Clinical trial NCT03437564
Conditions: Healthy Adult Participants
Sponsor: Takeda
Start date: 2018-02-16; Completion date: 2018-04-13
Enrollment: 28 participants; Allocation: RANDOMIZED; Intervention model: CROSSOVER

Brief summary:
The purpose of this study is to evaluate the bioequivalence of a single oral administration of a vortioxetine (Lu AA21004) 20 mg tablet in comparison with two of vortioxetine 10 mg tablets in Japanese healthy adult participants.

Detailed description:
The drug being tested in this study is called vortioxetine (Lu AA21004). Vortioxetine is being tested in Japanese healthy adult participants. This study will look at the bioequivalence of a single oral administration of a vortioxetine 20 mg tablet in comparison with two of vortioxetine 10 mg tablets, and also look at the safety of a single oral dose of vortioxetine 20 mg in Japanese healthy adult participants.

The study will enroll 28 (14 for each sequence) healthy participants. In case bioequivalence cannot be demonstrated with the number of participants initially planned, an add-on participant study may be conducted (as a maximum 28 participants additionally). Participants will be randomly assigned (by chance, like flipping a coin) to one of the two treatment groups.

* Treatment Group A: Vortioxetine 20 mg (one 20 mg tablet) in Period 1 + Vortioxetine 20 mg (two 10 mg tablets) in Period 2
* Treatment Group B: Vortioxetine 20 mg (two 10 mg tablets) in Period 1 + Vortioxetine 20 mg (one 20 mg tablet) in Period 2

This single-center trial will be conducted in Japan. The overall time to participate in this study is approximately 25 days. Participants will make two visits to the clinic and be hospitalized for ten days in total.

Arms: arm 1: Vortioxetine 20 mg (one 20 mg tablet) on Day 1 in Period 1 in a fasted state + vortioxetine 20 mg (two 10 mg tablets) on Day 1 in Period 2 in a fasted state. arm 2: Vortioxetine 20 mg (two 10 mg tablets) on Day 1 in Period 1 in a fasted state + vortioxetine 20 mg (one 20 mg tablet) on Day 1 in Period 2 in a fasted state.
Interventions: intervention 1: Vortioxetine
Intervention descriptions: intervention 1: Vortioxetine tablet

Protocol documents:
Prot_000.pdf: 
 
 
Title: A Randomized, Open-Label, 2×2 Crossover Phase 1 Study to Evaluate the 
Bioequivalence of Single Oral Dose of Lu AA21004 20 mg tablet and 2× Lu AA21004  
10 mg tablets in Healthy Adult Subjects 
 
NCT Number: NCT03437564 
Protocol Approve Date: 15-Feb-2018 
 
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. 
 
This may include, but is not limited to, redaction of the following: 
 
Named persons or organizations associated with the study. 
 
Patient identifiers within the text, tables, or figures or in by-patient data listings. 
 
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. 
 
If needed, certain appendices that contain a large volume of personally identifiable 
information or company confidential information may be removed in their entirety if it 
is considered that they do not add substantially to the interpretation of the data (eg, 
appendix of investigator’s curriculum vitae). 
 
Note; This document was translated into English as the language on original version 
was Japanese. 


Lu AA21004
Study No. Vortioxetine-1001
Page 1 of 51
Protocol
15 Feb 2018
Takeda Pharmaceutical Company Limited
PROTOCOL
A Randomized, Open-Label, 2×2 Crossover Phase 1 Study to Evaluate the 
Bioequivalence of Single Oral Dose of Lu AA21004 20 mg tablet and 2× Lu AA21004 
10 mg tablets in Healthy Adult Subjects
A Bioequivalence Study of the Lu AA21004 20 mg and 2×10 mg Tablets
Study Number:
Vortioxetine-1001
Compound:
Lu AA21004
Date:
15 February 2018
Version/Amendme
nt Number:
Amendment 1
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.


Lu AA21004
Study No. Vortioxetine-1001
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CONFIDENTIAL
TABLE OF CONTENTS
1.0
STUDY SUMMARY ........................................................................................................................... 5
2.0
SCHEMATIC OVERVIEW OF THE STUDY.................................................................................... 8
3.0
STUDY SCHEDULE........................................................................................................................... 9
4.0
INTRODUCTION.............................................................................................................................. 10
4.1
Background.................................................................................................................................. 10
4.2
Rationale for This Study .............................................................................................................. 10
4.3
Benefits/Risks .............................................................................................................................. 11
5.0
STUDY OBJECTIVES AND ENDPOINTS...................................................................................... 12
5.1
Hypothesis.................................................................................................................................... 12
5.2
Objectives..................................................................................................................................... 12
5.2.1
Primary Objective ............................................................................................................ 12
5.2.2
Secondary Objective ........................................................................................................ 12
5.3
Endpoints ..................................................................................................................................... 12
5.3.1
Primary Endpoints............................................................................................................ 12
5.3.2
Secondary Endpoints........................................................................................................ 12
6.0
STUDY DESIGN AND DESCRIPTION........................................................................................... 13
6.1
Study Design................................................................................................................................ 13
6.2
Rationale for Study Design, Dose, and Endpoints ....................................................................... 13
6.2.1
Rationale for Study Design .............................................................................................. 13
6.2.2
Rationale for Dose............................................................................................................ 13
6.2.3
Rationale for Washout Period .......................................................................................... 13
6.2.4
Rationale for Endpoints.................................................................................................... 14
6.2.5
Important Procedures based on Study Objectives: Time Points of the Procedures.......... 14
6.3
Start and End/Completion of the Study........................................................................................ 14
6.3.1
Definition of the Start of the Study .................................................................................. 14
6.3.2
Definition of the Completion of the Study....................................................................... 15
6.3.3
Definition of Study Termination ...................................................................................... 15
6.3.4
Criteria for Suspension or Termination of the Entire Study............................................. 15
6.3.5
Criteria for Suspension or Termination of a Study Site ................................................... 16
7.0
CRITERIA FOR SELECTION AND DISCONTINUATION OF SUBJECTS................................. 17
7.1
Inclusion Criteria.......................................................................................................................... 17
7.1.1
Rationale for the Inclusion Criteria.................................................................................. 17
7.2
Exclusion Criteria......................................................................................................................... 17
7.2.1
Rationale for the Exclusion Criteria................................................................................. 19
7.3
Excluded Medications, Dietary Products, and Foods................................................................... 19
7.4
Other Restrictions / Diet, Fluid, Activity Control........................................................................ 20
7.4.1
Foods and Beverages........................................................................................................ 20
7.4.2
Daily Activities ................................................................................................................ 20
7.5
Documentation of Subject Withdrawal Before Study Treatment................................................. 20
7.6
Criteria for Withdrawal of a Subject............................................................................................ 21
7.7
Procedures for Discontinuation or Withdrawal of a Subject........................................................ 22
7.8
Reserve Subjects .......................................................................................................................... 22
7.9
Replenishment of Subjects Whose Study Was Discontinued after Initiation of Study Drug 
Administration ............................................................................................................................. 22
8.0
CLINICAL STUDY MATERIAL MANAGEMENT........................................................................ 23


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Study No. Vortioxetine-1001
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8.1
Study Drug................................................................................................................................... 23
8.1.1
Study Drug Labeling ........................................................................................................ 23
8.1.2
Study Drug Storage and Management.............................................................................. 23
8.1.3
Study Drug Blinding ........................................................................................................ 23
8.1.4
Accountability and Destruction of Sponsor-Supplied Drugs ........................................... 23
9.0
STUDY PROCEDURES.................................................................................................................... 24
9.1
Administrative Procedures........................................................................................................... 24
9.1.1
Informed Consent............................................................................................................. 24
9.1.2
Eligibility Assessment...................................................................................................... 24
9.1.3
Medical History and Demographic Data.......................................................................... 24
9.1.4
Concomitant Medication.................................................................................................. 25
9.2
Study Procedures and Assessments.............................................................................................. 25
9.2.1
Physical Examination....................................................................................................... 25
9.2.2
Height and Body Weight.................................................................................................. 25
9.2.3
BMI .................................................................................................................................. 25
9.2.4
Vital Signs........................................................................................................................ 25
9.2.5
12-lead ECG..................................................................................................................... 25
9.2.6
Columbia-Suicide Severity Rating Scale (C-SSRS) ........................................................ 25
9.2.7
Study Drug Administration .............................................................................................. 26
9.2.8
Assessment of AEs........................................................................................................... 26
9.2.9
Laboratory Test Procedures and Assessment ................................................................... 26
9.3
Samples for Pharmacokinetics and CYP2D6 Polymorphism Assessments ................................. 27
9.3.1
Pharmacokinetic Measurements....................................................................................... 28
9.3.2
CYP2D6 Genotyping ....................................................................................................... 28
9.4
Hospitalization Period.................................................................................................................. 28
10.0
ADVERSE EVENTS ......................................................................................................................... 29
10.1
Definitions and Elements of AEs................................................................................................. 29
10.1.1
SAEs................................................................................................................................. 31
10.2
AE-related Procedures ................................................................................................................. 31
10.2.1
Assessment of the Severity of AEs .................................................................................. 31
10.2.2
Assessment of the Causality of AEs................................................................................. 31
10.2.3
Relationship to Study Procedures..................................................................................... 32
10.2.4
Start Date.......................................................................................................................... 32
10.2.5
Stop Date.......................................................................................................................... 32
10.2.6
Intermittent or Continuous AEs ....................................................................................... 32
10.2.7
Action Taken with Study Drug ........................................................................................ 32
10.2.8
Outcome ........................................................................................................................... 32
10.2.9
Collection and Reporting of AEs, SAEs and Liver Function Test Abnormalities ........... 33
10.2.10
Safety Reporting to Investigators, IRBs, and Regulatory Authorities.............................. 34
11.0
STATISTICAL METHODS............................................................................................................... 36
11.1
Statistical and Analytical Plans.................................................................................................... 36
11.1.1
Analysis Sets .................................................................................................................... 36
11.1.2
Analysis of Demographic and Other Baseline Characteristics......................................... 36
11.1.3
Pharmacokinetic Analysis ................................................................................................ 36
11.1.4
Safety Analysis................................................................................................................. 37
11.2
Determination of Sample Size...................................................................................................... 38


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Study No. Vortioxetine-1001
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12.0
QUALITY CONTROL AND QUALITY ASSURANCE.................................................................. 39
12.1
Study-Site Monitoring Visits ....................................................................................................... 39
12.2
Protocol Deviation ....................................................................................................................... 39
12.3
Quality Assurance Audits and Regulatory Agency Inspections................................................... 39
13.0
ETHICAL ASPECTS OF THE STUDY............................................................................................ 40
13.1
IRB Approval............................................................................................................................... 40
13.2
Subject Information, Informed Consent, and Subject Authorization........................................... 40
13.3
Subject Confidentiality................................................................................................................. 41
13.4
Publication, Disclosure, and Clinical Trial Registration Policy................................................... 41
13.4.1
Publication and Disclosure............................................................................................... 41
13.4.2
Clinical Trial Registration................................................................................................ 42
13.4.3
Clinical Trial Results Disclosure...................................................................................... 42
13.5
Insurance and Compensation for Injury....................................................................................... 42
14.0
STUDY ADMINISTRATIVE INFORMATION AND RELATED INFORMATION ..................... 43
14.1
Study Administrative Information ............................................................................................... 43
14.1.1
Study-related Contact Information................................................................................... 43
14.1.2
Investigator Agreement .................................................................................................... 43
14.1.3
Study-related Roles and Responsibilities ......................................................................... 43
14.1.4
List of Abbreviations........................................................................................................ 43
15.0
DATA MANAGEMENT AND RECORD KEEPING....................................................................... 44
15.1
eCRF ............................................................................................................................................ 44
15.2
Record Retention.......................................................................................................................... 44
16.0
REFERENCES................................................................................................................................... 46
17.0
APPENDICES.................................................................................................................................... 47
LIST OF IN-TEXT TABLES
Table 7.a
Excluded Medications, Dietary Products, and Foods ............................................................ 19
Table 8.a
Study Drug............................................................................................................................. 23
Table 9.a
Dose and Mode of Administration......................................................................................... 26
Table 9.b
Samples for Measurements.................................................................................................... 27
Table 9.c
Collection of Pharmacokinetic Samples (in Both Period 1 and Period 2) ............................. 28
Table 10.a
Takeda Medically Significant AE List .................................................................................. 31
LIST OF IN-TEXT FIGURES
Figure 2.a
Study Design Overview........................................................................................................... 8
LIST OF APPENDICES
Appendix A
Responsibilities of the Investigator........................................................................................ 47
Appendix B
Pregnancy and Contraception................................................................................................ 48
Appendix C
Time Windows for Study Procedures.................................................................................... 50
Appendix D
Blood Volume Table.............................................................................................................. 51


Lu AA21004
Study No. Vortioxetine-1001
Page 5 of 51
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CONFIDENTIAL
1.0
STUDY SUMMARY
Clinical Study Sponsor:
Takeda Pharmaceutical Company Limited
Compound:
Lu AA21004
Study Number: Vortioxetine-1001
Phase:1
Study Title:
A Randomized, Open-Label, 2×2 Crossover Phase 1 Study to Evaluate the Bioequivalence of Single Oral Dose of 
Lu AA21004 20 mg tablet and 2× Lu AA21004 10 mg tablets in Healthy Adult Subjects
Study Design:
This is a 2 x 2 crossover, open-label, comparative study in Japanese healthy adults to evaluate the bioequivalence between the 
Lu AA21004 20 mg tablet and the Lu AA21004 10 mg tablet after single dosing, and also to evaluate the safety of a single 
oral dose of Lu AA21004 20 mg.
Subjects will be randomized in a 1:1 ratio to either treatment sequence A or B.
This study consists of the screening period, Period 1, and Period 2. Subjects will receive one Lu AA21004 20 mg tablet or 
two Lu AA21004 10 mg tablets on Day 1 of Period 1 and Period 2. The interval between the Period 1 dosing and the Period 2 
dosing of the study drug will be at least 3 weeks.
If bioequivalence is not demonstrated with the initially planned number of subjects, an add-on subject study may be 
conducted in accordance with the “Partial Revision of Guideline for Bioequivalence Studies of Generic Products”.
Primary Objective:
To evaluate the bioequivalence between the Lu AA21004 20 mg tablet and the Lu AA21004 10 mg tablet after single dosing 
in Japanese healthy adults
Secondary Objective:
To evaluate the safety of a single dose of Lu AA21004 20 mg in Japanese healthy adults
Subject Population: Japanese healthy adult subjects
Planned Number of Subjects:
28 (14 per treatment sequence) 
If an add-on subject study is conducted, the maximum 
number of additional subjects will be 28 (14 per treatment 
sequence).
Planned Number of Sites:
1 site
Dose Levels: 
A single dose of either one Lu AA21004 20 mg tablet or two 
Lu AA21004 10 mg tablets will be given under fasted
conditions on Days 1 in Period 1 and Period 2.
Route of Administration: 
Oral
Duration of Treatment: 
Single dose × 2 periods (The interval between the Period 1 
dosing and the Period 2 dosing of the study drug will be at 
least 3 weeks.)
Planned Study Period:
Screening period: Day -28 to Day -1
Period 1 and Period 2: Day 1 to Day 25 (when the period 
between dosing of Period 1 and Period 2 is set as 3 weeks)
Inclusion Criteria: 
In order to be eligible for participation in this trial, the subject must: 
1. Be a healthy Japanese adult volunteer.
2. Understand the contents of the study and be capable of providing written consent to participate in the study.
3. Be willing to comply with all study procedures and restrictions. 
4. Aged between 20 and ≤45 years at the time of screening.
5. Have a BMI of ≥18.5 and ≤24.9 (kg/m2) and a body weight of ≥50 kg at the time of screening.
6. Be a extensive metabolizer (EM) based on CYP2D6 genotyping at the time of screening.
7. A female subject of childbearing potential with a non-sterilized male partner must agree to routinely use appropriate 
contraception during the study from the time of signing informed consent until 4 weeks after last dosing of the study drug.
Exclusion Criteria:
The subject must be excluded from participating in the trial if the subject:
1. Has received any investigational drugs within 90 days before screening for this study.
2. Previously received Lu AA21004 before participation in this study.
3. Is an employee of the sponsor or the study site, or immediate family member, or is in a dependent relationship with a study 
site employee who is involved in the conduct of this study (eg, spouse, parent, child, sibling) or who may be coerced to 
provide consent. 
4. Has uncontrolled, clinically relevant neurologic, cardiovascular, pulmonary, hepatic, renal, metabolic, gastrointestinal, or 
endocrine disease or other abnormality which may affect study participation or study results. 
5. Has a history of multiple episodes or severe allergies (eg, food, drug, latex allergy) or has had an anaphylactic reaction or 
significant intolerance to prescription drugs, OTC drugs, or foods. 


Lu AA21004
Study No. Vortioxetine-1001
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CONFIDENTIAL
6. Has a positive pregnancy test at the time of screening or Day −1.
7. Is a pregnant or lactating female.
8. Has a positive urine drug test at the time of screening or Day −1.
9. Has a history of drug abuse (defined as any illicit drug use) or has a history of alcohol dependence within 2 years before 
the start of screening or is unwilling to agree to abstain from alcohol and drugs throughout the study.
10. Consumes 6 or more servings of caffeinated beverages (containing about 720 mg of caffeine or more) such as coffee, tea, 
cola, or energy drinks per day.
11. Is a smoker who smoked cigarettes or used nicotine-containing products (such as nicotine patch) within 6 months before 
the Period 1 study drug administration. 
12. Used any of the excluded drugs, dietary products or foods during the period specified in the table in Section 7.3, or will 
need any of them during the study period.
13. Has any current or a history of gastrointestinal diseases that would be expected to influence the absorption of drugs (ie, 
malabsorption, esophageal reflux, peptic ulcer disease, erosive esophagitis, frequent [more than once per week] occurrence 
of heartburn), or any surgical intervention (gastrectomy, cholecystectomy etc.).
14. Has a history of cancer.
15. Has a positive test result for any of the following at the time of screening: hepatitis B surface antigen (HBsAg), hepatitis
C virus (HCV) antibody, human immunodeficiency virus (HIV) antibody/antigen, serological test for syphilis.
16. Has poor peripheral venous access. 
17. Has undergone whole blood collection of at least 200 mL within 4 weeks (28 days) or at least 400 mL within 12 weeks 
(84 days) prior to the start of Period 1 study drug administration. 
18. Has undergone whole blood collection of at least 800 mL in total within 52 weeks (364 days) prior to the start of Period 1
study drug administration. 
19. Has undergone blood component collection within 2 weeks (14 days) prior to the start of Period 1 study drug 
administration.
20. Has any clinically relevant abnormality in vital signs or 12-lead ECG at screening or on Day −1 of Period 1. 
21. Has abnormal laboratory test values at screening or on Day −1 of Period 1 indicating clinically relevant underlying 
disease, or showing alanine aminotransferase (ALT) and/or aspartate aminotransferase (AST) >1.5×ULN. 
22. Is unlikely to comply with the protocol requirements or is unsuitable as a subject of this study for any other reason in the
opinion of the investigator or sub-investigator.
Criteria for Evaluation: 
<Primary endpoints>
∙AUC from time 0 to the last quantifiable time point (AUClast) of Lu AA21004 
∙Maximum plasma concentration (Cmax) of Lu AA21004 
<Secondary endpoints>
∙AUC∞, tmax, MRT, λz , and t1/2z
∙Safety: adverse events (AEs), vital signs (sitting blood pressure, sitting pulse rate, body temperature (axillary)), resting 
12-lead electrocardiograms (ECGs), and laboratory test results
Statistical Considerations: 
1)
Plasma concentration and pharmacokinetic parameters
The descriptive statistics for plasma concentration of Lu AA21004 will be provided for each formulation (Lu AA21004 
20 mg tablet and 10 mg tablet) by visit and the mean and standard deviation of plasma concentration will be plotted for both 
formulations on the same graph. The descriptive statistics for PK parameter will be provided for each formulation.
2)
Bioequivalence assessment
The bioequivalence of Lu AA21004 20 mg tablet and 2× 10 mg tablets is evaluated.
The log-transformed (natural log) PK parameters AUClast and Cmax of Lu AA21004 will be analysed separately using analysis 
of variance (ANOVA) with dosing formulation, treatment sequence, administration period as fixed effects and the two-sided 
90% confidence interval (CIs) for the differences between the formulations and between the periods will be provided. The 
log-transformed (natural log) PK parameters AUC∞, MRT, λz and t1/2z of Lu AA21004 and tmax of Lu AA21004 will be 
analysed separately using ANOVA in the same manner (confidence coefficient 90%, 95%).
Rational for the Sample Size: 
Planned number of subjects is 28 (14 per treatment sequence).
The planned sample size was calculated based upon the analysis of logarithmically transformed AUClast and Cmax. If the 90% 
CIs for the ratios of Lu AA21004 20 mg tablets and 2× Lu AA21004 10 mg tablets (2× Lu AA21004 10 mg tablets/ 
Lu AA21004 20 mg tablet) geometric mean value of AUClast and Cmax are both be within the limits of 80.00% to 125.00%,
bioequivalence can be verified. It is hypothesize that there is no interaction between dosing formulation and administration 
period at AUClast and Cmax. Based on data from previous studies, the largest estimate of the within-subject coefficient of 
variation (CV) of AUClast and Cmaxwere up to 9.5% and 14.3% and a sample size of 24 would then provide a power of 99.8% 
and 91.5% for each correctly concluding bioequivalence even if the true ratio is 1.1. Given that the 90% CIs for the ratio of 
the geometric means for AUClast and Cmax must both be contained in 80.00% to 125.00% in order to conclude bioequivalence 
between the two treatments, 24 subjects provided an overall power of at least 91.3%, assuming that the two endpoints AUClast


Lu AA21004
Study No. Vortioxetine-1001
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15 Feb 2018
CONFIDENTIAL
and Cmax are independent.
Taking into account possible occurence of dropouts, planned number of subjects is 28.
In case bioequivalence cannot be demonstrated with the number of subjects initially planned due to the insufficiency of the 
number of subjects, an add-on subject study will be conducted in accordance with the Partial Revision of Guideline for 
Bioequivalence Studies of Generic Products, if applicable. The maximum number of additional subjects in the add-on subject 
study is 28 (14 per treatment sequence), which is determined based on study feasibility, but is not on statistical consideration.


Lu AA21004
Study No. Vortioxetine-1001
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2.0
SCHEMATIC OVERVIEW OF THE STUDY
The overview of the study design is shown in Figure 2.a. 
Figure 2.a Study Design Overview
Treatment 
sequence
Period 1
Period 2
Day 1 to 4
Day 5 to 21(a)
Day 1 to 4
A
One Lu AA21004 20 mg tablet 
Single dose under fasted condition
Washout
Two Lu AA21004 10 mg tablets
Single dose under fasted condition
B
Two Lu AA21004 10 mg tablets
Single dose under fasted condition
One Lu AA21004 20 mg tablet
Single dose under fasted condition
Period
Screening period
Administration term
Period 1
Period 2
Day(b)
−28 to −2
−1
1
2 to 3
4
5 to 20
21
1
2 to 3
4
Days from the Period 1 
study drug dossing (a)
-
-
1
2 to 3
4
5 to 20
21
22
23 to 24
25
Inpatient/Outpatient
Outpatient
Inpatient
No visit
Inpatient
Procedure
Informed consent,
screening
Admission
Study drug
administration
Discharge
Admission
Study drug
administration
Discharge
(a)
When the interval between the Period 1 dosing and the Period 2 dosing of the study drug is 3 weeks.
(b)
Day 1 is defined as the day of study drug administration in each of Period 1 and Period 2, with the day before Period 1
study drug administration referred to as Day −1 and the day before Period 2 study drug administration as Day 21.


Lu AA21004
Study No. Vortioxetine-1001
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3.0
STUDY SCHEDULE 
Screening 
period
Administration term
Period 1
Period 2
Treatment period
Washout 
period
Treatment period
Day1)
Screening 
-28 to -2
-1
1
2
3
4 9)
5 to 20
21
1
2
3
4 9)
Days from Period 1 study drug
administration2)
-
-
1
2
3
4
5 to 20
21
22
23
24
25
Informed consent
X
Demographic data, Height
X
Medical history, concurrent medical 
conditions, prior medication
X
Concomitant medication review
X
X
X
X
X
X
X
X
X
X
X
X
Adverse events monitoring3)
X
X
X
X
X
X
X
X
X
X
X
X
Physical examination4)
X
X
X
X
X
X
X
Body weight
X
X
Vital signs5)
X
X
X
X
X
X
X
12-lead ECG6)
X
X
X
Laboratory tests7)
X
X
X
X
X
Pharmacokinetic blood sampling8)
X
X
X
X
X
X
X
X
CYP2D6 genotyping blood sampling
X
Columbia-Suicide Severity Rating 
Scale (C-SSRS)
X
X
X
X
X
Study drug administration
X
X
Hospitalization
In
Out
In
Out
1)
Day 1 is defined as the day of study drug administration in each of Period 1 and Period 2, with the day before Period 1 
study drug administration referred to as Day −1 and the day before Period 2 study drug administration as Day 21. 
2)
When the interval between the Period 1 dosing and the Period 2 dosing of the study drug is 3 weeks. 
3)
AEs will be collected continuously from the time of signing of informed consent until the end of Period 2.
4)
Physical examination will be performed at 24 and 72 hours postdose.
5)
Vital signs will be measured at 24 and 72 hours postdose. 
6)
A 12-lead ECG will be performed at 72 hours postdose. 
7)
Immunology tests will be performed only at screening. Urine drug tests and pregnancy test will be performed only at 
screening, Day −1 and Day 21. Pregnancy test will be performed only in female subjects of childbearing potential. 
8)
Pharmacokinetic blood samples will be collected at Day 1 predose, 1, 2, 4, 6, 8, 10, 12, 14, 16, 24, 36, 48 and 72 hours 
postdose. 
9)
Or at discontinuation. 


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4.0
INTRODUCTION
4.1
Background
Lu AA21004 (generic name: vortioxetine hydrobromide) is a 5-HT3, 5-HT7 and 5-HT1D receptor antagonist, 
5-HT1B receptor partial agonist, 5-HT1A receptor agonist, and 5-HT transporter (5-HTT) inhibitor. This 
novel antidepressant with a different profile from existing medications has been under development.
Depression is a mental disease mainly characterized by a depressed mood and a loss of interest or pleasure, 
and is additionally characterized by thought or concentration difficulties, an appetite decrease or increase, 
anxiety, a feeling of worthlessness or guilt, and thoughts related to suicide (suicidal ideation) as well as 
somatic symptoms including sleep disturbances and fatigability.[1][2]
The course of depression varies from only 1 episode in a lifetime to a lifelong disorder with recurrent 
episodes, and some patients suffer from long-term depressive symptoms despite treatments. Depression is 
therefore a significant mental and social burden and economic loss for not only patients but also their 
family, which treatment is necessary.[3]
Depression is mainly treated with pharmacotherapy and psychotherapy, and these treatments are selected 
according to the severity and pathological condition.[3] As pharmacotherapy in patients with moderate to 
severe depression, antidepressants such as selective serotonin reuptake inhibitors, serotonin-norepinephrine 
reuptake inhibitors, and noradrenergic and specific serotonergic antidepressants have been widely used. 
These antidepressants, however, have problems such as patients with inadequate response and adverse 
effects; therefore, development of an antidepressant with a novel profile can broaden treatment options and 
optimize treatment for depression.
From the results of the clinical pharmacology studies, following pharmacokinetic profiles were shown. 
Lu AA21004 was slowly absorbed with tmax of approximately 7 to 11 hours, and the absolute 
bioavailability of Lu AA21004 was approximately 75%. Lu AA21004 was extensively metabolized in the 
liver, and CYP2D6 was shown to be the primary enzyme in metabolism of Lu AA21004 to the major 
metabolite Lu AA34443. The t1/2z of Lu AA21004 was approximately 66 hours, and two-thirds of its 
metabolites were excreted in urine, and one-third were excreted in feces.Based on the results of the clinical 
studies, treatment with Lu AA21004 at doses of 5 to 20 mg/day was safe and effective. As of December
2017, Lu AA21004 has been approved for marketing as a drug for the treatment of MDD in countries 
including the U.S., Europe and Australia.
In Japan, Lu AA21004 is being developed for treatment of major depression disorder and has been 
evaluated in four clinical pharmacology studies of CPH-001, CPH-002, CPH-003, and CPH-004 conducted 
in healthy adults or elderly individuals; two placebo-controlled short-term studies of CCT-002 and 
CCT-003 conducted in patients with major depressive disorder; and a long-term extension study of 
OCT-001 in patients who completed CCT-003. In all these studies, Lu AA21004 was well-tolerated 
without major safety issues. Currently, CCT-004 study is being conducted as a short-term 
placebo-controlled study for major depressive disorder patients.
4.2
Rationale for This Study
In the dissolution tests, the different strengths (10 mg and 20 mg) of commercial formulations in Japan 
showed different dissolution behaviors and did not meet bioequivalence criteria. Consequently, this study 
has been planned to evaluate the bioequivalence between Lu AA21004 20 mg tablet and 2× Lu AA21004


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10 mg tablets in accordance with the Partial Revision of Guideline for Bioequivalence Studies of Generic 
Products.[4]
4.3
Benefits/Risks
Subjects in this study will not benefit from this study. 
In the clinical pharmacology studies conducted to date in Japanese healthy adults or elderly individuals (ie,
CPH-001, CPH-002, CPH-003 and CPH-004) and clinical studies including Japanese major depressive 
disorder patients (ie, CCT-002, CCT-003 and OCT-001), Lu AA21004 at a dose of 2.5 to 40 mg was 
well-tolerated without major safety issues. Further detailed safety data on Lu AA21004 are provided in the 
Investigator’s Brochure.


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5.0
STUDY OBJECTIVES AND ENDPOINTS
5.1
Hypothesis
This study is planned on the basis of the following hypothesis: 
Lu AA21004 20 mg tablet and 2× Lu AA21004 10 mg tablets will be shown to be bioequivalent.
5.2
Objectives
5.2.1
Primary Objective
To evaluate the bioequivalence between the Lu AA21004 20 mg tablet and the Lu AA21004 10 mg tablet 
after single dosing in Japanese healthy adults. 
5.2.2
Secondary Objective
To evaluate the safety of a single dose of Lu AA21004 20 mg in Japanese healthy adults.
5.3
Endpoints 
5.3.1
Primary Endpoints 
●AUClast of Lu AA21004
●Cmax of Lu AA21004
5.3.2
Secondary Endpoints 
●AUC∞, tmax, MRT, λz and t1/2z of Lu AA21004
●Adverse events, vital signs, 12-lead ECG, and laboratory test values


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6.0
STUDY DESIGN AND DESCRIPTION
6.1
Study Design 
1)
Study design 
This is a 2 x 2 crossover, open-label, comparative study in Japanese healthy adults to evaluate the 
bioequivalence between the Lu AA21004 20 mg tablet and the Lu AA21004 10 mg tablet after single 
dosing, and also to evaluate the safety of a single oral dose of Lu AA21004 20 mg. 
Subjects will be randomized in a 1:1 ratio to either treatment sequence A or B. 
This study consists of the screening period, Period 1, and Period 2. Subjects will receive one Lu AA21004 
20 mg tablet or two Lu AA21004 10 mg tablets on Days 1 of Period 1 and Period 2. The interval between 
the Period 1 dosing and the Period 2 dosing of the study drug will be at least 3 weeks. 
If bioequivalence is not demonstrated with the initially planned number of subjects, an add-on subject study 
may be conducted in accordance with the “Partial Revision of Guideline for Bioequivalence Studies of 
Generic Products”. 
2)
Planned number of subjects
The planned number of subjects is 28 (14 per treatment sequence). If an add-on subject study is conducted, 
the maximum number of additional subjects will be 28 (14 per treatment sequence).
6.2
Rationale for Study Design, Dose, and Endpoints
6.2.1
Rationale for Study Design
A 2-period, 2-treatment, cross-over design, which allows bioequivalence evaluation with minimal effect on 
inter-subject variation, was selected for this study in accordance with the Partial Revision of Guideline for 
Bioequivalence Studies of Generic Products. 
Open-label design is adopted because the primary objective of the study is to evaluate the pharmacokinetic 
profile and to assess bioequivalence of Lu AA21004 tablets which is an objective indicator.
To eliminate all biases arising from arbitrary assignment of subjects, subjects will be randomized to receive 
the two treatments in either treatment sequence.
6.2.2
Rationale for Dose
Based on clinical data obtained so far, the clinical doses of Lu AA21004 for the treatment of major 
depression in Japanese patients are expected to be 10-20 mg/day, and 10 mg and 20 mg commercial tablets 
have been developed. For this study designed to evaluate the bioequivalence between Lu AA21004 20 mg
tablet and 2× 10 mg tablets, one Lu AA21004 20 mg tablet and two Lu AA21004 10 mg tablets will be 
used.
6.2.3
Rationale for Washout Period
In CPH-004 study (‘A Phase 1, Open-Label, Single-Dose, 2-Period Crossover Study to Assess 
Pharmacokinetics of Lu AA21004 and Effect of Food on the Pharmacokinetics after Oral Administration of
Lu AA21004 in Healthy Male Subjects’), in which 14 days interval between the Period 1 dosing and the 
Period 2 dosing of the study drug, plasma unchanged Lu AA21004 concentration at Period 2 predose was 


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higher than 11% of Cmax value of the Period 1 in the subject with the highest plasma unchanged
Lu AA21004 level in Period 1. Based on these results, it is set that the interval between the Period 1 dosing 
and the Period 2 dosing of the study drug will be at least 3 weeks in order for the plasma concentration at 
Period 2 predose to be decreased below 5% of Cmax in Period 1. Also, the Partial Revision of Guideline for 
Bioequivalence Studies of Generic Products recommends that there should be a washout period at least 5 
times longer than the apparent half-life of the investigational drug. The 3 weeks interval between the Period 
1 dosing and the Period 2 dosing of the study drug in this study is longer than 5 times of the apparent 
elimination half-life of Lu AA21004(about 66 hours) thus meets this guideline.
6.2.4
Rationale for Endpoints
6.2.4.1
Rationale for Pharmacokinetic Endpoints
AUClast and Cmax of unchanged Lu AA21004 will be evaluated in accordance with the Partial Revision of
Guideline for Bioequivalence Studies of Generic Products. Since the apparent elimination half-life of 
unchanged Lu AA21004 is very long (about 66 hours), the plasma concentration of Lu AA21004 will be 
evaluated until 72 hours postdose, in accordance with "Partial Revision of Guideline for Bioequivalence 
Studies of Generic Products".
6.2.4.2
Rationale for Safety Endpoints
Safety measures will include those commonly used in clinical pharmacology studies (Adverse events, Vital 
signs, Clinical laboratory tests, and 12-lead ECG assessment).
6.2.5
Important Procedures based on Study Objectives: Time Points of the 
Procedures
Blood sample collection for pharmacokinetic evaluation is the important procedure in this study. 
●For all time points of evaluation after administration of the study drug, the blood samples for
pharmacokinetic evaluation should be collected at a time as closest as possible to the scheduled time. 
●If blood sample collection and other procedures are scheduled for the same time, blood sample 
collection should be prioritized, with implementation of other procedures within the allowable window 
(Appendix C).
●The priority order of procedures may be changed based on agreement between the investigator and the 
sponsor. 
●Any unscheduled procedure required for emergency assessment for safety concerns must be prioritized 
over any scheduled procedures. 
6.3
Start and End/Completion of the Study
6.3.1
Definition of the Start of the Study
The time of the start of the entire study is defined as the time when the first subject has signed the informed 
consent form.


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6.3.2
Definition of the Completion of the Study
The time of the completion of the entire study is defined as the time when the last subject has completed 
the last planned or follow-up visit (or last contact related to a planned visit [possibly a telephone contact]), 
has been discontinued from the study, or has become lost to follow-up (ie, not reachable by the 
investigator).
6.3.3
Definition of Study Termination
Study termination for reasons other than safety are defined, such as below:
●When the study is terminated for non-safety reasons on the basis of certain findings on this study drug 
from nonclinical or other clinical studies with administration of this study drug (eg, findings on 
pharmacokinetics, pharmacodynamics, efficacy, or biological target).
●When the study is terminated for non-safety reasons on the basis of certain data that became available 
regarding another drug in the same class as this study drug or the same study methodology as this study.
●When the study is terminated for non-scientific and non-safety reasons, such as delay in subject
enrollment. 
Study termination for safety reasons are defined, such as below: 
●When the study is prematurely terminated because of unexpected safety concerns for subjects, raised 
from any clinical or nonclinical study of this study drug, another drug in the same class as this study 
drug, or the same study methodology as this study.
6.3.4
Criteria for Suspension or Termination of the Entire Study
6.3.4.1
Criteria for Suspension or Termination of the Study
The study will be temporarily suspended or prematurely terminated if one or both of the following criteria 
are met: 
●New information or other evaluation has been obtained regarding the safety or efficacy of the study 
drug that alters the known risk/benefit profile of Lu AA21004, and the risk is no longer acceptable for 
subjects participating in the study.
●Significant violation of Good Clinical Practice (GCP) has occurred that compromises the ability to 
achieve the primary study objective or compromises the safety of subjects.
6.3.4.2
Procedures for Suspension or Termination of the Study
In the event that the sponsor, institutional review board (IRB), or regulatory authority elects to terminate or 
suspend the study or 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 the applicable study site 
during the course of termination or study suspension.


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6.3.5
Criteria for Suspension or Termination of a Study Site
6.3.5.1
Criteria for Suspension or Termination of a Study Site
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 is permitted by the contractual agreement.
6.3.5.2
Procedures for Suspension or Termination of Participation of a Study 
Site
In the event that the sponsor, 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 the applicable study site during the course of termination 
or study suspension.


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7.0
CRITERIA FOR SELECTION AND DISCONTINUATION OF SUBJECTS
All inclusion/exclusion criteria, including test results, need to be confirmed prior to the study drug 
administration in Period 1.
7.1
Inclusion Criteria 
In order to be eligible for participation in this study, the subject must fulfill the following criteria: 
1.
Be a healthy Japanese adult volunteer.
2.
Understand the contents of the study and be capable of providing written consent to participate in the 
study.
3.
Be willing to comply with all study procedures and restrictions. 
4.
Aged between ≥20 and ≤45 years at the time of screening.
5.
Have a BMI of ≥18.5 and ≤24.9 (kg/m2) and a body weight of ≥50 kg at the time of screening.
6.
Be a extensive metabolizer (EM) based on CYP2D6 genotyping at the time of screening.
7.
A female subject of childbearing potential* with a non-sterilized male partner* must agree to routinely 
use appropriate contraception* during the study from the time of signing informed consent until 4 
weeks after last dosing of the study drug (*see Appendix B).
7.1.1
Rationale for the Inclusion Criteria
Inclusion criteria 1, 2, 3, 4 and 7: 
These are the standard inclusion criteria used in clinical pharmacology studies in healthy adults. 
Inclusion criterion 5: 
The body weight criterion is set because collecting 400 mL of whole blood from people weighing less 
than 50.0 kg has harmful effect on health, according to the “Law Enforcement Regulation on Securing a 
Stable Supply of Safe Blood Products” (Ministerial Ordinance No. 22 of the Ministry of Health and 
Welfare in 1956). [5]
The BMI criterion is set to correspond to the normal body weight range according to the diagnostic 
criteria for obesity proposed by the Japan Society for the Study of Obesity. [6]
Inclusion criterion 6: 
This criterion is set because the “Partial Revision of Guideline for Bioequivalence Studies of Generic 
Products” recommends that, if polymorphism is involved in clearance of the test drug, bioequivalence 
studies of the drug should be conducted in subjects with greater clearance.
7.2
Exclusion Criteria
The subject meeting any of the following criteria will be excluded from the study: 
1.
Has received any investigational drugs within 90 days before screening for this study.
2.
Previously received Lu AA21004 before participation in this study.
3.
Is an employee of the sponsor or the study site, or immediate family member, or is in a dependent 
relationship with a study site employee who is involved in the conduct of this study (eg, spouse, parent, 
child, sibling) or who may be coerced to provide consent. 


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4.
Has uncontrolled, clinically relevant neurologic, cardiovascular, pulmonary, hepatic, renal, metabolic, 
gastrointestinal, or endocrine disease or other abnormality which may affect study participation or 
study results. 
5.
Has a history of multiple episodes or severe allergies (eg, food, drug, latex allergy) or has had an 
anaphylactic reaction or significant intolerance to prescription drugs, OTC drugs, or foods. 
6.
Has a positive pregnancy test at the time of screening or Day −1.
7.
Is a pregnant or lactating female.
8.
Has a positive urine drug test at the time of screening or Day −1.
9.
Has a history of drug abuse (defined as any illicit drug use) or has a history of alcohol dependence
within 2 years before the start of screening or is unwilling to agree to abstain from alcohol and drugs 
throughout the study. 
10. Consumes 6 or more servings of caffeinated beverages (containing about 720 mg of caffeine or more) 
such as coffee, tea, cola, or energy drinks per day .
11. Is a smoker who smoked cigarettes or used nicotine-containing products (such as nicotine patch) 
within 6 months before the Period 1 study drug administration.
12. Used any of the excluded drugs, dietary products or foods during the period specified in the table in 
Section 7.3, or will need any of them during the study period. 
13. Has any current or a history of gastrointestinal diseases that would be expected to influence the 
absorption of drugs (ie, malabsorption, esophageal reflux, peptic ulcer disease, erosive esophagitis, 
frequent [more than once per week] occurrence of heartburn), or any surgical intervention
(gastrectomy, cholecystectomy etc.).
14. Has a history of cancer.
15. Has a positive test result for any of the following at the time of screening: hepatitis B surface antigen
(HBsAg), hepatitis C virus (HCV) antibody, human immunodeficiency virus (HIV) antibody/antigen, 
serological test for syphilis.
16. Has poor peripheral venous access. 
17. Has undergone whole blood collection of at least 200 mL within 4 weeks (28 days) or at least 400 mL 
within 12 weeks (84 days) prior to the start of Period 1 study drug administration. 
18. Has undergone whole blood collection of at least 800 mL in total within 52 weeks (364 days) prior to 
the start of Period 1 study drug administration. 
19. Has undergone blood component collection within 2 weeks (14 days) prior to the start of Period 1
study drug administration.
20. Has any clinically relevant abnormality in vital signs or 12-lead ECG at screening or on Day −1 of 
Period 1. 
21. Has abnormal laboratory test values at screening or on Day −1 of Period 1 indicating clinically 
relevant underlying disease, or showing alanine aminotransferase (ALT) and/or aspartate 
aminotransferase (AST) >1.5×upper limit of normal (ULN). 


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22. Is unlikely to comply with the protocol requirements or is unsuitable as a subject of this study for any 
other reason in the opinion of the investigator or sub-investigator.
7.2.1
Rationale for the Exclusion Criteria
Exclusion criterion 1: 
This is set to secure the safety of the subjects, with reference to the “General Considerations for Clinical 
Trials”. [7]
Exclusion criteria 2, 3, 4, 6, 7, 8, 9, 10, 11, 12, 14, 15, 16 and 22: 
These are set as the standard exclusion criteria used in clinical pharmacology studies in healthy adults
and also to secure the safety of the subjects. 
Exclusion criteria 5, 20 and 21: 
These are set to secure the safety of the subjects.
Exclusion criterion 13: 
This is set to secure the safety of the subjects, and also to avoid possible effects on pharmacokinetic 
assessments. 
Exclusion criteria 17, 18 and 19: 
These are set in line with “Law Enforcement Regulation on Securing a Stable Supply of Safe Blood 
Products” (Ministerial Ordinance No. 22 of the Ministry of Health and Welfare in 1956). [5]
7.3
Excluded Medications, Dietary Products, and Foods
Excluded medications, dietary products, and foods are shown in Table 7.a. 
Use of the concomitant drugs (prescribed or over-the-counter [OTC] drugs) and consumption of dietary 
products, or foods listed in Table 7.a is prohibited from the specified time point until discharge in Period 2
to avoid possible effects on the safety and pharmacokinetics. However, the use will be allowed when 
judged by the investigator or sub-investigator to be necessary for certain reasons such as onset of an 
adverse event.
Table 7.a Excluded Medications, Dietary Products, and Foods
From Period 1 Day −28 through the 
end of the study period 
From Period 1 Day -14 through the 
end of the study period 
From Period 1 Day -3 through the 
end of the study period
All prescription drugs
Vitamins
Alcohol-containing products
All OTC drugs
Foods and beverages containing 
grapefruit, Sweetie, Seville orange, 
shaddock, or other citrus fruits that 
inhibit CYP3A4
Caffeine-containing products
Dietary products (ie, products 
containing St. John’s wort, ginseng, 
kava kava, ginkgo, Chinese traditional 
medicines, or melatonin) 
Nicotine containing product
Subjects must be instructed not to take any medications including OTC products, without first consulting 
with the investigator or sub-investigator.


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7.4
Other Restrictions / Diet, Fluid, Activity Control
7.4.1
Foods and Beverages
On the day before blood collection for laboratory tests, the subjects must finish the last meal by 21:00 and 
then fast until blood collection in the next morning. If the examination (eg, screening examination) is 
performed in the afternoon, the blood collection will be performed after at least 10 hours of fasting from the 
last meal. 
During hospitalization, the subjects take given meals and are not allowed to take any other food. Meal 
menus will be same for each period.
The subjects must fast from at least 10 hours before the study drug administration. 
The subjects must fast until 4 hours after the study drug administration. If a meal and a test or blood 
collection are scheduled for the same time, the meal will be taken after the test/blood collection. 
Excessive drinking and eating should be avoided during the entire study period. 
Liquid intake will be prohibited from 1 hour before study drug administration until 4 hours postdose, with 
the exception of water (150 mL) to take the study drug.
7.4.2
Daily Activities
Smoking is not allowed during the study period.
Supine position is not allowed for 4 hours after the study drug administration, unless it is required for 
examinations. During hospitalization, light exercise will be performed for about 15 minutes a day.
Excessive exercise is not allowed during the study period. The subjects will be instructed not to change the 
lifestyle between Periods 1 and 2 and lead a regular life even during the washout period.
Blood donation is not allowed for at least 12 weeks after the final examination of this study. The 
investigator or sub-investigator will instruct the subjects on the prohibition of blood donation.
If a subject visits another medical institution during the study period, the subject should inform the 
investigator or sub-investigator in advance whenever possible. After the visit, the subject should inform the 
investigator or sub-investigator of the circumstance and treatment details. Also, the investigator or 
sub-investigator will contact the medical institution to notify that the subject is participating in this study.
7.5
Documentation of Subject Withdrawal Before Study Treatment
The investigator or sub-investigator will account for all subjects who signed informed consent. If a subject 
is withdrawn from the study before the study drug administration, the investigator or sub-investigator 
should complete the electronic case report form (eCRF) with the information.
The primary reason for subject withdrawal is recorded in the eCRF using the following categories: 
●Death
●AE
●Screen failure (failed to meet the inclusion criteria or did meet the exclusion criteria) <specify reason>
●Protocol deviation


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●Lost to follow-up 
●Voluntary withdrawal <specify reason>
●Study terminated by sponsor 
●Pregnancy
●Sample size sufficient 
●Other <specify reason >
Subject identification codes assigned to subjects who discontinued the study before the study drug 
administration should not be reused.
7.6
Criteria for Withdrawal of a Subject 
The primary reason for subject withdrawal is recorded in the eCRF using the following categories by the 
investigator or sub-investigator. If the subject is withdrawn from the study before the study drug 
administration, see Section 7.5.
1.
Death
The subject has died during the study period. 
Note: If a subject died during the study period, this event will be handled as a serious adverse event
(SAE). For the reporting procedures, see Section 10.2.9.3. 
2.
Adverse event (AE)
The subject has experienced an AE that requires discontinuation from the study because continued 
participation imposes an unacceptable risk to the subject’s health or the subject is unwilling to 
continue because of the AE.

Liver function test abnormalities 
If any liver function test abnormality meeting the criteria below occurs during study drug 
administration, the study drug administration will be immediately discontinued, and appropriate 
follow-up testing will be performed until the subject’s laboratory profile has returned to normal
or baseline (see Section 9.2.9.1): 
–
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%).
3.
Protocol deviation
After the start of study drug administration, the subject is found not to fulfil the eligibility criteria or 
not to comply with protocol requirements, and continued participation in the study poses an 
unacceptable risk to the subject’s health. 


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4.
Lost to follow-up 
The subject did not return to the study site, and attempts to contact the subject have been unsuccessful. 
The attempts to contact the subject should be recorded in the subject’s source document. 
5.
Voluntary withdrawal 
The subject requested to withdraw from the study. The reason for withdrawal, if obtained, will be
recorded in the eCRF. 
Note: Every effort should be made to determine the reason for the withdrawal where possible 
(withdrawal due to an AE is not categorized as “Voluntary withdrawal”). 
6.
Discontinuation of the entire study by the sponsor
The sponsor has decided to terminate the study. 
7.
Pregnancy of a subject
Note: If a subject was found to be pregnant, the subject will be immediately withdrawn from the study. 
For the procedures, see Appendix B. 
8.
Other 
Note: Specific details should be recorded in the eCRF. 
7.7
Procedures for Discontinuation or Withdrawal of a Subject
The investigator or sub-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 7.6. 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 or sub-investigator. In addition, efforts should be made to perform all procedures scheduled for 
Early Termination Visit if possible.
7.8
Reserve Subjects
For Period 1, some of the subjects who are assessed to be eligible based on the screening results may stand 
by as reserve subjects. If a subject scheduled to receive the study drug does not receive the study drug for 
certain reasons before study drug administration in Period 1, a reserve subject may be enrolled in the study 
to replace that subject. 
Subjects who discontinued after study drug administration will not be replaced by reserve subjects.
7.9
Replenishment of Subjects Whose Study Was Discontinued after Initiation of 
Study Drug Administration
If a subject who discontinued the study after the initiation of study drug administration, it is possible to 
newly incorporate another subject after consultation between the investigator and the sponsor.


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8.0
CLINICAL STUDY MATERIAL MANAGEMENT
8.1
Study Drug
[Drug products]
The study drugs are shown in Table 8.a.
Table 8.a Study Drug
Formulation
Active ingredient
Dosage form 
Strength
Lu AA21004 10 mg tablet
1-[2-(2,4-Dimethylphenylsulfanyl)phenyl]
piperazine hydrobromide
Tablet 
10 mg
Lu AA21004 20 mg tablet 
20 mg
[Packaging]
Fifteen tablets of 10 mg of Lu AA21004 tablet or 20 mg of Lu AA21004 tablet are placed in one bottle and 
the bottle is placed in an outer box.
8.1.1
Study Drug Labeling
Each outer box of the study drug is labeled with the following information: statement that the drug is for 
clinical trial use only, sponsor’s name and address, study drug name, lot number, storage condition and 
expiration date.
8.1.2
Study Drug Storage and Management
The study drugs should be stored at room temperature (1 to 30C).
The study drugs must be kept in an appropriate, limited-access, secure place until it is used or returned to 
the sponsor, or its designee for destruction. The study drugs must be stored under the conditions specified 
on the label, and remain in the original container until dispensed.
8.1.3
Study Drug Blinding
This is an open-label study.
8.1.4
Accountability and Destruction of Sponsor-Supplied Drugs
The study drug storage manager will receive the written procedures for handling, storage, and management 
of the study drugs prepared by the sponsor, and will appropriately manage the drugs in accordance with the 
procedures. The written procedures will be provided to the investigator as well. The written procedures will 
specify the procedures that are necessary to ensure appropriate receipt, handling, storage, management, and 
dispensing of the sponsor-supplied drugs, as well as retrieval of unused drugs from the subjects and their 
return to the sponsor or destruction.
The study drug storage manager will promptly return unused drugs to the sponsor after the study is closed 
at the study site.


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9.0
STUDY PROCEDURES 
The following sections describe the study procedures and data to be collected by the investigator or 
sub-investigator. For each procedure, subjects are to be assessed by the same investigator, sub-investigator 
or site personnel in principle. The study schedule is shown in Section 3.0. 
9.1
Administrative Procedures
9.1.1
Informed Consent
Informed consent must be obtained from each subject prior to any study procedures. Informed consent 
requirements are described in Section 13.2. 
9.1.1.1
Subject Identification Codes 
A unique subject identification code will be assigned to each subject at the time that informed consent is 
explained. This subject identification code will be used throughout the study. 
9.1.1.2
Assignment of Subjects 
The subjects in ascending order of the subject identification code will be randomized to either treatment 
sequence in accordance with the assignment list.
Each subject will be assigned with a subject number (4 digit number). This subject number will be used by 
the study site and the pharmacokinetic laboratory to identify the pharmacokinetic samples. The test tubes 
for pharmacokinetic measurements sent to the laboratory must be labeled with the subject numbers. The 
laboratory will use the subject numbers when reporting the measurement results. These subject numbers
should not be replaced by the subject identification codes. If a subject is replaced by a reserve subject, the 
treatment sequence assigned to the original subject will be used for the reserve subject. 
If a subject is withdrawn from the study after the start of study drug administration, and if a new subject is 
enrolled as a result of discussion between the investigator and the sponsor, the investigator will check with 
the sponsor regarding the newly enrolled subject’s subject number and treatment sequence. 
The assignment list will be prepared by the sponsor, and provided to the investigator before the start of the 
study, while the sponsor will retain its copy. Information on the assignment will be kept in a secure place 
with limited access to authorized personnel.
9.1.2
Eligibility Assessment
Each subject will be assessed based on the inclusion and exclusion criteria shown in Section 7.0. 
9.1.3
Medical History and Demographic Data
Demographic data to be obtained will include date of birth, sex, race (as reported by the subjects), height, 
body weight, caffeine and alcohol consumption, and smoking status.
Medical history to be obtained will include clinically relevant diseases and symptoms that resolved or 
disappeared within 1 year before signing of informed consent. Ongoing diseases and symptoms are 
regarded as concurrent medical conditions. Prior medication data to be obtained will include all drugs 
relevant to the eligibility criteria and safety assessments that stopped within 4 weeks (28 days) before 
signing of informed consent.


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9.1.4
Concomitant Medication
Concomitant medication is any drug given in addition to the study drug. These may be prescribed by a 
physician or obtained by the subject over the counter. Concomitant medication is not provided by the 
sponsor. Subjects will be asked whether they have used any medication other than the study drug (from 
signing of informed consent through the end of the study), and detailed use of all medications, including 
vitamins, OTC medications, and Chinese traditional medicines, must be recorded in the eCRF. The 
documentation for the drug should include its nonproprietary name, route of administration, start and end 
dates, and reason for use.
9.2
Study Procedures and Assessments
9.2.1
Physical Examination
Physical examination 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; (11) other.
9.2.2
Height and Body Weight
Height and body weight will be measured. Height (unit: cm) will be rounded to the nearest integer. Body 
weight (unit: kg) will be measured to the first decimal place. 
9.2.3
BMI
BMI will be calculated using the following formula: 
Metrics: BMI = Body weight (kg) / Height (m)2
BMI will be rounded to the first decimal place. Eligibility assessment will use the rounded BMI value.
9.2.4
Vital Signs
Vital signs will be measured in terms of body temperature (axillary), sitting blood pressure (systolic and 
diastolic) after resting for at least 5 minutes, and sitting pulse rate (beats per minute). 
9.2.5
12-lead ECG
A 12-lead ECG will be recorded. Subjects will rest for at least 5 minutes in a supine position before each 
12-lead ECG. 
The investigator or sub-investigator (or a specialist physician at the study site) will assess the ECG findings 
using one of the following categories: within normal or abnormal. If abnormal, then the investigator or 
sub-investigator (or a specialist physician at the study site) will determine whether the abnormality is 
clinically relevant. The time of 12-lead ECG will be recorded. The following parameters will be collected 
from the subject’s 12-lead ECG tracing, and recorded in the eCRF: heart rate, RR interval, PR interval, QT 
interval, QRS interval and QTcF interval (corrected using Fridericia’s formula). 
9.2.6
Columbia-Suicide Severity Rating Scale (C-SSRS)
C-SSRS will be conducted at the time specified in the study schedule. The investigator or sub-investigator
will assess the risk of suicide in study subjects based on the information obtained from C-SSRS and if 


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suicidal ideation or suicidal behavior is observed during the study period, it should be recorded in the eCRF 
as an AE.
9.2.7
Study Drug Administration 
One Lu AA21004 20 mg tablet or two Lu AA21004 10 mg tablets will be orally administered on Days 1 in
Period 1 and Period 2. Subjects will fast from at least 10 hours before study drug administration until 4 
hours postdose. With the exception of water (150 mL) to ingest the study drug, beverage intake will be 
prohibited from 1 hour before study drug administration until 4 hours postdose. 
The dose and mode of administration are shown in Table 9.a.
Table 9.a Dose and Mode of Administration
Treatment 
sequence 
Period 1
Period 2
Day 1 to Day 4
Day 5 to 21
Day 1 to Day 4
A
One Lu AA21004 20 mg tablet
Single dose under fasted condition(a)
Washout 
period
Two Lu AA21004 10 mg tablets
Single dose under fasted condition(a)
B
Two Lu AA21004 10 mg tablets
Single dose under fasted condition(a)
One Lu AA21004 20 mg tablet
Single dose under fasted condition(a)
(a) Oral administration with 150 mL of water under fasted condition (after fasting for at least 10 hours) 
9.2.8
Assessment of AEs 
Assessment of AEs will be started at the time of signing of informed consent. For details of AE collection 
and related procedures, see Section 10.2. 
9.2.9
Laboratory Test Procedures and Assessment
The following laboratory tests will be performed at the study site. Samples for laboratory tests will be 
collected after fasting for at least 10 hours according to the study schedule shown in Section 3.0. The blood 
collection volume is shown in Appendix D. 
The investigator or sub-investigator will be responsible for assessing and retaining the results of laboratory 
tests. The investigator will retain a copy of the reference values of laboratory tests. 
9.2.9.1
Laboratory Tests
Hematology tests 
The following hematology tests will be performed. 
Red blood cell count
White blood cell count and differential (lymphocytes, 
neutrophils, eosinophils , basophils, monocytes) 
Hemoglobin
Hematocrit
Platelet count
Blood chemistry tests
The following blood chemistry tests will be performed. 
Albumin 
ALT
ALP
AST
GGT
Total bilirubin 


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Direct bilirubin 
Total protein 
Creatinine 
Creatine kinase 
BUN
Potassium 
Sodium 
Chloride 
Calcium 
Inorganic phosphorus 
Glucose
Total cholesterol
HDL-cholesterol
LDL-cholesterol
Triglyceride
Uric acid
Urinalysis 
The following urinalysis will be performed. 
pH
Specific gravity 
Qualitative tests for protein, glucose, occult blood, 
urobilinogen, and ketone bodies
Other
Immunology tests 
HBsAg, HCV antibody, HIV antigen/antibody, serological test for syphilis
Urine drug tests
Phencyclidine, benzodiazepines, cocaine, antihypnotic agents, cannabinoids, morphine-like narcotics, barbiturates, and 
tricyclic antidepressants
Pregnancy test (Only in female subjects of childbearing potential) 
Urinary human chorionic gonadotropin 
Note: For immunology and urine drug tests, the investigator or sub-investigator will directly return the results to the subjects. 
The sponsor will not receive detailed results of these tests for the subjects (including reserve subjects) selected to be 
given the study drug, but will check the overall test results only (ie, presence or absence of positive results).
If subjects experienced ALT or AST >3×ULN, follow-up laboratory tests (at a minimum, ALP, 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. 
For liver function test abnormalities as SAEs, the criteria for reporting are described in Section 10.2.9.4, 
and the criteria for withdrawal of the subject are described in Section 7.6. 
9.3
Samples for Pharmacokinetics and CYP2D6 Polymorphism Assessments 
The samples for pharmacokinetic analysis and CYP2D6 genotyping will be collected at the study site 
according to the study schedule shown in Section 3.0. The blood collection volume is shown in Appendix
D. The samples for measurements are specified in Table 9.b. 
Table 9.b Samples for Measurements 
Name of sample
Matrix
Purpose of sample collection
Mandatory/
Optional
Pharmacokinetic sample
Plasma
Pharmacokinetic analysis
Mandatory
CYP2D6 genotyping sample
Whole blood
CYP2D6 genotyping
Mandatory


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9.3.1
Pharmacokinetic Measurements
The pharmacokinetic parameters will be calculated from plasma concentrations of unchanged Lu AA21004
in the pharmacokinetic analysis set. 
Term
Definition 
AUClast
Area under the plasma concentration-time curve from time 0 to time of the last quantifiable concentration
Calculation Formula:Time 0 is taken as t1, and the last time point when the concentration exceeding the 
lower limit of quantification (Clast) is taken as tn(= tlast)
AUClast=





n
i
i
i
i
i
t
t
C
C
2
1
1
)
(
2
)
(
AUC∞
Area under the plasma concentration-time curve from time 0 to infinity
Calculation Formula:AUC∞=AUClast+ Clast /λz
Cmax
Maximum plasma concentration (Observed value) 
tmax
Time to reach Cmax (Observed value) 
t1/2z
Apparent elimination half-life 
MRT∞,ev
Mean residence time
Calculation Formula:MRT∞,ev=AUMC∞/AUC∞
MRTlast,ev
The average residence time from 0 hour to time of the last quantifiable concentration
Calculation Formula:MRTlast,ev=AUMClast/AUClast
λz
Apparent elimination rate constant
AUMC∞
Area under the first moment time curve from 0 hour to infinity
Calculation Formula:AUMC∞=AUMClast + Clast×tlast/λz＋Clast /λz
2
AUMClast
Area under the first moment time curve from 0 hour to final determinable（By the trapezoidal method）
9.3.1.1
Pharmacokinetic Samples
The blood samples for pharmacokinetic analysis of unchanged Lu AA21004 will be collected according to 
Table 9.c.
The time of each sample collection will be recorded in the source documents and eCRF.
Table 9.c Collection of Pharmacokinetic Samples (in Both Period 1 and Period 2) 
Analyte
Matrix
Time points of sample collection 
Unchanged Lu AA21004 
Plasma 
Predose, 1, 2, 4, 6, 8, 10, 12, 14, 16, 24, 36, 48 and 72 hours postdose 
9.3.2
CYP2D6 Genotyping 
Blood samples for CYP2D6 genotyping will be collected.
9.4
Hospitalization Period
In both Period 1 and Period 2, the subjects will be admitted to the study site on the day before study drug
administration, and hospitalized for 5 days. During the hospitalization period, the investigator or 
sub-investigator will perform assessments and observations of the subjects according to the study schedule 
shown in Section 3.0. The subjects will be discharged from the study site, after no clinically relevant 
abnormalities in the physical condition was confirmed based on physical examination in 4 days after study 
drug administration in both Period 1 and Period 2.


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10.0
ADVERSE EVENTS
10.1
Definitions and Elements of AEs
An AE is defined as any untoward medical occurrence in a clinical trial subject who provided informed 
consent to participate in a study; it does not necessarily have to have a causal relationship with the 
treatment (including the study drug) or study participation.
An AE can therefore be any unfavorable and unintended sign (including clinically significant abnormal 
laboratory values), symptom, or disease temporally associated with the study participation whether or not it 
is considered related to the treatment (including the study drug) or study procedures.
An untoward finding generally may: 
●Indicate a new diagnosis or unexpected worsening of a pre-existing condition. (Intermittent 
manifestations of a pre-existing condition or underlying disease should not be considered 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 or sub-investigator for any reason.
Diagnoses vs. signs and symptoms: 
●Each event should be recorded to represent a single diagnosis. Accompanying signs (including 
abnormal laboratory values or ECG findings) or symptoms should NOT be recorded as additional AEs. 
If a diagnosis is unknown, sign(s) or symptom(s) should be recorded appropriately as an AE(s).
Laboratory values and ECG findings: 
●Changes in laboratory values or ECG parameters are only considered to be AEs if they are judged to be 
clinically significant by the investigator or sub-investigator (ie, if a certain action or intervention is 
required or if the investigator or sub-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 or 
finding is not considered an intervention. In addition, repeated or additional noninvasive testing for 
verification, evaluation or monitoring of an abnormality is not considered an intervention.
●If abnormal laboratory values or ECG findings are the result of pathology for which there is an overall 
diagnosis (eg, increased creatinine in renal failure), only the diagnosis should be reported 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 AEs. Baseline examinations , observations and 
evaluations (eg, laboratory tests, ECG, X-rays etc.) should NOT be recorded as AEs unless related to 
study procedures. However, if the subject experiences worsening of a concurrent medical condition 
(worsening after signing of informed consent), the worsening should be recorded appropriately as an 
AE. The investigator or sub-investigator should ensure that the event term recorded captures the 
worsening in the condition (eg, “worsening of…”).


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●If a subject has a pre-existing episodic concurrent medical condition (eg, asthma, epilepsy), any 
occurrence of an episode should only be captured as an AE if the condition becomes more frequent, 
serious or severe in nature. The investigator or sub-investigator should ensure that the AE term recorded 
captures the worsening in the condition from baseline (eg, “worsening of…”).
●If a subject has a pre-existing chronic concurrent medical condition (eg, cataract, rheumatoid arthritis), 
worsening of the condition should only be recorded as an AE if occurring to a greater extent to that 
which would be expected. The investigator or sub-investigator should ensure that the AE term recorded 
captures the worsening in the condition (eg, “worsening of…”).
Worsening of AEs: 
●If an AE which occurred before study drun administration was worsened after initial dosing of the study 
drug or an AE was worsened after any change in study treatment, the worsening should be recorded as a 
new AE. The investigator or sub-investigator should ensure that the AE term recorded captures the 
worsening in the condition (eg, “worsening of…”).
Changes in severity of AEs: 
●If the subject experiences changes in severity of an AE that are not related to a change in study 
treatment, the event should be captured once with the maximum severity recorded. 
Preplanned procedures (surgeries or therapies): 
●Preplanned procedures (surgeries or therapies) that were scheduled prior to signing of informed consent 
are not considered AEs. However, if a preplanned procedure is performed early (eg, as an emergency) 
due to a worsening of the pre-existing condition, the worsening of the condition should be recorded as 
an AE. Complications resulting from any planned surgery should be reported as AEs. 
Elective procedures (surgeries or therapies): 
●Elective procedures performed where there is no change in the subject’s medical condition (surgeries or 
therapies) should not be recorded as AEs, but should be documented in the subject’s source documents. 
Complications resulting from an elective surgery should be reported as AEs. 
Overdose: 
●An overdose is defined as the known intentional or accidental administration of the study drug or 
ingestion by the subject in an amount higher than the protocol-specified amount. Whether the episode is 
an overdose or not will be determined by the investigator or sub-investigator after discussion with the 
sponsor.
●All episodes of overdose (irrespective of occurrence of AEs) will be recorded on the Overdose page of 
the eCRF, so that important safety information on overdose can be entered into the database in a 
consistent manner. AEs associated with overdose will be recorded on the AE page of the eCRF as 
described in Section 10.0. 
●Serious AEs (SAEs) associated with overdose will be reported according to the procedures described in 
Section 10.2.9. 
●If an overdose of the study drug has occurred, the subject should be treated according to the symptoms. 


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10.1.1
SAEs
An SAE is defined as any untoward medical occurrence that:
1.
Results in death.
2.
Is life threatening.
●
The term “life threatening” refers to an event in which the subject was at risk of death at the time 
of the event; it does not refer to an event that hypothetically might have caused death if it were 
more severe. 
3.
Requires inpatient hospitalization or prolongation of existing hospitalization.
4.
Results in persistent or significant disability/incapacity.
5.
Leads to a congenital anomaly.
6.
Is a significant medical event that satisfies any of the following: 
●
May require intervention to prevent the 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.aTakeda Medically Significant AE List
Term
Acute respiratory failure/Acute respiratory distress 
syndrome (ARDS) 
Hepatic necrosis
Acute liver failure
Torsade de pointes / ventricular fibrillation / ventricular 
tachycardia
Anaphylactic shock
Acute renal failure
Malignant hypertension
Pulmonary hypertension
Convulsive seizure (including convulsion and epilepsy)
Agranulocytosis
Aplastic anaemia
Pulmonary fibrosis (including interstitial pneumonia)
Neuroleptic malignant syndrome / malignant hyperthermia
Spontaneous abortion / stillbirth and fetal death
Toxic epidermal necrolysis / Oculomucocutaneous 
syndrome (Stevens-Johnson syndrome)
Confirmed or suspected transmission of infectious agent by a 
medicinal product
Confirmed or suspected endotoxic shock
Note: Terms identified on the Medically Significant AE List represent the broad medical concepts to be considered as 
“Significant Medical Events” satisfying SAE reporting requirements.
10.2
AE-related Procedures 
10.2.1
Assessment of the Severity of AEs
The severity of AEs is categorized/defined 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.
10.2.2
Assessment of the Causality of AEs
The causality of each AE to the study drug will be assessed using the following categories/definitions: 


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Related:
An AE that follows a reasonable temporal sequence from administration of the study drug (including the 
course after withdrawal of the drug), or for which possible involvement of the drug is at least a 
reasonable possibility, ie, the relationship cannot be ruled out, although factors other than the relevant 
study drug (control 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 the relevant study 
drug (control drug) and/or that can reasonably be explained by other factors, such as underlying disease, 
concurrent disease, concomitant medication, or concurrent treatment.
10.2.3
Relationship to Study Procedures
A causal relationship between the adverse event and study procedures will be assessed. 
The causal relationship is assessed as “Related” if the investigator or sub-investigator considers that there is 
reasonable possibility that an event is due to a study procedure. Otherwise, the causality is assessed as “Not 
Related”
10.2.4
Start Date
The start date of an AE is the date on which signs or symptoms of the event were first noted by the subject 
or the investigator or sub-investigator.
10.2.5
Stop Date
The stop date of an AE is the date on which the event resolved (including resolution with sequelae) or the 
subject died.
10.2.6
Intermittent or Continuous AEs
Episodic AEs (eg, headache) or those which occur repeatedly over a period of consecutive days are 
“intermittent”. All other events are “continuous.”
10.2.7
Action Taken with Study Drug
●Drug withdrawn – the study drug administration was stopped due to the particular AE.
●Dose not changed – the particular AE did not require a change in the study drug dose. 
●Unknown –it has not been possible to determine what action has been taken after the AE onset.
●Not Applicable – the study drug administration was stopped for a reason other than the particular AE, 
eg, the study has been terminated, the subject died, dosing with study medication was already stopped 
before the onset of the AE, or an AE was seen prior to administration of the study drug.
10.2.8
Outcome
●Recovered/Resolved – Subject returned to first assessment status with respect to the AE.
●Recovering/Resolving – the severity is lowered by one or more categories; the diagnosis/sign/symptom 
has almost disappeared; the abnormal laboratory value improved but has not returned to the normal 
range or to baseline; the subject died not directly from the AE while the AE was “recovering/resolving”.
●Not recovered/Not resolved – there is no change in the diagnosis/sign/symptom; the severity of the 
diagnosis/sign/symptom or laboratory value at last observation is worse than that at onset; the event is 


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an irreversible congenital anomaly; the subject died not directly from the AE while the AE was “Not 
recovered/not resolved”.
●Resolved with sequelae – the subject recovered from the acute AE with remaining permanent or 
clinically significant impairment (eg, recovered from a cardiovascular accident but with persisting 
paralysis).
●Fatal – the AE was directly related to the death.
●Unknown – the course of the AE could not be determined at the end of the subject’s participation in the 
study for certain reasons such as hospital change or residence change.
10.2.9
Collection and Reporting of AEs, SAEs and Liver Function Test 
Abnormalities
10.2.9.1
Collection Period
Collection of AEs (AEs, SAEs, AEs of special interest, and liver function test abnormalities) will be started 
at the time of the subject’s signing of informed consent and continued until the end of Period 2. For 
subjects decided to be withdrawn from the study before initial dosing of the study drug, AEs will be 
collected until that time point. 
10.2.9.2
AE Reporting
At each study visit, the investigator or sub-investigator will assess whether any subjective AEs have 
occurred. A neutral question, such as “How have you been feeling since your last visit?” will be asked, and 
subjects will report any AEs occurring during the study. Subjects experiencing any SAE before first dosing
of the study drug must be monitored until the SAE resolves and clinically relevant laboratory abnormalities 
return to baseline or there is a satisfactory explanation for the observed change. Non-serious AEs occurring 
before first dosing of the study drug, whether or not related to the study procedure, need not to be 
followed-up for the purposes of the protocol.
All subjects experiencing AEs after first dosing of the study drug, whether or not related to the study drug, 
must be monitored until the symptoms resolve and clinically relevant laboratory abnormalities return to 
baseline or until there is a satisfactory explanation for the observed change. All AEs will be documented on 
the AE page of the eCRF, whether or not the investigator or sub-investigator concludes that the event is 
related to the study drug. The following information will be documented for each event: 
●Event term
●Start and stop date and time
●Frequency
●Severity
●Investigator’s or sub-investigator’s opinion of the causal relationship to the study drug (related or not 
related).
●Investigator’s or sub-investigator’s opinion of the causal relationship to study procedures, including 
details of the suspected procedure
●Action taken with the study drug 


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●Outcome of event
●Seriousness
●Timing of occurrence (after study drug administration)
10.2.9.3
SAE Reporting
When an SAE occurs during the AE collection period, it should be reported according to the following 
procedure: 
An SAE should be reported by the investigator or sub-investigator to the sponsor within 1 business day of 
the first onset or notification of the SAE, along with any relevant information. The investigator should 
submit the detailed SAE Form to the sponsor within 10 calendar days. The information should be 
completed as fully as possible and contain the following at a minimum: 
●A brief description of the event and the reason why the event is categorized as serious
●Subject identification code
●Investigator’s or sub-investigator’s name
●Name of the study drug
●Causality assessment
Any SAE spontaneously reported to the investigator or sub-investigator after the end of the AE collection 
period should be reported to the sponsor if considered related to the subject’s study participation. 
Reporting of SAEs occurring before initial dosing of the study drug will follow the procedure described for 
SAEs occurring during study treatment.
Follow-up of SAEs
If information not available at the time of the first report becomes available on a later date, the investigator 
or sub-investigator should complete a follow-up SAE form copy or provide other written documentation 
and promptly submit it to the sponsor. Copies of any relevant data from the hospital notes (eg, ECG, 
laboratory test values, discharge summary, postmortem results) should be sent to the sponsor, if requested.
All SAEs should be followed by the investigator or sub-investigator until resolution or final outcome 
confirmation of the event. 
10.2.9.4
Reporting of Liver Function Test Abnormalities
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 
10.2.9.3. The investigator or sub-investigator will contact the study monitor and investigate the subject 
details and possible alternative etiologies (eg, acute viral hepatitis A or B, other acute liver disease). 
Follow-up tests described in Section 9.2.9 will also be performed. 
10.2.10
Safety Reporting to Investigators, IRBs, and Regulatory Authorities
The sponsor will be responsible for reporting all serious unexpected suspected adverse reactions (SUSARs) 
and any other SAEs for expedited reporting to the regulatory authorities, investigators, and IRBs. Relative 
to the first awareness of the event by/or further provision to the sponsor or sponsor’s designee, SUSARs 


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will be submitted to the regulatory authorities as expedited reports within 7 days for fatal and 
life-threatening events and 15 days for other serious events, unless otherwise required by national 
regulations. The sponsor will also perform expedited reporting of other significant safety information that 
may greatly affect the current benefit-risk profile of the study drug or require a change to the study 
treatment or overall conduct of the study. The study site also will forward a copy of all expedited reports to 
the IRB.


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11.0
STATISTICAL METHODS
11.1
Statistical and Analytical Plans
A statistical analysis plan (SAP) will be prepared and finalized prior to database lock. This document will 
provide further details regarding the definition of analysis sets, analysis variables and analysis methodology 
to address all study objectives.
Analysis will be performed after database lock using the data obtained so far. Also, when an additional 
study is performed, another analysis will be performed using combined data of the first study with data of 
the additional study.
11.1.1
Analysis Sets
In this study, two kinds of analysis sets are defined: pharmacokinetics analysis set and safety analysis set. 
The sponsor will verify the validity of the definitions of the analysis sets as well as the rules for handling 
data prior to database lock.
11.1.1.1
Safety Analysis Set
The “safety analysis set” will be defined as all the subjects who received at least one dose of the study drug.
11.1.1.2
Pharmacokinetics Analysis Set
The “pharmacokinetics analysis set” is a subset of all treated subjects who had no major protocol violations, 
have completed the minimum element of the protocol, and had evaluable pharmacokinetic data.
11.1.2
Analysis of Demographic and Other Baseline Characteristics
Demographic and other baseline characteristics will be summarized using the pharmacokinetic analysis set 
and the safety analysis set.
11.1.3
Pharmacokinetic Analysis 
1.
Endpoints and their analytical method
[Endpoint]
Primary endpoints
●AUClast of Lu AA21004
●Cmax of Lu AA21004
Secondary endpoints
●AUC∞, tmax, MRT, λz and t1/2z of Lu AA21004
[Analytical method]
The following analyses will be based on the pharmacokinetic analysis set.
1)
Plasma concentration and pharmacokinetic parameters 
The descriptive statistics for plasma concentration of Lu AA21004 will be provided for each formulation 
(Lu AA21004 20 mg tablet and 10 mg tablet) by visit and the mean and standard deviation of plasma 


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concentration will be plotted for both formulations on the same graph. The descriptive statistics for PK
parameter will be provided for each formulation.
2)
Bioequivalence assessment
The bioequivalence of Lu AA21004 20 mg tablet and 2× 10 mg tablets is evaluated.
The log-transformed (natural log) PK parameters AUClast and Cmax of Lu AA21004 will be analysed 
separately using analysis of variance (ANOVA) with dosing formulation, treatment sequence, 
administration period as fixed effects and the two-sided 90% confidence interval (CIs) for the differences
between the formulations and between the periods will be provided. The log-transformed (natural log) PK 
parameters AUC∞, MRT, λz and t1/2z of Lu AA21004 and tmax of Lu AA21004 will be analysed separately
using ANOVA in the same manner (confidence coefficient 90%, 95%).
Bioequivalence for Lu AA21004 will be assessed based on "Guideline for Bioequivalence Studies of 
Generic Products". Formulations are considered to be bioequivalent if any of the following criteria are met.
If bioequivalence cannot be verified, it will be considered adding additional subjects.
●For the primary endpoints (AUClast and Cmax), the two-sided 90% CIs of the difference in the mean 
values of logarithmic parameters to be assessed between two treatments is within the acceptable range 
of ln(0.80) to ln(1.25).
3)
Methods of data transformation and handling of missing data
For plasma concentrations, values below the lower limit of quantification will be treated as Zero. Subjects 
with any missing pharmacokinetic data for some reasons (e.g., discontinuation, inadequate measurement) 
will be excluded from the pharmacokinetic analysis set, however, the PK parameters, such as t1/2z, will be 
calculated, as far as possible.
4)
Significance level and confidence coefficient
●Significance level: 5% (one-sided test)
●Confidence coefficient : 90% (two-sided) 
: 95% (two-sided)
11.1.4
Safety Analysis 
The following analyses will be based on the Safety Analysis Set.
11.1.4.1
Adverse Events
A treatment-emergent adverse event (TEAE) is defined as an adverse event whose date of onset occurs on 
or after the start of the study drug. Analyses will be performed for the following TEAE parameters by 
formulation. TEAEs will be coded using MedDRA dictionary. The frequency distribution will be provided 
using system organ class and preferred term for each formulation.
●All TEAE
●Drug-related TEAEs
●Intensity of TEAEs
●Intensity of drug-related TEAEs


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●TEAEs leading to study drug discontinuation
●Serious TEAEs
11.1.4.2
Assessment of Laboratory Data 
For continuous variables, the observed values and the changes from baseline will be summarized for each 
formulation at each visit using descriptive statistics. Case plots will also be presented for the observed 
values. For categorical variables, shift tables showing the number of subjects in each category at baseline 
and each post-baseline visit will be provided for each formulation.
11.1.4.3
Vital Signs
For continuous variables, the observed values and the changes from baseline will be summarized for each 
formulation at each visit using descriptive statistics.
11.1.4.4
Other Safety Parameters
The following analyses will be provided for 12-lead ECGs. For continuous variables, the observed values 
and the changes from baseline will be summarized for each formulation at each visit using descriptive 
statistics. Case plots will also be presented for the observed values. For categorical variables, shift tables 
showing the number of subjects in each category at baseline and each post-baseline visit will be provided 
for each formulation.
11.2
Determination of Sample Size 
Planned number of subjects is 28 (14 per treatment sequence).
The planned sample size was calculated based upon the analysis of logarithmically transformed AUClast and 
Cmax. If the 90% CIs for the ratios of Lu AA21004 20 mg tablets and 2× Lu AA21004 10 mg tablets (2×
Lu AA21004 10 mg tablets/ Lu AA21004 20 mg tablet) geometric mean value of AUClast and Cmax are both 
be within the limits of 80.00% to 125.00%, bioequivalence can be verified. It is hypothesize that there is no 
interaction between dosing formulation and administration period at AUClast and Cmax. Based on data from 
previous studies, the largest estimate of the within-subject coefficient of variation (CV) of AUClast and Cmax
were up to 9.5% and 14.3% and a sample size of 24 would then provide a power of 99.8% and 91.5% for 
each correctly concluding bioequivalence even if the true ratio is 1.1. Given that the 90% CIs for the ratio 
of the geometric means for AUClast and Cmax must both be contained in 80.00% to 125.00% in order to 
conclude bioequivalence between the two treatments, 24 subjects provided an overall power of at least 
91.3%, assuming that the two endpoints AUClast and Cmax are independent.
Taking into account possible occurence of dropouts, planned number of subjects is 28.
In case bioequivalence cannot be demonstrated with the number of subjects initially planned due to the 
insufficiency of the number of subjects, an add-on subject study will be conducted in accordance with the 
Partial Revision of Guideline for Bioequivalence Studies of Generic Products, if applicable. The maximum 
number of additional subjects in the add-on subject study is 28 (14 per treatment sequence), which is 
determined based on study feasibility, but is not on statistical consideration.


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12.0
QUALITY CONTROL AND QUALITY ASSURANCE 
12.1
Study-Site Monitoring Visits
Monitoring visits to the study site will be made by the sponsor or its designee (contract research 
organization [CRO]) periodically during the study to ensure that all aspects of the protocol are followed in 
the conduct of the study. 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 the study site 
will guarantee access to source documents by the sponsor or its designee and the IRB.
Study documents will be subject to reviews by the sponsor or its designee (as long as blinding is not 
jeopardized), including the Investigator’s Binder, study drug, subjects’ medical records, and informed 
consent documentation, for verification that the study is appropriately conducted in accordance with the 
protocol. In addition, consistency between eCRFs and related source documents will be checked. It is 
important that the investigator, sub-investigator and other study personnel are available during the 
monitoring visits and that sufficient time is devoted to the process.
12.2
Protocol Deviation
The investigator or sub-investigator may deviate and change from the protocol only for medically 
unavoidable reasons, for example to eliminate an immediate hazard to study subjects, without a prior 
written agreement with the sponsor or a prior approval from the IRB. In the event of a deviation or change, 
the investigator should notify the sponsor and the head of the study site of the deviation or change as well 
as its reason in a written form, and then retain a copy of the written form. When necessary, the investigator 
may consult and agree with the sponsor on a protocol amendment. If the protocol amendment is appropriate, 
the amendment proposal should be submitted to the head of the study site as soon as possible and an 
approval from the IRB should be obtained.
The investigator or sub-investigator should document all protocol deviations.
12.3
Quality Assurance Audits and Regulatory Agency Inspections 
The study site also may be subject to quality assurance audits by the sponsor or designees. In this 
circumstance, the sponsor-designated auditor will contact the site in advance to arrange an auditing visit. 
The auditor may ask to visit the facilities where laboratory samples are collected, where the medication is 
stored and prepared, and any other facility used during the study. In addition, there is the possibility that 
this study may be inspected by regulatory agencies, including those of foreign governments (eg, the Food 
and Drug Administration [FDA], the United Kingdom Medicines and Healthcare products Regulatory 
Agency [MHRA], Pharmaceuticals and Medical Devices Agency of Japan [PMDA]). If the study site is 
contacted for an inspection by a regulatory body, the sponsor should be notified immediately. The 
investigator and the head of the study site will guarantee access for quality assurance auditors to all study 
documents as described in Section 12.1. 


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13.0
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 
International Council for Harmonization of Technical Requirements for Pharmaceuticals for Human Use 
(ICH) Harmonized 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 A. 
13.1
IRB Approval 
IRBs must be constituted according to the applicable local requirements of each participating region. The 
sponsor or designee will require documentation noting all names and titles of members who make up the 
respective IRB. If any member of the IRB has direct participation in this study, written notification 
regarding his or her absence from voting must also be obtained.
The sponsor or 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 form must be obtained and submitted to the 
sponsor or designee before commencement of the study. 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. Until the site receives the notification, no protocol activities 
including screening may occur.
The study site must adhere to all requirements stipulated by its 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.
13.2
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 describes 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 further explains 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 the subject is free to withdraw at any time without giving a 
reason and without prejudice to further medical care.


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The investigator is responsible for the preparation, content, and IRB approval of the informed consent form. 
The informed consent form must be approved by both the IRB and the sponsor prior to use.
The informed consent form must be written in a language fully comprehensible to the prospective subject. 
It is the responsibility of the investigator or sub-investigator to explain the detailed elements of the 
informed consent form 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: (1) opportunity to inquire about details of the study and (2) ample time to 
decide whether or not to participate in the study. If the subject has decided to participate in the study, then 
the informed consent form must be signed and dated by the subject before participation in the study. The 
subject should be instructed to sign using their legal names, not nicknames, using blue or black ballpoint 
ink. The investigator or sub-investigator must also sign and date the informed consent form prior to subject 
entering into the study.
The investigator or sub-investigator will retain the original signed informed consent form. The investigator 
or sub-investigator will document the date the subject signs the informed consent in the subject’s medical 
record. A copy of the signed informed consent form shall be given to the subject.
If the informed consent form is revised, the investigator or sub-investigator will obtain re-consent of the 
subject in the same manner as the initial informed consent. The date of the re-consent will be recorded in 
the subject’s medical record, and a copy of the revised informed consent form shall be given to the subject.
13.3
Subject Confidentiality
The sponsor and designees affirm and uphold the principle of the subject’s right to protection against 
invasion of privacy. Throughout this study, a subject’s source data will only be linked to the sponsor’s 
clinical trial database or documentation via a subject identification code. As permitted by all applicable 
laws and regulations, limited subject attributes such as sex, age, or date of birth may be used to identify the 
subject and check the validity of the subject’s identification code.
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, MHRA, PMDA), 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 13.2).
Copies of any subject source documents may be provided to the sponsor only after removal of the subject’s 
personally identifiable information (ie, subject name, address, and other personal identifiers not recorded
on the subject’s eCRF). 
13.4
Publication, Disclosure, and Clinical Trial Registration Policy
13.4.1
Publication and Disclosure
The investigator will provide the sponsor with all results and all data obtained 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 


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agreement, public disclosure related to the protocol or study results (including publicly accessible websites) 
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. The investigator or sub-investigator 
needs to obtain a prior written approval from the sponsor to publish any information from the study 
externally such as to a professional association. 
13.4.2
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 Takeda-sponsored 
interventional clinical trials conducted 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 study site’s name, city, country, and recruiting status will be registered and available for public 
viewing.
13.4.3
Clinical Trial Results Disclosure
Takeda will post the results of clinical trials on ClinicalTrials.gov or other publicly accessible websites, as 
required by Takeda Policy/Standard, applicable laws and/or regulations.
13.5
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 required locally, the sponsor or sponsor’s designee will take out an insurance 
policy to prepare for possible compensation for health injury to study subjects. Subjects with health injury 
will be compensated and treated as stated in the study site agreement. If the investigator or sub-investigator 
has questions regarding compensation, he or she should contact the sponsor or sponsor’s designee.


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14.0
STUDY ADMINISTRATIVE INFORMATION AND RELATED INFORMATION
14.1
Study Administrative Information
14.1.1
Study-related Contact Information
Each study site will be provided with a list of contact information (Protocol Annex 1).
14.1.2
Investigator Agreement
Each study site will be provided with the investigator agreement form.
14.1.3
Study-related Roles and Responsibilities
Each study site will be provided with a list of contact information (Protocol Annex 1).
14.1.4
List of Abbreviations
Term
Definition
5-HT
5-hydroxytryptamine
5-HTT
5-hydroxytryptamine transporter
AE
adverse event
ALP
alkaline phosphatase
ALT
alanine aminotransferase
AST
aspartate aminotransferase
BMI
body mass index
BUN
blood urea nitrogen
C-SSRS
Columbia-Suicide Severity Rating Scale
CYP
cytochrome P450
EM
extensive metabolizer
FDA
Food and Drug Administration
FSH
follicle stimulating hormone
GCP
Good Clinical Practice
GGT
gamma-glutamyl transpeptidase
HDL
high-density lipoprotein
ICH
International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use
INR
international normalized ratio
LDL
low-density lipoprotein
MedDRA
Medical Dictionary for Regulatory Activities
MHRA
Medicines and Healthcare products Regulatory Agency
OTC
over-the-counter
PMDA
Pharmaceuticals and Medical Devices Agency
SAE
serious adverse event
SUSARs
serious unexpected suspected adverse reactions
TEAE
treatment emergent adverse event


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15.0
DATA MANAGEMENT AND RECORD KEEPING 
The full details of procedures for data management will be documented in the Data Management Plan. AEs 
and medical history including concurrent medical conditions will be coded using the Medical Dictionary 
for Regulatory Activities (MedDRA). Drugs will be coded using the World Health Organization (WHO) 
Drug Dictionary. 
15.1
eCRF
The investigator or sub-investigator will complete eCRFs for all subjects who signed the informed consent 
form. 
The sponsor or its designee will supply the study site with access to eCRFs. The sponsor will make 
arrangements to train appropriate site staff in the use of the eCRF. The eCRFs are used to transmit the 
information collected in the conduct of this study to the sponsor and regulatory authorities. eCRFs must be 
completed in English. Data are transcribed directly onto eCRFs.
After completion of the entry process, computer logic checks will be run to identify any inconsistent dates, 
missing data, questionable values, or other erroneous entries. Queries may be issued by the sponsor or its 
designees and will be answered by the study site. 
Changes or corrections to the eCRF are to be recorded in an audit trail designed to capture the data before 
and after the change/correction, person making the change/correction, date of the change/correction, and 
reason for the change/correction.
The investigator will review the eCRFs for completeness and accuracy, and electronically sign the 
designated page of the eCRFs. The investigator will take full responsibility for the accuracy and 
authenticity of all data entered on the eCRFs.
The following data will not be recorded directly into the eCRFs.
●Laboratory test results
●Drug concentration measurement results 
After the study database lock, any change, correction, or addition to the entries in the eCRF by the 
investigator or sub-investigator will require the eCRF change/correction record (Data Clarification Form). 
The investigator will review the Data Clarification Form for completeness and accuracy, and electronically 
sign the form.
The sponsor or its designee will review the eCRFs for accuracy and completeness at the study site during 
periodic visits. The sponsor or its designee will review the subjects’ 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 any information in the eCRFs should not be made available by the investigator or sub-investigator to 
third parties, except for authorized representatives of appropriate governmental health or regulatory 
authorities, without written permission of the sponsor.
15.2
Record Retention
To allow for inspections or audits by the regulatory authorities and the sponsor or its designees, the 
investigator and the head of the study site will agree to retain the following documents, including the 
records stipulated in Section 15.1 and study-specific documents. These documents include the subject 


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screening log, medical records, original signed and dated informed consent forms, electronic copies of
eCRFs including the audit trail, and drug accountability record. 
The investigator and the head of the study site are required to retain essential documents until the day 
specified as 1) or 2) below, whichever comes later. However, if the sponsor requests a longer time period 
for retention, the head of the study site will discuss the record retention period and method with the 
sponsor. 
1.
The day on which marketing approval of the study drug is obtained (or, if the drug development is 
discontinued, 3 years after the date of receipt of its notification).
2.
3 years after the date of early termination or completion of the study.
In addition, the investigator and the head of the study site will retain the essential documents until the time 
of receipt of a sponsor-issued notification stating that the retention is no longer required.


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16.0
REFERENCES 
[1]
Nakane Y, Arima K. Cause and Symptoms of Depression. Journal of Practical Pharmacy.
2000;51(2):826-34.
[2]
American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders, Fourth 
Edition. Translated by Takahashi S, Ono Y, Someya T. Igaku-Shoin. 2004.
[3]
Guideline for Clinical Evaluation of Antidepressants (Notification No. 1116-1 of the Evaluation and 
Licensing Division, Pharmaceutical and Food Safety Bureau, dated November 16, 2010).
[4]
Guideline for Bioequivalence Studies of Generic Products (Notification No. 0229-10 of the 
Evaluation and Licensing Division, Pharmaceutical and Food Safety Bureau, dated February 29,
2012).
[5]
Act on Securing a Stable Supply of Safe Blood Products (Ministerial Ordinance No. 22 of the 
Ministry of Health and Welfare, dated June 25, 1956). 
[6]
Japan Society for the Study of Obesity. Diagnostic Criteria for Obesity 2011. Journal of Japan Society 
for the Study of Obesity. 2011;10(Suppl). 
[7]
General Considerations for Clinical Trials (ICH-E8 guideline; Notification No. 380 of the Evaluation 
and Licensing Division, Pharmaceutical and Medical Safety Bureau, dated April 21, 1998).


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17.0
APPENDICES
Appendix A
Responsibilities of the Investigator 
1.
Conduct the study appropriately in accordance with the protocol and GCP, while respecting the human 
rights, safety, and wellbeing of the subjects.
2.
When part of important tasks related to the study are delegated to the sub-investigator or clinical 
research coordinator, prepare the lists of tasks to be delegated and responsible personnel, submit the 
lists to the head of the study site in advance and receive approval. 
3.
Prepare a written informed consent form, and update it as needed.
4.
Confirm the contents of the clinical study agreement.
5.
Provide the sub-investigators, clinical research coordinators, and other study staff with sufficient 
information about the protocol, drugs, and each person’s tasks, and give guidance and supervision.
6.
Screen subjects who meet the requirements of the protocol, provide explanation about the study in 
writing, and obtain written consent.
7.
Assume responsibility for all medical judgments related to the study.
8.
Ensure in collaboration with the head of the study site that sufficient medical treatment will be 
provided to subjects for all clinically significant adverse events related to the study, throughout and 
after the period of the subject’s participation in the study.
9.
If a subject is being treated at any other medical institution or department, with agreement of the 
subject, notify the physician of the other medical institution or department of the subject's 
participation in the study, as well as completion/discontination of the study in writing, and document 
such records.
10. If expedited reporting of SAEs etc. is required, immediately notify the head of the study site and the 
sponsor in writing.
11. Determine the need for unblinding of emergency key code for a subject in case of emergency (only for 
double-blind studies).
12. Prepare correct and complete eCRFs, electronically sign them, and submit them to the sponsor.
13. Check and confirm the entries in the eCRFs completed by the sub-investigator or transcribed from 
source data by the clinical research coordinator, electronically sign them, and submit them to the 
sponsor.
14. Discuss any proposals from the sponsor, including protocol amendments.
15. Notify the head of the study site of the completion of the study in writing.


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Appendix B
Pregnancy and Contraception
Female subjects and their male partners
From signing informed consent, throughout the duration of the study and for 4 weeks after last dose of the 
study drug, female subjects of childbearing potential* who are sexually active with a non-sterilized male 
partner** must use a method of contraception as described below .
In addition, they must be advised not to donate ova during this period.
* A woman of childbearing potential, i.e. fertile, following menarche and until becoming post-menopausal 
unless permanently sterile. Permanent sterilization methods include hysterectomy, and bilateral 
oophorectomy. A post-menopausal state is defined as no menses for 12 months without an alternative 
medical cause. A high follicle stimulating hormone (FSH) level in the post-menopausal range (FSH 
>40 IU/L) may be used to confirm a post-menopausal state in younger women (eg, those <45 year old) or 
women who are not using hormonal contraception or hormonal replacement therapy. However, in the 
absence of 12 months of amenorrhea, a single FSH measurement is insufficient. 
** Sterilized males should be at least one year post-bilateral vasectomy and have confirmed that they have 
obtained documentation of the absence of sperm in the ejaculate or have had bilateral orchidectomy.
Appropriate contraception are defined as the following methods;
●Combined (estrogen and progestogen) hormonal contraception associated with inhibition of ovulation: 
Combined pill.
●Intrauterine device (IUD).
●Intrauterine Contraceptive System (IUS)
●Bilateral tubal occlusion.
●Vasectomised partner (provided that partner is the sole sexual partner of the trial participant and that the 
vasectomised partner has received medical assessment of the surgical success).
●True sexual abstinence, only if this is in line with the preferred and usual lifestyle of the subject. True 
abstinence is defined as refraining from heterosexual intercourse during the entire period of the study, 
from 1 month prior to the first dose and 4 weeks after last dose.
●Male condom
Subjects will be provided with information on appropriate methods of contraception as part of the subject 
informed consent process and will be asked to sign a consent form stating that they understand the 
requirements for avoidance of pregnancy, donation of ova during the course of the study and up to 4 weeks 
after last dose of the study drug.
During the course of the study, pregnancy tests (Urinary human chorionic gonadotropin) will be performed 
only for female subjects of childbearing potential and all subjects will receive continued guidance with 
respect to the avoidance of pregnancy as part of the study procedures. Such guidance should include a 
reminder of the following:
●contraceptive requirements of the study


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●assessment of subject compliance through questions such as
∙Have you used the contraception consistently and correctly since the last visit?
∙Have you forgotten to use contraception since the last visit?
∙Are your menses late (even in female subjects with irregular or infrequent menstrual cycles a 
pregnancy test must be performed if the answer is “yes”)
∙Is there a chance you could be pregnant?
In addition to a negative pregnancy test (Urinary human chorionic gonadotropin) at Screening, female 
subjects of childbearing potential must also have confirmed menses in the month before first dosing (no 
delayed menses), a negative pregnancy test prior to receiving any dose of study medication. In addition, 
subjects must also have a negative pregnancy test (Urinary human chorionic gonadotropin) for one day 
before receiving the investigational drug at Period 2.
Pregnancy
If any subject is found to be pregnant during the study she should be withdrawn and any sponsor-supplied 
drug should be immediately discontinued.
If the female subject agrees to the primary care physician (obstetrician and gynecologist) being informed, 
the investigator or sub-investigator should notify the primary care physician that she was participating in a 
clinical study at the time she became pregnant and provide details of the study drug the subject received. 
If any subject is found to be pregnant during the study or up to 4 weeks after last dose of the study drug, all 
pregnancies will be followed up to final outcome and the outcome, including any premature termination,
Investigator or sub-investigator must report to the sponsor using the pregnancy form under the agreement
of the female subjects. An evaluation after the birth of the child will also be conducted.


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Appendix C
Time Windows for Study Procedures
For both Period 1 and Period 2
Test/Observation Item
Scheduled Time
Allowable Time Window
Screening examination (a)
Screening (Day -28 to Day -2) 
Same as left 
Physical examination
Day -1, Day 21
Between 24 hours before 
administration and just before dosing 
on Day 1
24 and 72 hours postdose 
1 hour
Body weight
Day -1
Same as left 
Vital signs 
Day -1, Day 21
Same as left 
24 and 72 hours postdose
1 hour
12−lead ECG
72 hours postdose
1 hour
Laboratory tests 
Day -1, Day 21
Same as left 
72 hours postdose
1 hour (b)
Pharmacokinetic blood sampling 
Predose on Day 1
Between rising and just before dosing 
on Day 1 
1, 2, 4, 6, 8, 10, 12, 14, and 16 hours postdose
5 minutes
24, 36, 48, and 72 hours postdose
10 minutes
C-SSRS
Day -1, Day 21
Same as left 
Day 4
Same as left
Day -1 is defined as the day before the Period 1 study drug administration. Day 21 is defined as the day before the Period 2
study drug administration. Day 1 is defined as the day of study drug administration in each of Period 1 and Period 2. 
(a)
Height, physical examination, body weight, vital signs, 12-lead ECG, laboratory test, blood collection for CYP2D6 
genotyping and C-SSRS.
(b)
For urinalysis, from the time of rising up to +1 hour of the scheduled time.


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Appendix D
Blood Volume Table
The total blood collection volume collected from each subject is shown below;
Sample Type
Sample 
Volume per 
each 
time(mL)
Number of Samples
Total 
Volume 
(mL)
Screening
period
Period 1
Period 2
Laboratory tests
Hematology
2
2
2
1
10
Serum chemistry
7
2
2
1
35
Immunology
10
1
0
0
10
CYP2D6 genotyping
5
1
0
0
5
PK assessment
4
0
14
14
112
Total volume
172 mL


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Takeda Pharmaceutical Company Limited
PROTOCOL
A Randomized, Open-Label, 2×2 Crossover Phase 1 Study to Evaluate the 
Bioequivalence of Single Oral Dose of Lu AA21004 20 mg tablet and 2× Lu AA21004 
10 mg tablets in Healthy Adult Subjects
A Bioequivalence Study of the Lu AA21004 20 mg and 2×10 mg Tablets
Study Number:
Vortioxetine-1001
Compound:
Lu AA21004
Date:
28 December 2017
Version/Amendme
nt Number:
First Version
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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Study No. Vortioxetine-1001
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TABLE OF CONTENTS
1.0
STUDY SUMMARY ........................................................................................................................... 5
2.0
SCHEMATIC OVERVIEW OF THE STUDY.................................................................................... 8
3.0
STUDY SCHEDULE........................................................................................................................... 9
4.0
INTRODUCTION.............................................................................................................................. 10
4.1
Background.................................................................................................................................. 10
4.2
Rationale for This Study .............................................................................................................. 10
4.3
Benefits/Risks .............................................................................................................................. 11
5.0
STUDY OBJECTIVES AND ENDPOINTS...................................................................................... 12
5.1
Hypothesis.................................................................................................................................... 12
5.2
Objectives..................................................................................................................................... 12
5.2.1
Primary Objective ............................................................................................................ 12
5.2.2
Secondary Objective ........................................................................................................ 12
5.3
Endpoints ..................................................................................................................................... 12
5.3.1
Primary Endpoints............................................................................................................ 12
5.3.2
Secondary Endpoints........................................................................................................ 12
6.0
STUDY DESIGN AND DESCRIPTION........................................................................................... 13
6.1
Study Design................................................................................................................................ 13
6.2
Rationale for Study Design, Dose, and Endpoints ....................................................................... 13
6.2.1
Rationale for Study Design .............................................................................................. 13
6.2.2
Rationale for Dose............................................................................................................ 13
6.2.3
Rationale for Washout Period .......................................................................................... 13
6.2.4
Rationale for Endpoints.................................................................................................... 14
6.2.5
Important Procedures based on Study Objectives: Time Points of the Procedures.......... 14
6.3
Start and End/Completion of the Study........................................................................................ 14
6.3.1
Definition of the Start of the Study .................................................................................. 14
6.3.2
Definition of the Completion of the Study....................................................................... 15
6.3.3
Definition of Study Termination ...................................................................................... 15
6.3.4
Criteria for Suspension or Termination of the Entire Study............................................. 15
6.3.5
Criteria for Suspension or Termination of a Study Site ................................................... 16
7.0
CRITERIA FOR SELECTION AND DISCONTINUATION OF SUBJECTS................................. 17
7.1
Inclusion Criteria.......................................................................................................................... 17
7.1.1
Rationale for the Inclusion Criteria.................................................................................. 17
7.2
Exclusion Criteria......................................................................................................................... 17
7.2.1
Rationale for the Exclusion Criteria................................................................................. 19
7.3
Excluded Medications, Dietary Products, and Foods................................................................... 19
7.4
Other Restrictions/Diet, Fluid, Activity Control.......................................................................... 19
7.4.1
Foods and Beverages........................................................................................................ 19
7.4.2
Daily Activities ................................................................................................................ 20
7.5
Documentation of Subject Withdrawal Before Study Treatment................................................. 20
7.6
Criteria for Withdrawal of a Subject............................................................................................ 21
7.7
Procedures for Discontinuation or Withdrawal of a Subject........................................................ 22
7.8
Reserve Subjects .......................................................................................................................... 22
7.9
Replenishment of Subjects Whose Study Was Discontinued after Initiation of Study Drug 
Administration ............................................................................................................................. 22
8.0
CLINICAL STUDY MATERIAL MANAGEMENT........................................................................ 23


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8.1
Study Drug................................................................................................................................... 23
8.1.1
Study Drug Labeling ........................................................................................................ 23
8.1.2
Study Drug Storage and Management.............................................................................. 23
8.1.3
Study Drug Blinding ........................................................................................................ 23
8.1.4
Accountability and Destruction of Sponsor-Supplied Drugs ........................................... 23
9.0
STUDY PROCEDURES.................................................................................................................... 24
9.1
Administrative Procedures........................................................................................................... 24
9.1.1
Informed Consent............................................................................................................. 24
9.1.2
Eligibility Assessment...................................................................................................... 24
9.1.3
Medical History and Demographic Data.......................................................................... 24
9.1.4
Concomitant Medication.................................................................................................. 25
9.2
Study Procedures and Assessments.............................................................................................. 25
9.2.1
Physical Examination....................................................................................................... 25
9.2.2
Height and Body Weight.................................................................................................. 25
9.2.3
BMI .................................................................................................................................. 25
9.2.4
Vital Signs........................................................................................................................ 25
9.2.5
12-lead ECG..................................................................................................................... 25
9.2.6
Study Drug Administration .............................................................................................. 25
9.2.7
Assessment of AEs........................................................................................................... 26
9.2.8
Laboratory Test Procedures and Assessment ................................................................... 26
9.3
Samples for Pharmacokinetics and CYP2D6 Polymorphism Assessments ................................. 27
9.3.1
Pharmacokinetic Measurements....................................................................................... 28
9.3.2
CYP2D6 Genotyping ....................................................................................................... 28
9.4
Hospitalization Period.................................................................................................................. 28
10.0
ADVERSE EVENTS ......................................................................................................................... 29
10.1
Definitions and Elements of AEs................................................................................................. 29
10.1.1
SAEs................................................................................................................................. 31
10.2
AE-related Procedures ................................................................................................................. 31
10.2.1
Assessment of the Severity of AEs .................................................................................. 31
10.2.2
Assessment of the Causality of AEs................................................................................. 31
10.2.3
Relationship to Study Procedures..................................................................................... 32
10.2.4
Start Date.......................................................................................................................... 32
10.2.5
Stop Date.......................................................................................................................... 32
10.2.6
Intermittent or Continuous AEs ....................................................................................... 32
10.2.7
Action Taken with Study Drug ........................................................................................ 32
10.2.8
Outcome ........................................................................................................................... 32
10.2.9
Collection and Reporting of AEs, SAEs and Liver Function Test Abnormalities ........... 33
10.2.10
Safety Reporting to Investigators, IRBs, and Regulatory Authorities.............................. 34
11.0
STATISTICAL METHODS............................................................................................................... 36
11.1
Statistical and Analytical Plans.................................................................................................... 36
11.1.1
Analysis Sets .................................................................................................................... 36
11.1.2
Analysis of Demographic and Other Baseline Characteristics......................................... 36
11.1.3
Pharmacokinetic Analysis ................................................................................................ 36
11.1.4
Safety Analysis................................................................................................................. 37
11.2
Determination of Sample Size...................................................................................................... 38
12.0
QUALITY CONTROL AND QUALITY ASSURANCE.................................................................. 39


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Study No. Vortioxetine-1001
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12.1
Study-Site Monitoring Visits ....................................................................................................... 39
12.2
Protocol Deviation ....................................................................................................................... 39
12.3
Quality Assurance Audits and Regulatory Agency Inspections................................................... 39
13.0
ETHICAL ASPECTS OF THE STUDY............................................................................................ 40
13.1
IRB Approval............................................................................................................................... 40
13.2
Subject Information, Informed Consent, and Subject Authorization........................................... 40
13.3
Subject Confidentiality................................................................................................................. 41
13.4
Publication, Disclosure, and Clinical Trial Registration Policy................................................... 41
13.4.1
Publication and Disclosure............................................................................................... 41
13.4.2
Clinical Trial Registration................................................................................................ 42
13.4.3
Clinical Trial Results Disclosure...................................................................................... 42
13.5
Insurance and Compensation for Injury....................................................................................... 42
14.0
STUDY ADMINISTRATIVE INFORMATION AND RELATED INFORMATION ..................... 43
14.1
Study Administrative Information ............................................................................................... 43
14.1.1
Study-related Contact Information................................................................................... 43
14.1.2
Investigator Agreement .................................................................................................... 43
14.1.3
Study-related Roles and Responsibilities ......................................................................... 43
14.1.4
List of Abbreviations........................................................................................................ 43
15.0
DATA MANAGEMENT AND RECORD KEEPING....................................................................... 44
15.1
eCRF ............................................................................................................................................ 44
15.2
Record Retention.......................................................................................................................... 44
16.0
REFERENCES................................................................................................................................... 46
17.0
APPENDICES.................................................................................................................................... 47
LIST OF IN-TEXT TABLES
Table 7.a
Excluded Medications, Dietary Products, and Foods ............................................................ 19
Table 8.a
Study Drug............................................................................................................................. 23
Table 9.a
Dose and Mode of Administration......................................................................................... 26
Table 9.b
Samples for Measurements.................................................................................................... 27
Table 9.c
Collection of Pharmacokinetic Samples (in Both Period 1 and Period 2) ............................. 28
Table 10.a
Takeda Medically Significant AE List .................................................................................. 31
LIST OF IN-TEXT FIGURES
Figure 2.a
Study Design Overview........................................................................................................... 8
LIST OF APPENDICES
Appendix A
Responsibilities of the Investigator........................................................................................ 47
Appendix B
Pregnancy and Contraception................................................................................................ 48
Appendix C
Time Windows for Study Procedures.................................................................................... 50
Appendix D
Blood Volume Table.............................................................................................................. 51


Lu AA21004
Study No. Vortioxetine-1001
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1.0
STUDY SUMMARY
Clinical Study Sponsor:
Takeda Pharmaceutical Company Limited
Compound:
Lu AA21004
Study Number: Vortioxetine-1001
Phase: 1
Study Title:
A Randomized, Open-Label, 2×2 Crossover Phase 1 Study to Evaluate the Bioequivalence of Single Oral Dose of 
Lu AA21004 20 mg tablet and 2× Lu AA21004 10 mg tablets in Healthy Adult Subjects
Study Design:
This is a 2 x 2 crossover, open-label, comparative study in Japanese healthy adults to evaluate the bioequivalence between the 
Lu AA21004 20 mg tablet and the Lu AA21004 10 mg tablet after single dosing, and also to evaluate the safety of a single 
oral dose of Lu AA21004 20 mg.
Subjects will be randomized in a 1:1 ratio to either treatment sequence A or B.
This study consists of the screening period, Period 1, and Period 2. Subjects will receive one Lu AA21004 20 mg tablet or 
two Lu AA21004 10 mg tablets on Day 1 of Period 1 and Period 2. The interval between the Period 1 dosing and the Period 2 
dosing of the study drug will be at least 3 weeks.
If bioequivalence is not demonstrated with the initially planned number of subjects, an add-on subject study may be 
conducted in accordance with the “Partial Revision of Guideline for Bioequivalence Studies of Generic Products”.
Primary Objective:
To evaluate the bioequivalence between the Lu AA21004 20 mg tablet and the Lu AA21004 10 mg tablet after single dosing 
in Japanese healthy adults
Secondary Objective:
To evaluate the safety of a single dose of Lu AA21004 20 mg in Japanese healthy adults
Subject Population: Japanese healthy adult subjects
Planned Number of Subjects:
28 (14 per treatment sequence)
If an add-on subject study is conducted, the maximum 
number of additional subjects will be 28 (14 per treatment 
sequence).
Planned Number of Sites:
1 site
Dose Levels:
A single dose of either one Lu AA21004 20 mg tablet or two 
Lu AA21004 10 mg tablets will be given under fasted
conditions on Days 1 in Period 1 and Period 2.
Route of Administration:
Oral
Duration of Treatment:
Single dose × 2 periods (The interval between the Period 1 
dosing and the Period 2 dosing of the study drug will be at 
least 3 weeks.)
Planned Study Period:
Screening period: Day -28 to Day -1
Period 1 and Period 2: Day 1 to Day 25 (when the period 
between dosing of Period 1 and Period 2 is set as 3 weeks)
Inclusion Criteria:
In order to be eligible for participation in this trial, the subject must:
1. Be a healthy Japanese adult volunteer.
2. Understand the contents of the study and be capable of providing written consent to participate in the study.
3. Be willing to comply with all study procedures and restrictions.
4. Aged between 20 and 45 years at the time of screening.
5. Have a BMI of ≥18.5 and ≤24.9 (kg/m2) and a body weight of ≥50 kg at the time of screening.
6. Be a extensive metabolizer (EM) based on CYP2D6 genotyping at the time of screening.
7. A female subject of childbearing potential with a non-sterilized male partner must agree to routinely use appropriate 
contraception during the study from the time of signing informed consent until 4 weeks after last dosing of the study drug.
Exclusion Criteria:
The subject must be excluded from participating in the trial if the subject:
1. Has received any investigational drugs within 90 days before screening for this study.
2. Previously received Lu AA21004 before participation in this study.
3. Is an employee of the sponsor or the study site, or immediate family member, or is in a dependent relationship with a study 
site employee who is involved in the conduct of this study (eg, spouse, parent, child, sibling) or who may be coerced to 
provide consent.
4. Has uncontrolled, clinically relevant neurologic, cardiovascular, pulmonary, hepatic, renal, metabolic, gastrointestinal, or 
endocrine disease or other abnormality which may affect study participation or study results.
5. Has a history of multiple episodes or severe allergies (eg, food, drug, latex allergy) or has had an anaphylactic reaction or 


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Study No. Vortioxetine-1001
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significant intolerance to prescription drugs, OTC drugs, or foods.
6. Has a positive pregnancy test at the time of screening or Day −1.
7. Is a pregnant or lactating female.
8. Has a positive urine drug test at the time of screening or Day −1.
9. Has a history of drug abuse (defined as any illicit drug use) or has a history of alcohol dependence within 2 years before 
the start of screening or is unwilling to agree to abstain from alcohol and drugs throughout the study.
10. Consumes 6 or more servings of caffeinated beverages (containing about 720 mg of caffeine or more) such as coffee, tea, 
cola, or energy drinks per day.
11. Is a smoker who smoked cigarettes or used nicotine-containing products (such as nicotine patch) within 6 months before 
the Period 1 study drug administration.
12. Used any of the excluded drugs, dietary products or foods during the period specified in the table in Section 7.3, or will 
need any of them during the study period.
13. Has any current or a history of gastrointestinal diseases that would be expected to influence the absorption of drugs (ie, 
malabsorption, esophageal reflux, peptic ulcer disease, erosive esophagitis, frequent [more than once per week] occurrence 
of heartburn), or any surgical intervention (gastrectomy, cholecystectomy etc.).
14. Has a history of cancer.
15. Has a positive test result for any of the following at the time of screening: hepatitis B surface antigen (HBsAg), hepatitis
C virus (HCV) antibody, human immunodeficiency virus (HIV) antibody/antigen, serological test for syphilis.
16. Has poor peripheral venous access.
17. Has undergone whole blood collection of at least 200 mL within 4 weeks (28 days) or at least 400 mL within 12 weeks 
(84 days) prior to the start of Period 1 study drug administration.
18. Has undergone whole blood collection of at least 800 mL in total within 52 weeks (364 days) prior to the start of Period 1
study drug administration.
19. Has undergone blood component collection within 2 weeks (14 days) prior to the start of Period 1 study drug 
administration.
20. Has any clinically relevant abnormality in vital signs or 12-lead ECG at screening or on Day −1 of Period 1.
21. Has abnormal laboratory test values at screening or on Day −1 of Period 1 indicating clinically relevant underlying 
disease, or showing alanine aminotransferase (ALT) and/or aspartate aminotransferase (AST) >1.5×ULN.
22. Is unlikely to comply with the protocol requirements or is unsuitable as a subject of this study for any other reason in the 
opinion of the investigator or sub-investigator.
Criteria for Evaluation:
<Primary endpoints>
∙AUC from time 0 to the last quantifiable time point (AUClast) of Lu AA21004
∙Maximum plasma concentration (Cmax) of Lu AA21004
<Secondary endpoints>
∙AUC∞, tmax, MRT, λz , and t1/2z
∙Safety: adverse events (AEs), vital signs (sitting blood pressure, sitting pulse rate, body temperature (axillary)), resting 
12-lead electrocardiograms (ECGs), and laboratory test results
Statistical Considerations:
1)
Plasma concentration and pharmacokinetic parameters
The descriptive statistics for plasma concentration of Lu AA21004 will be provided for each formulation (Lu AA21004 
20 mg tablet and 10 mg tablet) by visit and the mean and standard deviation of plasma concentration will be plotted for both 
formulations on the same graph. The descriptive statistics for PK parameter will be provided for each formulation.
2)
Bioequivalence assessment
The bioequivalence of Lu AA21004 20 mg tablet and 2× 10 mg tablets is evaluated.
The log-transformed(natural log) PK parameters AUClast and Cmax of Lu AA21004 will be analysed separately using analysis 
of variance (ANOVA) with dosing formulation, treatment sequence, administration period as fixed effects and the two-sided 
90% confidence interval (CIs) for the differences between the formulations and between the periods will be provided. The 
log-transformed(natural log) PK parameters AUC∞, MRT, λz and t1/2z of Lu AA21004 and tmax of Lu AA21004 will be 
analysed separately using ANOVA in the same manner (confidence coefficient 90%, 95%).
Rational for the Sample Size:
Planned number of subjects is 28 (14 per treatment sequence).
The planned sample size was calculated based upon the analysis of logarithmically transformed AUClast and Cmax. If the 90% 
CIs for the ratios of Lu AA21004 20 mg tablets and 2× Lu AA21004 10 mg tablets (2× Lu AA21004 10 mg tablets/ 
Lu AA21004 20 mg tablet) geometric mean value of AUClast and Cmax are both be within the limits of 80.00% to 125.00%,
bioequivalence can be verified. It is hypothesize that there is no interaction between dosing formulation and administration 
period at AUClast and Cmax. Based on data from previous studies, the largest estimate of the within-subject coefficient of 
variation (CV) of AUClast and Cmaxwere up to 9.5% and 14.3% and a sample size of 24 would then provide a power of 99.8% 
and 91.5% for each correctly concluding bioequivalence even if the true ratio is 1.1. Given that the 90% CIs for the ratio of 
the geometric means for AUClast and Cmax must both be contained in 80.00% to 125.00% in order to conclude bioequivalence 


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Study No. Vortioxetine-1001
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between the two treatments, 24 subjects provided an overall power of at least 91.3%, assuming that the two endpoints AUClast
and Cmax are independent.
Taking into account possible occurence of dropouts, planned number of subjects is 28.
In case bioequivalence cannot be demonstrated with the number of subjects initially planned due to the insufficiency of the 
number of subjects, an add-on subject study will be conducted in accordance with the Partial Revision of Guideline for 
Bioequivalence Studies of Generic Products, if applicable. The maximum number of additional subjects in the add-on subject 
study is 28 (14 per treatment sequence), which is determined based on study feasibility, but is not on statistical consideration.


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Study No. Vortioxetine-1001
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2.0
SCHEMATIC OVERVIEW OF THE STUDY
The overview of the study design is shown in Figure 2.a.
Figure 2.a Study Design Overview
Treatment 
sequence
Period 1
Period 2
Day 1 to 4
Day 5 to 21(a)
Day 1 to 4
A
One Lu AA21004 20 mg tablet
Single dose under fasted condition
Washout
Two Lu AA21004 10 mg tablets
Single dose under fasted condition
B
Two Lu AA21004 10 mg tablets
Single dose under fasted condition
One Lu AA21004 20 mg tablet
Single dose under fasted condition
Period
Screening period
Administration term
Period 1
Period 2
Day(b)
−28 to −2
−1
1
2 to 3
4
5 to 20
21
1
2 to 3
4
Days from the 
Period 1 study drug
dossing (a)
-
-
1
2 to 3
4
5 to 20
21
22
23 to 24
25
Inpatient/Outpatient Outpatient
Inpatient
No visit
Inpatient
Procedure
Informed consent,
screening
Admission
Study drug
administration
Discharge
Admission
Study drug
administration
Discharge
(a)
When the interval between the Period 1 dosing and the Period 2 dosing of the study drug is 3 weeks.
(b)
Day 1 is defined as the day of study drug administration in each of Period 1 and Period 2, with the day before Period 1
study drug administration referred to as Day −1 and the day before Period 2 study drug administration as Day 21.


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Study No. Vortioxetine-1001
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3.0
STUDY SCHEDULE
Screening 
period
Administration term
Period 1
Period 2
Treatment period
Washout 
period
Treatment period
Day1)
Screening 
-28 to -2
-1
1
2
3
4 9)
5～20
21
1
2
3
4 9)
Days from Period 1 study drug
administration2)
-
-
1
2
3
4
5～20
21
22
23
24
25
Informed consent
X
Demographic data, Height
X
Medical history, concurrent medical 
conditions, prior medication
X
Concomitant medication review
X
X
X
X
X
X
X
X
X
X
X
X
Adverse events monitoring3)
X
X
X
X
X
X
X
X
X
X
X
X
Physical examination4)
X
X
X
X
X
X
X
Body weight
X
X
Vital signs5)
X
X
X
X
X
X
X
12-lead ECG6)
X
X
X
Laboratory tests7)
X
X
X
X
X
Pharmacokinetic blood sampling8)
X
X
X
X
X
X
X
X
CYP2D6 genotyping blood sampling
X
Study drug administration
X
X
Hospitalization
In
Out
In
Out
1) Day 1 is defined as the day of study drug administration in each of Period 1 and Period 2, with the day before Period 1 
study drug administration referred to as Day −1 and the day before Period 2 study drug administration as Day 21.
2) When the interval between the Period 1 dosing and the Period 2 dosing of the study drug is 3 weeks.
3) AEs will be collected continuously from the time of signing of informed consent until the end of Period 2.
4) Physical examination will be performed at 24 and 72 hours postdose.
5) Vital signs will be measured at 24 and 72 hours postdose.
6) A 12-lead ECG will be performed at 72 hours postdose.
7) Immunology tests will be performed only at screening. Urine drug tests and pregnancy test will be performed only at 
screening, Day −1 and Day 21. Pregnancy test will be performed only in female subjects of childbearing potential.
8) Pharmacokinetic blood samples will be collected at Day 1 predose, 1, 2, 4, 6, 8, 10, 12, 14, 16, 24, 36, 48 and 72 hours 
postdose.
9) Or at discontinuation.


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Study No. Vortioxetine-1001
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4.0
INTRODUCTION
4.1
Background
Lu AA21004 (generic name: vortioxetine hydrobromide) is a 5-HT3, 5-HT7 and 5-HT1D receptor antagonist, 
5-HT1B receptor partial agonist, 5-HT1A receptor agonist, and 5-HT transporter (5-HTT) inhibitor. This 
novel antidepressant with a different profile from existing medications has been under development.
Depression is a mental disease mainly characterized by a depressed mood and a loss of interest or pleasure, 
and is additionally characterized by thought or concentration difficulties, an appetite decrease or increase, 
anxiety, a feeling of worthlessness or guilt, and thoughts related to suicide (suicidal ideation) as well as 
somatic symptoms including sleep disturbances and fatigability.[1][2]
The course of depression varies from only 1 episode in a lifetime to a lifelong disorder with recurrent 
episodes, and some patients suffer from long-term depressive symptoms despite treatments. Depression is 
therefore a significant mental and social burden and economic loss for not only patients but also their 
family, which treatment is necessary.[3]
Depression is mainly treated with pharmacotherapy and psychotherapy, and these treatments are selected 
according to the severity and pathological condition.[3] As pharmacotherapy in patients with moderate to 
severe depression, antidepressants such as selective serotonin reuptake inhibitors, serotonin-norepinephrine 
reuptake inhibitors , and noradrenergic and specific serotonergic antidepressants have been widely used. 
These antidepressants, however, have problems such as patients with inadequate response and adverse 
effects; therefore, development of an antidepressant with a novel profile can broaden treatment options and 
optimize treatment for depression.
From the results of the clinical pharmacology studies, following pharmacokinetic profiles were shown. 
Lu AA21004 was slowly absorbed with tmax of approximately 7 to 11 hours, and the absolute 
bioavailability of Lu AA21004 was approximately 75%. Lu AA21004 was extensively metabolized in the 
liver, and CYP2D6 was shown to be the primary enzyme in metabolism of Lu AA21004 to the major 
metabolite Lu AA34443. The t1/2z of Lu AA21004 was approximately 66 hours, and two-thirds of its 
metabolites were excreted in urine, and one-third were excreted in feces.Based on the results of the clinical 
studies, treatment with Lu AA21004 at doses of 5 to 20 mg/day was safe and effective. As of December
2017, Lu AA21004 has been approved for marketing as a drug for the treatment of MDD in countries 
including the U.S., Europe and Australia.
In Japan, Lu AA21004 is being developed for treatment of major depression disorder and has been 
evaluated in four clinical pharmacology studies of CPH-001, CPH-002, CPH-003, and CPH-004 conducted 
in healthy adults or elderly individuals; two placebo-controlled short-term studies of CCT-002 and 
CCT-003 conducted in patients with major depressive disorder; and a long-term extension study of 
OCT-001 in patients who completed CCT-003. In all these studies, Lu AA21004 was well-tolerated 
without major safety issues. Currently, CCT-004 study is being conducted as a short-term 
placebo-controlled study for major depressive disorder patients.
4.2
Rationale for This Study
In the dissolution tests, the different strengths (10 mg and 20 mg) of commercial formulations in Japan 
showed different dissolution behaviors and did not meet bioequivalence criteria. Consequently, this study 
has been planned to evaluate the bioequivalence between Lu AA21004 20 mg tablet and 2× Lu AA21004


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Study No. Vortioxetine-1001
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10 mg tablets in accordance with the Partial Revision of Guideline for Bioequivalence Studies of Generic 
Products.[4]
4.3
Benefits/Risks
Subjects in this study will not benefit from this study.
In the clinical pharmacology studies conducted to date in Japanese healthy adults or elderly individuals (ie,
CPH-001, CPH-002, CPH-003 and CPH-004) and clinical studies including Japanese major depressive 
disorder patients (ie, CCT-002, CCT-003 and OCT-001), Lu AA21004 at a dose of 2.5 to 40 mg was 
well-tolerated without major safety issues. Further detailed safety data on Lu AA21004 are provided in the 
Investigator’s Brochure.


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Study No. Vortioxetine-1001
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5.0
STUDY OBJECTIVES AND ENDPOINTS
5.1
Hypothesis
This study is planned on the basis of the following hypothesis:
Lu AA21004 20 mg tablet and 2× Lu AA21004 10 mg tablets will be shown to be bioequivalent.
5.2
Objectives
5.2.1
Primary Objective
To evaluate the bioequivalence between the Lu AA21004 20 mg tablet and the Lu AA21004 10 mg tablet 
after single dosing in Japanese healthy adults.
5.2.2
Secondary Objective
To evaluate the safety of a single dose of Lu AA21004 20 mg in Japanese healthy adults.
5.3
Endpoints
5.3.1
Primary Endpoints
●AUClast of Lu AA21004
●Cmax of Lu AA21004
5.3.2
Secondary Endpoints
●AUC∞, tmax, MRT, λz and t1/2z of Lu AA21004
●Adverse events, vital signs, 12-lead ECG, and laboratory test values


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6.0
STUDY DESIGN AND DESCRIPTION
6.1
Study Design
1)
Study design
This is a 2 × 2 crossover, open-label, comparative study in Japanese healthy adults to evaluate the 
bioequivalence between the Lu AA21004 20 mg tablet and the Lu AA21004 10 mg tablet after single 
dosing, and also to evaluate the safety of a single oral dose of Lu AA21004 20 mg.
Subjects will be randomized in a 1:1 ratio to either treatment sequence A or B.
This study consists of the screening period, Period 1, and Period 2. Subjects will receive one Lu AA21004 
20 mg tablet or two Lu AA21004 10 mg tablets on Days 1 of Period 1 and Period 2. The interval between 
the Period 1 dosing and the Period 2 dosing of the study drug will be at least 3 weeks.
If bioequivalence is not demonstrated with the initially planned number of subjects, an add-on subject study 
may be conducted in accordance with the “Partial Revision of Guideline for Bioequivalence Studies of 
Generic Products”.
2)
Planned number of subjects
The planned number of subjects is 28 (14 per treatment sequence). If an add-on subject study is conducted, 
the maximum number of additional subjects will be 28 (14 per treatment sequence).
6.2
Rationale for Study Design, Dose, and Endpoints
6.2.1
Rationale for Study Design
A 2-period, 2-treatment, cross-over design, which allows bioequivalence evaluation with minimal effect on 
inter-subject variation, was selected for this study in accordance with the Partial Revision of Guideline for 
Bioequivalence Studies of Generic Products.
Open-label design is adopted because the primary objective of the study is to evaluate the pharmacokinetic 
profile and to assess bioequivalence of Lu AA21004 tablets which is an objective indicator.
To eliminate all biases arising from arbitrary assignment of subjects, subjects will be randomized to receive 
the two treatments in either treatment sequence.
6.2.2
Rationale for Dose
Based on clinical data obtained so far, the clinical doses of Lu AA21004 for the treatment of major 
depression in Japanese patients are expected to be 10-20 mg/day, and 10 mg and 20 mg commercial tablets 
have been developed. For this study designed to evaluate the bioequivalence between Lu AA21004 20 mg
tablet and 2× 10 mg tablets, one Lu AA21004 20 mg tablet and two Lu AA21004 10 mg tablets will be 
used.
6.2.3
Rationale for Washout Period
In CPH-004 study (‘A Phase 1, Open-Label, Single-Dose, 2-Period Crossover Study to Assess 
Pharmacokinetics of Lu AA21004 and Effect of Food on the Pharmacokinetics after Oral Administration of
Lu AA21004 in Healthy Male Subjects’), in which 14 days interval between the Period 1 dosing and the 
Period 2 dosing of the study drug, plasma unchanged Lu AA21004 concentration at Period 2 predose was 


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higher than 11% of Cmax value of the Period 1 in the subject with the highest plasma unchanged
Lu AA21004 level in Period 1. Based on these results, it is set that the interval between the Period 1 dosing 
and the Period 2 dosing of the study drug will be at least 3 weeks in order for the plasma concentration at 
Period 2 predose to be decreased below 5% of Cmax in Period 1. Also, the Partial Revision of Guideline for 
Bioequivalence Studies of Generic Products recommends that there should be a washout period at least 5 
times longer than the apparent half-life of the investigational drug. The 3 weeks interval between the Period 
1 dosing and the Period 2 dosing of the study drug in this study is longer than 5 times of the apparent 
elimination half-life of Lu AA21004 (about 66 hours) thus meets this guideline.
6.2.4
Rationale for Endpoints
6.2.4.1
Rationale for Pharmacokinetic Endpoints
AUClast and Cmax of unchanged Lu AA21004 will be evaluated in accordance with the Partial Revision of
Guideline for Bioequivalence Studies of Generic Products. Since the apparent elimination half-life of 
unchanged Lu AA21004 is very long (about 66 hours), the plasma concentration of Lu AA21004 will be 
evaluated until 72 hours postdose, in accordance with "Partial Revision of Guideline for Bioequivalence 
Studies of Generic Products".
6.2.4.2
Rationale for Safety Endpoints
Safety measures will include those commonly used in clinical pharmacology studies (Adverse events, Vital 
signs, Clinical laboratory tests, and 12-lead ECG assessment).
6.2.5
Important Procedures based on Study Objectives: Time Points of the 
Procedures
Blood sample collection for pharmacokinetic evaluation is the important procedure in this study.
●For all time points of evaluation after administration of the study drug, the blood samples for
pharmacokinetic evaluation should be collected at a time as closest as possible to the scheduled time.
●If blood sample collection and other procedures are scheduled for the same time, blood sample 
collection should be prioritized, with implementation of other procedures within the allowable window 
(Appendix C).
●The priority order of procedures may be changed based on agreement between the investigator and the 
sponsor.
●Any unscheduled procedure required for emergency assessment for safety concerns must be prioritized
over any scheduled procedures.
6.3
Start and End/Completion of the Study
6.3.1
Definition of the Start of the Study
The time of the start of the entire study is defined as the time when the first subject has signed the informed 
consent form.


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6.3.2
Definition of the Completion of the Study
The time of the completion of the entire study is defined as the time when the last subject has completed 
the last planned or follow-up visit (or last contact related to a planned visit [possibly a telephone contact]), 
has been discontinued from the study, or has become lost to follow-up (ie, not reachable by the 
investigator).
6.3.3
Definition of Study Termination
Study termination for reasons other than safety are defined, such as below:
●When the study is terminated for non-safety reasons on the basis of certain findings on this study drug 
from nonclinical or other clinical studies with administration of this study drug (eg, findings on 
pharmacokinetics, pharmacodynamics, efficacy, or biological target).
●When the study is terminated for non-safety reasons on the basis of certain data that became available 
regarding another drug in the same class as this study drug or the same study methodology as this study.
●When the study is terminated for non-scientific and non-safety reasons, such as delay in subject
enrollment.
Study termination for safety reasons are defined, such as below:
●When the study is prematurely terminated because of unexpected safety concerns for subjects, raised 
from any clinical or nonclinical study of this study drug, another drug in the same class as this study 
drug, or the same study methodology as this study.
6.3.4
Criteria for Suspension or Termination of the Entire Study
6.3.4.1
Criteria for Suspension or Termination of the Study
The study will be temporarily suspended or prematurely terminated if one or both of the following criteria 
are met:
●New information or other evaluation has been obtained regarding the safety or efficacy of the study 
drug that alters the known risk/benefit profile of Lu AA21004, and the risk is no longer acceptable for 
subjects participating in the study.
●Significant violation of Good Clinical Practice (GCP) has occurred that compromises the ability to 
achieve the primary study objective or compromises the safety of subjects.
6.3.4.2
Procedures for Suspension or Termination of the Study
In the event that the sponsor, institutional review board (IRB), or regulatory authority elects to terminate or 
suspend the study or 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 the applicable study site 
during the course of termination or study suspension.


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6.3.5
Criteria for Suspension or Termination of a Study Site
6.3.5.1
Criteria for Suspension or Termination of a Study Site
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 is permitted by the contractual agreement.
6.3.5.2
Procedures for Suspension or Termination of Participation of a Study Site
In the event that the sponsor, 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 the applicable study site during the course of termination 
or study suspension.


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7.0
CRITERIA FOR SELECTION AND DISCONTINUATION OF SUBJECTS
All inclusion/exclusion criteria, including test results, need to be confirmed prior to the study drug 
administration in Period 1.
7.1
Inclusion Criteria
In order to be eligible for participation in this study, the subject must fulfill the following criteria:
1.
Be a healthy Japanese adult volunteer.
2.
Understand the contents of the study and be capable of providing written consent to participate in the 
study.
3.
Be willing to comply with all study procedures and restrictions.
4.
Aged between 20 and 45 years at the time of screening.
5.
Have a BMI of ≥18.5 and ≤24.9 (kg/m2) and a body weight of ≥50 kg at the time of screening.
6.
Be a extensive metabolizer (EM) based on CYP2D6 genotyping at the time of screening.
7.
A female subject of childbearing potential* with a non-sterilized male partner* must agree to routinely 
use appropriate contraception* during the study from the time of signing informed consent until 4 
weeks after last dosing of the study drug (*see Appendix B).
7.1.1
Rationale for the Inclusion Criteria
Inclusion criteria 1, 2, 3, 4 and 7:
These are the standard inclusion criteria used in clinical pharmacology studies in healthy adults. 
Inclusion criterion 5:
The body weight criterion is set because collecting 400 mL of whole blood from people weighing less 
than 50.0 kg has harmful effect on health, according to the “Law Enforcement Regulation on Securing a 
Stable Supply of Safe Blood Products” (Ministerial Ordinance No. 22 of the Ministry of Health and 
Welfare in 1956). [5]
The BMI criterion is set to correspond to the normal body weight range according to the diagnostic 
criteria for obesity proposed by the Japan Society for the Study of Obesity. [6]
Inclusion criterion 6:
This criterion is set because the “Partial Revision of Guideline for Bioequivalence Studies of Generic 
Products” recommends that, if polymorphism is involved in clearance of the test drug, bioequivalence 
studies of the drug should be conducted in subjects with greater clearance.
7.2
Exclusion Criteria
The subject meeting any of the following criteria will be excluded from the study:
1.
Has received any investigational drugs within 90 days before screening for this study.
2.
Previously received Lu AA21004 before participation in this study.
3.
Is an employee of the sponsor or the study site, or immediate family member, or is in a dependent 
relationship with a study site employee who is involved in the conduct of this study (eg, spouse, parent, 
child, sibling) or who may be coerced to provide consent.


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4.
Has uncontrolled, clinically relevant neurologic, cardiovascular, pulmonary, hepatic, renal, metabolic, 
gastrointestinal, or endocrine disease or other abnormality which may affect study participation or 
study results.
5.
Has a history of multiple episodes or severe allergies (eg, food, drug, latex allergy) or has had an 
anaphylactic reaction or significant intolerance to prescription drugs, OTC drugs, or foods.
6.
Has a positive pregnancy test at the time of screening or Day −1.
7.
Is a pregnant or lactating female.
8.
Has a positive urine drug test at the time of screening or Day −1.
9.
Has a history of drug abuse (defined as any illicit drug use) or has a history of alcohol dependence
within 2 years before the start of screening or is unwilling to agree to abstain from alcohol and drugs 
throughout the study.
10. Consumes 6 or more servings of caffeinated beverages (containing about 720 mg of caffeine or more) 
such as coffee, tea, cola, or energy drinks per day.
11. Is a smoker who smoked cigarettes or used nicotine-containing products (such as nicotine patch) 
within 6 months before the Period 1 study drug administration.
12. Used any of the excluded drugs, dietary products or foods during the period specified in the table in 
Section 7.3, or will need any of them during the study period.
13. Has any current or a history of gastrointestinal diseases that would be expected to influence the 
absorption of drugs (ie, malabsorption, esophageal reflux, peptic ulcer disease, erosive esophagitis, 
frequent [more than once per week] occurrence of heartburn), or any surgical intervention
(gastrectomy, cholecystectomy etc.).
14. Has a history of cancer.
15. Has a positive test result for any of the following at the time of screening: hepatitis B surface antigen
(HBsAg), hepatitis C virus (HCV) antibody, human immunodeficiency virus (HIV) antibody/antigen, 
serological test for syphilis.
16. Has poor peripheral venous access.
17. Has undergone whole blood collection of at least 200 mL within 4 weeks (28 days) or at least 400 mL 
within 12 weeks (84 days) prior to the start of Period 1 study drug administration.
18. Has undergone whole blood collection of at least 800 mL in total within 52 weeks (364 days) prior to 
the start of Period 1 study drug administration.
19. Has undergone blood component collection within 2 weeks (14 days) prior to the start of Period 1
study drug administration.
20. Has any clinically relevant abnormality in vital signs or 12-lead ECG at screening or on Day −1 of 
Period 1.
21. Has abnormal laboratory test values at screening or on Day −1 of Period 1 indicating clinically 
relevant underlying disease, or showing alanine aminotransferase (ALT) and/or aspartate 
aminotransferase (AST) >1.5×upper limit of normal (ULN).
22. Is unlikely to comply with the protocol requirements or is unsuitable as a subject of this study for any 
other reason in the opinion of the investigator or sub-investigator.


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7.2.1
Rationale for the Exclusion Criteria
Exclusion criterion 1:
This is set to secure the safety of the subjects, with reference to the “General Considerations for Clinical 
Trials”. [7]
Exclusion criteria 2, 3, 4, 6, 7, 8, 9, 10, 11, 12, 14, 15, 16 and 22:
These are set as the standard exclusion criteria used in clinical pharmacology studies in healthy adults
and also to secure the safety of the subjects.
Exclusion criteria 5, 20 and 21
These are set to secure the safety of the subjects.
Exclusion criterion 13:
This is set to secure the safety of the subjects, and also to avoid possible effects on pharmacokinetic 
assessments.
Exclusion criteria 17, 18 and 19:
These are set in line with “Law Enforcement Regulation on Securing a Stable Supply of Safe Blood 
Products” (Ministerial Ordinance No. 22 of the Ministry of Health and Welfare in 1956). [5]
7.3
Excluded Medications, Dietary Products, and Foods
Excluded medications, dietary products, and foods are shown in Table 7.a.
Use of the concomitant drugs (prescribed or over-the-counter [OTC] drugs) and consumption of dietary 
products, or foods listed in Table 7.a is prohibited from the specified time point until discharge in Period 2
to avoid possible effects on the safety and pharmacokinetics. However, the use will be allowed when 
judged by the investigator or sub-investigator to be necessary for certain reasons such as onset of an 
adverse event.
Table 7.a Excluded Medications, Dietary Products, and Foods
From Period 1 Day −28 through 
the end of the study period
From Period 1 Day -14 through 
the end of the study period
From Period 1 Day -3 through 
the end of the study period
All prescription drugs
Vitamins
Alcohol-containing products
All OTC drugs
Foods and beverages containing 
grapefruit, Sweetie, Seville orange, 
shaddock, or other citrus fruits that 
inhibit CYP3A4
Caffeine-containing products
Dietary products (ie, products 
containing St. John’s wort, ginseng, 
kava kava, ginkgo, Chinese traditional 
medicines, or melatonin)
Nicotine containing product
Subjects must be instructed not to take any medications including OTC products, without first consulting 
with the investigator or sub-investigator.
7.4
Other Restrictions/Diet, Fluid, Activity Control
7.4.1
Foods and Beverages
On the day before blood collection for laboratory tests, the subjects must finish the last meal by 21:00 and 
then fast until blood collection in the next morning. If the examination (eg, screening examination) is 


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performed in the afternoon, the blood collection will be performed after at least 10 hours of fasting from the 
last meal.
During hospitalization, the subjects take given meals and are not allowed to take any other food. Meal 
menus will be same for each period.
The subjects must fast from at least 10 hours before the study drug administration.
The subjects must fast until 4 hours after the study drug administration. If a meal and a test or blood 
collection are scheduled for the same time, the meal will be taken after the test/blood collection.
Excessive drinking and eating should be avoided during the entire study period.
Liquid intake will be prohibited from 1 hour before study drug administration until 4 hours postdose, with 
the exception of water (150 mL) to take the study drug.
7.4.2
Daily Activities
Smoking is not allowed during the study period.
Supine position is not allowed for 4 hours after the study drug administration, unless it is required for 
examinations. During hospitalization, light exercise will be performed for about 15 minutes a day.
Excessive exercise is not allowed during the study period. The subjects will be instructed not to change the 
lifestyle between Periods 1 and 2 and lead a regular life even during the washout period.
Blood donation is not allowed for at least 12 weeks after the final examination of this study. The 
investigator or sub-investigator will instruct the subjects on the prohibition of blood donation.
If a subject visits another medical institution during the study period, the subject should inform the 
investigator or sub-investigator in advance whenever possible. After the visit, the subject should inform the 
investigator or sub-investigator of the circumstance and treatment details. Also, the investigator or 
sub-investigator will contact the medical institution to notify that the subject is participating in this study.
7.5
Documentation of Subject Withdrawal Before Study Treatment
The investigator or sub-investigator will account for all subjects who signed informed consent. If a subject 
is withdrawn from the study before the study drug administration, the investigator or sub-investigator 
should complete the electronic case report form (eCRF) with the information.
The primary reason for subject withdrawal is recorded in the eCRF using the following categories:
●Death
●AE
●Screen failure (failed to meet the inclusion criteria or did meet the exclusion criteria) <specify reason>
●Protocol deviation
●Lost to follow-up
●Voluntary withdrawal <specify reason>
●Study terminated by sponsor
●Pregnancy


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●Sample size sufficient
●Other <specify reason >
Subject identification codes assigned to subjects who discontinued the study before the study drug 
administration should not be reused.
7.6
Criteria for Withdrawal of a Subject
The primary reason for subject withdrawal is recorded in the eCRF using the following categories by the 
investigator or sub-investigator. If the subject is withdrawn from the study before the study drug 
administration, see Section 7.5.
1.
Death
The subject has died during the study period.
Note: If a subject died during the study period, this event will be handled as a serious adverse event
(SAE). For the reporting procedures, see Section 10.2.9.3.
2.
Adverse event (AE)
The subject has experienced an AE that requires discontinuation from the study because continued 
participation imposes an unacceptable risk to the subject’s health or the subject is unwilling to 
continue because of the AE.

Liver function test abnormalities
If any liver function test abnormality meeting the criteria below occurs during study drug 
administration, the study drug administration will be immediately discontinued, and appropriate 
follow-up testing will be performed until the subject’s laboratory profile has returned to normal
or baseline (see Section 9.2.8.1):
–
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%).
3.
Protocol deviation
After the start of study drug administration, the subject is found not to fulfil the eligibility criteria or 
not to comply with protocol requirements, and continued participation in the study poses an 
unacceptable risk to the subject’s health.
4.
Lost to follow-up
The subject did not return to the study site, and attempts to contact the subject have been unsuccessful. 
The attempts to contact the subject should be recorded in the subject’s source document. 
5.
Voluntary withdrawal
The subject requested to withdraw from the study. The reason for withdrawal, if obtained, will be 
recorded in the eCRF.
Note: Every effort should be made to determine the reason for the withdrawal where possible 
(withdrawal due to an AE is not categorized as “Voluntary withdrawal”).


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6.
Discontinuation of the entire study by the sponsor
The sponsor has decided to terminate the study.
7.
Pregnancy of a subject
Note: If a subject was found to be pregnant, the subject will be immediately withdrawn from the study. 
For the procedures, see Appendix B.
8.
Other
Note: Specific details should be recorded in the eCRF.
7.7
Procedures for Discontinuation or Withdrawal of a Subject
The investigator or sub-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 7.6. 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 or sub-investigator. In addition, efforts should be made to perform all procedures scheduled for 
Early Termination Visit if possible.
7.8
Reserve Subjects
For Period 1, some of the subjects who are assessed to be eligible based on the screening results may stand 
by as reserve subjects. If a subject scheduled to receive the study drug does not receive the study drug for 
certain reasons before study drug administration in Period 1, a reserve subject may be enrolled in the study 
to replace that subject.
Subjects who discontinued after study drug administration will not be replaced by reserve subjects.
7.9
Replenishment of Subjects Whose Study Was Discontinued after Initiation of 
Study Drug Administration
If a subject who discontinued the study after the initiation of study drug administration, it is possible to 
newly incorporate another subject after consultation between the investigator and the sponsor.


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8.0
CLINICAL STUDY MATERIAL MANAGEMENT
8.1
Study Drug
[Drug products]
The study drugs are shown in Table 8.a.
Table 8.a Study Drug
Formulation
Active ingredient
Dosage form
Strength
Lu AA21004 10 mg tablet
1-[2-(2,4-Dimethylphenylsulfanyl)phenyl]
piperazine hydrobromide
Tablet
10 mg
Lu AA21004 20 mg tablet
20 mg
[Packaging]
Fifteen tablets of 10 mg of Lu AA21004 tablet or 20 mg of Lu AA21004 tablet are placed in one bottle and 
the bottle is placed in an outer box.
8.1.1
Study Drug Labeling
Each outer box of the study drug is labeled with the following information: statement that the drug is for 
clinical trial use only, sponsor’s name and address, study drug name, lot number, storage condition and 
expiration date.
8.1.2
Study Drug Storage and Management
The study drugs should be stored at room temperature (1 to 30C).
The study drugs must be kept in an appropriate, limited-access, secure place until it is used or returned to 
the sponsor, or its designee for destruction. The study drugs must be stored under the conditions specified 
on the label, and remain in the original container until dispensed.
8.1.3
Study Drug Blinding
This is an open-label study.
8.1.4
Accountability and Destruction of Sponsor-Supplied Drugs
The study drug storage manager will receive the written procedures for handling, storage, and management 
of the study drugs prepared by the sponsor, and will appropriately manage the drugs in accordance with the 
procedures. The written procedures will be provided to the investigator as well. The written procedures will 
specify the procedures that are necessary to ensure appropriate receipt, handling, storage, management, and 
dispensing of the sponsor-supplied drugs, as well as retrieval of unused drugs from the subjects and their 
return to the sponsor or destruction.
The study drug storage manager will promptly return unused drugs to the sponsor after the study is closed 
at the study site.


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9.0
STUDY PROCEDURES
The following sections describe the study procedures and data to be collected by the investigator or 
sub-investigator. For each procedure, subjects are to be assessed by the same investigator, sub-investigator 
or site personnel in principle. The study schedule is shown in Section 3.0.
9.1
Administrative Procedures
9.1.1
Informed Consent
Informed consent must be obtained from each subject prior to any study procedures. Informed consent 
requirements are described in Section 13.2.
9.1.1.1
Subject Identification Codes
A unique subject identification code will be assigned to each subject at the time that informed consent is 
explained. This subject identification code will be used throughout the study.
9.1.1.2
Assignment of Subjects
The subjects in ascending order of the subject identification code will be randomized to either treatment 
sequence in accordance with the assignment list.
Each subject will be assigned with a subject number (4 digit number). This subject number will be used by 
the study site and the pharmacokinetic laboratory to identify the pharmacokinetic samples. The test tubes 
for pharmacokinetic measurements sent to the laboratory must be labeled with the subject numbers. The 
laboratory will use the subject numbers when reporting the measurement results. These subject numbers
should not be replaced by the subject identification codes. If a subject is replaced by a reserve subject, the 
treatment sequence assigned to the original subject will be used for the reserve subject.
If a subject is withdrawn from the study after the start of study drug administration, and if a new subject is 
enrolled as a result of discussion between the investigator and the sponsor, the investigator will check with 
the sponsor regarding the newly enrolled subject’s subject number and treatment sequence.
The assignment list will be prepared by the sponsor, and provided to the investigator before the start of the 
study, while the sponsor will retain its copy. Information on the assignment will be kept in a secure place 
with limited access to authorized personnel.
9.1.2
Eligibility Assessment
Each subject will be assessed based on the inclusion and exclusion criteria shown in Section 7.0.
9.1.3
Medical History and Demographic Data
Demographic data to be obtained will include date of birth, sex, race (as reported by the subjects), height, 
body weight, caffeine and alcohol consumption, and smoking status.
Medical history to be obtained will include clinically relevant diseases and symptoms that resolved or 
disappeared within 1 year before signing of informed consent. Ongoing diseases and symptoms are 
regarded as concurrent medical conditions. Prior medication data to be obtained will include all drugs 
relevant to the eligibility criteria and safety assessments that stopped within 4 weeks (28 days) before 
signing of informed consent.


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9.1.4
Concomitant Medication
Concomitant medication is any drug given in addition to the study drug. These may be prescribed by a 
physician or obtained by the subject over the counter. Concomitant medication is not provided by the 
sponsor. Subjects will be asked whether they have used any medication other than the study drug (from 
signing of informed consent through the end of the study), and detailed use of all medications, including 
vitamins, OTC medications, and Chinese traditional medicines, must be recorded in the eCRF. The 
documentation for the drug should include its nonproprietary name, route of administration, start and end 
dates, and reason for use.
9.2
Study Procedures and Assessments
9.2.1
Physical Examination
Physical examination 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; (11) other.
9.2.2
Height and Body Weight
Height and body weight will be measured. Height (unit: cm) will be rounded to the nearest integer. Body 
weight (unit: kg) will be measured to the first decimal place.
9.2.3
BMI
BMI will be calculated using the following formula:
Metrics: BMI = Body weight (kg)/Height (m)2
BMI will be rounded to the first decimal place. Eligibility assessment will use the rounded BMI value.
9.2.4
Vital Signs
Vital signs will be measured in terms of body temperature (axillary), sitting blood pressure (systolic and 
diastolic) after resting for at least 5 minutes, and sitting pulse rate (beats per minute).
9.2.5
12-lead ECG
A 12-lead ECG will be recorded. Subjects will rest for at least 5 minutes in a supine position before each 
12-lead ECG.
The investigator or sub-investigator (or a specialist physician at the study site) will assess the ECG findings 
using one of the following categories: within normal or abnormal. If abnormal, then the investigator or 
sub-investigator (or a specialist physician at the study site) will determine whether the abnormality is 
clinically relevant. The time of 12-lead ECG will be recorded. The following parameters will be collected 
from the subject’s 12-lead ECG tracing, and recorded in the eCRF: heart rate, RR interval, PR interval, QT 
interval, QRS interval and QTcF interval (corrected using Fridericia’s formula).
9.2.6
Study Drug Administration
One Lu AA21004 20 mg tablet or two Lu AA21004 10 mg tablets will be orally administered on Days 1 in
Period 1 and Period 2. Subjects will fast from at least 10 hours before study drug administration until 4 


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hours postdose. With the exception of water (150 mL) to ingest the study drug, beverage intake will be 
prohibited from 1 hour before study drug administration until 4 hours postdose.
The dose and mode of administration are shown in Table 9.a.
Table 9.a Dose and Mode of Administration
Treatment 
sequence
Period 1
Period 2
Day 1 to Day 4
Day 5 to 21
Day 1 to Day 4
A
One Lu AA21004 20 mg tablet
Single dose under fasted condition(a)
Washout 
period
Two Lu AA21004 10 mg tablets
Single dose under fasted condition(a)
B
Two Lu AA21004 10 mg tablets
Single dose under fasted condition(a)
One Lu AA21004 20 mg tablet
Single dose under fasted condition(a)
(a) Oral administration with 150 mL of water under fasted condition (after fasting for at least 10 hours)
9.2.7
Assessment of AEs 
Assessment of AEs will be started at the time of signing of informed consent. For details of AE collection 
and related procedures, see Section 10.2.
9.2.8
Laboratory Test Procedures and Assessment
The following laboratory tests will be performed at the study site. Samples for laboratory tests will be 
collected after fasting for at least 10 hours according to the study schedule shown in Section 3.0. The blood 
collection volume is shown in Appendix D.
The investigator or sub-investigator will be responsible for assessing and retaining the results of laboratory 
tests. The investigator will retain a copy of the reference values of laboratory tests.
9.2.8.1
Laboratory Tests
Hematology tests
The following hematology tests will be performed.
Red blood cell count
White blood cell count and differential (lymphocytes, 
neutrophils, eosinophils , basophils, monocytes)
Hemoglobin
Hematocrit
Platelet count
Blood chemistry tests
The following blood chemistry tests will be performed.
Albumin
ALT
ALP
AST
GGT
Total bilirubin
Direct bilirubin
Total protein
Creatinine
Creatine kinase
BUN
Potassium
Sodium
Chloride
Calcium
Inorganic phosphorus
Glucose
Total cholesterol
HDL-cholesterol
LDL-cholesterol
Triglyceride
Uric acid


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Urinalysis
The following urinalysis will be performed.
pH
Specific gravity
Qualitative tests for protein, glucose, occult blood, 
urobilinogen, and ketone bodies
Other
Immunology tests
HBsAg, HCV antibody, HIV antigen/antibody, serological test for syphilis
Urine drug tests
Phencyclidine, benzodiazepines, cocaine, antihypnotic agents, cannabinoids, morphine-like narcotics, barbiturates, and 
tricyclic antidepressants
Pregnancy test (Only in female subjects of childbearing potential)
Urinary human chorionic gonadotropin
Note: For immunology and urine drug tests, the investigator or sub-investigator will directly return the results to the subjects. 
The sponsor will not receive detailed results of these tests for the subjects (including reserve subjects) selected to be 
given the study drug, but will check the overall test results only (ie, presence or absence of positive results).
If subjects experienced ALT or AST >3×ULN, follow-up laboratory tests (at a minimum, ALP, 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.
For liver function test abnormalities as SAEs, the criteria for reporting are described in Section 10.2.9.4, 
and the criteria for withdrawal of the subject are described in Section 7.6.
9.3
Samples for Pharmacokinetics and CYP2D6 Polymorphism Assessments
The samples for pharmacokinetic analysis and CYP2D6 genotyping will be collected at the study site 
according to the study schedule shown in Section 3.0. The blood collection volume is shown in Appendix
D. The samples for measurements are specified in Table 9.b.
Table 9.b Samples for Measurements
Name of sample
Matrix
Purpose of sample collection
Mandatory/
Optional
Pharmacokinetic sample
Plasma
Pharmacokinetic analysis
Mandatory
CYP2D6 genotyping sample
Whole blood
CYP2D6 genotyping
Mandatory


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9.3.1
Pharmacokinetic Measurements
The pharmacokinetic parameters will be calculated from plasma concentrations of unchanged Lu AA21004
in the pharmacokinetic analysis set.
Term
Definition
AUClast
Area under the plasma concentration-time curve from time 0 to time of the last quantifiable concentration
Calculation Formula:Time 0 is taken as t1, and the last time point when the concentration exceeding the 
lower limit of quantification (Clast) is taken as tn(= tlast)
AUClast=





n
i
i
i
i
i
t
t
C
C
2
1
1
)
(
2
)
(
AUC∞
Area under the plasma concentration-time curve from time 0 to infinity
Calculation Formula:AUC∞=AUClast + Clast/λz
Cmax
Maximum plasma concentration (Observed value)
tmax
Time to reach Cmax (Observed value)
t1/2z
Apparent elimination half-life
MRT∞,ev
Mean residence time
Calculation Formula:MRT∞,ev=AUMC∞/AUC∞
MRTlast,ev
The average residence time from 0 hour to time of the last quantifiable concentration
Calculation Formula:MRTlast,ev=AUMClast/AUClast
λz
Apparent elimination rate constant
AUMC∞
Area under the first moment time curve from 0 hour to infinity
Calculation Formula:AUMC∞=AUMClast + Clast×tlast/λz + Clast/λz
2
AUMClast
Area under the first moment time curve from 0 hour to final determinable (By the trapezoidal method)
9.3.1.1
Pharmacokinetic Samples
The blood samples for pharmacokinetic analysis of unchanged Lu AA21004 will be collected according to 
Table 9.c.
The time of each sample collection will be recorded in the source documents and eCRF.
Table 9.c Collection of Pharmacokinetic Samples (in Both Period 1 and Period 2)
Analyte
Matrix
Time points of sample collection
Unchanged Lu AA21004
Plasma
Predose, 1, 2, 4, 6, 8, 10, 12, 14, 16, 24, 36, 48 and 72 hours postdose
9.3.2
CYP2D6 Genotyping
Blood samples for CYP2D6 genotyping will be collected.
9.4
Hospitalization Period
In both Period 1 and Period 2, the subjects will be admitted to the study site on the day before study drug
administration, and hospitalized for 5 days. During the hospitalization period, the investigator or 
sub-investigator will perform assessments and observations of the subjects according to the study schedule 
shown in Section 3.0. The subjects will be discharged from the study site, after no clinically relevant 
abnormalities in the physical condition was confirmed based on physical examination in 4 days after study 
drug administration in both Period 1 and Period 2.


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10.0
ADVERSE EVENTS
10.1
Definitions and Elements of AEs
An AE is defined as any untoward medical occurrence in a clinical trial subject who provided informed 
consent to participate in a study; it does not necessarily have to have a causal relationship with the 
treatment (including the study drug) or study participation.
An AE can therefore be any unfavorable and unintended sign (including clinically significant abnormal 
laboratory values), symptom, or disease temporally associated with the study participation whether or not it 
is considered related to the treatment (including the study drug) or study procedures.
An untoward finding generally may:
●Indicate a new diagnosis or unexpected worsening of a pre-existing condition. (Intermittent 
manifestations of a pre-existing condition or underlying disease should not be considered 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 or sub-investigator for any reason.
Diagnoses vs. signs and symptoms:
●Each event should be recorded to represent a single diagnosis. Accompanying signs (including 
abnormal laboratory values or ECG findings) or symptoms should NOT be recorded as additional AEs. 
If a diagnosis is unknown, sign(s) or symptom(s) should be recorded appropriately as an AE(s).
Laboratory values and ECG findings:
●Changes in laboratory values or ECG parameters are only considered to be AEs if they are judged to be 
clinically significant by the investigator or sub-investigator (ie, if a certain action or intervention is 
required or if the investigator or sub-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 or 
finding is not considered an intervention. In addition, repeated or additional noninvasive testing for 
verification, evaluation or monitoring of an abnormality is not considered an intervention.
●If abnormal laboratory values or ECG findings are the result of pathology for which there is an overall 
diagnosis (eg, increased creatinine in renal failure), only the diagnosis should be reported 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 AEs. Baseline examinations , observations and 
evaluations (eg, laboratory tests, ECG, X-rays etc.) should NOT be recorded as AEs unless related to 
study procedures. However, if the subject experiences worsening of a concurrent medical condition 
(worsening after signing of informed consent), the worsening should be recorded appropriately as an 
AE. The investigator or sub-investigator should ensure that the event term recorded captures the 
worsening in the condition (eg, “worsening of…”).


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●If a subject has a pre-existing episodic concurrent medical condition (eg, asthma, epilepsy), any 
occurrence of an episode should only be captured as an AE if the condition becomes more frequent, 
serious or severe in nature. The investigator or sub-investigator should ensure that the AE term recorded 
captures the worsening in the condition from baseline (eg, “worsening of…”).
●If a subject has a pre-existing chronic concurrent medical condition (eg, cataract, rheumatoid arthritis), 
worsening of the condition should only be recorded as an AE if occurring to a greater extent to that 
which would be expected. The investigator or sub-investigator should ensure that the AE term recorded 
captures the worsening in the condition (eg, “worsening of…”).
Worsening of AEs:
●If an AE which occurred before study drun administration was worsened after initial dosing of the study 
drug or an AE was worsened after any change in study treatment, the worsening should be recorded as a 
new AE. The investigator or sub-investigator should ensure that the AE term recorded captures the 
worsening in the condition (eg, “worsening of…”).
Changes in severity of AEs:
●If the subject experiences changes in severity of an AE that are not related to a change in study 
treatment, the event should be captured once with the maximum severity recorded.
Preplanned procedures (surgeries or therapies):
●Preplanned procedures (surgeries or therapies) that were scheduled prior to signing of informed consent 
are not considered AEs. However, if a preplanned procedure is performed early (eg, as an emergency) 
due to a worsening of the pre-existing condition, the worsening of the condition should be recorded as 
an AE. Complications resulting from any planned surgery should be reported as AEs.
Elective procedures (surgeries or therapies):
●Elective procedures performed where there is no change in the subject’s medical condition (surgeries or 
therapies) should not be recorded as AEs, but should be documented in the subject’s source documents. 
Complications resulting from an elective surgery should be reported as AEs.
Overdose:
●An overdose is defined as the known intentional or accidental administration of the study drug or 
ingestion by the subject in an amount higher than the protocol-specified amount. Whether the episode is 
an overdose or not will be determined by the investigator or sub-investigator after discussion with the 
sponsor.
●All episodes of overdose (irrespective of occurrence of AEs) will be recorded on the Overdose page of 
the eCRF, so that important safety information on overdose can be entered into the database in a 
consistent manner. AEs associated with overdose will be recorded on the AE page of the eCRF as 
described in Section 10.0.
●Serious AEs (SAEs) associated with overdose will be reported according to the procedures described in 
Section 10.2.9.
●If an overdose of the study drug has occurred, the subject should be treated according to the symptoms.


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10.1.1
SAEs
An SAE is defined as any untoward medical occurrence that:
1.
Results in death.
2.
Is life threatening.

The term “life threatening” refers to an event in which the subject was at risk of death at the time 
of the event; it does not refer to an event that hypothetically might have caused death if it were 
more severe.
3.
Requires inpatient hospitalization or prolongation of existing hospitalization.
4.
Results in persistent or significant disability/incapacity.
5.
Leads to a congenital anomaly.
6.
Is a significant medical event that satisfies any of the following:

May require intervention to prevent the 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.aTakeda Medically Significant AE List
Term
Acute respiratory failure/Acute respiratory distress 
syndrome (ARDS)
Hepatic necrosis
Acute liver failure
Torsade de pointes / ventricular fibrillation / ventricular 
tachycardia
Anaphylactic shock
Acute renal failure
Malignant hypertension
Pulmonary hypertension
Convulsive seizure (including convulsion and epilepsy)
Agranulocytosis
Aplastic anaemia
Pulmonary fibrosis (including interstitial pneumonia)
Neuroleptic malignant syndrome / malignant hyperthermia
Spontaneous abortion / stillbirth and fetal death
Toxic epidermal necrolysis / Oculomucocutaneous 
syndrome (Stevens-Johnson syndrome)
Confirmed or suspected transmission of infectious agent by a 
medicinal product
Confirmed or suspected endotoxic shock
Note: Terms identified on the Medically Significant AE List represent the broad medical concepts to be considered as 
“Significant Medical Events” satisfying SAE reporting requirements.
10.2
AE-related Procedures
10.2.1
Assessment of the Severity of AEs
The severity of AEs is categorized/defined 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.
10.2.2
Assessment of the Causality of AEs
The causality of each AE to the study drug will be assessed using the following categories/definitions:


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Related:
An AE that follows a reasonable temporal sequence from administration of the study drug (including the 
course after withdrawal of the drug), or for which possible involvement of the drug is at least a 
reasonable possibility, ie, the relationship cannot be ruled out, although factors other than the relevant 
study drug (control 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 the relevant study 
drug (control drug) and/or that can reasonably be explained by other factors, such as underlying disease, 
concurrent disease, concomitant medication, or concurrent treatment.
10.2.3
Relationship to Study Procedures
A causal relationship between the adverse event and study procedures will be assessed.
The causal relationship is assessed as “Related” if the investigator or sub-investigator considers that there is 
reasonable possibility that an event is due to a study procedure. Otherwise, the causality is assessed as “Not 
Related”
10.2.4
Start Date
The start date of an AE is the date on which signs or symptoms of the event were first noted by the subject 
or the investigator or sub-investigator.
10.2.5
Stop Date
The stop date of an AE is the date on which the event resolved (including resolution with sequelae) or the 
subject died.
10.2.6
Intermittent or Continuous AEs
Episodic AEs (eg, headache) or those which occur repeatedly over a period of consecutive days are 
“intermittent”. All other events are “continuous.”
10.2.7
Action Taken with Study Drug

Drug withdrawn – the study drug administration was stopped due to the particular AE.

Dose not changed – the particular AE did not require a change in the study drug dose.

Unknown –it has not been possible to determine what action has been taken after the AE onset.

Not Applicable – the study drug administration was stopped for a reason other than the particular 
AE, eg, the study has been terminated, the subject died, dosing with study medication was 
already stopped before the onset of the AE, or an AE was seen prior to administration of the 
study drug.
10.2.8
Outcome

Recovered/Resolved – Subject returned to first assessment status with respect to the AE.

Recovering/Resolving – the severity is lowered by one or more categories; the 
diagnosis/sign/symptom has almost disappeared; the abnormal laboratory value improved but has 
not returned to the normal range or to baseline; the subject died not directly from the AE while 
the AE was “recovering/resolving”.

Not recovered/Not resolved – there is no change in the diagnosis/sign/symptom; the severity of 
the diagnosis/sign/symptom or laboratory value at last observation is worse than that at onset; the 


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event is an irreversible congenital anomaly; the subject died not directly from the AE while the 
AE was “Not recovered/not resolved”.

Resolved with sequelae – the subject recovered from the acute AE with remaining permanent or 
clinically significant impairment (eg, recovered from a cardiovascular accident but with 
persisting paralysis).

Fatal – the AE was directly related to the death.

Unknown – the course of the AE could not be determined at the end of the subject’s participation 
in the study for certain reasons such as hospital change or residence change.
10.2.9
Collection and Reporting of AEs, SAEs and Liver Function Test 
Abnormalities
10.2.9.1
Collection Period
Collection of AEs (AEs, SAEs, AEs of special interest, and liver function test abnormalities) will be started 
at the time of the subject’s signing of informed consent and continued until the end of Period 2. For 
subjects decided to be withdrawn from the study before initial dosing of the study drug, AEs will be 
collected until that time point.
10.2.9.2
AE Reporting
At each study visit, the investigator or sub-investigator will assess whether any subjective AEs have 
occurred. A neutral question, such as “How have you been feeling since your last visit?” will be asked, and 
subjects will report any AEs occurring during the study. Subjects experiencing any SAE before first dosing 
of the study drug must be monitored until the SAE resolves and clinically relevant laboratory abnormalities 
return to baseline or there is a satisfactory explanation for the observed change. Non-serious AEs occurring 
before first dosing of the study drug, whether or not related to the study procedure, need not to be 
followed-up for the purposes of the protocol.
All subjects experiencing AEs after first dosing of the study drug, whether or not related to the study drug, 
must be monitored until the symptoms resolve and clinically relevant laboratory abnormalities return to 
baseline or until there is a satisfactory explanation for the observed change. All AEs will be documented on 
the AE page of the eCRF, whether or not the investigator or sub-investigator concludes that the event is 
related to the study drug. The following information will be documented for each event:
●Event term
●Start and stop date and time
●Frequency
●Severity
●Investigator’s or sub-investigator’s opinion of the causal relationship to the study drug (related or not 
related).
●Investigator’s or sub-investigator’s opinion of the causal relationship to study procedures, including 
details of the suspected procedure
●Action taken with the study drug


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●Outcome of event
●Seriousness
●Timing of occurrence (after study drug administration)
10.2.9.3
SAE Reporting
When an SAE occurs during the AE collection period, it should be reported according to the following 
procedure:
An SAE should be reported by the investigator or sub-investigator to the sponsor within 1 business day of 
the first onset or notification of the SAE, along with any relevant information. The investigator should 
submit the detailed SAE Form to the sponsor within 10 calendar days. The information should be 
completed as fully as possible and contain the following at a minimum:
●A brief description of the event and the reason why the event is categorized as serious
●Subject identification code
●Investigator’s or sub-investigator’s name
●Name of the study drug
●Causality assessment
Any SAE spontaneously reported to the investigator or sub-investigator after the end of the AE collection 
period should be reported to the sponsor if considered related to the subject’s study participation.
Reporting of SAEs occurring before initial dosing of the study drug will follow the procedure described for 
SAEs occurring during study treatment.
Follow-up of SAEs
If information not available at the time of the first report becomes available on a later date, the investigator 
or sub-investigator should complete a follow-up SAE form copy or provide other written documentation 
and promptly submit it to the sponsor. Copies of any relevant data from the hospital notes (eg, ECG, 
laboratory test values, discharge summary, postmortem results) should be sent to the sponsor, if requested.
All SAEs should be followed by the investigator or sub-investigator until resolution or final outcome 
confirmation of the event.
10.2.9.4
Reporting of Liver Function Test Abnormalities
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 
10.2.9.3. The investigator or sub-investigator will contact the study monitor and investigate the subject 
details and possible alternative etiologies (eg, acute viral hepatitis A or B, other acute liver disease). 
Follow-up tests described in Section 9.2.8 will also be performed.
10.2.10
Safety Reporting to Investigators, IRBs, and Regulatory Authorities
The sponsor will be responsible for reporting all serious unexpected suspected adverse reactions (SUSARs) 
and any other SAEs for expedited reporting to the regulatory authorities, investigators, and IRBs. Relative 
to the first awareness of the event by/or further provision to the sponsor or sponsor’s designee, SUSARs 


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will be submitted to the regulatory authorities as expedited reports within 7 days for fatal and 
life-threatening events and 15 days for other serious events, unless otherwise required by national 
regulations. The sponsor will also perform expedited reporting of other significant safety information that 
may greatly affect the current benefit-risk profile of the study drug or require a change to the study 
treatment or overall conduct of the study. The study site also will forward a copy of all expedited reports to 
the IRB.


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11.0
STATISTICAL METHODS
11.1
Statistical and Analytical Plans
A statistical analysis plan (SAP) will be prepared and finalized prior to database lock. This document will 
provide further details regarding the definition of analysis sets, analysis variables and analysis methodology 
to address all study objectives.
Analysis will be performed after database lock using the data obtained so far. Also, when an additional 
study is performed, another analysis will be performed using combined data of the first study with data of 
the additional study.
11.1.1
Analysis Sets
In this study, two kinds of analysis sets are defined: pharmacokinetics analysis set and safety analysis set.
The sponsor will verify the validity of the definitions of the analysis sets as well as the rules for handling 
data prior to database lock.
11.1.1.1
Safety Analysis Set
The “safety analysis set” will be defined as all the subjects who received at least one dose of the study drug.
11.1.1.2
Pharmacokinetics Analysis Set
The “pharmacokinetics analysis set” is a subset of all treated subjects who had no major protocol violations, 
have completed the minimum element of the protocol, and had evaluable pharmacokinetic data.
11.1.2
Analysis of Demographic and Other Baseline Characteristics
Demographic and other baseline characteristics will be summarized using the pharmacokinetic analysis set 
and the safety analysis set.
11.1.3
Pharmacokinetic Analysis
1.
Endpoints and their analytical method
[Endpoint]
Primary endpoints
●AUClast of Lu AA21004
●Cmax of Lu AA21004
Secondary endpoints
●AUC∞, tmax, MRT, λz and t1/2z of Lu AA21004
[Analytical method]
The following analyses will be based on the pharmacokinetic analysis set.
1)
Plasma concentration and pharmacokinetic parameters
The descriptive statistics for plasma concentration of Lu AA21004 will be provided for each formulation 
(Lu AA21004 20 mg tablet and 10 mg tablet) by visit and the mean and standard deviation of plasma 


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concentration will be plotted for both formulations on the same graph. The descriptive statistics for PK
parameter will be provided for each formulation.
2)
Bioequivalence assessment
The bioequivalence of Lu AA21004 20 mg tablet and 2× 10 mg tablets is evaluated.
The log-transformed (natural log) PK parameters AUClast and Cmax of Lu AA21004 will be analysed 
separately using analysis of variance (ANOVA) with dosing formulation, treatment sequence, 
administration period as fixed effects and the two-sided 90% confidence interval (CIs) for the differences
between the formulations and between the periods will be provided. The log-transformed (natural log) PK 
parameters AUC∞, MRT, λz and t1/2z of Lu AA21004 and tmax of Lu AA21004 will be analysed separately
using ANOVA in the same manner (confidence coefficient 90%, 95%).
Bioequivalence for Lu AA21004 will be assessed based on "Guideline for Bioequivalence Studies of 
Generic Products". Formulations are considered to be bioequivalent if any of the following criteria are met.
If bioequivalence cannot be verified, it will be considered adding additional subjects.
●For the primary endpoints (AUClast and Cmax), the two-sided 90% CIs of the difference in the mean 
values of logarithmic parameters to be assessed between two treatments is within the acceptable range 
of ln(0.80) to ln(1.25).
3)
Methods of data transformation and handling of missing data
For plasma concentrations, values below the lower limit of quantification will be treated as Zero. Subjects 
with any missing pharmacokinetic data for some reasons (e.g., discontinuation, inadequate measurement) 
will be excluded from the pharmacokinetic analysis set, however, the PK parameters, such as t1/2z, will be 
calculated, as far as possible.
4)
Significance level and confidence coefficient
●Significance level: 5% (one-sided test)
●Confidence coefficient : 90% (two-sided)
: 95% (two-sided)
11.1.4
Safety Analysis
The following analyses will be based on the Safety Analysis Set.
11.1.4.1
Adverse Events
A treatment-emergent adverse event (TEAE) is defined as an adverse event whose date of onset occurs on 
or after the start of the study drug. Analyses will be performed for the following TEAE parameters by 
formulation. TEAEs will be coded using MedDRA dictionary. The frequency distribution will be provided 
using system organ class and preferred term for each formulation.
●All TEAE
●Drug-related TEAEs
●Intensity of TEAEs


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●Intensity of drug-related TEAEs
●TEAEs leading to study drug discontinuation
●Serious TEAEs
11.1.4.2
Assessment of Laboratory Data
For continuous variables, the observed values and the changes from baseline will be summarized for each 
formulation at each visit using descriptive statistics. Case plots will also be presented for the observed 
values. For categorical variables, shift tables showing the number of subjects in each category at baseline 
and each post-baseline visit will be provided for each formulation.
11.1.4.3
Vital Signs
For continuous variables, the observed values and the changes from baseline will be summarized for each 
formulation at each visit using descriptive statistics.
11.1.4.4
Other Safety Parameters
The following analyses will be provided for 12-lead ECGs. For continuous variables, the observed values 
and the changes from baseline will be summarized for each formulation at each visit using descriptive 
statistics. Case plots will also be presented for the observed values. For categorical variables, shift tables 
showing the number of subjects in each category at baseline and each post-baseline visit will be provided 
for each formulation.
11.2
Determination of Sample Size
Planned number of subjects is 28 (14 per treatment sequence).
The planned sample size was calculated based upon the analysis of logarithmically transformed AUClast and 
Cmax. If the 90% CIs for the ratios of Lu AA21004 20 mg tablets and 2× Lu AA21004 10 mg tablets (2×
Lu AA21004 10 mg tablets/Lu AA21004 20 mg tablet) geometric mean value of AUClast and Cmax are both 
be within the limits of 80.00% to 125.00%, bioequivalence can be verified. It is hypothesize that there is no 
interaction between dosing formulation and administration period at AUClast and Cmax. Based on data from 
previous studies, the largest estimate of the within-subject coefficient of variation (CV) of AUClast and Cmax
were up to 9.5% and 14.3% and a sample size of 24 would then provide a power of 99.8% and 91.5% for 
each correctly concluding bioequivalence even if the true ratio is 1.1. Given that the 90% CIs for the ratio 
of the geometric means for AUClast and Cmax must both be contained in 80.00% to 125.00% in order to 
conclude bioequivalence between the two treatments, 24 subjects provided an overall power of at least 
91.3%, assuming that the two endpoints AUClast and Cmax are independent.
Taking into account possible occurence of dropouts, planned number of subjects is 28.
In case bioequivalence cannot be demonstrated with the number of subjects initially planned due to the 
insufficiency of the number of subjects, an add-on subject study will be conducted in accordance with the 
Partial Revision of Guideline for Bioequivalence Studies of Generic Products, if applicable. The maximum 
number of additional subjects in the add-on subject study is 28 (14 per treatment sequence), which is 
determined based on study feasibility, but is not on statistical consideration.


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12.0
QUALITY CONTROL AND QUALITY ASSURANCE
12.1
Study-Site Monitoring Visits
Monitoring visits to the study site will be made by the sponsor or its designee (contract research 
organization [CRO]) periodically during the study to ensure that all aspects of the protocol are followed in 
the conduct of the study. 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 the study site 
will guarantee access to source documents by the sponsor or its designee and the IRB.
Study documents will be subject to reviews by the sponsor or its designee (as long as blinding is not 
jeopardized), including the Investigator’s Binder, study drug, subjects’ medical records, and informed 
consent documentation, for verification that the study is appropriately conducted in accordance with the 
protocol. In addition, consistency between eCRFs and related source documents will be checked. It is 
important that the investigator, sub-investigator and other study personnel are available during the 
monitoring visits and that sufficient time is devoted to the process.
12.2
Protocol Deviation
The investigator or sub-investigator may deviate and change from the protocol only for medically 
unavoidable reasons, for example to eliminate an immediate hazard to study subjects, without a prior 
written agreement with the sponsor or a prior approval from the IRB. In the event of a deviation or change, 
the investigator should notify the sponsor and the head of the study site of the deviation or change as well 
as its reason in a written form, and then retain a copy of the written form. When necessary, the investigator 
may consult and agree with the sponsor on a protocol amendment. If the protocol amendment is appropriate, 
the amendment proposal should be submitted to the head of the study site as soon as possible and an 
approval from the IRB should be obtained.
The investigator or sub-investigator should document all protocol deviations.
12.3
Quality Assurance Audits and Regulatory Agency Inspections
The study site also may be subject to quality assurance audits by the sponsor or designees. In this 
circumstance, the sponsor-designated auditor will contact the site in advance to arrange an auditing visit. 
The auditor may ask to visit the facilities where laboratory samples are collected, where the medication is 
stored and prepared, and any other facility used during the study. In addition, there is the possibility that 
this study may be inspected by regulatory agencies, including those of foreign governments (eg, the Food 
and Drug Administration [FDA], the United Kingdom Medicines and Healthcare products Regulatory 
Agency [MHRA], Pharmaceuticals and Medical Devices Agency of Japan [PMDA]). If the study site is 
contacted for an inspection by a regulatory body, the sponsor should be notified immediately. The 
investigator and the head of the study site will guarantee access for quality assurance auditors to all study 
documents as described in Section 12.1.


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13.0
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 
International Council for Harmonization of Technical Requirements for Pharmaceuticals for Human Use 
(ICH) Harmonized 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 A.
13.1
IRB Approval
IRBs must be constituted according to the applicable local requirements of each participating region. The 
sponsor or designee will require documentation noting all names and titles of members who make up the 
respective IRB. If any member of the IRB has direct participation in this study, written notification 
regarding his or her absence from voting must also be obtained.
The sponsor or 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 form must be obtained and submitted to the 
sponsor or designee before commencement of the study. 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. Until the site receives the notification, no protocol activities 
including screening may occur.
The study site must adhere to all requirements stipulated by its 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.
13.2
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 describes 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 further explains 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 the subject is free to withdraw at any time without giving a 
reason and without prejudice to further medical care.


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The investigator is responsible for the preparation, content, and IRB approval of the informed consent form. 
The informed consent form must be approved by both the IRB and the sponsor prior to use.
The informed consent form must be written in a language fully comprehensible to the prospective subject. 
It is the responsibility of the investigator or sub-investigator to explain the detailed elements of the 
informed consent form 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: (1) opportunity to inquire about details of the study and (2) ample time to 
decide whether or not to participate in the study. If the subject has decided to participate in the study, then 
the informed consent form must be signed and dated by the subject before participation in the study. The 
subject should be instructed to sign using their legal names, not nicknames, using blue or black ballpoint 
ink. The investigator or sub-investigator must also sign and date the informed consent form prior to subject 
entering into the study.
The investigator or sub-investigator will retain the original signed informed consent form. The investigator 
or sub-investigator will document the date the subject signs the informed consent in the subject’s medical 
record. A copy of the signed informed consent form shall be given to the subject.
If the informed consent form is revised, the investigator or sub-investigator will obtain re-consent of the 
subject in the same manner as the initial informed consent. The date of the re-consent will be recorded in 
the subject’s medical record, and a copy of the revised informed consent form shall be given to the subject.
13.3
Subject Confidentiality
The sponsor and designees affirm and uphold the principle of the subject’s right to protection against 
invasion of privacy. Throughout this study, a subject’s source data will only be linked to the sponsor’s 
clinical trial database or documentation via a subject identification code. As permitted by all applicable 
laws and regulations, limited subject attributes such as sex, age, or date of birth may be used to identify the 
subject and check the validity of the subject’s identification code.
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, MHRA, PMDA), 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 13.2).
Copies of any subject source documents may be provided to the sponsor only after removal of the subject’s 
personally identifiable information (ie, subject name, address, and other personal identifiers not recorded
on the subject’s eCRF).
13.4
Publication, Disclosure, and Clinical Trial Registration Policy
13.4.1
Publication and Disclosure
The investigator will provide the sponsor with all results and all data obtained 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 


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agreement, public disclosure related to the protocol or study results (including publicly accessible websites) 
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. The investigator or sub-investigator 
needs to obtain a prior written approval from the sponsor to publish any information from the study 
externally such as to a professional association.
13.4.2
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 Takeda-sponsored 
interventional clinical trials conducted 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 study site’s name, city, country, and recruiting status will be registered and available for public 
viewing.
13.4.3
Clinical Trial Results Disclosure
Takeda will post the results of clinical trials on ClinicalTrials.gov or other publicly accessible websites, as 
required by Takeda Policy/Standard, applicable laws and/or regulations.
13.5
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 required locally, the sponsor or sponsor’s designee will take out an insurance 
policy to prepare for possible compensation for health injury to study subjects. Subjects with health injury 
will be compensated and treated as stated in the study site agreement. If the investigator or sub-investigator 
has questions regarding compensation, he or she should contact the sponsor or sponsor’s designee.


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14.0
STUDY ADMINISTRATIVE INFORMATION AND RELATED INFORMATION
14.1
Study Administrative Information
14.1.1
Study-related Contact Information
Each study site will be provided with a list of contact information (Protocol Annex 1).
14.1.2
Investigator Agreement
Each study site will be provided with the investigator agreement form.
14.1.3
Study-related Roles and Responsibilities
Each study site will be provided with a list of contact information (Protocol Annex 1).
14.1.4
List of Abbreviations
Term
Definition
5-HT
5-hydroxytryptamine
5-HTT
5-hydroxytryptamine transporter
AE
adverse event
ALP
alkaline phosphatase
ALT
alanine aminotransferase
AST
aspartate aminotransferase
BMI
body mass index
BUN
blood urea nitrogen
CYP
cytochrome P450
EM
extensive metabolizer
FDA
Food and Drug Administration
FSH
follicle stimulating hormone
GCP
Good Clinical Practice
GGT
gamma-glutamyl transpeptidase
HDL
high-density lipoprotein
ICH
International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use
INR
international normalized ratio
LDL
low-density lipoprotein
MedDRA
Medical Dictionary for Regulatory Activities
MHRA
Medicines and Healthcare products Regulatory Agency
OTC
over-the-counter
PMDA
Pharmaceuticals and Medical Devices Agency
SAE
serious adverse event
SUSARs
serious unexpected suspected adverse reactions
TEAE
treatment emergent adverse event


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15.0
DATA MANAGEMENT AND RECORD KEEPING
The full details of procedures for data management will be documented in the Data Management Plan. AEs 
and medical history including concurrent medical conditions will be coded using the Medical Dictionary 
for Regulatory Activities (MedDRA). Drugs will be coded using the World Health Organization (WHO) 
Drug Dictionary.
15.1
eCRF
The investigator or sub-investigator will complete eCRFs for all subjects who signed the informed consent 
form.
The sponsor or its designee will supply the study site with access to eCRFs. The sponsor will make 
arrangements to train appropriate site staff in the use of the eCRF. The eCRFs are used to transmit the 
information collected in the conduct of this study to the sponsor and regulatory authorities. eCRFs must be 
completed in English. Data are transcribed directly onto eCRFs.
After completion of the entry process, computer logic checks will be run to identify any inconsistent dates, 
missing data, questionable values, or other erroneous entries. Queries may be issued by the sponsor or its 
designees and will be answered by the study site.
Changes or corrections to the eCRF are to be recorded in an audit trail designed to capture the data before 
and after the change/correction, person making the change/correction, date of the change/correction, and 
reason for the change/correction.
The investigator will review the eCRFs for completeness and accuracy, and electronically sign the 
designated page of the eCRFs. The investigator will take full responsibility for the accuracy and 
authenticity of all data entered on the eCRFs.
The following data will not be recorded directly into the eCRFs.
●Laboratory test results
●Drug concentration measurement results
After the study database lock, any change, correction, or addition to the entries in the eCRF by the 
investigator or sub-investigator will require the eCRF change/correction record (Data Clarification Form). 
The investigator will review the Data Clarification Form for completeness and accuracy, and electronically 
sign the form.
The sponsor or its designee will review the eCRFs for accuracy and completeness at the study site during 
periodic visits. The sponsor or its designee will review the subjects’ 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 any information in the eCRFs should not be made available by the investigator or sub-investigator to 
third parties, except for authorized representatives of appropriate governmental health or regulatory 
authorities, without written permission of the sponsor.
15.2
Record Retention
To allow for inspections or audits by the regulatory authorities and the sponsor or its designees, the 
investigator and the head of the study site will agree to retain the following documents, including the 
records stipulated in Section 15.1 and study-specific documents. These documents include the subject 


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screening log, medical records, original signed and dated informed consent forms, electronic copies of 
eCRFs including the audit trail, and drug accountability record.
The investigator and the head of the study site are required to retain essential documents until the day 
specified as 1) or 2) below, whichever comes later. However, if the sponsor requests a longer time period 
for retention, the head of the study site will discuss the record retention period and method with the 
sponsor.
1.
The day on which marketing approval of the study drug is obtained (or, if the drug development is 
discontinued, 3 years after the date of receipt of its notification).
2.
3 years after the date of early termination or completion of the study.
In addition, the investigator and the head of the study site will retain the essential documents until the time 
of receipt of a sponsor-issued notification stating that the retention is no longer required.


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16.0
REFERENCES
[1]
Nakane Y, Arima K. Cause and Symptoms of Depression. Journal of Practical Pharmacy.
2000;51(2):826-34.
[2]
American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders, Fourth 
Edition. Translated by Takahashi S, Ono Y, Someya T. Igaku-Shoin. 2004.
[3]
Guideline for Clinical Evaluation of Antidepressants (Notification No. 1116-1 of the Evaluation and 
Licensing Division, Pharmaceutical and Food Safety Bureau, dated November 16, 2010).
[4]
Guideline for Bioequivalence Studies of Generic Products (Notification No. 0229-10 of the 
Evaluation and Licensing Division, Pharmaceutical and Food Safety Bureau, dated February 29,
2012).
[5]
Act on Securing a Stable Supply of Safe Blood Products (Ministerial Ordinance No. 22 of the 
Ministry of Health and Welfare, dated June 25, 1956).
[6]
Japan Society for the Study of Obesity. Diagnostic Criteria for Obesity 2011. Journal of Japan Society 
for the Study of Obesity. 2011;10(Suppl).
[7]
General Considerations for Clinical Trials (ICH-E8 guideline; Notification No. 380 of the Evaluation 
and Licensing Division, Pharmaceutical and Medical Safety Bureau, dated April 21, 1998).


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17.0
APPENDICES
Appendix A
Responsibilities of the Investigator
1.
Conduct the study appropriately in accordance with the protocol and GCP, while respecting the human 
rights, safety, and wellbeing of the subjects.
2.
When part of important tasks related to the study are delegated to the sub-investigator or clinical 
research coordinator, prepare the lists of tasks to be delegated and responsible personnel, submit the 
lists to the head of the study site in advance and receive approval.
3.
Prepare a written informed consent form, and update it as needed.
4.
Confirm the contents of the clinical study agreement.
5.
Provide the sub-investigators, clinical research coordinators, and other study staff with sufficient 
information about the protocol, drugs, and each person’s tasks, and give guidance and supervision.
6.
Screen subjects who meet the requirements of the protocol, provide explanation about the study in 
writing, and obtain written consent.
7.
Assume responsibility for all medical judgments related to the study.
8.
Ensure in collaboration with the head of the study site that sufficient medical treatment will be 
provided to subjects for all clinically significant adverse events related to the study, throughout and 
after the period of the subject’s participation in the study.
9.
If a subject is being treated at any other medical institution or department, with agreement of the 
subject, notify the physician of the other medical institution or department of the subject's 
participation in the study, as well as completion/discontination of the study in writing, and document 
such records.
10. If expedited reporting of SAEs etc. is required, immediately notify the head of the study site and the 
sponsor in writing.
11. Determine the need for unblinding of emergency key code for a subject in case of emergency (only for 
double-blind studies).
12. Prepare correct and complete eCRFs, electronically sign them, and submit them to the sponsor.
13. Check and confirm the entries in the eCRFs completed by the sub-investigator or transcribed from 
source data by the clinical research coordinator, electronically sign them, and submit them to the 
sponsor.
14. Discuss any proposals from the sponsor, including protocol amendments.
15. Notify the head of the study site of the completion of the study in writing.


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Appendix B
Pregnancy and Contraception
Female subjects and their male partners
From signing informed consent, throughout the duration of the study and for 4 weeks after last dose of the 
study drug, female subjects of childbearing potential* who are sexually active with a non-sterilized male 
partner** must use a method of contraception as described below.
In addition, they must be advised not to donate ova during this period.
* A woman of childbearing potential, i.e. fertile, following menarche and until becoming post-menopausal 
unless permanently sterile. Permanent sterilization methods include hysterectomy, and bilateral 
oophorectomy. A post-menopausal state is defined as no menses for 12 months without an alternative 
medical cause. A high follicle stimulating hormone (FSH) level in the post-menopausal range (FSH 
>40 IU/L) may be used to confirm a post-menopausal state in younger women (eg, those <45 year old) or 
women who are not using hormonal contraception or hormonal replacement therapy. However, in the 
absence of 12 months of amenorrhea, a single FSH measurement is insufficient.
** Sterilized males should be at least one year post-bilateral vasectomy and have confirmed that they have 
obtained documentation of the absence of sperm in the ejaculate or have had bilateral orchidectomy.
Appropriate contraception are defined as the following methods;
●Combined (estrogen and progestogen) hormonal contraception associated with inhibition of ovulation: 
Combined pill.
●Intrauterine device (IUD).
●Intrauterine Contraceptive System (IUS)
●Bilateral tubal occlusion.
●Vasectomised partner (provided that partner is the sole sexual partner of the trial participant and that the 
vasectomised partner has received medical assessment of the surgical success).
●True sexual abstinence, only if this is in line with the preferred and usual lifestyle of the subject. True 
abstinence is defined as refraining from heterosexual intercourse during the entire period of the study, 
from 1 month prior to the first dose and 4 weeks after last dose.
●Male condom
Subjects will be provided with information on appropriate methods of contraception as part of the subject 
informed consent process and will be asked to sign a consent form stating that they understand the 
requirements for avoidance of pregnancy, donation of ova during the course of the study and up to 4 weeks 
after last dose of the study drug.
During the course of the study, pregnancy tests (Urinary human chorionic gonadotropin) will be performed 
only for female subjects of childbearing potential and all subjects will receive continued guidance with 
respect to the avoidance of pregnancy as part of the study procedures. Such guidance should include a 
reminder of the following:
●contraceptive requirements of the study


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●assessment of subject compliance through questions such as

Have you used the contraception consistently and correctly since the last visit?

Have you forgotten to use contraception since the last visit?

Are your menses late (even in female subjects with irregular or infrequent menstrual cycles a 
pregnancy test must be performed if the answer is “yes”)

Is there a chance you could be pregnant?
In addition to a negative pregnancy test (Urinary human chorionic gonadotropin) at Screening, female 
subjects of childbearing potential must also have confirmed menses in the month before first dosing (no 
delayed menses), a negative pregnancy test prior to receiving any dose of study medication. In addition, 
subjects must also have a negative pregnancy test (Urinary human chorionic gonadotropin) for one day 
before receiving the investigational drug at Period 2.
Pregnancy
If any subject is found to be pregnant during the study she should be withdrawn and any sponsor-supplied 
drug should be immediately discontinued.
If the female subject agrees to the primary care physician (obstetrician and gynecologist) being informed, 
the investigator or sub-investigator should notify the primary care physician that she was participating in a 
clinical study at the time she became pregnant and provide details of the study drug the subject received.
If any subject is found to be pregnant during the study or up to 4 weeks after last dose of the study drug, all 
pregnancies will be followed up to final outcome and the outcome, including any premature termination,
Investigator or sub-investigator must report to the sponsor using the pregnancy form under the agreement
of the female subjects. An evaluation after the birth of the child will also be conducted.


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Appendix C
Time Windows for Study Procedures
For both Period 1 and Period 2
Test/Observation Item
Scheduled Time
Allowable Time Window
Screening examination (a)
Screening (Day -28 to Day -2)
Same as left
Physical examination
Day -1, Day 21
Between 24 hours before 
administration and just before dosing 
on Day 1
24 and 72 hours postdose
±1 hour
Body weight
Day -1
Same as left
Vital signs
Day -1, Day 21
Same as left
24 and 72 hours postdose
±1 hour
12−lead ECG
72 hours postdose
±1 hour
Laboratory tests
Day -1, Day 21
Same as left
72 hours postdose
±1 hour (b)
Pharmacokinetic blood sampling
Predose on Day 1
Between rising and just before dosing 
on Day 1
1, 2, 4, 6, 8, 10, 12, 14, and 16 hours postdose
±5 minutes
24, 36, 48, and 72 hours postdose
±10 minutes
Day -1 is defined as the day before the Period 1 study drug administration. Day 21 is defined as the day before the Period 2
study drug administration. Day 1 is defined as the day of study drug administration in each of Period 1 and Period 2.
(a)
Height, physical examination, body weight, vital signs, 12-lead ECG, laboratory test and blood collection for CYP2D6 
genotyping
(b)
For urinalysis, from the time of rising up to +1 hour of the scheduled time.


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Appendix D
Blood Volume Table
The total blood collection volume collected from each subject is shown below;
Sample Type
Sample 
Volume per 
each time
(mL)
Number of Samples
Total Volume 
(mL)
Screening
period
Period 1
Period 2
Laboratory tests
Hematology
2
2
2
1
10
Serum chemistry
7
2
2
1
35
Immunology
10
1
0
0
10
CYP2D6 genotyping
5
1
0
0
5
PK assessment
4
0
14
14
112
Total volume
172 mL

SAP_001.pdf: 
 
 
Title: A Randomized, Open-Label, 2×2 Crossover Phase 1 Study to Evaluate the 
Bioequivalence of Single Oral Dose of Lu AA21004 20 mg tablet and 2× Lu AA21004  
10 mg tablets in Healthy Adult Subjects 
 
NCT Number: NCT03437564 
Statistical analysis plan Approve Date: 14 Jun-2018 
 
Certain information within this statistical analysis plan has been redacted (ie, specific 
content is masked irreversibly from view with a black/blue bar) to protect either 
personally identifiable information or company confidential information. 
 
This may include, but is not limited to, redaction of the following: 
 
Named persons or organizations associated with the study. 
 
Patient identifiers within the text, tables, or figures or in by-patient data listings. 
 
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. 
 
If needed, certain appendices that contain a large volume of personally identifiable 
information or company confidential information may be removed in their entirety if it 
is considered that they do not add substantially to the interpretation of the data (eg, 
appendix of investigator’s curriculum vitae). 
 
Note; This document was translated into English as the language on original version 
was Japanese. 


1.0 
TITLE PAGE 
 
STATISTICAL ANALYSIS PLAN 
STUDY NUMBER: Vortioxetine-1001 
A Randomized, Open-Label, 2×2 Crossover Phase 1 Study to Evaluate the Bioequivalence of 
Single Oral Dose of Lu AA21004 20 mg tablet and 2×Lu AA21004 10 mg tablets in Healthy 
Adult Subjects 
A Bioequivalence Study of the Lu AA21004 20 mg and 2×10 mg Tablets 
PHASE 1 
Version: 2 
Date: 14 June 2018 
 
 
 
 
Prepared by: 
 
 
 
Based on: 
Protocol Version: Amendment 1 
Protocol Date:  15 February 2018 
 
 
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


Vortioxetine-1001 
Page 2 of 28
Statistical Analysis Plan Version 2 
14 June 2018
 
CONFIDENTIAL 
1.1 
Approval Signatures 
Study Title: 
A Randomized, Open-Label, 2×2 Crossover Phase 1 Study to Evaluate 
the Bioequivalence of Single Oral Dose of Lu AA21004 20 mg tablet 
and 2×Lu AA21004 10 mg tablets in Healthy Adult Subjects 
A Bioequivalence Study of the Lu AA21004 20 mg and 2×10 mg Tablets 
 
Approvals: 
PPD


Vortioxetine-1001 
Page 3 of 28
Statistical Analysis Plan Version 2 
14 June 2018
 
CONFIDENTIAL 
2.0 
TABLE OF CONTENTS 
 
1.0 
TITLE PAGE .......................................................................................................................1 
1.1 
Approval Signatures.......................................................................................................2 
2.0 
TABLE OF CONTENTS .....................................................................................................3 
List of In-Text Tables ................................................................................................................4 
List of In-Text Figures ...............................................................................................................4 
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 ..................................................................................................8 
5.1 
PRIMARY ENDPOINTS ..............................................................................................8 
5.2 
SECONDARY ENDPOINTS ........................................................................................8 
6.0 
DETERMINATION OF SAMPLE SIZE ............................................................................9 
7.0 
METHODS OF ANALYSIS AND PRESENTATION .....................................................10 
7.1 
General Principles ........................................................................................................10 
7.1.1 
Study Definitions ...................................................................................................10 
7.1.2 
Definition of Study Days .......................................................................................10 
7.1.3 
Definition of Study Visit Windows .......................................................................10 
7.2 
Analysis Sets ................................................................................................................11 
7.3 
Disposition of Subjects ................................................................................................12 
7.3.1 
Study Information ..................................................................................................12 
7.3.2 
Screen Failures .......................................................................................................12 
7.3.3 
Subject Eligibility ..................................................................................................12 
7.3.4 
Disposition of Subjects ..........................................................................................14 
7.3.5 
Protocol Deviations and Analysis Sets ..................................................................14 
7.4 
Demographic and Other Baseline Characteristics .......................................................15 
7.5 
Medical History and Concurrent Medical Conditions .................................................16 
7.6 
Medication History and Concomitant Medications .....................................................16 
7.7 
Study Drug Exposure and Compliance ........................................................................16 
7.8 
Efficacy Analysis .........................................................................................................16 
7.8.1 
Primary Efficacy Endpoint(s) ................................................................................16 
7.8.2 
Secondary Efficacy Endpoint(s) ............................................................................16 
7.8.3 
Additional Efficacy Endpoint(s) ............................................................................16 
7.8.4 
Statistical/Analytical Issues ...................................................................................16 
7.9 
Pharmacokinetic/Pharmacodynamic Analysis .............................................................18 


Vortioxetine-1001 
Page 4 of 28
Statistical Analysis Plan Version 2 
14 June 2018
 
CONFIDENTIAL 
7.9.1 
Pharmacokinetic Analysis ......................................................................................18 
7.9.2 
Pharmacodynamic Analysis ...................................................................................20 
7.10 
Other Outcomes ...........................................................................................................20 
7.11 
Safety Analysis ............................................................................................................21 
7.11.1 Adverse Events ......................................................................................................21 
7.11.2 Clinical Laboratory Evaluations ............................................................................24 
7.11.3 Vital Signs ..............................................................................................................25 
7.11.4 12-Lead ECGs ........................................................................................................26 
7.11.5 Other Observations Related to Safety ....................................................................26 
7.12 
Interim Analysis ...........................................................................................................26 
7.13 
Changes in the Statistical Analysis Plan ......................................................................27 
8.0 
REFERENCES ..................................................................................................................28 
 
LIST OF IN-TEXT TABLES 
LIST OF IN-TEXT FIGURES 
Figure  4.a 
Schematic of Study Design ......................................................................................7 
 
 


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3.0 
LIST OF ABBREVIATIONS 
[This may be copied from the protocol and include all abbreviations used in the SAP] 
AE 
adverse event 
ALP 
alkaline phosphatase 
ALT 
alanine aminotransferase 
BMI 
body mass index 
BUN 
blood urea nitrogen 
CYP 
cytochrome P450 
ECG 
electrocardiogram 
GGT 
γ-glutamyl transferase 
HDL 
high-density lipoprotein 
ICH 
International Conference on Harmonisation 
LDH 
lactate dehydrogenase 
LDL 
low-density lipoprotein 
MedDRA 
Medical Dictionary for Regulatory Activities 
PT 
Preferred Term 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SOC 
System Organ Class 
 
 


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4.0 
OBJECTIVES 
4.1 
Primary Objectives 
To evaluate the bioequivalence of a single oral dose of a Lu AA21004 20 mg tablet in 
comparison with two Lu AA21004 10 mg tablets in Japanese healthy adult subjects 
4.2 
Secondary Objectives 
To assess the safety of a single oral dose of Lu AA21004 20 mg in Japanese healthy adult 
subjects 
4.3 
Additional Objectives 
Not applicable. 
4.4 
Study Design 
This is a 2×2 crossover, open-label, comparative study in Japanese healthy adults to evaluate 
the bioequivalence of a single oral dose of the Lu AA21004 20 mg tablet and the Lu 
AA21004 10 mg tablet, and also to evaluate the safety of a single oral dose of Lu AA21004 
20 mg. 
Subjects will be randomized in a 1:1 ratio to either treatment sequence A or B. 
This study consists of the screening period, Period 1, and Period 2. Subjects will receive one 
Lu AA21004 20 mg tablet or two Lu AA21004 10 mg tablets on Day 1 of Period 1 and 
Period 2. The interval between the Period 1 dosing and the Period 2 dosing of the study drug 
will be at least 3 weeks. 
If the bioequivalence is not demonstrated with the initially planned number of subjects, an 
add-on subject study may be conducted in accordance with the “Partial Revision of Guideline 
for Bioequivalence Studies of Generic Products”. 
 
 


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Period 
Screening period 
Administration term 
Period 1 
Period 2 
Day(b) 
-28 to -2 
-1 
1 
2 to 3 
4 
5 to 20 
21 
1 
2 to 3 
4 
Days from the 
Period 1 study drug 
dosing(a) 
- 
- 
1 
2 to 3 
4 
5 to 20 
21 
22 
23 to 24 
25 
Inpatient/Outpatient Outpatient 
Inpatient 
No 
visit 
Inpatient 
Procedure 
Informed consent, 
screening 
Admission 
Study drug 
administration 
 
Discharge 
 
Admission 
Study drug 
administration 
 
Discharge 
(a) When the interval between the Period 1 dosing and the Period 2 dosing of the study drug is 3 weeks. 
(b) Day 1 is defined as the day of study drug administration in each of Period 1 and Period 2, with the day prior to Period 1 
study drug administration referred to as Day -1 and the day prior to Period 2 study drug administration as Day 21. 
Figure 4.a 
Schematic of Study Design 
 
Treatment 
sequence 
Period 1 
Period 2 
Day 1 to 4 
Day 5 to 21(a) 
Day 1 to 4 
A 
One Lu AA21004 20 mg tablet 
Single dose under fasted condition 
Washout 
Two Lu AA21004 10 mg tablets 
Single dose under fasted condition 
B 
Two Lu AA21004 10 mg tablets 
Single dose under fasted condition 
One Lu AA21004 20 mg tablet 
Single dose under fasted condition 


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5.0 
ANALYSIS ENDPOINTS 
5.1 
PRIMARY ENDPOINTS 
AUClast of unchanged Lu AA21004 
Cmax of unchanged Lu AA21004 
5.2 
SECONDARY ENDPOINTS 
AUC∞, tmax, MRT, λz, and t1/2z of unchanged Lu AA21004 
Adverse events, vital signs, 12-lead ECG, and laboratory test values 
 


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6.0 
DETERMINATION OF SAMPLE SIZE 
Planned number of subjects is 28 (14 for each sequence). 
The planned sample size was calculated based upon the analysis of logarithmically 
transformed AUClast and Cmax. If the 90% CIs for the ratios of Lu AA 21004 20 mg tablets 
and 2×Lu AA 21004 10 mg tablets (2×Lu AA21004 10 mg tablets/ Lu AA21004 20 mg 
tablet) geometric mean value of AUClast and Cmax are both within the limits of 80.00% to 
125.00%, the bioequivalence can be verified. It is hypothesize that there is no interaction 
between dosing formulation and administration period at AUClast and Cmax. Based on data 
from previous studies, the largest estimate of the within-subject coefficient of variation (CV) 
of AUClast and Cmax were 9.5% and 14.3%, and a sample size of 24 would then provide a 
power of 99.8% and 91.5% for each to correctly conclude the bioequivalence even if the true 
ratio is 1.1. Given that the 90% CIs for the ratio of the geometric means for AUClast and 
Cmax must both be contained in 80.00% to 125.00% in order to conclude the bioequivalence 
between the two treatments, 24 subjects provided an overall power of at least 91.3%, 
assuming that the two endpoints AUClast and Cmax are independent. 
Taking into account possible occurrence of dropouts, planned number of subjects is 28. 
In case the bioequivalence cannot be demonstrated with the number of subjects initially 
planned due to the insufficiency of the number of subjects, an add-on subject study will be 
conducted in accordance with the “Partial Revision of Guideline for Bioequivalence Studies 
of Generic Products”, if applicable. The maximum number of additional subjects in the add-
on subject study is 28 (14 per sequence), which is determined based on study feasibility, but 
is not on statistical consideration. 
 


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7.0 
METHODS OF ANALYSIS AND PRESENTATION 
7.1 
General Principles 
7.1.1 Study Definitions 
• 
Treatment-emergent adverse event (TEAE): An adverse event which occurs on or after 
the start of study drug 
• 
Pretreatment event (PTE): An adverse event which occurs on or after informed consent 
to participate in a study but prior to administration of study drug 
• 
Descriptive statistics: Number of subjects, mean, standard deviation, maximum, 
minimum, and quartiles 
• 
Coefficient of variation (CV) (%): Standard deviation / mean × 100 
• 
Dose: 
- 
Lu AA21004 10 mg tablet 
- 
Lu AA21004 20 mg tablet 
• 
Treatment sequence: 
- 
A (One Lu AA21004 20 mg tablet => Two Lu AA21004 10 mg tablets) 
- 
B (Two Lu AA21004 10 mg tablets => One Lu AA21004 20 mg tablet) 
7.1.2 Definition of Study Days 
• 
Study Time (hour): The date/time of tests/observation/evaluation − the date/time of first 
dose of the study drug 
(rounded to 3 decimal places) 
 
• 
Study Day (day): The day before the first dose of the study drug will be defined as Day 
−1, and the day of the first dose of the study drug as Day 1. 
7.1.3 Definition of Study Visit Windows 
For all variables of test/observation/evaluation, evaluable data entered in the CRF according 
to the scheduled Study Time will be used as data. 
 
 


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7.2 
Analysis Sets 
• 
Safety analysis set: All subjects who received at least one dose of treatment period study 
drug 
• 
Pharmacokinetic analysis set: All subjects who received at least one dose of treatment 
period study drug and did not have any of the major protocol deviations listed below, 
meet the minimum requirements of the protocol, and had measurable pharmacokinetics. 
- 
Violation of inclusion criteria: Subjects who did not meet inclusion criteria #1, #4, 
#5, or #6 
- 
Violation of exclusion criteria: Subjects who met exclusion criteria #1, #4, #6, #7, #8, 
#9, #12, #13, #14, #15, or #21 
- 
Use of excluded medications: Subjects who took drugs (prescription or over-the-
counter drugs) listed in Table 7.a “Excluded Medications, Nutritional Supplements 
and Food” in section 7.3 of the protocol within the designated period 
- 
Violation of administration dose: Subjects who were given the study drug at a dose 
other than the dose specified in the protocol 
- 
Violation of dosing interval: Subjects who were given the Period 2 study drug 
without a washout period of at least 21 days after Period 1 study drug administration 
- 
Violation of dosing conditions: Subjects who were not given single oral doses under 
fasted condition in the morning (fasting of at least 10 hours prior to study drug 
administration) for all study drugs 
- 
Violation of pharmacokinetic measurement: Subjects who have one or more missing 
data or data determined to be non-evaluable for plasma concentration of Lu 
AA21004 
 
 


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7.3 
Disposition of Subjects 
7.3.1 Study Information 
Analysis Set: 
All Subjects Who Signed the Informed Consent Form 
Analysis 
Variable(s): 
Date First Subject Signed Informed Consent Form 
MedDRA Version 
SAS Version Used for Creating the Datasets 
Analytical 
Method(s): 
Study information shown in the analysis variables section will be provided. 
(1) 
Study Information 
 
7.3.2 Screen Failures 
Analysis Set: 
All Subjects Who Did Not Enter the Treatment Period 
Analysis 
Variable(s): 
[  ] shows categories (hereinafter, the same) 
Age (years) 
 
Gender 
[Male, Female] 
Analytical 
Method(s): 
The following summaries will be provided for the above analysis 
variable(s). 
(1) 
Frequency distributions for counting values and descriptive statistics 
for continuous variables 
 
7.3.3 Subject Eligibility 
Analysis Set: 
All Subjects Who Signed the Informed Consent Form 
Analysis 
Variable(s): 
Eligibility Status 
[Eligible for Entrance into the 
Treatment Period, Not Eligible for 
Entrance into the Treatment Period] 
Primary Reason for Subject Not 
Being Eligible 
[Adverse Event, Death, Lost to 
Follow-up, Pregnancy, Significant 
Protocol Deviation, Sample Size 
Sufficient, Screening Failure, Study 
Termination, Voluntary Withdrawal, 
Other] 
Analytical 
Method(s): 
The following summaries will be provided for the above analysis 
variable(s). 
When calculating percentages for the primary reasons for subject not being 
eligible, the total number of ineligible subjects will be used as the 


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denominator. 
 
(1) 
Frequency Distributions 
 
 
 


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7.3.4 Disposition of Subjects 
Analysis Set: 
All Subjects Who Entered the Treatment Period 
Analysis 
Variable(s): 
Study Completion Status 
[Completed All Planned Study Visits, 
Did Not Complete All Planned Study 
Visits] 
Reason for Discontinuation of 
Study Visits 
[Adverse Event, Death, Lost to 
Follow-up, Pregnancy, Significant 
Protocol Deviation, Study 
Termination, Voluntary Withdrawal, 
Other] 
Analytical 
Method(s): 
Frequency distributions will be provided by group and overall. When 
calculating percentages for the reasons for discontinuation, the total number 
of subjects who did not complete all planned study visits will be used as the 
denominator. 
 
(1) 
Frequency Distributions 
 
7.3.5 Protocol Deviations and Analysis Sets 
7.3.5.1 Protocol Deviations 
Analysis Set: 
All Subjects Who Entered the Treatment Period 
Analysis 
Variable(s): 
Significant Protocol Deviation 
[Entry Criteria, Concomitant 
Medication, Procedure Not Performed 
Per Protocol, Study Medication/Dose, 
Withdrawal Criteria, Major GCP 
Violations] 
Analytical 
Method(s): 
Frequency distributions will be provided by group and overall. 
A number of subjects with protocol deviation and frequency distributions of 
each deviation according to the above categories will be provided. A subject 
who has several deviations will be counted once in each appropriate 
category (overlapping). 
(1) 
Frequency Distributions 
 
 
 


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7.3.5.2 Analysis Sets 
Analysis Set: 
All Subjects Who Entered the Treatment Period 
Analysis 
Variable(s): 
Handling of Subjects 
[Categories are based on the 
specifications in Subject Evaluability 
List] 
Inclusion/Exclusion of Analysis 
Sets 
 
Safety Analysis Set 
[Included] 
Pharmacokinetic Analysis Set 
[Included] 
Analytical 
Method(s): 
Frequency distributions will be provided by group for (1), and by group and 
overall for (2). 
For (1), a subject who corresponds to several categories will be counted 
once in each appropriate category (overlapping). 
 
(1) 
Frequency distributions for handling of subjects in each analysis set 
(2) 
Frequency distributions for number of subjects included in each 
analysis set 
 
7.4 
Demographic and Other Baseline Characteristics 
Analysis Set: 
Safety Analysis Set 
Pharmacokinetic Analysis Set 
Analysis 
Variable(s): 
Age (years) 
 
Gender 
[Male, Female] 
Height (cm) 
 
Weight (kg) 
 
BMI (kg/m2) 
 
Smoking Classification 
[The subject has never smoked, The 
subject is a current smoker, The 
subject is an ex-smoker] 
Alcohol Classification 
[Everyday, 2 to 3 Days a Week, 2 to 3 
Days a Month, Never] 
Caffeine Classification 
[Yes, No] 
Analytical 
Method(s): 
Frequency distributions will be provided by group and overall. 
(1) 
Frequency distributions for counting values and descriptive statistics 
for continuous variables 


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7.5 
Medical History and Concurrent Medical Conditions 
Not applicable. 
7.6 
Medication History and Concomitant Medications 
Not applicable. 
 
7.7 
Study Drug Exposure and Compliance 
Analysis Set: Safety Analysis Set 
Analysis 
Variable(s): 
Number of Times the Study Drug was Taken 
[1, 2] 
Analytical 
Method(s): 
 
Frequency distributions will be provided by group and overall. 
(1) 
Frequency distributions for counting values 
 
7.8 
Efficacy Analysis 
Not applicable. 
7.8.1 Primary Efficacy Endpoint(s) 
Not applicable. 
7.8.2 Secondary Efficacy Endpoint(s) 
Not applicable. 
7.8.3 Additional Efficacy Endpoint(s) 
Not applicable. 
7.8.4 Statistical/Analytical Issues 
7.8.4.1 Adjustments for Covariates 
Not applicable. 
7.8.4.2 Handling of Dropouts or Missing Data 
Missing test results and data determined to be non-evaluable according to this document will 
not be used for hypothesis testing and estimations. 
For plasma concentrations and laboratory test results, values below the lower limit of 
quantification will be treated as zero when calculating the descriptive statistics. For 
laboratory test results, values above the upper limit of quantification will be treated as the 
upper limit value when calculating the descriptive statistics. 


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7.8.4.3 Multicenter Studies 
Not applicable. 
7.8.4.4 Multiple Comparison/Multiplicity 
Not applicable. 
7.8.4.5 Use of an "Efficacy Subset" of Subjects 
Not applicable. 
7.8.4.6 Active-Control Studies Intended to Show Equivalence or Non-Inferiority 
The bioequivalence for Lu AA21004 will be assessed based on “Partial Revision of 
Guideline for Bioequivalence Studies of Generic Products”. Formulations are considered to 
be bioequivalent if any of the following criteria are met. If the bioequivalence cannot be 
verified, it will be considered adding additional subjects. 
For the primary endpoints (AUClast and Cmax) of unchanged Lu AA21004, the two-sided 90% 
CIs of the difference in the mean values of logarithmic parameters to be assessed between 
two treatments is within the acceptable range of ln(0.80) to ln(1.25). 
 
7.8.4.7 Examination of Subgroups 
Not applicable. 
 
 
 


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7.9 
Pharmacokinetic/Pharmacodynamic Analysis 
7.9.1 Pharmacokinetic Analysis 
7.9.1.1 Plasma Concentrations 
Analysis Set: 
Pharmacokinetic Analysis Set 
Analysis 
Variable(s): 
Plasma Concentrations of Unchanged Lu AA21004 
Visit: 
Predose, 1, 2, 4, 6, 8, 10, 12, 14, 16, 24, 36, 48, and 72 Hours Postdose 
Analytical 
Method(s): 
The following summaries will be provided. 
(1) 
Descriptive Statistics of Plasma Concentrations for each treatment by 
Visit 
 
(2) 
Mean and Standard Deviation Plot of Plasma Concentrations for each 
treatment (vertical axis: normal scale) 
 
(3) 
Mean Plot of Plasma Concentrations for each treatment (vertical axis: 
common logarithmic scale) 
 
7.9.1.2 Pharmacokinetic Parameters 
Analysis Set: 
Pharmacokinetic Analysis Set 
Analysis 
Variable(s): 
Pharmacokinetic Parameters of Unchanged Lu AA21004 
AUClast 
AUCinf 
Cmax 
tmax 
t1/2z 
MRTinf, ev 
MRTlast, ev 
λz 
 
Treatment Ratio of Test Product to Reference Product in AUClast and Cmax 
of Unchanged Lu AA21004 (One Lu AA21004 20 mg tablet / Two Lu 
AA21004 10 mg tablets) 
(R(AUClast), R(Cmax)) 
Analytical 
Method(s): 
The following summaries will be provided by treatment. 
(1) 
Summary of Pharmacokinetic Parameters 
For AUClast, Cmax, and AUCinf, descriptive statistics, geometric 
mean, and CV will be provided. 
For tmax, descriptive statistics will be provided. 
For all other variables other than AUClast, Cmax, AUCinf, and tmax, 
descriptive statistics and CV will be provided. 
 


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7.9.1.3 Assessment of Bioequivalence 
Primary Endpoints 
Analysis Set: 
Pharmacokinetic Analysis Set 
Analysis 
Variable(s): 
Pharmacokinetic Parameters of Unchanged Lu AA21004 
AUClast 
Cmax 
 
Analytical 
Method(s): 
The following analysis will be performed for the above analysis variable(s) 
(1) 
The difference in the least square means between treatments (One Lu 
AA21004 20 mg tablet – Two Lu AA21004 10 mg tablets) and the 
two-sided 90% CIs will be provided using a crossover ANOVA 
model. The ANOVA model will include log-transformed (natural log) 
analysis variable as dependent variable, and treatment, group, and 
period as independent variables. 
 
Secondary Endpoints 
Analysis Set: 
Pharmacokinetic Analysis Set 
Analysis 
Variable(s): 
Pharmacokinetic Parameters of Unchanged Lu AA21004 
AUCinf 
tmax 
t1/2z 
 
MRTinf, ev 
MRTlast, ev 
λz 
Analytical 
Method(s): 
The following analysis will be performed for the above analysis variable(s). 
(1) 
For analysis variables other than tmax, the difference in the least 
square means between treatments (One Lu AA21004 20 mg tablet – 
Two Lu AA21004 10 mg tablets) and the two-sided 90% and 95% CIs 
will be provided using a crossover ANOVA model. The ANOVA 
model will include log-transformed (natural log) analysis variable as 
dependent variable, and treatment, group, and period as independent 
variables. 
(2) 
For tmax, the difference in the least square means between treatments 
(One Lu AA21004 20 mg tablet – Two Lu AA21004 10 mg tablets) 
and the two-sided 90% and 95% CIs will be provided using a 
crossover ANOVA model. The ANOVA model will include analysis 
variable as dependent variable, and treatment, group, and period as 
independent variables. 


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7.9.1.4 Individual Plasma Concentrations 
Analysis Set: 
All Subjects Who Entered the Treatment Period 
Analysis 
Variable(s): 
Plasma Concentrations of Unchanged Lu AA21004 
Visit: 
Predose, 1, 2, 4, 6, 8, 10, 12, 14, 16, 24, 36, 48, and 72 Hours Postdose 
Analytical 
Method(s): 
The following case plots will be provided. 
(1) 
Plot Over Time for Each Subject of Plasma Concentrations of Lu 
AA21004 (vertical axis: normal scale) 
 
7.9.2 Pharmacodynamic Analysis 
Not applicable. 
7.10 
Other Outcomes 
Not applicable. 
 
 


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7.11 
Safety Analysis 
7.11.1 Adverse Events 
7.11.1.1 Overview of Treatment-Emergent Adverse Events 
Analysis Set: Safety Analysis Set 
Analysis 
Variable(s): 
TEAE 
Categories: 
Relationship to Study Drug 
[Related, Not Related] 
 
Intensity 
[Mild, Moderate, Severe] 
Analytical 
Method(s): 
The following summaries will be provided by treatment. 
(1) 
Overview of TEAEs 
 
1) All TEAEs (number of events, number and percentage of subjects) 
 
2) Relationship of TEAEs to study drug (number of events, number 
and percentage of subjects) 
 
3) Intensity of TEAEs (number of events, number and percentage of 
subjects) 
 
4) TEAEs leading to study drug discontinuation (number of events, 
number and percentage of subjects) 
 
5) Serious TEAEs (number of events, number and percentage of 
subjects) 
 
6) Relationship of serious TEAEs to study drug (number of events, 
number and percentage of subjects) 
 
7) Serious TEAEs leading to study drug discontinuation (number of 
events, number and percentage of subjects) 
 
8) TEAEs resulting in death (number of events, number and 
percentage of subjects) 
 
TEAEs will be counted according to the rules below. 
When calculating percentages of subjects with occurrence of TEAE, the 
number of subjects who were treated by that treatment in the safety analysis 
set will be used as the denominator. 
[Number of subjects] 
• Summaries for 2) and 6) 
A subject with occurrences of TEAE in both categories (i.e., Related and 
Not Related) will be counted once in the Related category. 
• Summary for 3) 
A subject with multiple occurrences of TEAE will be counted once for the 


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TEAE with the maximum intensity. 
• Summaries other than 2), 3), and 6) 
A subject with multiple occurrences of TEAE will be counted only once. 
[Number of events] 
For each summary, the total number of events will be calculated. 
 
7.11.1.2 Displays of Treatment-Emergent Adverse events 
Analysis Set: Safety Analysis Set 
Analysis 
Variable(s): 
TEAE 
Categories: 
Intensity 
[Mild, Moderate, Severe] 
Analytical 
Method(s): 
The following summaries will be provided using frequency distribution by 
treatment. 
TEAEs will be coded using the MedDRA and will be summarized using 
System Organ Class (SOC) and Preferred Term (PT). SOC will be sorted 
alphabetically and PT will be sorted in decreasing frequency for tables 
provided by SOC and PT. SOC and PT will be sorted in decreasing frequency 
for tables provided by SOC only or PT only. 
 
(1) 
TEAEs by SOC and PT 
 
(2) 
TEAEs by SOC 
 
(3) 
TEAEs by PT 
 
(4) 
Drug-Related TEAEs by SOC and PT 
 
(5) 
Intensity of TEAEs by SOC and PT 
 
(6) 
Intensity of Drug-Related TEAEs by SOC and PT 
 
(7) 
TEAEs Leading to Study Drug Discontinuation by SOC and PT 
 
(8) 
Serious TEAEs by SOC and PT 
 
The frequency distribution will be provided according to the rules below. 
[Number of subjects] 
• Summary tables other than (5) and (6) 
A subject with multiple occurrences of TEAE within a SOC will be 
counted only once in that SOC. A subject with multiple occurrences of 
TEAE within a PT will be counted only once in that PT. When calculating 
percentages of subjects with occurrence of TEAE, the number of subjects 
who were treated by that treatment in the safety analysis set will be used as 
the denominator. 


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• Summary tables for (5) and (6) 
A subject with multiple occurrences of TEAE within a SOC or a PT will be 
counted only once for the TEAE with the maximum intensity. When 
calculating percentages of subjects with occurrence of TEAE, the number 
of subjects who were treated by that treatment in the safety analysis set will 
be used as the denominator. 
 
7.11.1.3 Displays of Pretreatment Events 
Analysis Set: All Subjects Who Signed the Informed Consent Form 
Analysis 
Variable(s): 
PTE 
Analytical 
Method(s): 
The following summaries will be provided using frequency distribution. 
PTEs will be coded using the MedDRA and will be summarized using SOC 
and PT. SOC will be sorted alphabetically and PT will be sorted in decreasing 
frequency. 
 
(1) 
PTEs by SOC and PT 
(2) 
Serious PTEs by SOC and PT 
 
The frequency distribution will be provided according to the rules below. 
[Number of subjects] 
A subject with multiple occurrences of TEAE within a SOC will be counted 
only once in that SOC. A subject with multiple occurrences of TEAE within a 
PT will be counted only once in that PT. 
 
 
 


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7.11.2 Clinical Laboratory Evaluations 
7.11.2.1 Hematology and Serum Chemistry 
Analysis Set: Safety Analysis Set 
Analysis 
Variable(s): 
Hematology 
Erythrocytes (RBC) 
Hemoglobin 
Hematocrit 
Platelets 
Leukocytes (WBC) 
 
WBC Differentials (Neutrophils/Leukocytes, Eosinophils/Leukocytes, 
Basophils/Leukocytes, Lymphocytes/Leukocytes, Monocytes/Leukocytes) 
Serum Chemistry 
Albumin 
ALT (GPT) 
ALP 
AST (GOT) 
GGT 
Total Bilirubin 
Direct Bilirubin 
Total Protein 
Creatinine 
Creatine Kinase 
(CPK) 
Blood Urea Nitrogen 
Potassium 
Sodium 
Chloride 
Calcium 
Phosphate 
Glucose 
Total Cholesterol 
HDL-Cholesterol 
LDL-Cholesterol 
Triglycerides 
Urate 
 
 
Categories: 
Adjudication 
Result Based on 
the Normal 
Reference Range 
[Low, Normal, or High Relative to the Normal Reference 
Range] 
Visit: 
Predose, 72 Hours Postdose 
Analytical 
Method(s): 
The following summaries will be provided by treatment. 
 
(1) 
Descriptive statistics for observed values and changes from baseline 
(each postdose visit − Predose) by visit 
 
(2) 
Plots over time for each subject 
 
(3) 
Shift tables on adjudication results based on the normal reference range 
showing the number of subjects in each category at Predose and each 
postdose visit 
 
 
 


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7.11.2.2 Urinalysis 
Analysis Set: Safety Analysis Set 
Analysis 
Variable(s): 
Specific Gravity 
 
pH 
 
Protein 
[-,  +-,  1+,  2+,  3+] 
Glucose 
[-,  +-,  1+,  2+,  3+,  4+] 
Occult blood 
[-,  +-,  1+,  2+,  3+] 
Urobilinogen 
[+-,  1+,  2+,  3+] 
Ketones 
[-,  +-,  1+,  2+,  3+] 
Categories: 
Adjudication Result 
Based on the 
Normal Reference 
Range 
[Low, Normal, or High Relative to the Normal 
Reference Range] 
Visit: 
Predose, 72 Hours Postdose 
Analytical 
Method(s): 
For specific gravity, summaries (1), (2), and (4) will be provided by 
treatment. 
For pH, summaries (4) will be provided by treatment. 
For each variable other than specific gravity and pH, summaries (3) will be 
provided by treatment. 
 
(1) 
Descriptive statistics for observed values and changes from baseline 
(each postdose visit − Predose) by visit 
 
(2) 
Plots over time for each subject 
 
(3) 
Shift tables showing the number of subjects in each category at Predose 
and each postdose visit 
 
(4) 
Shift tables on adjudication results based on the normal reference range 
showing the number of subjects in each category at Predose and each 
postdose visit 
 
7.11.3 Vital Signs 
Analysis Set: Safety Analysis Set 
Analysis 
Variable(s): 
Temperature (Armpit) 
 
Systolic Blood Pressure 
 
Diastolic Blood Pressure 
 
Pulse Rate 
 
Visit: 
Predose, 24 and 72 Hours Postdose 


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Analytical 
Method(s): 
The following summaries will be provided by treatment. 
 
(1) 
Descriptive statistics for observed values and changes from baseline 
(each postdose visit − Predose) by visit 
 
(2) 
Plots over time for each subject 
 
7.11.4 12-Lead ECGs 
Analysis 
Set: 
Safety Analysis Set 
Analysis 
Variable(s): 
Heart Rate 
 
RR Interval 
 
PR Interval 
 
QT Interval 
 
QRS Interval 
 
QTcF Interval 
 
Interpretation 
[Within Normal Limits, Abnormal but not Clinically 
Significant, Abnormal and Clinically Significant] 
Visit: 
Predose (Screening) and 72 Hours Postdose 
Analytical 
Method(s): 
For each variable other than 12-lead ECG interpretations, summaries (1) and 
(2) will be provided by treatment. 
For 12-lead ECG interpretation, summary (3) will be provided by treatment. 
 
(1) 
Descriptive statistics for observed values and changes from baseline 
(each postdose visit − Predose) by visit 
 
(2) 
Plots over time for each subject 
 
(3) 
Shift tables showing the number of subjects in each category at Predose 
and each postdose visit 
 
7.11.5 Other Observations Related to Safety 
Not applicable. 
7.12 
Interim Analysis 
Not applicable. 
 


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7.13 
Changes in the Statistical Analysis Plan 
 
Statistical Analysis Plan (Version 1: 13 March 2018→Version 2: 14 June 2018) 
Before change 
7.11.2.2 Urinalysis 
Analytical 
Method(s): 
For specific gravity, summaries (1), (2), and (4) will be provided by 
treatment. 
For each variable other than specific gravity, summaries (3) will be provided 
by treatment. 
 
After change 
Analytical 
Method(s): 
For specific gravity, summaries (1), (2), and (4) will be provided by 
treatment. 
For pH, summaries (4) will be provided by treatment. 
For each variable other than specific gravity and pH, summaries (3) will be 
provided by treatment. 
Reason for change 
Due to error in writing 
 


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8.0 
REFERENCES 
Not applicable.