject is noted to have an ALT or AST >3×ULN and total bilirubin >2×ULN for which an 
alternative etiology has not been identified, the event should be recorded as an SAE and reported 
as per Section 10.3.1. In addition, an LFT increases eCRF must be completed and transmitted with 
the SAE.
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 
overdose, an overdose eCRF form should be completed within 1 business day of the investigator’s 
awareness of the event.
10.1.6 Intensity 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.


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10.1.7 Causality of AEs
The relationship of each AE to study drug(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 medications 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 medications 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 investigator.
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 Drug

Drug withdrawn – a study drug is stopped due to the particular AE.

Dose not changed – the particular AE did not require stopping a study drug.

Unknown – only to be used if it has not been possible to determine what action has been taken.

Not Applicable – a study drug was stopped for a reason other than the particular AE, eg, the 
study has been terminated, the subject died, dosing with study drug was already stopped before 
the onset of the AE.

Dose Reduced – the dose was reduced due to the particular AE.

Dose Increased – the dose was increased due to the particular AE.


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
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 1 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 drug (Baseline 
Visit 1) or until screen failure. For subjects who discontinue prior to study drug 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 drug 
(Baseline Visit 1). Routine collection of AEs will continue for 4 weeks post the last dose of study 
medication.
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. 


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Nonserious 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 drug 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. Frequency.
4. Intensity.
5. Investigator’s opinion of the causal relationship between the event and administration of study 
drug(s) (related or not related) (not completed for PTEs).
6. Investigator’s opinion of the causal relationship to study procedure(s), including the details of 
the suspected procedure.
7. Action concerning study drug (not applicable for PTEs).
8. Outcome of event.
9. Seriousness.
All outcomes used in this study will not be used as a primary means to collect AEs. However, 
should the investigator become aware of a potential AE through the information collected with this 
instrument, proper follow-up with the subject for medical evaluation should be undertaken. 
Through this follow-up if it is determined that an AE not previously reported has been identified, 
normal reporting requirements should be applied.
10.2.1.3 AEs of Special Interest 
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.
If the AE of special interest/abnormality, which occurs during the treatment period or the 
follow-up period, is considered to be clinically significant based on the criteria below, it should be 
recorded in an AE Form or an SAE Form. The Form should be completed and reported to the 
clinical contract research organization (CRO)/Pharmacovigilance department within 24 hours.


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Special interest AE/abnormality criteria include: 

Laboratory value threshold, if applicable.

Premature termination for the AE of Special Interest, if applicable.

Any other specific criteria.
AEs of special interest have to be recorded as AEs in the eCRF. An evaluation form along with all 
other required documentation must be submitted to the sponsor.
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:

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 drug(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.
10.2.3 Reporting of Abnormal LFTs 
If a subject is noted to have ALT or AST elevated >3×ULN on 2 consecutive occasions, the 
abnormality should be recorded as an AE. In addition, an LFT Increases eCRF must be completed 
providing additional information on relevant recent history, risk factors, clinical signs and 
symptoms and results of any additional diagnostic tests performed.
If a subject is noted to have ALT or AST >3×ULN and total bilirubin >2×ULN for which an 
alternative etiology has not been identified, the event should be recorded as an SAE and reported 
as per Section 10.2.2. The investigator must contact the Medical Monitor for discussion of the 
relevant subject details and possible alternative etiologies, such as acute viral hepatitis A or B or 
other acute liver disease or medical history/concurrent medical conditions. Follow-up laboratory


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tests as described in Section 9.1.8 must also be performed. In addition, an LFT Increases eCRF 
must be completed and transmitted with the Takeda SAE form (as per Section 10.2.2).
10.3
Follow-up of SAEs
If information not available at the time of the first report becomes available at a later date, the 
investigator should complete a follow-up SAE form or provide other written documentation and 
fax it immediately within 24 hours of receipt. Copies of any relevant data from the hospital notes 
(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 or IECs, 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, including the European 
Medicines Agency, investigators, and IRBs or IECs, as applicable, in accordance with national 
regulations in the countries 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 report 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 a study drug/sponsor-supplied drug or that would be sufficient 
to consider changes in the study drug/sponsor-supplied drug administration or in the overall 
conduct of the trial. The study site also will forward a copy of all expedited reports to his or her 
IRB or IEC.


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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 medical conditions will be coded using the Medical 
Dictionary for Regulatory Activities (MedDRA). Drugs will be coded using the WHO Drug 
Dictionary.
12.1
eCRFs
Completed eCRFs are required for each subject who signs an informed consent.
The sponsor or its designee will supply study 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. 
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 e-sign 
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 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, or sign and seal, and date.
eCRFs will be reviewed for completeness and acceptability at the study site during periodic visits 
by the sponsor or its designee. 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 Council for Harmonisation (ICH) E6(R2) Section 4.9.5 requires the investigator to 
retain essential documents specified in ICH E6(R2) (Section 8) until at least 2 years after the last 
approval of a marketing application for a specified drug indication being investigated or, if an 
application is not approved, until at least 2 years after the investigation is discontinued and 
regulatory authorities are notified. In addition, ICH E6(R2) 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 study site agreement between the investigator and sponsor.
Refer to the 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 will be prepared and finalized prior to database lock. This document will 
provide further details regarding the definition of analysis variables and analysis methodology to 
address all study objectives.
A data review will be conducted prior to 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
In this study, 3 kinds of analysis sets are defined: full analysis set (FAS), per protocol set (PPS),
and safety analysis set. The definition of each analysis set will be described in the Handling Rules
for Analysis Data.
The FAS, used for primary effectiveness analysis, will include all subjects who were enrolled in 
the treatment period and received at least 1 dose of the study drug and completed at least 1 GAS 
assessment post-Baseline. In FAS effectiveness summaries, subjects will be considered as 
vortioxetine treated no matter what dose levels were received during the study.
A 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 prescribed by the 
treating physician, will be identified in the minutes of the subject evaluability assessment. 
The Safety Set will include all subjects who were enrolled and received at least 1 dose of study 
medication. In safety summaries, all subjects will be analyzed as vortioxetine-treated.
The sponsor will verify the validity of the definitions of the analysis sets as well as the rules for 
handling data, with consulting a medical expert as needed. If necessary, the Handling Rules for 
Analysis Data will be supplemented with new handling rules that were not discussed at the 
planning stage. The Handling Rules for Analysis Data must be finalized prior to database lock.
13.1.2 Analysis of Demographics and Other Baseline Characteristics
Baseline characteristics will be listed and summarized for demographics (sex, age, race, and body 
mass index), assessment of menopausal status, and medical history including psychiatric history.
Categorical variables will be summarized using frequencies and percentages. Continuous 
variables will be summarized using mean, SD, median, maximum, and minimum values. Study 
drug information, including dose, frequency, and duration will be summarized. An end of study 
form/study disposition summary will also be provided.
13.1.3 Effectiveness Analysis
The primary objective of the study is to determine the effectiveness of treatment with vortioxetine 
on subject goal achievement after changing antidepressant medication for treatment of MDD. The 


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primary endpoint is the proportion of subjects who changed to treatment with vortioxetine who 
achieve their individually identified goals as demonstrated by an outcome GAS Score of ≥50 at 
Week 12. This proportion will be summarized at Week 12. 
For the secondary endpoints of outcome measures of GAS Score, PHQ-9, PDQ-D, Q-LES-Q 
Score, WHO-5, and CGI-S, total scores and changes from Baseline will be summarized by each 
time point of Baseline, Week 6 (as appropriate) and by each time point of Baseline and Week 12. 
These changes from Baseline will be analyzed using paired t-tests. Also, for each of the outcome 
measurements, change from Baseline at Week 12 will be analyzed using paired t-tests. Tests of 
significance will be 2-tailed with alpha level at 0.05. CGI-I Scores will be summarized at Week 12 
using descriptive statistics.
Additional analysis will be performed for other additional endpoints, if necessary. 
13.1.4 Safety Analysis
AEs will be summarized using the safety analysis set. No statistical testing or inferential statistics 
will be generated.
All AEs will be coded using MedDRA. Data will be summarized using preferred term and primary 
system organ class.
13.2
Interim Analysis and Criteria for Early Termination
An interim analysis will be performed once 60 subjects complete the study. A futility assessment 
will be done at this time. If the futility criteria is met, the study may be stopped. The end of the 
study will be the date of the last safety follow-up visit of the last subject completed. 
13.3
Determination of Sample Size
As no formal hypothesis testing is performed for the primary endpoint, the purpose of sample size 
estimation is to determine the adequate sample size needed to provide a precise estimate for the 
response rate (GAS Score ≥50) with 95% CIs. 
Conservatively estimating that 50% of subjects will be responders (GAS>50) and that 100 subjects 
will complete the study, CIs will be +0.098 around the point estimate (proportion of responders).
Company Confidential Information


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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 guarantees 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 sponsor’s 
designee (as long as blinding is not jeopardized), including but not limited to the Investigator’s 
Binder, study drug, 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. 
The investigator should document all protocol deviations.


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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 Food and Drug Administration, 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 guarantees 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. 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 study. Until the site receives 
drug/notification no protocol activities, including screening may occur.
Study 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 trial database or documentation via a subject 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 the monitor or the sponsor’s designee, representatives from any 
regulatory authority (eg, Food and Drug Administration, 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 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 as recommended by the International Committee of Medical Journal 
Editors (www.icmje.org). All publications and presentations must be prepared in accordance with 
this section and the study site agreement and Good Publication Practice guidelines, Battisti et al 


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[31]. In the event of any discrepancy between the protocol and the study site agreement, the study 
site agreement will prevail.
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 all 
interventional clinical trials it sponsors anywhere in the world on ClinicalTrials.gov and/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 study 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 the sponsor providing this information to callers must provide the 
sponsor 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 and/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 study subjects. Refer to 
the 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 
20 July 2016. 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. Sanchez C, Asin KE, Artigas F. Vortioxetine, a novel antidepressant with multimodal activity: 
review of preclinical and clinical data. Pharmacol Ther 2015;145:43-57.
11. Trintellix (vortioxetine) tablets. Full Prescribing Information. Deerfield, IL: Takeda 
Pharmaceuticals America, Inc. and Lundbeck, Revised May 2016.
12. Marangell LB. Switching antidepressants for treatment-resistant major depression. J Clin 
Psychiatry 2001;62 Suppl 18:12-7.
13. Mullins CD, Shaya FT, Meng F, Wang J, Harrison D. Persistence, switching, and 
discontinuation rates among patients receiving sertraline, paroxetine, and citalopram. 
Pharmacotherapy 2005;25(5):660-7.


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14. Venturini F, Sung J, Nichol M, Sellner J. Utilization patterns of antidepressant medications in 
a patient population served by a primary care medical group. J Manag Care Spec Pharm 
1999;5(2):243-9.
15. Warden D, Rush AJ, Trivedi MH, Fava M, Wisniewski SR. The STAR*D Project results: a 
comprehensive review of findings. Curr Psychiatry Rep 2007;9(6):449-59.
16. Khandker RK, Kruzikas DT, McLaughlin TP. Pharmacy and medical costs associated with 
switching between venlafaxine and SSRI antidepressant therapy for the treatment of major 
depressive disorder. J Manag Care Pharm 2008;14(5):426-41.
17. Kiresuk TJ, Sherman RE. Goal attainment scaling: A general method for evaluating 
comprehensive community mental health programs. Community Ment Health J 
1968;4(6):443-53.
18. Goal Attainment Scaling (GAS) in Rehabilitation: A Practical Guide. Kings College London, 
The North West London Hospitals NHS Trust. 2009.
19. Kroenke K, Spitzer RL, Williams JB. The PHQ-9: validity of a brief depression severity 
measure. J Gen Intern Med 2001;16(9):606-13.
20. Lam R, Saragoussi D, Danchenko N, Lamy F, Rive B, Brevig T. Psychometric validation of 
Perceived Deficits Questionnaire - Depression (PDQ-D) in patients with major depressive 
disorder. Value in Health 2013;16(7):A330. ISPOR 16th Annual European Congress, Poster 
QL4.
21. 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.
22. Baudouin A, Clarys D, Vanneste S, Isingrini M. Executive functioning and processing speed in 
age-related differences in memory: contribution of a coding task. Brain Cogn 
2009;71(3):240-5.
23. Wechsler D. Adult Intelligence Scale. 3rd ed. San Antonio, TX: Psychological Corporation; 
1997.
24. Keefe RS, Davis VG, Atkins AS, Vaughan A, Patterson T, Narasimhan M, et al. Validation of 
a Computerized test of Functional Capacity. Schizophr Res 2016.
25. Posner K, Brown GK, Stanley B, Brent DA, Yershova KV, Oquendo MA, et al. The 
Columbia-Suicide Severity Rating Scale: initial validity and internal consistency findings from 
three multisite studies with adolescents and adults. Am J Psychiatry 2011;168(12):1266-77.
26. Endicott J, Nee J, Harrison W, Blumenthal R. Quality of Life Enjoyment and Satisfaction 
Questionnaire: a new measure. Psychopharmacol Bull 1993;29(2):321-6.
27. Wellbeing Measures in Primary Health Care/The Depcare Project. WHO Regional Office for 
Europe. 12-13 February 1998. Publication No. EUR/ICP/QCPH 05 01 03.


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28. Bech P. Measuring the dimension of psychological general well-being by the WHO-5. QOL 
Newsletter 2004;32:15-6.
29. Lam RW, Michalak EE, Yatham LN. A new clinical rating scale for work absence and 
productivity: validation in patients with major depressive disorder. BMC Psychiatry 
2009;9:78.
30. Wade AG, Fernandez JL, Francois C, Hansen K, Danchenko N, Despiegel N. Escitalopram 
and duloxetine in major depressive disorder: a pharmacoeconomic comparison using UK cost 
data. Pharmacoeconomics 2008;26(11):969-81.
31. Battisti WP, Wager E, Baltzer L, Bridges D, Cairns A, Carswell CI, et al. Good Publication 
Practice for Communicating Company-Sponsored Medical Research: GPP3. Ann Intern Med 
2015;163(6):461-4.


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Appendix A
Schedule of Study Procedures
Screening 
Treatment
Telephone 
Follow-up 
Visit 1 (a)
Baseline
Visit 2 (a) 
Day 1 
Visit 3 
Wk 2 
Telephone 
Contact
Visit 4
Wk 4
Visit 5 
Wk 6 
Telephone 
Contact
Visit 6
Wk 9
End of Study 
Visit 7 
Wk 12 /Early 
Termination
Visit 8
Wk 16 
Days -21 
up to -1 
Day 1 
Day 15 
(±3 
Days) 
Day 29
(±3 Days)
Day 43 
(±5 
Days) 
Day 64 
(±5 Days)
Day 85 
(±5 Days) 
Day 113 
(± 7 Days) 
Informed consent 
X
Eligibility criteria
X
X
Demographics, medical 
history, medication history
X
UDS (b)
X
X
MDD diagnosis confirmed 
by investigator judgment, 
antidepressant medication 
history & disease history
X
Height and weight (c) 
X
X
X
Hematology and limited 
serum chemistry
X
X
PGx sample collection (d)
X
X
Concurrent medical 
conditions
X
X
Concomitant medications 
X
X
X
X
X
X
X
Vital signs
X
GAS assessment
X
X
X
PHQ-9
X
X
X
X
Q-LES-Q
X
X
PDQ-D
X
X
X
C-SSRS
X
X
X
X
X
WHO-5
X
X
X
CGI-S
X
X
X
X
X
CGI-I
X
X
X
Footnotes are on last table page.
Company Confidential Information
Company Confidential Information
Company Confidential Information
Company Confidential Information


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Appendix A
Schedule of Study Procedures (continued)
Screening 
Treatment
Telephone 
Follow-up 
Visit 1 (a)
Baseline
Visit 2 (a) 
Day 1 
Visit 3 
Wk 2 
Telephone 
Contact
Visit 4
Wk 4
Visit 5 
Wk 6 
Telephone 
Contact
Visit 6
Wk 9
End of Study 
Visit 7 
Wk 12 /Early 
Termination
Visit 8
Wk 16 
Days -21 
up to -1 
Day 1 
Day 15 
(±3 
Days) 
Day 29
(±3 Days)
Day 43
(±5 
Days) 
Day 64
(±5 Days)
Day 85
(±5 Days) 
Day 113
(± 7 Days) 
Document factors for 
determining a
change/discontinuation 
from prior antidepressant 
(e)
X
PTE/AE assessment
X
X
X
X
X
X
X
X
Pregnancy testing and 
pregnancy avoidance 
counseling (f,g)
X
X
X
X
X
Access IxRT for subject 
ID/ medication ID/subject 
status
X
X
X
X
X
Dispense study drug 
X
X
X
Dose adjustment (as 
needed) (h)
X
X
Clinician and subject 
satisfaction with change in 
antidepressant
X
Clinician and subject 
satisfaction with GAS 
approach
X
Study drug 
return/accountability/ 
compliance
X
X
X
(a) Screening and Baseline Visits may be combined as determined appropriate per the investigator. Any procedure that is to be
performed at both visits should only be conducted once for a combined visit. 
(b) UDS to be done at Screening and Baseline. UDS kits will be supplied by the sponsor for the testing at the clinic. UDS results 
must be negative. This includes benzodiazepines and opiates for which there is no prescription (including oxycodone) at Screening 
and Baseline. Results must be confirmed prior to conducting the Baseline Visit.
(c) Height at Screening only; weight at Screening, Baseline, and Week 12.
(d) Subjects who signed an informed consent for PGx testing will have blood samples for PGx analysis and these will be collected 
as follows: 2×3 mL for DNA on Day 1; 2×2.5 mL for RNA predose on Day 1 and at Week 12 (Visit 6).
(e) To be collected at Screening or combined Screening/Baseline Visit. 


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(f) Urine hCG pregnancy tests will be performed at Screening and Baseline and for all other visits during the Treatment Period for 
women of childbearing potential only. Serum hCG pregnancy tests will be performed at Baseline and End of Study/Early 
Termination visits for all females. For combined Screening and Baseline Visits, there will be 1 urine and 1 serum hCG. Subjects 
may be enrolled with a negative urine hCG; however, if the serum hCG is positive the subject must be withdrawn from study drug 
immediately and withdrawn from the study as soon as possible.
(g) Subject who are women of childbearing potential 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 
of pregnancy and donation of ova during the course of the study and for 30 days after the last dose of study drug.
(h) Dose adjustments should occur during regularly scheduled visits, or subjects should return for an Unscheduled Visit.


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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 investigator agrees to assume the following responsibilities:
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 
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 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.


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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 or the subject’s 
legally acceptable representative may discontinue 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 drug(s), studying other therapies for subjects, 
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


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e) that the subject’s identity will remain confidential in the event that study results are 
published.
25. Female women of childbearing potential (eg, nonsterilized, premenopausal female subjects) 
who are sexually active must use highly effective contraception (as defined in the informed 
consent) from Screening throughout the duration of the study, and for 5 half lives PLUS 30 
days after last dose. Regular pregnancy tests will be performed throughout the study for all 
female women of childbearing potential. If a subject is found to be pregnant during study, 
study drug will be discontinued and the investigator will offer the subject the choice to receive 
unblinded treatment information.
26. 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 drug.

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
Detailed Description of Amendments to Text
This document describes changes in reference to Protocol Incorporating Amendment No. 1.
Page 2, Section 1.1 Contacts
Existing Text
Responsible Medical Officer 
(carries overall responsibility for the 
conduct of the study)
Steve Chen, MD
Takeda Pharmaceuticals USA
US Medical Affairs
224-554-3121
Revised Text
Responsible Medical Officer 
(carries overall responsibility for the 
conduct of the study)
Louis Mini, MD
Medical Head, CNS
Takeda Pharmaceuticals USA
US Medical Office
224-554-6195
Rationale for Amendment
Change in personnel.
Page 3, Section 1.1 Contacts
Page 5, Investigator Agreement
Page 61, Section 12.2 Record Retention
Existing Text

International Conference on Harmonisation E6 Good Clinical Practice: Consolidated 
Guideline.
Revised Text

International Council for Harmonisation E6(R2) Good Clinical Practice: Consolidated 
Guideline.
Rationale for Amendment
ICH name has changed and guidelines have been revised.


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Page 3, Section 1.2 Approval
Existing Text
Date
Date
Date
Date
Date
Revised Text
Rationale for Amendment
Change in personnel.
Personal Protected Data
Personal Protected Data
Personal Protected Data
Personal Protected Data
Personal Protected Data
Personal Protected Data


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Page 11, Section 2.0 Study Summary, Study Design, 5th Paragraph
Page 24, Section 6.1 Study Design, 9th Paragraph
Existing Text
A futility analysis will be performed at an interim analysis after approximately 60 subjects have 
completed Week 12.
Revised Text
A futility analysis may be performed at an interim analysis after approximately 60 subjects have 
completed the study.
Rationale for Amendment
Analysis will be completed once 60 subjects have completed the safety follow up.
Page 13, Section 2.0 Study Summary, Main Criteria for Exclusion, Criterion #4
Page 28, Section 7.2 Exclusion Criteria, Criterion #4
Existing Text
The subject has a significant risk of suicide according to the investigator’s clinical judgment or has 
made an actual suicide attempt in the previous 6 months prior to Screening or scores “yes” on 
items 4 or 5 in the Suicidal Ideation section of the C-SSRS. 
Revised Text
The subject has a significant risk of suicide according to the investigator’s clinical judgment or has 
made an actual suicide attempt in the previous 6 months prior to Screening or scores “yes” on 
items 4 or 5 in the past 6 months on the Suicidal Ideation section of the C-SSRS. 
Rationale for Amendment
The intent of this criterion is to exclude subjects who currently have significant risk of suicide 
(according to the investigator’s clinical judgment), or made an actual suicide attempt in the 
previous 6 months prior to Screening, or within the same time frame have had active suicidal 
ideation with some intent to act (item 4 of CSSRS) or have had active suicidal ideation with 
specific plan and intent to act (item 5 of CSSRS). A lifetime “yes” answer to items 4 and 5 will not 
exclude the subject, but a “yes” answer to past 6 months for items 4 and 5 is exclusionary.
Page 17, Section 3.3 List of Abbreviations
New and Revised Text
ICH
International Council for Harmonisation
STAR*D
Sequenced Treatment Alternatives to Relieve Depression
US
United States
WAIS-IV
Wechsler Adult Intelligence Scale Fourth Edition


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Rational for Amendment
Clarification of text. 
Page 20, Section 4.2 Rationale for the Proposed Study
Existing Text
Data from clinical studies regarding switching antidepressant medication rates is minimal and the 
rationale for the switch varies across studies [12]. Claims databases have shown switching rates for 
antidepressants have ranged from 2.78% to 13.7% [13,14]. The results of switching, in particular, 
multiple switching can lead to suboptimal outcomes for patients. Results of the STAR-D project 
showed that as the number of switches increased the burden of illness, including relapse rates, also 
increased. Relapse may trigger a pharmacologic switch [15]. Switching antidepressant agents has 
been shown to increase treatment costs and can be burdensome to the patient, so it is important to 
get the patient to the optimal treatment as early as possible in the therapeutic pathway [16]. 
Revised Text
Data from clinical studies regarding switching antidepressant medication rates is minimal and the 
rationale for the switch varies across studies [12]. Claims databases have shown switching rates for 
antidepressants have ranged from 2.78% to 13.7% [13,14]. The results of switching, in particular, 
multiple switching can lead to suboptimal outcomes for patients. Results of the Sequenced 
Treatment Alternatives to Relieve Depression (STAR*D) study showed that as the number of 
switches increased the burden of illness, including relapse rates, also increased. Relapse may 
trigger a pharmacologic switch [15]. Switching antidepressant agents has been shown to increase 
treatment costs and can be burdensome to the patient, so it is important to get the patient to the 
optimal treatment as early as possible in the therapeutic pathway [16]. 
Rational for Amendment 
Clarification of text.
Page 22, Section 5.2.3 Additional Endpoints
New Text

Summary of level of satisfaction with study treatment and the goal attainment approach among 
clinicians and subjects.
Rational for Amendment 
Documentation of antidepressant change, and satisfaction with change in treatment was noted in 
Section 9.3, but was not listed in the table of procedures in error. Clinician and subjects 
satisfaction with GAS is being added to assess the GAS approach in clinical practice and to guide 
future GAS work.


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Page 40, Section 9.1.7.5 
Existing Text
Revised Text
Rationale for Amendment
Page 43, Section 9.1.9 Contraception and Pregnancy Avoidance Procedure
Existing Text
From signing of informed consent, throughout the duration of the study, and for 4 weeks after last 
dose of study medication, female subjects of childbearing potential must use adequate 
contraception. In addition, they must be advised not to donate ova during this period.
Revised Text
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 must use adequate 
contraception. In addition, they must be advised not to donate ova during this period.
Rationale for Amendment
To keep language consistent with inclusion criteria. 
Page 44, Section 9.1.9.1 Definitions and Procedures for Contraception and Pregnancy 
Avoidance, Nonhormonal Methods
Existing Text
–
True sexual abstinence, only if this is in line with the preferred and usual lifestyle of 
the subject. True abstinence is defined as refraining from heterosexual intercourse 
during the entire period of the study, from 1 month prior to the first dose, throughout 
the duration of the study, and for 4 weeks after completion of the study.
Compa
ny 
Confide
ntial 
Informat
ion
Company Confidential Information
Company Confidential Information
Company Confidential Information


Vortioxetine
Study No. Vortioxetine-4003
Page 88 of 94
Protocol Amendment No. 1
18 August 2017
CONFIDENTIAL
Revised Text
–
True sexual abstinence, only if this is in line with the preferred and usual lifestyle of 
the subject. True abstinence is defined as refraining from heterosexual intercourse 
during the entire period of the study, from 1 month prior to the first dose, throughout 
the duration of the study, and for 30 days after completion of the study.
Rationale for Amendment
To keep language consistent with inclusion criteria. 
Page 45, Section 9.1.10 Pregnancy, 2nd Paragraph 
Existing Text
If the pregnancy occurs during administration of active study medication, eg, after Visit 2 or within
4 weeks 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 1.1.
Revised Text
If the pregnancy occurs during administration of active study medication, eg, after Visit 2 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 1.1.
Rationale for Amendment
To keep language consistent with inclusion criteria. 
Page 46, Section 9.1.11 PGx Sample Collection, 3rd Paragraph 
Existing Text
Two whole blood samples (2.5 mL per sample) for RNA isolation will be collected at the Baseline 
Visit before dosing and at the Week 12/Early Termination (Visit 6) into plastic K2EDTA 
spray-coated tubes, and stored under frozen conditions.
Revised Text
Two whole blood samples (2.5 mL per sample) for RNA isolation will be collected at the Baseline 
Visit before dosing and at the Week 12/Early Termination (Visit 6) into PAXgene tubes, and 
stored under frozen conditions.
Rationale for Amendment
Incorrect collection tube was listed.
Page 47, Section 9.3.1 Screening Visit 1 (Days -21 to -1)
Existing Text
Subjects will may be screened within 21 days prior to Baseline. Procedures to be completed during 
the Screening Visit are detailed in Appendix A. Subjects will be screened in accordance with 
predefined inclusion and exclusion criteria as described in Section 7.0. See Section 9.1.12 for 


Vortioxetine
Study No. Vortioxetine-4003
Page 89 of 94
Protocol Amendment No. 1
18 August 2017
CONFIDENTIAL
procedures for documenting screening failures. IxRT will be accessed for the subject screening 
number. The Screening and Baseline Visits may be combined if determined appropriate per the 
investigator. Any procedure that is to be performed at both visits should only be conducted once 
for a combined visit. 
Revised Text
Subjects will may be screened within 21 days prior to Baseline. Procedures to be completed during 
the Screening Visit are detailed in Appendix A. Subjects will be screened in accordance with 
predefined inclusion and exclusion criteria as described in Section 7.0. See Section 9.1.12 for 
procedures for documenting screening failures. IxRT will be accessed for the subject screening 
number. The factors for determining a change/discontinuation from the prior antidepressant 
as assessed by the subject and by the investigator will be collected. The Screening and 
Baseline Visits may be combined if determined appropriate per the investigator. Any procedure 
that is to be performed at both visits should only be conducted once for a combined visit. 
Rational for Amendment 
This was noted at Baseline only, but should collected at Screening or combined 
Screening/Baseline Visit.
Page 48, Section 9.3.5 Final Visit or Early Termination
Existing Text
The Final Visit will be performed at Visit 7 (Week 12) or at Early Termination Visit. For all 
subjects receiving study drug, the investigator must complete the End of Study eCRF page. 
Procedures to be completed during Final Visit/Early Termination Visit are detailed in Appendix A.
For subjects who permanently discontinue study drug early, all Final Visit/Early Termination 
assessments detailed in Appendix A should be performed in close proximity to, or at the time of, 
study drug discontinuation. 
The factors for determining a change/discontinuation from the prior antidepressant as assessed by 
the subject and by the investigator will be collected at the Final Visit and Early Termination (as 
applicable). Additionally at the End of Study Visit the Clinician satisfaction with the change in
antidepressant will be collected. 
Revised Text
The Final Visit will be performed at Visit 7 (Week 12) or at Early Termination Visit. For all 
subjects receiving study drug, the investigator must complete the End of Study eCRF page. 
Procedures to be completed during Final Visit/Early Termination Visit are detailed in Appendix A.
For subjects who permanently discontinue study drug early, all Final Visit/Early Termination 
assessments detailed in Appendix A should be performed in close proximity to, or at the time of, 
study drug discontinuation. 
At the End of Study Visit the Clinician and subject satisfaction with the antidepressant treatment
will be collected. In addition, Clinician and subject satisfaction with the GAS approach as a 


Vortioxetine
Study No. Vortioxetine-4003
Page 90 of 94
Protocol Amendment No. 1
18 August 2017
CONFIDENTIAL
method for establishing treatment goals, evaluating progress towards treatment goals, and 
improving communication between clinicians and patients will be collected.
Rational for Amendment 
Documentation of antidepressant change, and satisfaction with change in treatment was noted in 
Section 9.3, but was not listed in the table of procedures in error. Clinician and subjects 
satisfaction with GAS is being added to assess the GAS approach in clinical practice and to guide 
future GAS work.
Page 52, Section 10.1.4 SAEs, Criterion #5
Existing Text
Leads to a CONGENITAL ANOMALY/BIRTH DEFECT.
Revised Text
Is a CONGENITAL ANOMALY/BIRTH DEFECT.
Rationale for Amendment
Error in original text.
Page 64, Section 13.1.3 Effectiveness Analysis
New Text
Additional analysis will be performed for other additional endpoints, if necessary. 
Rationale for Amendment
To allow for analysis of additional endpoints.
Page 64, Section 13.2 Interim Analysis and Criteria for Early Termination
Existing Text
No further subjects will be enrolled once approximately 60 subjects have completed their Week 12 
visit. At this point, an interim futility analysis will be performed. If the futility criteria is met, the 
study will be stopped. Otherwise, an additional 60 subjects will be enrolled. The end of the study 
will be the date of the last safety follow-up visit of the last subject based either on the first 60 
completed subjects or the final 120 completed subjects. 
Revised Text
An interim analysis will be performed once 60 subjects complete the study. A futility 
assessment will be done at this time. If the futility criteria is met, the study may be stopped. The 
end of the study will be the date of the last safety follow-up visit of the last subject completed. 
Rationale for Amendment
Analysis will be completed once 60 subjects have completed, but enrollment will not be stopped.


Vortioxetine
Study No. Vortioxetine-4003
Page 91 of 94
Protocol Amendment No. 1
18 August 2017
CONFIDENTIAL
Page 74, Appendix A Schedule of Study Procedures Telephone Follow-up Window
Existing Text
Telephone 
Follow-up 
Visit 8
Wk 16 
Day 113 
(± 3 Days) 
Revised Text
Telephone 
Follow-up 
Visit 8
Wk 16 
Day 113 
(± 7 Days) 
Rationale for Amendment
Clarification of text to match the body of the protocol. 
Page 75, Appendix A Schedule of Study Procedures
Existing Text
Screening 
Treatment
Telephone 
Follow-up 
Visit 1 (a)
Baseline
Visit 2 (a) 
Day 1 
Visit 3 
Wk 2 
Telephone 
Contact
Visit 4
Wk 4
Visit 5 
Wk 6 
Telephone 
Contact
Visit 6
Wk 9
End of Study 
Visit 7 
Wk 12 /Early 
Termination
Visit 8
Wk 16 
Days -21 
up to -1 
Day 1 
Day 15 
(±3 
Days) 
Day 29
(±3 Days)
Day 43
(±5 
Days) 
Day 64
(±5 Days)
Day 85
(±5 Days) 
Day 113
(± 3 Days)
PTE/AE assessment
X
X
X
X
X
X
X
X
Pregnancy testing and 
pregnancy avoidance 
counseling (e,f)
X
X
X
X
X
Access IxRT for subject 
ID/ medication ID/subject 
status
X
X
X
X
X
Dispense study drug 
X
X
X
Dose adjustment (as 
needed) (g)
X
X


Vortioxetine
Study No. Vortioxetine-4003
Page 92 of 94
Protocol Amendment No. 1
18 August 2017
CONFIDENTIAL
Screening 
Treatment
Telephone 
Follow-up 
Visit 1 (a)
Baseline
Visit 2 (a) 
Day 1 
Visit 3 
Wk 2 
Telephone 
Contact
Visit 4
Wk 4
Visit 5 
Wk 6 
Telephone 
Contact
Visit 6
Wk 9
End of Study 
Visit 7 
Wk 12 /Early 
Termination
Visit 8
Wk 16 
Days -21 
up to -1 
Day 1 
Day 15 
(±3 
Days) 
Day 29
(±3 Days)
Day 43
(±5 
Days) 
Day 64
(±5 Days)
Day 85
(±5 Days) 
Day 113
(± 3 Days)
Study drug 
return/accountability/ 
compliance
X
X
X
(a) Screening and Baseline Visits may be combined as determined appropriate per the investigator. Any procedure that is to be
performed at both visits should only be conducted once for a combined visit. 
(b) UDS to be done at Screening and Baseline. UDS kits will be supplied by the sponsor for the testing at the clinic. UDS results 
must be negative. This includes benzodiazepines and opiates for which there is no prescription (including oxycodone) at Screening 
and Baseline. Results must be confirmed prior to conducting the Baseline Visit.
(c) Height at Screening only; weight at Screening, Baseline, and Week 12.
(d) Subjects who signed an informed consent for pharmacogenomic testing will have blood samples for PGx analysis and these will 
be collected as follows: 2×3 mL for DNA on Day 1; 2×2.5 mL for RNA predose on Day 1 and at Week 12 (Visit 6).
(e) Urine hCG pregnancy tests will be performed at Screening and Baseline and for all other visits during the Treatment Period for 
women of childbearing potential only. Serum hCG pregnancy tests will be performed at Baseline and End of Study/Early 
Termination visits for all females. For combined Screening and Baseline Visits, there will be 1 urine and 1 serum hCG. Subjects 
may be enrolled with a negative urine hCG; however if the serum hCG is positive the subject must be withdrawn from study drug
immediately and withdrawn from the study as soon as possible.
(f) Subject who are women of childbearing potential 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 
of pregnancy and donation of ova during the course of the study and for 4 weeks after the last dose of study drug.
(g) Dose adjustments should occur during regularly scheduled visits, or subjects should return for an Unscheduled Visit.
Revised Text
Screening 
Treatment
Telephone 
Follow-up 
Visit 1 (a)
Baseline
Visit 2 (a) 
Day 1 
Visit 3 
Wk 2 
Telephone 
Contact
Visit 4
Wk 4
Visit 5 
Wk 6 
Telephone 
Contact
Visit 6
Wk 9
End of Study 
Visit 7 
Wk 12 /Early 
Termination
Visit 8
Wk 16 
Days -21 
up to -1 
Day 1 
Day 15 
(±3 
Days) 
Day 29
(±3 Days)
Day 43
(±5 
Days) 
Day 64
(±5 Days)
Day 85
(±5 Days) 
Day 113
(± 7 Days) 
Document factors for 
determining a 
change/discontinuation 
from prior 
antidepressant (e)
X
PTE/AE assessment
X
X
X
X
X
X
X
X
Pregnancy testing and 
pregnancy avoidance 
counseling (f,g)
X
X
X
X
X


Vortioxetine
Study No. Vortioxetine-4003
Page 93 of 94
Protocol Amendment No. 1
18 August 2017
CONFIDENTIAL
Screening 
Treatment
Telephone 
Follow-up 
Visit 1 (a)
Baseline
Visit 2 (a) 
Day 1 
Visit 3 
Wk 2 
Telephone 
Contact
Visit 4
Wk 4
Visit 5 
Wk 6 
Telephone 
Contact
Visit 6
Wk 9
End of Study 
Visit 7 
Wk 12 /Early 
Termination
Visit 8
Wk 16 
Days -21 
up to -1 
Day 1 
Day 15 
(±3 
Days) 
Day 29
(±3 Days)
Day 43
(±5 
Days) 
Day 64
(±5 Days)
Day 85
(±5 Days) 
Day 113
(± 7 Days) 
Access IxRT for subject 
ID/ medication ID/subject 
status
X
X
X
X
X
Dispense study drug 
X
X
X
Dose adjustment (as 
needed) (h)
X
X
Clinician and subject 
satisfaction with change 
in antidepressant
X
Clinician and subject
satisfaction with GAS 
approach
X
Study drug 
return/accountability/ 
compliance
X
X
X
(a) Screening and Baseline Visits may be combined as determined appropriate per the investigator. Any procedure that is to be
performed at both visits should only be conducted once for a combined visit. 
(b) UDS to be done at Screening and Baseline. UDS kits will be supplied by the sponsor for the testing at the clinic. UDS results 
must be negative. This includes benzodiazepines and opiates for which there is no prescription (including oxycodone) at Screening 
and Baseline. Results must be confirmed prior to conducting the Baseline Visit.
(c) Height at Screening only; weight at Screening, Baseline, and Week 12.
(d) Subjects who signed an informed consent for PGx testing will have blood samples for PGx analysis and these will be collected 
as follows: 2×3 mL for DNA on Day 1; 2×2.5 mL for RNA predose on Day 1 and at Week 12 (Visit 6).
(e) To be collected at Screening or combined Screening/Baseline Visit.
(f) Urine hCG pregnancy tests will be performed at Screening and Baseline and for all other visits during the Treatment Period for 
women of childbearing potential only. Serum hCG pregnancy tests will be performed at Baseline and End of Study/Early 
Termination visits for all females. For combined Screening and Baseline Visits, there will be 1 urine and 1 serum hCG. Subjects 
may be enrolled with a negative urine hCG; however if the serum hCG is positive the subject must be withdrawn from study drug
immediately and withdrawn from the study as soon as possible.
(g) Subject who are women of childbearing potential 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 
of pregnancy and donation of ova during the course of the study and for 30 days after the last dose of study drug.
(h) Dose adjustments should occur during regularly scheduled visits, or subjects should return for an Unscheduled Visit.
Rationale for Amendment
Documentation of antidepressant change, and satisfaction with change in treatment was noted in 
Section 9.3, but was not listed in the table of procedures in error. Clinician and subjects 
satisfaction with GAS is being added to assess the GAS approach in clinical practice and to guide 
future GAS work. Footnote e was added and subsequent footnotes were renumbered. Footnote g 
was edited to match inclusion criteria and section 9.1.10.


Vortioxetine
Study No. Vortioxetine-4003
Page 94 of 94
Protocol Amendment No. 1
18 August 2017
CONFIDENTIAL
Page 80, Appendix C, Elements of the Subject Informed Consent, Item #25
Existing Text
Female women of childbearing potential (eg, nonsterilized, premenopausal female subjects) who 
are sexually active must use highly effective contraception (as defined in the informed consent) 
from Screening throughout the duration of the study, and for 5 half lives PLUS 4 weeks after last 
dose. Regular pregnancy tests will be performed throughout the study for all female women of 
childbearing potential. If a subject is found to be pregnant during study, study drug will be 
discontinued and the investigator will offer the subject the choice to receive unblinded treatment 
information.
Revised Text
Female women of childbearing potential (eg, nonsterilized, premenopausal female subjects) who 
are sexually active must use highly effective contraception (as defined in the informed consent) 
from Screening throughout the duration of the study, and for 5 half lives PLUS 30 days after last 
dose. Regular pregnancy tests will be performed throughout the study for all female women of 
childbearing potential. If a subject is found to be pregnant during study, study drug will be 
discontinued and the investigator will offer the subject the choice to receive unblinded treatment 
information.
Rationale for Amendment
To keep language consistent with inclusion criteria. 


 
  
 
 
 
 
 
 
 
 
ELECTRONIC SIGNATURES 
Signed by 
Meaning of Signature 
Server Date 
(dd-MMM-yyyy HH:mm ‘UTC’) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
090101d68069322a
Amendment 1 An Open-Label, Single-Arm, Multicenter, Prospective, Phase 4, Interventional, Flexible Dose
Study to Evaluate the Effectiveness of Vortioxetine on Goal Achievement After a Change in Antidepressant
Medication for the Treatment of Subjects With Major Depressive Disorder
Biostatistics Approval
22-Aug-2017 17:32 UTC
Pharmacovigilance Approval
22-Aug-2017 17:36 UTC
Clinical Operations Approval
22-Aug-2017 22:19 UTC
Clinical Science Approval
22-Aug-2017 22:53 UTC
Personal Protected Data

SAP_000.pdf: 
This may include, but is not limited to, redaction of the following: 


• Other information as needed to protect confidentiality of Takeda or partners, personal
information, or to otherwise protect the integrity of the clinical study.
Title: An Open-Label, Single-Arm, Multicenter, Prospective, Phase 4, Interventional, 
Flexible Dose Study to Evaluate the Effectiveness of Vortioxetine on Goal Achievement 
After a Change in Antidepressant Medication for the Treatment of Subjects With Major
Depressive Disorder
NCT Number:  NCT02972632
SAP Approve Date: 15 February 2018
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 information or company confidential information. 
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.


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Vortioxetine-4003 
Page 2 of 26
Statistical Analysis Plan [Ver 2.0] 
15 February, 2018
 
CONFIDENTIAL 
CONFIDENTIAL PROPERTY OF TAKEDA 
This document is a confidential communication of Takeda. Acceptance of this document 
constitutes the agreement by the recipient that no information contained herein will be published 
or disclosed without written authorization from Takeda. 


Personal Protected Data


Vortioxetine-4003 
Page 4 of 26
Statistical Analysis Plan [Ver 2.0] 
15 February, 2018
 
CONFIDENTIAL 
2.0 
TABLE OF CONTENTS 
1.0 
TITLE PAGE .......................................................................................................................1 
1.1 
Approval Signatures.......................................................................................................3 
2.0 
TABLE OF CONTENTS .....................................................................................................4 
List of In-Text Tables ................................................................................................................5 
List of In-Text Figures ...............................................................................................................5 
3.0 
LIST OF ABBREVIATIONS ..............................................................................................6 
4.0 
OBJECTIVES ......................................................................................................................8 
4.1 
Primary Objective ..........................................................................................................8 
4.2 
Secondary Objectives.....................................................................................................8 
4.3 
Additional Objectives ....................................................................................................8 
4.4 
Study Design ..................................................................................................................8 
5.0 
ANALYSIS ENDPOINTS ................................................................................................11 
5.1 
Primary Endpoint .........................................................................................................11 
5.2 
Secondary Endpoints ...................................................................................................11 
5.3 
Additional Endpoints ...................................................................................................12 
5.4 
Safety Assessments ......................................................................................................12 
6.0 
DETERMINATION OF SAMPLE SIZE ..........................................................................13 
7.0 
METHODS OF ANALYSIS AND PRESENTATION .....................................................14 
7.1 
General Principles ........................................................................................................14 
7.1.1 Definition of Study Days .......................................................................................14 
7.1.2 Definition of Visit Window ...................................................................................14 
7.2 
Analysis Sets ................................................................................................................15 
7.3 
Disposition of Subjects ................................................................................................15 
7.4 
Demographic and Other Baseline Characteristics .......................................................15 
7.5 
Medical History and Concurrent Medical Conditions .................................................15 
7.6 
Medication History and Concomitant Medications .....................................................16 
7.7 
Study Drug Exposure and Compliance ........................................................................16 
7.8 
Efficacy Analysis .........................................................................................................17 
7.8.1 Primary Efficacy Endpoint ....................................................................................17 
7.8.2 Secondary Efficacy Endpoint(s) ............................................................................18 
7.8.3 Additional Efficacy Endpoint(s) ............................................................................20 
7.8.4 Analyses for Secondary and Additional Endpoints ...............................................21 
7.9 
Safety Analysis ............................................................................................................22 
7.9.1 Adverse Events ......................................................................................................22 


Vortioxetine-4003 
Page 5 of 26
Statistical Analysis Plan [Ver 2.0] 
15 February, 2018
 
CONFIDENTIAL 
7.9.2 Vital Signs and Weight ..........................................................................................23 
7.9.3 Other Observations Related to Safety ....................................................................24 
7.10 
Interim Analysis ...........................................................................................................24 
7.11 
Changes in the Statistical Analysis Plan ......................................................................24 
8.0 
REFERENCES ..................................................................................................................25 
 
 
LIST OF IN-TEXT TABLES 
 
Appendix A. Criteria for Identification of Markedly Abnormal Values for Vital Signs 
 
 
LIST OF IN-TEXT FIGURES 
 Figure 2.a   Schematic of Study Design 
 
 


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Vortioxetine-4003 
Page 8 of 26
Statistical Analysis Plan [Ver 2.0] 
15 February, 2018
 
CONFIDENTIAL 
4.0 
OBJECTIVES 
4.1 
Primary Objective 
To determine the effectiveness of treatment with vortioxetine on subject goal achievement after a 
change in antidepressant medication for the treatment of major depressive disorder (MDD). 
4.2 
Secondary Objectives 
To determine the effectiveness of treatment with vortioxetine on depressive symptoms/outcomes, 
clinical global impression, cognitive impairment, and quality of life in subjects with MDD. 
4.3 
Additional Objectives 
• To determine the effectiveness of treatment with vortioxetine on cognitive performance and 
functionality in subjects with MDD. 
• To determine the effectiveness of treatment with vortioxetine on work performance in 
subjects with MDD. 
• To determine the effectiveness of treatment with vortioxetine on general health status and 
well-being in subjects with MDD. 
• To assess health care utilization and the safety and tolerability of vortioxetine in subjects 
with MDD. 
4.4 
Study Design 
This study is an open-label, single-arm, multicenter, prospective, phase 4, interventional, flexible 
dose study (as per the Trintellix US package insert) to determine the effectiveness of treatment 
with vortioxetine on subject goal achievement after a change in antidepressant medication for the 
treatment of MDD. 
This study is comprised of a 3-week Screening Period (maximum 21 days), to be followed by a 
12-week Treatment Period and a 4-week Safety Follow-up Period. Study visits will occur at 
Baseline (Day 1), and Weeks 2, 4 (Telephone), 6, 9 (Telephone), and 12. This study will enroll 
approximately 120 subjects and will be conducted at approximately 25 sites in the United States.  
This study will enroll men and women between the ages of 18 and 65, inclusive, with a primary 
diagnosis of MDD, who have previously been treated within 6 weeks of Screening or are 
currently being treated for a major depressive episode (MDE) with an approved antidepressant 
for 6 weeks or longer at an adequate dose. Subjects who are dissatisfied with their current or 
recent antidepressant and are interested in a change in antidepressant treatment will be eligible 
for Screening. 
The change in antidepressant medication will be based on the investigator’s judgment in 
collaboration with the subject’s level of dissatisfaction with their current or recent antidepressant 
treatment (ie, residual mood symptoms, intolerable side effects). Subjects also need to be eligible 


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CONFIDENTIAL 
per the Trintellix US package insert and sign and date a written, informed consent form and any 
required privacy authorization prior to the initiation of any study procedures. 
The investigator or the investigator’s designee will access the Interactive Response Technology 
(IxRT) at Screening to obtain the subject study number. At the Baseline Visit, if the subject has 
satisfied all of the inclusion criteria and none of the exclusion criteria for enrollment, the subject 
will be enrolled using the IxRT. Subjects will be instructed on when to take the first dose of 
study drug. The dosing (both initial and adjustments) will be determined by investigator or 
designee as per routine clinical practice and per approved Trintellix labeling. Subjects will 
determine treatment goals with their clinicians using the Goal Attainment Scale (GAS) adapted 
for an MDD population. The subject and clinician will work to establish 3 goals at Baseline. One 
goal will be determined based on the subject’s self-defined objectives. Two goals will be 
selected from the following predefined categories representing MDD residual symptoms, 
antidepressant side effects, and common reasons for a change in antidepressant medication, 
including but not limited to:  
MDD Domains 
Psychological 
Motivation 
Emotional 
Physical/ 
Functional 
Cognition 
Predefined goal 
categories: 
-Depressed mood 
-Anxious mood 
-Lack of 
motivation 
-Low self 
esteem 
-Anhedonia 
-Fatigue 
-Insomnia  
-Muscle 
tension  
-Sexual 
dysfunction 
-Weight gain 
-Problems 
concentrating 
-Short term memory 
problems 
-Difficulty staying 
focused  
-Difficulty paying 
attention 
-Problems thinking 
clearly 
 
A prepopulated list of categories will be provided in the structured guidance for goal assessment, 
including behavioral examples describing goals and observable benchmarks to help clinicians set 
the appropriate goals with subjects. Goals will be set at Baseline/Visit 1. Progress will be 
evaluated at the Week 6 visit. At the Final Visit the goals will be assessed based on levels of 
achievement on a 5-point scale. Investigators will be trained on goal setting/goal assessment and 
monitored for ability in key domains of goal setting (eg, attainability of goals, use of observable 
objectives and benchmarks, equidistance of scaling, general level of difficulty, goal 
differentiation, and overall quality). 
A safety follow-up phone call will be made 4 weeks after completion of the 12 weeks of 
treatment. Subjects who discontinue or who are withdrawn prior to study completion will come 
to the site for an Early Termination Visit as soon as possible and will be contacted for a safety 
follow-up 4 weeks after the last dose of study medication.  


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Enrollment caps may be implemented throughout the course of the study based on the patient 
reported outcome (ie, Patient Health Questionnaire (PHQ-9) and Perceived Deficits 
Questionnaire-Depression (PDQ-D)) scores at Baseline. 
A futility analysis will be performed at an interim analysis with approximately 60 subjects 
completing Week 12.  If the futility analysis indicates that the study should be discontinued, the 
final analyses will be conducted for all enrolled subjects.  Details for the futility analyses are in 
the Interim Analysis section of this SAP. 
Figure 4.a 
Schematic of Study Design 
 
(a) Recommended starting dosage is 10 mg/day as ideal dosage. Dosage may be decreased to 5 mg/day at discretion 
of the investigator or designee. 
(b) If all screening activities are completed and the subject meets the eligibility criteria the Screening and Baseline 
Visits can be combined into 1 visit. 
(c) Subjects currently on an antidepressant at Screening will be discontinued in a manner that is consistent with 
labeling recommendations and conventional medical practice prior to Baseline. 


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CONFIDENTIAL 
6.0 
DETERMINATION OF SAMPLE SIZE 
As no formal hypothesis testing is performed for the primary endpoint, the purpose of sample 
size estimation is to determine the adequate sample size needed to provide a precise estimate for 
the response rate (GAS Score ≥50) with 95% CIs.  
Conservatively estimating that 50% of subjects will be responders (GAS>50) and that 100 
subjects will complete the study, CIs will be +0.098 around the point estimate (proportion of 
responders). 


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7.0 
METHODS OF ANALYSIS AND PRESENTATION 
7.1 
General Principles  
This is an open-label study with a single treatment regimen and all comparisons are made to the 
conditions prior to the subject being switched to vortioxetine. 
Baseline values are defined as the last observed value before the first dose of study switch 
medication.  
All statistical analyses will be conducted using SAS® Version 9.2, or higher. 
All confidence intervals, statistical tests, and resulting P-values will be reported as 2-sided and 
will be assessed at α=0.05 significance level unless otherwise stated.  P-values will be rounded to 
3 decimal places prior to assessment of statistical significance.    
Means and medians will be presented to 1 more decimal place than the recorded data. The 
standard deviations (SDs) will be presented to 2 more decimal places than the recorded data. 
Confidence intervals about a parameter estimate will be presented using the same number of 
decimal places as the parameter estimate. 
Where appropriate, variables will be summarized descriptively by study visit. For the categorical 
variables, the count and proportions of each possible value will be tabulated. The denominator 
for the proportion will be based on the number of subjects who provided non-missing responses 
for the categorical variable. For continuous variables, the numbers of subjects with non-missing 
values, mean, median, SD, minimum, and maximum values will be tabulated.  
7.1.1     Definition of Study Days 
Study Day 1 is defined as the date on which a subject is administered their first dose of the 
vortioxetine medication. Other study days are defined relative to the Study Day 1 with Day 1 
being Study Day 1 and Day -1 being the day prior to Study Day 1. 
7.1.2    Definition of Visit Window 
 
The window definitions as stated will be applicable for all the summaries where study visit data 
is presented and where study visit data are compared with baseline data. The window 
conventions for safety and efficacy parameters are consecutive; that is, the lower or upper bound 
of the windows is the midpoint between 2 consecutive study visits. 
One or more results for a parameter may be obtained in a visit window. In such an event, the 
result with the closest date to the scheduled visit date will be used. In the event of 2 observations 
within a given visit window being equidistant to the scheduled visit date, the later observation 
will be used. 
 


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7.2 
Analysis Sets 
In this study, 3 kinds of analysis sets are defined: full analysis set (FAS), per protocol set (PPS) 
and safety analysis set.  
The FAS, used for primary effectiveness analysis, will include all subjects who were enrolled in 
the treatment period and received at least 1 dose of the study drug and completed at least 1 GAS 
assessment post-Baseline. In FAS effectiveness summaries, subjects will be considered as 
vortioxetine-treated no matter what dose levels were received during the study.  
A 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 
prescribed by the treating physician, will be identified in the minutes of the subject evaluability 
assessment.  
The Safety Analysis Set will include all subjects who were enrolled and received at least 1 dose 
of study medication. In safety summaries, all subjects will be analyzed as vortioxetine-treated. 
The sponsor will verify the validity of the definitions of the analysis sets as well as the rules for 
handling data, with consulting a medical expert as needed. If necessary, the Handling Rules for 
Analysis Data will be supplemented with new handling rules that were not discussed at the 
planning stage. The Handling Rules for Analysis Data must be finalized prior to database lock. 
7.3 
Disposition of Subjects 
A subject disposition summary will be provided. The categories will include all subjects who 
were enrolled, subjects who were not treated, subjects who discontinued from the study 
categorized by reason, and subjects who completed the study. The primary reasons for 
discontinuation will include AE, major protocol deviation, lost to follow-up, study termination, 
pregnancy, lack of efficacy, voluntary withdrawal, and other. 
A summary of screening failures and listings of inclusion/exclusion criteria responses for 
subjects with violations will also be provided.  
7.4 
Demographic and Other Baseline Characteristics 
Baseline characteristics will be listed and summarized for demographics (sex, age, race, and body 
mass index), and medical history for the safety analysis set. 
Categorical variables will be summarized using frequencies and percentages. Continuous 
variables will be summarized using mean, SD, median, maximum and minimum values.  
7.5 
Medical History and Concurrent Medical Conditions 
Medical history refers to the significant conditions/diseases that stopped at or prior to signing of 
informed consent. Concurrent medical conditions are those significant ongoing 
conditions/diseases present at signing of informed consent. 
Medical history and psychiatric history and concurrent medical conditions will be coded using 
the latest version of Medical Dictionary for Regulatory Activities (MedDRA) and will be 


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summarized in tables using System Organ Class (SOC) and MedDRA preferred term. The tables 
will include numbers and percentages of subjects and will be sorted in alphabetical order by 
system organ class and preferred term. A subject will only be counted once within a particular 
class even if he/she has multiple conditions/symptoms. Summaries will be based on the safety 
analysis set. 
All medical history and concurrent medical condition data will be presented in listings. 
7.6 
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 
30 days prior to signing of informed consent (ie, stop date < informed consent date).  
• Concomitant medication is defined as medication that the study subjects continued taking or 
took from signing of informed consent through end of study: 
– Concomitant medication that started and stopped prior to baseline (ie, stop date 
≥ informed consent date, and stop date ≤ first dose date). 
– Concomitant medication that started prior to and was ongoing at baseline (ie, start date 
< first dose date, and stop date > first dose date) or if coded as ongoing with no stop date. 
– Concomitant medication that started after baseline but before or at last dose (ie, start date 
≥ first dose date, and start date ≤ last dose date). 
– Concomitant medication that started prior to and was ongoing at baseline or that started 
after baseline (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. 
Medication history and concomitant medications will be coded using the latest 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 subjects with 
medications in each selected therapeutic class will also be presented. 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 the safety 
analysis set.  
All prior and concomitant medications data will be presented in listings. 
7.7 
Study Drug Exposure and Compliance 
The summary of study drug exposure and compliance will be based on the safety analysis set.  
Duration of exposure to study medication is defined as (date of last dose – date of first dose +1). 
Treatment duration will be summarized by duration category in weeks (1 to 2 weeks, 3 to 4 
weeks, 5 to 6 weeks, 7 to 8 weeks, 9 to 10 weeks, and 11 to >12 weeks) and the number and 


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percentage of subjects in each duration category. Treatment duration (days) will also be 
summarized using descriptive statistics (n, mean, SD, median, minimum, and maximum). 
Percent of study drug compliance is defined as {(number of tablets dispensed – number of tablets 
returned)/(date of last dose – date of first dose +1)}x100%. If a value for the number of returned 
tablets is missing or the return date is missing, then 100% compliance will be assigned for each 
day up to the number of tablets dispensed or up to the date of return whichever is earlier.  
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). 
All study drug administration and accountability data will be listed by 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 tablets 
dispensed and returned, and percent compliance.  
7.8 
Efficacy Analysis 
The primary objective of the study is to determine the effectiveness of treatment with 
vortioxetine on subject goal achievement after changing antidepressant medication for treatment 
of MDD. The primary endpoint is the proportion of subjects who changed to treatment with 
vortioxetine and achieved their individually identified goals as demonstrated by an outcome 
GAS Score of ≥50 at Week 12. This proportion will be summarized at Week 12.  All efficacy 
analyses will use the FAS. 
7.8.1 Primary Efficacy Endpoint 
The GAS is a tool to measure the progress each subject has towards achieving their 
individualized goals. While the outcome measure is unique to each subject, standardized scoring 
is applied to allow for statistical analysis.  
The GAS allows for 1 of 2 types of goals to be set: 
(1) Subject defined goals allow a “subject’s chief complaint” approach taken towards 
establishing the goal, with no specific limitations set for the type or focus of the goal, 
beyond requiring that it meets the basic standards of measurability, equidistance, and 
difficulty. 
(2) Domain-defined goals are more structured in nature, presenting the subject with an array 
of broadly defined domains and more specific subdomains. After selecting an appropriate 
domain and (where applicable) subdomain, the clinician will work with the subject to 
establish a specific goal that fits within the selected category. 
For GAS, a total of 3 goals will be selected, 1 subject defined and 2 from pre-defined domain 
categories. A 5-point rating scale will then be applied to each of the 3 goals. A semi-structured 
interview will be conducted with each subject to conduct goal-setting at the outset of the study. 


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Another evaluation will take place at Week 6 and Week 12/End of Study visits or at Early 
Termination Visit (as applicable) to determine the level of progress at that time, with assignment 
of appropriate scores. It takes subjects approximately 45 minutes to complete the GAS.  
 
Calculating the Overall GAS 
 
The goals identified are incorporated into the single GAS score by applying a formula: 
 
 
Overall GAS =  50 + 
10∗∑(𝑤𝑖𝑥𝑖)
√(1−𝜌) ∑𝑤𝑖
2+ 𝜌(∑𝑤𝑖)2   
 
Where: 
wi = the weight assigned to the ith goal (if equal weights, wi = 1) 
xi = the numerical value achieved (between –2 and + 2) 
 = the expected correlation of the goal scales   
(For practical purposes, most commonly approximates to =0.3) 
 
For this study, a choice of weight is based on importance of the goal.  Weight is 1, 2, and 3 for 
least important, moderately important and most important goals, respectively. The expected 
correlation of 0.3 was selected for this study. 
 
The GAS will be summarized for both Week  6 and Week 12 using both percents of response 
and as a continuous score.  An overall GAS score greater than 50 is considered as a response. 
 
7.8.2 Secondary Efficacy Endpoint(s) 
7.8.2.1 PHQ-9 
The PHQ-9 will be used as a secondary efficacy measure of depression severity. This is a well-
established patient reported outcome tool for assessment of change in depressive symptoms and 
is a sensitive measure of depression severity.  
The PHQ-9 consists of a 9-item scale originally developed for primary care settings, with 1 item 
corresponding to each of the 9 MDE symptom criteria for depression in DSM, asking if they 
have bothered the patient over the last 2 weeks. Each question is rated on a scale from 0 (not at 
all) to 3 (nearly every day). If any problems are answered 1 or higher, a final question on how 
difficult those problems made it to do work, take care of things at home, or get along with other 
people is completed rated from not difficult at all to extremely difficult. The 9 questions are 
summed to a total score ranging from 0 to 27 with higher scores reflecting greater severity. It 


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takes approximately 5 minutes to complete the PHQ-9.  The total score for the PHQ-9 is 
analyzed as a continuous variable. 
7.8.2.2 PDQ-D 
The PDQ-D, a validated version of the original PDQ specifically modified to depressed patients, 
will be used to evaluate self-reported cognitive complaints in patients with MDD. The PDQ was 
originally developed to assess cognitive complaints in patients with multiple sclerosis. However, 
it does address cognitive aspects highly relevant for depression, including attention and 
concentration, retrospective memory, prospective memory, and planning and organization. It 
takes approximately 10 minutes to complete the PDQ-D.  The score from the PDQ-D is analyzed 
as a continuous variable.   
7.8.2.3 Clinical Global Impression Scales 
The CGI was developed to provide global measures of the severity of a patient’s clinical 
condition during clinical studies. The CGI scales consist of 2 subscales: the CGI-S and the CGI-
I.  CGI-S and CGI-I raters will be required to have suitable experience and training (as deemed 
by sponsor) to be eligible to rate subjects within the study. The total time to score the CGI is 
approximately 1 to 2 minutes after the clinical interview. 
CGI-S 
The CGI-S is a clinician rated scale designed to assess global severity of illness and change in 
the clinical condition over time. The CGI-S provides the clinician’s impression of the patient’s 
current state of mental illness. The clinician uses his or her clinical experience of this patient 
population to rate the severity of the patient’s current mental illness on a 7-point scale ranging 
from 1 (normal - not at all ill) to 7 (among the most extremely ill patients).  The CGI-S is 
analyzed as a continuous variable. 
CGI-I 
The CGI-I assesses the subject’s improvement (or worsening). The clinician is required to assess 
the subject’s condition relative to Baseline (Randomization/Day 1) on a 7-point scale ranging 
from 1 (much improved) to 7 (much worsened). In all cases, the assessment should be made 
independent of whether the rater believes the improvement/worsening is drug-related or not.  The 
CGI-I is analyzed as a continuous variable. 
7.8.2.4 Q-LES-Q 
The Q-LES-Q is a scale designed to allow researchers to assess the degree of a subject’s quality 
of life in various areas of daily living. Ninety-one of the 93 items are assembled into 8 
categories: physical health/activities, feelings, work, household duties, school/course work, 
leisure time activities, social relations, and general activities. The items are grouped according to 
these categories and the items are each scored on a 5-point scale, from 1 (not at all or never) to 5 
(frequently or all the time), to indicate the degree of enjoyment or satisfaction experienced. 


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Vortioxetine-4003 
Page 22 of 26
Statistical Analysis Plan [Ver 2.0] 
15 February, 2018
 
CONFIDENTIAL 
In order to assess Goal Attainment Scaling as a sensitive, reliable measure of response to drug 
treatment for depression, a series of analyses will be performed to examine the GAS approach 
against other measures assessed in the study, as well as to evaluate change in GAS scores over 
time. A full description of the analysis will be described in a separate validation plan. 
 
7.9 
Safety Analysis 
7.9.1 Adverse Events 
All adverse events will be coded using the latest version of MedDRA. 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 from the safety analysis set 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). Adverse events 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 for calculating incidence rates.  
At the adverse event level, the summary tables will present the number of subjects reporting each 
of these MedDRA events, ie, the numbers 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. 
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 at least one event. 
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 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 


Vortioxetine-4003 
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Statistical Analysis Plan [Ver 2.0] 
15 February, 2018
 
CONFIDENTIAL 
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: 
• 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. 
• TEAEs by SOC and preferred term by sex (male and female) - number and percentage of 
subjects. 
• TEAEs by SOC and preferred term by age - number and percentage of subjects. 
• TEAEs by SOC - number and percentage of subjects. 
• TEAEs by preferred term - number and percentage of subjects. 
• Intensity of TEAEs by SOC and preferred term - number and percentage of subjects. 
• Relationship 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. 
• TEAEs leading to study discontinuation by SOC and preferred term - number and percentage 
of subjects. 
• Treatment-emergent Serious AEs by SOC and preferred term - number and percentage of 
subjects. 
• Most Frequent(>=5%) Treatment-emergent Non-serious AEs by SOC and preferred term - 
number and percentage of subjects. 
• Pretreatment Events by SOC and preferred term - number and percentage of subjects. 
SOCs will be sorted in alphabetical order. Within an SOC, adverse events will be sorted in 
descending order of total number of subjects with the preferred term.  
All adverse events will be presented in listing. Special listings for TEAEs leading to study 
discontinuation, SAEs and deaths will also be presented. 
7.9.2 Vital Signs and Weight 
Vital signs and weight at scheduled visits and their changes from Baseline will be summarized 
using descriptive statistics by visit and end of study. The number and percentage of subjects with 


Vortioxetine-4003 
Page 24 of 26
Statistical Analysis Plan [Ver 2.0] 
15 February, 2018
 
CONFIDENTIAL 
at least one post-Baseline MAV from vital signs during the treatment period will be presented for 
each variable over all visits. A listing of MAVs for vital signs will also be presented. 
The criteria for identification of MAV vital signs are given in Appendix A. 
7.9.3 Other Observations Related to Safety 
The C-SSRS Baseline/Screening will be administered at Screening and the Since-Last-Visit C-
SSRS will be administered at all other time points. The C-SSRS was developed by researchers at 
Columbia University as a tool to help systematically assess suicidal ideation and behavior in 
subjects during participation in a clinical trial of centrally acting drugs. The C-SSRS is 
composed of 3 questions addressing suicidal behavior and 5 questions addressing suicidal 
ideation, with sub-questions assessing severity. The tool is administered via an interview with 
the subject. If possible, the same interviewer should be used throughout the study for the same 
subject. It takes approximately 10 minutes to complete the C-SSRS.  
7.10 
Interim Analysis 
The responder rate based on GAS score >=50 will be calculated. The conditional probability of a 
responder rate of less than 50% at 120 subjects will be assessed; that is, using the data /trend of 
60 patients at the interim look, the probability of (responder rate < 50%) at the end of study (i.e., 
120 subjects) will be calculated.    
In addition, the change in PHQ9 and PDQ will be evaluated for internal decision making. 
The report to be prepared for the interim analysis should include the tables for the following: 
demographics, disposition, GAS Response percents, GAS change from baseline, PHQ-9, and 
PDQ-D.   
The end of the study will be the date of the last safety follow-up visit of the last subject based 
either on the first 60 completed subjects or the final 120 completed subjects.   
7.11 
Changes in the Statistical Analysis Plan  
To be identified. 


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Statistical Analysis Plan [Ver 2.0] 
15 February, 2018
 
CONFIDENTIAL 
8.0 
REFERENCES 
Turner-Stokes, Lynne;  Goal Attainment Scaling (GAS) in Rehabilitation: A Practical Guide.  
Clinical Rehabilitation 2009, 23: 362-370.   
 


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Statistical Analysis Plan [Ver 2.0] 
15 February, 2018
 
CONFIDENTIAL 
Appendix A. Criteria for Identification of Markedly Abnormal Values for Vital Signs 
 
Parameter 
Unit 
MAV Definition (a)  
Systolic Arterial BP 
mmHg  
< 85 mmHg or >180 mmHg  
Diastolic Arterial BP 
mmHg 
<50 mmHg or >110 mmHg 
Pulse 
beats per minute 
<50 bpm or >120 bpm 
Weight 
kg 
Change of 7% body weight 
BP=Blood pressure. 
(a) MAV criteria are applied to postbaseline values and changes relative to Baseline values, as appropriate.