Clinical trial NCT02932904
Conditions: Healthy Volunteers
Keywords: Drug therapy
Sponsor: Takeda
Start date: 2016-11-21; Completion date: 2017-06-09
Enrollment: 361 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of this study is to evaluate the effect of vortioxetine (10 and 20 mg, once daily) versus paroxetine (20 mg, once daily) on sexual functioning in healthy participants after 5 weeks of double-blind treatment.

Detailed description:
The drug being tested in this study is called vortioxetine. This study will look at the effect of treatment on sexual functioning in healthy participants.

The study will enroll approximately 352 participants. Participants will be randomly assigned (by chance, like flipping a coin) to one of the four treatment groups-which will remain undisclosed to the patient and study doctor during the study (unless there is an urgent medical need):

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

All participants will be asked to take one tablet/capsule, daily, orally for up to 5 weeks.

This multicenter trial will be conducted in United States. The overall time to participate in this study is approximately 7 weeks. Participants will be contacted by telephone 2 weeks after last dose of study drug for a follow-up assessment.

Arms: arm 1: Vortioxetine 10 mg, overencapsulated tablets, orally, once daily for up to 5 weeks. arm 2: Vortioxetine 10 mg, overencapsulated tablets, orally, once daily for up to 1 week followed by vortioxetine 20 mg, overencapsulated tablets, orally, once daily from Week 2, up to 4 weeks. arm 3: Paroxetine 20 mg, overencapsulated tablets, orally, once daily for up to 5 weeks. arm 4: Vortioxetine placebo matching-capsules, orally, once daily for up to 5 weeks.
Interventions: intervention 1: Vortioxetine intervention 2: Paroxetine intervention 3: Placebo
Intervention descriptions: intervention 1: Vortioxetine Overencapsulated Tablet intervention 2: Paroxetine Overencapsulated Tablets. intervention 3: Vortioxetine Placebo-matching Capsules.

Protocol documents:
Prot_000.pdf: 
This may include, but is not limited to, redaction of the following: 


•
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.
Title: Title: Randomized, Double-Blind, Parallel Group, Placebo- and Active-Controlled, Phase 4
Study Evaluating the Effect of Vortioxetine 10 and 20 mg/day vs Paroxetine 20 mg/day on Sexual
Functioning in Healthy Subjects
NCT Number: NCT02932904
Protocol Approve Date: 10 January 2017


TAKEDA PHARMACEUTICALS
PROTOCOL
A Randomized, Double-Blind, Parallel Group, Placebo- and Active-Controlled, Phase 4 
Study Evaluating the Effect of Vortioxetine 10 and 20 mg/day vs Paroxetine 20 mg/day on 
Sexual Functioning in Healthy Subjects
Effect of Vortioxetine, Paroxetine, and Placebo on Sexual Functioning
in Healthy Volunteers
Sponsor:
Takeda Development Center Americas, Inc.
One Takeda Parkway
Deerfield, IL 60015
Study Number:
Vortioxetine-4001
IND Number:
76,307
EudraCT Number:
Not applicable
Compound:
Vortioxetine
Amendment History: 
Date
Amendment Number
Amendment Type
Region
11 July 2016
Initial version
Not applicable
United States
10 January 2017
01
Substantial
United States
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 Americas, Inc. (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
North America (United States) Contact
Serious adverse event and pregnancy reporting
Takeda Development Center Americas, Inc.
Pharmacovigilance Department
Medical Monitor
(medical advice on protocol and study drug)
Responsible Medical Officer 
(carries overall responsibility for the conduct of the study)
PPD


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1.2
Approval 
REPRESENTATIVES OF TAKEDA 
This study will be conducted with the highest respect for the individual participants in accordance 
with the requirements of this study protocol and also in accordance with the following:

The ethical principles that have their origin in the Declaration of Helsinki.

International Conference on Harmonisation E6 Good Clinical Practice: Consolidated 
Guideline.

All applicable laws and regulations, including, without limitation, data privacy laws, clinical 
trial disclosure laws, and regulations.
SIGNATURES
The signature of the responsible Takeda medical officer can be found on the signature page.
Electronic Signatures are provided on the last page of this document.
Date
Date
Date
PPD
PPD
PPD


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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 Conference on Harmonisation, E6 Good Clinical Practice: Consolidated 
Guideline.

All applicable laws and regulations, including, without limitation, data privacy laws and 
regulations.

Regulatory requirements for reporting serious adverse events defined in Section 10.2 of this 
protocol.

Terms outlined in the study site agreement.

Appendix B – Responsibilities of the Investigator.
I further authorize that my personal information may be processed and transferred in accordance 
with the uses contemplated in Appendix D of this protocol.
Signature of Investigator
Date
Investigator Name (print or type)
Investigator’s Title
Location of Facility (City, State/Provence)
Location of Facility (Country)


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1.3
Protocol Amendment 01 Summary of Changes
This document describes the changes in reference to the Protocol Incorporating Amendment 
No. 01.
The primary purpose of this amendment is to update the protocol regarding eligibility criteria. 
Other minor changes in procedures are proposed. Minor grammatical and editorial changes are 
included for clarification purposes only. Full details on changes of text are given in Appendix F, 
including detailed rationale. The following is a summary of the changes made in the amendment:
1. Clarify inclusion and exclusion criteria. 
2. Update, correct, or clarify excluded medications and treatments.
3. Add that psychiatric history will be assessed as well as medical history.
4. Add instructions on the order in which the scales Changes in Sexual Functioning 
Questionnaire Short-Form (CSFQ-14) and Patient Global Impression of Improvement (PGI-I) 
should be completed. 
5. Update personnel changes.


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TABLE OF CONTENTS
1.0
ADMINISTRATIVE INFORMATION ...........................................................................2
1.1
Contacts.....................................................................................................................2
1.2
Approval....................................................................................................................3
1.3
Protocol Amendment 01 Summary of Changes ..........................................................5
2.0
STUDY SUMMARY ....................................................................................................11
3.0
STUDY REFERENCE INFORMATION ......................................................................16
3.1
Study-Related Responsibilities.................................................................................16
3.2
Coordinating Investigator.........................................................................................16
3.3
List of Abbreviations ...............................................................................................17
3.4
Corporate Identification...........................................................................................18
4.0
INTRODUCTION.........................................................................................................19
4.1
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
5.1.4
Safety Objective.................................................................................................21
5.2
Endpoints.................................................................................................................21
5.2.1
Primary Endpoint...............................................................................................21
5.2.2
Secondary Endpoints..........................................................................................21
5.2.3
Additional Endpoints .........................................................................................22
5.2.4
Safety Assessments............................................................................................22
6.0
STUDY DESIGN AND DESCRIPTION.......................................................................23
6.1
Study Design ...........................................................................................................23
6.2
Justification for Study Design, Dose, and Endpoints ................................................24
6.2.1
Study Design......................................................................................................24
6.2.2
Dose ..................................................................................................................24
6.2.3
Endpoints...........................................................................................................25
6.3
Premature Termination or Suspension of Study or Study Sites .................................25
6.3.1
Criteria for Premature Termination or Suspension of the Study..........................25
6.3.2
Criteria for Premature Termination or Suspension of Study Sites .......................25


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6.3.3
Procedures for Premature Termination or Suspension of the Study or the 
Participation of Study Sites ................................................................................26
7.0
SELECTION AND DISCONTINUATION/WITHDRAWAL OF SUBJECTS..............27
7.1
Inclusion Criteria .....................................................................................................27
7.2
Exclusion Criteria ....................................................................................................27
7.3
Excluded Medications and Treatments.....................................................................29
7.4
Criteria for Discontinuation or Withdrawal of a Subject...........................................32
7.5
Procedures for Discontinuation or Withdrawal of a Subject......................................33
8.0
CLINICAL STUDY MATERIAL MANAGEMENT.....................................................34
8.1
Study Drug and Materials ........................................................................................34
8.1.1
Dosage Form, Manufacturing, Packaging, and Labeling.....................................34
8.1.1.1
Study Drug ..............................................................................................34
8.1.1.2
Sponsor-Supplied Drug............................................................................35
8.1.2
Storage...............................................................................................................35
8.1.3
Dose and Regimen .............................................................................................35
8.1.4
Overdose............................................................................................................36
8.2
Study Drug Assignment and Dispensing Procedures ................................................36
8.3
Randomization Code Creation and Storage..............................................................37
8.4
Study Drug Blind Maintenance................................................................................37
8.5
Unblinding Procedure..............................................................................................37
8.6
Accountability and Destruction of Sponsor-Supplied Drugs.....................................38
9.0
STUDY PLAN ..............................................................................................................40
9.1
Study Procedures.....................................................................................................40
9.1.1
Informed Consent Procedure..............................................................................40
9.1.2
Subject Database and Authorization...................................................................40
9.1.3
Demographics, Medical History, Psychiatric History, and Medication History 
Procedure...........................................................................................................40
9.1.4
Physical Examination Procedure ........................................................................41
9.1.5
Weight, Height, and BMI...................................................................................41
9.1.6
Vital Sign Procedure..........................................................................................41
9.1.7
ECG Procedure..................................................................................................41
9.1.8
Sexual Functioning Assessments........................................................................42
9.1.8.1
CSFQ-14 .................................................................................................42
9.1.8.2
PGI-I Scale..............................................................................................42
9.1.9
C-SSRS..............................................................................................................42


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9.1.10 Documentation of Concomitant Medications......................................................42
9.1.11 Documentation of Concurrent Medical and/or Psychiatric Conditions................42
9.1.12 Procedures for Clinical Laboratory Samples.......................................................43
9.1.13 Contraception and Pregnancy Avoidance Procedure...........................................45
9.1.14 Pregnancy ..........................................................................................................46
9.1.15 PGx Sample Collection......................................................................................47
9.1.16 PK Sample Collection and Analysis ...................................................................48
9.1.16.1
Collection of Plasma for PK Sampling.....................................................48
9.1.16.2
Bioanalytical Methods.............................................................................48
9.1.17 Documentation of Screen Failure .......................................................................48
9.1.18 Documentation of Rescreening...........................................................................49
9.1.19 Documentation of Study Entrance......................................................................49
9.2
Monitoring Subject Treatment Compliance..............................................................49
9.3
Schedule of Observations and Procedures................................................................50
9.4
Biological Sample Retention and Destruction ..........................................................50
10.0
PRETREATMENT EVENTS AND ADVERSE EVENTS ............................................51
10.1
Definitions...............................................................................................................51
10.1.1 PTEs..................................................................................................................51
10.1.2 AEs....................................................................................................................51
10.1.3 Additional Points to Consider for PTEs and AEs................................................51
10.1.4 SAEs..................................................................................................................53
10.1.5 Special Interest Adverse Events .........................................................................54
10.1.5.1
Skin and Allergic Type Reactions............................................................54
10.1.5.2
Liver Injury .............................................................................................55
10.1.5.3
Overdose .................................................................................................55
10.1.6 Intensity of PTEs and AEs .................................................................................56
10.1.7 Causality of AEs ................................................................................................56
10.1.8 Relationship to Study Procedures.......................................................................56
10.1.9 Start Date...........................................................................................................56
10.1.10
Stop Date .....................................................................................................56
10.1.11
Frequency ....................................................................................................56
10.1.12
Action Concerning Study Drug ....................................................................56
10.1.13
Outcome.......................................................................................................57
10.2
Procedures...............................................................................................................57
10.2.1 Collection and Reporting of AEs........................................................................57


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10.2.1.1
PTE and AE Reporting ............................................................................57
10.2.1.2
Special Interest Adverse Event Reporting ................................................58
10.2.2 Collection and Reporting of SAEs......................................................................59
10.2.3 Reporting of Abnormal LFTs.............................................................................59
10.3
Follow-up of SAEs ..................................................................................................59
10.3.1 Safety Reporting to Investigators, IRBs, and Regulatory Authorities..................60
11.0
STUDY-SPECIFIC COMMITTEES .............................................................................61
12.0
DATA HANDLING AND RECORDKEEPING............................................................62
12.1
Case Report Forms (Electronic) ...............................................................................62
12.2
Record Retention .....................................................................................................62
13.0
STATISTICAL METHODS..........................................................................................64
13.1
Statistical and Analytical Plans ................................................................................64
13.1.1 Analysis Sets......................................................................................................64
13.1.2 Analysis of Demographics and Other Baseline Characteristics ...........................64
13.1.3 Efficacy Analysis...............................................................................................65
13.1.3.1
Primary Analysis .....................................................................................65
13.1.3.2
Secondary Analyses.................................................................................65
13.1.3.3
Additional Analyses ................................................................................65
13.1.4 PK Analysis .......................................................................................................66
13.1.5 PGx Analysis .....................................................................................................66
13.1.6 Safety Analysis ..................................................................................................66
13.2
Interim Analysis and Criteria for Early Termination ................................................66
13.3
Determination of Sample Size..................................................................................66
14.0
QUALITY CONTROL AND QUALITY ASSURANCE...............................................68
14.1
Study-Site Monitoring Visits ...................................................................................68
14.2
Protocol Deviations..................................................................................................68
14.3
Quality Assurance Audits and Regulatory Agency Inspections ................................68
15.0
ETHICAL ASPECTS OF THE STUDY........................................................................69
15.1
Institutional Review Board Approval.......................................................................69
15.2
Subject Information, Informed Consent, and Subject Authorization .........................70
15.3
Subject Confidentiality ............................................................................................71
15.4
Publication, Disclosure, and Clinical Trial Registration Policy.................................71
15.4.1 Publication and Disclosure.................................................................................71
15.4.2 Clinical Trial Registration..................................................................................72
15.4.3 Clinical Trial Results Disclosure ........................................................................72


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15.5
Insurance and Compensation for Injury....................................................................72
16.0
REFERENCES..............................................................................................................73
LIST OF IN-TEXT TABLES
Table 7.a
Excluded Medications and Treatments...............................................................30
Table 8.a
Dose and Regimen .............................................................................................36
Table 9.a
Approximate Blood Volume ..............................................................................43
Table 9.b
Clinical Laboratory Tests...................................................................................44
Table 10.a
Takeda Medically Significant AE List................................................................54
LIST OF IN-TEXT FIGURES
Figure 6.a
Schematic of Study Design ................................................................................24
LIST OF APPENDICES
Appendix A
Schedule of Study Procedures............................................................................75
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
Collection, Storage, and Shipment of Pharmacokinetic Samples.........................83
Appendix F
Detailed Description of Amendments to Text.....................................................85


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2.0
STUDY SUMMARY
Name of Sponsor:
Takeda Development Center Americas, Inc.
Compound:
Vortioxetine
Title of Protocol: A Randomized, Double-Blind, Parallel Group, 
Placebo- and Active-Controlled, Phase 4 Study Evaluating the 
Effect of Vortioxetine 10 and 20 mg/day vs Paroxetine 20 mg/day 
on Sexual Functioning in Healthy Subjects
IND No.:
76,307
EudraCT No.:
Not applicable
Study Number: Vortioxetine-4001
Phase: 4
Study Design:
This is a phase 4, multicenter, randomized, double-blind, placebo- and active-controlled (paroxetine), 4-arm, parallel 
group, fixed-dose study comparing the effect of vortioxetine (10 and 20 mg once daily [QD]) vs paroxetine (20 mg 
QD) on sexual functioning after 5 weeks of treatment in healthy adult men and women. This outpatient study will be 
conducted at approximately 15 sites in North America. Men and women will be enrolled in approximately equal 
proportions (ie, 50% men and 50% women, overall). Enrollment will be capped for each sex when the enrollment 
target has been met for that sex stratum.
Subjects will enter a Screening Period of up to 4 weeks. At Baseline (Day 0), eligible subjects will be equally (1:1:1:1) 
randomized to double-blind vortioxetine 10 mg, vortioxetine 20 mg, paroxetine 20 mg, or placebo and will be treated 
for 5 weeks. Randomization will be stratified by sex. Subjects allocated to vortioxetine 20 mg will initiate treatment at 
10 mg/day for the first week. Subsequently, the dose will be increased to 20 mg/day and remain at 20 mg/day until 
study completion. Subjects allocated to vortioxetine 10 mg will initiate treatment at 10 mg/day and remain at 
10 mg/day until study completion. Subjects allocated to paroxetine 20 mg will initiate treatment at 20 mg/day and 
remain at 20 mg/day until study completion. Subjects will be instructed to take their first dose of study drug the day 
after Baseline on Day 1, preferably in the morning. After randomization, subjects will be seen for weekly visits and 
receive a follow-up safety contact by telephone 2 weeks after the end of double-blind treatment. At the end of 5 weeks 
of treatment, or at early termination (ET), all subjects will abruptly discontinue study drug.
Sexual functioning will be assessed at each study visit using the CSFQ-14 (primary variable). The PGI-I scale will be 
administered at each study visit except at Screening and Baseline. Signs of suicidal risk will be assessed at each study 
visit using the Columbia-Suicide Severity Rating Scale (C-SSRS) and the investigator’s clinical judgment. Safety will 
be assessed throughout the study. A total of 6 sparse pharmacokinetic (PK) samples (trough samples) will be collected 
to measure plasma vortioxetine or paroxetine concentrations at Weeks 3, 4, and 5/ET (2 samples at each time point). A 
pharmacogenomic (PGx) blood sample for deoxyribonucleic acid (DNA) isolation will be collected predose at 
Baseline (Day 0), and 2 PGx blood samples for ribonucleic acid (RNA) isolation will be collected predose at Baseline 
(Day 0) and also at Week 5/ET (ie, 4 samples per subject). 
Primary Objective:

To evaluate the effect of vortioxetine (10 and 20 mg QD) vs paroxetine 20 mg QD on sexual functioning in 
healthy subjects after 5 weeks of double-blind treatment. 
Secondary Objectives:

To evaluate the effect of vortioxetine (10 and 20 mg QD) vs paroxetine 20 mg QD on sexual functioning in 
healthy subjects throughout the 5-week double-blind Treatment Period.

To evaluate the effect of paroxetine (20 mg QD) vs placebo on sexual functioning in healthy subjects throughout 
the 5-week double-blind Treatment Period.

To evaluate the effect of vortioxetine (10 and 20 mg QD) vs placebo on sexual functioning in healthy subjects 
throughout the 5-week double-blind Treatment Period.


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Additional Objectives:

To evaluate the effects of vortioxetine (10 and 20 mg QD) vs paroxetine (20 mg QD) on additional parameters of 
sexual functioning.

To evaluate the effect of vortioxetine (10 and 20 mg QD) and paroxetine (20 mg QD) vs placebo on additional 
parameters of sexual functioning.

To evaluate the subject’s perception of sexual functioning. 

To assess the treatment effect (vortioxetine, paroxetine, or placebo) on suicidal ideation and behavior. 
Safety Objective:

To evaluate the safety and tolerability of vortioxetine (10 and 20 mg QD) and paroxetine (20 mg QD) vs placebo.
Subject Population: Healthy men and women aged 18 to 40 years, inclusive.
Number of Subjects:
Per each of 4 treatment arms: 88
Estimated total: 352
Number of Sites: 
Approximately 15 sites in North America
Dose Levels:

Vortioxetine 10 mg

Vortioxetine 20 mg

Paroxetine 20 mg

Placebo
Route of Administration:
Oral
Duration of Treatment:
Single dose QD for 5 weeks
Period of Evaluation:
5 weeks, plus a 2-week follow-up
Main Criteria for Inclusion:

The subject is a healthy male or female aged 18 to 40 years, inclusive.

The subject has been in a steady relationship for ≥3 months and plans to remain in that relationship for the 
duration of the study, and is currently sexually active (≥2 times per week). Note: Partners are not allowed to enroll 
in this trial.

The subject has a body mass index of 18 to 35 kg/m2, inclusive, at the Screening and Baseline Visits.

If female, the subject has a regular menstrual cycle (note: amenorrhea resulting from hormonal contraceptives is 
not exclusionary).

The subject has normal sexual functioning, as defined by a CSFQ-14 total score >47 (men) or >41 (women) at the 
Screening and Baseline Visits. 

If female, the subject taking allowed hormonal contraceptives is on a stable dose for ≥3 months prior to the 
Baseline Visit and continues on the stable dose for the duration of the study. 
Main Criteria for Exclusion:

The subject has a clinically significant unstable illness or a history of depression or any other psychiatric illness.

The subject is positive for hepatitis B surface antigen, anti–hepatitis C virus antibodies, or human 
immunodeficiency virus at the Screening Visit or has any known sexually transmitted diseases.

The subject has a known history of or currently has increased intraocular pressure or is at risk of acute 
narrow-angle glaucoma.

The subject has a significant risk of suicide according to the investigator’s clinical judgment, or has made a 
suicide attempt at any time.

The subject has current sexual dysfunction, or a history of a diagnosis or treatment of sexual dysfunction.


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
The subject has had a surgical or medical procedure on reproductive/genitourinary organs (excluding 
uncomplicated cesarean section (C-section), vasectomy, and tubal ligation that do not impact sexual function).

If female, the subject has polycystic ovarian syndrome.

The subject has hypogonadism or has a free testosterone value outside the normal range at the Screening Visit that 
is indicative of hypogonadism.

The subject has a history of or current alcohol or other substance abuse or dependence (according to the 
Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revised [DSM-IV-TR] criteria).

The subject has habitual tobacco or other nicotine usage (equivalent to ≥10 cigarettes per day).
Main Criteria for Evaluation and Analyses:
Primary Endpoint

Change from Baseline in the CSFQ-14 total score difference for vortioxetine vs paroxetine after 5 weeks of 
treatment.
Secondary Endpoints

Change from Baseline in the CSFQ-14 total score difference for vortioxetine vs paroxetine at each visit assessed.

Change from Baseline in CSFQ-14 total score difference for paroxetine vs placebo at each visit assessed.

Change from Baseline in CSFQ-14 total score difference for vortioxetine vs placebo at each visit assessed. 

Percentage of subjects meeting criteria for sexual dysfunction (ie, CSFQ-14 total score ≤47 for men and ≤41 for 
women) at any visit during the 5-week double-blind Treatment Period.

Change from Baseline in CSFQ-14 subscales 5 dimensions (pleasure, desire/frequency, desire/interest, 
arousal/erection, and orgasm/ejaculation) and 3 phases of the sexual response cycle (desire, arousal, and 
orgasm/completion) at each visit assessed.
Additional Endpoints

Percentage of subjects meeting criteria for sexual dysfunction (ie, CSFQ-14 total score ≤47 for men and ≤41 for 
women) at any 2 consecutive visits during the 5-week double-blind Treatment Period.

Time to sexual dysfunction as assessed by the CSFQ-14.

Percentage of subjects with a shift in the CSFQ-14 from normal (ie, CSFQ-14 total score >47 for men and >41 for 
women) at Baseline to abnormal (ie, CSFQ-14 total score ≤47 for men and ≤41 for women) at each visit assessed.

Percentage of subjects showing decreased sexual function (ie, negative responders) according to the CSFQ-14 (ie, 
CSFQ-14 total score decrease from Baseline ≥3) at each visit assessed.

PGI-I score at each visit assessed.

C-SSRS at each visit assessed.
Safety Assessments

Adverse events (AEs), vital signs, clinical laboratory tests, weight, and physical examinations.
Statistical Considerations:
Primary Analysis
Mean change from Baseline in the CSFQ-14 total score difference for vortioxetine vs paroxetine after 5 weeks of 
treatment will be the primary endpoint. The primary analysis will be based on analysis of covariance (ANCOVA) 
using the last observation carried forward (LOCF) technique, with treatment, center, and sex as fixed factors, and 
baseline CSFQ-14 total score as covariate. The comparisons will be between each vortioxetine dose (10 or 20 mg) and 
paroxetine, and both statistical tests will be 2-sided. The Holm-Bonferroni method will be used to adjust for 
multiplicity and control the familywise type I error rate at a significance level of 0.05. If the smaller of the 2 p-values 
is <0.025, significance is obtained for the associated vortioxetine dose and the other dose will then be evaluated at a 
0.05 significance level. Although vortioxetine will be compared with paroxetine in the primary analysis, paroxetine 


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will also be compared with placebo to validate the study.
Secondary Analyses
Change from Baseline in CSFQ-14 total score for vortioxetine vs paroxetine, paroxetine vs placebo, and vortioxetine 
vs placebo at each visit will also be analyzed using ANCOVA and LOCF, with treatment, center, and sex as fixed 
factors, and baseline CSFQ-14 total score as covariate. Similar analyses will also be performed for the male and 
female subgroups. Comparisons to placebo will be made at the significance level of 0.05 outside of multiplicity 
control.
The percentage of subjects meeting criteria for sexual dysfunction (ie, CSFQ-14 total score ≤47 for men and ≤41 for 
women) at any visit (using LOCF) during the double-blind Treatment Period will be analyzed by logistic regression, 
adjusting for baseline CSFQ-14 total score, sex, and treatment.
Change from Baseline in CSFQ-14 subscales 5 dimensions and 3 phases of the sexual response cycle will be analyzed 
at all visits using ANCOVA and LOCF similar to the primary analysis.
Additional Analyses
The percentage of subjects meeting criteria for sexual dysfunction (ie, CSFQ-14 total score ≤47 for men and ≤41 for 
women) at any 2 consecutive visits (using LOCF) during the double-blind Treatment Period will be analyzed by 
logistic regression, adjusting for baseline CSFQ-14 total score, sex, and treatment.
Time to sexual dysfunction as assessed by the CSFQ-14 will be analyzed using a Cox model with an exact method to 
handle ties, with treatment and sex as factors.
CSFQ-14 shift from normal (ie, CSFQ-14 total score >47 for men and >41 for women) at Baseline to abnormal 
(ie, CSFQ-14 total score ≤47 for men and ≤41 for women), and CSFQ-14 negative responders (decrease from Baseline 
in CSFQ-14 total score ≥3) will be analyzed at all visits by logistic regression, adjusting for baseline CSFQ-14 total 
score, sex, and treatment.
PGI-I will be analyzed by study visit using ANCOVA and LOCF, with treatment, center, and sex as fixed factors.
C-SSRS will be summarized by study visit for each treatment group using descriptive statistics.
Safety Analyses
AEs will be coded using the Medical Dictionary for Regulatory Activities (MedDRA) and will be summarized by 
system organ class and preferred term for the double-blind Treatment Period and the entire study. AEs that were 
reported more than once by a subject during the double-blind Treatment Period will be counted only once for that 
subject at the maximum severity.
Absolute values and changes from Screening/Baseline for clinical laboratory tests, vital signs, and weight will be 
summarized for each treatment group using descriptive statistics. Clinical laboratory test and vital sign results that are 
outside the normal ranges and potentially clinically significant will be flagged and tabulated. Physical examination 
findings will also be summarized for each treatment group.
PK Analysis
Plasma concentrations of vortioxetine and paroxetine will be presented in the data listings. A population PK analysis 
will only be conducted if deemed necessary. If this analysis is conducted, the results will be reported in a separate 
population PK report.
PGx Analysis
DNA samples may be used to understand the mode of action of vortioxetine, and RNA samples may be used for 
subsequent pathway analysis. Also, since PGx is an evolving science, many genes and their functions are not yet fully 
understood. Future data may suggest a role of some of these genes in drug response, which may lead to additional 
hypothesis-generating exploratory research and diagnostic development using stored samples.


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Sample Size Justification: 
Approximately 352 male and female subjects will be randomized to 4 treatment arms.
Assuming an SD of 8.5 for the change from Baseline in CSFQ-14 total score, a total of 352 male and female subjects 
(88 subjects per arm) is sufficient to achieve ≥80% power to detect a difference of 4.0 for vortioxetine 20 mg vs 
paroxetine 20 mg or for vortioxetine 10 mg vs paroxetine 20 mg by a 2-sample t-test with a 0.025 2-sided significance 
level. Given the proposed Holm-Bonferroni method for multiplicity control, the power to achieve the significance for 
each vortioxetine dose is approximately 85%.


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3.0
STUDY REFERENCE INFORMATION
3.1
Study-Related Responsibilities 
The sponsor will perform all study-related activities with the exception of those identified in the 
Study-Related Responsibilities template. The identified vendors in the template for specific 
study-related activities will perform these activities in full or in partnership with the sponsor.
3.2
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
5-hydroxytryptamine (serotonin)
AE
adverse event
ALT
alanine aminotransferase
ANCOVA
analysis of covariance
ASEX
Arizona Sexual Experiences Scale
AST
aspartate aminotransferase
BMI
body mass index
C-section
cesarean section
CFR
Code of Federal Regulations
CSFQ-14
Changes in Sexual Functioning Questionnaire Short-Form
C-SSRS
Columbia-Suicide Severity Rating Scale
DNA
deoxyribonucleic acid
DRESS
drug reaction with eosinophilia and systemic symptoms
DSM-IV-TR
Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revised
ECG
electrocardiogram
eCRF
electronic case report form 
ET
Early Termination
FAS
full analysis set
FDA
Food and Drug Administration
GCP
Good Clinical Practice
GGT
-glutamyl transferase
HbA1c
glycosylated hemoglobin
HBr
hydrobromide
HBsAg
hepatitis B surface antigen
hCG
human chorionic gonadotropin
HCV
hepatitis C virus
HIPAA
Health Insurance Portability and Accountability Act
HIV
human immunodeficiency virus
ICH
International Conference on Harmonisation
ID
identification
INR
international normalized ratio
IRB
institutional review board
IUD
intrauterine device
IWRS
interactive web response system
K2EDTA
potassium ethylenediamine tetraacetic acid
LFT
liver function tests
LOCF
last observation carried forward
MedDRA
Medical Dictionary for Regulatory Activities
MDD
major depressive disorder


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OE
overencapsulated
PGI-I
Patient Global Impression of Improvement
PGx
pharmacogenomic(s)
PK
pharmacokinetic(s)
PPS
per-protocol analysis set
PTE
pretreatment event
QD
once daily
RCF
relative centrifugal force
RNA
ribonucleic acid
SAE
serious adverse event
SJS
Stevens-Johnson syndrome
SMS
short message service
SSRI
selective serotonin reuptake inhibitor
SUSAR
suspected unexpected serious adverse reaction
T4
thyroxine
TEN
toxic epidermal necrolysis
TESD
treatment-emergent sexual dysfunction
TSH
thyroid-stimulating hormone
ULN
upper limit of normal
US
United States
USP
United States Pharmacopeia
WHO
World Health Organization
3.4
Corporate Identification
TCAL
Takeda California, Inc.
TDC Americas
Takeda Development Center Americas, Inc.
TDC
TDC Japan, TDC Asia, TDC Europe and/or TDC Americas, as applicable
Takeda
TDC Japan, TDC Asia, TDC Europe and/or TDC Americas, as applicable


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4.0
INTRODUCTION
4.1
Background
The prevalence of major depressive disorder (MDD) in the United States is 8.3%, based on a 
recent World Health Organization (WHO) World Mental Health survey [1]. Furthermore, the 
burden is likely to grow over the coming years. According to the WHO, depression alone accounts 
for 4.3% of the global burden of disease and is among the largest single causes of disability 
worldwide (11% of all years lived with disability globally), particularly for women [2].
Depression poses an economic burden on the patients, their families and friends, and society. The 
ability of depressed patients or their caregivers to work and make productive contributions to the 
economy is reduced, whereas the utilization of treatment and support services is increased. The 
economic consequences of these health losses are significant: a recent study estimated that the 
cumulative global impact of mental disorders in terms of lost economic output will amount to 
US$ 16.3 million between 2011 and 2030 [2]. 
Unfortunately, most of the currently available antidepressants produce sexual dysfunction in men 
and women and affect all phases of sexual activity by decreasing desire, arousal, orgasm, and 
ejaculation [3-7]. Such side effects affect the patient’s quality of life, can lead to therapeutic 
noncompliance, and often interfere with recovery from a depressive episode [4,8-10]. In a study 
conducted by Hu et al (2004) [11], patients receiving antidepressant treatment were asked to rank 
which of the side effects they experienced were the most bothersome. In this population, sexual 
dysfunction was ranked as the most bothersome adverse event (AE), followed by 
drowsiness/fatigue, weight gain, and insomnia.
Despite being common, antidepressant-related sexual dysfunction is one of the most under 
reported AEs [11,12]. In a study by Montejo-Gonzalez et al (1997), only 14% of the patients 
spontaneously reported sexual-related AEs; when elicited by direct question, however, as many as 
58% of these patients reported sexual dysfunction [13].
Using an objective measurement to assess the rate of sexual dysfunction in a sample of individuals 
receiving antidepressant monotherapy, Clayton and Montejo (2006) [14] found that the prevalence 
of sexual dysfunction was on average 24% (ranging from 7% to 30%, depending on the 
medication).
Vortioxetine is an antidepressant agent approved in 66 countries worldwide, including in the 
United States (US) and the European Union since 2013, for treatment of MDD. It differs from 
preexisting antidepressants in that it combines 2 pharmacological modes of action: direct 
modulation of 5-hydroxytryptamine (5-HT) (serotonin) receptor activity and inhibition of the 
5-HT 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 
[15,16].
During the clinical development program, the efficacy, safety, and tolerability of vortioxetine in 
subjects with MDD was evaluated at doses from 1 to 20 mg/day in short-term efficacy studies of 
6 to 8 weeks’ duration and long-term safety studies up to 52 weeks’ duration. Vortioxetine was 


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safe and well-tolerated across the dose range evaluated. The efficacy of vortioxetine in the 
treatment of subjects with MDD was established in 6 randomized, double-blind, 
placebo-controlled, fixed-dose, 6- to 8-week 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 [17]. 
The long-term efficacy and maintenance of effect of vortioxetine treatment at doses of 5 and 
10 mg/day have been previously established in subjects with MDD [18].
4.2
Rationale for the Proposed Study
Treatment with antidepressants, particularly selective serotonin reuptake inhibitors (SSRIs), may 
be associated with sexual dysfunction including AEs at virtually all phases of sexual response 
(ie, desire, arousal, and orgasm), which can frequently result in poor treatment compliance and 
even antidepressant treatment discontinuation [5]. Results from phase 3 studies in acute depressed 
subjects indicate that vortioxetine is associated with less treatment-emergent sexual dysfunction 
(TESD) when compared with duloxetine, and is similar to placebo at the 5 and 10 mg doses, as 
assessed by data collected prospectively utilizing the Arizona Sexual Experiences Scale (ASEX) 
and by spontaneous reports of AEs during 8 weeks of treatment [17].
A subsequent study was conducted to evaluate the effects of vortioxetine in improving 
antidepressant-associated sexual dysfunction compared with another antidepressant using an 
objective measure, the Changes in Sexual Functioning Questionnaire Short-Form (CSFQ-14). In 
this study, adult subjects with MDD whose depressive symptoms were well treated with 1 of 
3 SSRIs, citalopram, sertraline, or citalopram, but who had abnormal sexual functioning, as 
assessed by the CSFQ-14, which in the investigator’s opinion was attributed to the subject’s 
current SSRI treatment, were switched to vortioxetine or escitalopram. Vortioxetine was 
statistically significantly superior to escitalopram in improving SSRI-induced sexual dysfunction 
as measured by the CSFQ-14 total score at Week 8 [19].
The objective of the current study is to further evaluate the effects of vortioxetine on sexual 
functioning as compared with paroxetine, an SSRI known to cause sexual dysfunction, in healthy 
subjects after 5 weeks of treatment. 
Pharmacogenomic (PGx) analysis may be conducted to evaluate the contribution of genetic 
variance on drug response (eg, safety and tolerability). The sampling of whole blood for PGx 
analysis is mandatory; every subject must consent to this procedure to participate in this study.


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5.0
STUDY OBJECTIVES AND ENDPOINTS
5.1
Objectives
5.1.1
Primary Objective 

To evaluate the effect of vortioxetine (10 and 20 mg once daily [QD]) vs paroxetine 20 mg QD 
on sexual functioning in healthy subjects after 5 weeks of double-blind treatment. 
5.1.2
Secondary Objectives

To evaluate the effect of vortioxetine (10 and 20 mg QD) vs paroxetine 20 mg QD on sexual 
functioning in healthy subjects throughout the 5-week double-blind Treatment Period.

To evaluate the effect of paroxetine (20 mg QD) vs placebo on sexual functioning in healthy 
subjects throughout the 5-week double-blind Treatment Period.

To evaluate the effect of vortioxetine (10 and 20 mg QD) vs placebo on sexual functioning in 
healthy subjects throughout the 5-week double-blind Treatment Period.
5.1.3
Additional Objectives

To evaluate the effects of vortioxetine (10 and 20 mg QD) vs paroxetine (20 mg QD) on 
additional parameters of sexual functioning.

To evaluate the effect of vortioxetine (10 and 20 mg QD) and paroxetine (20 mg QD) vs 
placebo on additional parameters of sexual functioning.

To evaluate the subject’s perception of sexual functioning. 

To assess the treatment effect (vortioxetine, paroxetine, or placebo) on suicidal ideation and 
behavior. 
5.1.4
Safety Objective

To evaluate the safety and tolerability of vortioxetine (10 and 20 mg QD) and paroxetine 
(20 mg QD) vs placebo.
5.2
Endpoints
5.2.1
Primary Endpoint

Change from Baseline in the CSFQ-14 total score difference for vortioxetine vs paroxetine 
after 5 weeks of treatment.
5.2.2
Secondary Endpoints

Change from Baseline in the CSFQ-14 total score difference for vortioxetine vs paroxetine at 
each visit assessed.


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
Change from Baseline in CSFQ-14 total score difference for paroxetine vs placebo at each visit 
assessed.

Change from Baseline in CSFQ-14 total score difference for vortioxetine vs placebo at each 
visit assessed. 

Percentage of subjects meeting criteria for sexual dysfunction (ie, CSFQ-14 total score ≤47 for 
men and ≤41 for women) at any visit during the 5-week double-blind Treatment Period.

Change from Baseline in CSFQ-14 subscales 5 dimensions (pleasure, desire/frequency, 
desire/interest, arousal/erection, and orgasm/ejaculation) and 3 phases of the sexual response 
cycle (desire, arousal, and orgasm/completion) at each visit assessed.
5.2.3
Additional Endpoints

Percentage of subjects meeting criteria for sexual dysfunction (ie, CSFQ-14 total score ≤47 for 
men and ≤41 for women) at any 2 consecutive visits during the 5-week double-blind Treatment 
Period.

Time to sexual dysfunction as assessed by the CSFQ-14.

Percentage of subjects with a shift in the CSFQ-14 from normal (ie, CSFQ-14 total score >47 
for men and >41 for women) at Baseline to abnormal (ie, CSFQ-14 total score ≤47 for men and 
≤41 for women) at each visit assessed.

Percentage of subjects showing decreased sexual function (ie, negative responders) according 
to the CSFQ-14 (ie, CSFQ-14 total score decrease from Baseline ≥3) at each visit assessed.

Patient Global Impression of Improvement (PGI-I) score at each visit assessed.

Columbia-Suicide Severity Rating Scale (C-SSRS) at each visit assessed.
5.2.4
Safety Assessments
Safety and tolerability will also be evaluated using the following general assessments:

AEs.

Vital signs.

Clinical laboratory tests.

Weight.

Physical examinations.


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6.0
STUDY DESIGN AND DESCRIPTION
6.1
Study Design
This is a phase 4, multicenter, randomized, double-blind, placebo- and active-controlled 
(paroxetine), 4-arm, parallel group, fixed-dose study comparing the effect of vortioxetine (10 and 
20 mg QD) vs paroxetine (20 mg QD) on sexual functioning after 5 weeks of treatment in healthy 
adult men and women. This outpatient study will be conducted at approximately 15 sites in North 
America. Men and women will be enrolled in approximately equal proportions (ie, 50% men and 
50% women, overall). Enrollment will be capped for each sex when the enrollment target has been 
met for that sex stratum.
After providing informed consent, subjects will be assessed for study eligibility during a Screening 
Period of up to 4 weeks. Healthy subjects who have normal sexual functioning (as defined by the 
CSFQ-14), have been in a steady relationship for ≥3 months, are currently sexually active, and 
meet all other study entry criteria will be enrolled. At Baseline (Day 0), eligible subjects will be 
equally (1:1:1:1) randomized to double-blind vortioxetine 10 mg, vortioxetine 20 mg, paroxetine 
20 mg, or placebo and will be treated for 5 weeks. Randomization will be stratified by sex. 
Subjects allocated to vortioxetine 20 mg will initiate treatment at 10 mg/day for the first week. 
Subsequently, the dose will be increased to 20 mg/day and remain at 20 mg/day until study 
completion. Subjects allocated to vortioxetine 10 mg will initiate treatment at 10 mg/day and 
remain at 10 mg/day until study completion. Subjects allocated to paroxetine 20 mg will initiate 
treatment at 20 mg/day and remain at 20 mg/day until study completion. Subjects will be 
instructed to take their first dose of study drug the day after Baseline on Day 1, preferably in the 
morning. After randomization, subjects will be seen for weekly visits and receive a follow-up 
safety contact 2 weeks after the end of double-blind treatment. At the end of 5 weeks of treatment, 
or at Early Termination (ET), all subjects will abruptly discontinue study drug.
Sexual functioning will be assessed at each study visit using the CSFQ-14 (primary variable). The 
PGI-I scale will be administered at each study visit except at Screening and Baseline. Signs of 
suicidal risk will be assessed at each study visit using the C-SSRS and the investigator’s clinical 
judgment. Safety will be assessed throughout the study. A total of 6 sparse pharmacokinetic (PK) 
samples (trough samples) will be collected to measure plasma vortioxetine or paroxetine 
concentrations at Weeks 3, 4, and 5/ET (2 samples at each time point). A PGx blood sample for 
deoxyribonucleic acid (DNA) isolation will be collected at Baseline (Day 0), and 2 PGx blood 
samples for ribonucleic acid (RNA) isolation will be collected at Baseline (Day 0) and also at 
Week 5/ET (ie, 4 samples per subject).
The end of the study is defined as the date the last subject completes the Final Visit (Week 5).
A schematic of the study design is presented in Figure 6.a. A schedule of study procedures is 
provided in Appendix A.


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Figure 6.a
Schematic of Study Design
Note: The Follow-up Contact will be conducted by telephone.
6.2
Justification for Study Design, Dose, and Endpoints
6.2.1
Study Design
Healthy adult subjects were chosen for inclusion in this study to eliminate the confounding effects 
on sexual function associated with psychiatric conditions and certain medical conditions. The 
duration of 5 weeks was selected to allow for sufficient time to evaluate the extent of sexual 
dysfunction.
Paroxetine was chosen as an active comparator as it is a commonly prescribed SSRI and is known 
to cause sexual dysfunction, thereby allowing for validation of the study (ie, the level of sexual 
dysfunction with paroxetine is worse than that of placebo). The level of sexual dysfunction with 
vortioxetine 10 and 20 mg will also be compared with placebo.
Since study drug compliance is known to impact the study results, a compliance technology 
vendor, AiCure, will be used to throughout the study to improve study drug compliance.
In addition, PK samples will be taken at 3 postbaseline study visits in order to assess plasma 
concentrations of vortioxetine and paroxetine. The compliance technology and/or PK 
concentration data will be used to define one or more modified full analysis set populations. 
6.2.2
Dose
Subjects will be dosed in accordance with the approved United States Package Insert for 
vortioxetine; therefore, vortioxetine doses of 10 and 20 mg will be evaluated. Based on 
prospective evaluation using the ASEX, the incidence of TESD increased as the dose of 
vortioxetine increases, although never statistically different from placebo; therefore, the chosen 
Day 0
(Visit 2)
Wk 5 
(Visit 7)
Screening
Baseline
Screening Period
(up to 4 weeks)
Double-Blind Treatment Period
(5 weeks)
Healthy Subjects
Vortioxetine 10 mg/day
Placebo
Vortioxetine 20 mg/day
Days -28 to -
1 (Visit 1)
Endpoint
Paroxetine 20 mg/day
Wk 1
(Visit 3)
Wk 2
(Visit 4)
Wk 3
(Visit 5)
Wk 4
(Visit 6)
Vortioxetine
10 mg/day
Wk 7 
(Follow-up)
Randomization


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doses of 10 and 20 mg for this study are considered clinically appropriate to evaluate sexual 
dysfunction as it includes the highest therapeutic dose of vortioxetine. 
A paroxetine dose of 20 mg/day was selected as it is the starting dose and lowest effective dose for 
maintenance treatment for depression. Furthermore, this dose of paroxetine is considered to have 
the lowest incidence of TESD, but it has also been shown to cause sexual dysfunction in healthy 
subjects.
6.2.3
Endpoints
The CSFQ-14 is a validated questionnaire designed to assess and detect changes in sexual 
functioning (see Section 9.1.8.1). In addition, it is recognized by the Food and Drug 
Administration (FDA) as an accepted tool to assess sexual functioning in clinical studies.
The PGI-I scale is a global self assessment used to rate the response of a subject’s condition to 
therapy or intervention (see Section 9.1.8.2). Although it was originally developed for assessment 
in women with stress urinary incontinence, it has been used for subject self assessment in other 
conditions due to its lack of specificity to medical conditions, and its sensitivity to change. 
Adequate measures have been implemented in 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 Sites
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 efficacy of the study drug that 
indicates a change in the known risk/benefit profile for the study drug, such that the 
risk/benefit is no longer acceptable for subjects participating in the study.

Significant violation of Good Clinical Practice (GCP) that compromises the ability to achieve 
the primary study objectives or compromises subject safety.
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.


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6.3.3
Procedures for Premature Termination or Suspension of the Study or the 
Participation of Study Sites
In the event that the sponsor, an institutional review board (IRB), 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 randomization. 
7.1
Inclusion Criteria
Subject eligibility is determined according to the following criteria prior to entry into the study: 
1. In the opinion of the investigator, the subject is capable of understanding and complying with 
protocol requirements.
2. The subject signs and dates a written, informed consent form and any required privacy 
authorization prior to the initiation of any study procedures. 
3. The subject is a healthy male or female aged 18 to 40 years, inclusive.
4. The subject has been in a steady relationship for ≥3 months and plans to remain in that 
relationship for the duration of the study, and is currently sexually active (≥2 times per week). 
Note: Partners are not allowed to enroll in this trial.
5. The subject has a body mass index (BMI) of 18 to 35 kg/m2, inclusive, at the Screening and 
Baseline Visits.
6. If female, the subject has a regular menstrual cycle (note: amenorrhea resulting from hormonal 
contraceptives is not exclusionary).
7. A female subject of childbearing potential* who is sexually active with a nonsterilized* male 
partner agrees to routinely use adequate contraception* from signing of informed consent 
throughout the duration of the study and for 30 days after the last dose.
*Definitions and acceptable methods of contraception are defined in 
Section 9.1.13 and reporting responsibilities are defined in Section 9.1.14.
8. The subject has normal sexual functioning, as defined by a CSFQ-14 total score >47 (men) or 
>41 (women) at the Screening and Baseline Visits.
9. If female, the subject taking allowed hormonal contraceptives is on a stable dose for ≥3 months 
prior to the Baseline Visit and continues on the stable dose for the duration of the study. 
7.2
Exclusion Criteria
Any subject who meets any of the following criteria will not qualify for entry into the study:
1. The subject has received any investigational compound within 30 days or 5 half-lives prior to 
the Screening Visit, whichever is longer.
2. The subject has received vortioxetine and/or paroxetine in a previous clinical study or as a 
therapeutic agent.
3. The subject has previously or is currently participating in this study.


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4. The subject is an immediate family member, study site employee, or is in a dependent 
relationship with a study site employee who is involved in conduct of this study (eg, spouse, 
parent, child, sibling) or may consent under duress.
5. The subject has a clinically significant unstable illness, for example, hepatic impairment or 
renal insufficiency, or a cardiovascular, pulmonary, gastrointestinal, endocrine, neurological, 
rheumatological, immunological, hematological, infectious, or dermatological disorder or 
metabolic disturbance. Note: For the purposes of this study, gastric bypass surgery is 
considered to be an unstable condition due to the impact on medication absorption.
6. The subject is positive for hepatitis B surface antigen (HBsAg), anti–hepatitis C virus (HCV) 
antibodies, or human immunodeficiency virus (HIV) at the Screening Visit or has any known 
sexually transmitted diseases.
7. The subject has 1 or more laboratory value outside the normal range, based on the blood or 
urine samples taken at the Screening or Baseline Visit, that are considered by the investigator 
to be clinically significant; or the subject has any of the following values at the Screening or 
Baseline Visit:
a) A serum creatinine value >1.5× the upper limits of normal (ULN).
b) A serum total bilirubin value >1.5×ULN.
c) A serum alanine aminotransferase (ALT) or aspartate aminotransferase (AST) value 
>2×ULN.
8. The subject has glycosylated hemoglobin (HbA1c) ≥7% at the Screening Visit.
9. The subject has a clinically significant abnormal electrocardiogram (ECG) at the Screening 
Visit as determined by the central reader and confirmed as clinically significant by the 
investigator. 
10. The subject has clinically significant abnormal vital signs at the Screening or Baseline Visit as 
determined by the investigator.
11. The subject has a known history of or currently has increased intraocular pressure or is at risk 
of acute narrow-angle glaucoma.
12. The subject has a history of depression or any other psychiatric illness including sleep 
disorders and premenstrual dysphoric disorder.
13. The subject has a significant risk of suicide according to the investigator’s clinical judgment, 
or has made a suicide attempt at any time.
14. The subject has current sexual dysfunction, or a history of a diagnosis or treatment of sexual 
dysfunction.
15. The subject has had a surgical or medical procedure on reproductive/genitourinary organs 
(excluding uncomplicated cesarean section (C-section), vasectomy, and tubal ligation that do 
not impact sexual functioning).


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16. If female, the subject has polycystic ovarian syndrome.
17. The subject has hypogonadism or has a free testosterone value outside the normal range at the 
Screening Visit that is indicative of hypogonadism.
18. The subject has a thyroid-stimulating hormone (TSH) value outside the normal range at the 
Screening Visit that is deemed clinically significant by the investigator. NOTE: Free thyroxine 
(T4) will be checked if TSH is out of range. If free T4 is abnormal the subject will be excluded.
19. The subject has a history of hypersensitivity or allergies to vortioxetine or paroxetine or any 
associated excipients.
20. The subject is required to take ≥1 excluded medication or it is anticipated that the subject will 
be required to take ≥1 of the excluded medications listed in Section 7.3 during the study.
21. The subject has a history of or current alcohol or other substance abuse or dependence 
(according to Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text 
Revised [DSM-IV-TR] criteria).
22. The subject has habitual tobacco or other nicotine-containing product usage (equivalent to ≥10 
cigarettes per day).
23. If female, the subject is pregnant or lactating or intending to become pregnant before, during, 
or within 30 days after participating in this study, or intending to donate ova during such time 
period. 
24. The subject is found to be a match in the subject registry database with a subject who has 
participated in another study within the last 30 days (or at any time for an excluded medical or 
psychiatric condition).
25. The subject has a disease or takes medication that, in the opinion of the investigator, could 
interfere with the assessments of sexual functioning, safety, or tolerability.
26. The subject, in the opinion of the investigator, is unlikely to comply with the clinical study 
protocol or is unsuitable for any reason.
7.3
Excluded Medications and Treatments
A list of excluded medications and treatments is provided in Table 7.a. Use of the excluded 
medications or treatments is prohibited from the time points specified until completion of all study 
procedures at the Final Visit/ET Visit, unless approved by the investigator and Takeda on a 
case-by-case basis. 


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Table 7.a
Excluded Medications and Treatments
Drug Class
Disallowed Prior to/From
Baseline and
During Study Unless
Otherwise Noted
Disallowed (X) During the Study 
[Sections Without (X) Indicate no Restriction]
Chronic
Use
Episodic
Use
Comments or Exceptions
Any investigational drug
<30 days before Screening or 
5 half-lives, whichever is 
longer
X
X
Analgesics
Narcotic 
analgesics
3 months
X
X
NSAIDs 
X
Up to 2 doses of ibuprofen or naproxen 
per week allowed. 
Aspirin is NOT allowed.
Cox-2 selective 
inhibitors
3 months
X
X
Acetaminophen
Anorexics
2 weeks
X
X
Antacids
Antiacne agents
Antianginal agents
3 months
X
X
Antiarrhythmics
3 months
X
X
Antibiotics
Rifampin is NOT allowed.
Antithrombic and 
anticoagulant agents 
3 months
X
X
Anticonvulsants 
3 months
X
X
Antidepressants (including 
MAOIs and RIMAs)
3 months
X
X
Antidiarrheal agents
Antifungal agents 
Antihistamines
X
X
Only loratadine, desloratadine, cetirizine, 
levocetirizine, mizolastine and 
fexofenadine are allowed.
Antihypertensives
3 months
X
X
Anti-impotence agents
3 months
X
X
Antimigraine agents 
(including triptans and 
dopamine antagonists)
2 weeks
X
X
Antinauseants, antiemetics 
(including dopamine 
antagonists)
2 weeks 
X
X
Only phosphoric acid and bismuth 
preparations are allowed.
Antineoplastics
3 months
X
X
Antiobesity agents
2 weeks
X
X
Antipsoriatic agents
Antimalarial 
Antipsychotics
3 months (6 months for depot)
X
X
Antivirals
Footnotes are on last table page.


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Table 7.a
Excluded Medications and Treatments (continued)
Drug Class
Disallowed Prior 
to/From
Baseline and
During Study Unless
Otherwise Noted
Disallowed (X) During the Study 
[Sections Without (X) Indicate no Restriction]
Chronic
Use
Episodic
Use
Comments or Exceptions
Anxiolytics (including 
benzodiazepines)
3 months
X
X
Beta blockers
3 months
X
X
Cough/cold agents 
X
Episodic treatment for up to 1 week is 
allowed.
Diuretics OTC
Herbal remedies, which are 
psychoactive (eg, St. Johns Wort, 
kava kava, valerian, and ginkgo 
biloba)
2 weeks
X
X
Melatonin is allowed.
Drugs metabolized by or that 
inhibit CYP2D6
2 weeks
X
X
Applies to CYP2D6 
substrates/inhibitors not mentioned 
elsewhere in this table.
H2 blockers, proton pump 
inhibitors
Hormones
X
X
Chronic and stable thyroid hormone 
replacement, parathyroid hormone, and 
its recombinant form (Forteo), 
contraceptives (oral, patch, injectables, 
and implants). 
Hypoglycemic agents 
3 months
X
X
Hypolipidemics
3 months
X
X
Insulin
3 months
X
X
Laxatives
Mood stabilizers 
3 months
X
X
Psychotropic agents not otherwise 
specified (including stimulants, 
narcotics, tryptophan, and 
dopamine agonists/antagonists)
3 months
X
X
Sedatives/hypnotics 
4 weeks
(see comments)
X
From 4 weeks prior to Baseline through 
end of study, only zolpidem, 
eszopiclone/zopiclone, zaleplon, and 
ramelteon allowed up to 2 nights per 
week and not the night before a study 
visit.
Footnotes are on last table page.


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Table 7.a
Excluded Medications and Treatments (continued)
Drug Class
Disallowed Prior 
to/From
Baseline and 
During Study Unless
Otherwise Noted
Disallowed (X) During the Study 
[Sections Without (X) Indicate no Restriction]
Chronic
Use
Episodic
Use
Comments or Exceptions
Steroids:
Systemic
2 weeks 
X
X
Injectable and anabolic steroids are also 
NOT allowed
Inhalant
Topical
Vaccines
COX-2=cyclooxygenase-2, CYP=cytochrome P450, H2 blockers=H2 receptor antagonists (acid reducers), MAOI=monoamine 
oxidase inhibitor, NSAID=nonsteroidal anti-inflammatory drug, OTC=over the counter, RIMA=reversible inhibitor of monoamine 
oxidase type A.
The list above does not include all of the excluded medications or supplements. Subjects must be 
instructed not to take any medications or supplements, including OTC products, throughout the 
duration of the study without first consulting with the investigator.
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 electronic case report form (eCRF) using the following categories. For 
screen failure subjects, refer to Section 9.1.17.
1. Pretreatment event (PTE) or AE. The subject has experienced a PTE or AE that requires ET 
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, see Section 9.1.12), if the following circumstances occur at any 
time during study drug treatment:
–
ALT or AST >8×ULN, or
–
ALT or AST >5×ULN and persists for >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 postrandomization 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.


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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 wishes to withdraw from the study. The reason for 
withdrawal, if provided, should be recorded in the eCRF.
Note: All attempts should be made to determine the underlying reason for the withdrawal and, 
where possible, the primary underlying reason should be recorded (ie, withdrawal due to an 
AE should not be recorded in the “voluntary withdrawal” category).
5. Study termination. The sponsor, IRB, or regulatory agency terminates the study.
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 9.1.14.
7. Noncompliance with study drug. This includes subjects who did not take the study drug for 
≥4 consecutive days and/or are <70% compliant between visits.
8. Other.
Note: The specific reasons should be recorded in the “specify” field of the eCRF.
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 ET 
Visit. Discontinued or withdrawn subjects will not be replaced. Discontinued or withdrawn 
subjects will receive a Follow-up Contact.


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8.0
CLINICAL STUDY MATERIAL MANAGEMENT
This section contains information regarding all medication and materials provided directly by the 
sponsor, and/or sourced by other means, that are required by the study protocol, including 
important sections describing the management of 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 encapsulated strengths of 10 and 20 mg.

Commercial paroxetine tablets in encapsulated strength of 20 mg.

Matching placebo capsules.
Vortioxetine 10 and 20 mg tablets are manufactured by Takeda or H. Lundbeck A/S, Valby, 
Denmark. Overencapsulation of the vortioxetine and paroxetine tablets and manufacturing of the 
matching placebo capsules (Swedish-Orange capsules with lactose monohydrate filler) is 
performed by Almac Clinical Services, Souderton, PA, USA.
The study drug will be packaged in high-density polyethylene bottles with child-resistant closures. 
Each bottle contains 7 daily doses plus 3 extra capsules for a total of 10 capsules per bottle. The 
daily dose is 1 capsule by oral administration.
Bottles of overencapsulated (OE) vortioxetine 10 and 20 mg tablets, OE paroxetine 20 mg tablets, 
and matching placebo capsules will be labeled with a single label and dispensed as double-blind 
for the 5-week treatment phase. The study drug will be identifiable by a unique medication 
identification (ID) number that will be assigned by an interactive web response system (IWRS). 
Each bottle will be labeled with pertinent study information.
8.1.1.1
Study Drug
Vortioxetine is a novel compound developed by Takeda and H. Lundbeck A/S as an antidepressant 
and treatment for MDD. Vortioxetine belongs to a new chemical class of psychotropics, the 
bis-aryl-sulfanyl amines, which possess unique properties compared with currently known 
psychotropics. This new class of compounds is structurally different from all currently known 
psychotropics.
Vortioxetine is commercially formulated as immediate-release tablets intended for oral 
administration. The study drug is film-coated tablets containing the hydrobromide (HBr) salt of 
vortioxetine. The tablets contain vortioxetine-HBr corresponding to 10 and 20 mg of vortioxetine 
base. Well known excipients are used to manufacture the tablet cores.
Paroxetine 20 mg tablets United States Pharmacopeia (USP) immediate release are commercially 
available. 


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8.1.1.2
Sponsor-Supplied Drug
Sponsor-supplied drugs referenced in other sections of the protocol include the following:

Commercial vortioxetine tablets in encapsulated strengths of 10 and 20 mg.

Commercial paroxetine tablets in encapsulated strength of 20 mg.

Matching placebo capsules.
8.1.2
Storage
Study drug should be stored at 25ºC (77ºF) with excursions permitted between 15ºC and 30ºC 
(59ºF -86ºF).
Vortioxetine 10 and 20 mg, paroxetine 20 mg, and matching placebo must be kept in an 
appropriate, limited-access, secure place until used or returned to the sponsor or designee for 
destruction. Vortioxetine 10 and 20 mg, paroxetine 20 mg, and matching placebo must be stored 
under the conditions specified on the label, and remain in the original container until dispensed. A 
daily temperature log of the drug storage area must be maintained at the site every working day.
8.1.3
Dose and Regimen
The investigator or designee should contact the IWRS to register each subject at the initial 
Screening Visit. At each applicable study visit (Visits 1-5), the investigator or designee should 
contact the IWRS to receive the appropriate study drug assignment for dispensation. The IWRS 
will provide the medication ID number for each bottle dispensed at each study visit. The 
medication ID number assigned should be recorded in the source document.
Subjects assigned to vortioxetine 20 mg will initiate treatment at 10 mg/day for the first week. 
Subsequently, the dose will be increased to 20 mg/day and remain at 20 mg/day until study 
completion. Subjects assigned to vortioxetine 10 mg will initiate treatment at 10 mg/day and 
remain at 10 mg/day until study completion. Subjects assigned to paroxetine 20 mg will initiate 
treatment at 20 mg/day and remain at 20 mg/day until study completion.
Subjects will be instructed to take 1 capsule per day, orally, at the same time of day, preferably in 
the morning, or as directed. The first dose is to be taken on Day 1, the day after the study drug has 
been dispensed to the subject. Study drug can be taken with or without food. The subject should be 
advised to be consistent in the dosing time throughout the duration of the study.
The investigator or designee will instruct the subject on the dosing procedures and study drug 
storage requirements. Subjects should return their unused study drug at each study visit to allow 
the investigator or designee to evaluate subjects’ compliance with the dosing instructions.
The daily dose and capsule count that will be provided to each treatment group is described in 
Table 8.a. 


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Table 8.a
Dose and Regimen
Treatment Group
Dose
Treatment Description
A
Placebo QD
1 placebo capsule
B
10 mg vortioxetine QD
1 OE vortioxetine 10 mg tablet 
C
20 mg vortioxetine QD
1 OE vortioxetine 20 mg tablet
D
20 mg paroxetine QD
1 OE paroxetine 20 mg tablet
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 
study protocol.
All cases of overdose (with or without associated AEs) will be documented on an Overdose page 
of the eCRF, in order to capture this important safety information consistently in the database. 
Cases of overdose without manifested signs or symptoms are not considered AEs. AEs associated 
with an overdose will be documented on an AE page of the eCRF, as described in Section 10.1.5.3.
Serious adverse events (SAEs) associated with overdose should be reported according to the 
procedure outlined in Section 10.2.2.
In the event of drug overdose, general symptomatic and supportive measures should be used, along 
with immediate gastric lavage where appropriate. Intravenous fluids should be administered as 
needed. As in all cases of drug overdose, respiration, pulse, blood pressure, and other appropriate 
signs should be monitored and general supportive 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 overdose. 
8.2
Study Drug Assignment and Dispensing Procedures
The investigator or investigator’s designee will access the IWRS at the Screening Visit to obtain 
the subject number. The investigator or investigator’s designee will access the IWRS to randomize 
the subject into the study should they meet the eligibility requirements. Subjects will be assigned 
in a 1:1:1:1 ratio to 1 of the 4 treatment arms of vortioxetine 10 mg, vortioxetine 20 mg, paroxetine 
20 mg, or placebo. Randomization will be stratified by sex. Men and women will be enrolled in 
equal proportions (ie, 50% men and 50% women, overall). Enrollment will be capped for each sex 
when the enrollment target has been met for that sex stratum.
During each IWRS contact, the investigator or designee will provide the necessary 
subject-identifying information, including the subject number assigned at Screening. The 
medication ID number of the study drug to be dispensed will then be provided by the IWRS. If 
sponsor-supplied drug is lost or damaged, the site can request a replacement from the IWRS (refer 
to IWRS manual provided separately). At subsequent drug-dispensing visits, the investigator or 


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designee will again contact the IWRS to request additional study drug for a subject. The 
medication ID number of the study drug to be dispensed will be provided by the IWRS.
Each subject should be instructed as follows:

The subject should keep sponsor-supplied drugs in original containers until the time of dosing.

The subject should take only 1 capsule per day as instructed. If the dose is missed in the 
morning, it is acceptable to take the dose later in the same day. If the subject misses a dose, he 
or she should not take twice the dose the next day. 

The subject should store sponsor-supplied drugs according to the label and keep them out of 
the reach of children.

The subject is to return sponsor-supplied drugs at each study visit.
8.3
Randomization Code Creation and Storage
Takeda randomization personnel or designee will generate the randomization schedule for the 
study; an IWRS will be used in a centralized fashion for subject randomization and study drug 
assignments with stratification by sex. All randomization information will be stored in a secured 
area, accessible only by authorized personnel. Target randomization is 50% men and 50% women; 
enrollment for each sex will be monitored and will be discontinued once the appropriate numbers 
of subjects have been enrolled for a sex stratum.
Subjects will be assigned in a 1:1:1:1 ratio, within each sex stratum, to the 4 treatment arms of 
vortioxetine 10 mg, vortioxetine 20 mg, paroxetine 20 mg, or placebo. Subject randomization 
across treatments and sex will be balanced at the study level.
8.4
Study Drug Blind Maintenance
The study drug blind will be maintained using the IWRS. The principal investigator at each study 
site will receive instructions for obtaining the study drug assignment through the IWRS. During 
regularly scheduled monitoring visits, a study monitor from the sponsor or a designee will perform 
an inventory of assigned and unassigned bottles of study drug. All assigned/unassigned study drug 
bottles will be reconciled and returned to the sponsor or a designee before study closure.
8.5
Unblinding Procedure
The study drug blind shall not be broken by the investigator unless information concerning the 
study drug is necessary for the medical treatment of the subject. If possible, the sponsor/designee 
should be notified before the study drug blind is broken. If a medical emergency requiring 
unblinding occurs, the investigator (or designee) at the site will contact the sponsor or designee 
(see medical monitor contact information listed in Section 1.1) to assess the necessity to break the 
study drug blind.
For unblinding a subject, the study drug blind can be obtained by accessing the IWRS. The 
sponsor/designee must be notified immediately if the study drug blind is broken. The date, time, 


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and reason the blind was broken must be recorded in the source documents and on the appropriate 
eCRF.
If any site personnel is unblinded, study drug must be stopped immediately and the subject must be 
withdrawn from the study. The reason for withdrawal should be recorded as “Protocol Deviation.”
8.6
Accountability and Destruction of Sponsor-Supplied Drugs
Drug supplies will be counted and reconciled at the site before being returned to the sponsor or 
designee.
The investigator or designee must ensure that the sponsor-supplied drug is used in accordance with 
the protocol and is dispensed only to subjects enrolled in the study. To document appropriate use 
of sponsor-supplied drug (vortioxetine 10 and 20 mg, paroxetine 20 mg, and placebo), the 
investigator or designee must maintain records of all sponsor-supplied drug delivery to the site, 
site inventory, dispensation and use by each subject, and return to the sponsor or designee.
Upon receipt of sponsor-supplied drug, the investigator or designee must verify the contents of the 
shipments against the packing list. The verifier should ensure that the quantity is correct, and the 
medication is in good condition. If quantity and conditions are acceptable, the investigator or 
designee should acknowledge the receipt of the shipment by recording in the IWRS. If there are 
any discrepancies between the packing list vs 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 the following:

Frequently verifying that actual inventory matches documented inventory.

Verifying that the log is completed for the drug lot (or medication ID number) used to prepare 
each dose.

Verifying that all containers used are documented accurately on the log.

Verifying that required fields are completed accurately and legibly.
If any dispensing errors or discrepancies are discovered, the sponsor must be notified immediately.
The IWRS will include all required information as a separate entry for each subject to whom 
sponsor-supplied drug is dispensed.
The investigator or designee must record the current inventory of all sponsor-supplied drugs
(vortioxetine 10 and 20 mg, paroxetine 20 mg, and placebo) 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 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 


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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. 
All study drug not returned to the site by a subject must be investigated by the site and 
appropriately documented on the drug accountability log.
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. 


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9.0
STUDY PLAN
9.1
Study Procedures
The following sections describe the study procedures to be performed 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. 
PGx informed consent is a component of the overall study informed consent. Collection of PGx 
blood samples is mandatory for each subject (see Section 9.1.15).
The Subject Database Authorization will also be a component of the overall study informed 
consent (see Section 9.1.2).
A unique subject ID number (subject number) will be assigned to each subject at the time that 
informed consent is obtained; this subject number will be used throughout the study.
9.1.2
Subject Database and Authorization
Clinical trial subject registries seek to reduce subjects from enrolling into multiple clinical trials by 
identifying duplicates before enrollment. This study will utilize one or more subject registry 
databases. At the time of providing the informed consent for the study, the investigator or designee 
will explain to the subject the IRB-approved Subject Database Authorization and witness the 
signature.
During Screening, site staff who have received training and login information to access the registry 
will enter the subject study ID and authorized subject identifiers. An immediate report detailing 
matches is generated and should be printed for source documentation. The report will specify 
either (1) no matches found, (2) a match was found with a subject participating in another study 
within 30 days, or (3) the subject matches with a subject who has prescreened/screened at another 
site. 
9.1.3
Demographics, Medical History, Psychiatric History, and Medication History 
Procedure
Demographic information to be obtained will include date of birth, sex, Hispanic ethnicity, race as 
described by the subject, and smoking status of the subject at Screening. 
Medical history 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 stopped at 
or prior to signing of informed consent. Ongoing medical and/or psychiatric conditions are 
considered concurrent conditions (see Section 9.1.11).


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Medication history information to be obtained includes any medication relevant to eligibility 
criteria and the efficacy/safety evaluation stopped at or within 90 days prior to signing of informed 
consent.
9.1.4
Physical Examination Procedure
A baseline physical examination (defined as the assessment prior to first dose of study drug) will 
consist of the following body systems: (1) eyes; (2) ears, nose, throat; (3) cardiovascular system; 
(4) respiratory system; (5) gastrointestinal system; (6) dermatologic system; (7) extremities; (8) 
musculoskeletal system; (9) nervous system; (10) lymph nodes; and (11) other. A genitourinary 
examination will not be required. 
All subsequent physical examinations should assess clinically significant changes from the 
assessment prior to the first dose of study drug (baseline examination).
9.1.5
Weight, Height, and BMI
A subject should have weight and height measured while wearing indoor clothing and with shoes 
off. The Takeda standard for collecting height is centimeters without decimal places and for 
weight it is kilograms (kg) with 1 decimal place. BMI should be derived as follows: 
BMI = weight (kg)/[height (m)]2
Note that although height is measured in centimeters, the BMI formula uses meters for height; 
meters can be determined by dividing centimeters by 100. Thus, for example, if height=176 cm 
(1.76 meters) and weight=79.2 kg, then BMI=79.2/1.762=25.56818 kg/m2.
BMI values will be reported to 1 decimal place by rounding. The above value should be captured 
as 25.6 kg/m2 in the database.
9.1.6
Vital Sign Procedure
Vital signs will include body temperature (oral or tympanic), pulse (beats per minute), and sitting
blood pressure (taken after 5 minutes in the sitting position).
When vital signs are scheduled at the same time as blood draws, the blood draw will take priority 
and vital signs will be obtained before or after the scheduled blood draw.
9.1.7
ECG Procedure
A standard 12-lead ECG will be recorded. The following parameters will be recorded 
electronically by a central reader from the subject’s ECG trace: heart rate, RR interval, PR interval, 
QT interval, QRS interval and corrected QT interval. The central reader will interpret the ECG 
using 1 of the following categories: within normal limits or abnormal. If interpreted as abnormal, 
the investigator will assess the findings as either abnormal clinically significant, or abnormal not 
clinically significant. The interpretation of the ECG will be recorded in the source documents and 
in the eCRF. ECG traces recorded on thermal paper will be photocopied to avoid degradation of 


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trace over time. Requirements for the ECG equipment and procedure for collecting and 
transferring information to the central reader will be provided in the site manual. 
9.1.8
Sexual Functioning Assessments
9.1.8.1
CSFQ-14
The CSFQ-14 is a structured self-reported questionnaire designed to measure illness- and
medication-related changes in sexual functioning that consists of 14 items measuring sexual
functioning as a total score (14 items) and on the subscales of pleasure (1 item), desire/frequency
(2 items), desire/interest (3 items), arousal (3 items), and orgasm (3 items). Two additional items
are included in the total score, but do not map to a specific phase of the sexual response cycle.
Lower scores are associated with worsened sexual functioning [20]. The subject should complete 
the CSFQ-14 scale before the PGI-I scale at all post-baseline visits.
9.1.8.2
PGI-I Scale
The PGI-I scale is a global self assessment used to rate the response of a subject’s condition to 
therapy or intervention. It consists of one question that asks the subject to rate their current 
condition compared to how it was prior to beginning treatment on a scale of 1 (very much better) to 
7 (very much worse). It was originally developed for assessment in women with stress urinary 
incontinence [21]. However, due to its lack of specificity for medical conditions, and its sensitivity 
to change, it has been used for subject self assessment in other conditions. The subject should 
complete the CSFQ-14 scale before the PGI-I scale at all post-baseline visits.
9.1.9
C-SSRS
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 study of 
centrally-acting drugs [22,23]. The C-SSRS is composed of 3 questions addressing suicidal 
behavior and 5 questions addressing suicidal ideation, with subquestions assessing the severity. 
The tool is administered via interview with the subject.
9.1.10
Documentation of Concomitant Medications
Concomitant medication is any drug given in addition to study drug. These may be prescribed by a 
physician or obtained by the subject over the counter. Concomitant medication is not provided by 
Takeda. At each study visit, subjects will be asked whether they have taken any medication other 
than study drug (used from signing of informed consent through the end of the study), and all 
medication including vitamin supplements, over-the-counter medications, and oral herbal 
preparations, must be recorded in the eCRF.
9.1.11
Documentation of Concurrent Medical and/or Psychiatric Conditions
Concurrent medical and/or psychiatric conditions are those significant ongoing conditions or 
diseases that are present at signing of informed consent. This includes clinically significant 


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laboratory, ECG, or physical examination abnormalities noted at the screening or baseline 
examination. The condition (ie, diagnosis) should be described.
9.1.12
Procedures for Clinical Laboratory Samples 
Laboratory samples will be collected at the time points stipulated in the Schedule of Study 
Procedures (Appendix A). The maximum volume of blood collected at any single visit is 
approximately 25 mL, and the approximate total volume of blood for the study is 88 mL 
(Table 9.a). Samples will be collected in accordance with acceptable laboratory procedures.
Details of these procedures and required safety monitoring will be given in the laboratory manual. 
Table 9.a
Approximate Blood Volume
Sample Type
Volume
per
Sample
Number of Samples (a)
Total 
Volume
Screening
Period
Baseline
Treatment
Period
Final Visit/
ET Visit
HBsAg, HCV, HIV
6 mL
1
---
---
---
6 mL
Free testosterone, 
TSH/free T4, HbA1c
2 mL
3 (b)
---
---
---
6 mL
Serum chemistry tests (c)
6 mL
1
1
---
1
18 mL
Hematology tests
2 mL
1
1
---
1
6 mL
PK analysis (d)
6 mL
---
---
4
2
36 mL
DNA isolation
6 mL
---
1
---
---
6 mL
RNA isolation
2.5 mL
---
2
---
2
10 mL
Total Blood Volume
88 mL
--- =not applicable.
(a) Does not include blood draws at any unscheduled visits.
(b) One 2 mL blood sample for each test.
(c) Includes serum pregnancy test for women of childbearing potential.
(d) For measurement of vortioxetine or paroxetine concentrations in plasma.
The clinical laboratory tests to be performed are listed in Table 9.b.


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Table 9.b
Clinical Laboratory Tests
Hematology
Serum Chemistry
Urinalysis
RBCs
WBCs
Hemoglobin
Hematocrit
Platelets 
Neutrophils
Eosinophils
Basophils
Lymphocytes
Monocytes
HbA1c (a)
ALT
Albumin
Alkaline phosphatase
AST
Total protein
Creatinine
Blood urea nitrogen
Creatine kinase
GGT
Potassium
Sodium
Total bilirubin
Direct bilirubin (b)
Calcium
Glucose (fasting or nonfasting)
INR (d)
Lipids (fasting or nonfasting):
Triglycerides
Total cholesterol
High-density lipoprotein cholesterol (direct)
Low-density lipoprotein cholesterol (Friedwald)
Specific gravity
pH
Glucose
Protein
Occult blood 
Microscopic battery:
WBCs, RBCs, epithelial
cells, casts (c)
Other:
Serum
Urine
HIV (a)
HBsAg (a)
HCV (a)
TSH, free T4 (e)
Free testosterone (a)
Drug screen: anabolic steroids, amphetamine, barbiturates, 
benzodiazepines, cannabinoids, cocaine metabolites, 
opiates, ethyl alcohol, methadone, phencyclidine, 
propoxyphene, methaqualone, and oxycodone (f)
Female subjects of childbearing potential
Female subjects of childbearing potential
Beta hCG (for pregnancy) (a)
Beta hCG (for pregnancy) (g)
GGT=-glutamyl transferase, hCG=human chorionic gonadotropin, RBC=red blood cell, WBC=white blood cell.
(a) To be performed at Screening only.
(b) To be performed only if total bilirubin ≥2 mg/dL. 
(c) Microscopic examination of sediment to be performed only if the dipstick results are positive.
(d) To be performed only if subjects experience ALT or AST >3×ULN as part of the required follow-up laboratory 
tests.
(e) TSH to be measured at Screening to exclude subjects with clinically significant thyroid dysfunction 
(hyperthyroidism or hypothyroidism), which may impact sexual functioning. If TSH value is outside the normal 
range, free T4 will be measured.
(f) To be performed at Screening, Baseline, and at any time at the discretion of the investigator.
(g) To be performed at all study visits except Screening.
The central laboratory will perform all clinical laboratory tests with the exception of the urine 
pregnancy (hCG) tests, which will be performed at the study site. The clinical laboratory test 
results will be returned to the investigator, who will be responsible for filing and reviewing these 


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results together with the data in the eCRF. The investigator is responsible for recording the 
interpretation of clinical significance of any abnormal laboratory results in the eCRF. The 
investigator will maintain a copy of the laboratory accreditation and the reference ranges for the 
laboratory used.
If subjects experience ALT or AST >3×ULN, follow-up laboratory tests (at a minimum, serum 
alkaline phosphatase, ALT, AST, total bilirubin, GGT, and INR) should be performed within a 
maximum of 7 days and preferably within 48 to 72 hours after the abnormality was noted.
(Please refer to Section 7.4 for discontinuation criteria, and Section 10.1.5.2 for the appropriate 
guidance on reporting of abnormal LFTs in relation to ALT or AST >3×ULN in conjunction with 
total bilirubin >2×ULN.)
If the ALT or AST remains elevated >3×ULN on these 2 consecutive occasions the investigator 
must contact the medical monitor for consideration of additional testing, close monitoring, 
possible discontinuation of study drug, and 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
for reporting requirements).
For subjects with positive drug screen results, confirmation testing should be performed (except 
for ethyl alcohol). If methadone testing is to be performed after vortioxetine administration, 
confirmation testing must be performed as false positives may occur.
9.1.13
Contraception and Pregnancy Avoidance Procedure
From signing of informed consent, throughout the duration of the study, and for 30 days after last 
dose of study drug, female subjects of childbearing potential* who are sexually active with a 
nonsterilized male partner** must use adequate contraception. In addition they must be advised 
not to donate ova during this period.
*Females NOT of childbearing potential are defined as those who have been surgically sterilized 
(hysterectomy, bilateral oophorectomy or tubal ligation) or who are postmenopausal (eg, defined 
as ≥1 year since last regular menses with a follicle-stimulating hormone level >40 IU/L or ≥5 years 
since last regular menses, confirmed before any study drug is implemented).
**Sterilized males should be ≥1 year postvasectomy and have confirmed that they have obtained 
documentation of the absence of sperm in the ejaculate.


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An acceptable method of contraception is defined as one that has no higher than a 1% failure rate. 
In this study, where medications and devices containing hormones are included, the only 
acceptable methods of contraception are as follows: 
Barrier methods (each time the 
subject has intercourse):
Intrauterine devices 
(IUDs):
Hormonal contraceptives:

Male condom PLUS spermicide.

Cap (plus spermicidal cream or 
jelly) PLUS male condom and 
spermicide.

Diaphragm (plus spermicidal 
cream or jelly) PLUS male 
condom and spermicide.

Copper T PLUS condom 
or spermicide.

Progesterone T PLUS 
condom or spermicide.

Implants.

Hormone shot/injection.

Combined pill.

Minipill.

Patch.

Vaginal ring PLUS male 
condom and spermicide.
Subjects will be provided with information on acceptable methods of contraception as part of the 
subject informed consent process and will be asked to sign a consent form stating that they 
understand the requirements for avoidance of pregnancy and donation of ova during the course of 
the study.
During the course of the study, regular urine hCG pregnancy tests will be performed only for 
women of childbearing potential and subjects will receive continued guidance with respect to the 
avoidance of pregnancy as part of the study procedures (Appendix A).
In addition to a negative serum hCG pregnancy test at Screening, subjects also must have a 
negative urine hCG pregnancy test at Baseline prior to receiving any dose of study drug.
9.1.14
Pregnancy
If any subject is found to be pregnant during the study she should be withdrawn and any 
sponsor-supplied drug (vortioxetine, paroxetine, or placebo) should be immediately discontinued. 
If the pregnancy occurs during administration of active study drug, eg, after the Baseline Visit or 
within 30 days of the last dose of active study drug, 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. 
Subjects randomized to placebo need not be followed.
If the female subject agrees to the primary care physician being informed, the investigator should 
notify the primary care physician that the subject was participating in a clinical study at the time 
she became pregnant and provide details of treatment the subject received (blinded or unblinded, 
as applicable).


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All pregnancies in subjects on active study drug, including comparator, will be followed up to final 
outcome, using the pregnancy form. Pregnancies will remain blinded to the study team. The 
outcome, including any premature termination, must be reported to the sponsor. An evaluation 
after the birth of the child will also be conducted.
9.1.15
PGx Sample Collection
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 to how the drug is 
broken down or how the drug affects the body. This is called a “PGx research study.” Specific 
purposes of such a study include the following:

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 drugs, and for improving the efficiency, design, and study 
methods of future research studies.
In the current study, collection of PGx blood samples is mandatory for each subject. PGx informed 
consent is a component of the overall study informed consent. 
One 6-mL whole blood sample for DNA isolation will be collected predose at Baseline (Day 0) 
from each subject in the study, into plastic potassium ethylenediamine tetraacetic acid (K2EDTA) 
spray-coated tubes, and stored under frozen conditions. If necessary and feasible, a second aliquot 
of blood may be collected if isolation of DNA from the first sample was not successful or possible. 
In addition, if the whole blood sample for DNA isolation is not collected at Baseline, it may be 
collected at any point in the study.
Two 2.5-mL whole blood samples for RNA isolation will be collected predose at Baseline (Day 0) 
and also at Week 5/ET from each subject in the study (ie, 4 samples per subject), into a PaxGene 
tube. 
Each PGx sample for a study subject should be identifiable on the requisition form with a 8-digit 
subject ID number (the 5-digit site number plus the 3-digit subject number).
The samples will be stored for no longer than 15 years after completion of the vortioxetine study. 
No samples will be stored for longer than permitted by the applicable law and samples will be 
destroyed upon notification from Takeda. “Stored samples” are defined as samples that are 
key-coded (the samples are stripped of all personal identifying information but a key links the 
samples to the clinical data collected from the sample donor) and are used in the analysis of study 
drug or related drugs.


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Detailed instructions for the handling and shipping of samples are provided in the study laboratory 
manual.
9.1.16
PK Sample Collection and Analysis
9.1.16.1
Collection of Plasma for PK Sampling
A total of six 6-mL PK blood samples (trough samples) will be collected from each subject at 
3 separate study visits (2 samples at each time point at Weeks 3, 4, and 5/ET). At Week 5/ET, the 
blood sample will be collected at the same time point as the blood sample for clinical laboratory 
tests. Subjects will be instructed to take the study drug immediately after PK blood samples are 
collected. The exact date and time of last dose prior to the scheduled PK visit as recorded on the 
subject diary, the exact time of PK blood draws, and the exact time of dose taken at the site at the 
PK visit will be recorded on the appropriate eCRF. 
Please refer to Appendix E for instructions for the collection, handling, and shipping of plasma 
samples for PK analysis. Samples collected from subjects in the vortioxetine and paroxetine 
groups will be analyzed by the bioanalytical laboratory to measure vortioxetine and paroxetine 
concentrations in plasma, respectively. Samples collected from subjects in the placebo groups will 
not be analyzed. The bioanalytical laboratory will be unblinded to select the subjects receiving 
vortioxetine or paroxetine.
9.1.16.2
Bioanalytical Methods
Plasma concentrations of vortioxetine and paroxetine will be measured by a validated 
high-performance liquid chromatography with tandem mass spectrometry method.
9.1.17
Documentation of Screen Failure
Investigators must account for all subjects who sign informed consent.
If the subject is found to be not eligible at the Screening Visit, the investigator should complete the 
eCRF. The IWRS should be contacted as a notification of screen failure. The primary reason for 
screen failure is recorded in the eCRF using the following categories:

PTE/AE.
Did not meet inclusion criteria or did meet exclusion criteria (specify reason).

Significant protocol deviation.

Lost to follow-up.

Voluntary withdrawal (specify reason).

Study termination.

Other (specify reason).
Subject numbers assigned to subjects who fail screening should not be reused.


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9.1.18
Documentation of Rescreening
Rescreening of subjects who do not meet eligibility requirements is not allowed. If the principal 
investigator believes in the appropriateness of the subject for the study and considers a rescreen, 
permission for this must be obtained from the medical monitor. Rescreening at the investigator’s 
discretion without prior approval from the medical monitor is not permitted.
9.1.19
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 Period.
If the subject is found to be not eligible for the Treatment Period, the investigator should record the 
primary reason for failure on the applicable eCRF.
9.2
Monitoring Subject Treatment Compliance
A digital compliance technology will be implemented in this study, as described below. Subjects 
will also be required to bring study drug containers to each clinic visit, regardless of whether the 
study drug container is empty.
Subjects will be monitored for compliance using AiCure’s artificial intelligence platform. The 
technology will be provided as a smartphone application. Subjects will use the smartphone 
application to monitor themselves taking the study drug. Subjects will either download the 
application to their own smartphone, or for subjects who do not have a smartphone or who do not 
wish to download the application to their own device, a smartphone-like device will be issued to 
them and must be returned at the end of their participation in the study. The Health Insurance 
Portability and Accountability Act (HIPAA)–compliant artificial intelligence software is able to 
identify and confirm the subject, the study drug, and ingestion of the study drug. 
The subjects will monitor themselves taking the study drug using the application each time they 
take the study drug during the study. At the required dosing time, the software provides a reminder 
and takes the subject through a multistep process: (1) subject identification; (2) study drug 
identification; (3) confirmation that the subject has placed the study drug in his or her mouth. After 
determination of medication adherence by the smartphone application, data captured will be 
encrypted and transmitted to a secure, centralized, web-based dashboard, which the study site can 
access through a roles-and-rules-restricted, HIPAA-compliant system. When a subject is initially 
registered, a residential and/or mobile phone number will be encrypted and stored onto the 
dashboard. Subjects will also be able to manually enter into their device at a later time period if 
they took study drug but did not have their device on them, or if it was not working at the time.
If the study drug is not taken or is not taken correctly, the study site will be notified through the 
dashboard as well as by email or short message service (SMS) messaging. Study sites will be able 
to intervene with the subject directly through the dashboard if the study drug is not taken or not 
taken correctly. In addition, subjects will receive an automated message to their device reminding 
them to take their study drug, or if there is a low battery. The device will ring if subjects are late in 
taking their study drug. Subjects will provide written consent to be contacted via SMS messaging 


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in accordance with their use of the AiCure platform, at the clinical site when agreeing to participate 
in the study. 
Subjects will be trained on how to use the application and will participate in a practice session at 
the Baseline Visit. During the practice session, subjects will be requested to take small practice 
pills to demonstrate that they are able to use the application. The practice pills are a commercially 
available product (ie, small white or colored candies) and will be provided by AiCure.
If a subject is persistently noncompliant with the study drug (eg, ≥4 consecutive doses missed 
and/or <70% compliant between visits), the medical monitor should be consulted to discuss 
whether it may be appropriate to withdraw the subject from the study. All subjects should be 
reinstructed about the dosing requirements during study contacts. The authorized study personnel 
conducting the re-education must document the process in the subject source records. 
9.3
Schedule of Observations and Procedures
The schedule for all study-related procedures for all evaluations is shown in Appendix A.
Assessments should be completed at the designated visit/time point(s).
9.4
Biological Sample Retention and Destruction
In this study, specimens for genome/gene analysis will be collected as described in Section 9.1.15. 
The genetic material will be preserved and initially stored at 
Central Laboratory and then at 
 for up to but not longer than 15 years or as required by applicable law. The 
sponsor has put into place a system to protect the subjects’ personal information to ensure optimal 
confidentiality and defined standard processes for sample and data collection, storage, analysis, 
and destruction.
The sponsor and researchers working with the sponsor will have access to the samples collected 
and any test results. All samples collected during the study will be stored securely with limited 
access and the sponsor will require anyone who works with the samples to agree to hold the 
research information and any results in confidence.
The sample will be labeled with a unique sample identifier similar to labeling in the main study but 
using a code that is different from the code attached to the health information and other clinical test 
results collected in the study. The sample and data are linked to personal health information with 
code numbers. This link means that the subject may be identified but only indirectly. The code 
numbers will be kept secure by or on behalf of the sponsor.
Subjects who consented and provided PGx blood samples for DNA and RNA analysis can 
withdraw their consent and request disposal of a stored sample at any time. The sponsor should be 
notified of any withdrawal of consent. Notify sponsor of consent withdrawal.
PPD
PPD


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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.
Diagnoses vs signs and symptoms:

Each event should be recorded to represent a single diagnosis. Accompanying signs (including 
abnormal laboratory values) 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 findings:

Changes in laboratory values are only considered to be PTEs or AEs if they are judged to be 
clinically significant (ie, if some action or intervention is required or if the investigator judges 
the change to be beyond the range of normal physiologic fluctuation). A laboratory re-test 
and/or continued monitoring of an abnormal value are not considered an intervention. In 


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addition, repeated or additional noninvasive testing for verification, evaluation, or monitoring 
of an abnormality is not considered an intervention.

If abnormal laboratory values 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, 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 appropriately 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 efficacy):

Insufficient clinical response, efficacy, or pharmacologic action, should NOT be recorded as 
an AE. The investigator must make the distinction between exacerbation of pre-existing illness 
and lack of therapeutic efficacy.
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.
Suicidality events:

A completed suicide is always an SAE based on its fatal outcome. Additionally, for the 
purpose of this development program, active suicidal behaviors such as “suicidal intention 
with a definite plan” and “suicide attempt” will also be collected as SAEs. Unless the event 
meets other serious criteria, suicidal thoughts or suicidal ideations that do not include a definite 
plan or action will be collected as nonserious AEs in accordance with the standard AE 
reporting requirements (eg, if a pre-existing suicidal ideation recorded on the screening 
C-SSRS got worse during the study, it should be reported as an AE). A subject presenting with 
self-mutilation or other types of self-injury should be questioned by the investigator to clarify 
if the action was suicidal in intent. If the event was suicidal in intent, the investigator should 
include suicidal behavior as part of the verbatim term on the eCRF, that is, “slit wrists/suicidal 
behavior.” Such an event will be collected as an SAE. Acts of self-mutilation or self-injury 
without suicidal intention, for example, self-imposed cigarette burns, will be collected as 
nonserious AEs.
10.1.4
SAEs
An SAE is defined as any untoward medical occurrence that at any dose:
1. Results in DEATH.
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.


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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).
Table 10.a
Takeda Medically Significant AE List 
Term
Acute respiratory failure/acute respiratory distress 
syndrome
Hepatic necrosis
Acute liver failure
Torsade de pointes/ventricular fibrillation/ventricular 
tachycardia
Anaphylactic shock
Acute renal failure
Malignant hypertension
Pulmonary hypertension
Convulsive seizure
Pulmonary fibrosis 
Agranulocytosis
Confirmed or suspected endotoxin shock
Aplastic anemia
Confirmed or suspected transmission of infectious agent by a 
medicinal product
TEN/SJS
Neuroleptic malignant syndrome/malignant hyperthermia
Spontaneous abortion/stillbirth and fetal death
SJS=Stevens-Johnson syndrome, TEN=Toxic epidermal necrolysis.
PTEs that fulfill 1 or more of the serious criteria above are also to be considered SAEs and should 
be reported and followed up in the same manner (see Sections 10.2.2 and 10.3).
10.1.5
Special Interest Adverse Events
A special interest AE (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 and would be described in protocols and instructions provided 
for investigators as to how and when they should be reported to Takeda.
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 TEN, 


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or SJS. For example, all subjects who develop rash should undergo a physical examination and be 
monitored for the appearance of any of the following features (and findings should be recorded):
a) Involvement of mucous membranes or conjunctiva.
b) The development of skin pain.
c) Urticaria, blistering, other skin lesions.
d) Any evidence of angioedema.
If there are subjects with symptoms of systemic reaction (eg, generalized rash), or signs of a severe 
rash (such as those outlined above), or if clinically appropriate, then the following laboratory tests 
should also be performed and the results 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, the Skin- or Allergy-Type 
Reaction page of the eCRF should be completed within 1 business day of the investigator’s 
awareness of the event. If the alternative causality has been identified, then the Skin- or 
Allergy-Type Reaction page of the eCRF should not be completed.
10.1.5.2
Liver Injury
Management of liver toxicity AEs is described in Section 7.4. 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 of the eCRF. The investigator must contact the medical monitor 
for consideration of immediate discontinuation of study drug and discussion of relevant subject 
details and possible alternative causalities.
For events that meet the criteria described in Section 7.4, the Liver Injury page of the eCRF should 
be completed within 1 business day of the investigator’s awareness of the event.
10.1.5.3
Overdose
Management of an overdose is described in Section 8.1.4. All cases of overdose (with or without 
associated AEs) will be documented as AEs. For events that meet the criteria of an overdose, the 
Overdose page of the eCRF should be completed within 1 business day of the investigator’s 
awareness of the event.


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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.
10.1.7
Causality of AEs
The relationship of each AE to study drug 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/PTEs (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.


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
Not Applicable – a study drug was stopped for a reason other than the particular AE, eg, the 
study has been terminated, the subject died, or dosing with study drug was already stopped 
before the onset of the AE.
10.1.13 Outcome

Recovered/Resolved – the 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; or 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; the event 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 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
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 (on Day 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 
(on Day 1). Routine collection of AEs will continue until the Follow-up Contact (Week 7).
10.2.1.1
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 and time.
3. Frequency.
4. Intensity.
5. Investigator’s opinion of the causal relationship between the event and administration of study 
drug (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.
The CSFQ-14, PGI-I scale, and C-SSRS 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 these instruments, 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.
10.2.1.2
Special Interest Adverse Event Reporting
If the subject experiences a skin rash or allergic-type event as described above, liver injury, or 
overdose during the Treatment Period or the safety Follow-up Period based on the criteria outlined 
in Section 10.1.5, the event should be reported on a specific page of the eCRF 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.


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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 ID 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, the LFT Increases page of the 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, 
other acute liver disease, or medical history/concurrent medical conditions. Follow-up laboratory 
tests as described in Section 9.1.12 must also be performed. In addition, the LFT Increases page of 
the 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 hospital notes 
(eg, ECGs, laboratory test results, discharge summary, postmortem results) should be sent to the 
addressee, if requested.


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All SAEs should be followed up until resolution or permanent outcome of the event. The timelines 
and procedure for follow-up reports are the same as those for the initial report.
10.3.1
Safety Reporting to Investigators, IRBs, and Regulatory Authorities
The sponsor will be responsible for reporting all suspected unexpected serious adverse reactions 
(SUSARs) and any other applicable SAEs to regulatory authorities, investigators, and IRBs, as 
applicable. 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 an 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 their IRB.


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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
Case Report Forms (Electronic)
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. 
The eCRFs must be completed in English.
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 to eCRFs are recorded in an audit trail that captures the old information, the new 
information, identification of the person making the correction, the date the correction was made, 
and the reason for change. Reasons for significant corrections should additionally be included. 
The principal investigator must review the eCRFs for completeness and accuracy and must sign 
and date the appropriate eCRFs as indicated. Furthermore, the investigator must retain full 
responsibility for the accuracy and authenticity of all data entered on the eCRFs.
After 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 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 copies of eCRFs, including the audit trail, and detailed records of drug disposition to 


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enable evaluations or audits from regulatory authorities, the sponsor, or its designees. Any source 
documentation printed on degradable thermal sensitive paper should be photocopied by the site 
and filed with the original in the subject’s chart to ensure long-term legibility. Furthermore, 
International Conference on Harmonisation (ICH) E6 Section 4.9.5 requires the investigator to 
retain essential documents specified in ICH E6 (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 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 unblinding of subject treatment 
assignments. This document will provide further details regarding the definition of analysis 
variables and analysis methodology to address all study objectives.
A blinded data review will be conducted prior to unblinding of subject treatment assignments. This 
review will assess the accuracy and completeness of the study database, subject evaluability, and 
appropriateness of the planned statistical methods.
13.1.1
Analysis Sets
The full analysis set (FAS) will include all subjects who were randomized, received at least 1 dose 
of double-blind study drug, and have at least 1 valid postbaseline value for assessment of the 
primary efficacy endpoint. In FAS efficacy summaries, subjects will be analyzed by the treatment 
to which they were randomized.
To adjust for treatment noncompliance, one or more modified FAS populations will be defined. 
The per-protocol analysis set (PPS) will include all subjects in the FAS who had no major protocol 
violations. Subjects to be excluded from the PPS, whether due to protocol violations or 
noncompliance to the dosing schedule, will be identified in the minutes of the subject evaluability 
assessment performed prior to unblinding.
The safety analysis set will include all subjects who were randomized and received at least 1 dose 
of double-blind study drug. In safety summaries, subjects will be analyzed according to the 
treatment they received. In the event that a subject receives more than 1 treatment, the actual 
treatment will be defined as the one that is used most frequently. If the 2 most common treatments 
are used with equal frequency, then the randomized treatment will be used as the actual treatment.
13.1.2
Analysis of Demographics and Other Baseline Characteristics
Baseline characteristics will be listed and summarized for demographics (sex, age, Hispanic 
ethnicity, race, and BMI), physical examinations (including assessment of menopausal status), and 
medical history (including psychiatric history).
Baseline values for efficacy and safety variables will be presented in the tables that summarize 
data per study visit; however, baseline efficacy data will also be presented separately for all 
subjects randomized.
For continuous variables, treatment groups will be compared using an analysis of variance with 
treatment and center as factors. For categorical variables, treatment groups will be compared using 
the Cochran-Mantel-Haenszel general association test, stratified by center. P-values will be 
displayed as descriptive statistics of comparability.


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13.1.3
Efficacy Analysis
13.1.3.1
Primary Analysis
Mean change from Baseline in the CSFQ-14 total score difference for vortioxetine vs paroxetine 
after 5 weeks of treatment will be the primary endpoint. The primary analysis will be based on 
analysis of covariance (ANCOVA) using the last observation carried forward (LOCF) technique, 
with treatment, center, and sex as fixed factors, and baseline CSFQ-14 total score as covariate. The 
comparisons will be between each vortioxetine dose (10 or 20 mg) and paroxetine, and both 
statistical tests will be 2-sided. The Holm-Bonferroni method will be used to adjust for multiplicity 
and control the familywise type I error rate at a significance level of 0.05. If the smaller of the 
2 p-values is <0.025, significance is obtained for the associated vortioxetine dose and the other 
dose will then be evaluated at a 0.05 significance level. Although vortioxetine will be compared 
with paroxetine in the primary analysis, paroxetine will also be compared with placebo to validate 
the study.
13.1.3.2
Secondary Analyses
Change from Baseline in CSFQ-14 total score for vortioxetine vs paroxetine, paroxetine vs 
placebo, and vortioxetine vs placebo at each visit will also be analyzed using ANCOVA and 
LOCF, with treatment, center, and sex as fixed factors, and baseline CSFQ-14 total score as 
covariate. Similar analyses will also be performed for the male and female subgroups. 
Comparisons to placebo will be made at the significance level of 0.05 outside of multiplicity 
control.
The percentage of subjects meeting criteria for sexual dysfunction (ie, CSFQ-14 total score ≤47 for 
men and ≤41 for women) at any visit (using LOCF) during the double-blind Treatment Period will 
be analyzed by logistic regression, adjusting for baseline CSFQ-14 total score, sex, and treatment.
Change from Baseline in CSFQ-14 subscales 5 dimensions and 3 phases of the sexual response 
cycle will be analyzed at all visits using ANCOVA and LOCF similar to the primary analysis.
13.1.3.3
Additional Analyses
The percentage of subjects meeting criteria for sexual dysfunction (ie, CSFQ-14 total score ≤47 for 
men and ≤41 for women) at any 2 consecutive visits (using LOCF) during the double-blind 
Treatment Period will be analyzed by logistic regression, adjusting for baseline CSFQ-14 total 
score, sex, and treatment.
Time to sexual dysfunction as assessed by the CSFQ-14 will be analyzed using a Cox model with 
an exact method to handle ties, with treatment and sex as factors.
CSFQ-14 shift from normal (ie, CSFQ-14 total score >47 for men and >41 for women) at Baseline 
to abnormal (ie, CSFQ-14 total score ≤47 for men and ≤41 for women), and CSFQ-14 negative 
responders (decrease from Baseline in CSFQ-14 total score ≥3) will be analyzed at all visits by 
logistic regression, adjusting for baseline CSFQ-14 total score, sex, and treatment.


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PGI-I will be analyzed by study visit using ANCOVA and LOCF, with treatment, center, and sex 
as fixed factors.
C-SSRS will be summarized by study visit for each treatment group using descriptive statistics.
13.1.4
PK Analysis
Plasma concentrations of vortioxetine and paroxetine will be presented in the data listings.
A population PK analysis will only be conducted for vortioxetine and/or paroxetine if deemed 
necessary. 
13.1.5
PGx Analysis
DNA samples may be used to analyze the mode of action of vortioxetine, and RNA samples may 
be used for subsequent pathway analysis. Also, since PGx is an evolving science, many genes and 
their functions are not yet fully understood. Future data may suggest a role of some of these genes 
in drug response, which may lead to additional hypothesis-generating exploratory research and 
diagnostic development using stored samples.
13.1.6
Safety Analysis
AEs
AEs will be reported throughout the study. AEs will be summarized using the safety analysis set.
The definition of treatment-emergent AEs will be provided in the statistical analysis plan. AEs will 
be coded using MedDRA and will be summarized by system organ class and preferred term for the 
double-blind Treatment Period and the entire study.
AEs that were reported more than once by a subject during the double-blind Treatment Period will 
be counted only once for that subject at the maximum severity.
Clinical Evaluations
Absolute values and changes from Screening/Baseline for clinical laboratory tests, vital signs, and 
weight will be summarized for each treatment group using descriptive statistics. Clinical 
laboratory test and vital sign results that are outside the normal ranges and potentially clinically 
significant will be flagged and tabulated. Physical examination findings will also be summarized 
for each treatment group.
13.2
Interim Analysis and Criteria for Early Termination
No interim analysis is planned.
13.3
Determination of Sample Size
Approximately 352 male and female subjects will be randomized to 4 treatment arms.


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Assuming an SD of 8.5 for the change from Baseline in CSFQ-14 total score, a total of 352 male 
and female subjects (88 subjects per arm) is sufficient to achieve ≥80% power to detect a 
difference of 4.0 for vortioxetine 20 mg vs paroxetine 20 mg or for vortioxetine 10 mg vs 
paroxetine 20 mg by a 2-sample t-test with a 0.025 2-sided significance level. Given the proposed 
Holm-Bonferroni method for multiplicity control, the power to achieve the significance for each 
vortioxetine dose is approximately 85%.


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14.0
QUALITY CONTROL AND QUALITY ASSURANCE
14.1
Study-Site Monitoring Visits
Monitoring visits to the study site will be made periodically during the study to ensure that all 
aspects of the protocol are followed. Source documents will be reviewed for verification of data 
recorded on the eCRFs. Source documents are defined as original documents, data, and records. 
The investigator and study site guarantee access to source documents by the sponsor or its 
designee (contract research organization) and by the IRB.
All aspects of the study and its documentation will be subject to review by the sponsor or its 
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, 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, 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 its designee 
for any significant deviation from the protocol.
14.3
Quality Assurance Audits and Regulatory Agency Inspections
The study site also may be subject to quality assurance audits by the sponsor or its 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 or 
where the study drug 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 the US regulatory agency, the 
FDA. If the study site is contacted for an inspection by the FDA, the sponsor should be notified 
immediately. The investigator and study site guarantee access for quality assurance auditors to all 
study documents as described in Section 14.1.


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15.0
ETHICAL ASPECTS OF THE STUDY
This study will be conducted with the highest respect for the individual participants (ie, subjects) 
according to the protocol, the ethical principles that have their origin in the Declaration of 
Helsinki, and the ICH Harmonised Tripartite Guideline for GCP. Each investigator will conduct 
the study according to applicable local or regional regulatory requirements and align his or her 
conduct in accordance with the “Responsibilities of the Investigator” that are listed in Appendix B. 
The principles of Helsinki are addressed through the protocol and through appendices containing 
requirements for informed consent and investigator responsibilities.
15.1
Institutional Review Board Approval
IRBs must be constituted according to the applicable state and federal requirements of each 
participating region. The sponsor or its designee will require documentation noting all names and 
titles of members who make up the respective IRB. If any member of the IRB 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 its designee will supply relevant documents for submission to the respective IRB 
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 for approval. The IRB’s written approval of the protocol and subject informed consent 
must be obtained and submitted to the sponsor or its designee before commencement of the study 
(ie, before shipment of the sponsor-supplied drug or study-specific screening activity). The IRB 
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 notify the 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 notification, no protocol activities, including 
screening may occur.
Study sites must adhere to all requirements stipulated by their respective IRB. This may include 
notification to the IRB 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, and submission of the investigator’s final status report to IRB. All IRB 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 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 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 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.
The subject 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 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 at the time of consent and prior to the subject 
entering into the study. The subject 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.
All revised informed consent forms must be reviewed and signed by relevant subjects 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.


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Subjects who consented and provided PGx samples for DNA and RNA analysis can withdraw 
their consent and request disposal of a stored sample at any time prior to analysis. Notify sponsor 
of consent withdrawal.
15.3
Subject Confidentiality
The sponsor and designees affirm and uphold the principle of the subject’s right to protection 
against invasion of privacy. Throughout this study, a subject’s source data will only be linked to 
the sponsor’s clinical study database or documentation via a subject ID 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 ID 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, FDA, Medicines and Healthcare products Regulatory Agency, 
Pharmaceuticals and Medical Devices Agency), the sponsor’s designated auditors, and the 
appropriate IRBs 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. All publications and presentations must be prepared in accordance with 
this section and the study site agreement. In the event of any discrepancy between the protocol and 
the study site agreement, the study site agreement will prevail.


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15.4.2
Clinical Trial Registration
In order to ensure that information on clinical trials reaches the public in a timely manner and to 
comply with applicable laws, regulations, and guidance, Takeda will, at a minimum, register 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 
08 October 2014. Available at: 
http://apps.who.int/iris/bitstream/10665/89966/1/9789241506021_eng.pdf?ua=1.
3. Rosen RC, Lane RM, Menza M. Effects of SSRIs on sexual function: a critical review. J Clin 
Psychopharmacol 1999;19(1):67-85.
4. Montejo AL, Llorca G, Izquierdo JA, Rico-Villademoros F. Incidence of sexual dysfunction 
associated with antidepressant agents: a prospective multicenter study of 1022 outpatients. 
Spanish Working Group for the Study of Psychotropic-Related Sexual Dysfunction. J Clin 
Psychiatry 2001;62 Suppl 3:10-21.
5. Clayton AH, Pradko JF, Croft HA, Montano CB, Leadbetter RA, Bolden-Watson C, et al. 
Prevalence of sexual dysfunction among newer antidepressants. J Clin Psychiatry 
2002;63(4):357-66.
6. Delgado PL, Brannan SK, Mallinckrodt CH, Tran PV, McNamara RK, Wang F, et al. Sexual 
functioning assessed in 4 double-blind placebo- and paroxetine-controlled trials of duloxetine 
for major depressive disorder. J Clin Psychiatry 2005;66(6):686-92.
7. Clayton A, Kornstein S, Prakash A, Mallinckrodt C, Wohlreich M. Changes in sexual 
functioning associated with duloxetine, escitalopram, and placebo in the treatment of patients 
with major depressive disorder. J Sex Med 2007;4(4 Pt 1):917-29.
8. Roose SP. Tolerability and patient compliance. J Clin Psychiatry 1999;60 Suppl 17:14-7; 
discussion 46-8.
9. Rothschild AJ. Sexual side effects of antidepressants. J Clin Psychiatry 2000;61 Suppl 
11:28-36.
10. Zajecka JM. Clinical issues in long-term treatment with antidepressants. J Clin Psychiatry 
2000;61 Suppl 2:20-5.
11. Hu XH, Bull SA, Hunkeler EM, Ming E, Lee JY, Fireman B, et al. Incidence and duration of 
side effects and those rated as bothersome with selective serotonin reuptake inhibitor treatment 
for depression: patient report versus physician estimate. J Clin Psychiatry 2004;65(7):959-65.
12. Papakostas GI. Tolerability of modern antidepressants. J Clin Psychiatry 2008;69 Suppl 
E1:8-13.
13. Montejo-Gonzalez AL, Llorca G, Izquierdo JA, Ledesma A, Bousono M, Calcedo A, et al. 
SSRI-induced sexual dysfunction: fluoxetine, paroxetine, sertraline, and fluvoxamine in a 
prospective, multicenter, and descriptive clinical study of 344 patients. J Sex Marital Ther 
1997;23(3):176-94.


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14. Clayton AH, Montejo AL. Major depressive disorder, antidepressants, and sexual dysfunction. 
J Clin Psychiatry 2006;67 Suppl 6:33-7.
15. 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.
16. 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.
17. TRINTELLIX (vortioxetine) Tablets. Package Insert. Deerfield, IL: Takeda Pharmaceuticals 
America, Inc., May 2016.
18. Boulenger JP, Loft H, Florea I. A randomized clinical study of Lu AA21004 in the prevention 
of relapse in patients with major depressive disorder. J Psychopharmacol 
2012;26(11):1408-16.
19. Jacobsen PL, Mahableshwarkar AR, Chen Y, Chrones L, Clayton AH. Effect of vortioxetine 
vs escitalopram on sexual functioning in adults with well-treated major depressive disorder 
experiencing SSRI-induced sexual dysfunction. J Sex Med 31 Aug 2015. 
doi:10.1111/jsm.12980.
20. Clayton AH, McGarvey EL, Clavet GJ. The Changes in Sexual Functioning Questionnaire 
(CSFQ): development, reliability, and validity. Psychopharmacol Bull 1997;33(4):731-45.
21. Yalcin I, Bump RC. Validation of two global impression questionnaires for incontinence. Am 
J Obstet Gynecol 2003;189(1):98-101.
22. Posner K, Oquendo MA, Gould M, Stanley B, Davies M. Columbia Classification Algorithm 
of Suicide Assessment (C-CASA): classification of suicidal events in the FDA's pediatric 
suicidal risk analysis of antidepressants. Am J Psychiatry 2007;164(7):1035-43.
23. Posner K, Melvin GA, Stanley B, Oquendo MA, Gould M. Factors in the assessment of 
suicidality in youth. CNS Spectr 2007;12(2):156-62.


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Appendix A
Schedule of Study Procedures
Study Day/Week:
Screening
Period
Base-
line
Double-Blind Treatment Period
Final Visit/
ET Visit (a)
Follow-up
Contact (b)
Days
-28 to -1
Day 0
Week 1 Week 2 Week 3 Week 4
Week 5
Week 7
Visit Windows (Days Relative to 
Baseline [Day 0]):
0
±3
±3
±3
±3
±3
±5
Visit Number:
1
2
3
4
5
6
7
Screening/Baseline Procedures
Informed consent
X
Subject registry database
X
Demographics, medical and/or 
psychiatric history, medication history
X
Height, BMI
X
ECG
X
HBsAg, HCV, HIV, free testosterone, 
TSH, free T4, HbA1c (c) 
X
Urine drug screen
X
X
Concurrent medical and psychiatric 
conditions
X
X (d)
Inclusion/exclusion criteria
X
X (d)
Eligibility verification
X
X (e)
Safety Assessments
Physical examination, weight
X
X
X
Vital signs
X
X
X
X
Concomitant medications
X
X
X
X
X
X
X
X
Hematology, serum chemistry, 
urinalysis
X
X (f)
X (f)
C-SSRS
X
X
X
X
X
X
X
PTE assessment (g)
X
X
AE assessments (h)
X
X
X
X
X
X
Pregnancy test (hCG) (i)
X
X
X
X
X
X
X
Sexual Functioning Assessments
CSFQ-14 (j)
X
X
X
X
X
X
X
PGI-I (j)
X
X
X
X
X
Other Blood Sampling
PK sample collection (k)
X
X
X
DNA PGx sample collection (l)
X
RNA PGx sample collection (m)
X
X
Clinical Supplies
Contact IWRS for subject ID/ 
medication ID/subject status
X
X
X
X
X
X
X


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Study Day/Week:
Screening
Period
Base-
line
Double-Blind Treatment Period
Final Visit/
ET Visit (a)
Follow-up
Contact (b)
Days
-28 to -1
Day 0
Week 1 Week 2 Week 3 Week 4
Week 5
Week 7
Study drug compliance technology 
X
X
X
X
X
X
Dispense study drug
X (n)
X
X
X
X
Study drug return/accountability/ 
compliance
X
X
X
X
X
(a) Final Visit procedures to be conducted for subjects who withdraw early, except for those who withdraw their consent and refuse 
further contact. 
(b) The Follow-up Contact will be conducted by telephone. 
(c) TSH to be measured at Screening to exclude subjects with clinically significant thyroid dysfunction (hyperthyroidism or 
hypothyroidism), which may impact sexual functioning. If TSH value is outside the normal range, free T4 will be measured.
(d) To be updated at Baseline.
(e) A prerandomization form must be approved by the
 medical monitor prior to randomization.
(f) Blood samples for clinical laboratory tests to be collected under fasting conditions at Baseline and Week 5/ET.
(g) PTEs to be assessed from the date of Screening up to the first dose of study drug on Day 1.
(h) AEs to be assessed daily from the first dose of study drug on Day 1 until the Follow-up Contact at Week 7.
(i) Serum test at Screening and urine test at all other visits. For women of child-bearing potential only.
(j) The subject should complete the CSFQ-14 before the PGI-I.
(k)Six PK blood samples to be collected for each subject (2 samples at each time point at Weeks 3, 4, and 5/ET) for measurement of 
plasma vortioxetine or paroxetine concentrations. At Week 5/ET, the blood sample will be collected at the same time point as the 
blood sample for clinical laboratory tests. Subjects will be instructed to take the study drug immediately after collection of the PK 
blood sample. 
(l) One 6-mL whole blood sample to be collected for DNA isolation predose at Baseline (Day 0) from each subject.
(m) Two 2.5-mL whole blood samples to be collected for RNA isolation predose at Baseline (Day 0) and also at Week 5/ET from 
each subject (ie, 4 samples per subject).
(n) Subjects are to be instructed to take the first dose of study drug on the morning of Day 1 (morning after Baseline).
PPD


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Appendix B
Responsibilities of the Investigator
Clinical research studies sponsored by the sponsor are subject to ICH GCP and all the applicable 
local laws and regulations. The responsibilities imposed on investigators by the FDA are 
summarized in the “Statement of Investigator” (Form FDA 1572), which must be completed and 
signed before the investigator may participate in this study. 
The investigator agrees to assume the following responsibilities by signing a Form FDA 1572:
1. Conduct the study in accordance with the protocol.
2. Personally conduct or supervise the staff who will assist in the protocol.
3. Ensure that study related procedures, including study specific (non routine/non standard panel) 
screening assessments are NOT performed on potential subjects, prior to the receipt of written 
approval from relevant governing bodies/authorities.
4. Ensure that all colleagues and employees assisting in the conduct of the study are informed of 
these obligations.
5. Secure prior approval of the study and any changes by an appropriate IRB that conform to 
21 Code of Federal Regulations (CFR) Part 56, ICH, and local regulatory requirements.
6. Ensure that the IRB will be responsible for initial review, continuing review, and approval of 
the protocol. Promptly report to the IRB 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 and issue 
a final report within 3 months of study completion.
7. Ensure that requirements for informed consent, as outlined in 21 CFR Part 50, ICH and local 
regulations, are met.
8. Obtain valid informed consent from each subject who participates in the study, and document 
the date of consent in the subject’s medical chart. Valid informed consent is the most current 
version approved by the IRB. 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.
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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Maintain current records of the receipt, administration, and disposition of sponsor-supplied drugs, 
and return all unused sponsor-supplied drugs to the sponsor.
11. 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, and 
the monitor may inspect the records. By signing a written informed consent form, the subject 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 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 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 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 PGx 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;
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 patients, 
developing a better understanding of disease, and improving the efficiency of future 
clinical studies;
d) that subjects agree not to restrict the use and disclosure of their personal information 
(including personal health information) upon withdrawal from the study to the extent that 
the restricted use or disclosure of such information may impact the scientific integrity of 
the research; and


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e) that the subject’s identity will remain confidential in the event that study results are 
published.
25. Female subjects of childbearing potential (eg, nonsterilized, premenopausal female subjects) 
who are sexually active must use adequate contraception (as defined in the informed consent) 
from Screening throughout the duration of the study and for 30 days after the last dose of study 
drug. Regular pregnancy tests will be performed throughout the study for all female subjects of 
childbearing potential. If a subject is found to be pregnant during study, study 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.
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.


Vortioxetine
Study No. Vortioxetine-4001
Page 83 of 88
Protocol Incorporating Amendment No. 01
10 January 2017
CONFIDENTIAL
Appendix E
Collection, Storage, and Shipment of Pharmacokinetic Samples
Instructions for processing of plasma samples for pharmacokinetic analysis of vortioxetine 
and paroxetine
1. Collect 6-mL of venous blood into a chilled Becton-Dickinson Vacutainer containing 
K2EDTA (for vortioxetine) or sodium heparin (for paroxetine).
2. Gently invert the Vacutainer several times to mix the additive with the collected blood prior to 
centrifugation and place immediately on ice.
3. Centrifuge the Vacutainers for 10 minutes at approximately 1100 to 1300 relative centrifugal 
force (RCF) at approximately 4°C in a refrigerated centrifuge. Note: If using a collection 
device other than a Becton-Dickinson Vacutainer refer to manufacturer’s instruction for proper 
centrifugation force and time.
4. Immediately following centrifugation, gently remove plasma from the packed cells. To ensure 
a more homogeneous sample, all plasma for each analyte should first be transferred into 1 
aliquot. From there, split the plasma evenly between the 2 aliquots. A minimum of 1.2 mL 
needs to be obtained for each sample. Labeling may include protocol number 
Vortioxetine-4001, matrix (plasma), subject ID (XXXX-XXX), nominal day and time, and 
either “SET 1” (for original sample) or “SET 2” (for duplicate sample).
5. Cap the labeled storage tubes and freeze the plasma samples immediately at approximately 
-20°C or lower. No more than 60 minutes should elapse between blood collection and freezing 
the plasma sample.
6. Keep samples frozen at approximately -20°C or lower until shipment to the central laboratory. 
Shipping of plasma for vortioxetine or paroxetine quantification
The following instructions are recommended unless they differ from the site’s standard operating 
procedures for labeling, packaging, or shipping of PK samples. 
1. Biological samples (plasma) should be shipped on dry ice to prevent thawing during transit. 
Samples should be shipped only on Monday, Tuesday, or Wednesday, and at least 2 days prior 
to a national holiday, in order to minimize the possibility of samples in transit over a weekend 
or holiday. If duplicate samples are to be shipped, send SET 1 samples and await confirmation 
of arrival before shipping the duplicate SET 2 samples. Samples may be shipped on other days 
with the permission of the sponsor.
2. Before shipping, make sure the sample tubes are tightly sealed. Separate each subject’s 
samples as follows:
3. Separate the duplicate SET 2 samples from the SET 1 samples.
4. Place SET 1 samples for each subject into a self-sealing bag (eg, Ziploc) containing additional 
absorbent material.


Vortioxetine
Study No. Vortioxetine-4001
Page 84 of 88
Protocol Incorporating Amendment No. 01
10 January 2017
CONFIDENTIAL
5. Using a permanent marker, write the subject ID, study drug (vortioxetine or paroxetine), 
sample matrix (plasma), number of samples, and “SET 1” on each self-sealing bag.
6. Place the bags of individual subject’s samples into a larger plastic bag so that samples are 
double bagged. Duplicate SET 2 samples should be returned to the freezer for storage. Repeat 
steps 3 through 6 above when preparing duplicate samples for shipment, except self-sealing 
bags should be marked “SET 2”.
7. An inventory of individual samples should accompany each shipment and should include the 
sponsor’s name (Takeda), protocol number (Vortioxetine-4001), investigator’s name, sample 
type (plasma), subject ID, nominal collection day and time, and intended sample storage 
conditions. When duplicate SET 2 samples are being shipped, make a copy of the original SET 
1 sample inventory and mark as “SET 2”. Place the inventory paperwork into a large 
self-sealing bag. SET 1 samples will be shipped first on dry ice, followed by shipment of 
duplicate SET 2 samples after SET 1 samples have been received by the central laboratory.
8. For sample packing, use dry ice generously (eg, 20 to 25 pounds per day of transit) to 
safeguard against longer than expected shipping times and delays. Use newspaper or other 
material to insulate the double-bagged samples from direct contact with the dry ice. Place the 
sample bundles into a polystyrene (eg, Styrofoam) container (or other suitable container) and 
fill the excess space with dry ice slabs or ice pellets (preferably the latter). Make a note of the 
estimated weight of the dry ice used per shipping container.
9. Place the inventory paperwork (in a large self-sealing bag) on top of the dry ice in the 
polystyrene container. Place the lid on the polystyrene container and seal completely with 
strapping tape. Place the polystyrene container in a cardboard shipping carton and seal 
securely with strapping tape.
10. Mark the outside of shipping carton(s) with a tally number (1 of 5, 2 of 5, etc). 
11. Affix an address label to each shipping carton. Use the preprinted air waybills provided by the 
central laboratory. 
12. Obtain the air waybill number and a receipt of shipment from the carrier.


Vortioxetine
Study No. Vortioxetine-4001
Page 85 of 88
Protocol Incorporating Amendment No. 01
10 January 2017
CONFIDENTIAL
Appendix F
Detailed Description of Amendments to Text
The primary section(s) of the protocol affected by the changes in Amendment No. 01 are indicated. 
The corresponding text has been revised throughout the protocol.
Change 1: Clarify inclusion and exclusion criteria.
The primary change occurs in Sections 7.1 Inclusion Criteria and 7.2 Exclusion Criteria: 
Initial 
wording:
Inclusion criterion #4: The subject has been in a steady relationship for ≥3 months and 
plans to remain in that relationship for the duration of the study, and is currently 
sexually active (≥2 times per week).
Inclusion criterion #6: If female, the subject has a regular menstrual cycle.
Exclusion criterion #12: The subject has a history of depression or any other 
psychiatric illness.
Exclusion criterion #15: The subject has had a surgical or medical procedure on 
reproductive/genitourinary organs (excluding uncomplicated vasectomy and tubal 
ligation).
Exclusion criterion #21: The subject has a history of or current alcohol or other 
substance abuse or dependence.
Amended 
or new 
wording:
Inclusion criterion #4: The subject has been in a steady relationship for ≥3 months and 
plans to remain in that relationship for the duration of the study, and is currently 
sexually active (≥2 times per week). Note: Partners are not allowed to enroll in this 
trial.
Inclusion criterion #6: If female, the subject has a regular menstrual cycle (note: 
amenorrhea resulting from hormonal contraceptives is not exclusionary). 
Exclusion criterion #12: The subject has a history of depression or any other 
psychiatric illness including sleep disorders and premenstrual dysphoric 
disorder.
Exclusion criterion #15: The subject has had a surgical or medical procedure on 
reproductive/genitourinary organs (excluding uncomplicated cesarean section 
(C-section), vasectomy, and tubal ligation that do not impact sexual functioning).
Exclusion criterion #21: The subject has a history of or current alcohol or other 
substance abuse or dependence (according to Diagnostic and Statistical Manual of 
Mental Disorders, Fourth Edition, Text Revised [DSM-IV-TR] criteria).


Vortioxetine
Study No. Vortioxetine-4001
Page 86 of 88
Protocol Incorporating Amendment No. 01
10 January 2017
CONFIDENTIAL
Rationale for Change:
Inclusion and exclusion criteria were revised to provide further specificity in response to questions 
from investigators about eligibility. 
The following section also contains this change:

Section 2.0 STUDY SUMMARY.
Change 2: Update, correct, or clarify excluded medications and treatments.
The primary change occurs in Section 7.3 Excluded Medications and Treatments, Table 7.a
Excluded Medications and Treatments: 
Description 
of changes:
Chronic use of NSAIDs is excluded only after Baseline, not excluded for 3 months 
prior to Baseline. Furthermore, episodic use is allowed: up to 2 doses of ibuprofen 
or naproxen per week is allowed. Aspirin is NOT allowed.
Added: antineoplastics are disallowed for 3 months Prior to/From Baseline
(already disallowed during the study as either chronic or episodic use).
Melatonin and topical steroids are not excluded before or during the study.
Rationale for Change:
The short half life of NSAIDs does not require a 3-month washout period and occasional use of 
ibuprofen or naproxen will not affect sexual function. Aspirin continues to be disallowed as it is 
counterindicated with paroxetine. Due to potential length of washout, antineoplastics must be 
stopped at least 3 months prior to start of study. Use of melatonin and topical steroids are allowed 
as they are not expected to affect sexual function.


Vortioxetine
Study No. Vortioxetine-4001
Page 87 of 88
Protocol Incorporating Amendment No. 01
10 January 2017
CONFIDENTIAL
Change 3: Add that psychiatric history will be assessed as well as medical history.
The primary change occurs in Section 9.1.3 Demographics, Medical History, Psychiatric History, 
and Medication History Procedure:
Initial 
wording:
Medical history to be obtained will include determining whether the subject has any 
significant conditions or diseases relevant to the disease under study that stopped at or 
prior to signing of informed consent. Ongoing conditions are considered concurrent 
medical conditions.
Amended 
or new 
wording:
Medical history 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 stopped at or prior to signing of informed consent. Ongoing medical
and/or psychiatric conditions are considered concurrent medical conditions.
Rationale for Change: Change made to clearly outline that an assessment of psychiatric disorders 
is required as they are exclusionary and may have an effect on the study outcome. 
The following sections also contain this change:

Section 9.1.11 Documentation of Concurrent Medical and/or Psychiatric Conditions. 

Appendix A
Schedule of Study Procedures.
Change 4: Add instructions on the order in which the scales Changes in Sexual Functioning 
Questionnaire Short-Form (CSFQ-14) and Patient Global Impression of Improvement (PGI-I) 
should be completed.
The primary change occurs in Section 9.1.8.1 CSFQ-14:
Added text:The subject should complete the CSFQ-14 scale before the PGI-I scale at all 
post-baseline visits.
Rationale for Change: The PGI-I is a global assessment which is more appropriate to complete 
after the specific questionnaire on sexual functioning (CSFQ-14).
The following sections also contain this change:

Section 9.1.8.2 PGI-I Scale

Appendix A
Schedule of Study Procedures, footnote (j).


Vortioxetine
Study No. Vortioxetine-4001
Page 88 of 88
Protocol Incorporating Amendment No. 01
10 January 2017
CONFIDENTIAL
Change 5: Update personnel changes.
The primary change occurs in Section 1.1 Contacts and Section 1.2 Approval:
Initial wording:
Responsible Medical Office
Amended or new wording:
Initial 
wording:
Signatures
Amended 
or new 
wording:
Rationale for Change: A new responsible medical monitor/signatory was installed.
PPD
PPD
PPD
PPD


 
  
 
 
 
 
 
 
 
 
ELECTRONIC SIGNATURES 
Signed by 
Meaning of Signature 
Server Date 
(dd-MMM-yyyy HH:mm ‘UTC’) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
090101d6805250a2
A Randomized, Double-Blind, Parallel Group, Placebo- and Active-Controlled, Phase 4 Study Evaluating the
Effect of Vortioxetine 10 and 20 mg/day vs Paroxetine 20 mg/day on Sexual Functioning in Healthy Subjects
Clinical Science Approval
11-Jan-2017 17:16 UTC
Clinical VP Approval
11-Jan-2017 18:14 UTC
Biostatistics Approval
12-Jan-2017 13:31 UTC
PPD

SAP_001.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: Randomized, Double-Blind, Parallel Group, Placebo- and Active-Controlled, Phase 4 
Study Evaluating the Effect of Vortioxetine 10 and 20 mg/day vs Paroxetine 20 mg/day on 
Sexual Functioning in Healthy Subjects 
NCT Number: NCT02932904
SAP Approve Date: 24 July 2017
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.


1.0 
TITLE PAGE 
STATISTICAL ANALYSIS PLAN 
STUDY NUMBER: Vortioxetine-4001 
Randomized, Double-Blind, Parallel Group, Placebo- and Active-Controlled, Phase 4 
Study Evaluating the Effect of Vortioxetine 10 and 20 mg/day vs Paroxetine 20 mg/day on 
Sexual Functioning in Healthy Subjects 
PHASE 4 
TAKEDA DEVELOPMENT CENTER AMERICAS, INC 
Version: Final 
Date: 24 July 2017 
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. 


PPD
PPD
PPD
PPD
PPD


Vortioxetine_4001 
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Statistical Analysis Plan {Final} 
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2.0 
TABLE OF CONTENTS 
1.0 
TITLE PAGE .......................................................................................................................1 
1.1 
Approval Signatures.......................................................................................................2 
2.0 
TABLE OF CONTENTS .....................................................................................................3 
3.0 
LIST OF ABBREVIATIONS ..............................................................................................5 
4.0 
OBJECTIVES ......................................................................................................................6 
4.1 
Primary Objectives.........................................................................................................6 
4.2 
Secondary Objectives.....................................................................................................6 
4.3 
Additional Objectives ....................................................................................................6 
4.4 
Study Design ..................................................................................................................6 
5.0 
ANALYSIS ENDPOINTS ..................................................................................................9 
6.0 
DETERMINATION OF SAMPLE SIZE ..........................................................................10 
7.0 
METHODS OF ANALYSIS AND PRESENTATION .....................................................11 
7.1 
General Considerations ................................................................................................11 
7.2 
Major Protocol Violations............................................................................................11 
7.3 
Analysis Sets ................................................................................................................13 
7.4 
Disposition of Subjects ................................................................................................14 
7.5 
Demographic and Baseline Characteristics .................................................................14 
7.6 
Medication History and Concurrent Medications ........................................................15 
7.7 
Medication History and Concomitant Medications .....................................................15 
7.8 
Study Drug Exposure and Compliance ........................................................................15 
7.9 
Efficacy Analysis .........................................................................................................16 
7.9.1 Overview of Primary, Secondary and Additional Variables .................................16 
7.9.2 Missing Items on Rating Scales .............................................................................16 
7.9.3 Primary Efficacy Endpoint(s) ................................................................................16 
7.9.4 Secondary Efficacy Endpoint(s) ............................................................................18 
7.9.5 Additional Endpoints .............................................................................................20 
7.10 
Analyses of Columbia-Suicide Severity Rating Scale (C-SSRS) ................................20 
7.11 
Pharmacokinetic/Pharmacodynamic Analysis .............................................................21 
7.12 
Pharmacogenomic Analyses ........................................................................................21 
7.13 
Safety Analysis ............................................................................................................21 
7.13.1 Adverse Events ......................................................................................................21 
7.13.2 Clinical Laboratory Evaluations ............................................................................21 
7.13.3 Liver Function Tests ..............................................................................................21 
 
CONFIDENTIAL 


Vortioxetine_4001 
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Statistical Analysis Plan {Final} 
24July2017
 
7.13.4 Vital Signs ..............................................................................................................23 
7.13.5 Physical Examinations ...........................................................................................25 
7.13.6 12-Lead ECGs ........................................................................................................25 
7.13.7 Pregnancy Test .......................................................................................................25 
7.13.8 Skin Rash and Allergic Type Reactions ................................................................25 
7.14 
Interim Analysis ...........................................................................................................25 
7.15 
Changes in the Statistical Analysis Plan ......................................................................25 
8.0 
REFERENCES ..................................................................................................................26 
 
CONFIDENTIAL 


Vortioxetine_4001 
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Statistical Analysis Plan {Final} 
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3.0 
LIST OF ABBREVIATIONS 
 
 
AE 
adverse event 
ALT 
alanine aminotransferase 
ANCOVA 
analysis of covariance 
ANOVA 
analysis of variance 
AST 
aspartate aminotransferase 
BMI 
body mass index 
BUN 
blood urea nitrogen 
CPK 
creatine phosphokinase 
CSFQ-14 
Changes in Sexual Functioning Questionnaire Short-Form 
CRF 
case report form 
ECG 
electrocardiogram 
FAS 
full analysis set 
GGT 
γ-glutamyl transferase 
HIV 
human immunodeficiency virus 
ICH 
International Conference on Harmonisation 
IVRS 
Interactive Voice Response System 
LDH 
lactate dehydrogenase 
LLN 
lower limit of normal 
LOCF 
last observation carried forward 
MedDRA 
Medical Dictionary for Regulatory Activities 
PD 
pharmacodynamics 
PGI-I 
Patient Global Impression of Improvement 
PGx 
pharmacogenomic 
PK 
pharmacokinetics 
QOL 
quality-of-life 
PRO 
patient-reported outcome 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SDB 
standard database 
TLGs 
tables, listings, and graphs 
ULN 
upper limit of normal 
WHODrug 
World Health Organization Drug Dictionary 
 
CONFIDENTIAL 


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Statistical Analysis Plan {Final} 
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4.0 
OBJECTIVES 
4.1 
Primary Objectives 
To evaluate the effect of vortioxetine (10 and 20 mg once daily [QD]) vs paroxetine 20 mg QD 
on sexual functioning in healthy subjects after 5 weeks of double-blind treatment.  
4.2 
Secondary Objectives 
• To evaluate the effect of vortioxetine (10 and 20 mg QD) vs paroxetine 20 mg QD on sexual 
functioning in healthy subjects throughout the 5-week double-blind Treatment Period. 
• To evaluate the effect of paroxetine (20 mg QD) vs placebo on sexual functioning in healthy 
subjects throughout the 5-week double-blind Treatment Period. 
• To evaluate the effect of vortioxetine (10 and 20 mg QD) vs placebo on sexual functioning in 
healthy subjects throughout the 5-week double-blind Treatment Period. 
 
4.3 
Additional Objectives 
• To evaluate the effects of vortioxetine (10 and 20 mg QD) vs paroxetine (20 mg QD) on 
additional parameters of sexual functioning. 
• To evaluate the effect of vortioxetine (10 and 20 mg QD) and paroxetine (20 mg QD) vs 
placebo on additional parameters of sexual functioning. 
• To evaluate the subject’s perception of sexual functioning.  
• To assess the treatment effect (vortioxetine, paroxetine, or placebo) on suicidal ideation and 
behavior.  
 
4.4 
Study Design 
This is a Phase 4, multicenter, randomized, double-blind, placebo- and active-controlled 
(paroxetine), 4-arm, parallel group, fixed-dose study comparing the effect of vortioxetine (10 and 
20 mg QD) vs paroxetine (20 mg QD) on sexual functioning after 5 weeks of treatment in 
healthy adult men and women. This outpatient study will be conducted at approximately 15 sites 
in North America. Men and women will be enrolled in approximately equal proportions (ie, 50% 
men and 50% women, overall). Enrollment will be capped for each sex when the enrollment 
target has been met for that sex stratum. 
After providing informed consent, subjects will be assessed for study eligibility during a 
Screening Period of up to 4 weeks. Healthy subjects who have normal sexual functioning (as 
defined by the CSFQ-14), have been in a steady relationship for ≥3 months, are currently 
sexually active, and meet all other study entry criteria will be enrolled. At Baseline (Day 0), 
eligible subjects will be equally (1:1:1:1) randomized to double-blind vortioxetine 10 mg, 
CONFIDENTIAL 


Vortioxetine_4001 
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Statistical Analysis Plan {Final} 
24July2017
 
vortioxetine 20 mg, paroxetine 20 mg, or placebo and will be treated for 5 weeks. Randomization 
will be stratified by sex. Subjects allocated to vortioxetine 20 mg will initiate treatment at 
10 mg/day for the first week. Subsequently, the dose will be increased to 20 mg/day and remain 
at 20 mg/day until study completion. Subjects allocated to vortioxetine 10 mg will initiate 
treatment at 10 mg/day and remain at 10 mg/day until study completion. Subjects allocated to 
paroxetine 20 mg will initiate treatment at 20 mg/day and remain at 20 mg/day until study 
completion. Subjects will be instructed to take their first dose of study drug the day after baseline 
on Day 1, preferably in the morning. After randomization, subjects will be seen for weekly visits 
and receive a follow-up safety contact 2 weeks after the end of double-blind treatment. At the 
end of 5 weeks of treatment, or at early termination, all subjects will abruptly discontinue study 
drug. 
Sexual functioning will be assessed at each study visit using the CSFQ-14 (primary variable). 
The PGI-I scale will be administered at each study visit during the double-blind Treatment 
Period and at the Final Visit. Signs of suicidal risk will be assessed at each study visit using the 
C-SSRS and the investigator’s clinical judgment. Safety will be assessed throughout the study. A 
total of 6 sparse pharmacokinetic (PK) samples (trough samples) will be collected to measure 
plasma vortioxetine or paroxetine concentrations at Weeks 3, 4, and 5/ET (2 samples at each 
time point). A PGx blood sample for deoxyribonucleic acid (DNA) isolation will be collected at 
Baseline (Day 0), and 2 PGx blood samples for ribonucleic acid (RNA) isolation will be 
collected at Baseline (Day 0) and also at Week 5/ET. 
The end of the study is defined as the date the last subject completes the Final Visit (Week 5). 
A schematic of the study design is presented in Figure 4.a. A schedule of study procedures is 
provided in Appendix A. 
CONFIDENTIAL 


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Statistical Analysis Plan {Final} 
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Figure 4.a 
Schematic of Study Design 
 
 
Note: The Follow-up Contact will be conducted by telephone. 
 
Day 0
(Visit 2) 
Wk 5 
(Visit 7) 
Screening Baseline 
Screening Period 
(up to 4 weeks) 
Double-Blind Treatment Period 
(5 weeks)
Healthy Subjects 
Vortioxetine 10 mg/day
Placebo
Vortioxetine 20 mg/day 
Days -28 to -
1 (Visit 1)
Endpoint 
Paroxetine 20 mg/day
Wk 1
(Visit 3)
Wk 2
(Visit 4)
Wk 3
(Visit 5)
Wk 4
(Visit 6) 
Vortioxetine 
10 mg/day 
Wk 7 
(Follow-up) 
Randomization 
 
CONFIDENTIAL 


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5.0 
ANALYSIS ENDPOINTS 
5.1 
Primary Endpoint 
• Change from Baseline in the CSFQ-14 total score difference for vortioxetine vs paroxetine 
after 5 weeks of treatment. 
5.2 
Secondary Endpoints 
• Change from Baseline in the CSFQ-14 total score difference for vortioxetine vs paroxetine at 
each visit assessed. 
• Change from Baseline in CSFQ-14 total score difference for paroxetine vs placebo at each 
visit assessed. 
• Change from Baseline in CSFQ-14 total score difference for vortioxetine vs placebo at each 
visit assessed.  
• Percentage of subjects meeting criteria for sexual dysfunction (ie, CSFQ-14 total score ≤47 
for men and ≤41 for women) at any visit during the 5-week double-blind Treatment Period. 
• Change from Baseline in CSFQ-14 subscales 5 dimensions (pleasure, desire/frequency, 
desire/interest, arousal/erection, and orgasm/ejaculation) and 3 phases of the sexual response 
cycle (desire, arousal, and orgasm/completion) at each visit assessed. 
5.3 
Additional Endpoints 
• Percentage of subjects meeting criteria for sexual dysfunction (ie, CSFQ-14 total score ≤47 
for men and ≤41 for women) at any 2 consecutive visits during the 5-week double-blind 
Treatment Period. 
• Time to sexual dysfunction as assessed by the CSFQ-14. 
• Percentage of subjects with a shift in the CSFQ-14 from normal (ie, CSFQ-14 total score >47 
for men and >41 for women) at Baseline to abnormal (ie, CSFQ-14 total score ≤47 for men 
and ≤41 for women) at each visit assessed. 
• Percentage of subjects showing decreased sexual function (ie, negative responders) according 
to the CSFQ-14 (ie, CSFQ-14 total score decrease from Baseline ≥3) at each visit assessed. 
• Patient Global Impression of Improvement (PGI-I) score at each visit assessed. 
• Columbia-Suicide Severity Rating Scale (C-SSRS) at each visit assessed. 
5.4 
Safety Assessments 
• Adverse events (AEs), vital signs, clinical laboratory tests, weight, and physical 
examinations. 
CONFIDENTIAL 


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Statistical Analysis Plan {Final} 
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6.0 
DETERMINATION OF SAMPLE SIZE 
Approximately 352 male and female subjects will be randomized to 4 treatment arms. 
Randomization will be stratified by sex. Men and women will be enrolled in approximately equal 
proportions (ie, 50% men and 50% women overall).  
Assuming an SD of 8.5 for the change from Baseline in CSFQ-14 total score, a total of 352 male 
and female subjects (88 subjects per arm) is sufficient to achieve ≥80% power to detect a 
difference of 4.0 for vortioxetine 20 mg vs paroxetine 20 mg or for vortioxetine 10 mg vs 
paroxetine 20 mg by a 2-sample t-test with a 0.025 2-sided significance level. Given the 
proposed Holm-Bonferroni method (see Section 7.9.3) for multiplicity control, the power to 
achieve the significance for each vortioxetine dose is approximately 85%. 
 
CONFIDENTIAL 


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7.0 
METHODS OF ANALYSIS AND PRESENTATION 
7.1 
General Considerations 
7.1.1 Statistical Software 
Statistical analysis will be performed using the SAS System®, Version 9.2 or greater, on a 
Windows platform. 
7.1.2 Summary Statistics and Precision 
All tabulations of analysis results will include summaries for the following treatment groups:  , 
vortioxetine 10mg/day, vortioxetine 20mg/day, paroxetine 20 mg/day and placebo. 
All confidence intervals, statistical tests, and resulting p-values will be reported as nominal 
2-sided and will be assessed at the 5% significance level. No adjustments will be made for 
multiplicity aside from those for the primary efficacy analysis.  
For continuous variables, descriptive statistics will include the number of subjects (n), mean, SD 
or standard error (SE), as appropriate, minimum, median, and maximum. The number of decimal 
places displayed for each statistic will be determined as follows: 
• Mean and median: 1 more than the number of decimal places allotted in the electronic case 
report form (eCRF) except for the CGI scales, where 2 decimal places will be reported. 
• SD and SE: 2 more than the number of decimal places allotted in the eCRF. 
• Minimum and maximum: equal to the number of decimal places allotted in the eCRF. 
• Confidence intervals will be presented using the same number of decimal places as the 
parameters (eg, mean). 
For categorical data, frequency counts and percentages will be presented. Percentages will be 
reported to 1 decimal place. 
The data summaries will be accompanied by individual subject data listings sorted by treatment, 
study center and subject identifier. All data available from eCRFs will be listed. The actual day 
relative to the start of treatment will be determined and included in the listings. 
Derived analysis datasets will be produced from raw data and laboratory data. This allows for 
convenient reviewing of the data as well as any necessary supplemental analyses. All data from 
the raw datasets will be included in the derived datasets. Derived dataset specifications will be 
developed to include the names and definitions of derived variables in the derived SAS datasets. 
7.1.3 Definition of Study Day and Study Visit Windows 
A windowing convention will be used to determine the analysis value for a given study visit that 
applies to observed data. 
Study Day -1 corresponds to the date of the Baseline visit, ie, the randomization date. Other 
study days are defined relative to Study Day 1, the date of first double-blind study drug dose. 
Relative day is calculated as (date of interest – date of first dose +1) for study days on or after the 
CONFIDENTIAL 


Vortioxetine_4001 
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Statistical Analysis Plan {Final} 
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date of first dose and as (date of interest – date of first dose) for study days prior to the first dose 
date. 
For each visit, a window will be defined such that the lower and upper bounds of each window is 
generally the midpoint between 2 consecutive study visits. The visit windows and applicable 
study day ranges are presented below in Table 7.a. 
Table 7.a 
Visit Windows 
Nominal 
Visit Week 
Nominal 
Visit Day 
CSFQ-14, PGI-I, C-SSRS 
Vital 
signs 
Lab, 
PE,Weight,  
PK 
Baseline 
-1 (a) 
≤1 (b) 
≤1 
≤1  
≤1 (b)  
1 
7 
2 – 10 
 
 
 
2 
14 
11 – 17 
2-24 
 
 
3 
21 
18 – 24 
 
  
2-24 
4 
28 
25 – 31 
  
 
25-31 
5 
35 
≥32 
≥25 
≥2 
≥32 
7 
49 
 
 
 
 
(a) Baseline day has been defined as Day -1 in keeping with Clinical Data Interchange Consortium standards. There 
is no Day 0. 
(b) No baseline assessment for PGI-I or pharmacokinetic (PK) sampling. 
  
More than 1 result for a parameter may be obtained in a visit window. In such an event, the result 
with the date closest to the scheduled visit day will be used. In the event of 2 observations 
equidistant to the scheduled visit day, the later of the observations will be used. Treatment Period 
Last Visit values will be defined irrespective of falling in a particular window. Hence, the 
windowed Week 8 value may be different than the Last Visit value. 
In general, the baseline value for a variable is defined as the last observation prior to the first 
dose of double-blind study medication (visit date ≤ first dose date), including the screening 
value, if necessary. 
Adverse events that start more than 30 days after the last dose of double-blind study medication 
(start date – last dose date >30) will be listed, but excluded from the summaries and analyses. 
For efficacy and other safety data, data that are obtained more than 7 days after the last dose of 
double-blind study medication (visit date – last dose date >7) will be listed, but excluded from 
summaries and analyses. For certain safety measurements such as laboratory tests, summary 
statistics for the last visit will be presented, which will display values closest to the last dose of 
the double-blind medication within the cutoff day for that variable. 
 
If the date of the first double-blind dose is missing due to the subject being lost to follow-up after 
being dispensed drug then the first dose dispensed date + 1 day will be used for analysis and 
summary purposes. Similarly, if the date of last double-blind dose is missing, then the date of the 
last double-blind drug dispense date + (the last number of doses dispensed – the last number of 
doses returned) - 1 will be used. 
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The study window convention will not be applied to the eCRF data listings. The data listings for 
eCRF data will display the raw data as collected and entered in the eCRF. For CSFQ-14 and 
PGI-I, windowed visits will be shown on the listings. 
7.1.4 Grouping of Centers 
Before unblinding the data, centers that are considered small (<8 subjects) will be pooled with 
geographically similar centers to minimize artifacts in the statistical analyses from imbalances in 
subject counts within the centers. 
The pooling of the centers will be reviewed and approved by the clinical team for agreement, and 
is then used in the appropriate analyses once the database is locked and unblinded. 
7.2 
Major Protocol Violations 
All subjects with major protocol violations will be identified in the minutes of the subject 
evaluability assessment performed prior to unblinding, and will be listed by study center and 
subject number. 
Subjects with the following major protocol violations will be excluded from the per protocol set 
(PPS): 
• No evaluable baseline CSFQ-14 assessment. 
• No evaluable post-baseline assessment of CSFQ-14. 
• Low study drug compliance (<70%) or missed study drug for 4 consecutive days. 
• Double-blind study medication exposure less than 7 days (last dose date – first dose date 
+1 <7). 
• Subjects switch treatment during study. 
Other major protocol violations will be identified by the study team prior to unblinding. 
 
7.3 
Analysis Sets 
The safety set will include all subjects who were randomized and received at least 1 dose of 
double-blind study medication. In safety summaries, subjects will be analyzed according to the 
treatment they received. In the event that a subject receives more than 1 treatment, the actual 
treatment will be defined as the 1 that is used most frequently. If the 2 most common treatments 
are used with equal frequency, then the randomized treatment will be used as the actual 
treatment. 
The full analysis set (FAS) will include all subjects who were randomized, received at least 
1 dose of study drug, and had at least 1 valid post-baseline value for assessment of primary 
efficacy. In FAS efficacy summaries, subjects will be analyzed by the treatment to which they 
were randomized. 
To adjust for treatment noncompliance, two modified FAS populations, mFAS1 and mFAS2, 
will be defined based on the PK data. The mFAS1 excludes subjects in the vortioxetine treatment 
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arm who had drug concentration below the limit of quantification at all study visits where PK is 
collected, while the mFAS2 excludes subjects in the vortioxetine treatment arm who had drug 
concentration below the limit of quantification at any study visit where PK is collected. The PPS 
will include all FAS subjects who had no major protocol violations. If more than 5% of the total 
subjects in the FAS have major protocol violations, analyses based on the PPS will be performed 
for the primary efficacy variable only. 
7.4 
Disposition of Subjects 
A subject disposition summary presented by treatment group and overall will be provided. The 
categories will include all subjects who were not treated, subjects who discontinued from the 
study early categorized by reason, subjects who completed the study, subjects who discontinued 
treatment early categorized by reason, and subjects who completed treatment. Post-
randomization discontinuation reasons include pretreatment event or adverse event, significant 
protocol deviation, lost to follow-up, voluntary withdrawal, study termination, pregnancy, non-
compliance with study drug, and other. A listing will be presented to describe study treatment, 
date of first dose, date of last dose, date of completion or early withdrawal, and the reason for 
early discontinuation. 
A summary of screening failures and listings of inclusion/exclusion criteria responses for 
subjects with violations will also be provided. 
7.5 
Demographic and Baseline Characteristics 
Demographic and baseline characteristics including sex, age, race, ethnicity, height, weight, 
body mass index (BMI), smoking habit, female reproductive status, menstruation condition, and 
sexual dysfunction status.  The demographic and baseline characteristics summary will be based 
on all randomized subjects. Summaries based on the full analysis set will also be created. 
Baseline values for efficacy parameters (CSFQ-14) will also be presented for each treatment 
group and overall based on all randomized subjects. 
Height and weight values will be presented in metric units (cm and kg). BMI is calculated as 
[weight (kg)/height (m) 2], using the weight collected at the first screening visit (Visit 1) in the 
study. 
Race is classified into Caucasian, Black, Asian, American Indian or Alaska Native, Native 
Hawaiian or Other Pacific Islander. In addition, ethnicity (Hispanic or Latino) is also captured. 
Female reproductive status is classified into four categories:  postmenopausal, surgically sterile, 
female of childbearing potential and NA/subject is male. Menstruation condition includes 
duration of menstruation and duration of menstrual cycle. 
For continuous variables, the number of non-missing values and the mean, median, SD, 
minimum and maximum will be tabulated by treatment group and overall. For the categorical 
variables, the count and percentages of each possible value will be tabulated by treatment group 
and overall. 
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For continuous variables, comparability of treatment groups will be assessed using an analysis of 
variance (ANOVA) with treatment and center as fixed factors. For discrete variables, 
comparability will be assessed using the Cochran-Mantel-Haenszel general association test, 
stratified by center. P-values will be displayed as descriptive statistics of comparability. 
All individual demographic and baseline data will be listed by treatment, study center and 
subject number. 
7.6 
Medical History and Concurrent Medical Conditions 
Medical history refers to the significant conditions/diseases that stopped at or prior to Screening 
(time of informed consent). Concurrent medical conditions are those significant ongoing 
conditions/diseases present at Screening (time of informed consent). 
Medical history and concurrent medical conditions will be coded using the Medical Dictionary 
for Regulatory Activities (MedDRA) version 13.0 and will be summarized by treatment group 
and overall using System Organ Class (SOC) and MedDRA preferred term. The table will 
include number and percentages of subjects with system organ class terms sorted alphabetically 
and preferred terms sorted by decreasing frequency based on the total number of subjects. A 
subject will only be counted once within a particular class even if he/she has multiple 
conditions/symptoms. Summaries will be based on all randomized subjects. 
All medical history and concurrent medical condition data will be listed by treatment, study 
center and subject number. The listing will contain subject identifier, whether there was any 
significant medical history or concurrent condition, including system organ class, preferred term 
and details of the medical history or condition. 
7.7 
Medication History and Concomitant Medications 
The medication history and concomitant medications are defined as follows: 
• Medication history refers to the medication that the study subjects stopped taking at or within 
90 days prior to the Screening Visit (ie, stop date <= first screening visit date). 
• Concomitant medication is defined as medication that the study subjects continued taking or 
took from Screening through end of study: 
– Concomitant medication that started and stopped prior to baseline (ie, stop date > first 
screening visit 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). 
– 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 taken during the study (ie, start date ≤ last dose date, and stop 
date > first dose date. 
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– 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 01MAR2016E version 
of the World Health Organization (WHO) Drug Dictionary and summarized by giving the 
number and percentage of subjects by preferred term, with preferred terms sorted by decreasing 
frequency based on the total number of subjects. If a subject reports taking 2 drugs belonging to 
the same preferred term, he/she will only be counted once within that preferred term. Summaries 
of medication history and concomitant medication will be based on all randomized subjects. 
All prior and concomitant medications will be listed by treatment, study center and subject 
number. The listings will contain subject identifier, WHO Drug preferred term and reported 
term, dose, unit, route, frequency, the indication for which the medication was being taken, start 
date, stop date, and whether the medication was ongoing. 
7.8 
Study Drug Exposure and Compliance 
The summary of study drug exposure and compliance will be based on the safety set. 
Duration of exposure to double-blind study medication is defined as (date of last dose – date of 
first dose +1).Treatment duration will be summarized by duration category in days (1 to 6 days, 7 
to 13 days, 14 to 20 days, 21 to 27 days, 28 to 34 days, and ≥35 days) and the number of subjects 
in each duration category by treatment group. Treatment duration (weeks) will also be 
summarized using descriptive statistics (n, mean, SD, median, minimum, and maximum). 
Percent of study drug compliance is defined as {(number of capsules dispensed – number of 
capsules returned)/(date of last dose – date of first dose +1)}x100%. If a value for the number of 
returned capsules is missing or the return date is missing, then 100% compliance will be assigned 
for each day up to the number of capsules dispensed or up to the date of return whichever is 
earlier. 
For each treatment group, study medication compliance will be summarized by compliance 
category (<80%, 80 to 120%, and ≥120%) and the number of subjects in each compliance 
category. Study medication compliance will also be summarized as a continuous variable using 
descriptive statistics (n, mean, SD, median, minimum, and maximum) for each treatment group. 
All study drug administration and accountability data will be listed by treatment, study site, and 
subject number. The following variables will be listed: subject identifier, visit number, first and 
last dose dates, medication identification number, date dispensed and returned, number of 
capsules dispensed and returned, and percent compliance. 
7.9 
Efficacy Analysis 
The analyses and summaries will be based on the FAS. 
7.9.1 Overview of Primary, Secondary and Additional Variables 
The primary, secondary and additional variables for this study are presented in Table 7. 
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Table 7.b 
Primary, Secondary and Additional Variables 
Parameter 
Description 
Variable  
Type (a) 
CSFQ-14 
CSFQ-14 total score 
1 
PGI-I 
PGI improvement 
2 
Sexual dysfunction (abnormal) 
assessed by CSFQ-14 
CSFQ-14 total score ≤47 for men or ≤41 for women 
3 
Time to sexual dysfunction 
Time to CSFQ-14 total score ≤47 for men or ≤41 
for women 
4 
C-SSRS 
Columbia-Suicide Severity Rating Scale 
2 
CSFQi 
CSFQ-14 single item i 
2 
CSFQ 5-dimensions: Pleasure 
CSFQ-14 item 1 
2 
CSFQ 5-dimensions: 
Desire/Frequency 
Sum of CSFQ-14 items 2 and 3 
1 
CSFQ 5-dimensions: 
Desire/Interest 
Sum of CSFQ-14 items 4, 5, and 6 
1 
CSFQ 5-dimensions: 
Arousal/Erection 
Sum of CSFQ-14 items 7, 8, and 9 
1 
CSFQ 5-dimensions: 
Orgasm/Ejaculation 
Sum of CSFQ-14 items 11, 12, and 13 
1 
CSFQ 3-phases: Desire 
Sum of CSFQ-14 items 2, 3, 4, 5, and 6 
1 
CSFQ 3-phases: Arousal 
Sum of CSFQ-14 items 7, 8, and 9 
1 
CSFQ 3-phases: 
Orgasm/Completion 
Sum of CSFQ-14 items 11, 12, and 13 
1 
∆CSFQ ≤-3 
CSFQ negative response ( ≥3 decrease from 
baseline) 
3 
Time to ∆CSFQ ≤-3 
Time to CSFQ negative response 
4 
(a) 1 = continuous; 2 = categorical; 3 = binary; 4 = time to event. 
7.9.2 Missing Items on Rating Scales 
Missing values for post-baseline assessments will be imputed by the last observed value 
immediately prior to the missing value carried forward (LOCF). This rule does not apply to 
individual items in a multiple-item assessment. LOCF is used after imputation, ie, LOCF values 
are not used for calculations of subscale/scale scores. 
The general rule when individual items are missing from a multiple-item assessment is as 
follows: the total score will be calculated using a SAS function CEIL, as CEIL[(sum of 
nonmissing items)×(total number of items)/(number of nonmissing items)]. If more than 20% of 
the items are missing, the total score will be set to missing. The implications of this rule are 
indicated in Table 7.c for each rating scale. The resulting calculated total scores will be used in 
all analyses. 
Table 7.c 
Number of Missing Items on Rating Scales Associated with a Missing Value 
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for Total Score 
Parameter 
Number of Missing Items 
CSFQ-14 
≥3 
CSFQi or CSFQ dimension or CSFQ 3-phases 
≥1 
 
7.9.3 Primary Efficacy Endpoint(s) 
Mean change from Baseline in the CSFQ-14 total score difference for vortioxetine vs paroxetine 
after 5 weeks of treatment will be the primary endpoint. The primary analysis will be based on 
analysis of covariance (ANCOVA) using the last observation carried forward (LOCF) technique, 
with treatment, center, and sex as fixed factors, and baseline CSFQ-14 total score as covariate. 
The comparisons will be between each vortioxetine dose (10 or 20 mg) and paroxetine, and both 
statistical tests will be 2-sided.  
The following example SAS code will be used for the ANCOVA analysis: 
Proc mixed data=all; 
– class treat center sex; 
– model Change= Baseline treat center sex; 
– lsmeans treat; 
In the above model, Baseline is the baseline value and Change is the change from baseline value. 
The Holm-Bonferroni method will be used to adjust for multiplicity and control the familywise 
type I error rate at a significance level of 0.05. If the smaller of the 2 P-values is <0.025, 
significance is obtained for the associated vortioxetine dose and the other dose will then be 
evaluated at a 0.05 significance level. Although vortioxetine will be compared with paroxetine in 
the primary analysis, paroxetine will also be compared with placebo to validate the study. The 
primary analyses will also be repeated based on the PPS if more than 5% of the total subjects in 
the FAS have major protocol violations. 
 
As supportive analyses, the sex-by-treatment interaction term will be added to the primary 
analysis model to further check the sex effect on the treatment. The similar ANCOVA analyses 
will also be performed using the observed case (OC) data. 
Change from Baseline in the CSFQ-14 total score will also be analyzed based on a mixed model 
for repeated measurements (MMRM) with treatment, center, week, treatment-by-week 
interaction and sex, as fixed effects, and baseline CSFQ-14 total score, and CSFQ-14 total score-
by-week as covariates. The effect at each time point for each treatment is allowed to vary freely 
and an unstructured covariance matrix is assumed.   
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The SAS code for the MMRM analysis will be as follows: 
Proc mixed data=all; 
– class week treat center subject; 
– model Change = baseline*week baseline treat center week week*treat sex /solution; 
– repeated week/subject=subject type=UN; 
– lsmeans week*treat / cl pdiff. 
The potential influence of covariates on the primary efficacy analyses will be investigated in 
ANCOVA model by adding main terms for the covariate as well as interaction terms with 
treatment.  Among the covariates to be investigated are sex, pooled center, race, baseline weight, 
BMI, and age. 
  
 For the primary efficacy variable (using both MMRM and ANCOVA), subgroup analyses by: 
• age (≤median, >median). 
• sex (female, male). 
• race (Caucasian, Non-Caucasian). 
• baseline CSFQ-14 total score (≤ median, > median). 
and other variables will be performed if each of the subgroups contains at least 20% of the total 
subjects in the study.   
 
7.9.4 Secondary Efficacy Endpoints 
Change from Baseline in CSFQ-14 total score for vortioxetine (10mg and 20mg separately) vs 
paroxetine, paroxetine vs placebo, and vortioxetine vs placebo at each visit will also be analyzed 
using ANCOVA and LOCF, with treatment, center, and sex as fixed factors, and baseline CSFQ-
14 total score as covariate. MMRM method will also be used in sensitivity analyses. Similar 
analyses will also be performed for the male and female subgroups. Comparisons to placebo will 
be made at the significance level of 0.05 outside of multiplicity control. 
The percentage of subjects meeting criteria for sexual dysfunction (ie, CSFQ-14 total score ≤47 
for men and ≤41 for women) at any visit (using both LOCF and OC) during the double-blind 
Treatment Period will be analyzed by logistic regression, adjusting for baseline CSFQ-14 total 
score, sex, and treatment.  
The following SAS code will be used for the logistic regression analysis: 
Proc logistic data=all descending; 
– class treat; 
– model resp = treat baseline sex; 
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In the above model, Baseline is the baseline value for the corresponding response variable.  
In addition, the sex effect on sexual dysfunction will also be investigated by the inclusion of the 
sex-treatment interaction term and the sex subgroup analysis. 
Change from Baseline in CSFQ-14 subscales 5 dimensions, 3 phases, and individual items of the 
sexual response cycle will be analyzed at all visits using ANCOVA (LOCF) and MMRM similar 
to the primary analysis. 
7.9.5 Additional Endpoints 
The percentage of subjects meeting criteria for sexual dysfunction (ie, CSFQ-14 total score ≤47 
for men and ≤41 for women) at any 2 consecutive visits (using LOCF) during the treatment 
period will be analyzed by logistic regression, adjusting for baseline CSFQ-14 total score, sex, 
and treatment. 
Time to sexual dysfunction as assessed by the CSFQ-14 and time to CSFQ-14 negative response 
(defined as the decrease from Baseline in CSFQ-14 total score ≥3) will be analyzed using a Cox 
model with an exact method to handle ties, with treatment and sex as factors. The SAS code for 
the time-to-event analysis will be as follows: 
proc phreg; 
– class treat; 
–  model T_Sexdys*status_1(0) = treat sex/ ties=exact; 
The analysis will also be supplemented with plots of Kaplan-Meier estimates of sexual 
dysfunction.   
CSFQ-14 shift from normal (ie, CSFQ-14 total score >47 for men and >41 for women) at 
Baseline to abnormal (ie, CSFQ-14 total score ≤47 for men and ≤41 for women), and CSFQ-14 
negative responders (decrease from Baseline in CSFQ-14 total score ≥3) will be analyzed at all 
visits by logistic regression, adjusting for baseline CSFQ-14 total score, sex, and treatment. 
PGI-I will be analyzed by study visit using ANCOVA and LOCF, with treatment, center, and sex 
as fixed factors. MMRM analysis will also be performed. 
 
7.10 
Analyses of Columbia-Suicide Severity Rating Scale (C-SSRS) 
The following summaries will be presented for C-SSRS scale in the safety analysis set: 
• Descriptive statistics by study visit. 
• Number of subjects with positive reports at baseline and during treatment. 
• A shift-table to demonstrate changes from baseline in C-SSRS scores during treatment. 
A subject with a positive report at baseline if the subject reported any of the following suicidal 
ideation or behavior: 
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• Active suicidal ideation with some intent to act, without specific plan. 
• Active suicidal ideation with specific plan and intent. 
• Any actual suicide attempt. 
• Any interrupted suicide attempt. 
• Any aborted suicide attempt. 
• Any preparatory acts or behavior. 
A subject with a positive report during treatment if the subject reported any of the following 
suicidal ideation or behavior: 
• Active suicidal ideation with some intent to act, without specific plan. 
• Active suicidal ideation with specific plan and intent. 
• Any actual suicide attempt. 
• Any interrupted suicide attempt. 
• Any aborted suicide attempt. 
• Any preparatory acts or behavior. 
• Completed suicide. 
7.11 
Pharmacokinetic/Pharmacodynamic Analysis 
Plasma concentrations of vortioxetine and paroxetine will be presented in the data listings. 
A population PK analysis will only be conducted for vortioxetine and/or paroxetine if deemed. 
7.12 
  Pharmacogenomic Analyses 
A pharmacogenomic analysis plan will be prepared prior to the exploratory pharmacogenomic 
analysis. This plan will describe the underlying hypotheses, the pharmacogenomic analysis set, 
genes that will be included in the analysis and the statistical methods to be used. 
7.13 
Safety Analysis 
Safety summaries will be based on the safety set. Conventions for the definition of baseline 
values and visit windowing are given in Section 7.1.3. Missing safety data will not be imputed. 
Safety summaries will include descriptive statistics for values, changes, and incidence of events 
for all treatment groups combined in addition to summary by treatment group.  
7.13.1 Adverse Events 
All adverse events will be coded using MedDRA version 19.0. In this dictionary, each verbatim 
term is coded to a lower level term, and then mapped to a preferred MedDRA term, which is then 
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mapped to an SOC. All adverse events will be included in the data listings but only 
treatment-emergent adverse events will be included in the summary tables. 
A treatment-emergent adverse event (TEAE) is defined as an adverse event with an onset that 
occurs after receiving study drug (AE start date ≥ first dose date) and within 30 days after 
receiving the last dose of study drug (AE start date – last dose date ≤30). A TEAE may also be a 
pretreatment adverse event or a concurrent medical condition diagnosed prior to the date of first 
dose of study drug that increases in severity after the start of dosing. Adverse events data with 
onset occurring more than 30 days after last dose of study drug (AE start date – last dose date 
>30) will be listed, but not included in the summary tables. Adverse events with missing onset 
dates will be summarized regardless of severity and relationship to study medication. 
Serious adverse events (SAEs) with onset that occurs after receiving study drug (AE start date 
≥ first dose date) and within 30 days after receiving the last dose of study drug (AE start 
date - last dose date ≤30) will be summarized. 
In the high-level adverse event summary tables, TEAEs will be summarized regardless of 
intensity and relationship to study drug. Within each subject, multiple reports of events that map 
to a common MedDRA term will be counted only once. 
At the adverse event level, the summary tables will present the number of subjects reporting each 
of these MedDRA events, ie, the number of subjects reporting 1 or more events that map to the 
given MedDRA term. 
At the SOC level, the summary tables will present the number of subjects reporting 1 or more 
events that map to the given SOC. That is, the number of subjects reported at the SOC level will 
be less than or equal to the sum of the subject counts across all adverse events within that SOC. 
In selected summaries (TEAEs overview, and TEAEs by SOC and preferred term), adverse 
events will be summarized by the number of events reported in addition to the number and 
percentage of subjects with events. 
For the summary of TEAEs by SOC, preferred term and maximum intensity, if a subject 
experiences more than 1 episode of a particular coded adverse event, the subject will be counted 
only once by the maximum intensity of the episode (preferred term). Similarly, if a subject has 
more than 1 adverse event within an SOC, the subject will be counted only once by the 
maximum intensity in that SOC. Adverse events with missing severity will be classified as 
having the highest severity. 
TEAEs classified in the eCRF as possibly or probably related to the study medication will also 
be summarized by preferred term and SOC. If a subject experiences more than 1 episode of a 
particular coded adverse event, the subject will be counted only once by the most related report 
for the preferred term. Similarly, if a subject has more than 1 adverse event within an SOC, the 
subject will be counted only once by the most related report in that SOC. Adverse events with 
missing relationship will be classified as having the highest relationship to study drug. 
The following summaries will be presented: 
• Overview of TEAEs during the study - number and percentage of subjects, number of events. 
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• Pretreatment adverse events by SOC and preferred term. 
• TEAEs by SOC and preferred term - number and percentage of subjects, number of events. 
• TEAEs by SOC and preferred term by sex (male and female) - number and percentage of 
subjects, number of events. 
• TEAEs by SOC and preferred term by age group (≤median, >median) - number and 
percentage of subjects, number of events. 
• TEAEs by SOC - number and percentage of subjects. 
• TEAEs by preferred term - number and percentage of subjects. 
• Intensity of TEAEs by SOC and preferred term - number and percentage of subjects. 
• Drug-related TEAEs by SOC and preferred term - number and percentage of subjects, 
number of events. 
• Intensity of 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, number of events. 
• Treatment-emergent SAEs by SOC and preferred term - number and percentage of subjects, 
number of events. 
SOCs will be sorted by alphabetical order. Within an SOC, adverse events will be sorted in 
descending order of total number of subjects with the preferred term among all the treatment 
groups. 
All adverse events will be listed by treatment, study center, subject number and onset date of the 
adverse event. The listing will contain: subject identifier, age, sex, body weight, race, adverse 
event (preferred term and reported term), SOC, onset date, end date or whether the event was 
ongoing, duration, frequency, intensity (mild, moderate or severe), action taken concerning study 
drug (change in concomitant medication, change in IMP, or subject withdrawal), causality to 
study drug (not related or related), the outcome (recovered, recovering, not recovered, recovered 
with sequelae,  unknown, or fatal), whether the adverse event was an SAE. 
Special listings for TEAEs leading to study discontinuation, SAEs, deaths, and if needed, AE of 
special interest will also be presented. 
7.13.2 Clinical Laboratory Evaluations 
The following clinical laboratory parameters will be summarized: 
• Serum chemistry including blood urea nitrogen (BUN), sodium, alkaline phosphatase, 
potassium, calcium,creatinine, glucose, γ-Glutamyl transferase, alanine aminotransferase 
(ALT), aspartate aminotransferase (AST), total bilirubin, albumin, creatine kinase, and total 
protein. 
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• Lipids including cholesterol total, triglycerides, high-density lipoprotein (HDL), and 
low-density lipoprotein (LDL). 
• Hematology including white blood cell count (WBC), red blood cell count (RBC), 
hemoglobin, hematocrit, platelets, neutrophils, eosinophils, basophils, lymphocytes, and 
monocytes. 
• Urinalysis including specific gravity, pH, protein, glucose, and occult blood. 
For each laboratory parameter, the following will be displayed for each scheduled time point 
(each visit and end of study). 
• Summary statistics (n, mean, SD, median, minimum, and maximum) by treatment group and 
overall for the actual values and change from Baseline values. 
• Shift tables for the change from Baseline to each post-baseline time point will be presented. 
For these tables each subject will be categorized as low, normal, or high for the baseline 
value, and low, normal, or high for each post-Baseline time point, according to the central 
laboratory reference ranges. The number of subjects in each of the combinations of shifts will 
be presented. 
Potentially clinically significant (PCS) laboratory values, as defined in A Randomized, Double-
Blind, Parallel Group, Placebo- and Active-Controlled, Phase 4 Study Evaluating the Effect of 
Vortioxetine 10 and 20 mg/day vs Paroxetine 20 mg/day on Sexual Functioning in Healthy 
Subjects. Takeda Development Center Americas, Inc ., Protocol No. Vortioxetine-4001 
Incorporating Amendment No. 01, dated 10 January 2017, will be summarized by treatment 
group and overall. The number and percentage of subjects with PCS values observed post-
Baseline in each of the applicable laboratory parameters will be presented. 
A listing of all laboratory data will be provided. Laboratory data outside of the normal reference 
range will be flagged on the listing along with values meeting PCS criteria. The listing will also 
include the age (at consent) and sex of the subject. Listings of PCS laboratory values will also be 
presented. Thyroid stimulating hormone, Free T4 (c), and direct bilirubin will not be summarized 
but will be listed. 
When lab values are recorded in the form of “<x” or “>y”, “x” will be used for “<x” and “y” will 
be used for “>y” in the PCS summary tables. However, these values will be displayed as is when 
the individual subject data listings are presented. 
Summaries and listings of laboratory data will be presented, as appropriate, in Systeme 
International (SI) and conventional units. 
7.13.3 Liver Function Tests 
Liver function tests will be summarized by visit. Number and percentage of subjects who meet 
liver function test criteria will be summarized by treatment. 
CONFIDENTIAL 


Vortioxetine_4001 
Page 25 of 31
Statistical Analysis Plan {Final} 
24July2017
 
7.13.4 Vital Signs 
Vital signs and weight at scheduled visits and their changes from Baseline will be summarized 
for each treatment group and overall using descriptive statistics by visit and end of study. The 
number and percentage of subjects with at least one post-Baseline PCS vital sign value during 
the double-blind treatment period will be presented for each variable over all visits. A listing of 
PCS vital signs values will also be presented. 
The criteria for identification of PCS vital signs values are given in Appendix C. 
7.13.5 Physical Examinations 
All physical examination findings will be listed by treatment, study center and subject number. 
The following variables will be listed: subject identifier, age, sex, study visit, visit date. 
7.13.6 12-Lead ECGs 
ECG variables at Baseline will be summarized for each treatment group and overall using 
descriptive statistics.  
7.13.7 Pregnancy Test 
For females, pregnancy test results will be listed by treatment, study center and subject number. 
7.13.8 Skin Rash and Allergic Type Reactions 
Any subject who develops a rash will undergo and assessment to characterize the nature and 
location of the rash. Data collected regarding these reactions will be listed by treatment, study 
center and subject number. 
7.14 
Interim Analysis 
Not applicable.   
  
7.15 
Changes in the Statistical Analysis Plan  
Not applicable. 
CONFIDENTIAL 


Vortioxetine_4001 
Page 26 of 31
Statistical Analysis Plan {Final} 
24July2017
 
8.0 
REFERENCES 
1. A Randomized, Double-Blind, Parallel Group, Placebo- and Active-Controlled, Phase 4 
Study Evaluating the Effect of Vortioxetine 10 and 20 mg/day vs Paroxetine 20 mg/day on 
Sexual Functioning in Healthy Subjects. Takeda Development Center Americas, Inc ., 
Protocol No. Vortioxetine-4001 Incorporating Amendment No. 01, dated 10 January 2017. 
CONFIDENTIAL 


Vortioxetine_4001 
Page 27 of 31
Statistical Analysis Plan {Final} 
24July2017
 
Appendix A Schedule of Study Procedures 
Study Day/Week: 
Screening 
Period 
Base- 
line 
Double-Blind Treatment Period 
Final Visit/ 
ET Visit (a) 
Follow-up 
Contact (b) 
Days 
-28 to -1 
Day 0 Week 1 Week 2 Week 3 Week 4 
Week 5 
Week 7 
Visit Windows (Days Relative to 
Baseline [Day 0]): 
 
0 
±3 
±3 
±3 
±3 
±3 
±5 
Visit Number: 
1 
2 
3 
4 
5 
6 
7 
 
Screening/Baseline Procedures 
 
 
 
 
 
 
 
 
Informed consent 
X 
 
 
 
 
 
 
 
Subject registry database 
X 
 
 
 
 
 
 
 
Demographics, medical and/or 
psychiatric history, medication history 
X 
 
 
 
 
 
 
 
Height, BMI 
X 
 
 
 
 
 
 
 
ECG 
X 
 
 
 
 
 
 
 
HBsAg, HCV, HIV, free testosterone, 
TSH, free T4, HbA1c (c)  
X 
 
 
 
 
 
 
 
Urine drug screen 
X 
X 
 
 
 
 
 
 
Concurrent medical and psychiatric 
conditions 
X 
X (d) 
 
 
 
 
 
 
Inclusion/exclusion criteria 
X 
X (d) 
 
 
 
 
 
 
Eligibility verification 
X 
X (e) 
 
 
 
 
 
 
Safety Assessments 
 
 
 
 
 
 
 
 
Physical examination, weight 
X 
X 
 
 
 
 
X 
 
Vital signs 
X 
X 
 
X 
 
 
X 
 
Concomitant medications 
X 
X 
X 
X 
X 
X 
X 
X 
Hematology, serum chemistry, 
urinalysis 
X 
X (f) 
 
 
 
 
X (f) 
 
C-SSRS 
X 
X 
X 
X 
X 
X 
X 
 
PTE assessment (g) 
X 
X 
 
 
 
 
 
 
AE assessments (h) 
 
 
X 
X 
X 
X 
X 
X 
Pregnancy test (hCG) (i) 
X 
X 
X 
X 
X 
X 
X 
 
Sexual Functioning Assessments 
 
 
 
 
 
 
 
 
CSFQ-14 (j) 
X 
X 
X 
X 
X 
X 
X 
 
PGI-I (j) 
 
 
X 
X 
X 
X 
X 
 
Other Blood Sampling 
 
 
 
 
 
 
 
 
PK sample collection (k) 
 
 
 
 
X 
X 
X 
 
DNA PGx sample collection (l) 
 
X 
 
 
 
 
 
 
RNA PGx sample collection (m) 
 
X 
 
 
 
 
X 
 
Clinical Supplies 
 
 
 
 
 
 
 
 
Contact IWRS for subject ID/ 
medication ID/subject status 
X 
X 
X 
X 
X 
X 
X 
 
CONFIDENTIAL 


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Vortioxetine_4001 
Page 29 of 31
Statistical Analysis Plan {Final} 
24July2017
 
Appendix B    Criteria for Identification of Potentially Clinically Significant Laboratory 
Values 
Parameter 
Unit Type 
Unit (a) 
PCS Definition 
Hematology 
 
 
 
Hemoglobin 
SI 
g/L 
Low: ≤0.9×LLN 
 
conventional 
g/dL 
Low: ≤0.9×LLN 
Erythrocytes (red cell count [RBC]) 
SI 
10^12/L 
High: ≥1.1×ULN, Low: ≤0.9×LLN 
 
conventional 
10^12/L 
High: ≥1.1×ULN, Low: ≤0.9×LLN 
Hematocrit (packed cell volume) 
SI 
Fraction of 1.00 
Low: ≤0.9×LLN 
 
conventional 
% 
Low: ≤0.9×LLN 
Total leucocytes (white cell count 
[WBC]) 
SI 
10^9/L 
High: ≥16, Low: ≤2.8 
 
conventional 
10^9/L 
High: ≥16, Low: ≤2.8 
Neutrophils 
SI 
10^9/L 
High: ≥15, Low: ≤1.4 
 
conventional 
10^9/L 
High: ≥15, Low: ≤1.4 
Lymphocytes 
SI 
10^9/L 
High: ≥7.0, Low: ≤0.6 
 
conventional 
10^9/L 
High: ≥7.0, Low: ≤0.6 
Monocytes 
SI 
10^9/L 
High: ≥2.5 
 
conventional 
10^9/L 
High: ≥2.5 
Eosinophils 
SI 
10^9/L 
High: ≥0.6 
 
conventional 
10^9/L 
High: ≥0.6 
Basophils 
SI 
10^9/L 
High: ≥0.6 
 
conventional 
10^9/L 
High: ≥0.6 
Thrombocytes (platelet count) 
SI 
10^9/L 
High: ≥700, Low: ≤75 
 
conventional 
10^9/L 
High: ≥700, Low: ≤75 
Blood Chemistry 
 
 
 
Total bilirubin 
SI 
µmol/L 
High: ≥34.2 
 
conventional 
mg/dL 
High: ≥2.0 
Alkaline phosphatase 
both 
U/L 
High: ≥3×ULN 
Aspartate aminotransferase (AST) 
both 
U/L 
High: ≥3×ULN 
Alanine aminotransferase (ALT) 
both 
U/L 
High: ≥3×ULN 
Albumin 
SI 
g/L 
Low: ≤25 
 
conventional 
g/dL 
Low: ≤2.5 
CONFIDENTIAL 


Vortioxetine_4001 
Page 30 of 31
Statistical Analysis Plan {Final} 
24July2017
 
Appendix B     Criteria for Identification of Potentially Clinically Significant Laboratory 
Values (continued) 
Parameter 
Unit Type 
Unit (a) 
PCS Definition 
Sodium 
SI 
mmol/L 
High: ≥155, Low: ≤125 
 
conventional 
mEq/L 
High: ≥155, Low: ≤125 
Potassium 
SI 
mmol/L 
High: ≥5.5, Low: ≤3.0 
 
conventional 
mEq/L 
High: ≥5.5, Low: ≤3.0 
Calcium (total) 
SI 
mmol/L 
High: ≥3.0, Low: ≤1.75 
 
conventional 
mg/dL 
High: ≥12.0, Low: ≤7.0 
Creatinine 
SI 
µmol/L 
High: ≥175 
 
conventional 
mg/dL 
High: ≥2.0 
Creatine phosphokinase (CPK) 
both 
U/L 
High: ≥2×ULN 
Uric acid 
SI 
µmol/L 
High: ≥1.3×ULN, Low: ≤0.7×LLN 
 
conventional 
mg/dL 
High: ≥1.3×ULN, Low: ≤0.7×LLN 
Glucose (non-fasting) 
SI 
mmol/L 
High: ≥13.9, Low: ≤2.8 
 
conventional 
mg/dL 
High: ≥250, Low: ≤50 
Cholesterol (total) 
SI 
mmol/L 
High: ≥7.8 
 
conventional 
mg/dL 
High: ≥302 
Triglycerides 
SI 
mmol/L 
High: ≥3.40 
 
conventional 
mg/dL 
High: ≥301 
High density lipoproteins (HDL) 
cholesterol 
SI 
mmol/L 
Low: <0.9 
 
conventional 
mg/dL 
Low: <35 
Low density lipoproteins (LDL) 
cholesterol 
SI 
mmol/L 
High: ≥5.0 
 
conventional 
mg/dL 
High: ≥193 
Urinalysis 
 
 
 
Glucose 
 
 
N/A 
Protein 
 
 
N/A 
Occult Blood 
 
 
N/A 
Pregnancy 
 
 
N/A 
(a) Systeme International (SI) units, conventional units and conversion factors were obtained from Laposata, 
Michael. SI Unit Conversion Guide. Boston: NEJM Books, 1992. 
LLN=lower limit of normal range; N/A=not applicable; PCS=potentially clinically significant; ULN=upper limit of 
normal range, 
CONFIDENTIAL 


Vortioxetine_4001 
Page 31 of 31
Statistical Analysis Plan {Final} 
24July2017
 
Appendix C Criteria for Identification of Potentially Clinically Significant Vital Signs 
Parameter 
Unit 
PCS Definition (a) 
Systolic Arterial Pressure 
mmHg 
Low: < 85 
High: > 180 
Diastolic Arterial Pressure 
mmHg 
Low: < 50 
High: > 110 
Pulse 
bpm 
Low: < 50 
High: > 120 
Body Temperature 
oC 
Low: < 35.6 
High: > 37.7 
 
oF 
Low: < 96.1 
High: > 99.9 
Weight 
kg 
Change of ≥7% body weight 
BP=Blood pressure. 
(a) PCS criteria are applied to postbaseline values and changes relative to Baseline values, as appropriate. 
CONFIDENTIAL