Clinical trial NCT02389816
Conditions: Major Depressive Disorder
Keywords: Drug therapy
Sponsor: Takeda
Start date: 2015-04-10; Completion date: 2018-03-16
Enrollment: 493 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of this study is to evaluate the efficacy of two fixed doses of vortioxetine (Lu AA21004; 10 or 20 mg/day) after 8 weeks of treatment in patients with major depressive disorder (MDD) in Japan.

Detailed description:
This is a randomized, double-blind, placebo-controlled, parallel-group, phase III study to assess the efficacy and safety of 8-week treatment of two fixed doses of Vortioxetine (Lu AA21004; 10 or 20 mg/day) in Japanese participants with major depressive disorder (MDD).

Arms: arm 1: Placebo tablets, orally, once daily for up to Week 8 arm 2: Vortioxetine 10 mg tablets, orally, once daily for up to Week 8 arm 3: Vortioxetine 10 mg tablets, orally, once daily for up to Week 1 followed by vortioxetine 20 mg tablets, orally, once daily for up to Week 8
Interventions: intervention 1: Placebo intervention 2: Vortioxetine
Intervention descriptions: intervention 1: Placebo tablets intervention 2: Vortioxetine tablets

Protocol documents:
Prot_000.pdf: 
 
 
Title: A Randomized, Double-Blind, Placebo-Controlled, Parallel-Group, Phase III Study 
to Assess the Efficacy and Safety of Lu AA21004 in Patients with Major Depressive 
Disorder 
NCT Number: NCT02389816 
Protocol Approve Date: 18-Aug-2015 
 
Certain information within this protocol has been redacted (ie, specific content is 
masked irreversibly from view with a black/blue bar) to protect either personally 
identifiable information 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. : Lu AA21004/CCT-004
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CONFIDENTIAL
PROTOCOL
<Title>
A Randomized, Double-Blind, Placebo-Controlled, Parallel-Group, Phase III Study to 
Evaluate the Efficacy and Safety of Once Daily Oral Lu AA21004 in Patients with Major 
Depressive Disorder
<Short Title>
A Phase III Study of Lu AA21004 in Patients with Major Depressive Disorder
Sponsor:
Takeda Pharmaceutical Company Limited
1-1, Doshomachi 4-chome, Chuo-ku, Osaka-shi
Study Number:
Lu AA21004/CCT-004
Edition:
Protocol Incorporating Amendment No. 2
IND Number:
Not Applicable
EudraCT Number:
Not Applicable
Compound:
Lu AA21004
Date:
18 August 2015
Amendment History
Date
Amendment Number
Region
9 January 2015
Initial Protocol
All Study Sites
7 May 2015
Amendment 1
All Study Sites
18 August 2015
Amendment 2
All Study Sites
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. : Lu AA21004/CCT-004
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1.0
ADMINISTRATIVE INFORMATION AND PRINCIPLES OF CLINICAL 
STUDIES
1.1
Contacts and Responsibilities of Study-Related Activities
Refer to the attachment.
1.2
Principles of Clinical Studies
This study will be conducted with the highest respect for the individual participants in 
accordance with the requirements of this study protocol and also in accordance with the 
following:

The ethical principles that have their origin in the Declaration of Helsinki.

International Conference on Harmonisation E6 Good Clinical Practice: Consolidated 
Guideline.

All applicable laws and regulations, including, without limitation, data privacy laws, clinical 
trial disclosure laws, and regulations.


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Study No. : Lu AA21004/CCT-004
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TABLE OF CONTENTS
1.0
ADMINISTRATIVE INFORMATION AND PRINCIPLES OF CLINICAL 
STUDIES........................................................................................................................2
1.1
Contacts and Responsibilities of Study-Related Activities..........................................2
1.2
Principles of Clinical Studies .....................................................................................2
2.0
STUDY SUMMARY ......................................................................................................8
3.0
LIST OF ABBREVIATIONS........................................................................................12
4.0
INTRODUCTION.........................................................................................................14
4.1
Background .............................................................................................................14
4.1.1
Clinical Pharmacology.......................................................................................14
4.1.2
Overseas Phase II/III Clinical Studies.................................................................15
4.1.3
Japanese Phase II/III Clinical Studies.................................................................16
4.2
Rationale for the Proposed Study.............................................................................17
5.0
STUDY OBJECTIVES AND ENDPOINTS..................................................................18
5.1
Objectives................................................................................................................18
5.1.1
Primary Objective ..............................................................................................18
5.1.2
Secondary Objectives.........................................................................................18
5.1.3
Additional Objectives.........................................................................................18
5.2
Endpoints.................................................................................................................18
5.2.1
Efficacy Endpoints.............................................................................................18
5.2.1.1 Primary Endpoint .........................................................................................18
5.2.1.2 Secondary Endpoints....................................................................................18
5.2.2
Pharmacokinetic Endpoint .................................................................................19
5.2.3
Safety Endpoints................................................................................................19
6.0
STUDY DESIGN AND DESCRIPTION.......................................................................20
6.1
Study Design ...........................................................................................................20
6.2
Justification for Study Design, Dose, and Endpoints ................................................21
6.2.1
Subject Population .............................................................................................21
6.2.2
Study Design......................................................................................................21
6.2.3
Doses.................................................................................................................22
6.2.4
Endpoints...........................................................................................................22
6.3
Premature Termination or Suspension of Study or Study Site...................................23
6.3.1
Criteria for Premature Termination or Suspension of the Study..........................23
6.3.2
Criteria for Premature Termination or Suspension of Study Sites .......................23


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Study No. : Lu AA21004/CCT-004
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6.3.3
Procedures for Premature Termination or Suspension of the Study or the 
Participation of Study Sites ................................................................................23
7.0
SELECTION AND DISCONTINUATION/WITHDRAWAL OF SUBJECTS..............24
7.1
Inclusion Criteria .....................................................................................................24
7.2
Exclusion Criteria ....................................................................................................25
7.3
Excluded Medications and Treatments.....................................................................28
7.4
Diet, Fluid, and Activity Control..............................................................................31
7.5
Criteria for Discontinuation or Withdrawal of a Subject...........................................32
7.5.1
Additional Guidance for Withdrawal Criteria.....................................................33
7.6
Procedures for Discontinuation or Withdrawal of a Subject......................................33
8.0
CLINICAL TRIAL MATERIAL MANAGEMENT ......................................................34
8.1
Study Medication.....................................................................................................34
8.1.1
Dosage Form, Manufacturing, Packaging, and Labeling.....................................34
8.1.2
Storage...............................................................................................................34
8.1.3
Dose and Regimen .............................................................................................35
8.1.4
Overdose............................................................................................................35
8.2
Study Drug Assignment and Dispensing Procedures ................................................36
8.3
Randomization Code Creation and Storage..............................................................36
8.4
Study Drug Blind Maintenance................................................................................36
8.5
Unblinding Procedure..............................................................................................36
8.6
Accountability and Destruction of Sponsor-Supplied Drugs.....................................37
9.0
STUDY PLAN ..............................................................................................................38
9.1
Study Procedures.....................................................................................................38
9.1.1
Informed Consent Procedure..............................................................................38
9.1.1.1 Pharmacogenomic Informed Consent Procedure...........................................38
9.1.2
Demographics, Medical History, and Medication History Procedure..................38
9.1.3
Diagnosis of MDD.............................................................................................38
9.1.4
Assessments of Major Depressive Episode.........................................................39
9.1.4.1 Current Major Depressive Episode ...............................................................39
9.1.4.2 Past Major Depressive Episode ....................................................................39
9.1.5
Physical Examination Procedure ........................................................................40
9.1.6
Weight, Height, and BMI...................................................................................40
9.1.7
Vital Sign Procedure..........................................................................................40
9.1.8
Efficacy Evaluation............................................................................................40
9.1.8.1 Rating and Rating Training for MDD...........................................................40
9.1.8.2 Social Function Assessment .........................................................................42


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Study No. : Lu AA21004/CCT-004
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9.1.8.3 Cognitive Function Assessments ..................................................................42
9.1.8.4 Self-report Assessment of Depressive Symptoms and Assessment 
Monitoring ...................................................................................................42
9.1.9
Suicidal Risk Assessments .................................................................................43
9.1.10 Documentation of Concomitant Medications......................................................43
9.1.11 Documentation of Concurrent Medical Conditions.............................................43
9.1.12 Procedures for Clinical Laboratory Samples.......................................................43
9.1.13 Contraception and Pregnancy Avoidance Procedure...........................................45
9.1.14 Pregnancy ..........................................................................................................45
9.1.15 ECG Procedure..................................................................................................46
9.1.16 Pharmacogenomic Sample Collection ................................................................46
9.1.17 Pharmacokinetic Sample Collection and Analysis ..............................................46
9.1.17.1
Collection of Blood for Pharmacokinetic Sampling ................................46
9.1.17.2
Bioanalytical Methods............................................................................46
9.1.18 Documentation of Screen Failure Prior to Entrance into Placebo Lead-in 
Period ................................................................................................................46
9.1.19 Documentation of Study Entrance into Placebo Lead-in Period..........................47
9.1.20 Documentation of Screen Failure Prior to Randomization ..................................47
9.1.21 Documentation of Randomization......................................................................48
9.2
Monitoring Subject Treatment Compliance..............................................................48
9.3
Schedule of Observations and Procedures................................................................48
9.3.1
Screening Period................................................................................................48
9.3.2
Placebo Lead-in Period ......................................................................................49
9.3.3
Start of Double-blind Treatment Period/Randomization .....................................50
9.3.4
Double-blind Treatment Period..........................................................................51
9.3.5
End of Double-blind Treatment Period or Early Termination .............................53
9.3.6
Follow-up Period ...............................................................................................54
9.3.7
Post Study Care..................................................................................................54
9.4
Biological Sample Retention and Destruction ..........................................................54
10.0
PRETREATMENT EVENTS AND ADVERSE EVENTS ............................................56
10.1
Definitions...............................................................................................................56
10.1.1 PTEs..................................................................................................................56
10.1.2 AEs....................................................................................................................56
10.1.3 Additional Points to Consider for PTEs and AEs................................................56
10.1.4 SAEs..................................................................................................................58
10.1.5 Special Interest AEs...........................................................................................60


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Study No. : Lu AA21004/CCT-004
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10.1.5.1
Skin and Allergic Reaction.....................................................................60
10.1.5.2
Hepatic Impairment................................................................................60
10.1.5.3
Overdose ................................................................................................61
10.1.6 Severity of PTEs and AEs..................................................................................61
10.1.7 Causality of AEs ................................................................................................61
10.1.8 Relationship to Study Procedures.......................................................................61
10.1.9 Start Date...........................................................................................................62
10.1.10
Stop Date .....................................................................................................62
10.1.11
Frequency ....................................................................................................62
10.1.12
Action Concerning Study Medication...........................................................62
10.1.13
Outcome.......................................................................................................63
10.2
Procedures...............................................................................................................63
10.2.1 Collection and Reporting of AEs........................................................................63
10.2.1.1
PTE and AE Collection Period ...............................................................63
10.2.1.2
PTE and AE Reporting ...........................................................................64
10.2.1.3
Special Interest AE Reporting.................................................................65
10.2.2 Collection and Reporting of SAEs......................................................................65
10.2.3 Reporting of Abnormal Liver Function Tests .....................................................66
10.3
Follow-up of SAEs ..................................................................................................66
10.3.1 Safety Reporting to Investigators, IRBs, and Regulatory Authorities..................66
11.0
STUDY-SPECIFIC COMMITTEES .............................................................................67
12.0
DATA HANDLING AND RECORDKEEPING............................................................68
12.1
eCRFs......................................................................................................................68
12.2
Record Retention .....................................................................................................68
13.0
STATISTICAL METHODS..........................................................................................70
13.1
Statistical and Analytical Plans ................................................................................70
13.1.1 Analysis Sets......................................................................................................70
13.1.2 Analysis of Demographics and Other Baseline Characteristics ...........................70
13.1.3 Efficacy Analysis...............................................................................................70
13.1.4 Pharmacokinetic Analysis ..................................................................................72
13.1.5 Safety Analysis ..................................................................................................72
13.2
Interim Analysis and Criteria for Early Termination ................................................72
13.3
Determination of Sample Size..................................................................................72
14.0
QUALITY CONTROL AND QUALITY ASSURANCE...............................................74
14.1
Study-Site Monitoring Visits ...................................................................................74


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Study No. : Lu AA21004/CCT-004
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14.2
Protocol Deviations..................................................................................................74
14.3
Quality Assurance Audits and Regulatory Agency Inspections ................................74
15.0
ETHICAL ASPECTS OF THE STUDY........................................................................75
15.1
IRB Approval ..........................................................................................................75
15.2
Subject Information, Informed Consent, and Subject Authorization .........................75
15.3
Subject Confidentiality ............................................................................................76
15.4
Publication, Disclosure, and Clinical Trial Registration Policy.................................77
15.4.1 Publication and Disclosure.................................................................................77
15.4.2 Clinical Trial Registration..................................................................................77
15.4.3 Clinical Trial Results Disclosure ........................................................................77
15.5
Insurance and Compensation for Injury....................................................................78
16.0
REFERENCES..............................................................................................................79
LIST OF IN-TEXT TABLES
Table 7.a
List of Prohibited or Restricted Concomitant Medications..................................28
Table 8.a
Study Medication...............................................................................................34
Table 8.b
Dose and Regimen .............................................................................................35
Table 9.a
Clinical Laboratory Tests...................................................................................44
Table 10.a
Takeda Medically Significant AE List................................................................59
LIST OF IN-TEXT FIGURES
Figure 6.a
Schematic of Study Design ................................................................................21
LIST OF APPENDICES
Appendix A
Schedule of Study Procedures............................................................................80
Appendix B
Responsibilities of the Investigator.....................................................................82
Appendix C
Detailed Description of Amendments to Text.....................................................83


Lu AA21004
Study No. : Lu AA21004/CCT-004
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2.0
STUDY SUMMARY
Name of Sponsor:
Takeda Pharmaceutical Company Limited
Compound:
Lu AA21004
Title of Protocol:
A Randomized, Double-Blind, Placebo-Controlled, Parallel-Group, 
Phase III Study to Evaluate the Efficacy and Safety of Once Daily 
Oral Lu AA21004 in Patients with Major Depressive Disorder
IND No.:
Not Applicable
EudraCT No.:
Not Applicable
Study Number: Lu AA21004/CCT-004
Phase: 3
Study Design:
This is a randomized, double-blind, placebo-controlled, parallel-group, phase III study to evaluate the efficacy and 
safety of 8-week treatment of 2 fixed doses of Lu AA21004 (10 or 20 mg/day) in Japanese subjects with major 
depressive disorder (MDD).
This study consists of a 1- to 3-week screening period, a 1-week single-blind placebo lead-in period, an 8-week 
double-blind treatment period and a 4-week safety follow-up period. Subjects who fulfill all inclusion criteria and 
none of exclusion criteria at the start of screening period (Visit 1) and at the start of placebo lead-in period (Visit 2) 
will move into the placebo lead-in period and receive placebo once daily for 1 week in a single-blind manner. 
Afterwards, these who fulfill all the inclusion criteria and none of the exclusion criteria at the start of double-blind 
treatment period (Visit 3) will move into the double-blind treatment period and will be randomized in a 1:1:1 ratio to 
one of the following treatment groups: the placebo group, the Lu AA21004 10 mg/day group or the Lu AA21004 
20 mg/day group. Subjects in the placebo group and the Lu AA21004 10 mg/day group will receive placebo and 
Lu AA21004 10 mg, respectively, once daily from the day after Visit 3 for 8 weeks in a double-blind manner. 
Subjects in the Lu AA21004 20 mg/day group will receive Lu AA21004 10 mg once daily from the day after Visit 3 
for 1 week and thereafter Lu AA21004 20 mg once daily for 7 weeks in a double-blind manner. Subjects in any
treatment groups will visit study sites at Week 1, 2, 4, 6 and 8 during the double-blind treatment period for
examinations/observations/assessments.
A safety follow-up contact (visit or phone call) will be made 4 weeks after the completion of the double-blind 
treatment period. Subjects who prematurely discontinue the study during the placebo lead-in period or the double-
blind treatment period will be requested to visit the study site for the end-of study assessments within 7 days after 
the discontinuation decision is made wherever possible, and will be contacted 4 weeks after the last dose of the 
study medication for safety follow-up.
Primary Objective:
• To evaluate the efficacy of 2 fixed doses of Lu AA21004 (10 or 20 mg/day) after 8 weeks of treatment in Japanese 
patients with MDD.
Secondary Objectives:
• To evaluate the safety and tolerability of 2 fixed doses of Lu AA21004 (10 or 20 mg/day) after 8 weeks of 
treatment in Japanese patients with MDD.
• To evaluate the efficacy of Lu AA21004 (10 or 20 mg/day) on cognitive functions after 8 weeks of treatment in 
Japanese patients with MDD.
Additional Objective:
• To analyze the plasma concentrations of Lu AA21004 and its metabolites Lu AA34443 and Lu AA39835 using
population pharmacokinetic analyses.
Subject Population:
Male and female subjects, aged between 20 and 75 years (both inclusive), with recurrent MDD according to 
Diagnostic and Statistical Manual of Mental Disorders, 4th edition, Text Revision (DSM-IV-TR) criteria.


Lu AA21004
Study No. : Lu AA21004/CCT-004
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Number of Subjects:
Randomized subjects: 480 (160 per group)
Number of Sites:
Approximately 60 sites
Dose Levels:
Placebo lead-in period:
Placebo once daily
Double-blind treatment period:
Lu AA21004 (10 or 20 mg) or placebo once daily
Route of Administration:
Oral
Duration of Treatment:
9 weeks in total
Placebo lead-in period: 1 week
Double-blind treatment period: 8 weeks
Period of Evaluation:
14 to 16 weeks in total
Screening period: 1 to 3 weeks
Placebo lead-in period: 1 week
Double-blind treatment period: 8 weeks
Safety follow-up period: 4 weeks
Main Criteria for Inclusion:
• The subject suffers from recurrent MDD as the primary diagnosis according to DSM-IV-TR criteria (classification 
code 296.3x).
• The subject is a man or a woman aged 20 to 75 years (both inclusive) at the time of informed consent.
• The reported duration of the current major depressive episode is 3 to 12 months (both inclusive) at the start of 
screening period.
• The subject has a Montgomery-Åsberg Depression Rating Scale (MADRS) total score ≥26, a Hamilton 
Depression Rating Scale (HAM-D17) total score ≥18, and a clinical global impression scale-Severity (CGI-S) 
score ≥4 at the start of screening period, the start of placebo lead-in period and the start of the double-blind 
treatment period.
Main Criteria for Exclusion:
• The subject has any following current or past history of psychiatric disorder and/or neurological disorder:
- Any current psychiatric disorder other than MDD as defined by DSM-IV-TR (To be assessed by Mini
International Neuropsychiatric Interview: MINI). A subject who exhibits symptoms of anxiety is eligible unless 
the subject fulfills the diagnostic criteria for a current anxiety disorder per DSM-IV-TR.
- Current diagnosis or history of manic, mixed or hypomanic episode, MDD with psychotic features, 
schizophrenia or any other psychotic disorder (including substance-related mental disorders, or mental disorders 
due to a general medical condition) as defined by DSM-IV-TR.
- Current diagnosis or history of any substance-related disorder (except nicotine and caffeine-related disorders) as 
defined by DSM-IV-TR.
- The subject with a positive urine drug screening result at the start of screening period or the start of placebo 
lead-in period. In case that a subject showed positive test result at the start of screening period because the test 
was conducted before washout of pretreatment drugs, the subject is eligible as long as he/she shows negative 
result at the start of placebo lead-in period.
- Presence or history of any clinically significant neurological disorder (including epilepsy).
- Any neurodegenerative disorder (e.g. Alzheimer’s disease, Parkinson’s disease, multiple sclerosis, Huntington’s 
disease).
- Any DSM-IV-TR axis II disorder.
• The subject has the current or previous major depressive episode which were considered by the investigator to 
have been resistant to 2 or more adequate antidepressants treatments of at least 6 weeks duration each at sufficient 
doses.


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Study No. : Lu AA21004/CCT-004
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• The subject has received any augmentation therapy (e.g. lithium, T3/T4, lamotrigine, sodium valproate, 
carbamazepine, additional atypical antipsychotic, or concomitant use of other antidepressant, etc.) for the current 
major depressive episode.
• In the opinion of the investigator, the subject has experienced significant number of major depressive episodes in 
the past, and is suspected of disease other than MDD.
• In the opinion of the investigator, the subject has experienced the first major depressive episode at his/her young 
age, and is suspected of disease other than MDD.
• The subject has a MADRS total score at the start of double-blind treatment period that has improved or aggravated 
by 25% or more from the score at the start of placebo lead-in period.
• The subject is at significant risk of suicide or has a score ≥5 on Item 10 (suicidal thoughts) of the MADRS at the 
start of screening period, the start of placebo lead-in period or the start of double-blind treatment period, or has 
attempted suicide within 6 months prior to the start of screening period.
• The subject has experienced any environmental change (e.g. temporary retirement, returnment, change of 
residence) considered by the investigator to have the potential to impact on the efficacy evaluation, or plans such 
environmental changes during the study.
• The subject has a clinically significant unstable illness, for example, hepatic impairment or renal insufficiency, or 
a cardiovascular, pulmonary, gastrointestinal, endocrine, neurological, rheumatologic, immunologic, infectious, 
neoplastic, skin and subcutaneous tissue disorders, eye disorders, or metabolic disturbance.
Main Criteria for Evaluation and Analyses:
Efficacy Endpoints
Primary Endpoint
• Change from baseline (i.e. at the start of double-blind treatment) in the MADRS total score after 8 weeks of 
treatment
Secondary Endpoints
• MADRS response after 8 weeks of treatment (last observation carried forward [LOCF])
(MADRS response is defined as a ≥50% decrease in the MADRS total score from baseline).
• MADRS remission after 8 weeks of treatment (LOCF)
(MADRS remission is defined as the MADRS total score of ≤10).
• Change from baseline in the HAM-D17 total score after 8 weeks of treatment (LOCF).
• Clinical global impression scale-Improvement (CGI-I) score after 8 weeks of treatment (LOCF).
• Change from baseline in the CGI-S score after 8 weeks of treatment (LOCF).
• Change from baseline in the Sheehan Disability Scale (SDS) total score after 8 weeks of treatment (LOCF).
• Change from baseline in the Digit Symbol Substitution Test (DSST) score after 8 weeks of treatment (LOCF).
• Change from baseline in the Perceived Deficits Questionnaire (PDQ-5) score after 8 weeks of treatment (LOCF).
Pharmacokinetic Endpoint
• Plasma concentrations of Lu AA21004 and its metabolites Lu AA34443 and Lu AA39835.
Safety Endpoints
• Adverse events
• Weight
• Vital signs
• Electrocardiograms (ECGs)
• Clinical laboratory tests (serum chemistry, hematology and urinalysis)
• Columbia-Suicide Severity Rating Scale (C-SSRS)


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Study No. : Lu AA21004/CCT-004
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Statistical Considerations:
Change from baseline (i.e. the start of double-blind treatment period) in the MADRS total score after 8 weeks of 
treatment is the primary efficacy endpoint. Comparisons between each Lu AA21004 treatment group and the 
placebo group at Week 8 of the double-blind treatment period will be performed using the full analysis set (FAS)
based on Mixed Model for Repeated Measures (MMRM) analysis of covariance with the change from baseline in 
the MADRS total score as a dependent variable, and visit, treatment group, visit-by-treatment group interaction and
baseline MADRS total score-by-time point interaction as fixed effects. An unstructured variance-covariance matrix 
will be used to model the within-subject errors and Satterthwaite's method will be used to approximate the degrees 
of freedom. Holm's step-down method will be used to adjust the multiplicity for the comparisons.
Sample Size Justification:
A number of subjects planned to be enrolled in this study is 480 (160 per group). Assuming the true mean 
differences of 3.5 for the change from baseline in the MADRS total score between each Lu AA21004 group and the 
placebo group, this sample size will provide greater than 80% power to detect the difference between each 
Lu AA21004 group and the placebo group by 2-sample t-test. In addition, assuming the true mean differences of 3.0 
for the change from baseline in the MADRS total score between each Lu AA21004 group and the placebo group,
this sample size will provide greater than 80% power to detect the difference between either the Lu AA21004 10 mg 
or 20 mg group and the placebo group. These power calculations assume a common standard deviation of 9.5 for the 
change from baseline in the MADRS total score, with a 2-sided level of 0.025.


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Study No. : Lu AA21004/CCT-004
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3.0
LIST OF ABBREVIATIONS
5-HT
5-hydroxytryptamine
5-HTT
5-hydroxytryptamine transporter
ADHD
attention deficit hyperactivity disorder
AE
adverse event
ANCOVA
analysis of co-variance
ALT
alanine aminotransferase
AST
aspartate aminotransferase
AUC
area under the plasma concentration-time curve
BMI
body mass index
BUN
blood urea nitrogen
Cavg
average plasma concentration at steady state
CGI-I
clinical global impression scale-Improvement
CGI-S
clinical global impression scale-Severity
Cmax
maximum observed plasma concentration
COX
cyclooxygenase
CRO
contract research organization
C-SSRS
Columbia-Suicide Severity Rating Scale
CYP
cytochrome P-450
DSM-IV-TR
Diagnostic and Statistical Manual of Mental Disorders, 4th Edition, Text Revision
DSST
Digit Symbol Substitution Test
FDA
Food and Drug Administration
GCP
Good Clinical Practice
γ-GTP
-glutamyl transferase
HAM-D
Hamilton Depression Rating Scale
hCG
Human chorionic gonadotropin
HDL
high-density lipoprotein
ICH
International Conference on Harmonisation
INR
international normalized ratio
LDL
low-density lipoprotein
LOCF
Last Observation Carried Forward
MADRS
Montgomery Åsberg Depression Rating Scale
MAOI
monoamine oxidase inhibitor
MedDRA
Medical Dictionary for Regulatory Activities
MHRA
Medicines and Healthcare products Regulatory Agency
MINI
Mini International Neuropsychiatric Interview
MMRM
Mixed Model for Repeated Measures
NaSSA
noradrenergic and specific serotonergic antidepressant
NSAIDs
non-steroidal anti-inflammatory drug
PDQ
Perceived Deficits Questionnaire
PMDA
Pharmaceutical and Medical Devices Agency


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PT
Preferred Term
PTE
Pretreatment Event
PTP
press through package
QIDS
Quick Inventory of Depressive Symptomatology
SAE
serious adverse event
SDS
Sheehan Disability Scale
SNRI
serotonin norepinephrine reuptake inhibitor
SOC
System Organ Class
SSRI
selective serotonin reuptake inhibitor
SUSARs
Suspected unexpected serious adverse reactions
TEAE
treatment emergent adverse event
TSH
thyroid-stimulating hormone
WHO
World Health Organization


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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 in Japan and overseas. As of December 2014, Lu AA21004 has been
approved for marketing as a drug for the treatment of MDD in countries including the U.S., 
Europe and Australia.
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] With advances of basic research and clinical studies, the etiology and 
pathology of depression have been gradually revealed, but not fully elucidated so far.
Depression is a common disease worldwide, with the estimated lifetime prevalence above 10%. 
The onset age is estimated to be from 20 to 50 years old in half of patients; however, the onset in 
children and the elderly has been also reported.[3] In the U.S., the prevalence of depression in 
aged 18 to 29 years is approximately 3-fold higher than that in more than 60 years, and, after 
early adolescence, the prevalence in women is 1.5 to 3-fold higher than in men, showing that the 
prevalence of depression varies widely depending on age and sex.[4]
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]
The goal of treatment for depression is to improve patients' mental and social quality of life by 
effectively alleviating the depressive symptoms. 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 (SSRIs), serotonin-
norepinephrine reuptake inhibitors (SNRIs), and noradrenergic and specific serotonergic 
antidepressants (NaSSAs) 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.
4.1.1
Clinical Pharmacology
Results of clinical pharmacology studies in Japan and overseas are summarized below.
Lu AA21004 was slowly absorbed after oral administration, and the Tmax was approximately 7 
to 11 hours. The absolute bioavailability of Lu AA21004 was approximately 75%. The 


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pharmacokinetics of Lu AA21004 was linear within the dose range between 2.5 and 60 mg. The 
plasma concentration of Lu AA21004 reached steady state after approximately 2-week multiple 
doses, and the accumulation index was 5 to 6 based on AUC following multiple doses of 5 to 
20 mg/day. There was no food effect on the pharmacokinetics of Lu AA21004.
Lu AA21004 was extensively metabolized in the liver, primarily through oxidation or glucuronic
acid conjugation, and CYP2D6 was shown to be the primary enzyme in metabolism of 
Lu AA21004 to the major metabolite Lu AA34443. Lu AA34443 was pharmacologically 
inactive, and the active metabolite Lu AA39835 did not cross the blood-brain barrier, although 
Lu AA39835 was slightly detected in plasma, suggesting that these metabolites are less likely to 
contribute to the pharmacological effect of Lu AA21004. In addition, Lu AA21004 and its 
metabolites did not induce or inhibit CYP isozymes in vitro, suggesting that clinical significant 
drug-drug interactions with Lu AA21004 are less likely to occur.
The T1/2 of Lu AA21004 was approximately 66 hours, and two- thirds of its metabolites were 
excreted in urine, and one-third were excreted in feces. The excretion of unchanged Lu AA21004
was slightly noted in feces.
After multiple doses of Lu AA21004, 5-HTT occupancy in raphe nuclei was approximately 50% 
at doses of 5 mg/day, 65% at 10 mg/day, and 80% or more at 20 mg/day.
Based on results of studies in Caucasian and Japanese subjects, there were no statistically 
significant differences in the pharmacokinetics and 5-HTT occupancy of Lu AA21004 between 
the races.
4.1.2
Overseas Phase II/III Clinical Studies
A total of 12 overseas placebo-controlled, double-blind, short-term studies (Studies 11492A, 
11984A, 303, 304, 305, 13267A, 315, 316, 317, CCT-002, 12541A and 14122A) were conducted 
to evaluate the efficacy of Lu AA21004 for the treatment of MDD. Study CCT-002 was a 
multinational study including Japan.
The changes from baseline in the Montgomery-Åsberg Depression Rating Scale (MADRS) total 
score were analyzed by mixed model repeated measures (MMRM) in the individual studies; and 
the results of the 11 of 12 studies mentioned above except for Study 12541A for elderly patients
were used for meta-analysis. As for the mean changes from baseline in the MADRS total score at 
Week 6 or 8, the differences of the Lu AA21004 5, 10 and 20 mg group compared to the placebo 
group were -2.3 (p = 0.007), -3.6 (p < 0.001) and -4.6 (p < 0.001), respectively, and all of them 
were statistically significant. In addition, although the mean difference between the 15 mg group 
and placebo group was -2.6, not statistically significant. MADRS response rate (MADRS
response is defined as a ≥50% decrease from baseline in the MADRS total score) in the subjects 
treated with Lu AA21004 was 46% to 49%, whereas that in the subjects treated with placebo was 
34% (p < 0.01). These results suggested Lu AA21004 at doses of 5 to 20 mg/day was effective.
For comprehensive safety evaluation including the above-mentioned short-term studies and long-
term studies (Studies 11492C, 11984B, 301, 13267B and 314), treatment with Lu AA21004 at 
doses of 5 to 20 mg/day was safe and well tolerated. The most common TEAE in the 


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Lu AA21004 groups was nausea, and gastrointestinal TEAEs were occurred more frequently in 
female than male. Most TEAEs were mild or moderate and occurred within the first 2 weeks of 
treatment. In addition, TEAEs were usually transient, and did not generally lead to 
discontinuation of the study medication.
Abrupt discontinuation of antidepressants may result in discontinuation symptoms, however, 
there were no clinically relevant differences in the incidence or nature of discontinuation 
symptoms between the Lu AA21004 groups and placebo group.
The incidence of self-report sexual dysfunction in the Lu AA21004 groups was low, and was 
similar to that in the placebo group. In the study using a rating scale (Arizona Sexual Experience 
Scale) for sexual dysfunction, the incidence of sexual dysfunction at doses of 5 to 15 mg/day of 
Lu AA21004 was similar to that of placebo, but that at 20 mg/day was higher than placebo.
Lu AA21004 had no clinically significant effect on weight, heart rate, blood pressure, and 
hepatic and renal functions. Moreover, Lu AA21004 also had no clinically significant effect on
ECG parameters (QT interval, QTc interval, PR interval and QRS interval). In a thorough QTc 
study in healthy adult subjects, Lu AA21004 at doses up to 40 mg/day had no potential for 
prolongation of QT/QTc intervals.
4.1.3
Japanese Phase II/III Clinical Studies
In Japan, 2 placebo-controlled, short-term studies (Study CCT-002 [multinational study] and 
Study CCT-003 [Japan local study]) were conducted in subjects with MDD. In addition, a long-
term extension study (Study OCT-001) was conducted in those who completed Study CCT-003.
Study CCT-002 was conducted in 14 countries including Japan, Europe and the Asia Pacific 
region to evaluate the efficacy and safety of Lu AA21004 at doses of 5, 10 and 20 mg/day. For 
the mean changes from baseline in the MADRS total score at Week 8 (last observation carried 
forward [LOCF]) in the primary efficacy analysis (analysis of covariance [ANCOVA]), the mean 
differences of the Lu AA21004 5, 10 and 20 mg group compared to the placebo group were -
0.61 (p = 0.91), -1.69 (p = 0.30) and -1.82 (p = 0.24), respectively. In addition, in the same 
analysis for Japanese population, the mean differences of the Lu AA21004 5, 10 and 20 mg 
group compared to the placebo group were 0.89, -2.74 and -3.45, respectively.
In Study CCT-002, Most TEAEs were mild or moderate, and TEAEs reported in more than 5% 
of subjects in any Lu AA21004 groups were nausea, nasopharyngitis, headache, dizziness, 
constipation, dry mouth, and insomnia. Of these, TEAEs with higher (≥2-fold) incidence in any 
Lu AA21004 groups than that in placebo group were nausea, constipation, dry mouth, dizziness 
and insomnia.
In Study CCT-003, the efficacy and safety of Lu AA21004 at doses of 5 and 10 mg/day were 
evaluated in Japanese subjects with MDD. For the mean changes from baseline in the MADRS
total score at Week 8 (LOCF) in the primary efficacy analysis (ANCOVA), the mean differences 
of the Lu AA21004 5 and 10 mg group compared to the placebo group were -2.03 (p = 0.10) and 
-1.04 (p = 0.40), respectively.


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In Study CCT-003, TEAEs reported in more than 5% of subjects in any Lu AA21004 groups 
were nausea, diarrhoea, nasopharyngitis, somnolence, headache, and suicidal ideation. Of these, 
TEAEs with higher (≥2-fold) incidence in the Lu AA21004 groups than that in the placebo group 
were nausea and suicidal ideation. For suicidal ideation, the incidence in the 10 mg group (8 
subjects; 6.6%) was higher than in the placebo group (2 subjects; 1.6%) and 5 mg group (1 
subject; 0.8%). In general, most TEAEs were mild or moderate, suggesting that there were no 
significant safety concerns about Lu AA21004.
In the open-label long-term extension study (Study OCT-001), the safety of 52 week treatment of 
Lu AA21004 at flexible doses of 5 to 20 mg/day was evaluated in subjects who completed Study 
CCT-003. In Study OCT-001, TEAEs reported in more than 5% of subjects were 
nasopharyngitis, nausea, seasonal allergy, headache, weight increased, diarrhoea, vomiting, 
alanine aminotransferase (ALT) increased, somnolence, malaise, influenza, and blood creatine 
phosphokinase increased. No long-term specific TEAEs were observed, and most TEAEs were 
mild or moderate, suggesting that there were no significant safety concerns in a long-term 
treatment of Lu AA21004.
4.2
Rationale for the Proposed Study
In Europe and the U.S., the efficacy and safety of Lu AA21004 were demonstrated at doses of 5 
to 20 mg/day and Lu AA21004 has already been approved for marketing. For 2 short-term 
studies (Studies CCT-002 and CCT-003) including Japanese MDD patients, there are no 
statistically significant differences in the efficacy between any Lu AA21004 groups and the 
placebo group; however, in Study CCT-002, changes from baseline in the MADRS total score in 
the 10 and 20 mg groups were grater than in the placebo group in both overall population and 
Japanese population, and these results appeared to be supported by the result of 10 mg group in 
Study CCT-003.
Based on these results, if a statistically significant difference between the Lu AA21004 10 or
20 mg group and the placebo group is shown in the planned study (Study CCT-004), it is 
considered that the hypothesis of the efficacy of Lu AA21004 at doses of 10 and 20 mg in the 
Japanese population in Study CCT-002 can be verified.
The results of Studies CCT-002, CCT-003 and OCT-001 suggested that there were no significant 
safety concerns about Lu AA21004 at the dose up to 20 mg, but further data collection may 
provide more appropriate safety evaluation.
From the above, this study is designed as an additional phase III study to evaluate the efficacy 
and safety of Lu AA21004 in Japanese patients with MDD.
Pharmacogenomic analyses may be conducted to evaluate a possible contribution of genetic
polymorphism on drug response affecting the efficacy and safety of Lu AA21004. Participation 
of subjects in pharmacogenomic sample collection is optional.
As pharmacogenomics is an evolving science, many genes and their functions are not yet fully 
understood. Future data may suggest a role of some of these genes in drug response, which may 
lead to additional hypothesis-generating exploratory research with banked samples.


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5.0
STUDY OBJECTIVES AND ENDPOINTS
5.1
Objectives
5.1.1
Primary Objective

To evaluate the efficacy of 2 fixed doses of Lu AA21004 (10 or 20 mg/day) after 8 weeks of 
treatment in Japanese patients with MDD.
5.1.2
Secondary Objectives

To evaluate the safety and tolerability of 2 fixed doses of Lu AA21004 (10 or 20 mg/day) 
after 8 weeks of treatment in Japanese patients with MDD.

To evaluate the efficacy of Lu AA21004 (10 or 20 mg/day) on cognitive functions after 8 
weeks of treatment in Japanese patients with MDD.
5.1.3
Additional Objectives

To analyze the plasma concentrations of Lu AA21004 and its metabolites Lu AA34443 and 
Lu AA39835 using population pharmacokinetic analyses.
5.2
Endpoints
5.2.1
Efficacy Endpoints
5.2.1.1
Primary Endpoint

Change from baseline (i.e. at the start of the double-blind treatment period) in the MADRS
total score after 8 weeks of treatment.
5.2.1.2
Secondary Endpoints

MADRS response after 8 weeks of treatment (LOCF).
(MADRS response is defined as a ≥50% decrease in the MADRS total score from baseline).

MADRS remission after 8 weeks of treatment (LOCF).
(MADRS remission is defined as the MADRS total score of ≤10).

Change from baseline in the Hamilton Depression Rating Scale (HAM-D17) total score after 
8 weeks of treatment (LOCF).

Clinical global impression scale-Improvement (CGI-I) score after 8 weeks of treatment 
(LOCF).

Change from baseline in the clinical global impression scale-Severity (CGI-S) score after 8 
weeks of treatment (LOCF).

Change from baseline in the Sheehan Disability Scale (SDS) score after 8 weeks of treatment
(LOCF).


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
Change from baseline in the Digit Symbol Substitution Test (DSST) score after 8 weeks of 
treatment (LOCF).

Change from baseline in the Perceived Deficits Questionnaire (PDQ-5) score after 8 weeks 
of treatment (LOCF).
5.2.2
Pharmacokinetic Endpoint

Plasma concentrations of Lu AA21004 and its metabolites Lu AA34443 and Lu AA39835.
5.2.3
Safety Endpoints

Adverse events

Weight

Vital signs

Electrocardiograms (ECGs)

Clinical laboratory tests (serum chemistry, hematology and urinalysis)

Columbia-Suicide Severity Rating Scale (C-SSRS)


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6.0
STUDY DESIGN AND DESCRIPTION
6.1
Study Design
This is a randomized, double-blind, placebo-controlled, parallel-group, phase III study to 
evaluate the efficacy and safety of 8-week treatment of 2 fixed doses of Lu AA21004 (10 or 
20 mg/day) in Japanese subjects with MDD.
This study consists of a 1-to 3-week screening period, a 1-week single-blind placebo lead-in 
period, an 8-week double-blind treatment period and a 4-week safety follow-up period. Subjects 
who fulfill all inclusion criteria and none of exclusion criteria at the start of screening period 
(Visit 1) and at the start of placebo lead-in period (Visit 2) will move into the placebo lead-in 
period and receive placebo once daily for 1 week in a single-blind manner. Afterwards, these 
who fulfill all the inclusion criteria and none of the exclusion criteria at the start of double-blind 
treatment period (Visit 3) will move into the double-blind treatment period and will be 
randomized in a 1:1:1 ratio to one of the following treatment groups: the placebo group, the 
Lu AA21004 10 mg/day group or the Lu AA21004 20 mg/day group. Subjects in the placebo 
group and the Lu AA21004 10 mg/day group will receive placebo and Lu AA21004 10 mg, 
respectively, once daily from the day after Visit 3 for 8 weeks in a double-blind manner. Subjects 
in the Lu AA21004 20 mg/day group will receive Lu AA21004 10 mg once daily from the day 
after Visit 3 for 1 week and thereafter Lu AA21004 20 mg once daily for 7 weeks in a double-
blind manner. Subjects in any treatment groups will visit study sites at Week 1, 2, 4, 6 and 8 
during the double-blind treatment period for examinations/observations/assessments.
A safety follow-up contact (visit or phone call) will be made 4 weeks after the completion of the 
double-blind treatment period. Subjects who prematurely discontinue the study during the 
placebo lead-in period or the double-blind treatment period will be requested to visit the study 
site for the end-of study assessments within 7 days after the discontinuation decision is made 
wherever possible, and will be contacted 4 weeks after the last dose of the study medication for 
safety follow-up.
A schematic of the study design is shown in Figure 6.a.
A schedule of examinations/observations/assessments is listed in Appendix A.


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Screening
Period
Placebo Lead-
in Period
(Single-blind)
Double-blind Treatment Period
Follow-up Period
W -4 to -2
W -1
W 1
W 2
W 3
W 4
W 5
W 6
W 7
W 8
W 9
W 10
W 11
W 12
V1
V2
V3a)
V4
V5
V6
V7
V8
Placebo QD
Placebo QD
Lu AA21004 10 mg QD
Lu AA21004 20 mg QD b)
10 mg b)
Randomization
End of Treatment
Safety
Follow-up c)
W: week, V: visit, QD: once daily
a) Subjects will be randomized on the day of visit at the start of double-blind treatment period (Day -1). Subjects 
will start the double-blind treatment from the next day (Day 1).
b) Subjects will receive 10 mg/day for the first 1 week, and then increase the dose to 20 mg/day from the 2nd week.
c) Safety follow-up assessment will be conducted by visit to the site or on telephone.
Figure 6.a
Schematic of Study Design
6.2
Justification for Study Design, Dose, and Endpoints
6.2.1
Subject Population
It has been reported that the placebo response rate in subjects with single major depressive 
episode is higher than that in subjects with recurrent major depressive episode.[5] Since it is 
important to exclude subjects with high placebo response from clinical studies of antidepressants, 
subjects with recurrent major depressive episode are eligible for this study. In order to 
adequately evaluate the efficacy and safety, subjects with moderate to severe MDD are eligible 
for this study, and subjects with mental disorder other than MDD are excluded from this study.
6.2.2
Study Design
This study is designed based on Guideline for Clinical Evaluation of Antidepressants 
(Notification No. 1116-1 of PFSB/ELD dated 16 November 2010).[3]
A double-blind, randomized, placebo-controlled study is designed for adequate evaluation of the 
drug efficacy and safety and is used as a standard study design for antidepressants. The use of 
placebo has continued to be a subject of discussion on the grounds of possible worsening of 
depressive symptoms or potential increase in suicidal risk; however, there is no evidence that 
assignment to placebo results in permanent harm or an increased risk of committing suicide. 
Subjects at significant risk of suicide are ineligible for this study. Furthermore, suicidal risk of a 
subject will be assessed using C-SSRS at every visit.


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The subjects will be informed about the possibility of receiving placebo, the possible risks with 
placebo, and their right to withdraw from the study at any time. To a subject who discontinues 
the study, any other appropriate treatment will be provided based on the investigator’s decision.
In addition, a 1-week placebo lead-in period is set prior to the double-blind treatment period to 
exclude subjects who highly respond to placebo from the study, and thereby subjects who have 
significantly improvement or aggravation of depressive symptoms during the placebo lead-in 
period will be excluded.
Justification for sample size is described in Section 13.3.
6.2.3
Doses
In overseas phases II and III studies, the efficacy of Lu AA21004 at doses of 5, 10 and 
20 mg/day was shown, with no significant safety concerns. In addition, based on the results of 
meta-analyses in 11 placebo-controlled, double-blind, short-term studies, the differences of the 
mean changes from baseline in the MADRS total score at Week 6 or 8 between the Lu AA21004 
5, 10 or 20 mg group and the placebo group were -2.3 (p =0.007), -3.6 (p <0.001), and -4.6 (p
<0.001), respectively, showing that the difference with the placebo group became greater with 
the dose increase of Lu AA21004.
In Study CCT-002 for subjects with MDD including Japanese, Lu AA21004 was safe up to a 
dose of 20 mg/day. And although no statistically significant differences had been demonstrated 
in the efficacy between the Lu AA21004 groups and the placebo group, the efficacy of 
Lu AA21004 in the 10 and 20 mg groups was grater than in the placebo group in both overall 
population and Japanese population.
From the results of previous Japanese and overseas studies above, since there were no significant 
safety concerns about Lu AA21004 up to a dose of 20 mg/day and Lu AA21004 at doses of 10 
and 20 mg/day is expected to be effective, these 2 doses will be assessed in this study.
6.2.4
Endpoints
MADRS or HAM-D is recommended for efficacy assessments in Guideline for Clinical 
Evaluation of Antidepressants (Notification No. 1116-1 of PFSB/ELD dated 16 November 
2010).[3] Based on the guideline, the MADRS, which is designed to be sensitive to the changes
in severity of core symptom of depression, will be used for the primary endpoint evaluation [6],
and the HAM-D for the secondary endpoint evaluation in this study.[7] CGI-S and CGI-I will be 
used to assess subject’s overall severity and improvement of depression.[8] In addition to these 
objective assessments of symptoms, SDS will be used in this study to assess patient’s subjective 
treatment effects on social function disabilities due to depression.[9]
Results of overseas studies of Lu AA21004 showed that Lu AA21004 improved cognitive 
functions in subjects with MDD. In this study, DSST and PDQ-5 will be used to explore the 
effect of Lu AA21004 on cognitive functions in Japanese subjects with MDD.
Safety and tolerability of Lu AA21004 will be evaluated by monitoring of AEs, vital signs, 
weight, clinical laboratory tests, ECGs, and physical examinations. In addition with these safety 


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evaluations, since it is important to assess suicidal risk for clinical evaluation of antidepressants, 
suicidal risk will be assessed using C-SSRS at each visit in this study.[10][11]
6.3
Premature Termination or Suspension of Study or Study Site
6.3.1
Criteria for Premature Termination or Suspension of the Study
The study will be completed as planned unless 1 or more of the following criteria are satisfied 
that require temporary suspension or early termination of the study.

New information or other evaluation regarding the safety or efficacy of the study medication 
that indicates a change in the known risk/benefit profile for the product, such that the 
risk/benefit is no longer acceptable for subjects participating in the study.

Significant violation of Good Clinical Practice (GCP) that compromises the ability to achieve 
the primary study objectives or compromises subject safety.
6.3.2
Criteria for Premature Termination or Suspension of Study Sites
A study site may be terminated prematurely or suspended if the site (including the investigator) 
is found in significant violation of GCP, protocol, or contractual agreement, is unable to ensure 
adequate performance of the study, or as otherwise permitted by the contractual agreement.
6.3.3
Procedures for Premature Termination or Suspension of the Study or the 
Participation of Study Sites
In the event that the sponsor, an institutional review board (IRB), or regulatory authority elects to 
terminate or suspend the study or the participation of a study site, a study-specific procedure for 
early termination or suspension will be provided by the sponsor; the procedure will be followed 
by applicable study sites during the course of termination or study suspension.


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7.0
SELECTION AND DISCONTINUATION/WITHDRAWAL OF SUBJECTS
All entry criteria, including test results, need to be confirmed prior to randomization.
7.1
Inclusion Criteria
Subject eligibility is determined according to the following criteria:
1. In the opinion of the investigator, the subject is capable of understanding and complying with 
protocol requirements.
2. The subject signs and dates a written, informed consent form prior to the initiation of any 
study procedures.
3. The subject suffer from recurrent MDD as the primary diagnosis according to DSM-IV-TR 
criteria (classification code 296.3x).
4. The subject is a man or a woman aged 20 to 75 years (both inclusive) at the time of informed 
consent.
5. The reported duration of the current major depressive episode is 3 to 12 months (both
inclusive) at the start of screening period.
6. The subject has a MADRS total score ≥26, a HAM-D17 total score ≥18, and a CGI-S score 
≥4 at the start of screening period, the start of placebo lead-in period and the start of double-
blind treatment period.
7. A female subject of childbearing potential* who is sexually active with a nonsterilized male 
partner agrees to use routinely adequate contraception from signing of informed consent to 
the end of the follow-up period.
* Definitions of a female subject of childbearing potential are defined in Section 9.1.13
Contraception and Pregnancy Avoidance Procedure, and reporting responsibilities of 
pregnancy are defined in Section 9.1.14 Pregnancy.
<Justification for Inclusion Criteria>
Criteria 1 and 2 were set as standard requirements to conduct clinical studies.
Criterion 3 was set to identify the target disease and diagnostic criteria for this study. In addition,
in order to reduce the possibility of enrolling subjects who highly respond to placebo, the
primary diagnosis was set as recurrent MDD.
Criterion 4 was set for the lower limit of age as 20 years old because it was the adult age under
the Civil Code. In addition, since the previous pivotal phase II or III studies set 75 years old as 
the upper limit of age, the upper limit of age in this study was set as 75 years old in the light of
the possible comparison with the previous data.
Criterion 5 was set to enroll subjects who had persistent major depressive episode for at least 3 
months in consideration of diagnostic certainty. The upper limit of episode duration was set as 12 


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months since, in general, subjects with chronic depressive symptoms are highly likely to have 
other concurrent mental disorder and the low possibility that the depressive symptoms would 
completely disappear with antidepressant drugs.
Criterion 6 was set to enroll subjects with moderate or more severe MDD in severity as eligible 
for this study.
Criterion 7 was set with respect to the safety risk related to pregnancy in female subjects.
7.2
Exclusion Criteria
Any subject who meets any of the following criteria will not qualify for entry into the study:
1. The subject has any following current or past history of psychiatric disorder and/or 
neurological disorder:
–
Any current psychiatric disorder other than MDD as defined by DSM-IV-TR (To be 
assessed by Mini International Neuropsychiatric Interview: MINI). A subject who 
exhibits symptoms of anxiety is eligible unless the subject fulfills the diagnostic criteria 
for a current anxiety disorder per DSM-IV-TR.
–
Current diagnosis or history of manic, mixed or hypomanic episode, MDD with psychotic 
features, schizophrenia or any other psychotic disorder (including substance-related 
mental disorders, or mental disorders due to a general medical condition) as defined by 
DSM-IV-TR.
–
Current diagnosis or history of any substance-related disorder (except nicotine and 
caffeine-related disorders) as defined by DSM-IV-TR.
–
The subject with a positive urine drug screening result at the start of screening period or 
the start of placebo lead-in period. In case that a subject showed positive test result at the 
start of screening period because the test was conducted before washout of pretreatment 
drug, the subject is eligible as long as he/she shows negative result at the start of placebo 
lead-in period.
–
Presence or history of any clinically significant neurological disorder (including 
epilepsy).
–
Any neurodegenerative disorder (e.g. Alzheimer’s disease, Parkinson’s disease, multiple 
sclerosis, Huntington’s disease).
–
Any DSM-IV-TR axis II disorder.
2. The subject has the current or previous major depressive episode which were considered by 
the investigator to have been resistant to 2 or more adequate antidepressants treatments of at 
least 6 weeks duration each at sufficient doses.


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3. The subject has received any augmentation therapy (e.g. lithium, T3/T4, lamotrigine, sodium 
valproate, carbamazepine, additional atypical antipsychotic, or concomitant use of other 
antidepressant, etc.) for the current major depressive episode.
4. In the opinion of the investigator, the subject has experienced significant number of major 
depressive episodes in the past, and is suspected of disease other than MDD.
5. In the opinion of the investigator, the subject has experienced the first major depressive 
episode at his/her young age, and is suspected of disease other than MDD.
6. The subject has a MADRS total score at the start of double-blind treatment period that has
improved or aggravated by 25% or more from the score at the start of placebo lead-in period.
7. The subject is significantly non-compliant with the study medication in the placebo lead-in 
period; e.g., not taking the study medication for 6 or more consecutive days.
8. The subject has received electroconvulsive therapy, vagus nerve stimulation, or repetitive 
transcranial magnetic stimulation therapy within 6 months prior to the screening period, or 
plans to initiate such therapy during the study.
9. The subject is receiving cognitive-behavioral therapy or psychotherapy at the time of 
informed consent, or plans to initiate such therapy during the study.
10. The subject is at significant risk of suicide or has a score ≥5 on Item 10 (suicidal thoughts) of 
the MADRS at the start of screening period, the start of placebo lead-in period or the start of 
double-blind treatment period, or has attempted suicide within 6 months prior to the start of 
screening period.
11. The subject has experienced any environmental change (e.g. temporary retirement, 
returnment, change of residence) considered by the investigator to have the potential to 
impact on the efficacy evaluation, or plans such environmental changes during the study.
12. The subject is currently receiving drug therapy for thyroid dysfunction.
13. The subject is currently receiving hormonal therapy for gynecological disease.
14. The subject has taken excluded medications during the protocol-specified period, or will
require to take excluded medications during the study.
15. The subject has previously received vortioxetine.
16. The subject has received study medication in a previous clinical study of Lu AA21004 
(including this study).
17. The subject has a clinically significant chronic liver disease.
18. The subject has a history of severe allergy or hypersensitivity to drugs.
19. The subject has a clinically significant unstable illness, for example, hepatic impairment or 
renal insufficiency, or a cardiovascular, pulmonary, gastrointestinal, endocrine, neurological, 
rheumatologic, immunologic, infectious, neoplastic, skin and subcutaneous tissue disorders, 
eye disorders, or metabolic disturbance.


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20. The subject has clinically significant abnormal vital signs as determined by the investigator 
at the start of screening period, placebo lead-in period, or double-blind treatment period.
21. The subject has clinically significant abnormal ECG as determined by the investigator, at the 
start of the screening period, placebo lead-in period, or double-blind treatment period.
22. The subject has clinically significant abnormal findings of clinical laboratory tests as 
determined by the investigator, or has alanine aminotransferase (ALT) or aspartate 
aminotransferase (AST) >2 × ULN at the start of screening period or placebo lead-in period.
23. If female, the subject is pregnant or lactating.
24. The subject has a disease or takes medications that could, in the opinion of the investigator, 
interfere with the evaluation of the safety, tolerability, or efficacy.
25. The subject is, in the opinion of the investigator, unsuitable for this study for any other 
reason.
<Justification for Exclusion Criteria>
Criteria 1, 4, and 5 were set to exclude subjects or the possible subjects with concurrent mental 
or neurological disorder other than MDD and to adequately evaluate the efficacy and safety for 
the target disease.
Criterion 2 was set to exclude subjects or the possible subjects with refractory major depression 
and include adequate subjects for the evaluation of drug effect.
Criterion 3 was set to exclude subjects who have received augmentation therapy and include 
adequate subjects for the evaluation of drug effect since subjects who are required to receive 
augmentation therapy may have refractory major depression or concurrent mental or 
neurological disorder other than MDD.
Criterion 6 was set to exclude subjects who highly respond to placebo and include adequate 
subjects for the evaluation of drug effect. Subjects who abruptly worsen their symptoms in a 
short time are also excluded from the study in consideration of the appropriateness of drug effect 
evaluation and the safety of subjects.
Criterion 7 was set because it influences the evaluation in the placebo lead-in period.
Criteria 8, 9, 11 to 13 were set because they could influence the evaluation of efficacy.
Criteria 10, 17 to 22 were set with respect to the safety of subjects.
Criteria 14 and 24 were set because they could influence the evaluation of efficacy and safety.
Criterion 15 was set because the bias toward Lu AA21004 based on their treatment experience 
could influence the evaluation of the efficacy and safety.
Criterion 16 was set to avoid duplicated evaluation of subjects.
Criterion 23 was set with respect to the safety risk for pregnant women, fetuses, neonates, or 
nursing infant.


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Criterion 25 was set to exclude subjects who are considered to be unsuitable for this study for 
any other reason.
7.3
Excluded Medications and Treatments
Subjects must be instructed not to take any medications including over-the-counter products, 
without first consulting with the investigator.
Any treatments for depression other than the study medication, including electroconvulsive
therapy, vagus nerve stimulation, repetitive transcranial magnetic stimulation, cognitive-
behavioral therapy or psychotherapy are prohibited during the study.
A list of prohibited/restricted concomitant medication is provided in Table 7.a.
Table 7.a
List of Prohibited or Restricted Concomitant Medications
Drug Class
Comments or Exceptions
84 days before the start of double-blind treatment period (Day -84) through the end of double-blind treatment period 
(Visit 8) or early termination
(1)
Any investigational drug
Start of the screening period (Visit 1) through the end of double-blind treatment period (Visit 8) or early termination
(2)
Antidepressants
Including MAOIs.
(3)
Anxiolytics (tranquilizers)
Including benzodiazepines.
(4)
Hypnotics
Non-benzodiazepines (zolpidem, zopiclone, and eszopiclone) are allowed. 
However, use of these drugs should be kept to the minimum necessary, and 
use for 2 or more consecutive days and use at the night before a study visit 
are NOT allowed. In addition, the type and dose of non-benzodiazepines 
should NOT be changed from the start of placebo lead-in period (Visit 2) to 
the end of double-blind treatment period (Visit 8) or early termination.
(5)
Antipsychotics
Depot antipsychotics are prohibited within 6 months prior to the start of 
double-blind treatment period.
(6)
Mood stabilizers
Including lithium, valproate, valpromide.
(7)
Psychoactive herbal 
remedies/supplements
Including St. Johns Wort, kava kava, valerian, ginkgo biloba.
(8)
Psychotropic agents not 
otherwise specified
Including tryptophan, melatonin, and dopamine agonists.
(9)
Analeptics
(10) Anti-ADHD
(11) Anti-Alzheimer's disease
(12) Anticonvulsants
(13) Anti-Parkinson’s disease
(14) Erectile dysfunction drugs
(15) Anorexics
(16) Antimigraines


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(17) Antiemetics/antinauseants
Including dopamine antagonists. Only phosphoric acid preparations, bismuth 
and cola syrup are allowed.
(18) Interferon
(19) Systemic steroids
Oral preparation and injection are NOT allowed.
(20) Antibiotics
Rifampicin (oral preparation and injection) is NOT allowed.
Start of the placebo lead-in period (Visit 2) through the end of double-blind treatment period (Visit 8) or early 
termination
(21) Antiarrhythmics of class Ia, Ic
(22) Antiulcer drugs
Omeprazole, cimetidine, and sulpiride are NOT allowed.
(23) Anticoagulants/antiplatelet 
treatment
Including low dose of aspirin as antiplatelet treatment. Low-molecular 
weight heparins are allowed as needed.
(24) Antidiarrheal agents
Loperamide, bismuth, and kaolin preparations are allowed.
(25) Antihistamines
Loratadine, desloratadine, cetirizine, levocetirizine, mizolastine, and 
fexofenadine are allowed.
(26) Antineoplastics
(27) Hormones
Chronic use for contraception or treatment of benign prostatic hyperplasia 
are allowed.
(28) Hypoglycemic agents
Chronic use is allowed.
(29) Insulin
Chronic use is allowed without major change of dose or administration.
(30) Calcium antagonist
Chronic use is allowed without major change of dose or administration.
(31) Narcotic analgesics
Topical administration including for dental use is allowed.
(32) NSAIDs
Episodic use is allowed. Selective COX-2 inhibitors, acetaminophen, and 
topical NSAIDs are allowed.
(33) Cough/cold agents
Episodic use is allowed. However, chronic use of preparations containing 
ephedrine, pseudoephedrine, and codeine are NOT allowed for more than 1-
week treatment.
MAOI = monoamine oxidase inhibitor, ADHD = attention deficit hyperactivity disorder,
NSAIDs = nonsteroidal anti-inflammatory drugs, COX-2 = cyclooxygenase-2
<Justification for Prohibited or Restricted Concomitant Medications>
(1) was set since other investigational drug could influence the evaluation of the efficacy and 
safety.
(2) was set since antidepressants could influence the evaluation of the efficacy. Especially, 
concomitant use of monoamine oxidase inhibitors (MAOIs) was prohibited because concomitant 
use of MAOIs could enhance serotonin action and influence the evaluation of the efficacy, and 
because the safety of subjects should be ensured.
(3) was set since anxiolytics (tranquilizers) could improve anxiety which was known to an 
accompanying symptom of depression and influence the evaluation of the efficacy.
(4) was set since hypnotics could improve insomnia which was known to an accompanying 
symptom of depression and influence the evaluation of the efficacy. Concomitant use of non-


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benzodiazepines was allowed as needed because the extent of anxiolytic and carry-over effects 
of non-benzodiazepines was relatively weak, and thus these effects had only a small influence on 
efficacy evaluation.
(5) to (13) were set since these drugs had psychotropic activity or central nervous effects and 
could influence the evaluation of the efficacy.
(14) was set since erectile dysfunction drugs could improve sexual dysfunction and could 
influence the evaluation of the efficacy and safety.
(15) was set since anorexics influence the appetite assessment related to depression.
(16) and (17) were set since antimigraines and antiemetics/antinauseants could act on serotonin 
receptors and influence the evaluation of the efficacy and safety. Especially, concomitant use of 
antiemetics/antinauseants was prohibited because adverse events associated with the study 
medication should be appropriately evaluated.
(18) and (19) were set since interferon and systemic steroids could induce depressive symptoms 
and influence the evaluation of the efficacy.
(20) was set since antibiotics could decrease the plasma drug concentration by inducing drug 
metabolic enzymes and influence the evaluation of the efficacy and safety.
(21) and (22) were set since antiarrhythmics of class Ia, Ic, and antiulcer drugs could increase the 
plasma drug concentration by inhibiting drug metabolic enzymes and influence the evaluation of 
the efficacy and safety
(23) was set since concomitant use of anticoagulants/antiplatelet treatment drugs could enhance 
bleeding tendency.
(24) was set since gastrointestinal adverse events associated with the study medication should be 
appropriately evaluated.
(25) was set since drowsiness, an adverse drug reaction of antihistamines, could attenuate 
insomnia, which was known to an accompanying symptom of depression and influence the 
evaluation of the efficacy. Concomitant use of only loratadine, desloratadine, cetirizine, 
levocetirizine, mizolastine, and fexofenadine, which are considered to cause less drowsiness, was
allowed.
(26) was set since antineoplastics could influence the evaluation of the efficacy and safety.
(27) and (28) were set since hormones and hypoglycemic agents could influence the evaluation 
of the efficacy and safety. However, chronic use of these drugs at a certain dose was allowed as 
having little influence on the evaluation.
(29) and (30) were set since insulin and calcium antagonists could induce depressive symptoms.
However, chronic use of insulin or calcium antagonist at a certain dose was allowed as having 
little influence on the efficacy evaluation.
(31) was set since analgesic action of narcotic analgesics could influence the evaluation of the 
efficacy. However, topical administration such as for dental use is allowed since narcotic 


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analgesics have only a small influence on the evaluation.
(32) was set since the concomitant use of NSAIDs could cause upper gastrointestinal bleeding. 
However, the episodic use of NSAIDs as well as the concomitant use of selective COX-2 
inhibitors, acetaminophen, and topical NSAIDs was allowed since these treatments had a 
relatively lower effect on gastrointestinal adverse events.
(33) was set since some cough/cold agents increase the serotonin concentration of the central 
nervous system. Concomitant use of ephedrine and codeine for more than 1 week was not 
allowed due to their addictiveness.
7.4
Diet, Fluid, and Activity Control
The investigator or study collaborator should instruct subjects on the following items:
1. The subject must be punctual for visit, undergo physical examination and predefined 
examinations. If the subject cannot visit, he/she should inform the investigator or study 
collaborator as soon as possible.
2. If the subject experiences a worsening of conditions on any day the site visit is not scheduled, 
he/she should inform the investigator or study collaborator of the worsening by telephone or 
other manners as soon as possible and seek instructions.
3. The subject must take the study medication as instructed by the investigator. If the subject is 
noncompliant with study treatment, he/she should inform the investigator or study 
collaborator of the noncompliance with treatment at visit. The subject must return unused 
study medication and study medication sheets at visit.
4. The subject must not take any medications including over-the-counter products other than 
medications as instructed by the investigator without advance consulting (except for
emergency).
5. If the subject consults other medical institution from the time of informed consent to the end 
of the follow-up period, notify the physician of medical institution of the subject’s 
participation in this study.
6. If the subject consults other medical institution from the time of informed consent to the end 
of the follow-up period, notify the investigator of the circumstances and therapy.
7. The subject must visit the site under fasted conditions at Visits 2, 3 and 8 or Early 
Termination Visit. For visits serum chemistry test is scheduled, the subject visits the site 
under fasted conditions wherever possible.
8. Female subject of childbearing potential who is sexually active with a nonsterilized male 
partner must routinely use adequate contraception from the time of informed consent to the 
end of the follow-up period.


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7.5
Criteria for Discontinuation or Withdrawal of a Subject
The primary reason for discontinuation or withdrawal of the subject from the study or study 
medication should be recorded in the case report form (eCRF) using the following categories. 
For the subject who prematurely discontinues the study before entry into the placebo lead-in 
period or randomization, refer to Section 9.1.18 or 9.1.20, respectively.
1. Pretreatment event (PTE) or adverse event (AE)
The subject has experienced a pretreatment event (PTE) or AE that requires early termination 
because continued participation imposes an unacceptable risk to the subject’s health or the 
subject is unwilling to continue because of the PTE or AE.
2. Liver function test (LFT) abnormalities
Study medication should be discontinued immediately with appropriate clinical follow-up 
(including repeat laboratory tests, until a subject’s laboratory profile has returned to 
normal/baseline status, see Section 9.1.12), if the following circumstances occur at any time 
during study medication treatment:
–
alanine aminotransferase (ALT) or aspartate aminotransferase (AST) >8 × upper limit of 
normal (ULN), or
–
ALT or AST >5 × ULN and persists for more than 2 weeks, or
–
ALT or AST >3 × ULN in conjunction with elevated total bilirubin >2 × ULN or 
international normalized ratio (INR) >1.5, or
–
ALT or AST >3 × ULN with appearance of fatigue, nausea, vomiting, right upper 
quadrant pain or tenderness, fever, rash and/or eosinophilia (>5%).
3. Significant protocol deviation
The discovery post-randomization that the subject failed to meet protocol entry criteria or did 
not adhere to protocol requirements, and continued participation poses an unacceptable risk 
to the subject’s health.
4. Lost to follow-up
The subject did not return to the clinic and attempts to contact the subject were unsuccessful. 
Attempts to contact the subject must be documented.
5. Voluntary withdrawal
The subject wishes to withdraw from the study. The reason for withdrawal, if provided, 
should be recorded in the eCRF.
Note: All attempts should be made to determine the underlying reason for the withdrawal 
and, where possible, the primary underlying reason should be recorded. (i.e., 
withdrawal due to an AE or lack of efficacy should not be recorded in the “voluntary 
withdrawal” category.)
6. Study termination
The sponsor, IRB, or regulatory agency terminates the study.


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7. Pregnancy
The subject is found to be pregnant.
Note: If the subject is found to be pregnant, the subject must be withdrawn immediately. The 
procedure is described in Section 9.1.14.
8. Lack of efficacy
The investigator has determined that the subject is not benefiting from study treatment; and, 
continued participation would pose an unacceptable risk to the subject.
9. Medication noncompliance
The subject did not take the study medication for 6 or more consecutive days.
10. Other
Note: The specific reasons should be recorded in the “specify” field of the eCRF.
7.5.1
Additional Guidance for Withdrawal Criteria
Any signs of suicidal risk will be assessed throughout the study by C-SSRS and MADRS
assessments and clinical judgment of the investigator. If the subject has a significant risk of 
suicide in the opinion of the investigator, or the subject has the MADRS score of ≥5 on item 10 
(suicidal thoughts), the subject will prematurely discontinue the study.
If subject’s underlying diseases become exacerbated, and the investigator concludes any 
excluded medications or treatment is required, the subject will prematurely discontinue the study.
7.6
Procedures for Discontinuation or Withdrawal of a Subject
The investigator may discontinue a subject’s study participation at any time during the study 
when the subject meets the study termination criteria described in Section 7.5. In addition, a 
subject may discontinue his or her participation without giving a reason at any time during the 
study. Should a subject’s participation be discontinued, the primary criterion for termination 
must be recorded by the investigator. In addition, efforts should be made to perform all 
procedures scheduled for the Early Termination Visit.


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8.0
CLINICAL TRIAL MATERIAL MANAGEMENT
This section contains information regarding all medication provided directly by the sponsor, 
and/or sourced by other means, that are required by the study protocol, including important 
sections describing the management of clinical trial material.
8.1
Study Medication
8.1.1
Dosage Form, Manufacturing, Packaging, and Labeling
In this protocol, the term study medication refers to all or any of the drugs defined below.
Table 8.a
Study Medication
Name
Active Substance
Dosage Form
Strength
Manufacture
Lu AA21004 tablet
1-[2-(2,4-dimethyl-phenyl
sulfanyl)-phenyl]-piperazine, 
hydrobromide
Indistinguishable round 
biconvex tablets
10 mg
or
20 mg
Takeda 
Pharmaceutical
Company Limited
Placebo tablet
None
–
The study medications are identical in appearance.
As for the study medications for the placebo lead-in period, 14 tablets of placebo are packaged in 
1 press-through pack (PTP) sheet, and a single sheet is enclosed in an outer carton. The 1 outer 
carton (including 7 days’ spare tablets) will be provided to each subject in the placebo lead-in 
period.
As for the study medications for the double-blind treatment period, 14 tablets of Lu AA21004 or 
placebo are packaged in 1 PTP sheet. For Week 1 in the double-blind treatment period, 1 sheet 
(including 7 days’ spare tablets) is enclosed in an Inner Carton 1, and, for Weeks 2 to 8 in the 
double-blind treatment period, 5 sheets (including 21 days’ spare tablets) are enclosed in an 
Inner Carton 2. Inner Cartons 1 and 2 are packed together in an outer carton. The 1 outer carton 
will be provided to each subject in the double-blind treatment period.
The outer carton is labeled with a note that the formulation therein is used for a clinical study and 
pertinent information of the name and quantity of the study medication, the sponsor’s name and 
address, manufacturing number, and storage conditions.
8.1.2
Storage
The study medications should be stored at room temperature (1°C to 30°C).
The study medication must be kept in an appropriate, limited-access, secure place until it is used 
or returned to the sponsor or designee for destruction. The study medication must be stored under 
the conditions specified on the label, and remain in the original container until dispensed. A daily 
temperature log of the drug storage area must be maintained every working day.


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8.1.3
Dose and Regimen
For the placebo lead-in period, administration of the study medication will be started on the day 
after Visit 2, and subjects will orally take 1 tablet of placebo once daily.
For the double-blind treatment period, administration of the study medication will be started on 
the day after Visit 3, and subjects will orally take 1 tablet of Lu AA21004 at a dose of 10 mg or 
20 mg or placebo once daily.
The investigator or designee should instruct subjects to take the study medication at the same 
time, a certain time in the morning to the extent possible, throughout the study. The study 
medication can be taken under both fed and fasted conditions.
At each visit, subjects will be provided with necessary and sufficient amount of the study 
medications to be used by next visit by the investigator or designee. The investigator or designee 
must instruct subjects to bring the all remaining study medication and container (PTP sheets) at 
each visit.
The dose (tablet count) that will be provided to each group and regimen are shown in Table 8.b.
Table 8.b
Dose and Regimen
Treatment Group
Regimen
Tablet Count/Dose
Placebo
Lead-in Period
Double-blind Treatment 
Period
(Week 1)
Double-blind Treatment 
Period
(Weeks 2 to 8)
Placebo Group
Oral,
once daily
Placebo tablet ×1
Placebo tablet ×1
Placebo tablet ×1
Lu AA21004
10 mg/day Group
Oral,
once daily
Placebo tablet ×1
Lu AA21004
10 mg tablet ×1
Lu AA21004
10 mg tablet × 1
Lu AA21004
20 mg/day Group
Oral,
once daily
Placebo tablet ×1
Lu AA21004
10 mg tablet ×1
Lu AA21004
20 mg tablet ×1
8.1.4
Overdose
An overdose is defined as a known deliberate or accidental administration of the study 
medication to or by a study subject, at a dose above that which is assigned to that individual 
subject according to the study protocol. This includes any concomitant medication received at a 
dose greater than that prescribed to the subject.
All cases of overdose will be documented as AEs on an AE page of the eCRF according to 
Section 10.2.1, and should be reported as a special interest AE according to Section 10.2.1.3
(with or without associated AEs). Serious adverse events (SAEs) associated with an overdose 
should be reported according to the procedure in Section 10.2.2.
In the event of an overdose of the study medication, the investigator should take general 
symptomatic and supportive treatment, along with immediate gastric lavage where appropriate.
Intravenous fluids should be administered as needed. As in all cases of drug overdose, 


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respiration, pulse, blood pressure, and other appropriate signs should be monitored and general 
supportive treatment should be conducted.
8.2
Study Drug Assignment and Dispensing Procedures
Subjects will be assigned to receive the next available medication ID number allocated to each 
study site. The Medication ID Number will be entered onto the eCRF.
8.3
Randomization Code Creation and Storage
Randomization personnel (a person designated by the sponsor) will generate the randomization 
code. All randomization information will be stored in a secured area, accessible only by 
authorized personnel.
8.4
Study Drug Blind Maintenance
The emergency key code administration center will maintain the emergency key code until its 
breaking for an emergency or completion of database lock of all subjects.
Since analytical results of the plasma concentration may jeopardize maintenance of study
blinding, the analytical laboratory will keep the final analytical results and not disclose to a third 
party until unblinding of the study. The analytical laboratory will report the results to the sponsor 
after they receive the notification of unblinding of the study. However, the analytical laboratory 
may disclose the results to the sponsor through a responsible person for randomization before 
unblinding of the study taking measures to secure the blinding such as reassignment of the 
medication number so that persons in the laboratory may not identify a subject. The detailed 
procedure will be specified in the separately created manual for handling of biological specimen 
for pharmacokinetic analysis.
8.5
Unblinding Procedure
The study drug blind shall not be broken by the investigator unless information concerning the 
study drug is necessary for the medical treatment of the subject.
For unblinding, the investigator may contact the emergency key code administration center and 
obtain allocation information of the study medication.
The date, time, and reason the blind is broken must be recorded in the document called Record of 
Early Blind-Breaking, and the same information (except the time) must be recorded on the 
eCRF.
If any site personnel are unblinded, study drug must be stopped immediately and the subject 
must be withdrawn from the study.
For details of unblinding procedure, refer to the manual for Breaking of Emergency Key Code.


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8.6
Accountability and Destruction of Sponsor-Supplied Drugs
The site designee will receive the procedures for handling, storage, and management of study
drug created by the sponsor, according to which the site designee will appropriately manage the 
sponsor-supplied drug. The investigator will also receive those procedures from the sponsor. The 
procedures include those for ensuring appropriate receipt, handling, storage, management, 
dispensation of the sponsor-supplied drug, and collection of unused medications from the subject 
as well as return of them to the sponsor or destruction of them.
The site designee will immediately return unused medications to the sponsor after the study is 
closed at the site.


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9.0
STUDY PLAN
9.1
Study Procedures
The following sections describe the study procedures and data to be collected. For each
procedure, subjects are to be assessed by the same investigator whenever possible. The Schedule 
of Study Procedures is located in Appendix A.
9.1.1
Informed Consent Procedure
The requirements of the informed consent are described in Section 15.2.
Informed consent must be obtained prior to the subject entering into the study, and before any 
protocol-directed procedures are performed.
A unique subject identification number (subject number) will be assigned to each subject at the 
time that informed consent is explained; this subject number will be used throughout the study.
9.1.1.1
Pharmacogenomic Informed Consent Procedure
A separate informed consent form pertaining to pharmacogenomic research must be obtained 
prior to collecting a sample for Pharmacogenomic Research for this study (see Section 9.1.16). 
The provision of consent to research in pharmacogenomics is independent of consent to the other 
aspects of the study.
9.1.2
Demographics, Medical History, and Medication History Procedure
Demographic information to be obtained will include date of birth, sex, alcohol use, and smoking 
status of the subject at Screening.
Medical history to be obtained will include determining whether the subject has any mental 
disorders other than MDD (including dysthymic disorder, generalized anxiety disorder, 
obsessive-compulsive disorder, as defined by DSM-IV-TR) that resolved within 1 year prior to 
signing of informed consent. Medical history of MDD (past major depressive episode) to be 
obtained will include determining whether the subject had MDD according to Section 9.1.4.2.
Medication history information to be obtained includes any medication that stopped prior to 
signing of informed consent and used for treatment of the current major depressive episode or 
accompanying symptoms. Name of medication used, dose level, unit, dose frequency, route of 
administration, and the dates of the initial dose and the last dose must be recorded.
9.1.3
Diagnosis of MDD
Diagnosis of MDD and other psychiatric disorders must be based on DSM-IV-TR criteria. In 
addition, the Mini International Neuropsychiatric Interview (MINI) must be used as an auxiliary 
diagnostic tool. MINI is a structured diagnostic interview designed to provide a brief 
standardized evaluation of major Axis I psychiatric disorders in DSM-IV-TR. The investigator 
can use the MINI after a training session for diagnosis of MDD. Only the version provided by 
the sponsor that has been validated in Japanese will be used in this study.


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9.1.4
Assessments of Major Depressive Episode
9.1.4.1
Current Major Depressive Episode
The following items will be assessed for the current major depressive episode.
–
Start date
–
Symptom (Select from 9 symptoms listed below as defined by DSM-IV-TR.)
–
Psychotherapy (yes or no)
<Symptoms of Major Depressive Episode>
(1) Depressed mood most of the day, nearly every day, as indicated by either subjective 
report (e.g., feels sad or empty) or observation made by others (e.g., appears tearful).
(2) Markedly diminished interest or pleasure in all, or almost all, activities most of the 
day, nearly every day (as indicated by either subjective account or observation made 
by others).
(3) Significant weight loss when not dieting or weight gain (e.g., a change of more than 
5% of weight in a month), or decrease or increase in appetite nearly every day.
(4) Insomnia or hypersomnia nearly every day.
(5) Psychomotor agitation or retardation nearly every day (observable by others, not 
merely subjective feelings of restlessness or being slowed down).
(6) Fatigue or loss of energy nearly every day.
(7) Feelings of worthlessness or excessive or inappropriate guilt (which may be 
delusional) nearly every day (not merely self-reproach or guilt about being sick).
(8) Diminished ability to think or concentrate, or indecisiveness, nearly every day (either 
by subjective account or as observed by others).
(9) Recurrent thoughts of death (not just fear of dying), recurrent suicidal ideation 
without a specific plan, or a suicide attempt or a specific plan for committing suicide.
9.1.4.2
Past Major Depressive Episode
The following items will be assessed for past major depressive episode.
–
Start date and duration of each past major depressive episode.
–
Antidepressant drug treatment for each past major depressive episode (yes or no).
If the subject has received an antidepressant drug, category of the drug (select from 
SSRIs, SNRIs, or other antidepressant drugs.) and duration will be recorded.


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9.1.5
Physical Examination Procedure
A 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; and (11) other.
All subsequent physical examinations should assess clinically significant changes from the
examinations prior to first dose.
9.1.6
Weight, Height, and BMI
A subject should have weight and height measured while wearing indoor clothing and with shoes 
off. Height will be collected in centimeters without decimal places, and weight will be collected
in kilograms (kg) to 1 decimal place. The BMI will be calculated by the sponsor to 1 decimal 
place with the formula provided below:
Metric: BMI = weight (kg)/height (m)2
9.1.7
Vital Sign Procedure
Vital signs will include body temperature (infra-axillary measurement), sitting blood pressure 
(resting more than 5 minutes), and pulse (bpm).
9.1.8
Efficacy Evaluation
The efficacy will be evaluated using rating scales (MADRS, HAM-D, CGI-S/I, SDS, DSST, and 
PDQ-5). These assessments should be performed by the investigator who has sufficient 
experience in clinical practice of diagnosing and treating MDD and who was approved by the 
sponsor as a rater in this study. The same rater should, whenever possible, assess the same 
subject throughout the study.
In principle, the MADRS should be performed first at visits that the above-mentioned multiple 
rating scales will be performed. Efficacy data using these rating scales should be recorded in 
eCRF by the next visit of the subject at the latest.
In addition, self-report of depressive symptoms by subjects will be performed using Quick 
Inventory of Depressive Symptomatology (QIDS-J). For QIDS-J, any sequencing order with 
other rating scales is allowed. QIDS-J data will not be recorded in the eCRF.
9.1.8.1
Rating and Rating Training for MDD
Montgomery-Åsberg Depression Rating Scale (MADRS)
The MADRS will be used for a primary efficacy measurement. The MADRS is a depression 
rating scale consisting of 10 items representing the core symptoms of depression.[6] The 
MADRS is rated using Structured Interview Guide for MADRS (SIGMA). The rating should be 
based on a clinical interview with the subject, moving from broadly phrased questions about 
symptoms to more detailed questions. The rating is performed based on the most severe 


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condition of the subject during the past 1 week, and each item is rated from 0 to 6. Item 1 and 
Items 3 to 10 are based on subject report, and Item 2 is based on the observation of the subjects. 
The rater must decide whether the rating for each item lies on the defined scale steps (0, 2, 4, 6) 
or between them (1, 3, 5). Each item score and the total score of all items should be recorded on 
the eCRF.
Before the first rating, the investigators (hereinafter referred to as [potential] raters in this 
section) will attend a MADRS training session. Potential raters will watch and score a recorded 
MADRS interview (video/DVD). A discussion will follow the training session to achieve 
alignment among raters on the scoring of each individual item.
The sponsor will qualify the raters who achieve the scoring in the training session, and issue a 
certificate. No subject may be rated before the rater receives the certificate. For potential raters 
who cannot attend the training session or who are not qualified in the training session, similar 
MADRS training will be held in each study sites.
If a rater is changed or added during the course of the study, the newly appointed rater must 
complete all training requirements satisfactorily and must be approved by the sponsor.
Hamilton Depression Rating Scale (HAM-D)
The HAM-D is a depression rating scale that assesses overall symptoms of depression including 
somatic symptoms. The rater must rate each item score between 0 to 2/3/4 based on a clinical 
interview with the subject.[7] The rating should be based on patient’s condition during the past 1 
week prior to the time of assessment. The HAM-D21 is used for rating, and total score of the 
first 17 items is used as HAM-D17 total score. Each item score and the HAM-D17 total score 
should be recorded on the eCRF. Prior to the first rating, potential raters will attend a session on 
concerns to be addressed for the rating of HAM-D.
Clinical Global Impression Scale (CGI)
The CGI consists of 2 sub-scales: CGI-S and CGI-I.[8] The CGI-S assesses the physician’s 
impression of the subject’s current mental disorder state. The rater should use his/her total 
clinical experience with this subject population and rate the current severity of the subject’s 
mental disorder on a 7-point scale. The CGI-I assesses the subject’s improvement (or 
worsening). The rater is required to assess the subject’s condition relative to baseline* on a 7-
point scale. In all cases, the assessment should be made independent of whether the rater believes 
the improvement is study medication-related or not. Each score of CGI-S and CGI-I should be 
recorded on the eCRF. Prior to the first rating, potential raters will attend a rating session on 
concerns to be addressed for the rating of CGI.
* The start day of the double-blind treatment period (Visit 3) is defined as baseline. However, for 
the assessment at the start of double-blind treatment period (Visit 3) or early termination visit 
prior to the start of double-blind treatment period, CGI should be assessed comparing with the 
score at the start of placebo lead-in period (Visit 2).


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9.1.8.2
Social Function Assessment
Sheehan Disability Scale (SDS)
The SDS is a scale that assesses disabilities in 3 social function domains subjectively.[9] The 
subject self-rates the extent to which his or her work/school, social life/leisure activities, and 
home life/family responsibilities are impaired by his or her symptoms on a 10-point visual 
analog scale. The SDS also addresses the number of days the above functions were lost or under-
productive due to the symptoms. Each item score should be recorded on the eCRF. Prior to the 
first rating, potential raters will attend a rating session on concerns to be addressed for the rating 
of SDS.
9.1.8.3
Cognitive Function Assessments
Digit Symbol Substitution Test (DSST)
The DSST is a test battery used for assessment of cognitive functions. In the DSST, subjects are 
shown 9 digit-symbol pairs and required to pair the same digit and symbol combination. Levels 
of cognitive functions are assessed by the number of correct symbols (0 to 133 scores) within the 
time limit. DSST scores should be recorded on the eCRF. Subjects will complete the sample 
items prior to the actual test, but the results of the sample items should not be recorded on the 
eCRF. Prior to the first rating, potential raters will attend a rating session on concerns to be 
addressed for the assessment of DSST.
Perceived Deficits Questionnaire (PDQ-5)
The PDQ-5 is a self-report questionnaire by subjects used for assessment of their cognitive 
functions. PDQ-5 consists of 5 questions and provides an assessment of several domains of 
cognitive functions: attention, retrospective memory, prospective memory, and planning and 
organization. Sub-scores of each item score (0 to 4 scores) and the total score of all items should 
be recorded on the eCRF. Prior to the first rating, potential raters will attend a rating session on 
concerns to be addressed for the assessment of PDQ-5.
9.1.8.4
Self-report Assessment of Depressive Symptoms and Assessment Monitoring
Quick Inventory of Depressive Symptomatology (QIDS-J)
The QIDS-J is a basic self-report depression scale, and the partially revised version provided by 
the sponsor will be used for this study. Subjects will enter the responses to each questions of the 
QIDS-J into the terminal. The rater should not see the responses and not record them on the 
eCRF. The responses will be reviewed by the expert who has adequate experience in assessment 
of depression. Appropriateness of the efficacy evaluation will be monitored by comparing with 
results of other efficacy evaluation of the relevant subject.


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9.1.9
Suicidal Risk Assessments
Columbia-Suicide Severity Rating Scale (C-SSRS)
The C-SSRS was developed by researchers at Columbia University as a tool to help 
systematically assess suicidal ideation and behavior in subjects during participation in a clinical 
study. The C-SSRS is composed of 3 questions addressing suicidal behavior and 5 questions 
addressing suicidal ideation, with subquestions assessing the severity. The tool is administered 
via interview with the subject.[10][11] Responses to each question will be recorded on the eCRF.
Prior to the first rating, potential raters will attend a rating session on concerns to be addressed 
for the assessment of C-SSRS.
9.1.10 Documentation of Concomitant Medications
Concomitant medication is any drug given in addition to the study medication. These may be 
prescribed by a physician or obtained by the subject over the counter. Concomitant medication is 
not provided by the sponsor. At each study visit, subjects will be asked whether they have taken 
any medication other than the study medication (used from signing of informed consent through 
Visit 8 or Early Termination Visit ), and all medication including vitamin supplements, over-the-
counter medications, and oral herbal preparations must be recorded in the eCRF.
9.1.11 Documentation of Concurrent Medical Conditions
Concurrent medical conditions are those significant ongoing conditions or diseases that are 
present at signing of informed consent, except for accompanying symptoms of MDD. This 
includes clinically significant laboratory, vital sign, ECG, or physical examination abnormalities
noted at the first examination after signing of informed consent in the opinion of the investigator. 
The condition (i.e., diagnosis) should be described.
9.1.12
Procedures for Clinical Laboratory Samples
The items of clinical laboratory tests are shown in Table 9.a. Samples will be collected and 
handled in accordance with the separate operation manual. For clinical laboratory tests, the 
maximum volume of blood at any single visit is approximately 10 mL.


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Table 9.a
Clinical Laboratory Tests
Hematology
Serum Chemistry
Red blood cells (RBC)
White blood cells (WBC)
Hemoglobin
Hematocrit
Platelets
Neutrophils
Eosinophils
Basophils
Lymphocytes
Monocytes
Albumin
AST
ALT
γ-GTP
Alkaline phosphatase
Total bilirubin
Direct bilirubin
(Conjugated bilirubin)
Creatinine
Creatine kinase
Blood urea nitrogen (BUN)
Uric acid
Glucose (fasting or non-fasting) a)
Total protein
Potassium
Sodium
Calcium
Chloride
Lipids (fasting or non-fasting) a)
Triglycerides
Total Cholesterol
High-density lipoprotein cholesterol
Low-density lipoprotein cholesterol 
(direct measurement)
Hormonal Test (Visit 1 only)
Urinalysis
Thyroid stimulating hormone (TSH) b)
Free T4
b)
Protein (qualitative)
Glucose (qualitative)
Occult blood (qualitative)
Urine pH
Microscopic examination c)
(white blood cells, red blood cells, and 
casts)
Pregnancy test (female subjects of childbearing potential only)
Urine human chorionic gonadotropin (hCG)
Urine Drug Screening d)
Amphetamines (including methamphetamine), barbiturates, benzodiazepines, cannabinoids, cocaines, morphines, 
phencyclidines, and tricyclic antidepressants
a) Blood will be collected under fasted conditions at Visits 2, 3 and 8 or Early Termination Visit. For other visits, 
blood will be collected under fasted conditions wherever possible.
b) TSH will be measured at Visit 1, and when TSH value is outside the normal range, free T4 will be measured. If a 
clinically significant abnormality of thyroid gland is found based on the results of TSH and free T4, the subject 
will be excluded from the study.
c) Microscopic examination will be performed if abnormality is found in any item in urinalysis.
d) If the subject has a positive urine drug result, he/she will be excluded from the study. However, when the subject 
has a positive urine test result at Visit 1 because the urine test was performed prior to washout of pretreatment 
drug, the subject is eligible for the study if he/she has a negative drug test result at Visit 2.
The central laboratory will perform laboratory tests for hematology, serum chemistry, urinalysis, 
and hormonal test. The local laboratory will perform the pregnancy test and urine drug screening.
The results of laboratory tests will be returned to the investigator, who is responsible for 
reviewing and filing these results.
If subjects experience ALT or AST >3 × ULN, follow-up laboratory tests (at a minimum, serum 
alkaline phosphatase, ALT, AST, total bilirubin, γ-GTP, and INR) should be performed within a 
maximum of 7 days and preferably within 48-72 hours after the abnormality was noted. If the 
ALT or AST remains elevated >3 × ULN on these 2 consecutive occasions, the abnormality 
should be recorded as a special interest AE (hepatic impairment) by the investigator, and follow


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the procedure specified in Sections 10.1.5.2 and 10.2.1.3. After additional examinations and 
detailed monitoring, the investigator must contact the sponsor for consideration of possible 
discontinuation of the study medication, discussion of the relevant subject details and possible 
alternative etiologies.
If subjects experience ALT or AST >3 × ULN and total bilirubin >2 × ULN, the investigator 
must refer to instructions in Section 7.5 Criteria for Discontinuation or Withdrawal of a Subject 
and Section 10.2.3 Reporting of Abnormal Liver Function Tests.
9.1.13 Contraception and Pregnancy Avoidance Procedure
From signing of informed consent, throughout the duration of the study, to the end of the follow-
up period, female subjects of childbearing potential (e.g., non-sterilized or premenopausal female 
subjects) who are sexually active with a nonsterilized male partner must use adequate 
contraception. Subjects will be provided with information on acceptable methods of 
contraception as part of the subject informed consent process and will be asked to sign a consent 
form stating that they understand the requirements for avoidance of pregnancy during the course 
of the study. During the course of the study, regular urine human chorionic gonadotropin (hCG) 
pregnancy tests will be performed, and subjects will receive continued guidance with respect to 
the avoiding pregnancy as part of the study procedures (Appendix A).
At visits when pregnancy tests are performed, subjects must be confirmed of having a negative 
urine hCG pregnancy test, as well as at the follow-up examination.
9.1.14 Pregnancy
If any subject is found to be pregnant during the study she should be withdrawn and any study 
medication should be immediately discontinued.
If the pregnancy occurs during administration of active study medication from the start of the 
study medication in the double-blind treatment period to the end of the follow-up period, the 
pregnancy should be reported immediately, using a pregnancy notification form, to the contact 
listed in the attachment.
Should the pregnancy occur during or after administration of blinded drug, the investigator must 
inform the subject of their right to receive treatment information. If the subject chooses to 
receive unblinded treatment information, the individual blind should be broken by the 
investigator. Subjects randomized to placebo need not be followed.
If the female subject agrees to the primary care physician being informed, the investigator should 
notify the primary care physician (obstetrics and gynecology specialist) that the subject was 
participating in a clinical study at the time she became pregnant and provide details of treatment 
the subject received (blinded or unblinded, as applicable).
All pregnancies will be followed up to final outcome, using the pregnancy form. The outcome, 
including any premature termination, must be reported to the sponsor. An evaluation after the 
birth of the child will also be conducted.


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9.1.15 ECG Procedure
A standard 12-lead ECG will be recorded. The investigator (or a qualified observer at the study
site) will interpret the ECG using 1 of the following categories: within normal limits, abnormal 
but not clinically significant, or abnormal and clinically significant. The following parameters 
will be recorded on the eCRF from the subject’s ECG trace: RR interval, PR interval, QT 
interval, QRS interval, and QTcB interval. QTcF interval will be calculated by the sponsor. ECG 
traces recorded on thermal paper should be photocopied to avoid degradation of trace over time.
9.1.16 Pharmacogenomic Sample Collection
One 5-mL whole blood sample for pharmacogenomics will be collected at the start of placebo 
lead-in period (Visit 2) or at the earliest possible time during the study from subjects who signed 
informed consent of pharmacogenomics and entered into the placebo lead-in period for possible 
exploratory investigation of markers enabling the prediction of drug response. 
Pharmacogenomic sample should not be collected from any subject who has received 
comparable bone marrow transplant or whole blood transfusion within 6 months of any sample 
collection.
See the separately created procedure for collecting, handling, and storage of pharmacogenomic 
samples.
9.1.17 Pharmacokinetic Sample Collection and Analysis
9.1.17.1 Collection of Blood for Pharmacokinetic Sampling
Blood samples will be collected in concurrence with blood collection for clinical laboratory tests. 
The exact date and time of the blood collection and dosing times of the last 2 doses prior to the 
blood collection will be recorded on the eCRF. Refer to the separately created procedure for 
collection, handling, and shipping of blood samples.
Since drug concentrations of subjects in the placebo group will not be measured, the assignment 
personnel will send an operation manual to the central laboratory to identify samples of subjects 
in the placebo group. Drug concentration data will be reported to the sponsor after unblinding of 
the study.
9.1.17.2 Bioanalytical Methods
Plasma concentrations of Lu AA21004 and its metabolites (Lu AA34443 and Lu AA39835) will 
be analyzed with the validated LC/MS/MS method.
9.1.18 Documentation of Screen Failure Prior to Entrance into Placebo Lead-in Period
For all subjects who signed informed consent and prematurely discontinue the study prior to 
entry into the placebo lead-in period, the investigator should complete the eCRF. The registration 
center should be contacted as a notification of screen failure prior to entry into the placebo lead-
in period.


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The primary reason for screen failure prior to entry into the placebo lead-in period will be 
recorded in the eCRF using the following categories:

PTE/AE

Did not meet inclusion criteria or did meet exclusion criteria <specify the reason.>

Significant protocol deviation

Lost to follow-up

Voluntary withdrawal <specify the reason.>

Study termination

Other <specify the reason.>
The identification numbers assigned to subjects who prematurely discontinues prior to entry into
the placebo lead-in period should not be reused.
9.1.19 Documentation of Study Entrance into Placebo Lead-in Period
Only subjects who meet all of the inclusion criteria and none of the exclusion criteria at the start 
of placebo lead-in period are eligible for entrance into the placebo lead-in period.
If the subject is found to be not eligible for the placebo lead-in period, the investigator should 
record the primary reason for failure on the applicable eCRF.
9.1.20 Documentation of Screen Failure Prior to Randomization
For all subjects who prematurely discontinue the study after entry into the placebo lead-in period 
and prior to randomization, the investigator should complete the eCRF. The registration center
should be contacted as a notification of discontinuation after entry into the placebo lead-in period 
and prior to randomization.
The primary reason for screen failure after entry into the placebo lead-in period and prior to 
randomization is recorded in the eCRF using the following categories:

PTE/AE

Did not meet inclusion criteria or did meet exclusion criteria <specify the reason.>

Significant protocol deviation

Lost to follow-up

Voluntary withdrawal <specify the reason.>

Study termination

Other <specify the reason.>


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The end-of-study evaluation will be performed for all subjects who prematurely discontinue the 
study after entry into the placebo lead-in period and prior to randomization according to Section 
9.3.5.
9.1.21 Documentation of Randomization
Only subjects who meet all of the inclusion criteria and none of the exclusion criteria are eligible 
for randomization and entrance into the double-blind treatment period.
If the subject is found to be not eligible for randomization, the investigator should record the 
primary reason for screen failure on the eCRF.
9.2
Monitoring Subject Treatment Compliance
Subjects will be required to bring unused study medication containers (PTP sheets)/unused 
medications to each dispensing site visit. The dates of the initial and last dosing, as well as any 
details where a subject takes more or less of the study medications than the specified dose, will 
be recorded on the eCRF.
If a subject is significantly noncompliant with the study medication (e.g., 6 or more consecutive 
doses missed), it may be appropriate to withdraw the subject from the study. All subjects should 
be reinstructed about the dosing requirement during study contacts. The authorized study 
personnel conducting the re-education must document the process in the subject source records.
9.3
Schedule of Observations and Procedures
The schedule for all study-related procedures for all evaluations is shown in Appendix A. 
Assessments should be completed at the designated visit/time point(s).
9.3.1
Screening Period
Informed consent must be obtained prior to the initiation of any study procedures.
The examinations/observations/assessments listed below will be performed at the start of 
screening period (Days -32 to -12; Visit 1). Subjects will be screened in accordance with 
predefined inclusion and exclusion criteria as described in Section 7.0. See Section 9.1.18 for 
procedures for documenting a subject who prematurely discontinues the study prior to entry into
the placebo lead-in period.

Demographics, medical history, and medication history

Diagnosis of MDD

Assessments of the major depressive episode

Physical examination

Weight and height

Vital signs


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
Concomitant medications

Concurrent medical conditions

Clinical laboratory tests

Pregnancy test (female subjects of childbearing potential only)

Urine drug screening

ECG procedure

C-SSRS

PTE assessment

MADRS

HAM-D

CGI-S
9.3.2
Placebo Lead-in Period
The examinations/observations/assessments listed below will be performed at the start of placebo 
lead-in period (Day -8 ± 3; Visit 2). Subjects will be screened in accordance with predefined 
inclusion and exclusion criteria as described in Section 7.0. Subjects assessed to be eligible will 
enter the placebo lead-in period. See Section 9.1.18 for procedures for documenting subjects who 
prematurely discontinue the study prior to entry into the placebo lead-in period.

Physical examination

Weight

Vital signs

Concomitant medications

Clinical laboratory tests (fasted)

Pregnancy test (female subjects of childbearing potential only)

Urine drug screening.

Blood sampling for pharmacogenomics* (subjects who provided written consent only)

ECG procedure

C-SSRS

PTE assessment

MADRS

HAM-D


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
CGI-S

SDS

DSST

PDQ-5

QIDS-J

Dispense of the study medication (for the placebo lead-in treatment)
* Blood sampling for pharmacogenomics will be performed at the start of placebo lead-in period 
(Visit 2) or at the earliest possible time during the study.
9.3.3
Start of Double-blind Treatment Period/Randomization
The examinations/observations/assessments listed below will be performed at the start of double-
blind treatment period (Day -1; Visit 3). Subjects will be screened in accordance with predefined 
inclusion and exclusion criteria as described in Section 7.0. Subjects assessed to be eligible will 
be randomized according to Section 8.2 and enter the double-blind treatment period. See Section 
9.1.20 for documenting subjects who prematurely discontinue the study after entry into the 
placebo lead-in period and prior to randomization.
The examinations/observations/assessments at Visit 3 should be regarded as baseline
evaluations.

Physical examination

Weight

Vital signs

Concomitant medications

Clinical laboratory tests (fasted)

Pregnancy test (female subjects of childbearing potential only)

ECG procedure

C-SSRS

PTE/AE assessment

MADRS

HAM-D

CGI-S

CGI-I (assessed comparing with a CGI score at Visit 2).

SDS


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
DSST

PDQ-5

QIDS-J

Randomization

Dispense of the study medication (for the double-blind treatment [Inner Carton 1])

Collection of the study medication dispensed at the last visit/Consultation about subjects' 
compliance
9.3.4
Double-blind Treatment Period
Visit 4
The examinations/observations/assessments listed below will be performed at 1 week after the 
start of double-blind treatment period (Day 7 ± 1; Visit 4).

Vital signs

Concomitant medications

C-SSRS

PTE/AE assessment

MADRS

CGI-S

CGI-I (assessed comparing with a CGI score at Visit 3).

DSST

PDQ-5

QIDS-J

Dispense of the study medication (for the double-blind treatment [Inner Carton 2])

Collection of the study medication dispensed at the last visit/Consultation about subjects' 
compliance
Visit 5
The examinations/observations/assessments listed below will be performed at 2 weeks after the 
start of double-blind treatment period (Day 14 ± 3; Visit 5).

Vital signs

Concomitant medications

C-SSRS


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
PTE/AE assessment

MADRS

CGI-S

CGI-I (assessed comparing with a CGI score at Visit 3).

QIDS-J

Dispense of the study medication (for the double-blind treatment [Inner Carton 2])

Collection of the study medication dispensed at the last visit/Consultation about subjects' 
compliance
Visit 6
The examinations/observations/assessments listed below will be performed at 4 weeks after the 
start of double-blind treatment period (Day 28 ± 3; Visit 6).

Weight

Vital signs

Concomitant medications.

Clinical laboratory tests

Pregnancy test (female subjects of childbearing potential only)

Pharmacokinetic sampling

ECG procedure

C-SSRS

PTE/AE assessment

MADRS

CGI-S

CGI-I (assessed comparing with a CGI score at Visit 3).

QIDS-J

Dispense of the study medication (for the double-blind treatment [Inner Carton 2])

Collection of the study medication dispensed at the last visit/Consultation about subjects' 
compliance
Visit 7
The examinations/observations/assessments listed below will be performed at 6 weeks after the 
start of double-blind treatment period (Day 42 ± 3; Visit 7).


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
Vital signs

Concomitant medications

C-SSRS

PTE/AE assessment

MADRS

CGI-S

CGI-I (assessed comparing with a CGI score at Visit 3).

QIDS-J

Dispense of the study medication (for the double-blind treatment [Inner Carton 2])

Collection of the study medication dispensed at the last visit/Consultation about subjects' 
compliance
9.3.5
End of Double-blind Treatment Period or Early Termination
The examinations/observations/assessments listed below will be performed at 8 weeks after the 
start of double-blind treatment period (Day 56 ± 3; Visit 8) as evaluation at the end of double-
blind treatment period. Subjects who prematurely discontinue the study during the placebo lead-
in period or double-blind treatment period will be requested to visit the study site for early 
termination examinations/observations/assessments within 7 days after the day of study 
discontinuation wherever possible.

Physical examination

Weight

Vital signs

Concomitant medications

Clinical laboratory tests (fasted)

Pregnancy test (female subjects of childbearing potential only)

Pharmacokinetic sampling (not performed at early termination)

ECG procedure

C-SSRS

PTE/AE assessment

MADRS

HAM-D

CGI-S


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
CGI-I*

SDS

DSST

PDQ-5

QIDS-J

Collection of the study medication dispensed at the last visit/Consultation about subjects' 
compliance
* The CGI-I score will be assessed comparing with that at Visit 3. However, at early termination 
prior to Visit 3, the CGI-I score will be assessed by comparing with that at Visit 2.
For all randomized subjects, the investigator must complete the End of Study eCRF page.
After evaluation at the end of double-blind treatment period or early termination, standard 
therapy may be performed as needed.
9.3.6
Follow-up Period
A safety follow-up assessment will be conducted at 12 weeks after the start of double-blind 
treatment period (Day 84 ± 5). For subjects who prematurely discontinue the study during the 
placebo lead-in period or double-blind treatment period, the follow-up assessments will be made 
28 ± 5 days after the last dose of the study medication. The follow-up assessments may either be 
conducted as a visit to the site or as a telephone contact. In the follow-up, the following will be 
assessed: outcomes of AEs continuing at Visit 8 or early termination visit, new SAEs developing
during the follow-up period, and special interest AEs will be assessed. Female subjects of child-
bearing potential will be asked to confirm whether they are pregnant or not.
9.3.7
Post Study Care
The study medication will not be available upon completion of the subject’s participation in the 
study.
9.4
Biological Sample Retention and Destruction
Samples of 5-mL whole blood collected for pharmacogenomics will be stored frozen at the 
pharmacogenomic specimen storage facility (see the contact listed in the attachment 1; 
hereinafter referred to as specimen storage facility).
The collected samples will be retained for 20 years from the day when a first pharmacogenomic 
sample was collected during the study.
When subjects request disposal of a stored sample during the retention period, the site will ask 
the specimen storage facility to destroy the sample via the sponsor according to the procedure. 
The specimen storage facility will destroy the sample in accordance with the procedure, and 
notify the site and sponsor. However, any samples should not be destroyed if all the documents 


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(including medical records) have been destroyed which could identify the subject, and it is 
impossible to link the sample to the subject.
Even if the sample can be linked to the subject, when pharmacogenomic investigation has been 
conducted, the remaining sample will be destroyed and the results of pharmacogenomic 
investigation of the anonymized subject will be retained by the sponsor.
The sponsor will build a management system required for protection of the subject’s personal 
information, define standards for collecting, storage, and destruction of samples, and prepare 
appropriate procedures.


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10.0
PRETREATMENT EVENTS AND ADVERSE EVENTS
10.1
Definitions
10.1.1 PTEs
A PTE is defined as any untoward medical occurrence in a clinical investigation subject who has 
signed informed consent to participate in a study but prior to administration of any study 
medication; it does not necessarily have to have a causal relationship with study participation.
10.1.2 AEs
An AE is defined as any untoward medical occurrence in a clinical investigation subject 
administered a drug; it does not necessarily have to have a causal relationship with this 
treatment.
An AE can therefore be any unfavorable and unintended sign (e.g., a clinically significant 
abnormal laboratory finding), symptom, or disease temporally associated with the use of a drug 
whether or not it is considered related to the drug.
10.1.3 Additional Points to Consider for PTEs and AEs
An untoward finding generally may:

Indicate a new diagnosis or unexpected worsening of a pre-existing condition. (Intermittent 
events for pre-existing conditions underlying disease should not be considered PTEs or AEs.)

Necessitate therapeutic intervention.

Require an invasive diagnostic procedure.

Require discontinuation or a change in dose of study medication or a concomitant 
medication.

Be considered unfavorable by the investigator for any reason.

PTEs/AEs caused by a study procedure (e.g., a bruise after blood draw) should be recorded 
as a PTE/AE.
Diagnoses vs. signs and symptoms:

Each event should be recorded to represent a single diagnosis. Accompanying signs 
(including abnormal laboratory values or ECG findings) or symptoms should NOT be 
recorded as additional AEs. If a diagnosis is unknown, sign(s) or symptom(s) should be 
recorded appropriately as a PTE(s) or as an AE(s).
Laboratory values and ECG findings:

Changes in laboratory values or ECG parameters are only considered to be PTEs or AEs if 
they are judged to be clinically significant (i.e., if some action or intervention is required or if 
the investigator judges the change to be beyond the range of normal physiologic fluctuation). 


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A laboratory re-test and/or continued monitoring of an abnormal value are not considered an 
intervention. In addition, repeated or additional noninvasive testing for verification, 
evaluation, or monitoring of an abnormality is not considered an intervention.

If abnormal laboratory values or ECG findings are the result of pathology for which there is 
an overall diagnosis (e.g., increased creatinine in renal failure), the diagnosis only should be 
reported appropriately as a PTE or as an AE.
Pre-existing conditions:

Of pre-existing conditions (present at the time of signing of informed consent), events that 
are considered accompanying symptoms of MDD should NOT be recorded as concurrent 
medical conditions, PTEs, or AEs.

Other pre-existing conditions are considered concurrent medical conditions and should NOT 
be recorded as PTEs or AEs. Baseline evaluations (e.g., laboratory tests, ECG, X-rays) 
should NOT be recorded as PTEs unless related to study procedures. However, if the subject 
experiences an abnormality (e.g., internal bleeding due to blood sampling) associated with
the baseline evaluations, the abnormality should be recorded as a PTE and recorded on eCRF.
If the subject experiences a worsening or complication of such a concurrent condition, the 
worsening or complication should be recorded appropriately as a PTE (worsening or 
complication occurs before start of study medication) or an AE (worsening or complication 
occurs after start of study medication). The investigator should ensure that the event term 
recorded captures the change in the condition (e.g., “worsening of hypertension”).

If a subject has a pre-existing episodic condition (e.g., asthma, epilepsy) any occurrence of an 
episode should only be captured as a PTE/AE if the episodes become more frequent, serious 
or severe in nature, that is, the investigator should ensure that the AE term recorded captures 
the change in the condition from Baseline (e.g., “worsening of…”).

If a subject has a degenerative concurrent condition (e.g., cataracts, rheumatoid arthritis), 
worsening of the condition should only be captured as a PTE/AE if occurring to a greater 
extent to that which would be expected. Again, the investigator should ensure that the AE 
term recorded captures the change in the condition (e.g., “worsening of…”).
Worsening of PTEs or AEs:

If the subject experiences a worsening or complication of a PTE after starting administration 
of the study medication, the worsening or complication should be recorded appropriately as 
an AE. The investigator should ensure that the AE term recorded captures the change in the 
condition (e.g., “worsening of…”).

If the subject experiences a worsening or complication of an AE after any change in study 
medication, the worsening or complication should be recorded as a new AE. The investigator 
should ensure that the AE term recorded captures the change in the condition (e.g., 
“worsening of…”).


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Changes in severity of AEs /Serious PTEs:

If the subject experiences changes in severity of an AE/serious PTE, the event should be 
captured once with the maximum severity recorded.
Preplanned surgeries or procedures:

Preplanned procedures (surgeries or therapies) that were scheduled prior to signing of 
informed consent are not considered PTEs or AEs. However, if a preplanned procedures is 
performed early (e.g., as an emergency) due to a worsening of the pre-existing condition, the 
worsening of the condition should be captured appropriately as a PTE or an AE. 
Complications resulting from any planned surgery should be reported as AEs.
Elective surgeries or procedures:

Elective procedures (e.g., cosmetic surgery) performed where there is no change in the 
subject’s medical condition should not be recorded as PTEs or AEs, but should be 
documented in the subject’s source documents. Complications resulting from an elective 
surgery should be reported as AEs.
Insufficient clinical response (lack of efficacy):

Insufficient clinical response, efficacy, or pharmacologic action, should NOT be recorded as 
an AE. The investigator must make the distinction between exacerbation of pre-existing 
illness and lack of therapeutic efficacy.
Overdose:

All cases of overdose with any medication, including the case without manifested side 
effects, are considered AEs and will be recorded on the AE page of the eCRF. In addition, 
cases of overdose will be reported as special interest AEs.
Suicidality events:

A completed suicide is always captured as an SAE based on its fatal outcome. Furthermore, 
active suicidal behavior such as suicidal ideation with a specific plan and suicide attempt will 
also be collected as an SAE.

Unless the event in question meets the definition of "serious," suicidal thoughts or suicidal 
ideation without a specific plan or action will be collected as a non-serious AE in accordance 
with the standard AE reporting requirements.

A subject who presents with self-mutilation should be asked by the investigator to clarify 
whether the subject was attempting suicide. If the subject was attempting suicide, the 
behavior will be collected as an SAE, and the specific suicidal behavior (e.g., wrist cutting) 
will be recorded in the eCRF. If the subject was not attempting suicide, the behavior will be 
collected as a non-serious AE in accordance with the standard AE reporting requirements.
10.1.4 SAEs
An SAE is defined as any untoward medical occurrence that at any dose:


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1. Results in DEATH.
2. Is LIFE THREATENING.*
3. Requires inpatient HOSPITALIZATION or prolongation of existing hospitalization.
4. Results in persistent or significant DISABILITY/INCAPACITY.
5. Leads to a CONGENITAL ANOMALY/BIRTH DEFECT.
6. Is an IMPORTANT MEDICAL EVENT that satisfies any of the following:
• May require intervention to prevent items 1 through 5 above.
• May expose the subject to danger, even though the event is not immediately life threatening 
or fatal or does not result in hospitalization.
• Includes any event or synonym described in the Takeda Medically Significant AE List 
(Table 10.a).
* 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.
Table 10.a
Takeda Medically Significant AE List
Term
Acute respiratory failure/acute respiratory distress 
syndrome (ARDS)
Torsade de pointes / ventricular fibrillation
/ ventricular tachycardia
Malignant hypertension
Convulsive seizure (including seizure and epilepsy)
Agranulocytosis
Aplastic anemia
Toxic epidermal necrolysis/Stevens-Johnson syndrome
Hepatic necrosis
Acute liver failure
Anaphylactic shock
Acute renal failure
Pulmonary hypertension
Pulmonary fibrosis (including interstitial lung disease)
Neuroleptic malignant syndrome / malignant 
hyperthermia
Spontaneous abortion / stillbirth and fetal death
Confirmed or suspected transmission of infectious agent 
by a medicinal product
Confirmed or suspected endotoxin shock
The following events are also to be considered SAEs.

Completed suicide

Active suicidal ideation

Active suicidal behavior such as suicide attempt

Self-injury with suicide attempt


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PTEs that fulfill 1 or more of the serious criteria above are also to be considered SAEs and 
should be reported and followed up in the same manner (see Sections 10.2.2 and 10.3).
10.1.5 Special Interest AEs
A Special Interest Adverse Event (serious or non-serious) is 1 of scientific and medical concern 
specific to the compound or program. In this study, skin reaction, allergic reaction, hepatic 
impairment, and overdose are defined as special interest AEs. Ongoing monitoring and 
communication by the investigator to Takeda may be appropriate, and if the events occur, they 
will be reported according to Section 10.2.1.3. Such events may require further investigation in 
order to characterize and understand them.
10.1.5.1 Skin and Allergic Reaction
When the causal relationship between rash or allergic reaction and the study medication is 
assessed as probable or possible, rash or allergic reaction will be reported as a special interest AE
according to Section 10.2.1.3 after the nature and the site are characterized. When the causal 
relationship between rash or allergic reaction and the study medication is assessed as not related, 
rash or allergic reaction is not required to be reported as a special interest AE.
When rash or allergic reaction develops, the subject should be adequately examined for any 
clinical features that may suggest the development of drug reaction with eosinophilia and 
systemic symptoms (DRESS), toxic epidermal necrolysis (TEN), or Stevens-Johnson syndrome 
(SJS). In addition, the subject should be monitored for the appearance of any of the following 
signs:
a)
Involvement of mucous membrane or the conjunctiva
b)
Development of skin pain
c)
Urticaria, blistering, or other types of skin lesions
d)
Angioedema
If a subject presents with symptoms of a systemic reaction (e.g., generalized rash), or signs of 
severe rash, or if it is clinically necessary, the following laboratory parameters should also be 
investigated and monitored accordingly: complete blood count with differentials, liver and renal 
function tests, and urinalysis. If deemed necessary by the investigator, subjects should be 
received examination by a dermatologist, and photographs of the skin rash and/or skin biopsies 
will be obtained as needed.
10.1.5.2 Hepatic Impairment
If a subject has ALT or AST >3 × ULN, and follow-up laboratory tests (see Section 9.1.12) also 
shows ALT or AST >3 × ULN, it should be reported as a special interest AE according to 
Section 10.2.1.3. In addition, the relevant subject details and possible alternative etiologies other 
than the study medication should be investigated.


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If the abnormality falls under a drug-induced liver function abnormality that may lead to severe 
hepatic impairment (see Section 10.2.3), it should also be reported as an SAE.
10.1.5.3 Overdose
For overdose, refer to Section 8.1.4. All cases of overdose will be documented as AEs on an AE
page of the eCRF and should be reported as special interest AEs according to Section 10.2.1.3
(with or without associated adverse events).
10.1.6 Severity of PTEs and AEs
The different categories of intensity (severity) are characterized as follows:
Mild:
The event is transient and easily tolerated by the subject.
Moderate:
The event causes the subject discomfort and interrupts the subject’s usual activities.
Severe:
The event causes considerable interference with the subject’s usual activities.
10.1.7 Causality of AEs
The relationship of each AE to study medication(s) will be assessed using the following 
categories:
Probable:
An AE that has a strong temporal relationship to the study medication(s), or recurs on re-challenge, 
and another etiology is unlikely or significantly less likely.
Possible:
An AE that has a suggestive temporal relationship to the study medication(s), and an alternative 
etiology is equally or less likely.
Not Related:
An AE that does not follow a reasonable temporal sequence from administration of the study 
medication(s) or that can reasonably be explained by other factors, such as underlying diseases, 
concurrent medical conditions, concomitant drugs and concurrent treatments (that is, there is no 
causal relationship between the study medication and the AE).
An AE is considered causally related to the use of the study medication when the causality 
assessment is probable or possible.
10.1.8 Relationship to Study Procedures
Relationship (causality) to study procedures should be determined for all PTEs and AEs.
The relationship should be assessed as Related if the investigator considers that there is 
reasonable possibility that an event is due to a study procedure. Otherwise, the relationship 
should be assessed as Not Related.


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10.1.9 Start Date
The start date of AEs/PTEs will be determined based on the criteria described below.
AE/PTE
Start Date
Signs, symptoms, and diseases (diagnosis)
Date when the subject or the investigator first notices the 
sign or symptom of the AE
Asymptomatic disease
Date when a definite diagnosis is determined based on 
the results of diagnostic testing. Even if obsolete findings 
are indicated based on the test findings or the 
approximate time of onset can be estimated, the date 
when a definite diagnosis is made should be recorded.
Worsening of concurrent medical conditions or PTEs
Date when the subject or the investigator first notices 
worsening of the disease or symptom.
Normal in the initial assessment after signing of informed 
consent but abnormal in the subsequent assessment (for 
PTEs)
Abnormal in the assessment after the start of the study 
medication (for AEs)
Date when the test is performed in which a clinically 
significant abnormal test value is observed
Abnormal in the initial assessment after signing of 
informed consent and has worsened in the subsequent 
assessment (for PTEs)
Abnormal in the assessment at the start of the study 
medication and has worsened in the subsequent 
assessment (for AEs)
Date when the test is performed in which a medically 
significant elevation, reduction, increase or decrease in 
clinical laboratory test values is observed
10.1.10 Stop Date
The stop date of the AE/PTE is the date at which the subject recovered, the event resolved but 
with sequelae or the subject died. The AE/PTE not determined to have resolved at the end of the 
study is assessed as ongoing 
10.1.11 Frequency
Episodic AEs/PTEs (e.g., constipation, diarrhea, vomiting) or those which occur repeatedly over 
a period of consecutive days are intermittent. All other events are continuous.
10.1.12 Action Concerning Study Medication
The action taken for the study medication is classified and defined as follows:
Drug withdrawn
The study medication is stopped due to the particular AE (including withdrawal at the subject’s 
discretion).
Dose not changed
The dose is not changed even after the occurrence of the particular AE.
This shall apply in case the study medication is stopped due to another AE.
This shall also apply, for example, in case the study medication is stopped for any reason other 
than intervention for the particular AE, such as the subject’s negligence.


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Unknown
For example, attempts to contact the subject are unsuccessful and the course of the particular 
AE after the start date cannot be followed.
Not Applicable
For example, the study medication has already been completed or stopped before the onset of 
the particular AE.
10.1.13 Outcome
The outcome of AEs/PTEs is classified as follows:
Category
Assessment Criteria
Recovered/Resolved
• The symptom or finding has disappeared or resolved.
• The abnormal laboratory value has improved to the normal range or to the level at baseline 
(for AEs) or at the first assessment after signing of informed consent (for PTEs).
Recovering/Resolving
• The intensity is lowered by at least 1 grade.
• The symptom or finding has almost disappeared.
• The abnormal laboratory value has improved, but not to the normal range or the level at 
baseline (for AEs) or at the first assessment after signing of informed consent (for PTEs).
• The subject died from a cause other than the particular AE/PTE with the condition 
remaining “recovering/resolving” (no need to record the date of death).
Not recovered/not 
resolved
• There is no change in the symptom, finding, or laboratory value.
• The intensity of the symptom, finding, or laboratory value on the last day of the observed 
period has got worsen than when it started.
• An irreversible congenital anomaly.
• The subject died from another cause with the particular AE/PTE state remaining “Not 
recovered/not resolved” AE/PTE (no need to record the date of death).
Resolved with 
sequelae
• The subject recovered from an acute AE/PTE but was left with impairment that interferes 
with the subject’s daily life.
Fatal
• There is a direct relationship between the death and the AE/PTE.
• The direct relationship indicates that the AE/PTE caused or apparently contributed to the 
death.
• The outcome of another AE/PTE reported in the same subject that is not determined 
(considered or estimated) as the cause of the death is not assessed as “fatal.”
• If the outcome is “fatal,” the date of death should be recorded.
Unknown
• The course of the AE/PTE after the start date cannot be followed up as specified in the 
protocol due to hospital change or residence change.
10.2
Procedures
10.2.1 Collection and Reporting of AEs
10.2.1.1 PTE and AE Collection Period
Collection of PTEs will commence from the time the subject signs the informed consent to 
participate in the study and continue until the subject is first administered study medication in the 


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placebo lead-in period. For subjects who discontinue prior to the first study medication 
administration in the placebo lead-in period, PTEs are collected until the subject discontinues 
study participation.
Collection of AEs will commence from the time that the subject is first administered study 
medication in the placebo lead-in period. Routine collection of AEs will continue until Visit 8 or 
Early Termination Visit.
Collection of SAEs or special interest AEs will continue until the end of the follow-up period.
10.2.1.2 PTE and AE Reporting
At each study visit, the investigator will assess whether any subjective AEs have occurred. A 
neutral question, such as “How have you been feeling since your last visit?” may be asked. 
Subjects may report AEs occurring at any other time during the study.
Subjects experiencing a serious PTE must be monitored until the symptoms subside and any 
clinically relevant changes in laboratory values have returned to baseline or until there is a 
satisfactory explanation for the change (for permanent or irreversible PTEs). Non-serious PTEs, 
related or unrelated to the study procedure, need not to be followed-up for the purposes of the 
protocol.
All subjects experiencing AEs, whether considered associated with the use of the study 
medication or not, must be monitored until the symptoms subside and any clinically relevant 
changes in laboratory values have returned to baseline or until there is a satisfactory explanation 
for the change (for permanent or irreversible AEs). All PTEs and AEs will be documented in the 
PTE/AE page of the eCRF, whether or not the investigator concludes that the event is related to 
the drug treatment. The following information will be documented for each event:
1. Event term
2. Start and stop date
3. Frequency
4. Severity
5. Investigator’s opinion of the causal relationship between the event and administration of 
study medication(s) (probable, possible, not related) (not completed for PTEs).
6. Investigator’s opinion of the causal relationship to study procedure(s), including the details 
of the suspected procedure.
7. Action concerning study medication (not applicable for PTEs)
8. Outcome of event
9. Seriousness
10. Classification as special interest AEs (Yes or No)


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C-SSRS will not be used as a primary means to collect AEs. However, should the investigator
become aware of a potential AE through the information collected with this instrument, proper 
follow-up with the patient for medical evaluation should be undertaken. If it is determined that 
an AE not previously reported has been identified through this follow-up, normal reporting 
requirements should be applied.
AEs and serious PTEs will be followed up until resolution or until the investigator judges that 
further follow-up is not necessary.
10.2.1.3 Special Interest AE Reporting
If the special interest AE (refer to Section 10.1.5) occurs through the AE collection period, it 
should be reported to Safety Information Emergency Call Center, in principle (described in the 
separate contact information list) within 1 business day of first onset or subject’s notification of 
the event. The investigator should complete the Rash and Allergic Reaction, Hepatic Impairment 
or Overdose Form within 10 business days and report to Safety Information Emergency Call 
Center, in principle. In addition, the investigator should submit to the sponsor the original Rash 
and Allergic Reaction, Hepatic Impairment or Overdose Form.
The special interest AEs have to be recorded as AEs in the eCRF.
10.2.2 Collection and Reporting of SAEs
When an SAE occurs through the AE collection period it should be reported according to the 
following procedure. PTEs that fulfill the serious criteria described in Section 10.1.4 are also to 
be considered SAEs and should be reported in the same manner.
The investigator should report the SAEs with information required in the SAE form to Safety 
Information Emergency Call Center, in principle, within 1 business day of the first onset or 
subject’s notification of the event. The investigator should prepare the completed SAE form 
within 10 calendar days and submit to Safety Information Emergency Call Center, in principle.
In addition, the investigator should submit to the sponsor the original SAE form.
For the report within 1 business day, the information should be completed as fully as possible but 
contain, at a minimum:

A short description of the event and the reason why the event is categorized as serious.

Subject identification number.

Investigator’s name.

Name of the study medication(s).

Causality assessment.
Any SAE spontaneously reported to the investigator following the AE collection period should 
be also reported to the sponsor if considered related to study participation. Reporting of Serious 
PTEs will follow the procedure described for SAEs.


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10.2.3 Reporting of Abnormal Liver Function Tests
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 investigator must contact the sponsor for 
discussion of the relevant subject details and possible alternative etiologies, such as acute viral 
hepatitis A or B or other acute liver disease or medical history/concurrent medical conditions. 
Follow-up laboratory tests must also be performed (see Section 9.1.12). If the investigator
considers that such liver function abnormality cannot be explained by any factor other than the 
study medication, the event should be reported as a SAE (see Section 10.2.2).
10.3
Follow-up of SAEs
If information not available at the time of the detailed report becomes available at a later date, 
the investigator should complete a follow-up SAE form copy or provide other written 
documentation and report it immediately to the sponsor or Safety Information Emergency Call 
Center. Copies of any relevant data from the hospital notes (e.g., ECGs, laboratory tests, 
discharge summary, postmortem results) should be sent to the addressee, if requested.
All SAEs should be followed up until resolution or permanent outcome of the event.
10.3.1 Safety Reporting to Investigators, IRBs, and Regulatory Authorities
The sponsor will be responsible for reporting all suspected unexpected serious adverse reactions 
(SUSARs) and any other applicable SAEs to regulatory authorities, investigators, and the head of 
the study site, as applicable, in accordance with national regulations in the countries where the 
study is conducted. Relative to the first awareness of the event by/or further provision to the 
sponsor or sponsor’s designee (CRO), SUSARs will be submitted to the regulatory authorities as 
expedited report within 7 days for fatal and life-threatening events and 15 days for other serious 
events. The sponsor will also prepare an expedited report for other safety issues where these 
might materially alter the current benefit-risk assessment of the study medication or that would 
be sufficient to consider changes in the administration of study medication or in the overall 
conduct of the trial. The study site also will forward a copy of all expedited reports to his or her 
IRB.


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11.0
STUDY-SPECIFIC COMMITTEES
No steering committee, data safety monitoring committee, or clinical endpoint committee will be 
used in this study.


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12.0
DATA HANDLING AND RECORDKEEPING
The full details of procedures for data handling will be documented in the Data Management 
Plan. AEs, PTEs, medical history, and concurrent conditions will be coded using the Medical 
Dictionary for Regulatory Activities (MedDRA). Drugs will be coded using the World Health 
Organization (WHO) Drug Dictionary.
12.1
eCRFs
Completed eCRFs are required for each subject who signs an informed consent.
The sponsor or its designee will supply investigative sites with access to eCRFs. The sponsor 
will make arrangements to train appropriate site staff (the investigator, subinvestigators, and 
other study collaborators) in the use of the eCRF. These forms are used to transmit the 
information collected in the performance of this study to the sponsor and regulatory authorities. 
eCRFs must be completed in English. Data are transcribed directly onto eCRFs.
Corrections to eCRFs are recorded in an audit trail that captures the old information, the new 
information, identification of the person making the correction, the date the correction was made, 
and the reason for change.
The investigator must review the eCRFs for completeness and accuracy and must sign the 
appropriate eCRFs. Furthermore, the investigator must retain full responsibility for the accuracy 
and authenticity of all data entered on the eCRFs.
The following data will not be recorded into the eCRFs.

Laboratory test values measured at the central laboratory

Observed drug concentrations
After the lock of the clinical study database, any change of, modification of, or addition to the 
data on the eCRFs should be made by the investigator with use of change and modification 
records of the eCRFs (Data Clarification Form) provided by the sponsor. The investigator must 
review the data change for completeness and accuracy, and must sign, or sign and seal, and date.
eCRFs will be reviewed for completeness and acceptability at the study site during periodic visits 
by the sponsor or its designee. The sponsor or its designee will be permitted to review the 
subject’s medical and hospital records pertinent to the study to ensure accuracy of the eCRFs. 
The completed eCRFs are the sole property of the sponsor and should not be made available in 
any form to third parties, except for authorized representatives of appropriate governmental 
health or regulatory authorities, without written permission of the sponsor.
12.2
Record Retention
The investigator and the head of the institution agree to keep the records stipulated in Section 
12.1 and those documents that include (but are not limited to) the study-specific documents, the 
identification log of all participating subjects, medical records, source worksheets, all original 
signed and dated informed consent forms, electronic copy of eCRFs, including the audit trail, 


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and detailed records of drug disposition to enable evaluations or audits from regulatory 
authorities, the sponsor or its designees. The investigator and the head of the institution are 
required to retain essential relevant 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 institution should discuss how long and how to retain those documents with the 
sponsor.
1)
The day on which marketing approval of the study drug is obtained (or the day 3 years after 
the date of notification in the case that the investigation is discontinued.)
2)
The day 3 years after the date of early termination or completion of the clinical study.
In addition, the investigator and the head of the institution should retain the essential relevant 
documents until the receipt of a sponsor-issued notification to state the retention is no longer 
required.


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13.0
STATISTICAL METHODS
13.1
Statistical and Analytical Plans
A statistical analysis plan (SAP) will be prepared and finalized prior to unblinding of subject’s 
treatment assignment. This document will provide further details regarding the definition of 
analysis variables and analysis methodology to address all study objectives.
A blinded data review will be conducted prior to unblinding of subject’s treatment assignment. 
This review will assess the accuracy and completeness of the study database, subject 
evaluability, and appropriateness of the planned statistical methods.
13.1.1 Analysis Sets
In this study, 3 kinds of analysis sets are defined: full analysis set (FAS), per protocol set (PPS), 
and safety analysis set.
The FAS, which will be used as a primary analysis set for efficacy analysis, is defined as "all 
subjects who were randomized and received at least 1 dose of the study medication in the 
double-blind treatment period."
The exact definition of each analysis set is specified in the Data Handling Rules for Statistical 
Analysis.
The sponsor will verify the validity of the definitions of the analysis sets as well as the rules for 
handling data, consulting a medical expert as needed. The Data Handling Rules for Statistical 
Analysis must be finalized prior to database lock.
13.1.2 Analysis of Demographics and Other Baseline Characteristics
Major background and demographic characteristics will be summarized overall and by treatment 
group.
13.1.3 Efficacy Analysis
Primary Efficacy Analysis for Primary Endpoint
The primary endpoint for this study is the change from baseline (i.e. at the start of double-blind 
treatment period) in the MADRS total score after 8 weeks of treatment.
Comparisons between each Lu AA21004 treatment group and the placebo group at Week 8 of 
the double-blind treatment period will be performed using the FAS based on MMRM analysis of 
covariance with the change from baseline in the MADRS total score as a dependent variable, and 
visit, treatment group, visit-by-treatment group interaction and baseline MADRS total score-by-
visit interaction as fixed effects. An unstructured variance-covariance matrix will be used to 
model the within-subject errors and Satterthwaite's method will be used to approximate the 
degrees of freedom. Holm's step down method will be used to adjust the multiplicity for the 
comparisons. More specifically, let H01, H02 be a family of hypotheses as follows:


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H01: μPlacebo = μ10 mg
H02: μPlacebo = μ20 mg
Then let P1 and P2 denote the unadjusted p-values of tests for H01 and H02, respectively. Order 
the p-values from the smallest to the largest, P(1) , P(2) and let the corresponding null hypotheses 
be H(1) , H(2) . Holm's step-down method proceeds as follows:
Step 1: if P(1) > 0.025, retain both null hypotheses H(1) and H(2), and stop. If P(1) ≤0.025, reject 
null hypothesis H(1) and go to Step 2.
Step 2: if P(2) > 0.05, retain null hypothesis H(2). If P(2) ≤0.05, reject null hypothesis H(2).
Secondary Efficacy Analyses for Primary Endpoint
To check the robustness of the results, the same analysis as used for the primary efficacy analysis 
will be performed using the PPS.
For the FAS, an analysis of covariance (ANCOVA) model with the change from baseline in the 
MADRS total score after 8 weeks of treatment (values at Week 8 [LOCF] −baseline) as a 
dependent variable, treatment group as a fixed effect and the baseline MADRS total score as a 
covariate will be applied for comparisons between the placebo group and each Lu AA21004 
treatment group.
Analyses for Secondary Endpoints
MADRS response (MADRS response is defined as a ≥50% decrease from baseline in the 
MADRS total score) and MADRS remission (MADRS remission is defined as the MADRS total 
score ≤10) after 8 weeks of treatment (LOCF) will be compared between treatment groups using 
logistic regression analysis including the baseline MADRS total score and treatment groups in 
the model.
The change from baseline in the HAM-D17 total score after 8 weeks of treatment (values at 
Week 8 [LOCF] −baseline) will be analyzed using an ANCOVA model with treatment groups 
as a fixed effect and the baseline HAM-D17 total score as a covariate.
The CGI-I score after 8 weeks of treatment (LOCF) will be analyzed using an ANCOVA model 
with treatment groups as a fixed effect and the baseline CGI-S score as a covariate.
The change from baseline in the CGI-S score after 8 weeks of treatment (values at Week 8 
[LOCF] −baseline) will be analyzed using an ANCOVA model with treatment groups as a fixed 
effect and the baseline CGI-S score as a covariate.
The change from baseline in the SDS score after 8 weeks of treatment (values at Week 8 [LOCF] 
−baseline) will be analyzed using an ANCOVA model with treatment groups as a fixed effect 
and the baseline SDS score as a covariate.
The change from baseline in the DSST score after 8 weeks of treatment (values at Week 8 
[LOCF] −baseline) will be analyzed using an ANCOVA model with treatment groups as a fixed 
effect and the baseline DSST score as a covariate.


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The change from baseline in the PDQ-5 score after 8 weeks of treatment (values at Week 8 
[LOCF] −baseline) will be analyzed using an ANCOVA model with treatment groups as a fixed 
effect and the baseline PDQ-5 score as a covariate.
Two-sided tests with significance level at 5% will be used for all statistical tests. Ninety-five 
percent confidence intervals will be presented along with the P-values.
13.1.4 Pharmacokinetic Analysis
The population pharmacokinetic analysis of Lu AA21004 and its metabolites Lu AA34443 and 
Lu AA39835 will be performed using the nonlinear mixed effect model (NONMEM). 
Pharmacokinetic parameters of individual subjects (e.g., AUC[0-tau], Cavg, Cmax) will be 
estimated and their correlation with relevant pharmacodynamic parameters (efficacy and 
tolerability/safety) will be explored. The population pharmacokinetic analysis plan will be 
prepared separately.
13.1.5 Safety Analysis
AEs
The definition of treatment-emergent adverse events (TEAE) will be described in the statistical 
analysis plan (SAP). TEAEs will be summarized using the safety analysis set. TEAEs will be 
coded using the MedDRA and will be summarized by system organ class (SOC) and preferred 
term (PT). No statistical testing or inferential statistics will be generated.
A subject who has developed a same TEAE more than once will be counted as 1 subject in the 
severity category corresponding to the maximum severity of the event.
Clinical Laboratory Test, Weight, Vital Signs, and ECG
Summary statistics of observed values and changes at each time point (values at each time point 
in the double-blind treatment period −baseline) will be calculated for clinical laboratory tests, 
vital signs, ECG parameters, and weight for each treatment group. Incidences of values that are 
outside normal ranges and are potentially and clinically significant will be calculated.
C-SSRS
Descriptive statistics of C-SSRS will be calculated at each time point for each treatment group.
13.2
Interim Analysis and Criteria for Early Termination
No interim analysis is planned.
13.3
Determination of Sample Size
A number of subjects planned to be enrolled in this study is 480 (160 per group). Assuming the 
true mean differences of 3.5 for the change from baseline in the MADRS total score between 
each Lu AA21004 group and the placebo group, this sample size will provide greater than 80% 
power to detect the difference between each Lu AA21004 group and the placebo group by 2-
sample t-test. In addition, assuming the true mean differences of 3.0 for the change from baseline 


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in the MADRS total score between each Lu AA21004 group and the placebo group, this sample 
size will provide greater than 80% power to detect the difference between either the 
Lu AA21004 10 mg or 20 mg group and the placebo group. These power calculations assume a 
common standard deviation of 9.5 for the change from baseline in the MADRS total score, with 
a 2-sided level of 0.025.


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14.0
QUALITY CONTROL AND QUALITY ASSURANCE
14.1
Study-Site Monitoring Visits
Monitoring visits to the study site will be made periodically during the study to ensure that all 
aspects of the protocol are followed. Source documents will be reviewed for verification of data 
recorded on the eCRFs. Source documents are defined as original documents, data, and records. 
The investigator and the head of the institution guarantee access to source documents by the 
sponsor or its designee (CRO) and by the IRB.
All aspects of the study and its documentation will be subject to review by the sponsor or 
designee, including but not limited to the Investigator’s Binder, study medication, subject 
medical records, and informed consent documentation. It is important that the investigator, the 
subinvestigator, and other study personnel are available during the monitoring visits and that 
sufficient time is devoted to the process.
14.2
Protocol Deviations
The investigator can deviate and change from the protocol for any medically unavoidable reason, 
for example, to eliminate an immediate hazard to study subjects, without a prior written 
agreement with the sponsor or a prior approval from IRB. In the event of a deviation or change, 
the investigator should notify the sponsor and the head of the 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 site as 
soon as possible, and an approval from IRB should be obtained.
The investigator should document all protocol deviations.
14.3
Quality Assurance Audits and Regulatory Agency Inspections
The study site also may be subject to quality assurance audits by the sponsor or designees. In this 
circumstance, the sponsor-designated auditor will contact the site in advance to arrange an 
auditing visit. The auditor may ask to visit the facilities where laboratory samples are collected, 
where the medication is stored and prepared, and any other facility used during the study. In 
addition, there is the possibility that this study may be inspected by regulatory agencies, 
including those of foreign governments (e.g., the FDA, the United Kingdom Medicines and 
Healthcare products Regulatory Agency). 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 institution guarantee access for quality assurance auditors to all study documents as described 
in Section 14.1.


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15.0
ETHICAL ASPECTS OF THE STUDY
This study will be conducted with the highest respect for the individual participants (i.e., 
subjects) according to the protocol, the ethical principles that have their origin in the Declaration 
of Helsinki, and the ICH Harmonised Tripartite Guideline for GCP. Each investigator will 
conduct the study according to applicable regulatory requirements and align his or her conduct in 
accordance with the “Responsibilities of the Investigator” that are listed in Appendix B.
15.1
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 abstinence 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 must be obtained and submitted to the sponsor or designee before 
commencement of the study (i.e., before shipment of the sponsor-supplied drug or signing of 
informed consent). The IRB approval must refer to the study by exact protocol title, number, and 
version date; identify versions of other documents (e.g., informed consent form) reviewed; and 
state the approval date. The sponsor will ship drug once the sponsor has confirmed the adequacy 
of site regulatory documentation. Until the site receives drug no protocol activities, including the 
informed consent procedure may occur.
Sites must adhere to all requirements stipulated by their respective IRB. This may include 
notification to the IRB regarding protocol amendments, updates to the informed consent form, 
recruitment materials intended for viewing by subjects, local safety reporting requirements, 
reports and updates regarding the ongoing review of the study at intervals specified by the 
respective IRB, and submission of the investigator’s final status report to IRB. All IRB approvals 
and relevant documentation for these items must be provided to the sponsor or its designee.
Subject incentives should not exert undue influence for participation. Payments to subjects must 
be approved by the IRB and sponsor.
Regarding pharmacogenomic investigation using collected and stored specimens, analysis will 
be carried out at the time when detail is determined. The sponsor will create a research protocol 
for pharmacogenomics investigations, and a research protocol will require prior approval of the 
company IRB in Japan.
15.2
Subject Information, Informed Consent, and Subject Authorization
Written consent documents will embody the elements of informed consent as described in the 
Declaration of Helsinki and the ICH Guidelines for GCP and will be in accordance with all 


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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. The informed consent form will detail the 
requirements of the participant and the fact that he or she is free to withdraw at any time without 
giving a reason and without prejudice to his or her further medical care.
The investigator is responsible for the preparation, content, and IRB approval of the informed 
consent form. The informed consent form must be approved by the IRB 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 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 ample opportunity to: (1) inquire about details of the study and (2) 
decide whether or not to participate in the study. If the subject determines he or she will 
participate in the study, then the informed consent form must be signed and/or sealed, and dated 
by the subject at the time of consent and prior to the subject entering into the study. The subject 
should be instructed to sign and/or seal using their legal names, not nicknames, using blue or 
black ballpoint ink. The investigator must also sign and/or seal, and date the informed consent 
form at the time of consent and prior to subject entering into the study.
Once signed and/or sealed, the original informed consent form will be stored in the investigator’s 
site file. The investigator must document the date the subject signs the informed consent in the 
subject’s medical record. A copy of the signed and/or sealed informed consent form shall be 
given to the subject.
All revised informed consent forms must be reviewed and signed by relevant subjects in the 
same manner as the original informed consent. The date the revised consent was obtained should 
be recorded in the subject’s medical record, and the subject should receive a copy of the revised 
informed consent form.
The informed consent form for pharmacogenomic research in the clinical study of Lu AA21004 
will be used to explain the pharmacogenomic research to subjects after explanation of the
informed consent for the entry into the study. Pharmacogenomic samples will be collected from 
subjects who have consented to both the study and the pharmacogenomic research.
15.3
Subject Confidentiality
The sponsor and designees affirm and uphold the principle of the subject’s right to protection 
against invasion of privacy. Throughout this study, a subject’s source data will only be linked to 
the sponsor’s clinical study database or documentation via a unique identification number. As 
permitted by all applicable laws and regulations, limited subject attributes, such as sex, age, or 
date of birth, may be used to verify the subject and accuracy of the subject’s unique 
identification number.


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To comply with ICH Guidelines for GCP and to verify compliance with this protocol, the 
sponsor requires the investigator to permit its monitor or designee’s monitor, representatives 
from any regulatory authority (e.g., FDA, Medicines and Healthcare products Regulatory 
Agency, Pharmaceuticals and Medical Devices Agency), the sponsor’s designated auditors, and 
the appropriate IRBs to review the subject’s original medical records (source data or documents), 
including, but not limited to, laboratory test result reports, ECG reports, admission and discharge 
summaries for hospital admissions occurring during a subject’s study participation, and autopsy 
reports. Access to a subject’s original medical records requires the specific authorization of the 
subject as part of the informed consent process (see Section 15.2).
Copies of any subject source documents that are provided to the sponsor must have certain 
personally identifiable information removed (i.e., subject name, address, and other identifier 
fields not collected on the subject’s eCRF).
15.4
Publication, Disclosure, and Clinical Trial Registration Policy
15.4.1 Publication and Disclosure
The investigator is obliged to provide the sponsor with complete test results and all data derived 
by the investigator from the study. During the study, only the sponsor may make study 
information available to other study investigators or to regulatory agencies, except as required by 
law or regulation. Except as otherwise allowable in the study site agreement, any public 
disclosure (including publicly accessible websites) related to the protocol or study results 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 needs to obtain a prior written approval from the sponsor to publish any 
information from the study externally such as to a professional association.
15.4.2 Clinical Trial Registration
In order to ensure that information on clinical trials reaches the public in a timely manner and to 
comply with applicable laws, regulations, and guidance, Takeda will, at a minimum register 
interventional clinical trials it sponsors anywhere in the world on ClinicalTrials.gov or other 
publicly accessible websites (JAPIC-CTI) before start of study, as defined in Takeda 
Policy/Standard. Takeda contact information, along with investigator’s city, state (for US 
investigators), country, and recruiting status will be registered and available for public viewing.
15.4.3 Clinical Trial Results Disclosure
Takeda will post the results of clinical trials on ClinicalTrials.gov or other publicly accessible 
websites (JAPIC-CTI), as required by Takeda Policy/Standard, applicable laws and/or 
regulations.


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15.5
Insurance and Compensation for Injury
Each subject in the study must be insured in accordance with the regulations applicable to the 
site where the subject is participating. If a local underwriter is required, then the sponsor or 
sponsor’s designee will obtain clinical study insurance against the risk of injury to clinical study 
subjects.
Refer to the Clinical Study Site Agreement regarding the sponsor’s policy on subject 
compensation and treatment for injury. If the investigator has questions regarding this policy, he 
or she should contact the sponsor or sponsor’s designee.


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16.0
REFERENCES
[1] Nakane Y, Arima K. Cause and Symptom of Depression. The Journal of Practical Pharmacy. 
2000;51(2):826-34.
[2] American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders, 
Fourth Edition, Text Revision. Translated by Takahashi S, Ono Y, Someya T. Igaku-Shoin. 
2004.
[3] Guideline for Clinical Evaluation of Antidepressants (Pharmaceutical and Food Safety 
Bureau, Evaluation and Licensing Division; Notification No.1116-1 dated November 16 in 
2010) (in Japanese).
[4] American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders, 
Fifth Edition. Translated by Takahashi S, Ono Y, Someya T, Kanba S, Ozaki N, Mimura M,  
Murai T.. Igaku-Shoin. 2014.
[5] Bialik RJ, Ravindran AV, Bakish D, Lapierre YD., 1995. A Comparison of Placebo 
Responders and Nonresponders in Subgroups of Depressive Disorder. J Psychiatry Neurosci. 
1995;20:265-70.
[6] Montgomery SA, Asberg M. A new depression scale designed to be sensitive to change. Br J 
Psychiatry. 1979;134:382-9.
[7] Hamilton M. Development of a rating scale for primary depressive illness. Br J Soc Clin 
Psychol. 1967;6:278-96.
[8] Guy W. ECDEU Assessment Manual for Psychopharmacology (Revised). Rockville, MD: 
US Department of Health, Education, and Welfare; Public Health Service; Alcohol, Drug 
Abuse, and Mental Health Administration; National Institute of Mental Health, 
Psychopharmacology Research Branch; 1976. p.193-198
[9] Olfson M, Fireman B, Weissman MM, Leon AC, Sheehan DV, Kathol RG, et al. Mental 
disorders and disability among patients in a primary care group practice. Am J Psychiatry.
1997;154:1734-40.
[10]Posner K, Oquendo MA, Gould M, Stanley B, Davies M. Columbia Classification 
Algorithm of Suicide Assessment (C-CASA): Classification of Suicidal Events in the FDA’s 
Pediatric Suicidal Risk Analysis of Antidepressants. Am J Psychiatry. 2007;164(7):1035-43.
[11]Posner K, Melvin GA, Stanley B, Oquendo MA, Gould M. Factors in the Assessment of 
Suicidality in Youth. CNS Spectr. 2007;12(2):156-62.


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Appendix A
Schedule of Study Procedures
Screening 
Period
Placebo 
Lead-in 
Period (a)
Double-blind Treatment Period
Follow-up
Period
Visit Number
1
2
3
4
5
6
7
8/ET (c)
Follow-up (d)
Week (b)
-4 to -2
-1
0
1
2
4
6
8/ET (c)
12 (d)
Day (b)
-32 to -12
-8
-1
7
14
28
42
56/ET (c)
84 (d)
Visit Window (Days) (b)
-
±3
0
±1
±3
±3
±3
±3/-
±5
Informed consent
X (e)
Inclusion/exclusion criteria
X
X (f)
X (f)
Demographics, medical history,
medication history
X
Diagnosis of MDD
X
Assessments of major depressive 
episode
X
Physical examination
X
X
X
X
Weight, height (g)
X
X
X
X
X
Vital signs
X
X
X
X
X
X
X
X
Concomitant medications
X
X
X
X
X
X
X
X
Concurrent medical conditions
X
Clinical laboratory tests (h)
X
X
X
X
X
Pregnancy test (i)
X
X
X
X
X
(-)
Urine drug screening
X
X
Pharmacokinetic sampling
X
(X)
Pharmacogenomic sampling (j)
(X)
ECG
X
X
X
X
X
C-SSRS
X
X
X
X
X
X
X
X
PTE/AE assessment (k)
X
X
X
X
X
X
X
X
(-)
<Assessments with Rating Scales>
MADRS
X
X
X
X
X
X
X
X
HAM-D
X
X
X
X
CGI-S
X
X
X
X
X
X
X
X
CGI-I (l)
X
X
X
X
X
X
SDS
X
X
X
DSST (m)
X
X
X
X
PDQ-5
X
X
X
X
QIDS-J
X
X
X
X
X
X
X
<Clinical Supply>
Randomization
X
Dispense study medication (n)
X
X
X
X
X
X
Drug return/accountability/compliance
X
X
X
X
X
X


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ET = early termination
(a)
In the placebo lead-in period, subjects will receive the study medication in a single-blind manner.
(b)
The visit day in the double-blind treatment period is defined as Week 0 (Day -1). The day after Day -1 is 
defined as Day 1. All visit windows are in reference to the date of scheduled visit.
(c)
Subjects who prematurely discontinue the study during the placebo lead-in period or double-blind treatment 
period will be requested to visit the study site for the end-of study examinations within 7 days after the day of 
study discontinuation, wherever possible, and will be assessed in the same way as at Visit 8 (except for blood 
sampling for pharmacokinetics).
(d)
Safety follow-up assessments will be conducted. For subjects who prematurely discontinue the study during the 
placebo lead-in period or double-blind treatment period, the follow-up assessments will be made 28 ± 5 days 
after the last dose of the study medication. The follow-up assessments can either be conducted as a visit to the 
site or as a telephone contact. In the follow-up, the following will be assessed: outcomes of AEs continuing at
Visit 8 (or the end-of study assessments if administration of the study medication is discontinued), new SAEs 
developed during the follow-up period, and special interest AEs. Female subjects of child-bearing potential will 
be asked to confirm whether they are pregnant or not.
(e)
Informed consent must be obtained prior to the initiation of any study procedure including washout of excluded
medications. Informed consent may be obtained prior to the visit window of Visit 1.
(f)
Update at Visits 2 and 3.
(g)
Height is measured at only Visit 1.
(h)
Clinical laboratory tests will be performed under fasted conditions at Visits 2, 3 and 8 or Early Termination 
Visit, and at other visits wherever possible.
(i)
For women of child-bearing potential.
(j)
Only for subjects who consent to provide pharmacogenomic samples, separately from consent of participation 
in the study. Pharmacogenomic samples for analyses will be collected at Visit 2 or thereafter, as soon as 
possible, during the study.
(k)
PTEs will be collected prior to study medication administration in the placebo lead-in period, and AEs will be 
collected after study medication administration.
(l)
The CGI-I score will be assessed by comparison with that at Visit 3. However, at Visit 3 or early termination 
prior to Visit 3, the score will be assessed by comparison with that at Visit 2.
(m) Subjects will complete the sample items prior to the actual test.
(n)
At Visit 2, subjects will be dispensed the study medication for the placebo lead-in period. At Visit 3, subjects 
will be dispensed the study medication for the double-blind treatment period, Inner Carton 1, and Inner Carton 
2 at Visits 4 to 7, with a necessary and sufficient amount of the study medication by next visit.


Lu AA21004
Study No. : Lu AA21004/CCT-004
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18 August 2015
CONFIDENTIAL
Appendix B
Responsibilities of the Investigator
1. Conduct the appropriate study in accordance with the protocol and GCP considering the 
rights, safety, and wellbeing of human subjects.
2. When a part of the important activities related to the study are delegated to the investigator or 
the study collaborator, prepare the lists of activities to be delegated and responsible 
personnel, submit the lists to the director of the site in advance to get them accepted.
3. Prepare a written informed consent form and other written information, and update as 
appropriate.
4. Confirm the contents of the clinical study agreement.
5. Provide necessary information on the protocol, medications, and responsibilities of individual 
personnel to the investigator and the study collaborator, and provide guidance and 
supervision.
6. Screen subjects who meet the requirements of the protocol, provide the explanation of the 
study in writing, and obtain the written consent.
7. Assume responsibility for all the medical judgement related to the study.
8. Ensure in collaboration with the director of the site that sufficient information on all 
clinically significant adverse events related to the study are provided to subjects throughout 
and beyond the period when subjects participate in the study.
9. If a subject consults other medical institution or other department, notify the physician of the 
medical institution or department of the subject’s participation in the study, as well as the end 
and termination of the study in writing, and document such records.
10. In case of urgent report of an SAE, immediately notify the director of the site and the sponsor 
in writing.
11. Determine the need of emergency key code blinding of a subject in case of emergency.
12. Prepare correct and complete eCRFs, and submit them to the sponsor with electronic 
signature.
13. Check and confirm the contents of eCRFs prepared by the sub-investigator or transcribed 
from the source data by the study collaborator, and submit them to the sponsor with 
electronic signature.
14. Discuss any proposal from the sponsor including update of the protocol.
15. Notify the director of the site of the end of the study in writing.


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Study No. : Lu AA21004/CCT-004
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CONFIDENTIAL
Appendix C
Detailed Description of Amendments to Text
The following describes changes from the initial protocol.
Page 42, Section 9.1.8.3 Cognitive Function Assessments, Digit Symbol Substitution Test 
(DSST)
Existing Text
.......At a start of the placebo lead-in period (Visit 2), subjects will complete the sample items
prior to the actual test, but the results of the sample items should not be recorded on the eCRF. 
Prior to the first rating, potential raters will attend a rating session on concerns to be addressed 
for the assessment of DSST.
Revised Text
.......Subjects will complete the sample items prior to the actual test, but the results of the sample 
items should not be recorded on the eCRF. Prior to the first rating, potential raters will attend a 
rating session on concerns to be addressed for the assessment of DSST.
Rationale for Amendment
To clarify to complete the sample items in every DSST assessment.
Page 80, Appendix A Schedule of Study Procedures
Existing Text
Screening Period
Placebo Lead-in Period (a)
Visit Number
1
2
DSST
X (m)
Revised Text
Screening Period
Placebo Lead-in Period (a)
Visit Number
1
2
DSST (m)
X
Rationale for Amendment
To clarify to complete the sample items in every DSST assessment.


Lu AA21004 
Study No. : Lu AA21004/CCT-004 
Page 1 of 90
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CONFIDENTIAL 
 
PROTOCOL 
 
<Title> 
A Randomized, Double-Blind, Placebo-Controlled, Parallel-Group, Phase III Study to 
Evaluate the Efficacy and Safety of Once Daily Oral Lu AA21004 in Patients with Major 
Depressive Disorder 
 
<Short Title> 
A Phase III Study of Lu AA21004 in Patients with Major Depressive Disorder 
Sponsor: 
Takeda Pharmaceutical Company Limited 
1-1, Doshomachi 4-chome, Chuo-ku, Osaka-shi 
Study Number: 
Lu AA21004/CCT-004 
Edition: 
Protocol Incorporating Amendment No. 1 
IND Number: 
Not Applicable 
EudraCT Number: 
Not Applicable 
Compound: 
Lu AA21004 
Date: 
7 May 2015 
 
Amendment History 
Date 
Amendment Number
Region 
9 January 2015 
Initial Protocol
All Study Sites 
7 May 2015 
Amendment 1
All Study Sites 
 
CONFIDENTIAL PROPERTY OF TAKEDA 
This document is a confidential communication of Takeda. Acceptance of this document constitutes the agreement 
by the recipient that no information contained herein will be published or disclosed without written authorization 
from Takeda except to the extent necessary to obtain informed consent from those persons to whom the drug may be 
administered. Furthermore, the information is only meant for review and compliance by the recipient, his or her staff, 
and applicable institutional review committee and regulatory agencies to enable conduct of the study. 


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1.0 
ADMINISTRATIVE INFORMATION AND PRINCIPLES OF CLINICAL 
STUDIES 
1.1 
Contacts and Responsibilities of Study-Related Activities 
Refer to the attachment. 
1.2 
Principles of Clinical Studies 
This study will be conducted with the highest respect for the individual participants in 
accordance with the requirements of this study protocol and also in accordance with the 
following: 
• The ethical principles that have their origin in the Declaration of Helsinki. 
• International Conference on Harmonisation E6 Good Clinical Practice: Consolidated 
Guideline. 
• All applicable laws and regulations, including, without limitation, data privacy laws, clinical 
trial disclosure laws, and regulations. 


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TABLE OF CONTENTS 
1.0 
ADMINISTRATIVE INFORMATION AND PRINCIPLES OF CLINICAL 
STUDIES ........................................................................................................................ 2 
1.1 
Contacts and Responsibilities of Study-Related Activities .......................................... 2 
1.2 
Principles of Clinical Studies ..................................................................................... 2 
2.0 
STUDY SUMMARY ...................................................................................................... 8 
3.0 
LIST OF ABBREVIATIONS ........................................................................................ 12 
4.0 
INTRODUCTION ......................................................................................................... 14 
4.1 
Background ............................................................................................................. 14 
4.1.1 Clinical Pharmacology ....................................................................................... 14 
4.1.2 Overseas Phase II/III Clinical Studies................................................................. 15 
4.1.3 Japanese Phase II/III Clinical Studies ................................................................. 16 
4.2 
Rationale for the Proposed Study ............................................................................. 17 
5.0 
STUDY OBJECTIVES AND ENDPOINTS .................................................................. 18 
5.1 
Objectives ................................................................................................................ 18 
5.1.1 Primary Objective .............................................................................................. 18 
5.1.2 Secondary Objectives ......................................................................................... 18 
5.1.3 Additional Objectives......................................................................................... 18 
5.2 
Endpoints................................................................................................................. 18 
5.2.1 Efficacy Endpoints ............................................................................................. 18 
5.2.1.1 Primary Endpoint ......................................................................................... 18 
5.2.1.2 Secondary Endpoints .................................................................................... 18 
5.2.2 Pharmacokinetic Endpoint ................................................................................. 19 
5.2.3 Safety Endpoints ................................................................................................ 19 
6.0 
STUDY DESIGN AND DESCRIPTION ....................................................................... 20 
6.1 
Study Design ........................................................................................................... 20 
6.2 
Justification for Study Design, Dose, and Endpoints ................................................ 21 
6.2.1 Subject Population ............................................................................................. 21 
6.2.2 Study Design...................................................................................................... 21 
6.2.3 Doses ................................................................................................................. 22 
6.2.4 Endpoints ........................................................................................................... 22 
6.3 
Premature Termination or Suspension of Study or Study Site ................................... 23 
6.3.1 Criteria for Premature Termination or Suspension of the Study .......................... 23 
6.3.2 Criteria for Premature Termination or Suspension of Study Sites ....................... 23 


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6.3.3 Procedures for Premature Termination or Suspension of the Study or the 
Participation of Study Sites ................................................................................ 23 
7.0 
SELECTION AND DISCONTINUATION/WITHDRAWAL OF SUBJECTS .............. 24 
7.1 
Inclusion Criteria ..................................................................................................... 24 
7.2 
Exclusion Criteria .................................................................................................... 25 
7.3 
Excluded Medications and Treatments ..................................................................... 28 
7.4 
Diet, Fluid, and Activity Control .............................................................................. 31 
7.5 
Criteria for Discontinuation or Withdrawal of a Subject ........................................... 31 
7.5.1 Additional Guidance for Withdrawal Criteria ..................................................... 33 
7.6 
Procedures for Discontinuation or Withdrawal of a Subject...................................... 33 
8.0 
CLINICAL TRIAL MATERIAL MANAGEMENT ...................................................... 34 
8.1 
Study Medication ..................................................................................................... 34 
8.1.1 Dosage Form, Manufacturing, Packaging, and Labeling ..................................... 34 
8.1.2 Storage ............................................................................................................... 34 
8.1.3 Dose and Regimen ............................................................................................. 35 
8.1.4 Overdose ............................................................................................................ 35 
8.2 
Study Drug Assignment and Dispensing Procedures ................................................ 36 
8.3 
Randomization Code Creation and Storage .............................................................. 36 
8.4 
Study Drug Blind Maintenance ................................................................................ 36 
8.5 
Unblinding Procedure .............................................................................................. 36 
8.6 
Accountability and Destruction of Sponsor-Supplied Drugs ..................................... 36 
9.0 
STUDY PLAN .............................................................................................................. 38 
9.1 
Study Procedures ..................................................................................................... 38 
9.1.1 Informed Consent Procedure .............................................................................. 38 
9.1.1.1 Pharmacogenomic Informed Consent Procedure ........................................... 38 
9.1.2 Demographics, Medical History, and Medication History Procedure .................. 38 
9.1.3 Diagnosis of MDD ............................................................................................. 38 
9.1.4 Assessments of Major Depressive Episode ......................................................... 39 
9.1.4.1 Current Major Depressive Episode ............................................................... 39 
9.1.4.2 Past Major Depressive Episode .................................................................... 39 
9.1.5 Physical Examination Procedure ........................................................................ 40 
9.1.6 Weight, Height, and BMI ................................................................................... 40 
9.1.7 Vital Sign Procedure .......................................................................................... 40 
9.1.8 Efficacy Evaluation ............................................................................................ 40 
9.1.8.1 Rating and Rating Training for MDD ........................................................... 40 
9.1.8.2 Social Function Assessment ......................................................................... 42 


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9.1.8.3 Cognitive Function Assessments .................................................................. 42 
9.1.8.4 Self-report Assessment of Depressive Symptoms and Assessment 
Monitoring ................................................................................................... 42 
9.1.9 Suicidal Risk Assessments ................................................................................. 43 
9.1.10 Documentation of Concomitant Medications ...................................................... 43 
9.1.11 Documentation of Concurrent Medical Conditions ............................................. 43 
9.1.12 Procedures for Clinical Laboratory Samples ....................................................... 43 
9.1.13 Contraception and Pregnancy Avoidance Procedure ........................................... 45 
9.1.14 Pregnancy .......................................................................................................... 45 
9.1.15 ECG Procedure .................................................................................................. 46 
9.1.16 Pharmacogenomic Sample Collection ................................................................ 46 
9.1.17 Pharmacokinetic Sample Collection and Analysis .............................................. 46 
9.1.17.1 
Collection of Blood for Pharmacokinetic Sampling ................................ 46 
9.1.17.2 
Bioanalytical Methods ............................................................................ 46 
9.1.18 Documentation of Screen Failure Prior to Entrance into Placebo Lead-in 
Period ................................................................................................................ 46 
9.1.19 Documentation of Study Entrance into Placebo Lead-in Period .......................... 47 
9.1.20 Documentation of Screen Failure Prior to Randomization .................................. 47 
9.1.21 Documentation of Randomization ...................................................................... 48 
9.2 
Monitoring Subject Treatment Compliance .............................................................. 48 
9.3 
Schedule of Observations and Procedures ................................................................ 48 
9.3.1 Screening Period ................................................................................................ 48 
9.3.2 Placebo Lead-in Period ...................................................................................... 49 
9.3.3 Start of Double-blind Treatment Period/Randomization ..................................... 50 
9.3.4 Double-blind Treatment Period .......................................................................... 51 
9.3.5 End of Double-blind Treatment Period or Early Termination ............................. 53 
9.3.6 Follow-up Period ............................................................................................... 54 
9.3.7 Post Study Care .................................................................................................. 54 
9.4 
Biological Sample Retention and Destruction .......................................................... 54 
10.0 
PRETREATMENT EVENTS AND ADVERSE EVENTS ............................................ 56 
10.1 
Definitions ............................................................................................................... 56 
10.1.1 PTEs .................................................................................................................. 56 
10.1.2 AEs .................................................................................................................... 56 
10.1.3 Additional Points to Consider for PTEs and AEs ................................................ 56 
10.1.4 SAEs .................................................................................................................. 58 
10.1.5 Special Interest AEs ........................................................................................... 60 


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10.1.5.1 
Skin and Allergic Reaction ..................................................................... 60 
10.1.5.2 
Hepatic Impairment ................................................................................ 60 
10.1.5.3 
Overdose ................................................................................................ 61 
10.1.6 Severity of PTEs and AEs .................................................................................. 61 
10.1.7 Causality of AEs ................................................................................................ 61 
10.1.8 Relationship to Study Procedures ....................................................................... 61 
10.1.9 Start Date ........................................................................................................... 62 
10.1.10 
Stop Date ..................................................................................................... 62 
10.1.11 
Frequency .................................................................................................... 62 
10.1.12 
Action Concerning Study Medication ........................................................... 62 
10.1.13 
Outcome....................................................................................................... 63 
10.2 
Procedures ............................................................................................................... 63 
10.2.1 Collection and Reporting of AEs ........................................................................ 63 
10.2.1.1 
PTE and AE Collection Period ............................................................... 63 
10.2.1.2 
PTE and AE Reporting ........................................................................... 64 
10.2.1.3 
Special Interest AE Reporting ................................................................. 65 
10.2.2 Collection and Reporting of SAEs ...................................................................... 65 
10.2.3 Reporting of Abnormal Liver Function Tests ..................................................... 66 
10.3 
Follow-up of SAEs .................................................................................................. 66 
10.3.1 Safety Reporting to Investigators, IRBs, and Regulatory Authorities .................. 66 
11.0 
STUDY-SPECIFIC COMMITTEES ............................................................................. 67 
12.0 
DATA HANDLING AND RECORDKEEPING ............................................................ 68 
12.1 
eCRFs ...................................................................................................................... 68 
12.2 
Record Retention ..................................................................................................... 68 
13.0 
STATISTICAL METHODS .......................................................................................... 70 
13.1 
Statistical and Analytical Plans ................................................................................ 70 
13.1.1 Analysis Sets...................................................................................................... 70 
13.1.2 Analysis of Demographics and Other Baseline Characteristics ........................... 70 
13.1.3 Efficacy Analysis ............................................................................................... 70 
13.1.4 Pharmacokinetic Analysis .................................................................................. 72 
13.1.5 Safety Analysis .................................................................................................. 72 
13.2 
Interim Analysis and Criteria for Early Termination ................................................ 72 
13.3 
Determination of Sample Size .................................................................................. 72 
14.0 
QUALITY CONTROL AND QUALITY ASSURANCE............................................... 74 
14.1 
Study-Site Monitoring Visits ................................................................................... 74 


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14.2 
Protocol Deviations.................................................................................................. 74 
14.3 
Quality Assurance Audits and Regulatory Agency Inspections ................................ 74 
15.0 
ETHICAL ASPECTS OF THE STUDY ........................................................................ 75 
15.1 
IRB Approval .......................................................................................................... 75 
15.2 
Subject Information, Informed Consent, and Subject Authorization ......................... 75 
15.3 
Subject Confidentiality ............................................................................................ 76 
15.4 
Publication, Disclosure, and Clinical Trial Registration Policy ................................. 77 
15.4.1 Publication and Disclosure ................................................................................. 77 
15.4.2 Clinical Trial Registration .................................................................................. 77 
15.4.3 Clinical Trial Results Disclosure ........................................................................ 77 
15.5 
Insurance and Compensation for Injury .................................................................... 78 
16.0 
REFERENCES .............................................................................................................. 79 
 
LIST OF IN-TEXT TABLES 
Table 7.a 
List of Prohibited or Restricted Concomitant Medications .................................. 28 
Table 8.a 
Study Medication ............................................................................................... 34 
Table 8.b 
Dose and Regimen ............................................................................................. 35 
Table 9.a 
Clinical Laboratory Tests ................................................................................... 44 
Table 10.a 
Takeda Medically Significant AE List ................................................................ 59 
 
LIST OF IN-TEXT FIGURES 
Figure 6.a 
Schematic of Study Design ................................................................................ 21 
 
LIST OF APPENDICES 
Appendix A 
Schedule of Study Procedures ............................................................................ 80 
Appendix B 
Responsibilities of the Investigator ..................................................................... 82 
Appendix C 
Detailed Description of Amendments to Text ..................................................... 83 
 


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Study No. : Lu AA21004/CCT-004 
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CONFIDENTIAL 
2.0 
STUDY SUMMARY 
Name of Sponsor: 
Takeda Pharmaceutical Company Limited 
Compound:
Lu AA21004 
Title of Protocol: 
A Randomized, Double-Blind, Placebo-Controlled, Parallel-Group, 
Phase III Study to Evaluate the Efficacy and Safety of Once Daily 
Oral Lu AA21004 in Patients with Major Depressive Disorder 
IND No.:
Not Applicable 
EudraCT No.:
Not Applicable 
Study Number: Lu AA21004/CCT-004 
Phase: 3
Study Design: 
This is a randomized, double-blind, placebo-controlled, parallel-group, phase III study to evaluate the efficacy and 
safety of 8-week treatment of 2 fixed doses of Lu AA21004 (10 or 20 mg/day) in Japanese subjects with major 
depressive disorder (MDD). 
This study consists of a 1- to 3-week screening period, a 1-week single-blind placebo lead-in period, an 8-week 
double-blind treatment period and a 4-week safety follow-up period. Subjects who fulfill all inclusion criteria and 
none of exclusion criteria at the start of screening period (Visit 1) and at the start of placebo lead-in period (Visit 2) 
will move into the placebo lead-in period and receive placebo once daily for 1 week in a single-blind manner. 
Afterwards, these who fulfill all the inclusion criteria and none of the exclusion criteria at the start of double-blind 
treatment period (Visit 3) will move into the double-blind treatment period and will be randomized in a 1:1:1 ratio to 
one of the following treatment groups: the placebo group, the Lu AA21004 10 mg/day group or the Lu AA21004 
20 mg/day group. Subjects in the placebo group and the Lu AA21004 10 mg/day group will receive placebo and 
Lu AA21004 10 mg, respectively, once daily from the day after Visit 3 for 8 weeks in a double-blind manner. 
Subjects in the Lu AA21004 20 mg/day group will receive Lu AA21004 10 mg once daily from the day after Visit 3 
for 1 week and thereafter Lu AA21004 20 mg once daily for 7 weeks in a double-blind manner. Subjects in any 
treatment groups will visit study sites at Week 1, 2, 4, 6 and 8 during the double-blind treatment period for 
examinations/observations/assessments. 
A safety follow-up contact (visit or phone call) will be made 4 weeks after the completion of the double-blind 
treatment period. Subjects who prematurely discontinue the study during the placebo lead-in period or the double-
blind treatment period will be requested to visit the study site for the end-of study assessments within 7 days after 
the discontinuation decision is made wherever possible, and will be contacted 4 weeks after the last dose of the 
study medication for safety follow-up. 
Primary Objective: 
• To evaluate the efficacy of 2 fixed doses of Lu AA21004 (10 or 20 mg/day) after 8 weeks of treatment in Japanese 
patients with MDD. 
Secondary Objectives: 
• To evaluate the safety and tolerability of 2 fixed doses of Lu AA21004 (10 or 20 mg/day) after 8 weeks of 
treatment in Japanese patients with MDD. 
• To evaluate the efficacy of Lu AA21004 (10 or 20 mg/day) on cognitive functions after 8 weeks of treatment in 
Japanese patients with MDD. 
Additional Objective: 
• To analyze the plasma concentrations of Lu AA21004 and its metabolites Lu AA34443 and Lu AA39835 using 
population pharmacokinetic analyses. 
Subject Population: 
Male and female subjects, aged between 20 and 75 years (both inclusive), with recurrent MDD according to 
Diagnostic and Statistical Manual of Mental Disorders, 4th edition, Text Revision (DSM-IV-TR) criteria. 


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Study No. : Lu AA21004/CCT-004 
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CONFIDENTIAL 
Number of Subjects: 
Randomized subjects: 480 (160 per group) 
Number of Sites:
Approximately 60 sites 
Dose Levels: 
Placebo lead-in period:  
Placebo once daily 
Double-blind treatment period:  
Lu AA21004 (10 or 20 mg) or placebo once daily 
Route of Administration: 
Oral 
Duration of Treatment: 
9 weeks in total 
Placebo lead-in period: 1 week 
Double-blind treatment period: 8 weeks 
Period of Evaluation:
14 to 16 weeks in total 
Screening period: 1 to 3 weeks 
Placebo lead-in period: 1 week 
Double-blind treatment period: 8 weeks 
Safety follow-up period: 4 weeks 
Main Criteria for Inclusion: 
• The subject suffers from recurrent MDD as the primary diagnosis according to DSM-IV-TR criteria (classification 
code 296.3x). 
• The subject is a man or a woman aged 20 to 75 years (both inclusive) at the time of informed consent. 
• The reported duration of the current major depressive episode is 3 to 12 months (both inclusive) at the start of 
screening period. 
• The subject has a Montgomery-Åsberg Depression Rating Scale (MADRS) total score ≥26, a Hamilton 
Depression Rating Scale (HAM-D17) total score ≥18, and a clinical global impression scale-Severity (CGI-S) 
score ≥4 at the start of screening period, the start of placebo lead-in period and the start of the double-blind 
treatment period. 
Main Criteria for Exclusion: 
• The subject has any following current or past history of psychiatric disorder and/or neurological disorder: 
- Any current psychiatric disorder other than MDD as defined by DSM-IV-TR (To be assessed by Mini 
International Neuropsychiatric Interview: MINI). A subject who exhibits symptoms of anxiety is eligible unless 
the subject fulfills the diagnostic criteria for a current anxiety disorder per DSM-IV-TR. 
- Current diagnosis or history of manic, mixed or hypomanic episode, MDD with psychotic features, 
schizophrenia or any other psychotic disorder (including substance-related mental disorders, or mental disorders 
due to a general medical condition) as defined by DSM-IV-TR. 
- Current diagnosis or history of any substance-related disorder (except nicotine and caffeine-related disorders) as 
defined by DSM-IV-TR. 
- The subject with a positive urine drug screening result at the start of screening period or the start of placebo 
lead-in period. In case that a subject showed positive test result at the start of screening period because the test 
was conducted before washout of pretreatment drugs, the subject is eligible as long as he/she shows negative 
result at the start of placebo lead-in period. 
- Presence or history of any clinically significant neurological disorder (including epilepsy). 
- Any neurodegenerative disorder (e.g. Alzheimer’s disease, Parkinson’s disease, multiple sclerosis, Huntington’s 
disease). 
- Any DSM-IV-TR axis II disorder. 
• The subject has the current or previous major depressive episode which were considered by the investigator to 
have been resistant to 2 or more adequate antidepressants treatments of at least 6 weeks duration each at sufficient 
doses. 


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CONFIDENTIAL 
• The subject has received any augmentation therapy (e.g. lithium, T3/T4, lamotrigine, sodium valproate, 
carbamazepine, additional atypical antipsychotic, or concomitant use of other antidepressant, etc.) for the current 
major depressive episode. 
• In the opinion of the investigator, the subject has experienced significant number of major depressive episodes in 
the past, and is suspected of disease other than MDD. 
• In the opinion of the investigator, the subject has experienced the first major depressive episode at his/her young 
age, and is suspected of disease other than MDD. 
• The subject has a MADRS total score at the start of double-blind treatment period that has improved or aggravated 
by 25% or more from the score at the start of placebo lead-in period. 
• The subject is at significant risk of suicide or has a score ≥5 on Item 10 (suicidal thoughts) of the MADRS at the 
start of screening period, the start of placebo lead-in period or the start of double-blind treatment period, or has 
attempted suicide within 6 months prior to the start of screening period. 
• The subject has experienced any environmental change (e.g. temporary retirement, returnment, change of 
residence) considered by the investigator to have the potential to impact on the efficacy evaluation, or plans such 
environmental changes during the study. 
• The subject has a clinically significant unstable illness, for example, hepatic impairment or renal insufficiency, or 
a cardiovascular, pulmonary, gastrointestinal, endocrine, neurological, rheumatologic, immunologic, infectious, 
neoplastic, skin and subcutaneous tissue disorders, eye disorders, or metabolic disturbance. 
Main Criteria for Evaluation and Analyses:
Efficacy Endpoints 
Primary Endpoint 
• Change from baseline (i.e. at the start of double-blind treatment) in the MADRS total score after 8 weeks of 
treatment 
Secondary Endpoints 
• MADRS response after 8 weeks of treatment (last observation carried forward [LOCF]) 
(MADRS response is defined as a ≥50% decrease in the MADRS total score from baseline). 
• MADRS remission after 8 weeks of treatment (LOCF) 
(MADRS remission is defined as the MADRS total score of ≤10). 
• Change from baseline in the HAM-D17 total score after 8 weeks of treatment (LOCF). 
• Clinical global impression scale-Improvement (CGI-I) score after 8 weeks of treatment (LOCF). 
• Change from baseline in the CGI-S score after 8 weeks of treatment (LOCF). 
• Change from baseline in the Sheehan Disability Scale (SDS) total score after 8 weeks of treatment (LOCF). 
• Change from baseline in the Digit Symbol Substitution Test (DSST) score after 8 weeks of treatment (LOCF). 
• Change from baseline in the Perceived Deficits Questionnaire (PDQ-5) score after 8 weeks of treatment (LOCF). 
Pharmacokinetic Endpoint 
• Plasma concentrations of Lu AA21004 and its metabolites Lu AA34443 and Lu AA39835. 
Safety Endpoints 
• Adverse events 
• Weight 
• Vital signs 
• Electrocardiograms (ECGs) 
• Clinical laboratory tests (serum chemistry, hematology and urinalysis) 
• Columbia-Suicide Severity Rating Scale (C-SSRS) 


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Statistical Considerations: 
Change from baseline (i.e. the start of double-blind treatment period) in the MADRS total score after 8 weeks of 
treatment is the primary efficacy endpoint. Comparisons between each Lu AA21004 treatment group and the 
placebo group at Week 8 of the double-blind treatment period will be performed using the full analysis set (FAS) 
based on Mixed Model for Repeated Measures (MMRM) analysis of covariance with the change from baseline in 
the MADRS total score as a dependent variable, and visit, treatment group, visit-by-treatment group interaction and 
baseline MADRS total score-by-time point interaction as fixed effects. An unstructured variance-covariance matrix 
will be used to model the within-subject errors and Satterthwaite's method will be used to approximate the degrees 
of freedom. Holm's step-down method will be used to adjust the multiplicity for the comparisons. 
Sample Size Justification: 
A number of subjects planned to be enrolled in this study is 480 (160 per group). Assuming the true mean 
differences of 3.5 for the change from baseline in the MADRS total score between each Lu AA21004 group and the 
placebo group, this sample size will provide greater than 80% power to detect the difference between each 
Lu AA21004 group and the placebo group by 2-sample t-test. In addition, assuming the true mean differences of 3.0 
for the change from baseline in the MADRS total score between each Lu AA21004 group and the placebo group, 
this sample size will provide greater than 80% power to detect the difference between either the Lu AA21004 10 mg 
or 20 mg group and the placebo group. These power calculations assume a common standard deviation of 9.5 for the 
change from baseline in the MADRS total score, with a 2-sided level of 0.025. 
 


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3.0 
LIST OF ABBREVIATIONS 
5-HT 
5-hydroxytryptamine
5-HTT 
5-hydroxytryptamine transporter
ADHD 
attention deficit hyperactivity disorder
AE 
adverse event 
ANCOVA 
analysis of co-variance
ALT 
alanine aminotransferase
AST 
aspartate aminotransferase
AUC 
area under the plasma concentration-time curve
BMI 
body mass index
BUN 
blood urea nitrogen
Cavg 
average plasma concentration at steady state
CGI-I 
clinical global impression scale-Improvement
CGI-S 
clinical global impression scale-Severity
Cmax 
maximum observed plasma concentration
COX 
cyclooxygenase
CRO 
contract research organization
C-SSRS 
Columbia-Suicide Severity Rating Scale
CYP 
cytochrome P-450
DSM-IV-TR 
Diagnostic and Statistical Manual of Mental Disorders, 4th Edition, Text Revision
DSST 
Digit Symbol Substitution Test
FDA 
Food and Drug Administration
GCP 
Good Clinical Practice
γ-GTP 
γ-glutamyl transferase 
HAM-D 
Hamilton Depression Rating Scale
hCG 
Human chorionic gonadotropin
HDL 
high-density lipoprotein
ICH 
International Conference on Harmonisation
INR 
international normalized ratio
LDL 
low-density lipoprotein
LOCF 
Last Observation Carried Forward
MADRS 
Montgomery Åsberg Depression Rating Scale
MAOI 
monoamine oxidase inhibitor
MedDRA 
Medical Dictionary for Regulatory Activities
MHRA 
Medicines and Healthcare products Regulatory Agency
MINI 
Mini International Neuropsychiatric Interview
MMRM 
Mixed Model for Repeated Measures
NaSSA 
noradrenergic and specific serotonergic antidepressant
NSAIDs 
non-steroidal anti-inflammatory drug
PDQ 
Perceived Deficits Questionnaire
PMDA 
Pharmaceutical and Medical Devices Agency


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PT 
Preferred Term
PTE 
Pretreatment Event
PTP 
press through package
QIDS 
Quick Inventory of Depressive Symptomatology
SAE 
serious adverse event
SDS 
Sheehan Disability Scale
SNRI 
serotonin norepinephrine reuptake inhibitor
SOC 
System Organ Class
SSRI 
selective serotonin reuptake inhibitor
SUSARs 
Suspected unexpected serious adverse reactions
TEAE 
treatment emergent adverse event
TSH 
thyroid-stimulating hormone
WHO 
World Health Organization
 


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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 in Japan and overseas. As of December 2014, Lu AA21004 has been 
approved for marketing as a drug for the treatment of MDD in countries including the U.S., 
Europe and Australia. 
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] With advances of basic research and clinical studies, the etiology and 
pathology of depression have been gradually revealed, but not fully elucidated so far. 
Depression is a common disease worldwide, with the estimated lifetime prevalence above 10%. 
The onset age is estimated to be from 20 to 50 years old in half of patients; however, the onset in 
children and the elderly has been also reported.[3] In the U.S., the prevalence of depression in 
aged 18 to 29 years is approximately 3-fold higher than that in more than 60 years, and, after 
early adolescence, the prevalence in women is 1.5 to 3-fold higher than in men, showing that the 
prevalence of depression varies widely depending on age and sex.[4] 
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] 
The goal of treatment for depression is to improve patients' mental and social quality of life by 
effectively alleviating the depressive symptoms. 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 (SSRIs), serotonin-
norepinephrine reuptake inhibitors (SNRIs), and noradrenergic and specific serotonergic 
antidepressants (NaSSAs) 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. 
4.1.1 
Clinical Pharmacology 
Results of clinical pharmacology studies in Japan and overseas are summarized below. 
Lu AA21004 was slowly absorbed after oral administration, and the Tmax was approximately 7 
to 11 hours. The absolute bioavailability of Lu AA21004 was approximately 75%. The 


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pharmacokinetics of Lu AA21004 was linear within the dose range between 2.5 and 60 mg. The 
plasma concentration of Lu AA21004 reached steady state after approximately 2-week multiple 
doses, and the accumulation index was 5 to 6 based on AUC following multiple doses of 5 to 
20 mg/day. There was no food effect on the pharmacokinetics of Lu AA21004. 
Lu AA21004 was extensively metabolized in the liver, primarily through oxidation or glucuronic 
acid conjugation, and CYP2D6 was shown to be the primary enzyme in metabolism of 
Lu AA21004 to the major metabolite Lu AA34443. Lu AA34443 was pharmacologically 
inactive, and the active metabolite Lu AA39835 did not cross the blood-brain barrier, although 
Lu AA39835 was slightly detected in plasma, suggesting that these metabolites are less likely to 
contribute to the pharmacological effect of Lu AA21004. In addition, Lu AA21004 and its 
metabolites did not induce or inhibit CYP isozymes in vitro, suggesting that clinical significant 
drug-drug interactions with Lu AA21004 are less likely to occur. 
The T1/2 of Lu AA21004 was approximately 66 hours, and two- thirds of its metabolites were 
excreted in urine, and one-third were excreted in feces. The excretion of unchanged Lu AA21004 
was slightly noted in feces. 
After multiple doses of Lu AA21004, 5-HTT occupancy in raphe nuclei was approximately 50% 
at doses of 5 mg/day, 65% at 10 mg/day, and 80% or more at 20 mg/day. 
Based on results of studies in Caucasian and Japanese subjects, there were no statistically 
significant differences in the pharmacokinetics and 5-HTT occupancy of Lu AA21004 between 
the races. 
4.1.2 
Overseas Phase II/III Clinical Studies 
A total of 12 overseas placebo-controlled, double-blind, short-term studies (Studies 11492A, 
11984A, 303, 304, 305, 13267A, 315, 316, 317, CCT-002, 12541A and 14122A) were conducted 
to evaluate the efficacy of Lu AA21004 for the treatment of MDD. Study CCT-002 was a 
multinational study including Japan. 
The changes from baseline in the Montgomery-Åsberg Depression Rating Scale (MADRS) total 
score were analyzed by mixed model repeated measures (MMRM) in the individual studies; and 
the results of the 11 of 12 studies mentioned above except for Study 12541A for elderly patients 
were used for meta-analysis. As for the mean changes from baseline in the MADRS total score at 
Week 6 or 8, the differences of the Lu AA21004 5, 10 and 20 mg group compared to the placebo 
group were -2.3 (p = 0.007), -3.6 (p < 0.001) and -4.6 (p < 0.001), respectively, and all of them 
were statistically significant. In addition, although the mean difference between the 15 mg group 
and placebo group was -2.6, not statistically significant. MADRS response rate (MADRS 
response is defined as a ≥ 50% decrease from baseline in the MADRS total score) in the subjects 
treated with Lu AA21004 was 46% to 49%, whereas that in the subjects treated with placebo was 
34% (p < 0.01). These results suggested Lu AA21004 at doses of 5 to 20 mg/day was effective. 
For comprehensive safety evaluation including the above-mentioned short-term studies and long-
term studies (Studies 11492C, 11984B, 301, 13267B and 314), treatment with Lu AA21004 at 
doses of 5 to 20 mg/day was safe and well tolerated. The most common TEAE in the 


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Lu AA21004 groups was nausea, and gastrointestinal TEAEs were occurred more frequently in 
female than male. Most TEAEs were mild or moderate and occurred within the first 2 weeks of 
treatment. In addition, TEAEs were usually transient, and did not generally lead to 
discontinuation of the study medication. 
Abrupt discontinuation of antidepressants may result in discontinuation symptoms, however, 
there were no clinically relevant differences in the incidence or nature of discontinuation 
symptoms between the Lu AA21004 groups and placebo group. 
The incidence of self-report sexual dysfunction in the Lu AA21004 groups was low, and was 
similar to that in the placebo group. In the study using a rating scale (Arizona Sexual Experience 
Scale) for sexual dysfunction, the incidence of sexual dysfunction at doses of 5 to 15 mg/day of 
Lu AA21004 was similar to that of placebo, but that at 20 mg/day was higher than placebo. 
Lu AA21004 had no clinically significant effect on weight, heart rate, blood pressure, and 
hepatic and renal functions. Moreover, Lu AA21004 also had no clinically significant effect on 
ECG parameters (QT interval, QTc interval, PR interval and QRS interval). In a thorough QTc 
study in healthy adult subjects, Lu AA21004 at doses up to 40 mg/day had no potential for 
prolongation of QT/QTc intervals. 
4.1.3 
Japanese Phase II/III Clinical Studies 
In Japan, 2 placebo-controlled, short-term studies (Study CCT-002 [multinational study] and 
Study CCT-003 [Japan local study]) were conducted in subjects with MDD. In addition, a long-
term extension study (Study OCT-001) was conducted in those who completed Study CCT-003. 
Study CCT-002 was conducted in 14 countries including Japan, Europe and the Asia Pacific 
region to evaluate the efficacy and safety of Lu AA21004 at doses of 5, 10 and 20 mg/day. For 
the mean changes from baseline in the MADRS total score at Week 8 (last observation carried 
forward [LOCF]) in the primary efficacy analysis (analysis of covariance [ANCOVA]), the mean 
differences of the Lu AA21004 5, 10 and 20 mg group compared to the placebo group were -
0.61 (p = 0.91), -1.69 (p = 0.30) and -1.82 (p = 0.24), respectively. In addition, in the same 
analysis for Japanese population, the mean differences of the Lu AA21004 5, 10 and 20 mg 
group compared to the placebo group were 0.89, -2.74 and -3.45, respectively. 
In Study CCT-002, Most TEAEs were mild or moderate, and TEAEs reported in more than 5% 
of subjects in any Lu AA21004 groups were nausea, nasopharyngitis, headache, dizziness, 
constipation, dry mouth, and insomnia. Of these, TEAEs with higher (≥ 2-fold) incidence in any 
Lu AA21004 groups than that in placebo group were nausea, constipation, dry mouth, dizziness 
and insomnia. 
In Study CCT-003, the efficacy and safety of Lu AA21004 at doses of 5 and 10 mg/day were 
evaluated in Japanese subjects with MDD. For the mean changes from baseline in the MADRS 
total score at Week 8 (LOCF) in the primary efficacy analysis (ANCOVA), the mean differences 
of the Lu AA21004 5 and 10 mg group compared to the placebo group were -2.03 (p = 0.10) and 
-1.04 (p = 0.40), respectively. 


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In Study CCT-003, TEAEs reported in more than 5% of subjects in any Lu AA21004 groups 
were nausea, diarrhoea, nasopharyngitis, somnolence, headache, and suicidal ideation. Of these, 
TEAEs with higher (≥2-fold) incidence in the Lu AA21004 groups than that in the placebo group 
were nausea and suicidal ideation. For suicidal ideation, the incidence in the 10 mg group (8 
subjects; 6.6%) was higher than in the placebo group (2 subjects; 1.6%) and 5 mg group (1 
subject; 0.8%). In general, most TEAEs were mild or moderate, suggesting that there were no 
significant safety concerns about Lu AA21004. 
In the open-label long-term extension study (Study OCT-001), the safety of 52 week treatment of 
Lu AA21004 at flexible doses of 5 to 20 mg/day was evaluated in subjects who completed Study 
CCT-003. In Study OCT-001, TEAEs reported in more than 5% of subjects were 
nasopharyngitis, nausea, seasonal allergy, headache, weight increased, diarrhoea, vomiting, 
alanine aminotransferase (ALT) increased, somnolence, malaise, influenza, and blood creatine 
phosphokinase increased. No long-term specific TEAEs were observed, and most TEAEs were 
mild or moderate, suggesting that there were no significant safety concerns in a long-term 
treatment of Lu AA21004. 
4.2 
Rationale for the Proposed Study 
In Europe and the U.S., the efficacy and safety of Lu AA21004 were demonstrated at doses of 5 
to 20 mg/day and Lu AA21004 has already been approved for marketing. For 2 short-term 
studies (Studies CCT-002 and CCT-003) including Japanese MDD patients, there are no 
statistically significant differences in the efficacy between any Lu AA21004 groups and the 
placebo group; however, in Study CCT-002, changes from baseline in the MADRS total score in 
the 10 and 20 mg groups were grater than in the placebo group in both overall population and 
Japanese population, and these results appeared to be supported by the result of 10 mg group in 
Study CCT-003. 
Based on these results, if a statistically significant difference between the Lu AA21004 10 or 
20 mg group and the placebo group is shown in the planned study (Study CCT-004), it is 
considered that the hypothesis of the efficacy of Lu AA21004 at doses of 10 and 20 mg in the 
Japanese population in Study CCT-002 can be verified. 
The results of Studies CCT-002, CCT-003 and OCT-001 suggested that there were no significant 
safety concerns about Lu AA21004 at the dose up to 20 mg, but further data collection may 
provide more appropriate safety evaluation. 
From the above, this study is designed as an additional phase III study to evaluate the efficacy 
and safety of Lu AA21004 in Japanese patients with MDD. 
Pharmacogenomic analyses may be conducted to evaluate a possible contribution of genetic 
polymorphism on drug response affecting the efficacy and safety of Lu AA21004. Participation 
of subjects in pharmacogenomic sample collection is optional. 
As pharmacogenomics is an evolving science, many genes and their functions are not yet fully 
understood. Future data may suggest a role of some of these genes in drug response, which may 
lead to additional hypothesis-generating exploratory research with banked samples. 


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5.0 
STUDY OBJECTIVES AND ENDPOINTS 
5.1 
Objectives 
5.1.1 
Primary Objective 
• To evaluate the efficacy of 2 fixed doses of Lu AA21004 (10 or 20 mg/day) after 8 weeks of 
treatment in Japanese patients with MDD. 
5.1.2 
Secondary Objectives 
• To evaluate the safety and tolerability of 2 fixed doses of Lu AA21004 (10 or 20 mg/day) 
after 8 weeks of treatment in Japanese patients with MDD. 
• To evaluate the efficacy of Lu AA21004 (10 or 20 mg/day) on cognitive functions after 8 
weeks of treatment in Japanese patients with MDD. 
5.1.3 
Additional Objectives 
• To analyze the plasma concentrations of Lu AA21004 and its metabolites Lu AA34443 and 
Lu AA39835 using population pharmacokinetic analyses. 
5.2 
Endpoints 
5.2.1 
Efficacy Endpoints 
5.2.1.1 Primary Endpoint 
• Change from baseline (i.e. at the start of the double-blind treatment period) in the MADRS 
total score after 8 weeks of treatment. 
5.2.1.2 Secondary Endpoints 
• MADRS response after 8 weeks of treatment (LOCF). 
(MADRS response is defined as a ≥50% decrease in the MADRS total score from baseline). 
• MADRS remission after 8 weeks of treatment (LOCF). 
(MADRS remission is defined as the MADRS total score of ≤10). 
• Change from baseline in the Hamilton Depression Rating Scale (HAM-D17) total score after 
8 weeks of treatment (LOCF). 
• Clinical global impression scale-Improvement (CGI-I) score after 8 weeks of treatment 
(LOCF). 
• Change from baseline in the clinical global impression scale-Severity (CGI-S) score after 8 
weeks of treatment (LOCF). 
• Change from baseline in the Sheehan Disability Scale (SDS) score after 8 weeks of treatment 
(LOCF). 


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• Change from baseline in the Digit Symbol Substitution Test (DSST) score after 8 weeks of 
treatment (LOCF). 
• Change from baseline in the Perceived Deficits Questionnaire (PDQ-5) score after 8 weeks 
of treatment (LOCF). 
5.2.2 
Pharmacokinetic Endpoint 
• Plasma concentrations of Lu AA21004 and its metabolites Lu AA34443 and Lu AA39835. 
5.2.3 
Safety Endpoints 
• Adverse events 
• Weight 
• Vital signs 
• Electrocardiograms (ECGs) 
• Clinical laboratory tests (serum chemistry, hematology and urinalysis) 
• Columbia-Suicide Severity Rating Scale (C-SSRS) 


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6.0 
STUDY DESIGN AND DESCRIPTION 
6.1 
Study Design 
This is a randomized, double-blind, placebo-controlled, parallel-group, phase III study to 
evaluate the efficacy and safety of 8-week treatment of 2 fixed doses of Lu AA21004 (10 or 
20 mg/day) in Japanese subjects with MDD. 
This study consists of a 1-to 3-week screening period, a 1-week single-blind placebo lead-in 
period, an 8-week double-blind treatment period and a 4-week safety follow-up period. Subjects 
who fulfill all inclusion criteria and none of exclusion criteria at the start of screening period 
(Visit 1) and at the start of placebo lead-in period (Visit 2) will move into the placebo lead-in 
period and receive placebo once daily for 1 week in a single-blind manner. Afterwards, these 
who fulfill all the inclusion criteria and none of the exclusion criteria at the start of double-blind 
treatment period (Visit 3) will move into the double-blind treatment period and will be 
randomized in a 1:1:1 ratio to one of the following treatment groups: the placebo group, the 
Lu AA21004 10 mg/day group or the Lu AA21004 20 mg/day group. Subjects in the placebo 
group and the Lu AA21004 10 mg/day group will receive placebo and Lu AA21004 10 mg, 
respectively, once daily from the day after Visit 3 for 8 weeks in a double-blind manner. Subjects 
in the Lu AA21004 20 mg/day group will receive Lu AA21004 10 mg once daily from the day 
after Visit 3 for 1 week and thereafter Lu AA21004 20 mg once daily for 7 weeks in a double-
blind manner. Subjects in any treatment groups will visit study sites at Week 1, 2, 4, 6 and 8 
during the double-blind treatment period for examinations/observations/assessments. 
A safety follow-up contact (visit or phone call) will be made 4 weeks after the completion of the 
double-blind treatment period. Subjects who prematurely discontinue the study during the 
placebo lead-in period or the double-blind treatment period will be requested to visit the study 
site for the end-of study assessments within 7 days after the discontinuation decision is made 
wherever possible, and will be contacted 4 weeks after the last dose of the study medication for 
safety follow-up. 
A schematic of the study design is shown in Figure 6.a. 
A schedule of examinations/observations/assessments is listed in Appendix A. 


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 Screening 
Period 
Placebo 
Lead-in 
Period 
(Single-
blind) 
Double-blind Treatment Period 
Follow-up Period 
 
 
 
W -4 to -2 
W -1 
W 1 
W 2 
W 3
W 4
W 5
W 6
W 7
W 8
W 9 
W 10 W 11 W 12
 
V1 
V2 
V3a) 
V4 
V5 
 
V6 
 
V7
 
V8
 
 
 
 
 
 
 
Placebo QD 
Placebo QD 
 
 
 
 
 
 
 
Lu AA21004 10 mg QD 
 
 
 
 
 
 
 
 
Lu AA21004 20 mg QD b) 
 
 
 
 
 
 
 
 
10 mg b) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Randomization 
 
End of Treatment 
 
Safety 
Follow-up c)
W: week, V: visit, QD: once daily 
a) Subjects will be randomized on the day of visit at the start of double-blind treatment period (Day -1). Subjects 
will start the double-blind treatment from the next day (Day 1). 
b) Subjects will receive 10 mg/day for the first 1 week, and then increase the dose to 20 mg/day from the 2nd week. 
c) Safety follow-up assessment will be conducted by visit to the site or on telephone. 
Figure 6.a 
Schematic of Study Design 
 
6.2 
Justification for Study Design, Dose, and Endpoints 
6.2.1 
Subject Population 
It has been reported that the placebo response rate in subjects with single major depressive 
episode is higher than that in subjects with recurrent major depressive episode.[5] Since it is 
important to exclude subjects with high placebo response from clinical studies of antidepressants, 
subjects with recurrent major depressive episode are eligible for this study. In order to 
adequately evaluate the efficacy and safety, subjects with moderate to severe MDD are eligible 
for this study, and subjects with mental disorder other than MDD are excluded from this study. 
6.2.2 
Study Design 
This study is designed based on Guideline for Clinical Evaluation of Antidepressants 
(Notification No. 1116-1 of PFSB/ELD dated 16 November 2010).[3] 
A double-blind, randomized, placebo-controlled study is designed for adequate evaluation of the 
drug efficacy and safety and is used as a standard study design for antidepressants. The use of 
placebo has continued to be a subject of discussion on the grounds of possible worsening of 
depressive symptoms or potential increase in suicidal risk; however, there is no evidence that 
assignment to placebo results in permanent harm or an increased risk of committing suicide. 


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Subjects at significant risk of suicide are ineligible for this study. Furthermore, suicidal risk of a 
subject will be assessed using C-SSRS at every visit. 
The subjects will be informed about the possibility of receiving placebo, the possible risks with 
placebo, and their right to withdraw from the study at any time. To a subject who discontinues 
the study, any other appropriate treatment will be provided based on the investigator’s decision. 
In addition, a 1-week placebo lead-in period is set prior to the double-blind treatment period to 
exclude subjects who highly respond to placebo from the study, and thereby subjects who have 
significantly improvement or aggravation of depressive symptoms during the placebo lead-in 
period will be excluded. 
Justification for sample size is described in Section 13.3. 
6.2.3 
Doses 
In overseas phases II and III studies, the efficacy of Lu AA21004 at doses of 5, 10 and 
20 mg/day was shown, with no significant safety concerns. In addition, based on the results of 
meta-analyses in 11 placebo-controlled, double-blind, short-term studies, the differences of the 
mean changes from baseline in the MADRS total score at Week 6 or 8 between the Lu AA21004 
5, 10 or 20 mg group and the placebo group were -2.3 (p =0.007), -3.6 (p <0.001), and -4.6 (p 
<0.001), respectively, showing that the difference with the placebo group became greater with 
the dose increase of Lu AA21004. 
In Study CCT-002 for subjects with MDD including Japanese, Lu AA21004 was safe up to a 
dose of 20 mg/day. And although no statistically significant differences had been demonstrated 
in the efficacy between the Lu AA21004 groups and the placebo group, the efficacy of 
Lu AA21004 in the 10 and 20 mg groups was grater than in the placebo group in both overall 
population and Japanese population. 
From the results of previous Japanese and overseas studies above, since there were no significant 
safety concerns about Lu AA21004 up to a dose of 20 mg/day and Lu AA21004 at doses of 10 
and 20 mg/day is expected to be effective, these 2 doses will be assessed in this study. 
6.2.4 
Endpoints 
MADRS or HAM-D is recommended for efficacy assessments in Guideline for Clinical 
Evaluation of Antidepressants (Notification No. 1116-1 of PFSB/ELD dated 16 November 
2010).[3] Based on the guideline, the MADRS, which is designed to be sensitive to the changes 
in severity of core symptom of depression, will be used for the primary endpoint evaluation [6], 
and the HAM-D for the secondary endpoint evaluation in this study.[7] CGI-S and CGI-I will be 
used to assess subject’s overall severity and improvement of depression.[8] In addition to these 
objective assessments of symptoms, SDS will be used in this study to assess patient’s subjective 
treatment effects on social function disabilities due to depression.[9] 
Results of overseas studies of Lu AA21004 showed that Lu AA21004 improved cognitive 
functions in subjects with MDD. In this study, DSST and PDQ-5 will be used to explore the 
effect of Lu AA21004 on cognitive functions in Japanese subjects with MDD. 


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Safety and tolerability of Lu AA21004 will be evaluated by monitoring of AEs, vital signs, 
weight, clinical laboratory tests, ECGs, and physical examinations. In addition with these safety 
evaluations, since it is important to assess suicidal risk for clinical evaluation of antidepressants, 
suicidal risk will be assessed using C-SSRS at each visit in this study.[10][11] 
6.3 
Premature Termination or Suspension of Study or Study Site 
6.3.1 
Criteria for Premature Termination or Suspension of the Study 
The study will be completed as planned unless 1 or more of the following criteria are satisfied 
that require temporary suspension or early termination of the study. 
• New information or other evaluation regarding the safety or efficacy of the study medication 
that indicates a change in the known risk/benefit profile for the product, such that the 
risk/benefit is no longer acceptable for subjects participating in the study. 
• Significant violation of Good Clinical Practice (GCP) that compromises the ability to achieve 
the primary study objectives or compromises subject safety. 
6.3.2 
Criteria for Premature Termination or Suspension of Study Sites 
A study site may be terminated prematurely or suspended if the site (including the investigator) 
is found in significant violation of GCP, protocol, or contractual agreement, is unable to ensure 
adequate performance of the study, or as otherwise permitted by the contractual agreement. 
6.3.3 
Procedures for Premature Termination or Suspension of the Study or the 
Participation of Study Sites 
In the event that the sponsor, an institutional review board (IRB), or regulatory authority elects to 
terminate or suspend the study or the participation of a study site, a study-specific procedure for 
early termination or suspension will be provided by the sponsor; the procedure will be followed 
by applicable study sites during the course of termination or study suspension. 


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7.0 
SELECTION AND DISCONTINUATION/WITHDRAWAL OF SUBJECTS 
All entry criteria, including test results, need to be confirmed prior to randomization. 
7.1 
Inclusion Criteria 
Subject eligibility is determined according to the following criteria: 
1. In the opinion of the investigator, the subject is capable of understanding and complying with 
protocol requirements. 
2. The subject signs and dates a written, informed consent form prior to the initiation of any 
study procedures. 
3. The subject suffer from recurrent MDD as the primary diagnosis according to DSM-IV-TR 
criteria (classification code 296.3x). 
4. The subject is a man or a woman aged 20 to 75 years (both inclusive) at the time of informed 
consent. 
5. The reported duration of the current major depressive episode is 3 to 12 months (both 
inclusive) at the start of screening period. 
6. The subject has a MADRS total score ≥26, a HAM-D17 total score ≥18, and a CGI-S score 
≥4 at the start of screening period, the start of placebo lead-in period and the start of double-
blind treatment period. 
7. A female subject of childbearing potential* who is sexually active with a nonsterilized male 
partner agrees to use routinely adequate contraception from signing of informed consent to 
the end of the follow-up period. 
* Definitions of a female subject of childbearing potential are defined in Section 9.1.13 
Contraception and Pregnancy Avoidance Procedure, and reporting responsibilities of 
pregnancy are defined in Section 9.1.14 Pregnancy. 
 
<Justification for Inclusion Criteria> 
Criteria 1 and 2 were set as standard requirements to conduct clinical studies. 
Criterion 3 was set to identify the target disease and diagnostic criteria for this study. In addition, 
in order to reduce the possibility of enrolling subjects who highly respond to placebo, the 
primary diagnosis was set as recurrent MDD. 
Criterion 4 was set for the lower limit of age as 20 years old because it was the adult age under 
the Civil Code. In addition, since the previous pivotal phase II or III studies set 75 years old as 
the upper limit of age, the upper limit of age in this study was set as 75 years old in the light of 
the possible comparison with the previous data. 
Criterion 5 was set to enroll subjects who had persistent major depressive episode for at least 3 
months in consideration of diagnostic certainty. The upper limit of episode duration was set as 12 


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months since, in general, subjects with chronic depressive symptoms are highly likely to have 
other concurrent mental disorder and the low possibility that the depressive symptoms would 
completely disappear with antidepressant drugs. 
Criterion 6 was set to enroll subjects with moderate or more severe MDD in severity as eligible 
for this study. 
Criterion 7 was set with respect to the safety risk related to pregnancy in female subjects. 
 
7.2 
Exclusion Criteria 
Any subject who meets any of the following criteria will not qualify for entry into the study: 
1. The subject has any following current or past history of psychiatric disorder and/or 
neurological disorder: 
– Any current psychiatric disorder other than MDD as defined by DSM-IV-TR (To be 
assessed by Mini International Neuropsychiatric Interview: MINI). A subject who 
exhibits symptoms of anxiety is eligible unless the subject fulfills the diagnostic criteria 
for a current anxiety disorder per DSM-IV-TR. 
– Current diagnosis or history of manic, mixed or hypomanic episode, MDD with psychotic 
features, schizophrenia or any other psychotic disorder (including substance-related 
mental disorders, or mental disorders due to a general medical condition) as defined by 
DSM-IV-TR. 
– Current diagnosis or history of any substance-related disorder (except nicotine and 
caffeine-related disorders) as defined by DSM-IV-TR. 
– The subject with a positive urine drug screening result at the start of screening period or 
the start of placebo lead-in period. In case that a subject showed positive test result at the 
start of screening period because the test was conducted before washout of pretreatment 
drug, the subject is eligible as long as he/she shows negative result at the start of placebo 
lead-in period. 
– Presence or history of any clinically significant neurological disorder (including epilepsy). 
– Any neurodegenerative disorder (e.g. Alzheimer’s disease, Parkinson’s disease, multiple 
sclerosis, Huntington’s disease). 
– Any DSM-IV-TR axis II disorder. 
2. The subject has the current or previous major depressive episode which were considered by 
the investigator to have been resistant to 2 or more adequate antidepressants treatments of at 
least 6 weeks duration each at sufficient doses. 
3. The subject has received any augmentation therapy (e.g. lithium, T3/T4, lamotrigine, sodium 
valproate, carbamazepine, additional atypical antipsychotic, or concomitant use of other 
antidepressant, etc.) for the current major depressive episode. 


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4. In the opinion of the investigator, the subject has experienced significant number of major 
depressive episodes in the past, and is suspected of disease other than MDD. 
5. In the opinion of the investigator, the subject has experienced the first major depressive 
episode at his/her young age, and is suspected of disease other than MDD. 
6. The subject has a MADRS total score at the start of double-blind treatment period that has 
improved or aggravated by 25% or more from the score at the start of placebo lead-in period. 
7. The subject is significantly non-compliant with the study medication in the placebo lead-in 
period; e.g., not taking the study medication for 6 or more consecutive days. 
8. The subject has received electroconvulsive therapy, vagus nerve stimulation, or repetitive 
transcranial magnetic stimulation therapy within 6 months prior to the screening period, or 
plans to initiate such therapy during the study. 
9. The subject is receiving cognitive-behavioral therapy or psychotherapy at the time of 
informed consent, or plans to initiate such therapy during the study. 
10. The subject is at significant risk of suicide or has a score ≥5 on Item 10 (suicidal thoughts) of 
the MADRS at the start of screening period, the start of placebo lead-in period or the start of 
double-blind treatment period, or has attempted suicide within 6 months prior to the start of 
screening period. 
11. The subject has experienced any environmental change (e.g. temporary retirement, 
returnment, change of residence) considered by the investigator to have the potential to 
impact on the efficacy evaluation, or plans such environmental changes during the study. 
12. The subject is currently receiving drug therapy for thyroid dysfunction. 
13. The subject is currently receiving hormonal therapy for gynecological disease. 
14. The subject has taken excluded medications during the protocol-specified period, or will 
require to take excluded medications during the study. 
15. The subject has previously received vortioxetine. 
16. The subject has received study medication in a previous clinical study of Lu AA21004 
(including this study). 
17. The subject has a clinically significant chronic liver disease. 
18. The subject has a history of severe allergy or hypersensitivity to drugs. 
19. The subject has a clinically significant unstable illness, for example, hepatic impairment or 
renal insufficiency, or a cardiovascular, pulmonary, gastrointestinal, endocrine, neurological, 
rheumatologic, immunologic, infectious, neoplastic, skin and subcutaneous tissue disorders, 
eye disorders, or metabolic disturbance. 
20. The subject has clinically significant abnormal vital signs as determined by the investigator 
at the start of screening period, placebo lead-in period, or double-blind treatment period. 


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21. The subject has clinically significant abnormal ECG as determined by the investigator, at the 
start of the screening period, placebo lead-in period, or double-blind treatment period. 
22. The subject has clinically significant abnormal findings of clinical laboratory tests as 
determined by the investigator, or has alanine aminotransferase (ALT) or aspartate 
aminotransferase (AST) >2 × ULN at the start of screening period or placebo lead-in period. 
23. If female, the subject is pregnant or lactating. 
24. The subject has a disease or takes medications that could, in the opinion of the investigator, 
interfere with the evaluation of the safety, tolerability, or efficacy. 
25. The subject is, in the opinion of the investigator, unsuitable for this study for any other 
reason. 
<Justification for Exclusion Criteria> 
Criteria 1, 4, and 5 were set to exclude subjects or the possible subjects with concurrent mental 
or neurological disorder other than MDD and to adequately evaluate the efficacy and safety for 
the target disease. 
Criterion 2 was set to exclude subjects or the possible subjects with refractory major depression 
and include adequate subjects for the evaluation of drug effect. 
Criterion 3 was set to exclude subjects who have received augmentation therapy and include 
adequate subjects for the evaluation of drug effect since subjects who are required to receive 
augmentation therapy may have refractory major depression or concurrent mental or 
neurological disorder other than MDD. 
Criterion 6 was set to exclude subjects who highly respond to placebo and include adequate 
subjects for the evaluation of drug effect. Subjects who abruptly worsen their symptoms in a 
short time are also excluded from the study in consideration of the appropriateness of drug effect 
evaluation and the safety of subjects. 
Criterion 7 was set because it influences the evaluation in the placebo lead-in period. 
Criteria 8, 9, 11 to 13 were set because they could influence the evaluation of efficacy. 
Criteria 10, 17 to 22 were set with respect to the safety of subjects. 
Criteria 14 and 24 were set because they could influence the evaluation of efficacy and safety. 
Criterion 15 was set because the bias toward Lu AA21004 based on their treatment experience 
could influence the evaluation of the efficacy and safety. 
Criterion 16 was set to avoid duplicated evaluation of subjects. 
Criterion 23 was set with respect to the safety risk for pregnant women, fetuses, neonates, or 
nursing infant. 
Criterion 25 was set to exclude subjects who are considered to be unsuitable for this study for 
any other reason. 


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7.3 
Excluded Medications and Treatments 
Subjects must be instructed not to take any medications including over-the-counter products, 
without first consulting with the investigator. 
Any treatments for depression other than the study medication, including electroconvulsive 
therapy, vagus nerve stimulation, repetitive transcranial magnetic stimulation, cognitive-
behavioral therapy or psychotherapy are prohibited during the study. 
A list of prohibited/restricted concomitant medication is provided in Table 7.a. 
Table 7.a 
List of Prohibited or Restricted Concomitant Medications 
Drug Class 
Comments or Exceptions
84 days before the start of double-blind treatment period (Day -84) through the end of double-blind treatment period 
(Visit 8) or early termination 
(1) Any investigational drug 
 
Start of the screening period (Visit 1) through the end of double-blind treatment period (Visit 8) or early termination
(2) Antidepressants 
Including MAOIs.
(3) Anxiolytics (tranquilizers) 
Including benzodiazepines.
(4) Hypnotics 
Non-benzodiazepines (zolpidem, zopiclone, and eszopiclone) are allowed. 
However, use of these drugs should be kept to the minimum necessary, and 
use for 2 or more consecutive days and use at the night before a study visit 
are NOT allowed. In addition, the type and dose of non-benzodiazepines 
should NOT be changed from the start of placebo lead-in period (Visit 2) to 
the end of double-blind treatment period (Visit 8) or early termination. 
(5) Antipsychotics 
Depot antipsychotics are prohibited within 6 months prior to the start of 
double-blind treatment period. 
(6) Mood stabilizers 
Including lithium, valproate, valpromide.
(7) Psychoactive herbal 
remedies/supplements 
Including St. Johns Wort, kava kava, valerian, ginkgo biloba. 
(8) Psychotropic agents not 
otherwise specified 
Including tryptophan, melatonin, and dopamine agonists. 
(9) Analeptics 
 
(10) Anti-ADHD 
 
(11) Anti-Alzheimer's disease 
 
(12) Anticonvulsants 
 
(13) Anti-Parkinson’s disease 
 
(14) Erectile dysfunction drugs 
 
(15) Anorexics 
 
(16) Antimigraines 
 
(17) Antiemetics/antinauseants 
Including dopamine antagonists. Only phosphoric acid preparations, bismuth 
and cola syrup are allowed. 
(18) Interferon 
 
(19) Systemic steroids 
Oral preparation and injection are NOT allowed.


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(20) Antibiotics 
Rifampicin (oral preparation and injection) is NOT allowed. 
Start of the placebo lead-in period (Visit 2) through the end of double-blind treatment period (Visit 8) or early 
termination 
(21) Antiarrhythmics of class Ia, Ic 
 
(22) Antiulcer drugs 
Omeprazole, cimetidine, and sulpiride are NOT allowed. 
(23) Anticoagulants/antiplatelet 
treatment 
Including low dose of aspirin as antiplatelet treatment. Low-molecular 
weight heparins are allowed as needed. 
(24) Antidiarrheal agents 
Loperamide, bismuth, and kaolin preparations are allowed. 
(25) Antihistamines 
Loratadine, desloratadine, cetirizine, levocetirizine, mizolastine, and 
fexofenadine are allowed. 
(26) Antineoplastics 
 
(27) Hormones 
Chronic use for contraception or treatment of benign prostatic hyperplasia 
are allowed. 
(28) Hypoglycemic agents 
Chronic use is allowed.
(29) Insulin 
Chronic use is allowed without major change of dose or administration.
(30) Calcium antagonist 
Chronic use is allowed without major change of dose or administration.
(31) Narcotic analgesics 
Topical administration including for dental use is allowed. 
(32) NSAIDs 
Episodic use is allowed. Selective COX-2 inhibitors, acetaminophen, and 
topical NSAIDs are allowed. 
(33) Cough/cold agents 
Episodic use is allowed. However, chronic use of preparations containing 
ephedrine, pseudoephedrine, and codeine are NOT allowed for more than 1-
week treatment. 
MAOI = monoamine oxidase inhibitor, ADHD = attention deficit hyperactivity disorder, 
NSAIDs = nonsteroidal anti-inflammatory drugs, COX-2 = cyclooxygenase-2 
 
<Justification for Prohibited or Restricted Concomitant Medications> 
(1) was set since other investigational drug could influence the evaluation of the efficacy and 
safety. 
(2) was set since antidepressants could influence the evaluation of the efficacy. Especially, 
concomitant use of monoamine oxidase inhibitors (MAOIs) was prohibited because concomitant 
use of MAOIs could enhance serotonin action and influence the evaluation of the efficacy, and 
because the safety of subjects should be ensured. 
(3) was set since anxiolytics (tranquilizers) could improve anxiety which was known to an 
accompanying symptom of depression and influence the evaluation of the efficacy. 
(4) was set since hypnotics could improve insomnia which was known to an accompanying 
symptom of depression and influence the evaluation of the efficacy. Concomitant use of non-
benzodiazepines was allowed as needed because the extent of anxiolytic and carry-over effects 
of non-benzodiazepines was relatively weak, and thus these effects had only a small influence on 
efficacy evaluation. 
(5) to (13) were set since these drugs had psychotropic activity or central nervous effects and 


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could influence the evaluation of the efficacy. 
(14) was set since erectile dysfunction drugs could improve sexual dysfunction and could 
influence the evaluation of the efficacy and safety. 
(15) was set since anorexics influence the appetite assessment related to depression. 
(16) and (17) were set since antimigraines and antiemetics/antinauseants could act on serotonin 
receptors and influence the evaluation of the efficacy and safety. Especially, concomitant use of 
antiemetics/antinauseants was prohibited because adverse events associated with the study 
medication should be appropriately evaluated. 
(18) and (19) were set since interferon and systemic steroids could induce depressive symptoms 
and influence the evaluation of the efficacy. 
(20) was set since antibiotics could decrease the plasma drug concentration by inducing drug 
metabolic enzymes and influence the evaluation of the efficacy and safety. 
(21) and (22) were set since antiarrhythmics of class Ia, Ic, and antiulcer drugs could increase the 
plasma drug concentration by inhibiting drug metabolic enzymes and influence the evaluation of 
the efficacy and safety 
(23) was set since concomitant use of anticoagulants/antiplatelet treatment drugs could enhance 
bleeding tendency. 
(24) was set since gastrointestinal adverse events associated with the study medication should be 
appropriately evaluated. 
(25) was set since drowsiness, an adverse drug reaction of antihistamines, could attenuate 
insomnia, which was known to an accompanying symptom of depression and influence the 
evaluation of the efficacy. Concomitant use of only loratadine, desloratadine, cetirizine, 
levocetirizine, mizolastine, and fexofenadine, which are considered to cause less drowsiness, was 
allowed. 
(26) was set since antineoplastics could influence the evaluation of the efficacy and safety. 
(27) and (28) were set since hormones and hypoglycemic agents could influence the evaluation 
of the efficacy and safety. However, chronic use of these drugs at a certain dose was allowed as 
having little influence on the evaluation. 
(29) and (30) were set since insulin and calcium antagonists could induce depressive symptoms. 
However, chronic use of insulin or calcium antagonist at a certain dose was allowed as having 
little influence on the efficacy evaluation. 
(31) was set since analgesic action of narcotic analgesics could influence the evaluation of the 
efficacy. However, topical administration such as for dental use is allowed since narcotic 
analgesics have only a small influence on the evaluation. 
(32) was set since the concomitant use of NSAIDs could cause upper gastrointestinal bleeding. 
However, the episodic use of NSAIDs as well as the concomitant use of selective COX-2 
inhibitors, acetaminophen, and topical NSAIDs was allowed since these treatments had a 


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relatively lower effect on gastrointestinal adverse events. 
(33) was set since some cough/cold agents increase the serotonin concentration of the central 
nervous system. Concomitant use of ephedrine and codeine for more than 1 week was not 
allowed due to their addictiveness. 
 
7.4 
Diet, Fluid, and Activity Control 
The investigator or study collaborator should instruct subjects on the following items: 
1. The subject must be punctual for visit, undergo physical examination and predefined 
examinations. If the subject cannot visit, he/she should inform the investigator or study 
collaborator as soon as possible. 
2. If the subject experiences a worsening of conditions on any day the site visit is not scheduled, 
he/she should inform the investigator or study collaborator of the worsening by telephone or 
other manners as soon as possible and seek instructions. 
3. The subject must take the study medication as instructed by the investigator. If the subject is 
noncompliant with study treatment, he/she should inform the investigator or study 
collaborator of the noncompliance with treatment at visit. The subject must return unused 
study medication and study medication sheets at visit. 
4. The subject must not take any medications including over-the-counter products other than 
medications as instructed by the investigator without advance consulting (except for 
emergency). 
5. If the subject consults other medical institution from the time of informed consent to the end 
of the follow-up period, notify the physician of medical institution of the subject’s 
participation in this study. 
6. If the subject consults other medical institution from the time of informed consent to the end 
of the follow-up period, notify the investigator of the circumstances and therapy. 
7. The subject must visit the site under fasted conditions at Visits 2, 3 and 8 or Early 
Termination Visit. For visits serum chemistry test is scheduled, the subject visits the site 
under fasted conditions wherever possible. 
8. Female subject of childbearing potential who is sexually active with a nonsterilized male 
partner must routinely use adequate contraception from the time of informed consent to the 
end of the follow-up period. 
7.5 
Criteria for Discontinuation or Withdrawal of a Subject 
The primary reason for discontinuation or withdrawal of the subject from the study or study 
medication should be recorded in the case report form (eCRF) using the following categories. 
For the subject who prematurely discontinues the study before entry into the placebo lead-in 
period or randomization, refer to Section 9.1.18 or 9.1.20, respectively. 


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1. Pretreatment event (PTE) or adverse event (AE) 
The subject has experienced a pretreatment event (PTE) or AE that requires early termination 
because continued participation imposes an unacceptable risk to the subject’s health or the 
subject is unwilling to continue because of the PTE or AE. 
2. Liver function test (LFT) abnormalities 
Study medication should be discontinued immediately with appropriate clinical follow-up 
(including repeat laboratory tests, until a subject’s laboratory profile has returned to 
normal/baseline status, see Section 9.1.12), if the following circumstances occur at any time 
during study medication treatment: 
– alanine aminotransferase (ALT) or aspartate aminotransferase (AST) >8 × upper limit of 
normal (ULN), or 
– ALT or AST >5 × ULN and persists for more than 2 weeks, or 
– ALT or AST >3 × ULN in conjunction with elevated total bilirubin >2 × ULN or 
international normalized ratio (INR) >1.5, or 
– ALT or AST >3 × ULN with appearance of fatigue, nausea, vomiting, right upper 
quadrant pain or tenderness, fever, rash and/or eosinophilia (>5%). 
3. Significant protocol deviation 
The discovery post-randomization that the subject failed to meet protocol entry criteria or did 
not adhere to protocol requirements, and continued participation poses an unacceptable risk 
to the subject’s health. 
4. Lost to follow-up 
The subject did not return to the clinic and attempts to contact the subject were unsuccessful. 
Attempts to contact the subject must be documented. 
5. Voluntary withdrawal 
The subject wishes to withdraw from the study. The reason for withdrawal, if provided, 
should be recorded in the eCRF. 
Note: All attempts should be made to determine the underlying reason for the withdrawal and, 
where possible, the primary underlying reason should be recorded. (i.e., withdrawal 
due to an AE or lack of efficacy should not be recorded in the “voluntary withdrawal” 
category.) 
6. Study termination 
The sponsor, IRB, or regulatory agency terminates the study. 
7. Pregnancy 
The subject is found to be pregnant. 
Note: If the subject is found to be pregnant, the subject must be withdrawn immediately. The 
procedure is described in Section 9.1.14. 


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8. Lack of efficacy 
The investigator has determined that the subject is not benefiting from study treatment; and, 
continued participation would pose an unacceptable risk to the subject. 
9. Medication noncompliance 
The subject did not take the study medication for 6 or more consecutive days. 
10. Other 
Note: The specific reasons should be recorded in the “specify” field of the eCRF. 
7.5.1 
Additional Guidance for Withdrawal Criteria 
Any signs of suicidal risk will be assessed throughout the study by C-SSRS and MADRS 
assessments and clinical judgment of the investigator. If the subject has a significant risk of 
suicide in the opinion of the investigator, or the subject has the MADRS score of ≥5 on item 10 
(suicidal thoughts), the subject will prematurely discontinue the study. 
If subject’s underlying diseases become exacerbated, and the investigator concludes any 
excluded medications or treatment is required, the subject will prematurely discontinue the study. 
7.6 
Procedures for Discontinuation or Withdrawal of a Subject 
The investigator may discontinue a subject’s study participation at any time during the study 
when the subject meets the study termination criteria described in Section 7.5. In addition, a 
subject may discontinue his or her participation without giving a reason at any time during the 
study. Should a subject’s participation be discontinued, the primary criterion for termination 
must be recorded by the investigator. In addition, efforts should be made to perform all 
procedures scheduled for the Early Termination Visit. 


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8.0 
CLINICAL TRIAL MATERIAL MANAGEMENT 
This section contains information regarding all medication provided directly by the sponsor, 
and/or sourced by other means, that are required by the study protocol, including important 
sections describing the management of clinical trial material. 
8.1 
Study Medication 
8.1.1 
Dosage Form, Manufacturing, Packaging, and Labeling 
In this protocol, the term study medication refers to all or any of the drugs defined below. 
Table 8.a 
Study Medication 
Name 
Active Substance
Dosage Form
Strength 
Manufacture
Lu AA21004 tablet 
1-[2-(2,4-dimethyl-phenyl
sulfanyl)-phenyl]-piperazine, 
hydrobromide 
Indistinguishable round 
biconvex tablets 
10 mg 
or 
20 mg 
Takeda 
Pharmaceutical 
Company Limited 
Placebo tablet 
None 
– 
 
The study medications are identical in appearance. 
As for the study medications for the placebo lead-in period, 14 tablets of placebo are packaged in 
1 press-through pack (PTP) sheet, and a single sheet is enclosed in an outer carton. The 1 outer 
carton (including 7 days’ spare tablets) will be provided to each subject in the placebo lead-in 
period. 
As for the study medications for the double-blind treatment period, 14 tablets of Lu AA21004 or 
placebo are packaged in 1 PTP sheet. For Week 1 in the double-blind treatment period, 1 sheet 
(including 7 days’ spare tablets) is enclosed in an Inner Carton 1, and, for Weeks 2 to 8 in the 
double-blind treatment period, 5 sheets (including 21 days’ spare tablets) are enclosed in an 
Inner Carton 2. Inner Cartons 1 and 2 are packed together in an outer carton. The 1 outer carton 
will be provided to each subject in the double-blind treatment period. 
The outer carton is labeled with a note that the formulation therein is used for a clinical study and 
pertinent information of the name and quantity of the study medication, the sponsor’s name and 
address, manufacturing number, and storage conditions. 
8.1.2 
Storage 
The study medications should be stored at room temperature (1°C to 30°C). 
The study medication must be kept in an appropriate, limited-access, secure place until it is used 
or returned to the sponsor or designee for destruction. The study medication must be stored under 
the conditions specified on the label, and remain in the original container until dispensed. A daily 
temperature log of the drug storage area must be maintained every working day. 


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8.1.3 
Dose and Regimen 
For the placebo lead-in period, administration of the study medication will be started on the day 
after Visit 2, and subjects will orally take 1 tablet of placebo once daily. 
For the double-blind treatment period, administration of the study medication will be started on 
the day after Visit 3, and subjects will orally take 1 tablet of Lu AA21004 at a dose of 10 mg or 
20 mg or placebo once daily. 
The investigator or designee should instruct subjects to take the study medication at the same 
time, a certain time in the morning to the extent possible, throughout the study. The study 
medication can be taken under both fed and fasted conditions. 
At each visit, subjects will be provided with necessary and sufficient amount of the study 
medications to be used by next visit by the investigator or designee. The investigator or designee 
must instruct subjects to bring the all remaining study medication and container (PTP sheets) at 
each visit. 
The dose (tablet count) that will be provided to each group and regimen are shown in Table 8.b. 
Table 8.b 
Dose and Regimen 
Treatment Group 
Regimen 
Tablet Count/Dose
Placebo 
Lead-in Period 
Double-blind Treatment 
Period 
(Week 1) 
Double-blind Treatment 
Period 
(Weeks 2 to 8) 
Placebo Group 
Oral, 
once daily 
Placebo tablet ×1 
Placebo tablet ×1 
Placebo tablet ×1 
Lu AA21004 
10 mg/day Group 
Oral, 
once daily 
Placebo tablet ×1 
Lu AA21004
10 mg tablet ×1 
Lu AA21004
10 mg tablet × 1 
Lu AA21004 
20 mg/day Group 
Oral, 
once daily 
Placebo tablet ×1 
Lu AA21004
10 mg tablet ×1 
Lu AA21004
20 mg tablet ×1 
 
8.1.4 
Overdose 
An overdose is defined as a known deliberate or accidental administration of the study 
medication to or by a study subject, at a dose above that which is assigned to that individual 
subject according to the study protocol. This includes any concomitant medication received at a 
dose greater than that prescribed to the subject. 
All cases of overdose will be documented as AEs on an AE page of the eCRF according to 
Section 10.2.1, and should be reported as a special interest AE according to Section 10.2.1.3 
(with or without associated AEs). Serious adverse events (SAEs) associated with an overdose 
should be reported according to the procedure in Section 10.2.2. 
In the event of an overdose of the study medication, the investigator should take general 
symptomatic and supportive treatment, along with immediate gastric lavage where appropriate. 
Intravenous fluids should be administered as needed. As in all cases of drug overdose, respiration, 


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pulse, blood pressure, and other appropriate signs should be monitored and general supportive 
treatment should be conducted. 
8.2 
Study Drug Assignment and Dispensing Procedures 
Subjects will be assigned to receive the next available medication ID number allocated to each 
study site. The Medication ID Number will be entered onto the eCRF. 
8.3 
Randomization Code Creation and Storage 
Randomization personnel (a person designated by the sponsor) will generate the randomization 
code. All randomization information will be stored in a secured area, accessible only by 
authorized personnel. 
8.4 
Study Drug Blind Maintenance 
The emergency key code administration center will maintain the emergency key code until its 
breaking for an emergency or completion of database lock of all subjects. 
Since analytical results of the plasma concentration may jeopardize maintenance of study 
blinding, the analytical laboratory will keep the final analytical results and not disclose to a third 
party until unblinding of the study. The analytical laboratory will report the results to the sponsor 
after they receive the notification of unblinding of the study. However, the analytical laboratory 
may disclose the results to the sponsor through a responsible person for randomization before 
unblinding of the study taking measures to secure the blinding such as reassignment of the 
medication number so that persons in the laboratory may not identify a subject. The detailed 
procedure will be specified in the separately created manual for handling of biological specimen 
for pharmacokinetic analysis. 
8.5 
Unblinding Procedure 
The study drug blind shall not be broken by the investigator unless information concerning the 
study drug is necessary for the medical treatment of the subject. 
For unblinding, the investigator may contact the emergency key code administration center and 
obtain allocation information of the study medication. 
The date, time, and reason the blind is broken must be recorded in the document called Record of 
Early Blind-Breaking, and the same information (except the time) must be recorded on the eCRF. 
If any site personnel are unblinded, study drug must be stopped immediately and the subject 
must be withdrawn from the study. 
For details of unblinding procedure, refer to the manual for Breaking of Emergency Key Code. 
8.6 
Accountability and Destruction of Sponsor-Supplied Drugs 
The site designee will receive the procedures for handling, storage, and management of study 
drug created by the sponsor, according to which the site designee will appropriately manage the 


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sponsor-supplied drug. The investigator will also receive those procedures from the sponsor. The 
procedures include those for ensuring appropriate receipt, handling, storage, management, 
dispensation of the sponsor-supplied drug, and collection of unused medications from the subject 
as well as return of them to the sponsor or destruction of them. 
The site designee will immediately return unused medications to the sponsor after the study is 
closed at the site. 


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9.0 
STUDY PLAN 
9.1 
Study Procedures 
The following sections describe the study procedures and data to be collected. For each 
procedure, subjects are to be assessed by the same investigator whenever possible. The Schedule 
of Study Procedures is located in Appendix A. 
9.1.1 
Informed Consent Procedure 
The requirements of the informed consent are described in Section 15.2. 
Informed consent must be obtained prior to the subject entering into the study, and before any 
protocol-directed procedures are performed. 
A unique subject identification number (subject number) will be assigned to each subject at the 
time that informed consent is explained; this subject number will be used throughout the study. 
9.1.1.1 Pharmacogenomic Informed Consent Procedure 
A separate informed consent form pertaining to pharmacogenomic research must be obtained 
prior to collecting a sample for Pharmacogenomic Research for this study (see Section 9.1.16). 
The provision of consent to research in pharmacogenomics is independent of consent to the other 
aspects of the study. 
9.1.2 
Demographics, Medical History, and Medication History Procedure 
Demographic information to be obtained will include date of birth, sex, alcohol use, and smoking 
status of the subject at Screening. 
Medical history to be obtained will include determining whether the subject has any mental 
disorders other than MDD (including dysthymic disorder, generalized anxiety disorder, 
obsessive-compulsive disorder, as defined by DSM-IV-TR) that resolved within 1 year prior to 
signing of informed consent. Medical history of MDD (past major depressive episode) to be 
obtained will include determining whether the subject had MDD according to Section 9.1.4.2. 
Medication history information to be obtained includes any medication that stopped prior to 
signing of informed consent and used for treatment of the current major depressive episode or 
accompanying symptoms. Name of medication used, dose level, unit, dose frequency, route of 
administration, and the dates of the initial dose and the last dose must be recorded. 
9.1.3 
Diagnosis of MDD 
Diagnosis of MDD and other psychiatric disorders must be based on DSM-IV-TR criteria. In 
addition, the Mini International Neuropsychiatric Interview (MINI) must be used as an auxiliary 
diagnostic tool. MINI is a structured diagnostic interview designed to provide a brief 
standardized evaluation of major Axis I psychiatric disorders in DSM-IV-TR. The investigator 
can use the MINI after a training session for diagnosis of MDD. Only the version provided by 
the sponsor that has been validated in Japanese will be used in this study. 


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9.1.4 
Assessments of Major Depressive Episode 
9.1.4.1 Current Major Depressive Episode 
The following items will be assessed for the current major depressive episode. 
– Start date 
– Symptom (Select from 9 symptoms listed below as defined by DSM-IV-TR.) 
– Psychotherapy (yes or no) 
<Symptoms of Major Depressive Episode> 
(1) Depressed mood most of the day, nearly every day, as indicated by either subjective 
report (e.g., feels sad or empty) or observation made by others (e.g., appears tearful). 
(2) Markedly diminished interest or pleasure in all, or almost all, activities most of the 
day, nearly every day (as indicated by either subjective account or observation made 
by others). 
(3) Significant weight loss when not dieting or weight gain (e.g., a change of more than 
5% of weight in a month), or decrease or increase in appetite nearly every day. 
(4) Insomnia or hypersomnia nearly every day. 
(5) Psychomotor agitation or retardation nearly every day (observable by others, not 
merely subjective feelings of restlessness or being slowed down). 
(6) Fatigue or loss of energy nearly every day. 
(7) Feelings of worthlessness or excessive or inappropriate guilt (which may be 
delusional) nearly every day (not merely self-reproach or guilt about being sick). 
(8) Diminished ability to think or concentrate, or indecisiveness, nearly every day (either 
by subjective account or as observed by others). 
(9) Recurrent thoughts of death (not just fear of dying), recurrent suicidal ideation 
without a specific plan, or a suicide attempt or a specific plan for committing suicide.
 
9.1.4.2 Past Major Depressive Episode 
The following items will be assessed for past major depressive episode. 
– Start date and duration of each past major depressive episode. 
– Antidepressant drug treatment for each past major depressive episode (yes or no). 
If the subject has received an antidepressant drug, category of the drug (select from 
SSRIs, SNRIs, or other antidepressant drugs.) and duration will be recorded. 


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9.1.5 
Physical Examination Procedure 
A 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; and (11) other. 
All subsequent physical examinations should assess clinically significant changes from the 
examinations prior to first dose. 
9.1.6 
Weight, Height, and BMI 
A subject should have weight and height measured while wearing indoor clothing and with shoes 
off. Height will be collected in centimeters without decimal places, and weight will be collected 
in kilograms (kg) to 1 decimal place. The BMI will be calculated by the sponsor to 1 decimal 
place with the formula provided below: 
Metric: BMI = weight (kg)/height (m)2 
9.1.7 
Vital Sign Procedure 
Vital signs will include body temperature (infra-axillary measurement), sitting blood pressure 
(resting more than 5 minutes), and pulse (bpm). 
9.1.8 
Efficacy Evaluation 
The efficacy will be evaluated using rating scales (MADRS, HAM-D, CGI-S/I, SDS, DSST, and 
PDQ-5). These assessments should be performed by the investigator who has sufficient 
experience in clinical practice of diagnosing and treating MDD and who was approved by the 
sponsor as a rater in this study. The same rater should, whenever possible, assess the same 
subject throughout the study. 
In principle, the MADRS should be performed first at visits that the above-mentioned multiple 
rating scales will be performed. Efficacy data using these rating scales should be recorded in 
eCRF by the next visit of the subject at the latest. 
In addition, self-report of depressive symptoms by subjects will be performed using Quick 
Inventory of Depressive Symptomatology (QIDS-J). For QIDS-J, any sequencing order with 
other rating scales is allowed. QIDS-J data will not be recorded in the eCRF. 
9.1.8.1 Rating and Rating Training for MDD 
Montgomery-Åsberg Depression Rating Scale (MADRS) 
The MADRS will be used for a primary efficacy measurement. The MADRS is a depression 
rating scale consisting of 10 items representing the core symptoms of depression.[6] The 
MADRS is rated using Structured Interview Guide for MADRS (SIGMA). The rating should be 
based on a clinical interview with the subject, moving from broadly phrased questions about 
symptoms to more detailed questions. The rating is performed based on the most severe 


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condition of the subject during the past 1 week, and each item is rated from 0 to 6. Item 1 and 
Items 3 to 10 are based on subject report, and Item 2 is based on the observation of the subjects. 
The rater must decide whether the rating for each item lies on the defined scale steps (0, 2, 4, 6) 
or between them (1, 3, 5). Each item score and the total score of all items should be recorded on 
the eCRF. 
Before the first rating, the investigators (hereinafter referred to as [potential] raters in this 
section) will attend a MADRS training session. Potential raters will watch and score a recorded 
MADRS interview (video/DVD). A discussion will follow the training session to achieve 
alignment among raters on the scoring of each individual item. 
The sponsor will qualify the raters who achieve the scoring in the training session, and issue a 
certificate. No subject may be rated before the rater receives the certificate. For potential raters 
who cannot attend the training session or who are not qualified in the training session, similar 
MADRS training will be held in each study sites. 
If a rater is changed or added during the course of the study, the newly appointed rater must 
complete all training requirements satisfactorily and must be approved by the sponsor. 
Hamilton Depression Rating Scale (HAM-D) 
The HAM-D is a depression rating scale that assesses overall symptoms of depression including 
somatic symptoms. The rater must rate each item score between 0 to 2/3/4 based on a clinical 
interview with the subject.[7] The rating should be based on patient’s condition during the past 1 
week prior to the time of assessment. The HAM-D21 is used for rating, and total score of the 
first 17 items is used as HAM-D17 total score. Each item score and the HAM-D17 total score 
should be recorded on the eCRF. Prior to the first rating, potential raters will attend a session on 
concerns to be addressed for the rating of HAM-D. 
Clinical Global Impression Scale (CGI) 
The CGI consists of 2 sub-scales: CGI-S and CGI-I.[8] The CGI-S assesses the physician’s 
impression of the subject’s current mental disorder state. The rater should use his/her total 
clinical experience with this subject population and rate the current severity of the subject’s 
mental disorder on a 7-point scale. The CGI-I assesses the subject’s improvement (or worsening). 
The rater is required to assess the subject’s condition relative to baseline* on a 7-point scale. In 
all cases, the assessment should be made independent of whether the rater believes the 
improvement is study medication-related or not. Each score of CGI-S and CGI-I should be 
recorded on the eCRF. Prior to the first rating, potential raters will attend a rating session on 
concerns to be addressed for the rating of CGI. 
* The start day of the double-blind treatment period (Visit 3) is defined as baseline. However, for 
the assessment at the start of double-blind treatment period (Visit 3) or early termination visit 
prior to the start of double-blind treatment period, CGI should be assessed comparing with the 
score at the start of placebo lead-in period (Visit 2). 


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9.1.8.2 Social Function Assessment 
Sheehan Disability Scale (SDS) 
The SDS is a scale that assesses disabilities in 3 social function domains subjectively.[9] The 
subject self-rates the extent to which his or her work/school, social life/leisure activities, and 
home life/family responsibilities are impaired by his or her symptoms on a 10-point visual 
analog scale. The SDS also addresses the number of days the above functions were lost or under-
productive due to the symptoms. Each item score should be recorded on the eCRF. Prior to the 
first rating, potential raters will attend a rating session on concerns to be addressed for the rating 
of SDS. 
9.1.8.3 Cognitive Function Assessments 
Digit Symbol Substitution Test (DSST) 
The DSST is a test battery used for assessment of cognitive functions. In the DSST, subjects are 
shown 9 digit-symbol pairs and required to pair the same digit and symbol combination. Levels 
of cognitive functions are assessed by the number of correct symbols (0 to 133 scores) within the 
time limit. DSST scores should be recorded on the eCRF. At a start of the placebo lead-in period 
(Visit 2), subjects will complete the sample items prior to the actual test, but the results of the 
sample items should not be recorded on the eCRF. Prior to the first rating, potential raters will 
attend a rating session on concerns to be addressed for the assessment of DSST. 
Perceived Deficits Questionnaire (PDQ-5) 
The PDQ-5 is a self-report questionnaire by subjects used for assessment of their cognitive 
functions. PDQ-5 consists of 5 questions and provides an assessment of several domains of 
cognitive functions: attention, retrospective memory, prospective memory, and planning and 
organization. Sub-scores of each item score (0 to 4 scores) and the total score of all items should 
be recorded on the eCRF. Prior to the first rating, potential raters will attend a rating session on 
concerns to be addressed for the assessment of PDQ-5. 
9.1.8.4 Self-report Assessment of Depressive Symptoms and Assessment Monitoring 
Quick Inventory of Depressive Symptomatology (QIDS-J) 
The QIDS-J is a basic self-report depression scale, and the partially revised version provided by 
the sponsor will be used for this study. Subjects will enter the responses to each questions of the 
QIDS-J into the terminal. The rater should not see the responses and not record them on the 
eCRF. The responses will be reviewed by the expert who has adequate experience in assessment 
of depression. Appropriateness of the efficacy evaluation will be monitored by comparing with 
results of other efficacy evaluation of the relevant subject. 


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9.1.9 
Suicidal Risk Assessments 
Columbia-Suicide Severity Rating Scale (C-SSRS) 
The C-SSRS was developed by researchers at Columbia University as a tool to help 
systematically assess suicidal ideation and behavior in subjects during participation in a clinical 
study. The C-SSRS is composed of 3 questions addressing suicidal behavior and 5 questions 
addressing suicidal ideation, with subquestions assessing the severity. The tool is administered 
via interview with the subject.[10][11] Responses to each question will be recorded on the eCRF. 
Prior to the first rating, potential raters will attend a rating session on concerns to be addressed 
for the assessment of C-SSRS. 
9.1.10 Documentation of Concomitant Medications 
Concomitant medication is any drug given in addition to the study medication. These may be 
prescribed by a physician or obtained by the subject over the counter. Concomitant medication is 
not provided by the sponsor. At each study visit, subjects will be asked whether they have taken 
any medication other than the study medication (used from signing of informed consent through 
Visit 8 or Early Termination Visit ), and all medication including vitamin supplements, over-the-
counter medications, and oral herbal preparations must be recorded in the eCRF. 
9.1.11 Documentation of Concurrent Medical Conditions 
Concurrent medical conditions are those significant ongoing conditions or diseases that are 
present at signing of informed consent, except for accompanying symptoms of MDD. This 
includes clinically significant laboratory, vital sign, ECG, or physical examination abnormalities 
noted at the first examination after signing of informed consent in the opinion of the investigator. 
The condition (i.e., diagnosis) should be described. 
9.1.12  Procedures for Clinical Laboratory Samples 
The items of clinical laboratory tests are shown in Table 9.a. Samples will be collected and 
handled in accordance with the separate operation manual. For clinical laboratory tests, the 
maximum volume of blood at any single visit is approximately 10 mL. 


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Table 9.a 
Clinical Laboratory Tests 
Hematology 
Serum Chemistry
Red blood cells (RBC) 
White blood cells (WBC) 
Hemoglobin 
Hematocrit 
Platelets 
Neutrophils 
Eosinophils 
Basophils 
Lymphocytes 
Monocytes 
Albumin
AST 
ALT 
γ-GTP 
Alkaline phosphatase 
Total bilirubin 
Direct bilirubin 
(Conjugated bilirubin) 
Creatinine 
Creatine kinase 
Blood urea nitrogen (BUN) 
Uric acid 
Glucose (fasting or non-fasting) a)
Total protein 
Potassium 
Sodium 
Calcium 
Chloride 
Lipids (fasting or non-fasting) a) 
Triglycerides 
Total Cholesterol 
High-density lipoprotein cholesterol 
Low-density lipoprotein cholesterol 
(direct measurement) 
Hormonal Test (Visit 1 only) 
Urinalysis
Thyroid stimulating hormone (TSH) b) 
Free T4 b) 
Protein (qualitative)
Glucose (qualitative) 
Occult blood (qualitative) 
Urine pH
Microscopic examination c) 
(white blood cells, red blood cells, and 
casts) 
Pregnancy test (female subjects of childbearing potential only)
Urine human chorionic gonadotropin (hCG)
Urine Drug Screening d) 
Amphetamines (including methamphetamine), barbiturates, benzodiazepines, cannabinoids, cocaines, morphines, 
phencyclidines, and tricyclic antidepressants 
a) Blood will be collected under fasted conditions at Visits 2, 3 and 8 or Early Termination Visit. For other visits, 
blood will be collected under fasted conditions wherever possible. 
b) TSH will be measured at Visit 1, and when TSH value is outside the normal range, free T4 will be measured. If a 
clinically significant abnormality of thyroid gland is found based on the results of TSH and free T4, the subject 
will be excluded from the study. 
c) Microscopic examination will be performed if abnormality is found in any item in urinalysis. 
d) If the subject has a positive urine drug result, he/she will be excluded from the study. However, when the subject 
has a positive urine test result at Visit 1 because the urine test was performed prior to washout of pretreatment 
drug, the subject is eligible for the study if he/she has a negative drug test result at Visit 2. 
The central laboratory will perform laboratory tests for hematology, serum chemistry, urinalysis, 
and hormonal test. The local laboratory will perform the pregnancy test and urine drug screening. 
The results of laboratory tests will be returned to the investigator, who is responsible for 
reviewing and filing these results. 
If subjects experience ALT or AST >3 × ULN, follow-up laboratory tests (at a minimum, serum 
alkaline phosphatase, ALT, AST, total bilirubin, γ-GTP, and INR) should be performed within a 
maximum of 7 days and preferably within 48-72 hours after the abnormality was noted. If the 
ALT or AST remains elevated >3 × ULN on these 2 consecutive occasions, the abnormality 
should be recorded as a special interest AE (hepatic impairment) by the investigator, and follow 


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the procedure specified in Sections 10.1.5.2 and 10.2.1.3. After additional examinations and 
detailed monitoring, the investigator must contact the sponsor for consideration of possible 
discontinuation of the study medication, discussion of the relevant subject details and possible 
alternative etiologies. 
If subjects experience ALT or AST >3 × ULN and total bilirubin >2 × ULN, the investigator 
must refer to instructions in Section 7.5 Criteria for Discontinuation or Withdrawal of a Subject 
and Section 10.2.3 Reporting of Abnormal Liver Function Tests. 
9.1.13 Contraception and Pregnancy Avoidance Procedure 
From signing of informed consent, throughout the duration of the study, to the end of the follow-
up period, female subjects of childbearing potential (e.g., non-sterilized or premenopausal female 
subjects) who are sexually active with a nonsterilized male partner must use adequate 
contraception. Subjects will be provided with information on acceptable methods of 
contraception as part of the subject informed consent process and will be asked to sign a consent 
form stating that they understand the requirements for avoidance of pregnancy during the course 
of the study. During the course of the study, regular urine human chorionic gonadotropin (hCG) 
pregnancy tests will be performed, and subjects will receive continued guidance with respect to 
the avoiding pregnancy as part of the study procedures (Appendix A). 
At visits when pregnancy tests are performed, subjects must be confirmed of having a negative 
urine hCG pregnancy test, as well as at the follow-up examination. 
9.1.14 Pregnancy 
If any subject is found to be pregnant during the study she should be withdrawn and any study 
medication should be immediately discontinued. 
If the pregnancy occurs during administration of active study medication from the start of the 
study medication in the double-blind treatment period to the end of the follow-up period, the 
pregnancy should be reported immediately, using a pregnancy notification form, to the contact 
listed in the attachment. 
Should the pregnancy occur during or after administration of blinded drug, the investigator must 
inform the subject of their right to receive treatment information. If the subject chooses to 
receive unblinded treatment information, the individual blind should be broken by the 
investigator. Subjects randomized to placebo need not be followed. 
If the female subject agrees to the primary care physician being informed, the investigator should 
notify the primary care physician (obstetrics and gynecology specialist) that the subject was 
participating in a clinical study at the time she became pregnant and provide details of treatment 
the subject received (blinded or unblinded, as applicable). 
All pregnancies will be followed up to final outcome, using the pregnancy form. The outcome, 
including any premature termination, must be reported to the sponsor. An evaluation after the 
birth of the child will also be conducted. 


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9.1.15 ECG Procedure 
A standard 12-lead ECG will be recorded. The investigator (or a qualified observer at the study 
site) will interpret the ECG using 1 of the following categories: within normal limits, abnormal 
but not clinically significant, or abnormal and clinically significant. The following parameters 
will be recorded on the eCRF from the subject’s ECG trace: RR interval, PR interval, QT 
interval, QRS interval, and QTcB interval. QTcF interval will be calculated by the sponsor. ECG 
traces recorded on thermal paper should be photocopied to avoid degradation of trace over time. 
9.1.16 Pharmacogenomic Sample Collection 
One 5-mL whole blood sample for pharmacogenomics will be collected at the start of placebo 
lead-in period (Visit 2) or at the earliest possible time during the study from subjects who signed 
informed consent of pharmacogenomics and entered into the placebo lead-in period for possible 
exploratory investigation of markers enabling the prediction of drug response. 
Pharmacogenomic sample should not be collected from any subject who has received 
comparable bone marrow transplant or whole blood transfusion within 6 months of any sample 
collection. 
See the separately created procedure for collecting, handling, and storage of pharmacogenomic 
samples. 
9.1.17 Pharmacokinetic Sample Collection and Analysis 
9.1.17.1 Collection of Blood for Pharmacokinetic Sampling 
Blood samples will be collected in concurrence with blood collection for clinical laboratory tests. 
The exact date and time of the blood collection and dosing times of the last 2 doses prior to the 
blood collection will be recorded on the eCRF. Refer to the separately created procedure for 
collection, handling, and shipping of blood samples. 
Since drug concentrations of subjects in the placebo group will not be measured, the assignment 
personnel will send an operation manual to the central laboratory to identify samples of subjects 
in the placebo group. Drug concentration data will be reported to the sponsor after unblinding of 
the study. 
9.1.17.2 Bioanalytical Methods 
Plasma concentrations of Lu AA21004 and its metabolites (Lu AA34443 and Lu AA39835) will 
be analyzed with the validated LC/MS/MS method. 
9.1.18 Documentation of Screen Failure Prior to Entrance into Placebo Lead-in Period 
For all subjects who signed informed consent and prematurely discontinue the study prior to 
entry into the placebo lead-in period, the investigator should complete the eCRF. The registration 
center should be contacted as a notification of screen failure prior to entry into the placebo lead-
in period. 


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The primary reason for screen failure prior to entry into the placebo lead-in period will be 
recorded in the eCRF using the following categories: 
• PTE/AE 
• Did not meet inclusion criteria or did meet exclusion criteria <specify the reason.> 
• Significant protocol deviation 
• Lost to follow-up 
• Voluntary withdrawal <specify the reason.> 
• Study termination 
• Other <specify the reason.> 
The identification numbers assigned to subjects who prematurely discontinues prior to entry into 
the placebo lead-in period should not be reused. 
9.1.19 Documentation of Study Entrance into Placebo Lead-in Period 
Only subjects who meet all of the inclusion criteria and none of the exclusion criteria at the start 
of placebo lead-in period are eligible for entrance into the placebo lead-in period. 
If the subject is found to be not eligible for the placebo lead-in period, the investigator should 
record the primary reason for failure on the applicable eCRF. 
9.1.20 Documentation of Screen Failure Prior to Randomization 
For all subjects who prematurely discontinue the study after entry into the placebo lead-in period 
and prior to randomization, the investigator should complete the eCRF. The registration center 
should be contacted as a notification of discontinuation after entry into the placebo lead-in period 
and prior to randomization. 
The primary reason for screen failure after entry into the placebo lead-in period and prior to 
randomization is recorded in the eCRF using the following categories: 
• PTE/AE 
• Did not meet inclusion criteria or did meet exclusion criteria <specify the reason.> 
• Significant protocol deviation 
• Lost to follow-up 
• Voluntary withdrawal <specify the reason.> 
• Study termination 
• Other <specify the reason.> 


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The end-of-study evaluation will be performed for all subjects who prematurely discontinue the 
study after entry into the placebo lead-in period and prior to randomization according to Section 
9.3.5. 
9.1.21 Documentation of Randomization 
Only subjects who meet all of the inclusion criteria and none of the exclusion criteria are eligible 
for randomization and entrance into the double-blind treatment period. 
If the subject is found to be not eligible for randomization, the investigator should record the 
primary reason for screen failure on the eCRF. 
9.2 
Monitoring Subject Treatment Compliance 
Subjects will be required to bring unused study medication containers (PTP sheets)/unused 
medications to each dispensing site visit. The dates of the initial and last dosing, as well as any 
details where a subject takes more or less of the study medications than the specified dose, will 
be recorded on the eCRF. 
If a subject is significantly noncompliant with the study medication (e.g., 6 or more consecutive 
doses missed), it may be appropriate to withdraw the subject from the study. All subjects should 
be reinstructed about the dosing requirement during study contacts. The authorized study 
personnel conducting the re-education must document the process in the subject source records. 
9.3 
Schedule of Observations and Procedures 
The schedule for all study-related procedures for all evaluations is shown in Appendix A. 
Assessments should be completed at the designated visit/time point(s). 
9.3.1 
Screening Period 
Informed consent must be obtained prior to the initiation of any study procedures. 
The examinations/observations/assessments listed below will be performed at the start of 
screening period (Days -32 to -12; Visit 1). Subjects will be screened in accordance with 
predefined inclusion and exclusion criteria as described in Section 7.0. See Section 9.1.18 for 
procedures for documenting a subject who prematurely discontinues the study prior to entry into 
the placebo lead-in period. 
• Demographics, medical history, and medication history 
• Diagnosis of MDD 
• Assessments of the major depressive episode 
• Physical examination 
• Weight and height 
• Vital signs 


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• Concomitant medications 
• Concurrent medical conditions 
• Clinical laboratory tests 
• Pregnancy test (female subjects of childbearing potential only) 
• Urine drug screening 
• ECG procedure 
• C-SSRS 
• PTE assessment 
• MADRS 
• HAM-D 
• CGI-S 
9.3.2 
Placebo Lead-in Period 
The examinations/observations/assessments listed below will be performed at the start of placebo 
lead-in period (Day -8 ± 3; Visit 2). Subjects will be screened in accordance with predefined 
inclusion and exclusion criteria as described in Section 7.0. Subjects assessed to be eligible will 
enter the placebo lead-in period. See Section 9.1.18 for procedures for documenting subjects who 
prematurely discontinue the study prior to entry into the placebo lead-in period. 
• Physical examination 
• Weight 
• Vital signs 
• Concomitant medications 
• Clinical laboratory tests (fasted) 
• Pregnancy test (female subjects of childbearing potential only) 
• Urine drug screening. 
• Blood sampling for pharmacogenomics* (subjects who provided written consent only) 
• ECG procedure 
• C-SSRS 
• PTE assessment 
• MADRS 
• HAM-D 


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• CGI-S 
• SDS 
• DSST 
• PDQ-5 
• QIDS-J 
• Dispense of the study medication (for the placebo lead-in treatment) 
* Blood sampling for pharmacogenomics will be performed at the start of placebo lead-in period 
(Visit 2) or at the earliest possible time during the study. 
9.3.3 
Start of Double-blind Treatment Period/Randomization 
The examinations/observations/assessments listed below will be performed at the start of double-
blind treatment period (Day -1; Visit 3). Subjects will be screened in accordance with predefined 
inclusion and exclusion criteria as described in Section 7.0. Subjects assessed to be eligible will 
be randomized according to Section 8.2 and enter the double-blind treatment period. See Section 
9.1.20 for documenting subjects who prematurely discontinue the study after entry into the 
placebo lead-in period and prior to randomization. 
The examinations/observations/assessments at Visit 3 should be regarded as baseline evaluations. 
• Physical examination 
• Weight 
• Vital signs 
• Concomitant medications 
• Clinical laboratory tests (fasted) 
• Pregnancy test (female subjects of childbearing potential only) 
• ECG procedure 
• C-SSRS 
• PTE/AE assessment 
• MADRS 
• HAM-D 
• CGI-S 
• CGI-I (assessed comparing with a CGI score at Visit 2). 
• SDS 
• DSST 


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• PDQ-5 
• QIDS-J 
• Randomization 
• Dispense of the study medication (for the double-blind treatment [Inner Carton 1]) 
• Collection of the study medication dispensed at the last visit/Consultation about subjects' 
compliance 
9.3.4 
Double-blind Treatment Period 
Visit 4 
The examinations/observations/assessments listed below will be performed at 1 week after the 
start of double-blind treatment period (Day 7 ± 1; Visit 4). 
• Vital signs 
• Concomitant medications 
• C-SSRS 
• PTE/AE assessment 
• MADRS 
• CGI-S 
• CGI-I (assessed comparing with a CGI score at Visit 3). 
• DSST 
• PDQ-5 
• QIDS-J 
• Dispense of the study medication (for the double-blind treatment [Inner Carton 2]) 
• Collection of the study medication dispensed at the last visit/Consultation about subjects' 
compliance 
Visit 5 
The examinations/observations/assessments listed below will be performed at 2 weeks after the 
start of double-blind treatment period (Day 14 ± 3; Visit 5). 
• Vital signs 
• Concomitant medications 
• C-SSRS 
• PTE/AE assessment 


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• MADRS 
• CGI-S 
• CGI-I (assessed comparing with a CGI score at Visit 3). 
• QIDS-J 
• Dispense of the study medication (for the double-blind treatment [Inner Carton 2]) 
• Collection of the study medication dispensed at the last visit/Consultation about subjects' 
compliance 
Visit 6 
The examinations/observations/assessments listed below will be performed at 4 weeks after the 
start of double-blind treatment period (Day 28 ± 3; Visit 6). 
• Weight 
• Vital signs 
• Concomitant medications. 
• Clinical laboratory tests 
• Pregnancy test (female subjects of childbearing potential only) 
• Pharmacokinetic sampling 
• ECG procedure 
• C-SSRS 
• PTE/AE assessment 
• MADRS 
• CGI-S 
• CGI-I (assessed comparing with a CGI score at Visit 3). 
• QIDS-J 
• Dispense of the study medication (for the double-blind treatment [Inner Carton 2]) 
• Collection of the study medication dispensed at the last visit/Consultation about subjects' 
compliance 
Visit 7 
The examinations/observations/assessments listed below will be performed at 6 weeks after the 
start of double-blind treatment period (Day 42 ± 3; Visit 7). 
• Vital signs 


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• Concomitant medications 
• C-SSRS 
• PTE/AE assessment 
• MADRS 
• CGI-S 
• CGI-I (assessed comparing with a CGI score at Visit 3). 
• QIDS-J 
• Dispense of the study medication (for the double-blind treatment [Inner Carton 2]) 
• Collection of the study medication dispensed at the last visit/Consultation about subjects' 
compliance 
9.3.5 
End of Double-blind Treatment Period or Early Termination 
The examinations/observations/assessments listed below will be performed at 8 weeks after the 
start of double-blind treatment period (Day 56 ± 3; Visit 8) as evaluation at the end of double-
blind treatment period. Subjects who prematurely discontinue the study during the placebo lead-
in period or double-blind treatment period will be requested to visit the study site for early 
termination examinations/observations/assessments within 7 days after the day of study 
discontinuation wherever possible. 
• Physical examination 
• Weight 
• Vital signs 
• Concomitant medications 
• Clinical laboratory tests (fasted) 
• Pregnancy test (female subjects of childbearing potential only) 
• Pharmacokinetic sampling (not performed at early termination) 
• ECG procedure 
• C-SSRS 
• PTE/AE assessment 
• MADRS 
• HAM-D 
• CGI-S 
• CGI-I* 


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• SDS 
• DSST 
• PDQ-5 
• QIDS-J 
• Collection of the study medication dispensed at the last visit/Consultation about subjects' 
compliance 
* The CGI-I score will be assessed comparing with that at Visit 3. However, at early termination 
prior to Visit 3, the CGI-I score will be assessed by comparing with that at Visit 2. 
For all randomized subjects, the investigator must complete the End of Study eCRF page. 
After evaluation at the end of double-blind treatment period or early termination, standard 
therapy may be performed as needed. 
9.3.6 
Follow-up Period 
A safety follow-up assessment will be conducted at 12 weeks after the start of double-blind 
treatment period (Day 84 ± 5). For subjects who prematurely discontinue the study during the 
placebo lead-in period or double-blind treatment period, the follow-up assessments will be made 
28 ± 5 days after the last dose of the study medication. The follow-up assessments may either be 
conducted as a visit to the site or as a telephone contact. In the follow-up, the following will be 
assessed: outcomes of AEs continuing at Visit 8 or early termination visit, new SAEs developing 
during the follow-up period, and special interest AEs will be assessed. Female subjects of child-
bearing potential will be asked to confirm whether they are pregnant or not. 
9.3.7 
Post Study Care 
The study medication will not be available upon completion of the subject’s participation in the 
study. 
9.4 
Biological Sample Retention and Destruction 
Samples of 5-mL whole blood collected for pharmacogenomics will be stored frozen at the 
pharmacogenomic specimen storage facility (see the contact listed in the attachment 1; 
hereinafter referred to as specimen storage facility). 
The collected samples will be retained for 20 years from the day when a first pharmacogenomic 
sample was collected during the study. 
When subjects request disposal of a stored sample during the retention period, the site will ask 
the specimen storage facility to destroy the sample via the sponsor according to the procedure. 
The specimen storage facility will destroy the sample in accordance with the procedure, and 
notify the site and sponsor. However, any samples should not be destroyed if all the documents 
(including medical records) have been destroyed which could identify the subject, and it is 
impossible to link the sample to the subject. 


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Even if the sample can be linked to the subject, when pharmacogenomic investigation has been 
conducted, the remaining sample will be destroyed and the results of pharmacogenomic 
investigation of the anonymized subject will be retained by the sponsor. 
The sponsor will build a management system required for protection of the subject’s personal 
information, define standards for collecting, storage, and destruction of samples, and prepare 
appropriate procedures. 


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10.0 
PRETREATMENT EVENTS AND ADVERSE EVENTS 
10.1 
Definitions 
10.1.1 PTEs 
A PTE is defined as any untoward medical occurrence in a clinical investigation subject who has 
signed informed consent to participate in a study but prior to administration of any study 
medication; it does not necessarily have to have a causal relationship with study participation. 
10.1.2 AEs 
An AE is defined as any untoward medical occurrence in a clinical investigation subject 
administered a drug; it does not necessarily have to have a causal relationship with this treatment. 
An AE can therefore be any unfavorable and unintended sign (e.g., a clinically significant 
abnormal laboratory finding), symptom, or disease temporally associated with the use of a drug 
whether or not it is considered related to the drug. 
10.1.3 Additional Points to Consider for PTEs and AEs 
An untoward finding generally may: 
• Indicate a new diagnosis or unexpected worsening of a pre-existing condition. (Intermittent 
events for pre-existing conditions underlying disease should not be considered PTEs or AEs.) 
• Necessitate therapeutic intervention. 
• Require an invasive diagnostic procedure. 
• Require discontinuation or a change in dose of study medication or a concomitant medication. 
• Be considered unfavorable by the investigator for any reason. 
• PTEs/AEs caused by a study procedure (e.g., a bruise after blood draw) should be recorded 
as a PTE/AE. 
Diagnoses vs. signs and symptoms: 
• Each event should be recorded to represent a single diagnosis. Accompanying signs 
(including abnormal laboratory values or ECG findings) or symptoms should NOT be 
recorded as additional AEs. If a diagnosis is unknown, sign(s) or symptom(s) should be 
recorded appropriately as a PTE(s) or as an AE(s). 
Laboratory values and ECG findings: 
• Changes in laboratory values or ECG parameters are only considered to be PTEs or AEs if 
they are judged to be clinically significant (i.e., if some action or intervention is required or if 
the investigator judges the change to be beyond the range of normal physiologic fluctuation). 
A laboratory re-test and/or continued monitoring of an abnormal value are not considered an 


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intervention. In addition, repeated or additional noninvasive testing for verification, 
evaluation, or monitoring of an abnormality is not considered an intervention. 
• If abnormal laboratory values or ECG findings are the result of pathology for which there is 
an overall diagnosis (e.g., increased creatinine in renal failure), the diagnosis only should be 
reported appropriately as a PTE or as an AE. 
Pre-existing conditions: 
• Of pre-existing conditions (present at the time of signing of informed consent), events that 
are considered accompanying symptoms of MDD should NOT be recorded as concurrent 
medical conditions, PTEs, or AEs. 
• Other pre-existing conditions are considered concurrent medical conditions and should NOT 
be recorded as PTEs or AEs. Baseline evaluations (e.g., laboratory tests, ECG, X-rays) 
should NOT be recorded as PTEs unless related to study procedures. However, if the subject 
experiences an abnormality (e.g., internal bleeding due to blood sampling) associated with 
the baseline evaluations, the abnormality should be recorded as a PTE and recorded on eCRF. 
If the subject experiences a worsening or complication of such a concurrent condition, the 
worsening or complication should be recorded appropriately as a PTE (worsening or 
complication occurs before start of study medication) or an AE (worsening or complication 
occurs after start of study medication). The investigator should ensure that the event term 
recorded captures the change in the condition (e.g., “worsening of hypertension”). 
• If a subject has a pre-existing episodic condition (e.g., asthma, epilepsy) any occurrence of an 
episode should only be captured as a PTE/AE if the episodes become more frequent, serious 
or severe in nature, that is, the investigator should ensure that the AE term recorded captures 
the change in the condition from Baseline (e.g., “worsening of…”). 
• If a subject has a degenerative concurrent condition (e.g., cataracts, rheumatoid arthritis), 
worsening of the condition should only be captured as a PTE/AE if occurring to a greater 
extent to that which would be expected. Again, the investigator should ensure that the AE 
term recorded captures the change in the condition (e.g., “worsening of…”). 
Worsening of PTEs or AEs: 
• If the subject experiences a worsening or complication of a PTE after starting administration 
of the study medication, the worsening or complication should be recorded appropriately as 
an AE. The investigator should ensure that the AE term recorded captures the change in the 
condition (e.g., “worsening of…”). 
• If the subject experiences a worsening or complication of an AE after any change in study 
medication, the worsening or complication should be recorded as a new AE. The investigator 
should ensure that the AE term recorded captures the change in the condition (e.g., 
“worsening of…”). 


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Changes in severity of AEs /Serious PTEs: 
• If the subject experiences changes in severity of an AE/serious PTE, the event should be 
captured once with the maximum severity recorded. 
Preplanned surgeries or procedures: 
• Preplanned procedures (surgeries or therapies) that were scheduled prior to signing of 
informed consent are not considered PTEs or AEs. However, if a preplanned procedures is 
performed early (e.g., as an emergency) due to a worsening of the pre-existing condition, the 
worsening of the condition should be captured appropriately as a PTE or an AE. 
Complications resulting from any planned surgery should be reported as AEs. 
Elective surgeries or procedures: 
• Elective procedures (e.g., cosmetic surgery) performed where there is no change in the 
subject’s medical condition should not be recorded as PTEs or AEs, but should be 
documented in the subject’s source documents. Complications resulting from an elective 
surgery should be reported as AEs. 
Insufficient clinical response (lack of efficacy): 
• Insufficient clinical response, efficacy, or pharmacologic action, should NOT be recorded as 
an AE. The investigator must make the distinction between exacerbation of pre-existing 
illness and lack of therapeutic efficacy. 
Overdose: 
• All cases of overdose with any medication, including the case without manifested side effects, 
are considered AEs and will be recorded on the AE page of the eCRF. In addition, cases of 
overdose will be reported as special interest AEs. 
Suicidality events: 
• A completed suicide is always captured as an SAE based on its fatal outcome. Furthermore, 
active suicidal behavior such as suicidal ideation with a specific plan and suicide attempt will 
also be collected as an SAE. 
• Unless the event in question meets the definition of "serious," suicidal thoughts or suicidal 
ideation without a specific plan or action will be collected as a non-serious AE in accordance 
with the standard AE reporting requirements. 
• A subject who presents with self-mutilation should be asked by the investigator to clarify 
whether the subject was attempting suicide. If the subject was attempting suicide, the 
behavior will be collected as an SAE, and the specific suicidal behavior (e.g., wrist cutting) 
will be recorded in the eCRF. If the subject was not attempting suicide, the behavior will be 
collected as a non-serious AE in accordance with the standard AE reporting requirements. 
10.1.4 SAEs 
An SAE is defined as any untoward medical occurrence that at any dose: 


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1. Results in DEATH. 
2. Is LIFE THREATENING.* 
3. Requires inpatient HOSPITALIZATION or prolongation of existing hospitalization. 
4. Results in persistent or significant DISABILITY/INCAPACITY. 
5. Leads to a CONGENITAL ANOMALY/BIRTH DEFECT. 
6. Is an IMPORTANT MEDICAL EVENT that satisfies any of the following: 
• May require intervention to prevent items 1 through 5 above. 
• May expose the subject to danger, even though the event is not immediately life threatening 
or fatal or does not result in hospitalization. 
• Includes any event or synonym described in the Takeda Medically Significant AE List 
(Table 10.a). 
* 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. 
Table 10.a 
Takeda Medically Significant AE List 
Term 
Acute respiratory failure/acute respiratory distress 
syndrome (ARDS) 
Torsade de pointes / ventricular fibrillation 
/ ventricular tachycardia 
Malignant hypertension 
Convulsive seizure (including seizure and epilepsy) 
Agranulocytosis 
Aplastic anemia 
Toxic epidermal necrolysis/Stevens-Johnson syndrome 
Hepatic necrosis
Acute liver failure 
Anaphylactic shock 
Acute renal failure 
Pulmonary hypertension 
Pulmonary fibrosis (including interstitial lung disease) 
Neuroleptic malignant syndrome / malignant 
hyperthermia 
Spontaneous abortion / stillbirth and fetal death 
Confirmed or suspected transmission of infectious agent 
by a medicinal product 
Confirmed or suspected endotoxin shock 
 
The following events are also to be considered SAEs. 
• Completed suicide 
• Active suicidal ideation 
• Active suicidal behavior such as suicide attempt 
• Self-injury with suicide attempt 


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PTEs that fulfill 1 or more of the serious criteria above are also to be considered SAEs and 
should be reported and followed up in the same manner (see Sections 10.2.2 and 10.3). 
10.1.5 Special Interest AEs 
A Special Interest Adverse Event (serious or non-serious) is 1 of scientific and medical concern 
specific to the compound or program. In this study, skin reaction, allergic reaction, hepatic 
impairment, and overdose are defined as special interest AEs. Ongoing monitoring and 
communication by the investigator to Takeda may be appropriate, and if the events occur, they 
will be reported according to Section 10.2.1.3. Such events may require further investigation in 
order to characterize and understand them. 
10.1.5.1 Skin and Allergic Reaction 
When the causal relationship between rash or allergic reaction and the study medication is 
assessed as probable or possible, rash or allergic reaction will be reported as a special interest AE 
according to Section 10.2.1.3 after the nature and the site are characterized. When the causal 
relationship between rash or allergic reaction and the study medication is assessed as not related, 
rash or allergic reaction is not required to be reported as a special interest AE. 
When rash or allergic reaction develops, the subject should be adequately examined for any 
clinical features that may suggest the development of drug reaction with eosinophilia and 
systemic symptoms (DRESS), toxic epidermal necrolysis (TEN), or Stevens-Johnson syndrome 
(SJS). In addition, the subject should be monitored for the appearance of any of the following 
signs: 
a) Involvement of mucous membrane or the conjunctiva 
b) Development of skin pain 
c) Urticaria, blistering, or other types of skin lesions 
d) Angioedema 
If a subject presents with symptoms of a systemic reaction (e.g., generalized rash), or signs of 
severe rash, or if it is clinically necessary, the following laboratory parameters should also be 
investigated and monitored accordingly: complete blood count with differentials, liver and renal 
function tests, and urinalysis. If deemed necessary by the investigator, subjects should be 
received examination by a dermatologist, and photographs of the skin rash and/or skin biopsies 
will be obtained as needed. 
10.1.5.2 Hepatic Impairment 
If a subject has ALT or AST >3 × ULN, and follow-up laboratory tests (see Section 9.1.12) also 
shows ALT or AST >3 × ULN, it should be reported as a special interest AE according to 
Section 10.2.1.3. In addition, the relevant subject details and possible alternative etiologies other 
than the study medication should be investigated. 


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If the abnormality falls under a drug-induced liver function abnormality that may lead to severe 
hepatic impairment (see Section 10.2.3), it should also be reported as an SAE. 
10.1.5.3 Overdose 
For overdose, refer to Section 8.1.4. All cases of overdose will be documented as AEs on an AE 
page of the eCRF and should be reported as special interest AEs according to Section 10.2.1.3 
(with or without associated adverse events). 
10.1.6 Severity of PTEs and AEs 
The different categories of intensity (severity) are characterized as follows: 
Mild: 
The event is transient and easily tolerated by the subject.
Moderate: 
The event causes the subject discomfort and interrupts the subject’s usual activities. 
Severe: 
The event causes considerable interference with the subject’s usual activities. 
 
10.1.7 Causality of AEs 
The relationship of each AE to study medication(s) will be assessed using the following 
categories: 
Probable: 
An AE that has a strong temporal relationship to the study medication(s), or recurs on re-challenge, 
and another etiology is unlikely or significantly less likely. 
Possible: 
An AE that has a suggestive temporal relationship to the study medication(s), and an alternative 
etiology is equally or less likely. 
Not Related: 
An AE that does not follow a reasonable temporal sequence from administration of the study 
medication(s) or that can reasonably be explained by other factors, such as underlying diseases, 
concurrent medical conditions, concomitant drugs and concurrent treatments (that is, there is no 
causal relationship between the study medication and the AE). 
 
An AE is considered causally related to the use of the study medication when the causality 
assessment is probable or possible. 
10.1.8 Relationship to Study Procedures 
Relationship (causality) to study procedures should be determined for all PTEs and AEs. 
The relationship should be assessed as Related if the investigator considers that there is 
reasonable possibility that an event is due to a study procedure. Otherwise, the relationship 
should be assessed as Not Related. 


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10.1.9 Start Date 
The start date of AEs/PTEs will be determined based on the criteria described below. 
AE/PTE 
Start Date 
Signs, symptoms, and diseases (diagnosis) 
Date when the subject or the investigator first notices the 
sign or symptom of the AE 
Asymptomatic disease 
Date when a definite diagnosis is determined based on 
the results of diagnostic testing. Even if obsolete findings 
are indicated based on the test findings or the 
approximate time of onset can be estimated, the date 
when a definite diagnosis is made should be recorded. 
Worsening of concurrent medical conditions or PTEs 
Date when the subject or the investigator first notices 
worsening of the disease or symptom. 
Normal in the initial assessment after signing of informed 
consent but abnormal in the subsequent assessment (for 
PTEs) 
Abnormal in the assessment after the start of the study 
medication (for AEs) 
Date when the test is performed in which a clinically 
significant abnormal test value is observed 
Abnormal in the initial assessment after signing of 
informed consent and has worsened in the subsequent 
assessment (for PTEs) 
Abnormal in the assessment at the start of the study 
medication and has worsened in the subsequent 
assessment (for AEs) 
Date when the test is performed in which a medically 
significant elevation, reduction, increase or decrease in 
clinical laboratory test values is observed 
 
10.1.10 Stop Date 
The stop date of the AE/PTE is the date at which the subject recovered, the event resolved but 
with sequelae or the subject died. The AE/PTE not determined to have resolved at the end of the 
study is assessed as ongoing 
10.1.11 Frequency 
Episodic AEs/PTEs (e.g., constipation, diarrhea, vomiting) or those which occur repeatedly over 
a period of consecutive days are intermittent. All other events are continuous. 
10.1.12 Action Concerning Study Medication 
The action taken for the study medication is classified and defined as follows: 
Drug withdrawn 
The study medication is stopped due to the particular AE (including withdrawal at the subject’s 
discretion). 
Dose not changed 
The dose is not changed even after the occurrence of the particular AE. 
This shall apply in case the study medication is stopped due to another AE. 
This shall also apply, for example, in case the study medication is stopped for any reason other 
than intervention for the particular AE, such as the subject’s negligence. 


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Unknown 
For example, attempts to contact the subject are unsuccessful and the course of the particular 
AE after the start date cannot be followed. 
Not Applicable 
For example, the study medication has already been completed or stopped before the onset of 
the particular AE. 
 
10.1.13 Outcome 
The outcome of AEs/PTEs is classified as follows: 
Category 
Assessment Criteria
Recovered/Resolved 
• The symptom or finding has disappeared or resolved.
• The abnormal laboratory value has improved to the normal range or to the level at baseline 
(for AEs) or at the first assessment after signing of informed consent (for PTEs). 
Recovering/Resolving 
• The intensity is lowered by at least 1 grade.
• The symptom or finding has almost disappeared. 
• The abnormal laboratory value has improved, but not to the normal range or the level at 
baseline (for AEs) or at the first assessment after signing of informed consent (for PTEs). 
• The subject died from a cause other than the particular AE/PTE with the condition 
remaining “recovering/resolving” (no need to record the date of death). 
Not recovered/not 
resolved 
• There is no change in the symptom, finding, or laboratory value. 
• The intensity of the symptom, finding, or laboratory value on the last day of the observed 
period has got worsen than when it started. 
• An irreversible congenital anomaly. 
• The subject died from another cause with the particular AE/PTE state remaining “Not 
recovered/not resolved” AE/PTE (no need to record the date of death). 
Resolved with 
sequelae 
• The subject recovered from an acute AE/PTE but was left with impairment that interferes 
with the subject’s daily life. 
Fatal 
• There is a direct relationship between the death and the AE/PTE. 
• The direct relationship indicates that the AE/PTE caused or apparently contributed to the 
death. 
• The outcome of another AE/PTE reported in the same subject that is not determined 
(considered or estimated) as the cause of the death is not assessed as “fatal.” 
• If the outcome is “fatal,” the date of death should be recorded. 
Unknown 
• The course of the AE/PTE after the start date cannot be followed up as specified in the 
protocol due to hospital change or residence change. 
 
10.2 
Procedures 
10.2.1 Collection and Reporting of AEs 
10.2.1.1 PTE and AE Collection Period 
Collection of PTEs will commence from the time the subject signs the informed consent to 
participate in the study and continue until the subject is first administered study medication in the 


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placebo lead-in period. For subjects who discontinue prior to the first study medication 
administration in the placebo lead-in period, PTEs are collected until the subject discontinues 
study participation. 
Collection of AEs will commence from the time that the subject is first administered study 
medication in the placebo lead-in period. Routine collection of AEs will continue until Visit 8 or 
Early Termination Visit. 
Collection of SAEs or special interest AEs will continue until the end of the follow-up period. 
10.2.1.2 PTE and AE Reporting 
At each study visit, the investigator will assess whether any subjective AEs have occurred. A 
neutral question, such as “How have you been feeling since your last visit?” may be asked. 
Subjects may report AEs occurring at any other time during the study. 
Subjects experiencing a serious PTE must be monitored until the symptoms subside and any 
clinically relevant changes in laboratory values have returned to baseline or until there is a 
satisfactory explanation for the change (for permanent or irreversible PTEs). Non-serious PTEs, 
related or unrelated to the study procedure, need not to be followed-up for the purposes of the 
protocol. 
All subjects experiencing AEs, whether considered associated with the use of the study 
medication or not, must be monitored until the symptoms subside and any clinically relevant 
changes in laboratory values have returned to baseline or until there is a satisfactory explanation 
for the change (for permanent or irreversible AEs). All PTEs and AEs will be documented in the 
PTE/AE page of the eCRF, whether or not the investigator concludes that the event is related to 
the drug treatment. The following information will be documented for each event: 
1. Event term 
2. Start and stop date 
3. Frequency 
4. Severity 
5. Investigator’s opinion of the causal relationship between the event and administration of 
study medication(s) (probable, possible, not related) (not completed for PTEs). 
6. Investigator’s opinion of the causal relationship to study procedure(s), including the details 
of the suspected procedure. 
7. Action concerning study medication (not applicable for PTEs) 
8. Outcome of event 
9. Seriousness 
10. Classification as special interest AEs (Yes or No) 


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C-SSRS will not be used as a primary means to collect AEs. However, should the investigator 
become aware of a potential AE through the information collected with this instrument, proper 
follow-up with the patient for medical evaluation should be undertaken. If it is determined that 
an AE not previously reported has been identified through this follow-up, normal reporting 
requirements should be applied. 
AEs and serious PTEs will be followed up until resolution or until the investigator judges that 
further follow-up is not necessary. 
10.2.1.3 Special Interest AE Reporting 
If the special interest AE (refer to Section 10.1.5) occurs through the AE collection period, it 
should be reported to Safety Information Emergency Call Center, in principle (described in the 
separate contact information list) within 1 business day of first onset or subject’s notification of 
the event. The investigator should complete the Rash and Allergic Reaction, Hepatic Impairment 
or Overdose Form within 10 business days and report to Safety Information Emergency Call 
Center, in principle. In addition, the investigator should submit to the sponsor the original Rash 
and Allergic Reaction, Hepatic Impairment or Overdose Form. 
The special interest AEs have to be recorded as AEs in the eCRF. 
10.2.2 Collection and Reporting of SAEs 
When an SAE occurs through the AE collection period it should be reported according to the 
following procedure. PTEs that fulfill the serious criteria described in Section 10.1.4 are also to 
be considered SAEs and should be reported in the same manner. 
The investigator should report the SAEs with information required in the SAE form to Safety 
Information Emergency Call Center, in principle, within 1 business day of the first onset or 
subject’s notification of the event. The investigator should prepare the completed SAE form 
within 10 calendar days and submit to Safety Information Emergency Call Center, in principle. 
In addition, the investigator should submit to the sponsor the original SAE form. 
For the report within 1 business day, the information should be completed as fully as possible but 
contain, at a minimum: 
• A short description of the event and the reason why the event is categorized as serious. 
• Subject identification number. 
• Investigator’s name. 
• Name of the study medication(s). 
• Causality assessment. 
Any SAE spontaneously reported to the investigator following the AE collection period should 
be also reported to the sponsor if considered related to study participation. Reporting of Serious 
PTEs will follow the procedure described for SAEs. 


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10.2.3 Reporting of Abnormal Liver Function Tests 
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 investigator must contact the sponsor for 
discussion of the relevant subject details and possible alternative etiologies, such as acute viral 
hepatitis A or B or other acute liver disease or medical history/concurrent medical conditions. 
Follow-up laboratory tests must also be performed (see Section 9.1.12). If the investigator 
considers that such liver function abnormality cannot be explained by any factor other than the 
study medication, the event should be reported as a SAE (see Section 10.2.2). 
10.3 
Follow-up of SAEs 
If information not available at the time of the detailed report becomes available at a later date, 
the investigator should complete a follow-up SAE form copy or provide other written 
documentation and report it immediately to the sponsor or Safety Information Emergency Call 
Center. Copies of any relevant data from the hospital notes (e.g., ECGs, laboratory tests, 
discharge summary, postmortem results) should be sent to the addressee, if requested. 
All SAEs should be followed up until resolution or permanent outcome of the event. 
10.3.1 Safety Reporting to Investigators, IRBs, and Regulatory Authorities 
The sponsor will be responsible for reporting all suspected unexpected serious adverse reactions 
(SUSARs) and any other applicable SAEs to regulatory authorities, investigators, and the head of 
the study site, as applicable, in accordance with national regulations in the countries where the 
study is conducted. Relative to the first awareness of the event by/or further provision to the 
sponsor or sponsor’s designee (CRO), SUSARs will be submitted to the regulatory authorities as 
expedited report within 7 days for fatal and life-threatening events and 15 days for other serious 
events. The sponsor will also prepare an expedited report for other safety issues where these 
might materially alter the current benefit-risk assessment of the study medication or that would 
be sufficient to consider changes in the administration of study medication or in the overall 
conduct of the trial. The study site also will forward a copy of all expedited reports to his or her 
IRB. 


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11.0 
STUDY-SPECIFIC COMMITTEES 
No steering committee, data safety monitoring committee, or clinical endpoint committee will be 
used in this study. 


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12.0 
DATA HANDLING AND RECORDKEEPING 
The full details of procedures for data handling will be documented in the Data Management 
Plan. AEs, PTEs, medical history, and concurrent conditions will be coded using the Medical 
Dictionary for Regulatory Activities (MedDRA). Drugs will be coded using the World Health 
Organization (WHO) Drug Dictionary. 
12.1 
eCRFs 
Completed eCRFs are required for each subject who signs an informed consent. 
The sponsor or its designee will supply investigative sites with access to eCRFs. The sponsor 
will make arrangements to train appropriate site staff (the investigator, subinvestigators, and 
other study collaborators) in the use of the eCRF. These forms are used to transmit the 
information collected in the performance of this study to the sponsor and regulatory authorities. 
eCRFs must be completed in English. Data are transcribed directly onto eCRFs. 
Corrections to eCRFs are recorded in an audit trail that captures the old information, the new 
information, identification of the person making the correction, the date the correction was made, 
and the reason for change. 
The investigator must review the eCRFs for completeness and accuracy and must sign the 
appropriate eCRFs. Furthermore, the investigator must retain full responsibility for the accuracy 
and authenticity of all data entered on the eCRFs. 
The following data will not be recorded into the eCRFs. 
• Laboratory test values measured at the central laboratory 
• Observed drug concentrations 
After the lock of the clinical study database, any change of, modification of, or addition to the 
data on the eCRFs should be made by the investigator with use of change and modification 
records of the eCRFs (Data Clarification Form) provided by the sponsor. The investigator must 
review the data change for completeness and accuracy, and must sign, or sign and seal, and date. 
eCRFs will be reviewed for completeness and acceptability at the study site during periodic visits 
by the sponsor or its designee. The sponsor or its designee will be permitted to review the 
subject’s medical and hospital records pertinent to the study to ensure accuracy of the eCRFs. 
The completed eCRFs are the sole property of the sponsor and should not be made available in 
any form to third parties, except for authorized representatives of appropriate governmental 
health or regulatory authorities, without written permission of the sponsor. 
12.2 
Record Retention 
The investigator and the head of the institution agree to keep the records stipulated in Section 
12.1 and those documents that include (but are not limited to) the study-specific documents, the 
identification log of all participating subjects, medical records, source worksheets, all original 
signed and dated informed consent forms, electronic copy of eCRFs, including the audit trail, 


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and detailed records of drug disposition to enable evaluations or audits from regulatory 
authorities, the sponsor or its designees. The investigator and the head of the institution are 
required to retain essential relevant 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 institution should discuss how long and how to retain those documents with the 
sponsor. 
1) The day on which marketing approval of the study drug is obtained (or the day 3 years after 
the date of notification in the case that the investigation is discontinued.) 
2) The day 3 years after the date of early termination or completion of the clinical study. 
In addition, the investigator and the head of the institution should retain the essential relevant 
documents until the receipt of a sponsor-issued notification to state the retention is no longer 
required. 


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13.0 
STATISTICAL METHODS 
13.1 
Statistical and Analytical Plans 
A statistical analysis plan (SAP) will be prepared and finalized prior to unblinding of subject’s 
treatment assignment. This document will provide further details regarding the definition of 
analysis variables and analysis methodology to address all study objectives. 
A blinded data review will be conducted prior to unblinding of subject’s treatment assignment. 
This review will assess the accuracy and completeness of the study database, subject evaluability, 
and appropriateness of the planned statistical methods. 
13.1.1 Analysis Sets 
In this study, 3 kinds of analysis sets are defined: full analysis set (FAS), per protocol set (PPS), 
and safety analysis set. 
The FAS, which will be used as a primary analysis set for efficacy analysis, is defined as "all 
subjects who were randomized and received at least 1 dose of the study medication in the 
double-blind treatment period." 
The exact definition of each analysis set is specified in the Data Handling Rules for Statistical 
Analysis. 
The sponsor will verify the validity of the definitions of the analysis sets as well as the rules for 
handling data, consulting a medical expert as needed. The Data Handling Rules for Statistical 
Analysis must be finalized prior to database lock. 
13.1.2 Analysis of Demographics and Other Baseline Characteristics 
Major background and demographic characteristics will be summarized overall and by treatment 
group. 
13.1.3 Efficacy Analysis 
Primary Efficacy Analysis for Primary Endpoint 
The primary endpoint for this study is the change from baseline (i.e. at the start of double-blind 
treatment period) in the MADRS total score after 8 weeks of treatment. 
Comparisons between each Lu AA21004 treatment group and the placebo group at Week 8 of 
the double-blind treatment period will be performed using the FAS based on MMRM analysis of 
covariance with the change from baseline in the MADRS total score as a dependent variable, and 
visit, treatment group, visit-by-treatment group interaction and baseline MADRS total score-by-
visit interaction as fixed effects. An unstructured variance-covariance matrix will be used to 
model the within-subject errors and Satterthwaite's method will be used to approximate the 
degrees of freedom. Holm's step down method will be used to adjust the multiplicity for the 
comparisons. More specifically, let H01, H02 be a family of hypotheses as follows: 


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H01: μPlacebo = μ10 mg 
H02: μPlacebo = μ20 mg 
Then let P1 and P2 denote the unadjusted p-values of tests for H01 and H02, respectively. Order 
the p-values from the smallest to the largest, P(1) , P(2) and let the corresponding null hypotheses 
be H(1) , H(2) . Holm's step-down method proceeds as follows: 
Step 1: if P(1) > 0.025, retain both null hypotheses H(1) and H(2), and stop. If P(1) ≤ 0.025, reject 
null hypothesis H(1) and go to Step 2. 
Step 2: if P(2) > 0.05, retain null hypothesis H(2). If P(2) ≤ 0.05, reject null hypothesis H(2). 
Secondary Efficacy Analyses for Primary Endpoint 
To check the robustness of the results, the same analysis as used for the primary efficacy analysis 
will be performed using the PPS. 
For the FAS, an analysis of covariance (ANCOVA) model with the change from baseline in the 
MADRS total score after 8 weeks of treatment (values at Week 8 [LOCF] − baseline) as a 
dependent variable, treatment group as a fixed effect and the baseline MADRS total score as a 
covariate will be applied for comparisons between the placebo group and each Lu AA21004 
treatment group. 
Analyses for Secondary Endpoints 
MADRS response (MADRS response is defined as a ≥50% decrease from baseline in the 
MADRS total score) and MADRS remission (MADRS remission is defined as the MADRS total 
score ≤10) after 8 weeks of treatment (LOCF) will be compared between treatment groups using 
logistic regression analysis including the baseline MADRS total score and treatment groups in 
the model. 
The change from baseline in the HAM-D17 total score after 8 weeks of treatment (values at 
Week 8 [LOCF] − baseline) will be analyzed using an ANCOVA model with treatment groups 
as a fixed effect and the baseline HAM-D17 total score as a covariate. 
The CGI-I score after 8 weeks of treatment (LOCF) will be analyzed using an ANCOVA model 
with treatment groups as a fixed effect and the baseline CGI-S score as a covariate. 
The change from baseline in the CGI-S score after 8 weeks of treatment (values at Week 8 
[LOCF] − baseline) will be analyzed using an ANCOVA model with treatment groups as a fixed 
effect and the baseline CGI-S score as a covariate. 
The change from baseline in the SDS score after 8 weeks of treatment (values at Week 8 [LOCF] 
− baseline) will be analyzed using an ANCOVA model with treatment groups as a fixed effect 
and the baseline SDS score as a covariate. 
The change from baseline in the DSST score after 8 weeks of treatment (values at Week 8 
[LOCF] − baseline) will be analyzed using an ANCOVA model with treatment groups as a fixed 
effect and the baseline DSST score as a covariate. 


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The change from baseline in the PDQ-5 score after 8 weeks of treatment (values at Week 8 
[LOCF] − baseline) will be analyzed using an ANCOVA model with treatment groups as a fixed 
effect and the baseline PDQ-5 score as a covariate. 
Two-sided tests with significance level at 5% will be used for all statistical tests. Ninety-five 
percent confidence intervals will be presented along with the P-values. 
13.1.4 Pharmacokinetic Analysis 
The population pharmacokinetic analysis of Lu AA21004 and its metabolites Lu AA34443 and 
Lu AA39835 will be performed using the nonlinear mixed effect model (NONMEM). 
Pharmacokinetic parameters of individual subjects (e.g., AUC[0-tau], Cavg, Cmax) will be 
estimated and their correlation with relevant pharmacodynamic parameters (efficacy and 
tolerability/safety) will be explored. The population pharmacokinetic analysis plan will be 
prepared separately. 
13.1.5 Safety Analysis 
AEs 
The definition of treatment-emergent adverse events (TEAE) will be described in the statistical 
analysis plan (SAP). TEAEs will be summarized using the safety analysis set. TEAEs will be 
coded using the MedDRA and will be summarized by system organ class (SOC) and preferred 
term (PT). No statistical testing or inferential statistics will be generated. 
A subject who has developed a same TEAE more than once will be counted as 1 subject in the 
severity category corresponding to the maximum severity of the event. 
Clinical Laboratory Test, Weight, Vital Signs, and ECG 
Summary statistics of observed values and changes at each time point (values at each time point 
in the double-blind treatment period − baseline) will be calculated for clinical laboratory tests, 
vital signs, ECG parameters, and weight for each treatment group. Incidences of values that are 
outside normal ranges and are potentially and clinically significant will be calculated. 
C-SSRS 
Descriptive statistics of C-SSRS will be calculated at each time point for each treatment group. 
13.2 
Interim Analysis and Criteria for Early Termination 
No interim analysis is planned. 
13.3 
Determination of Sample Size 
A number of subjects planned to be enrolled in this study is 480 (160 per group). Assuming the 
true mean differences of 3.5 for the change from baseline in the MADRS total score between 
each Lu AA21004 group and the placebo group, this sample size will provide greater than 80% 
power to detect the difference between each Lu AA21004 group and the placebo group by 2-
sample t-test. In addition, assuming the true mean differences of 3.0 for the change from baseline 


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in the MADRS total score between each Lu AA21004 group and the placebo group, this sample 
size will provide greater than 80% power to detect the difference between either the 
Lu AA21004 10 mg or 20 mg group and the placebo group. These power calculations assume a 
common standard deviation of 9.5 for the change from baseline in the MADRS total score, with 
a 2-sided level of 0.025. 


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14.0 
QUALITY CONTROL AND QUALITY ASSURANCE 
14.1 
Study-Site Monitoring Visits 
Monitoring visits to the study site will be made periodically during the study to ensure that all 
aspects of the protocol are followed. Source documents will be reviewed for verification of data 
recorded on the eCRFs. Source documents are defined as original documents, data, and records. 
The investigator and the head of the institution guarantee access to source documents by the 
sponsor or its designee (CRO) and by the IRB. 
All aspects of the study and its documentation will be subject to review by the sponsor or 
designee, including but not limited to the Investigator’s Binder, study medication, subject 
medical records, and informed consent documentation. It is important that the investigator, the 
subinvestigator, and other study personnel are available during the monitoring visits and that 
sufficient time is devoted to the process. 
14.2 
Protocol Deviations 
The investigator can deviate and change from the protocol for any medically unavoidable reason, 
for example, to eliminate an immediate hazard to study subjects, without a prior written 
agreement with the sponsor or a prior approval from IRB. In the event of a deviation or change, 
the investigator should notify the sponsor and the head of the 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 site as 
soon as possible, and an approval from IRB should be obtained. 
The investigator should document all protocol deviations. 
14.3 
Quality Assurance Audits and Regulatory Agency Inspections 
The study site also may be subject to quality assurance audits by the sponsor or designees. In this 
circumstance, the sponsor-designated auditor will contact the site in advance to arrange an 
auditing visit. The auditor may ask to visit the facilities where laboratory samples are collected, 
where the medication is stored and prepared, and any other facility used during the study. In 
addition, there is the possibility that this study may be inspected by regulatory agencies, 
including those of foreign governments (e.g., the FDA, the United Kingdom Medicines and 
Healthcare products Regulatory Agency). 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 institution guarantee access for quality assurance auditors to all study documents as described 
in Section 14.1. 


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15.0 
ETHICAL ASPECTS OF THE STUDY 
This study will be conducted with the highest respect for the individual participants (i.e., 
subjects) according to the protocol, the ethical principles that have their origin in the Declaration 
of Helsinki, and the ICH Harmonised Tripartite Guideline for GCP. Each investigator will 
conduct the study according to applicable regulatory requirements and align his or her conduct in 
accordance with the “Responsibilities of the Investigator” that are listed in Appendix B. 
15.1 
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 abstinence 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 must be obtained and submitted to the sponsor or designee before 
commencement of the study (i.e., before shipment of the sponsor-supplied drug or signing of 
informed consent). The IRB approval must refer to the study by exact protocol title, number, and 
version date; identify versions of other documents (e.g., informed consent form) reviewed; and 
state the approval date. The sponsor will ship drug once the sponsor has confirmed the adequacy 
of site regulatory documentation. Until the site receives drug no protocol activities, including the 
informed consent procedure may occur. 
Sites must adhere to all requirements stipulated by their respective IRB. This may include 
notification to the IRB regarding protocol amendments, updates to the informed consent form, 
recruitment materials intended for viewing by subjects, local safety reporting requirements, 
reports and updates regarding the ongoing review of the study at intervals specified by the 
respective IRB, and submission of the investigator’s final status report to IRB. All IRB approvals 
and relevant documentation for these items must be provided to the sponsor or its designee. 
Subject incentives should not exert undue influence for participation. Payments to subjects must 
be approved by the IRB and sponsor. 
Regarding pharmacogenomic investigation using collected and stored specimens, analysis will 
be carried out at the time when detail is determined. The sponsor will create a research protocol 
for pharmacogenomics investigations, and a research protocol will require prior approval of the 
company IRB in Japan. 
15.2 
Subject Information, Informed Consent, and Subject Authorization 
Written consent documents will embody the elements of informed consent as described in the 
Declaration of Helsinki and the ICH Guidelines for GCP and will be in accordance with all 


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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. The informed consent form will detail the 
requirements of the participant and the fact that he or she is free to withdraw at any time without 
giving a reason and without prejudice to his or her further medical care. 
The investigator is responsible for the preparation, content, and IRB approval of the informed 
consent form. The informed consent form must be approved by the IRB 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 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 ample opportunity to: (1) inquire about details of the study and (2) 
decide whether or not to participate in the study. If the subject determines he or she will 
participate in the study, then the informed consent form must be signed and/or sealed, and dated 
by the subject at the time of consent and prior to the subject entering into the study. The subject 
should be instructed to sign and/or seal using their legal names, not nicknames, using blue or 
black ballpoint ink. The investigator must also sign and/or seal, and date the informed consent 
form at the time of consent and prior to subject entering into the study. 
Once signed and/or sealed, the original informed consent form will be stored in the investigator’s 
site file. The investigator must document the date the subject signs the informed consent in the 
subject’s medical record. A copy of the signed and/or sealed informed consent form shall be 
given to the subject. 
All revised informed consent forms must be reviewed and signed by relevant subjects in the 
same manner as the original informed consent. The date the revised consent was obtained should 
be recorded in the subject’s medical record, and the subject should receive a copy of the revised 
informed consent form. 
The informed consent form for pharmacogenomic research in the clinical study of Lu AA21004 
will be used to explain the pharmacogenomic research to subjects after explanation of the 
informed consent for the entry into the study. Pharmacogenomic samples will be collected from 
subjects who have consented to both the study and the pharmacogenomic research. 
15.3 
Subject Confidentiality 
The sponsor and designees affirm and uphold the principle of the subject’s right to protection 
against invasion of privacy. Throughout this study, a subject’s source data will only be linked to 
the sponsor’s clinical study database or documentation via a unique identification number. As 
permitted by all applicable laws and regulations, limited subject attributes, such as sex, age, or 
date of birth, may be used to verify the subject and accuracy of the subject’s unique 
identification number. 


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To comply with ICH Guidelines for GCP and to verify compliance with this protocol, the 
sponsor requires the investigator to permit its monitor or designee’s monitor, representatives 
from any regulatory authority (e.g., FDA, Medicines and Healthcare products Regulatory 
Agency, Pharmaceuticals and Medical Devices Agency), the sponsor’s designated auditors, and 
the appropriate IRBs to review the subject’s original medical records (source data or documents), 
including, but not limited to, laboratory test result reports, ECG reports, admission and discharge 
summaries for hospital admissions occurring during a subject’s study participation, and autopsy 
reports. Access to a subject’s original medical records requires the specific authorization of the 
subject as part of the informed consent process (see Section 15.2). 
Copies of any subject source documents that are provided to the sponsor must have certain 
personally identifiable information removed (i.e., subject name, address, and other identifier 
fields not collected on the subject’s eCRF). 
15.4 
Publication, Disclosure, and Clinical Trial Registration Policy 
15.4.1 Publication and Disclosure 
The investigator is obliged to provide the sponsor with complete test results and all data derived 
by the investigator from the study. During the study, only the sponsor may make study 
information available to other study investigators or to regulatory agencies, except as required by 
law or regulation. Except as otherwise allowable in the study site agreement, any public 
disclosure (including publicly accessible websites) related to the protocol or study results 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 needs to obtain a prior written approval from the sponsor to publish any 
information from the study externally such as to a professional association. 
15.4.2 Clinical Trial Registration 
In order to ensure that information on clinical trials reaches the public in a timely manner and to 
comply with applicable laws, regulations, and guidance, Takeda will, at a minimum register 
interventional clinical trials it sponsors anywhere in the world on ClinicalTrials.gov or other 
publicly accessible websites (JAPIC-CTI) before start of study, as defined in Takeda 
Policy/Standard. Takeda contact information, along with investigator’s city, state (for US 
investigators), country, and recruiting status will be registered and available for public viewing. 
15.4.3 Clinical Trial Results Disclosure 
Takeda will post the results of clinical trials on ClinicalTrials.gov or other publicly accessible 
websites (JAPIC-CTI), as required by Takeda Policy/Standard, applicable laws and/or 
regulations. 


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15.5 
Insurance and Compensation for Injury 
Each subject in the study must be insured in accordance with the regulations applicable to the 
site where the subject is participating. If a local underwriter is required, then the sponsor or 
sponsor’s designee will obtain clinical study insurance against the risk of injury to clinical study 
subjects. 
Refer to the Clinical Study Site Agreement regarding the sponsor’s policy on subject 
compensation and treatment for injury. If the investigator has questions regarding this policy, he 
or she should contact the sponsor or sponsor’s designee. 


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16.0 
REFERENCES 
[1] Nakane Y, Arima K. Cause and Symptom of Depression. The Journal of Practical Pharmacy. 
2000;51(2):826-34. 
[2] American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders, 
Fourth Edition, Text Revision. Translated by Takahashi S, Ono Y, Someya T. Igaku-Shoin. 
2004. 
[3] Guideline for Clinical Evaluation of Antidepressants (Pharmaceutical and Food Safety 
Bureau, Evaluation and Licensing Division; Notification No.1116-1 dated November 16 in 
2010) (in Japanese). 
[4] American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders, 
Fifth Edition. Translated by Takahashi S, Ono Y, Someya T, Kanba S, Ozaki N, Mimura M,  
Murai T.. Igaku-Shoin. 2014. 
[5] Bialik RJ, Ravindran AV, Bakish D, Lapierre YD., 1995. A Comparison of Placebo 
Responders and Nonresponders in Subgroups of Depressive Disorder. J Psychiatry Neurosci. 
1995;20:265-70. 
[6] Montgomery SA, Asberg M. A new depression scale designed to be sensitive to change. Br J 
Psychiatry. 1979;134:382-9. 
[7] Hamilton M. Development of a rating scale for primary depressive illness. Br J Soc Clin 
Psychol. 1967;6:278-96. 
[8] Guy W. ECDEU Assessment Manual for Psychopharmacology (Revised). Rockville, MD: 
US Department of Health, Education, and Welfare; Public Health Service; Alcohol, Drug 
Abuse, and Mental Health Administration; National Institute of Mental Health, 
Psychopharmacology Research Branch; 1976. p.193-198 
[9] Olfson M, Fireman B, Weissman MM, Leon AC, Sheehan DV, Kathol RG, et al. Mental 
disorders and disability among patients in a primary care group practice. Am J Psychiatry. 
1997;154:1734-40. 
[10] Posner K, Oquendo MA, Gould M, Stanley B, Davies M. Columbia Classification 
Algorithm of Suicide Assessment (C-CASA): Classification of Suicidal Events in the FDA’s 
Pediatric Suicidal Risk Analysis of Antidepressants. Am J Psychiatry. 2007;164(7):1035-43. 
[11] Posner K, Melvin GA, Stanley B, Oquendo MA, Gould M. Factors in the Assessment of 
Suicidality in Youth. CNS Spectr. 2007;12(2):156-62. 


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Appendix A Schedule of Study Procedures 
 
Screening 
Period 
Placebo 
Lead-in 
Period (a) 
Double-blind Treatment Period 
Follow-up
Period 
Visit Number 
1 
2
3
4
5
6
7 
8/ET (c) Follow-up (d)
Week (b) 
-4 to -2
-1
0
1
2
4
6 
8/ET (c) 
12 (d)
Day (b) 
-32 to -12
-8
-1
7
14
28
42 
56/ET (c) 
84 (d)
Visit Window (Days) (b) 
- 
±3
0
±1
±3
±3
±3 
±3/- 
±5
Informed consent 
X (e)
 
 
Inclusion/exclusion criteria 
X 
X (f)
X (f)
 
 
Demographics, medical history, 
medication history 
X 
 
 
 
 
 
 
 
 
Diagnosis of MDD 
X 
 
 
Assessments of major depressive 
episode 
X 
 
 
 
 
 
 
 
 
Physical examination 
X 
X
X
 
X 
Weight, height (g) 
X 
X
X
X
 
X 
Vital signs 
X 
X
X
X
X
X
X 
X 
Concomitant medications 
X 
X
X
X
X
X
X 
X 
Concurrent medical conditions 
X 
 
 
Clinical laboratory tests (h) 
X 
X
X
X
 
X 
Pregnancy test (i) 
X 
X
X
X
 
X 
(-)
Urine drug screening 
X 
X
 
 
Pharmacokinetic sampling 
 
X
 
(X) 
Pharmacogenomic sampling (j) 
 
(X)
 
 
ECG 
X 
X
X
X
 
X 
C-SSRS 
X 
X
X
X
X
X
X 
X 
PTE/AE assessment (k) 
X 
X
X
X
X
X
X 
X 
(-)
<Assessments with Rating Scales> 
MADRS 
X 
X
X
X
X
X
X 
X 
HAM-D 
X 
X
X
 
X 
CGI-S 
X 
X
X
X
X
X
X 
X 
CGI-I (l) 
 
X
X
X
X
X 
X 
SDS 
 
X
X
 
X 
DSST 
 
X (m)
X
X
 
X 
PDQ-5 
 
X
X
X
 
X 
QIDS-J 
 
X
X
X
X
X
X 
X 
<Clinical Supply> 
Randomization 
 
X
 
 
Dispense study medication (n) 
 
X
X
X
X
X
X 
 
Drug return/accountability/compliance 
 
X
X
X
X
X 
X 
 


Lu AA21004 
Study No. : Lu AA21004/CCT-004 
Page 81 of 90
Protocol Incorporating Amendment No. 1
7 May 2015
 
CONFIDENTIAL 
ET = early termination 
(a) In the placebo lead-in period, subjects will receive the study medication in a single-blind manner. 
(b) The visit day in the double-blind treatment period is defined as Week 0 (Day -1). The day after Day -1 is 
defined as Day 1. All visit windows are in reference to the date of scheduled visit. 
(c) Subjects who prematurely discontinue the study during the placebo lead-in period or double-blind treatment 
period will be requested to visit the study site for the end-of study examinations within 7 days after the day of 
study discontinuation, wherever possible, and will be assessed in the same way as at Visit 8 (except for blood 
sampling for pharmacokinetics). 
(d) Safety follow-up assessments will be conducted. For subjects who prematurely discontinue the study during the 
placebo lead-in period or double-blind treatment period, the follow-up assessments will be made 28 ± 5 days 
after the last dose of the study medication. The follow-up assessments can either be conducted as a visit to the 
site or as a telephone contact. In the follow-up, the following will be assessed: outcomes of AEs continuing at 
Visit 8 (or the end-of study assessments if administration of the study medication is discontinued), new SAEs 
developed during the follow-up period, and special interest AEs. Female subjects of child-bearing potential will 
be asked to confirm whether they are pregnant or not. 
(e) Informed consent must be obtained prior to the initiation of any study procedure including washout of excluded 
medications. Informed consent may be obtained prior to the visit window of Visit 1. 
(f) 
Update at Visits 2 and 3. 
(g) Height is measured at only Visit 1. 
(h) Clinical laboratory tests will be performed under fasted conditions at Visits 2, 3 and 8 or Early Termination 
Visit, and at other visits wherever possible. 
(i) 
For women of child-bearing potential. 
(j) 
Only for subjects who consent to provide pharmacogenomic samples, separately from consent of participation 
in the study. Pharmacogenomic samples for analyses will be collected at Visit 2 or thereafter, as soon as 
possible, during the study. 
(k) PTEs will be collected prior to study medication administration in the placebo lead-in period, and AEs will be 
collected after study medication administration. 
(l) 
The CGI-I score will be assessed by comparison with that at Visit 3. However, at Visit 3 or early termination 
prior to Visit 3, the score will be assessed by comparison with that at Visit 2. 
(m) Subjects will complete the sample items prior to the actual test. 
(n) At Visit 2, subjects will be dispensed the study medication for the placebo lead-in period. At Visit 3, subjects 
will be dispensed the study medication for the double-blind treatment period, Inner Carton 1, and Inner Carton 
2 at Visits 4 to 7, with a necessary and sufficient amount of the study medication by next visit. 


Lu AA21004 
Study No. : Lu AA21004/CCT-004 
Page 82 of 90
Protocol Incorporating Amendment No. 1
7 May 2015
 
CONFIDENTIAL 
Appendix B Responsibilities of the Investigator 
1. Conduct the appropriate study in accordance with the protocol and GCP considering the 
rights, safety, and wellbeing of human subjects. 
2. When a part of the important activities related to the study are delegated to the investigator or 
the study collaborator, prepare the lists of activities to be delegated and responsible personnel, 
submit the lists to the director of the site in advance to get them accepted. 
3. Prepare a written informed consent form and other written information, and update as 
appropriate. 
4. Confirm the contents of the clinical study agreement. 
5. Provide necessary information on the protocol, medications, and responsibilities of individual 
personnel to the investigator and the study collaborator, and provide guidance and 
supervision. 
6. Screen subjects who meet the requirements of the protocol, provide the explanation of the 
study in writing, and obtain the written consent. 
7. Assume responsibility for all the medical judgement related to the study. 
8. Ensure in collaboration with the director of the site that sufficient information on all 
clinically significant adverse events related to the study are provided to subjects throughout 
and beyond the period when subjects participate in the study. 
9. If a subject consults other medical institution or other department, notify the physician of the 
medical institution or department of the subject’s participation in the study, as well as the end 
and termination of the study in writing, and document such records. 
10. In case of urgent report of an SAE, immediately notify the director of the site and the sponsor 
in writing. 
11. Determine the need of emergency key code blinding of a subject in case of emergency. 
12. Prepare correct and complete eCRFs, and submit them to the sponsor with electronic 
signature. 
13. Check and confirm the contents of eCRFs prepared by the sub-investigator or transcribed 
from the source data by the study collaborator, and submit them to the sponsor with 
electronic signature. 
14. Discuss any proposal from the sponsor including update of the protocol. 
15. Notify the director of the site of the end of the study in writing. 


Lu AA21004 
Study No. : Lu AA21004/CCT-004 
Page 83 of 90
Protocol Incorporating Amendment No. 1
7 May 2015
 
CONFIDENTIAL 
Appendix C Detailed Description of Amendments to Text 
The following describes changes from the initial protocol. 
 
Page 8, Section 2.0 STUDY SUMMARY, Study Design 
(Page 22, Section 6.1 Study Design) 
Existing Text 
This study consists of a 2-week screening period, a 1-week single-blind placebo lead-in period, 
an 8-week double-blind treatment period and a 4-week follow-up period… 
Revised Text 
This study consists of a 1-to 3-week screening period, a 1-week single-blind placebo lead-in 
period, an 8-week double-blind treatment period, and a 4-week follow-up period… 
Rationale for Amendment 
Correction for appropriate description. 
 
Page 9, Section 2.0 STUDY SUMMARY, Period of Evaluation 
Existing Text 
15 weeks in total 
Screening period: 2 weeks 
Placebo lead-in period: 1 week 
Double-blind treatment period: 8 weeks 
Safety follow-up period: 4 weeks 
Revised Text 
14 to 16 weeks in total 
Screening period: 1 to 3 weeks 
Placebo lead-in period: 1 week 
Double-blind treatment period: 8 weeks 
Safety follow-up period: 4 weeks 
Rationale for Amendment 
Correction for appropriate description. 
 
Page 12, Section 3.0 LIST OF ABBREVIATIONS 
Existing Text 
NSAIDs 
non-steroid anti-inflammatory drug 


Lu AA21004 
Study No. : Lu AA21004/CCT-004 
Page 84 of 90
Protocol Incorporating Amendment No. 1
7 May 2015
 
CONFIDENTIAL 
PDQ 
Perceived Deficits Questionaire 
Revised Text 
NSAIDs 
non-steroidal anti-inflammatory drug 
PDQ 
Perceived Deficits Questionnaire 
Rationale for Amendment 
Correction of erroneous description. 
 
Page 21, Section 6.1 Study Design, Figure 6.a Schematic of Study Design 
Existing Text 
 
 
前観察期 
プラセボリ
ードイン期 
（単盲検） 
二重盲検期 
追跡調査期 
 
 
 
W -3 
W -2 
W -1 
W 1 
W 2 
W 3
W 4
W 5
W 6
W 7
W 8
W 9
W 10
W 11 W 12 
 
V1 
V2 
V3a) 
V4 
V5 
 
V6 
 
V7
 
V8
 
 
 
  
 
 
 
プラセボQD 
プラセボQD 
 
 
 
 
 
 
Lu AA21004 10 mg QD 
 
 
 
 
 
 
 
Lu AA21004 20 mg QD b) 
 
 
 
 
 
 
 
10 mg b) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
無作為化 
 
 
 
 
二重盲検期用 
治験薬投与終了
 
安全性の
追跡調査c)
 
Screening 
Period 
Placebo  
Lead-in  
Period 
(Single-blind) 
Double-blind Treatment Period
Follow-up Period 
Randomization 
End of  
Treatment 
Safety 
Follow-up c)
Placebo QD 
Placebo QD


Lu AA21004 
Study No. : Lu AA21004/CCT-004 
Page 85 of 90
Protocol Incorporating Amendment No. 1 
7 May 2015
 
CONFIDENTIAL 
Revised Text 
 
Rationale for Amendment 
Correction for appropriate description. 
 
Page 28, Section 7.3 Excluded Medications and Treatments, 
Table 7.a List of Prohibited or Restricted Concomitant Drugs, (4) Hypnotics 
Existing Text 
Non-benzodiazepines (zolpidem, zopiclone, and eszopiclone) are allowed. However, use of these 
drugs should be kept to the minimum necessary, and use for 2 consecutive days and use at the 
night before a study visit are NOT allowed. In addition, the type and dose of non-
benzodiazepines should NOT be changed from the start of placebo lead-in period (Visit 2) to the 
end of double-blind treatment period (Visit 8) or early termination. 
Revised Text 
Non-benzodiazepines (zolpidem, zopiclone, and eszopiclone) are allowed. However, use of these 
drugs should be kept to the minimum necessary, and use for 2 or more consecutive days and use 
at the night before a study visit are NOT allowed. In addition, the type and dose of non-
benzodiazepines should NOT be changed from the start of placebo lead-in period (Visit 2) to the 
end of double-blind treatment period (Visit 8) or early termination. 
Rationale for Amendment 
Correction of an omission. 
 
 
前観察期 
プラセボリ
ードイン期 
（単盲検） 
二重盲検期 
追跡調査期 
 
 
 
W -4～-2 
W -1 
W 1 
W 2 
W 3 
W 4
W 5
W 6
W 7
W 8
W 9
W 10
W 11 W 12 
 
V1 
V2 
V3a) 
V4 
V5 
 
V6
 
V7 
 
V8
 
 
 
  
 
 
 
プラセボQD 
プラセボQD 
 
 
 
 
 
 
Lu AA21004 10 mg QD 
 
 
 
 
 
 
 
Lu AA21004 20 mg QD b) 
 
 
 
 
 
 
 
10 mg b) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
無作為化 
 
二重盲検期用 
治験薬投与終了
 
安全性の 
追跡調査c)
 
Screening 
Period 
Placebo  
Lead-in  
Period 
(Single-blind) 
Double-blind Treatment Period 
Follow-up Period 
Randomization 
End of  
Treatment 
Safety 
Follow-up c)
Placebo QD 
Placebo QD
-4 to -2 


Lu AA21004 
Study No. : Lu AA21004/CCT-004 
Page 86 of 90
Protocol Incorporating Amendment No. 1
7 May 2015
 
CONFIDENTIAL 
Page 31, Section 7.4, Diet, Fluid, and Activity Control 
Existing Text 
7. The subject must visit the site under fasted conditions at Visits 3 and 8 or Early Termination 
Visit. For visit serum chemistry test is scheduled, the subject visits the site under fasted 
conditions wherever possible. 
Revised Text 
7. The subject must visit the site under fasted conditions at Visits 2, 3 and 8 or Early 
Termination Visit. For visit serum chemistry test is scheduled, the subject visits the site 
under fasted conditions wherever possible. 
Rationale for Amendment 
Correction of an omission. 
 
Page 40, Section 9.1.5 Physical Examination Procedure 
Existing Text 
All subsequent physical examinations after administration of the study medication in the double-
blind treatment period should assess clinically significant changes from the examinations at the 
start of double-blind treatment period (Visit 3). 
Revised Text 
All subsequent physical examinations should assess clinically significant changes from the 
examinations prior to first dose. 
Rationale for Amendment 
Correction of erroneous description. 
 
Page 40, Section 9.1.8.1 Rating and Rating Training for MDD 
Montgomery-Åsberg Depression Rating Scale (MADRS) 
Existing Text 
The MADRS will be used for a primary efficacy measurement. The MADRS is a depression 
rating scale consisting of 10 items representing the core symptoms of depression.[6] The 
MADRS is rated using Structured Interview Guide for MADRS (SIGMA). The rating should be 
based on a clinical interview with the subject, moving from broadly phrased questions about 
symptoms to more detailed questions. The rating is performed based on the most severe 
condition of the subject during the past 1 week, and each item is rated from 0 to 6. Items 2 to 10 
are based upon subject report, and Item 1 is based on the observation of the subjects... 


Lu AA21004 
Study No. : Lu AA21004/CCT-004 
Page 87 of 90
Protocol Incorporating Amendment No. 1
7 May 2015
 
CONFIDENTIAL 
Revised Text 
The MADRS will be used for a primary efficacy measurement. The MADRS is a depression 
rating scale consisting of 10 items representing the core symptoms of depression.[6] The 
MADRS is rated using Structured Interview Guide for MADRS (SIGMA). The rating should be 
based on a clinical interview with the subject, moving from broadly phrased questions about 
symptoms to more detailed questions. The rating is performed based on the most severe 
condition of the subject during the past 1 week, and each item is rated from 0 to 6. Item 1 and 
Items 3 to 10 are based upon subject report, and Item 2 is based on the observation of the 
subjects... 
Rationale for Amendment 
Correction of erroneous description. 
 
Page 44, Section 9.1.12 Procedures for Clinical Laboratory Samples, 
Table 9.a Clinical Laboratory Tests 
Existing Text 
Hormonal Test 
Thyroid stimulating hormone (TSH) 
Free T4 b) 
b) When TSH value is outside the normal range, free T4 will be measured. If a clinically significant abnormality of 
thyroid gland is found based on the results of TSH and free T4, the subject will be excluded from the study. 
Revised Text 
Hormonal Test (Visit 1 only) 
Thyroid stimulating hormone (TSH) b) 
Free T4 b) 
b) TSH will be measured at Visit 1, and when TSH value is outside the normal range, free T4 will be measured. 
If a clinically significant abnormality of thyroid gland is found based on the results of TSH and free T4, the 
subject will be excluded from the study. 
Rationale for Amendment 
Correction of omissions. 
 
Page 44, Section 9.1.12 Procedures for Clinical Laboratory Samples, 
Table 9.a Clinical Laboratory Tests 
Existing Text 
a) Blood will be collected under fasted conditions at Visits 3 and 8 or Early Termination Visit. 
For other visits, blood will be collected under fasted conditions wherever possible. 


Lu AA21004 
Study No. : Lu AA21004/CCT-004 
Page 88 of 90
Protocol Incorporating Amendment No. 1
7 May 2015
 
CONFIDENTIAL 
Revised Text 
a) Blood will be collected under fasted conditions at Visits 2, 3 and 8 or Early Termination 
Visit. For other visits, blood will be collected under fasted conditions wherever possible. 
Rationale for Amendment 
Correction of an omission. 
 
Page 48, Section 9.3.1 Screening 
Existing Text 
The examinations/observations/assessments listed below will be performed at the start of the 
screening period (Day -22 ± 10; Visit 1). Subjects will be screened in accordance with 
predefined inclusion and exclusion criteria as described in Section 7.0. See Section 9.1.18 for 
procedures for documenting a subject who prematurely discontinues the study prior to entry into 
the placebo lead-in period. 
Revised Text 
The examinations/observations/assessments listed below will be performed at the start of the 
screening period (Day -32 to -12; Visit 1). Subjects will be screened in accordance with 
predefined inclusion and exclusion criteria as described in Section 7.0. See Section 9.1.18 for 
procedures for documenting a subject who prematurely discontinues the study prior to entry into 
the placebo lead-in period. 
Rationale for Amendment 
Correction for appropriate description. 
 
Page 49, Section 9.3.2 Placebo Lead-in Period 
Existing Text 
• Clinical laboratory tests 
Revised Text 
• Clinical laboratory tests (fasted) 
Rationale for Amendment 
Correction of an omission. 
 


Lu AA21004 
Study No. : Lu AA21004/CCT-004 
Page 89 of 90
Protocol Incorporating Amendment No. 1
7 May 2015
 
CONFIDENTIAL 
Page 70, Section 13.1.1 Analysis Sets 
Existing Text 
The sponsor will verify the validity of the definitions of the analysis sets as well as the rules for 
handling data, consulting a medical expert as needed. The Data Handling Rules for Statistical 
Analysis must be finalized prior to unblinding. 
Revised Text 
The sponsor will verify the validity of the definitions of the analysis sets as well as the rules for 
handling data, consulting a medical expert as needed. The Data Handling Rules for Statistical 
Analysis must be finalized prior to database lock. 
Rationale for Amendment 
Correction of erroneous description. 
 
Page 80, Appendix A Schedule of Study Procedures 
Existing Text 
 
Screening Period 
Visit Number 
1 
Week (b) 
-3 
Day (b) 
-22 
Visit Window (Day) (b)  
±10 
 
Revised Text 
 
Screening Period 
Visit Number 
1 
Week (b) 
-4 to -2 
Day (b) 
-32 to -12 
Visit Window (Day) (b) 
- 
 
Rationale for Amendment 
Correction for appropriate description. 
 


Lu AA21004 
Study No. : Lu AA21004/CCT-004 
Page 90 of 90
Protocol Incorporating Amendment No. 1
7 May 2015
 
CONFIDENTIAL 
Page 81, Appendix A Schedule of Study Procedures 
Existing Text 
(h) Clinical laboratory tests will be performed under fasted conditions at Visits 3 and 8 or Early 
Termination Visit, and at other visits wherever possible. 
Revised Text 
(h) Clinical laboratory tests will be performed under fasted conditions at Visits 2, 3 and 8 or 
Early Termination Visit, and at other visits wherever possible. 
Rationale for Amendment 
Correction of an omission. 
 


Lu AA21004 
Study No. : Lu AA21004/CCT-004 
Page 1 of 82
Initial Protocol 
9 January 2015
 
CONFIDENTIAL 
 
PROTOCOL 
 
<Title> 
A Randomized, Double-Blind, Placebo-Controlled, Parallel-Group, Phase III Study to 
Evaluate the Efficacy and Safety of Once Daily Oral Lu AA21004 in Patients with Major 
Depressive Disorder 
 
<Short Title> 
A Phase III Study of Lu AA21004 in Patients with Major Depressive Disorder 
Sponsor: 
Takeda Pharmaceutical Company Limited 
1-1, Doshomachi 4-chome, Chuo-ku, Osaka-shi 
Study Number: 
Lu AA21004/CCT-004 
Edition: 
Initial Protocol 
IND Number: 
Not Applicable 
EudraCT Number: 
Not Applicable 
Compound: 
Lu AA21004 
Date: 
9 January 2015 
 
 
 
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. : Lu AA21004/CCT-004 
Page 2 of 82
Initial Protocol 
9 January 2015
 
CONFIDENTIAL 
1.0 
ADMINISTRATIVE INFORMATION AND PRINCIPLES OF CLINICAL 
STUDIES 
1.1 
Contacts and Responsibilities of Study-Related Activities 
Refer to the attachment. 
1.2 
Principles of Clinical Studies 
This study will be conducted with the highest respect for the individual participants in 
accordance with the requirements of this study protocol and also in accordance with the 
following: 
 The ethical principles that have their origin in the Declaration of Helsinki. 
 International Conference on Harmonisation E6 Good Clinical Practice: Consolidated 
Guideline.  
 All applicable laws and regulations, including, without limitation, data privacy laws, clinical 
trial disclosure laws, and regulations. 


Lu AA21004 
Study No. : Lu AA21004/CCT-004 
Page 3 of 82
Initial Protocol 
9 January 2015
 
CONFIDENTIAL 
TABLE OF CONTENTS 
1.0 
ADMINISTRATIVE INFORMATION AND PRINCIPLES OF CLINICAL 
STUDIES .............................................................................................................................2 
1.1 
Contacts and Responsibilities of Study-Related Activities ...........................................2 
1.2 
Principles of Clinical Studies .........................................................................................2 
2.0 
STUDY SUMMARY...........................................................................................................8 
3.0 
LIST OF ABBREVIATIONS ............................................................................................12 
4.0 
INTRODUCTION .............................................................................................................14 
4.1 
Background ..................................................................................................................14 
4.1.1 Clinical Pharmacology ...........................................................................................14 
4.1.2 Overseas Phase II/III Clinical Studies ...................................................................15 
4.1.3 Japanese Phase II/III Clinical Studies ....................................................................16 
4.2 
Rationale for the Proposed Study ................................................................................17 
5.0 
STUDY OBJECTIVES AND ENDPOINTS .....................................................................18 
5.1 
Objectives ....................................................................................................................18 
5.1.1 Primary Objective ..................................................................................................18 
5.1.2 Secondary Objectives.............................................................................................18 
5.1.3 Additional Objectives ............................................................................................18 
5.2 
Endpoints .....................................................................................................................18 
5.2.1 Efficacy Endpoints .................................................................................................18 
5.2.1.1 
Primary Endpoint ........................................................................................18 
5.2.1.2 
Secondary Endpoints ...................................................................................18 
5.2.2 Pharmacokinetic Endpoint .....................................................................................19 
5.2.3 Safety Endpoints ....................................................................................................19 
6.0 
STUDY DESIGN AND DESCRIPTION ..........................................................................20 
6.1 
Study Design ................................................................................................................20 
6.2 
Justification for Study Design, Dose, and Endpoints ..................................................21 
6.2.1 Subject Population .................................................................................................21 
6.2.2 Study Design ..........................................................................................................21 
6.2.3 Doses ......................................................................................................................22 
6.2.4 Endpoints ...............................................................................................................22 
6.3 
Premature Termination or Suspension of Study or Study Site ....................................23 
6.3.1 Criteria for Premature Termination or Suspension of the Study ...........................23 
6.3.2 Criteria for Premature Termination or Suspension of Study Sites ........................23 


Lu AA21004 
Study No. : Lu AA21004/CCT-004 
Page 4 of 82
Initial Protocol 
9 January 2015
 
CONFIDENTIAL 
6.3.3 Procedures for Premature Termination or Suspension of the Study or the 
Participation of Study Sites ....................................................................................23 
7.0 
SELECTION AND DISCONTINUATION/WITHDRAWAL OF SUBJECTS ...............24 
7.1 
Inclusion Criteria .........................................................................................................24 
7.2 
Exclusion Criteria ........................................................................................................25 
7.3 
Excluded Medications and Treatments ........................................................................28 
7.4 
Diet, Fluid, and Activity Control .................................................................................31 
7.5 
Criteria for Discontinuation or Withdrawal of a Subject .............................................31 
7.5.1 Additional Guidance for Withdrawal Criteria .......................................................33 
7.6 
Procedures for Discontinuation or Withdrawal of a Subject .......................................33 
8.0 
CLINICAL TRIAL MATERIAL MANAGEMENT .........................................................34 
8.1 
Study Medication .........................................................................................................34 
8.1.1 Dosage Form, Manufacturing, Packaging, and Labeling ......................................34 
8.1.2 Storage ...................................................................................................................34 
8.1.3 Dose and Regimen .................................................................................................35 
8.1.4 Overdose ................................................................................................................35 
8.2 
Study Drug Assignment and Dispensing Procedures ..................................................36 
8.3 
Randomization Code Creation and Storage .................................................................36 
8.4 
Study Drug Blind Maintenance ...................................................................................36 
8.5 
Unblinding Procedure ..................................................................................................36 
8.6 
Accountability and Destruction of Sponsor-Supplied Drugs.......................................36 
9.0 
STUDY PLAN ...................................................................................................................38 
9.1 
Study Procedures .........................................................................................................38 
9.1.1 Informed Consent Procedure .................................................................................38 
9.1.1.1 
Pharmacogenomic Informed Consent Procedure ........................................38 
9.1.2 Demographics, Medical History, and Medication History Procedure ...................38 
9.1.3 Diagnosis of MDD .................................................................................................38 
9.1.4 Assessments of Major Depressive Episode ...........................................................39 
9.1.4.1 
Current Major Depressive Episode .............................................................39 
9.1.4.2 
Past Major Depressive Episode ...................................................................39 
9.1.5 Physical Examination Procedure ...........................................................................40 
9.1.6 Weight, Height, and BMI.......................................................................................40 
9.1.7 Vital Sign Procedure ..............................................................................................40 
9.1.8 Efficacy Evaluation ................................................................................................40 
9.1.8.1 
Rating and Rating Training for MDD .........................................................40 
9.1.8.2 
Social Function Assessment ........................................................................42 


Lu AA21004 
Study No. : Lu AA21004/CCT-004 
Page 5 of 82
Initial Protocol 
9 January 2015
 
CONFIDENTIAL 
9.1.8.3 
Cognitive Function Assessments ................................................................42 
9.1.8.4 
Self-report Assessment of Depressive Symptoms and Assessment 
Monitoring...................................................................................................42 
9.1.9 Suicidal Risk Assessments .....................................................................................43 
9.1.10 Documentation of Concomitant Medications ........................................................43 
9.1.11 Documentation of Concurrent Medical Conditions ...............................................43 
9.1.12 Procedures for Clinical Laboratory Samples .........................................................43 
9.1.13 Contraception and Pregnancy Avoidance Procedure .............................................45 
9.1.14 Pregnancy ...............................................................................................................45 
9.1.15 ECG Procedure ......................................................................................................46 
9.1.16 Pharmacogenomic Sample Collection ...................................................................46 
9.1.17 Pharmacokinetic Sample Collection and Analysis ................................................46 
9.1.17.1 Collection of Blood for Pharmacokinetic Sampling ...................................46 
9.1.17.2 Bioanalytical Methods ................................................................................46 
9.1.18 Documentation of Screen Failure Prior to Entrance into Placebo Lead-in 
Period .....................................................................................................................46 
9.1.19 Documentation of Study Entrance into Placebo Lead-in Period ...........................47 
9.1.20 Documentation of Screen Failure Prior to Randomization ....................................47 
9.1.21 Documentation of Randomization .........................................................................48 
9.2 
Monitoring Subject Treatment Compliance.................................................................48 
9.3 
Schedule of Observations and Procedures ...................................................................48 
9.3.1 Screening Period ....................................................................................................48 
9.3.2 Placebo Lead-in Period ..........................................................................................49 
9.3.3 Start of Double-blind Treatment Period/Randomization .......................................50 
9.3.4 Double-blind Treatment Period .............................................................................51 
9.3.5 End of Double-blind Treatment Period or Early Termination ...............................53 
9.3.6 Follow-up Period ...................................................................................................54 
9.3.7 Post Study Care ......................................................................................................54 
9.4 
Biological Sample Retention and Destruction .............................................................54 
10.0 
PRETREATMENT EVENTS AND ADVERSE EVENTS ..............................................56 
10.1 
Definitions....................................................................................................................56 
10.1.1 PTEs .......................................................................................................................56 
10.1.2 AEs .........................................................................................................................56 
10.1.3 Additional Points to Consider for PTEs and AEs ..................................................56 
10.1.4 SAEs ......................................................................................................................58 
10.1.5 Special Interest AEs ...............................................................................................60 


Lu AA21004 
Study No. : Lu AA21004/CCT-004 
Page 6 of 82
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9 January 2015
 
CONFIDENTIAL 
10.1.5.1 Skin and Allergic Reaction .........................................................................60 
10.1.5.2 Hepatic Impairment .....................................................................................60 
10.1.5.3 Overdose .....................................................................................................61 
10.1.6  Severity of PTEs and AEs ...................................................................................61 
10.1.7  Causality of AEs ..................................................................................................61 
10.1.8  Relationship to Study Procedures ........................................................................61 
10.1.9  Start Date .............................................................................................................62 
10.1.10 Stop Date .............................................................................................................62 
10.1.11 Frequency ............................................................................................................62 
10.1.12 Action Concerning Study Medication .................................................................62 
10.1.13 Outcome ...............................................................................................................63 
10.2 
Procedures ....................................................................................................................63 
10.2.1 Collection and Reporting of AEs ...........................................................................63 
10.2.1.1 PTE and AE Collection Period ...................................................................63 
10.2.1.2 PTE and AE Reporting ................................................................................64 
10.2.1.3 Special Interest AE Reporting .....................................................................65 
10.2.2 Collection and Reporting of SAEs .........................................................................65 
10.2.3 Reporting of Abnormal Liver Function Tests ........................................................66 
10.3 
Follow-up of SAEs ......................................................................................................66 
10.3.1 Safety Reporting to Investigators, IRBs, and Regulatory Authorities ...................66 
11.0 
STUDY-SPECIFIC COMMITTEES .................................................................................67 
12.0 
DATA HANDLING AND RECORDKEEPING ..............................................................68 
12.1 
eCRFs ...........................................................................................................................68 
12.2 
Record Retention .........................................................................................................68 
13.0 
STATISTICAL METHODS ..............................................................................................70 
13.1 
Statistical and Analytical Plans ....................................................................................70 
13.1.1 Analysis Sets ..........................................................................................................70 
13.1.2 Analysis of Demographics and Other Baseline Characteristics ............................70 
13.1.3 Efficacy Analysis ...................................................................................................70 
13.1.4 Pharmacokinetic Analysis ......................................................................................72 
13.1.5 Safety Analysis ......................................................................................................72 
13.2 
Interim Analysis and Criteria for Early Termination ...................................................72 
13.3 
Determination of Sample Size .....................................................................................72 
14.0 
QUALITY CONTROL AND QUALITY ASSURANCE .................................................74 
14.1 
Study-Site Monitoring Visits .......................................................................................74 


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14.2 
Protocol Deviations ......................................................................................................74 
14.3 
Quality Assurance Audits and Regulatory Agency Inspections ..................................74 
15.0 
ETHICAL ASPECTS OF THE STUDY ...........................................................................75 
15.1 
IRB Approval ...............................................................................................................75 
15.2 
Subject Information, Informed Consent, and Subject Authorization ..........................75 
15.3 
Subject Confidentiality ................................................................................................76 
15.4 
Publication, Disclosure, and Clinical Trial Registration Policy ..................................77 
15.4.1 Publication and Disclosure ....................................................................................77 
15.4.2 Clinical Trial Registration......................................................................................77 
15.4.3 Clinical Trial Results Disclosure ...........................................................................77 
15.5 
Insurance and Compensation for Injury .......................................................................78 
16.0 
REFERENCES ..................................................................................................................79 
 
LIST OF IN-TEXT TABLES 
Table 7.a 
List of Prohibited or Restricted Concomitant Medications ...................................28 
Table 8.a 
Study Medication ...................................................................................................34 
Table 8.b 
Dose and Regimen .................................................................................................35 
Table 9.a 
Clinical Laboratory Tests .......................................................................................44 
Table 10.a 
Takeda Medically Significant AE List ..................................................................59 
 
LIST OF IN-TEXT FIGURES 
Figure 6.a 
Schematic of Study Design ....................................................................................21 
 
LIST OF APPENDICES 
Appendix A 
Schedule of Study Procedures ...............................................................................80 
Appendix B 
Responsibilities of the Investigator ........................................................................82 
 


Lu AA21004 
Study No. : Lu AA21004/CCT-004 
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2.0 
STUDY SUMMARY 
Name of Sponsor: 
Takeda Pharmaceutical Company Limited 
Compound: 
Lu AA21004 
Title of Protocol: 
A Randomized, Double-Blind, Placebo-Controlled, Parallel-Group, 
Phase III Study to Evaluate the Efficacy and Safety of Once Daily 
Oral Lu AA21004 in Patients with Major Depressive Disorder 
IND No.: 
Not Applicable 
EudraCT No.: 
Not Applicable 
Study Number: Lu AA21004/CCT-004 
Phase: 3 
Study Design: 
This is a randomized, double-blind, placebo-controlled, parallel-group, phase III study to evaluate the efficacy and 
safety of 8-week treatment of 2 fixed doses of Lu AA21004 (10 or 20 mg/day) in Japanese subjects with major 
depressive disorder (MDD). 
This study consists of a 2-week screening period, a 1-week single-blind placebo lead-in period, an 8-week double-
blind treatment period and a 4-week safety follow-up period. Subjects who fulfill all inclusion criteria and none of 
exclusion criteria at the start of screening period (Visit 1) and at the start of placebo lead-in period (Visit 2) will 
move into the placebo lead-in period and receive placebo once daily for 1 week in a single-blind manner. 
Afterwards, these who fulfill all the inclusion criteria and none of the exclusion criteria at the start of double-blind 
treatment period (Visit 3) will move into the double-blind treatment period and will be randomized in a 1:1:1 ratio to 
one of the following treatment groups: the placebo group, the Lu AA21004 10 mg/day group or the Lu AA21004 
20 mg/day group. Subjects in the placebo group and the Lu AA21004 10 mg/day group will receive placebo and 
Lu AA21004 10 mg, respectively, once daily from the day after Visit 3 for 8 weeks in a double-blind manner. 
Subjects in the Lu AA21004 20 mg/day group will receive Lu AA21004 10 mg once daily from the day after Visit 3 
for 1 week and thereafter Lu AA21004 20 mg once daily for 7 weeks in a double-blind manner. Subjects in any 
treatment groups will visit study sites at Week 1, 2, 4, 6 and 8 during the double-blind treatment period for 
examinations/observations/assessments. 
A safety follow-up contact (visit or phone call) will be made 4 weeks after the completion of the double-blind 
treatment period. Subjects who prematurely discontinue the study during the placebo lead-in period or the double-
blind treatment period will be requested to visit the study site for the end-of study assessments within 7 days after 
the discontinuation decision is made wherever possible, and will be contacted 4 weeks after the last dose of the 
study medication for safety follow-up. 
Primary Objective: 
• To evaluate the efficacy of 2 fixed doses of Lu AA21004 (10 or 20 mg/day) after 8 weeks of treatment in Japanese 
patients with MDD. 
Secondary Objectives: 
• To evaluate the safety and tolerability of 2 fixed doses of Lu AA21004 (10 or 20 mg/day) after 8 weeks of 
treatment in Japanese patients with MDD. 
• To evaluate the efficacy of Lu AA21004 (10 or 20 mg/day) on cognitive functions after 8 weeks of treatment in 
Japanese patients with MDD. 
Additional Objective: 
• To analyze the plasma concentrations of Lu AA21004 and its metabolites Lu AA34443 and Lu AA39835 using 
population pharmacokinetic analyses. 
Subject Population: 
Male and female subjects, aged between 20 and 75 years (both inclusive), with recurrent MDD according to 
Diagnostic and Statistical Manual of Mental Disorders, 4th edition, Text Revision (DSM-IV-TR) criteria. 


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Number of Subjects: 
Randomized subjects: 480 (160 per group) 
Number of Sites: 
Approximately 60 sites 
Dose Levels: 
Placebo lead-in period:  
Placebo once daily 
Double-blind treatment period:  
Lu AA21004 (10 or 20 mg) or placebo once daily 
Route of Administration: 
Oral 
Duration of Treatment: 
9 weeks in total 
Placebo lead-in period: 1 week 
Double-blind treatment period: 8 weeks 
Period of Evaluation: 
15 weeks in total 
Screening period: 2 weeks 
Placebo lead-in period: 1 week 
Double-blind treatment period: 8 weeks 
Safety follow-up period: 4 weeks 
Main Criteria for Inclusion: 
• The subject suffers from recurrent MDD as the primary diagnosis according to DSM-IV-TR criteria (classification 
code 296.3x). 
• The subject is a man or a woman aged 20 to 75 years (both inclusive) at the time of informed consent. 
• The reported duration of the current major depressive episode is 3 to 12 months (both inclusive) at the start of 
screening period. 
• The subject has a Montgomery-Åsberg Depression Rating Scale (MADRS) total score ≥26, a Hamilton 
Depression Rating Scale (HAM-D17) total score ≥18, and a clinical global impression scale-Severity (CGI-S) 
score ≥4 at the start of screening period, the start of placebo lead-in period and the start of the double-blind 
treatment period. 
Main Criteria for Exclusion: 
• The subject has any following current or past history of psychiatric disorder and/or neurological disorder: 
- Any current psychiatric disorder other than MDD as defined by DSM-IV-TR (To be assessed by Mini 
International Neuropsychiatric Interview: MINI). A subject who exhibits symptoms of anxiety is eligible unless 
the subject fulfills the diagnostic criteria for a current anxiety disorder per DSM-IV-TR. 
- Current diagnosis or history of manic, mixed or hypomanic episode, MDD with psychotic features, 
schizophrenia or any other psychotic disorder (including substance-related mental disorders, or mental disorders 
due to a general medical condition) as defined by DSM-IV-TR. 
- Current diagnosis or history of any substance-related disorder (except nicotine and caffeine-related disorders) as 
defined by DSM-IV-TR. 
- The subject with a positive urine drug screening result at the start of screening period or the start of placebo 
lead-in period. In case that a subject showed positive test result at the start of screening period because the test 
was conducted before washout of pretreatment drugs, the subject is eligible as long as he/she shows negative 
result at the start of placebo lead-in period. 
- Presence or history of any clinically significant neurological disorder (including epilepsy). 
- Any neurodegenerative disorder (e.g. Alzheimer’s disease, Parkinson’s disease, multiple sclerosis, Huntington’s 
disease). 
- Any DSM-IV-TR axis II disorder. 
• The subject has the current or previous major depressive episode which were considered by the investigator to 
have been resistant to 2 or more adequate antidepressants treatments of at least 6 weeks duration each at sufficient 
doses. 


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Study No. : Lu AA21004/CCT-004 
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• The subject has received any augmentation therapy (e.g. lithium, T3/T4, lamotrigine, sodium valproate, 
carbamazepine, additional atypical antipsychotic, or concomitant use of other antidepressant, etc.) for the current 
major depressive episode. 
• In the opinion of the investigator, the subject has experienced significant number of major depressive episodes in 
the past, and is suspected of disease other than MDD. 
• In the opinion of the investigator, the subject has experienced the first major depressive episode at his/her young 
age, and is suspected of disease other than MDD. 
• The subject has a MADRS total score at the start of double-blind treatment period that has improved or aggravated 
by 25% or more from the score at the start of placebo lead-in period. 
• The subject is at significant risk of suicide or has a score ≥5 on Item 10 (suicidal thoughts) of the MADRS at the 
start of screening period, the start of placebo lead-in period or the start of double-blind treatment period, or has 
attempted suicide within 6 months prior to the start of screening period. 
• The subject has experienced any environmental change (e.g. temporary retirement, returnment, change of 
residence) considered by the investigator to have the potential to impact on the efficacy evaluation, or plans such 
environmental changes during the study. 
• The subject has a clinically significant unstable illness, for example, hepatic impairment or renal insufficiency, or 
a cardiovascular, pulmonary, gastrointestinal, endocrine, neurological, rheumatologic, immunologic, infectious, 
neoplastic, skin and subcutaneous tissue disorders, eye disorders, or metabolic disturbance. 
Main Criteria for Evaluation and Analyses: 
Efficacy Endpoints 
Primary Endpoint 
• Change from baseline (i.e. at the start of double-blind treatment) in the MADRS total score after 8 weeks of 
treatment 
Secondary Endpoints 
• MADRS response after 8 weeks of treatment (last observation carried forward [LOCF]) 
(MADRS response is defined as a ≥50% decrease in the MADRS total score from baseline). 
• MADRS remission after 8 weeks of treatment (LOCF) 
(MADRS remission is defined as the MADRS total score of ≤10). 
• Change from baseline in the HAM-D17 total score after 8 weeks of treatment (LOCF). 
• Clinical global impression scale-Improvement (CGI-I) score after 8 weeks of treatment (LOCF). 
• Change from baseline in the CGI-S score after 8 weeks of treatment (LOCF). 
• Change from baseline in the Sheehan Disability Scale (SDS) total score after 8 weeks of treatment (LOCF). 
• Change from baseline in the Digit Symbol Substitution Test (DSST) score after 8 weeks of treatment (LOCF). 
• Change from baseline in the Perceived Deficits Questionnaire (PDQ-5) score after 8 weeks of treatment (LOCF). 
Pharmacokinetic Endpoint 
• Plasma concentrations of Lu AA21004 and its metabolites Lu AA34443 and Lu AA39835. 
Safety Endpoints 
• Adverse events 
• Weight 
• Vital signs 
• Electrocardiograms (ECGs) 
• Clinical laboratory tests (serum chemistry, hematology and urinalysis) 
• Columbia-Suicide Severity Rating Scale (C-SSRS) 


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Statistical Considerations: 
Change from baseline (i.e. the start of double-blind treatment period) in the MADRS total score after 8 weeks of 
treatment is the primary efficacy endpoint. Comparisons between each Lu AA21004 treatment group and the 
placebo group at Week 8 of the double-blind treatment period will be performed using the full analysis set (FAS) 
based on Mixed Model for Repeated Measures (MMRM) analysis of covariance with the change from baseline in 
the MADRS total score as a dependent variable, and visit, treatment group, visit-by-treatment group interaction and 
baseline MADRS total score-by-time point interaction as fixed effects. An unstructured variance-covariance matrix 
will be used to model the within-subject errors and Satterthwaite's method will be used to approximate the degrees 
of freedom. Holm's step-down method will be used to adjust the multiplicity for the comparisons. 
Sample Size Justification: 
A number of subjects planned to be enrolled in this study is 480 (160 per group). Assuming the true mean 
differences of 3.5 for the change from baseline in the MADRS total score between each Lu AA21004 group and the 
placebo group, this sample size will provide greater than 80% power to detect the difference between each 
Lu AA21004 group and the placebo group by 2-sample t-test. In addition, assuming the true mean differences of 3.0 
for the change from baseline in the MADRS total score between each Lu AA21004 group and the placebo group, 
this sample size will provide greater than 80% power to detect the difference between either the Lu AA21004 10 mg 
or 20 mg group and the placebo group. These power calculations assume a common standard deviation of 9.5 for the 
change from baseline in the MADRS total score, with a 2-sided level of 0.025. 
 


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3.0 
LIST OF ABBREVIATIONS 
5-HT 
5-hydroxytryptamine 
5-HTT 
5-hydroxytryptamine transporter 
ADHD 
attention deficit hyperactivity disorder 
AE 
adverse event 
ANCOVA 
analysis of co-variance 
ALT 
alanine aminotransferase 
AST 
aspartate aminotransferase 
AUC 
area under the plasma concentration-time curve 
BMI 
body mass index 
BUN 
blood urea nitrogen 
Cavg 
average plasma concentration at steady state 
CGI-I 
clinical global impression scale-Improvement 
CGI-S 
clinical global impression scale-Severity 
Cmax 
maximum observed plasma concentration 
COX 
cyclooxygenase  
CRO 
contract research organization 
C-SSRS 
Columbia-Suicide Severity Rating Scale 
CYP 
cytochrome P-450 
DSM-IV-TR 
Diagnostic and Statistical Manual of Mental Disorders, 4th Edition, Text Revision 
DSST 
Digit Symbol Substitution Test 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
γ-GTP 
-glutamyl transferase 
HAM-D 
Hamilton Depression Rating Scale 
hCG 
Human chorionic gonadotropin 
HDL 
high-density lipoprotein 
ICH 
International Conference on Harmonisation 
INR 
international normalized ratio 
LDL 
low-density lipoprotein 
LOCF 
Last Observation Carried Forward 
MADRS 
Montgomery Åsberg Depression Rating Scale 
MAOI 
monoamine oxidase inhibitor 
MedDRA 
Medical Dictionary for Regulatory Activities 
MHRA 
Medicines and Healthcare products Regulatory Agency 
MINI 
Mini International Neuropsychiatric Interview 
MMRM 
Mixed Model for Repeated Measures 
NaSSA 
noradrenergic and specific serotonergic antidepressant 
NSAIDs 
non-steroid anti-inflammatory drug 
PDQ 
Perceived Deficits Questionaire 
PMDA 
Pharmaceutical and Medical Devices Agency 


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PT 
Preferred Term 
PTE 
Pretreatment Event 
PTP 
press through package 
QIDS 
Quick Inventory of Depressive Symptomatology  
SAE 
serious adverse event 
SDS 
Sheehan Disability Scale 
SNRI 
serotonin norepinephrine reuptake inhibitor 
SOC 
System Organ Class 
SSRI 
selective serotonin reuptake inhibitor 
SUSARs 
Suspected unexpected serious adverse reactions 
TEAE 
treatment emergent adverse event 
TSH 
thyroid-stimulating hormone 
WHO 
World Health Organization 
 


Lu AA21004 
Study No. : Lu AA21004/CCT-004 
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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 in Japan and overseas. As of December 2014, Lu AA21004 has been 
approved for marketing as a drug for the treatment of MDD in countries including the U.S., 
Europe and Australia. 
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] With advances of basic research and clinical studies, the etiology and 
pathology of depression have been gradually revealed, but not fully elucidated so far. 
Depression is a common disease worldwide, with the estimated lifetime prevalence above 10%. 
The onset age is estimated to be from 20 to 50 years old in half of patients; however, the onset in 
children and the elderly has been also reported.[3] In the U.S., the prevalence of depression in 
aged 18 to 29 years is approximately 3-fold higher than that in more than 60 years, and, after 
early adolescence, the prevalence in women is 1.5 to 3-fold higher than in men, showing that the 
prevalence of depression varies widely depending on age and sex.[4] 
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] 
The goal of treatment for depression is to improve patients' mental and social quality of life by 
effectively alleviating the depressive symptoms. 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 (SSRIs), serotonin-
norepinephrine reuptake inhibitors (SNRIs), and noradrenergic and specific serotonergic 
antidepressants (NaSSAs) 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. 
4.1.1 
Clinical Pharmacology 
Results of clinical pharmacology studies in Japan and overseas are summarized below. 
Lu AA21004 was slowly absorbed after oral administration, and the Tmax was approximately 7 
to 11 hours. The absolute bioavailability of Lu AA21004 was approximately 75%. The 


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pharmacokinetics of Lu AA21004 was linear within the dose range between 2.5 and 60 mg. The 
plasma concentration of Lu AA21004 reached steady state after approximately 2-week multiple 
doses, and the accumulation index was 5 to 6 based on AUC following multiple doses of 5 to 
20 mg/day. There was no food effect on the pharmacokinetics of Lu AA21004. 
Lu AA21004 was extensively metabolized in the liver, primarily through oxidation or glucuronic 
acid conjugation, and CYP2D6 was shown to be the primary enzyme in metabolism of 
Lu AA21004 to the major metabolite Lu AA34443. Lu AA34443 was pharmacologically 
inactive, and the active metabolite Lu AA39835 did not cross the blood-brain barrier, although 
Lu AA39835 was slightly detected in plasma, suggesting that these metabolites are less likely to 
contribute to the pharmacological effect of Lu AA21004. In addition, Lu AA21004 and its 
metabolites did not induce or inhibit CYP isozymes in vitro, suggesting that clinical significant 
drug-drug interactions with Lu AA21004 are less likely to occur. 
The T1/2 of Lu AA21004 was approximately 66 hours, and two- thirds of its metabolites were 
excreted in urine, and one-third were excreted in feces. The excretion of unchanged Lu AA21004 
was slightly noted in feces. 
After multiple doses of Lu AA21004, 5-HTT occupancy in raphe nuclei was approximately 50% 
at doses of 5 mg/day, 65% at 10 mg/day, and 80% or more at 20 mg/day. 
Based on results of studies in Caucasian and Japanese subjects, there were no statistically 
significant differences in the pharmacokinetics and 5-HTT occupancy of Lu AA21004 between 
the races. 
4.1.2 
Overseas Phase II/III Clinical Studies 
A total of 12 overseas placebo-controlled, double-blind, short-term studies (Studies 11492A, 
11984A, 303, 304, 305, 13267A, 315, 316, 317, CCT-002, 12541A and 14122A) were conducted 
to evaluate the efficacy of Lu AA21004 for the treatment of MDD. Study CCT-002 was a 
multinational study including Japan. 
The changes from baseline in the Montgomery-Åsberg Depression Rating Scale (MADRS) total 
score were analyzed by mixed model repeated measures (MMRM) in the individual studies; and 
the results of the 11 of 12 studies mentioned above except for Study 12541A for elderly patients 
were used for meta-analysis. As for the mean changes from baseline in the MADRS total score at 
Week 6 or 8, the differences of the Lu AA21004 5, 10 and 20 mg group compared to the placebo 
group were -2.3 (p = 0.007), -3.6 (p < 0.001) and -4.6 (p < 0.001), respectively, and all of them 
were statistically significant. In addition, although the mean difference between the 15 mg group 
and placebo group was -2.6, not statistically significant. MADRS response rate (MADRS 
response is defined as a ≥ 50% decrease from baseline in the MADRS total score) in the subjects 
treated with Lu AA21004 was 46% to 49%, whereas that in the subjects treated with placebo was 
34% (p < 0.01). These results suggested Lu AA21004 at doses of 5 to 20 mg/day was effective. 
For comprehensive safety evaluation including the above-mentioned short-term studies and long-
term studies (Studies 11492C, 11984B, 301, 13267B and 314), treatment with Lu AA21004 at 
doses of 5 to 20 mg/day was safe and well tolerated. The most common TEAE in the 


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Lu AA21004 groups was nausea, and gastrointestinal TEAEs were occurred more frequently in 
female than male. Most TEAEs were mild or moderate and occurred within the first 2 weeks of 
treatment. In addition, TEAEs were usually transient, and did not generally lead to 
discontinuation of the study medication. 
Abrupt discontinuation of antidepressants may result in discontinuation symptoms, however, 
there were no clinically relevant differences in the incidence or nature of discontinuation 
symptoms between the Lu AA21004 groups and placebo group. 
The incidence of self-report sexual dysfunction in the Lu AA21004 groups was low, and was 
similar to that in the placebo group. In the study using a rating scale (Arizona Sexual Experience 
Scale) for sexual dysfunction, the incidence of sexual dysfunction at doses of 5 to 15 mg/day of 
Lu AA21004 was similar to that of placebo, but that at 20 mg/day was higher than placebo. 
Lu AA21004 had no clinically significant effect on weight, heart rate, blood pressure, and 
hepatic and renal functions. Moreover, Lu AA21004 also had no clinically significant effect on 
ECG parameters (QT interval, QTc interval, PR interval and QRS interval). In a thorough QTc 
study in healthy adult subjects, Lu AA21004 at doses up to 40 mg/day had no potential for 
prolongation of QT/QTc intervals. 
4.1.3 
Japanese Phase II/III Clinical Studies 
In Japan, 2 placebo-controlled, short-term studies (Study CCT-002 [multinational study] and 
Study CCT-003 [Japan local study]) were conducted in subjects with MDD. In addition, a long-
term extension study (Study OCT-001) was conducted in those who completed Study CCT-003. 
Study CCT-002 was conducted in 14 countries including Japan, Europe and the Asia Pacific 
region to evaluate the efficacy and safety of Lu AA21004 at doses of 5, 10 and 20 mg/day. For 
the mean changes from baseline in the MADRS total score at Week 8 (last observation carried 
forward [LOCF]) in the primary efficacy analysis (analysis of covariance [ANCOVA]), the mean 
differences of the Lu AA21004 5, 10 and 20 mg group compared to the placebo group were -
0.61 (p = 0.91), -1.69 (p = 0.30) and -1.82 (p = 0.24), respectively. In addition, in the same 
analysis for Japanese population, the mean differences of the Lu AA21004 5, 10 and 20 mg 
group compared to the placebo group were 0.89, -2.74 and -3.45, respectively. 
In Study CCT-002, Most TEAEs were mild or moderate, and TEAEs reported in more than 5% 
of subjects in any Lu AA21004 groups were nausea, nasopharyngitis, headache, dizziness, 
constipation, dry mouth, and insomnia. Of these, TEAEs with higher (≥ 2-fold) incidence in any 
Lu AA21004 groups than that in placebo group were nausea, constipation, dry mouth, dizziness 
and insomnia. 
In Study CCT-003, the efficacy and safety of Lu AA21004 at doses of 5 and 10 mg/day were 
evaluated in Japanese subjects with MDD. For the mean changes from baseline in the MADRS 
total score at Week 8 (LOCF) in the primary efficacy analysis (ANCOVA), the mean differences 
of the Lu AA21004 5 and 10 mg group compared to the placebo group were -2.03 (p = 0.10) and 
-1.04 (p = 0.40), respectively. 


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In Study CCT-003, TEAEs reported in more than 5% of subjects in any Lu AA21004 groups 
were nausea, diarrhoea, nasopharyngitis, somnolence, headache, and suicidal ideation. Of these, 
TEAEs with higher (≥2-fold) incidence in the Lu AA21004 groups than that in the placebo group 
were nausea and suicidal ideation. For suicidal ideation, the incidence in the 10 mg group (8 
subjects; 6.6%) was higher than in the placebo group (2 subjects; 1.6%) and 5 mg group (1 
subject; 0.8%). In general, most TEAEs were mild or moderate, suggesting that there were no 
significant safety concerns about Lu AA21004. 
In the open-label long-term extension study (Study OCT-001), the safety of 52 week treatment of 
Lu AA21004 at flexible doses of 5 to 20 mg/day was evaluated in subjects who completed Study 
CCT-003. In Study OCT-001, TEAEs reported in more than 5% of subjects were 
nasopharyngitis, nausea, seasonal allergy, headache, weight increased, diarrhoea, vomiting, 
alanine aminotransferase (ALT) increased, somnolence, malaise, influenza, and blood creatine 
phosphokinase increased. No long-term specific TEAEs were observed, and most TEAEs were 
mild or moderate, suggesting that there were no significant safety concerns in a long-term 
treatment of Lu AA21004. 
4.2 
Rationale for the Proposed Study 
In Europe and the U.S., the efficacy and safety of Lu AA21004 were demonstrated at doses of 5 
to 20 mg/day and Lu AA21004 has already been approved for marketing. For 2 short-term 
studies (Studies CCT-002 and CCT-003) including Japanese MDD patients, there are no 
statistically significant differences in the efficacy between any Lu AA21004 groups and the 
placebo group; however, in Study CCT-002, changes from baseline in the MADRS total score in 
the 10 and 20 mg groups were grater than in the placebo group in both overall population and 
Japanese population, and these results appeared to be supported by the result of 10 mg group in 
Study CCT-003. 
Based on these results, if a statistically significant difference between the Lu AA21004 10 or 
20 mg group and the placebo group is shown in the planned study (Study CCT-004), it is 
considered that the hypothesis of the efficacy of Lu AA21004 at doses of 10 and 20 mg in the 
Japanese population in Study CCT-002 can be verified. 
The results of Studies CCT-002, CCT-003 and OCT-001 suggested that there were no significant 
safety concerns about Lu AA21004 at the dose up to 20 mg, but further data collection may 
provide more appropriate safety evaluation. 
From the above, this study is designed as an additional phase III study to evaluate the efficacy 
and safety of Lu AA21004 in Japanese patients with MDD. 
Pharmacogenomic analyses may be conducted to evaluate a possible contribution of genetic 
polymorphism on drug response affecting the efficacy and safety of Lu AA21004. Participation 
of subjects in pharmacogenomic sample collection is optional. 
As pharmacogenomics is an evolving science, many genes and their functions are not yet fully 
understood. Future data may suggest a role of some of these genes in drug response, which may 
lead to additional hypothesis-generating exploratory research with banked samples. 


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5.0 
STUDY OBJECTIVES AND ENDPOINTS 
5.1 
Objectives 
5.1.1 
Primary Objective 
 To evaluate the efficacy of 2 fixed doses of Lu AA21004 (10 or 20 mg/day) after 8 weeks of 
treatment in Japanese patients with MDD. 
5.1.2 
Secondary Objectives 
 To evaluate the safety and tolerability of 2 fixed doses of Lu AA21004 (10 or 20 mg/day) 
after 8 weeks of treatment in Japanese patients with MDD. 
 To evaluate the efficacy of Lu AA21004 (10 or 20 mg/day) on cognitive functions after 8 
weeks of treatment in Japanese patients with MDD. 
5.1.3 
Additional Objectives 
 To analyze the plasma concentrations of Lu AA21004 and its metabolites Lu AA34443 and 
Lu AA39835 using population pharmacokinetic analyses. 
5.2 
Endpoints 
5.2.1 
Efficacy Endpoints 
5.2.1.1 
Primary Endpoint 
 Change from baseline (i.e. at the start of the double-blind treatment period) in the MADRS 
total score after 8 weeks of treatment. 
5.2.1.2 
Secondary Endpoints 
 MADRS response after 8 weeks of treatment (LOCF). 
(MADRS response is defined as a ≥50% decrease in the MADRS total score from baseline). 
 MADRS remission after 8 weeks of treatment (LOCF). 
(MADRS remission is defined as the MADRS total score of ≤10). 
 Change from baseline in the Hamilton Depression Rating Scale (HAM-D17) total score after 
8 weeks of treatment (LOCF). 
 Clinical global impression scale-Improvement (CGI-I) score after 8 weeks of treatment 
(LOCF). 
 Change from baseline in the clinical global impression scale-Severity (CGI-S) score after 8 
weeks of treatment (LOCF). 
 Change from baseline in the Sheehan Disability Scale (SDS) score after 8 weeks of treatment 
(LOCF). 


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 Change from baseline in the Digit Symbol Substitution Test (DSST) score after 8 weeks of 
treatment (LOCF). 
 Change from baseline in the Perceived Deficits Questionnaire (PDQ-5) score after 8 weeks 
of treatment (LOCF). 
5.2.2 
Pharmacokinetic Endpoint 
 Plasma concentrations of Lu AA21004 and its metabolites Lu AA34443 and Lu AA39835. 
5.2.3 
Safety Endpoints 
 Adverse events 
 Weight 
 Vital signs 
 Electrocardiograms (ECGs) 
 Clinical laboratory tests (serum chemistry, hematology and urinalysis) 
 Columbia-Suicide Severity Rating Scale (C-SSRS) 


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6.0 
STUDY DESIGN AND DESCRIPTION 
6.1 
Study Design 
This is a randomized, double-blind, placebo-controlled, parallel-group, phase III study to 
evaluate the efficacy and safety of 8-week treatment of 2 fixed doses of Lu AA21004 (10 or 
20 mg/day) in Japanese subjects with MDD. 
This study consists of a 2-week screening period, a 1-week single-blind placebo lead-in period, 
an 8-week double-blind treatment period and a 4-week safety follow-up period. Subjects who 
fulfill all inclusion criteria and none of exclusion criteria at the start of screening period (Visit 1) 
and at the start of placebo lead-in period (Visit 2) will move into the placebo lead-in period and 
receive placebo once daily for 1 week in a single-blind manner. Afterwards, these who fulfill all 
the inclusion criteria and none of the exclusion criteria at the start of double-blind treatment 
period (Visit 3) will move into the double-blind treatment period and will be randomized in a 
1:1:1 ratio to one of the following treatment groups: the placebo group, the Lu AA21004 
10 mg/day group or the Lu AA21004 20 mg/day group. Subjects in the placebo group and the 
Lu AA21004 10 mg/day group will receive placebo and Lu AA21004 10 mg, respectively, once 
daily from the day after Visit 3 for 8 weeks in a double-blind manner. Subjects in the 
Lu AA21004 20 mg/day group will receive Lu AA21004 10 mg once daily from the day after 
Visit 3 for 1 week and thereafter Lu AA21004 20 mg once daily for 7 weeks in a double-blind 
manner. Subjects in any treatment groups will visit study sites at Week 1, 2, 4, 6 and 8 during the 
double-blind treatment period for examinations/observations/assessments. 
A safety follow-up contact (visit or phone call) will be made 4 weeks after the completion of the 
double-blind treatment period. Subjects who prematurely discontinue the study during the 
placebo lead-in period or the double-blind treatment period will be requested to visit the study 
site for the end-of study assessments within 7 days after the discontinuation decision is made 
wherever possible, and will be contacted 4 weeks after the last dose of the study medication for 
safety follow-up. 
A schematic of the study design is shown in Figure 6.a.  
A schedule of examinations/observations/assessments is listed in Appendix A. 


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Screening 
Period 
Placebo  
Lead-in  
Period 
(Single-blind) 
Double-blind Treatment Period 
Follow-up Period 
 
 
 W -3 W -2 
W -1 
W 1 
W 2 
W 3
W 4
W 5
W 6
W 7
W 8
W 9 
W 10 W 11 W 12
 
V1 
V2 
V3a) 
V4 
V5 
 
V6 
 
V7
 
V8
 
 
 
 
 
 
 
Placebo QD 
Placebo QD 
 
 
 
 
 
 
 
Lu AA21004 10 mg QD 
 
 
 
 
 
 
 
 
Lu AA21004 20 mg QD b) 
 
 
 
 
 
 
 
 
10 mg b) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Randomization 
 
End of Treatment 
 
Safety 
Follow-up c)
W: week, V: visit, QD: once daily 
a) Subjects will be randomized on the day of visit at the start of double-blind treatment period (Day -1). Subjects 
will start the double-blind treatment from the next day (Day 1). 
b) Subjects will receive 10 mg/day for the first 1 week, and then increase the dose to 20 mg/day from the 2nd week.  
c) Safety follow-up assessment will be conducted by visit to the site or on telephone. 
Figure 6.a 
Schematic of Study Design 
 
6.2 
Justification for Study Design, Dose, and Endpoints 
6.2.1 
Subject Population 
It has been reported that the placebo response rate in subjects with single major depressive 
episode is higher than that in subjects with recurrent major depressive episode.[5] Since it is 
important to exclude subjects with high placebo response from clinical studies of antidepressants, 
subjects with recurrent major depressive episode are eligible for this study. In order to 
adequately evaluate the efficacy and safety, subjects with moderate to severe MDD are eligible 
for this study, and subjects with mental disorder other than MDD are excluded from this study. 
6.2.2 
Study Design 
This study is designed based on Guideline for Clinical Evaluation of Antidepressants 
(Notification No. 1116-1 of PFSB/ELD dated 16 November 2010).[3] 
A double-blind, randomized, placebo-controlled study is designed for adequate evaluation of the 
drug efficacy and safety and is used as a standard study design for antidepressants. The use of 
placebo has continued to be a subject of discussion on the grounds of possible worsening of 
depressive symptoms or potential increase in suicidal risk; however, there is no evidence that 
assignment to placebo results in permanent harm or an increased risk of committing suicide. 


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Subjects at significant risk of suicide are ineligible for this study. Furthermore, suicidal risk of a 
subject will be assessed using C-SSRS at every visit. 
The subjects will be informed about the possibility of receiving placebo, the possible risks with 
placebo, and their right to withdraw from the study at any time. To a subject who discontinues 
the study, any other appropriate treatment will be provided based on the investigator’s decision. 
In addition, a 1-week placebo lead-in period is set prior to the double-blind treatment period to 
exclude subjects who highly respond to placebo from the study, and thereby subjects who have 
significantly improvement or aggravation of depressive symptoms during the placebo lead-in 
period will be excluded. 
Justification for sample size is described in Section 13.3. 
6.2.3 
Doses 
In overseas phases II and III studies, the efficacy of Lu AA21004 at doses of 5, 10 and 
20 mg/day was shown, with no significant safety concerns. In addition, based on the results of 
meta-analyses in 11 placebo-controlled, double-blind, short-term studies, the differences of the 
mean changes from baseline in the MADRS total score at Week 6 or 8 between the Lu AA21004 
5, 10 or 20 mg group and the placebo group were -2.3 (p =0.007), -3.6 (p <0.001), and -4.6 (p 
<0.001), respectively, showing that the difference with the placebo group became greater with 
the dose increase of Lu AA21004. 
In Study CCT-002 for subjects with MDD including Japanese, Lu AA21004 was safe up to a 
dose of 20 mg/day. And although no statistically significant differences had been demonstrated 
in the efficacy between the Lu AA21004 groups and the placebo group, the efficacy of 
Lu AA21004 in the 10 and 20 mg groups was grater than in the placebo group in both overall 
population and Japanese population. 
From the results of previous Japanese and overseas studies above, since there were no significant 
safety concerns about Lu AA21004 up to a dose of 20 mg/day and Lu AA21004 at doses of 10 
and 20 mg/day is expected to be effective, these 2 doses will be assessed in this study. 
6.2.4 
Endpoints 
MADRS or HAM-D is recommended for efficacy assessments in Guideline for Clinical 
Evaluation of Antidepressants (Notification No. 1116-1 of PFSB/ELD dated 16 November 
2010).[3] Based on the guideline, the MADRS, which is designed to be sensitive to the changes 
in severity of core symptom of depression, will be used for the primary endpoint evaluation [6], 
and the HAM-D for the secondary endpoint evaluation in this study.[7] CGI-S and CGI-I will be 
used to assess subject’s overall severity and improvement of depression.[8] In addition to these 
objective assessments of symptoms, SDS will be used in this study to assess patient’s subjective 
treatment effects on social function disabilities due to depression.[9] 
Results of overseas studies of Lu AA21004 showed that Lu AA21004 improved cognitive 
functions in subjects with MDD. In this study, DSST and PDQ-5 will be used to explore the 
effect of Lu AA21004 on cognitive functions in Japanese subjects with MDD. 


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Safety and tolerability of Lu AA21004 will be evaluated by monitoring of AEs, vital signs, 
weight, clinical laboratory tests, ECGs, and physical examinations. In addition with these safety 
evaluations, since it is important to assess suicidal risk for clinical evaluation of antidepressants, 
suicidal risk will be assessed using C-SSRS at each visit in this study.[10][11] 
6.3 
Premature Termination or Suspension of Study or Study Site 
6.3.1 
Criteria for Premature Termination or Suspension of the Study 
The study will be completed as planned unless 1 or more of the following criteria are satisfied 
that require temporary suspension or early termination of the study. 
 New information or other evaluation regarding the safety or efficacy of the study medication 
that indicates a change in the known risk/benefit profile for the product, such that the 
risk/benefit is no longer acceptable for subjects participating in the study. 
 Significant violation of Good Clinical Practice (GCP) that compromises the ability to achieve 
the primary study objectives or compromises subject safety. 
6.3.2 
Criteria for Premature Termination or Suspension of Study Sites 
A study site may be terminated prematurely or suspended if the site (including the investigator) 
is found in significant violation of GCP, protocol, or contractual agreement, is unable to ensure 
adequate performance of the study, or as otherwise permitted by the contractual agreement. 
6.3.3 
Procedures for Premature Termination or Suspension of the Study or the 
Participation of Study Sites 
In the event that the sponsor, an institutional review board (IRB), or regulatory authority elects to 
terminate or suspend the study or the participation of a study site, a study-specific procedure for 
early termination or suspension will be provided by the sponsor; the procedure will be followed 
by applicable study sites during the course of termination or study suspension. 


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7.0 
SELECTION AND DISCONTINUATION/WITHDRAWAL OF SUBJECTS 
All entry criteria, including test results, need to be confirmed prior to randomization. 
7.1 
Inclusion Criteria 
Subject eligibility is determined according to the following criteria: 
1. In the opinion of the investigator, the subject is capable of understanding and complying with 
protocol requirements. 
2. The subject signs and dates a written, informed consent form prior to the initiation of any 
study procedures. 
3. The subject suffer from recurrent MDD as the primary diagnosis according to DSM-IV-TR 
criteria (classification code 296.3x). 
4. The subject is a man or a woman aged 20 to 75 years (both inclusive) at the time of informed 
consent. 
5. The reported duration of the current major depressive episode is 3 to 12 months (both 
inclusive) at the start of screening period. 
6. The subject has a MADRS total score ≥26, a HAM-D17 total score ≥18, and a CGI-S score 
≥4 at the start of screening period, the start of placebo lead-in period and the start of double-
blind treatment period. 
7. A female subject of childbearing potential* who is sexually active with a nonsterilized male 
partner agrees to use routinely adequate contraception from signing of informed consent to 
the end of the follow-up period. 
* Definitions of a female subject of childbearing potential are defined in Section 9.1.13 
Contraception and Pregnancy Avoidance Procedure, and reporting responsibilities of 
pregnancy are defined in Section 9.1.14 Pregnancy. 
 
<Justification for Inclusion Criteria> 
Criteria 1 and 2 were set as standard requirements to conduct clinical studies. 
Criterion 3 was set to identify the target disease and diagnostic criteria for this study. In addition, 
in order to reduce the possibility of enrolling subjects who highly respond to placebo, the 
primary diagnosis was set as recurrent MDD. 
Criterion 4 was set for the lower limit of age as 20 years old because it was the adult age under 
the Civil Code. In addition, since the previous pivotal phase II or III studies set 75 years old as 
the upper limit of age, the upper limit of age in this study was set as 75 years old in the light of 
the possible comparison with the previous data.  
Criterion 5 was set to enroll subjects who had persistent major depressive episode for at least 3 
months in consideration of diagnostic certainty. The upper limit of episode duration was set as 12 


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months since, in general, subjects with chronic depressive symptoms are highly likely to have 
other concurrent mental disorder and the low possibility that the depressive symptoms would 
completely disappear with antidepressant drugs.  
Criterion 6 was set to enroll subjects with moderate or more severe MDD in severity as eligible 
for this study.  
Criterion 7 was set with respect to the safety risk related to pregnancy in female subjects.  
 
7.2 
Exclusion Criteria 
Any subject who meets any of the following criteria will not qualify for entry into the study: 
1. The subject has any following current or past history of psychiatric disorder and/or 
neurological disorder: 
– Any current psychiatric disorder other than MDD as defined by DSM-IV-TR (To be 
assessed by Mini International Neuropsychiatric Interview: MINI). A subject who 
exhibits symptoms of anxiety is eligible unless the subject fulfills the diagnostic criteria 
for a current anxiety disorder per DSM-IV-TR. 
– Current diagnosis or history of manic, mixed or hypomanic episode, MDD with psychotic 
features, schizophrenia or any other psychotic disorder (including substance-related 
mental disorders, or mental disorders due to a general medical condition) as defined by 
DSM-IV-TR. 
– Current diagnosis or history of any substance-related disorder (except nicotine and 
caffeine-related disorders) as defined by DSM-IV-TR. 
– The subject with a positive urine drug screening result at the start of screening period or 
the start of placebo lead-in period. In case that a subject showed positive test result at the 
start of screening period because the test was conducted before washout of pretreatment 
drug, the subject is eligible as long as he/she shows negative result at the start of placebo 
lead-in period. 
– Presence or history of any clinically significant neurological disorder (including epilepsy). 
– Any neurodegenerative disorder (e.g. Alzheimer’s disease, Parkinson’s disease, multiple 
sclerosis, Huntington’s disease). 
– Any DSM-IV-TR axis II disorder. 
2. The subject has the current or previous major depressive episode which were considered by 
the investigator to have been resistant to 2 or more adequate antidepressants treatments of at 
least 6 weeks duration each at sufficient doses. 
3. The subject has received any augmentation therapy (e.g. lithium, T3/T4, lamotrigine, sodium 
valproate, carbamazepine, additional atypical antipsychotic, or concomitant use of other 
antidepressant, etc.) for the current major depressive episode. 


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4. In the opinion of the investigator, the subject has experienced significant number of major 
depressive episodes in the past, and is suspected of disease other than MDD. 
5. In the opinion of the investigator, the subject has experienced the first major depressive 
episode at his/her young age, and is suspected of disease other than MDD. 
6. The subject has a MADRS total score at the start of double-blind treatment period that has 
improved or aggravated by 25% or more from the score at the start of placebo lead-in period. 
7. The subject is significantly non-compliant with the study medication in the placebo lead-in 
period; e.g., not taking the study medication for 6 or more consecutive days. 
8. The subject has received electroconvulsive therapy, vagus nerve stimulation, or repetitive 
transcranial magnetic stimulation therapy within 6 months prior to the screening period, or 
plans to initiate such therapy during the study. 
9. The subject is receiving cognitive-behavioral therapy or psychotherapy at the time of 
informed consent, or plans to initiate such therapy during the study. 
10. The subject is at significant risk of suicide or has a score ≥5 on Item 10 (suicidal thoughts) of 
the MADRS at the start of screening period, the start of placebo lead-in period or the start of 
double-blind treatment period, or has attempted suicide within 6 months prior to the start of 
screening period. 
11. The subject has experienced any environmental change (e.g. temporary retirement, 
returnment, change of residence) considered by the investigator to have the potential to 
impact on the efficacy evaluation, or plans such environmental changes during the study. 
12. The subject is currently receiving drug therapy for thyroid dysfunction. 
13. The subject is currently receiving hormonal therapy for gynecological disease. 
14. The subject has taken excluded medications during the protocol-specified period, or will 
require to take excluded medications during the study. 
15. The subject has previously received vortioxetine. 
16. The subject has received study medication in a previous clinical study of Lu AA21004 
(including this study). 
17. The subject has a clinically significant chronic liver disease. 
18. The subject has a history of severe allergy or hypersensitivity to drugs. 
19. The subject has a clinically significant unstable illness, for example, hepatic impairment or 
renal insufficiency, or a cardiovascular, pulmonary, gastrointestinal, endocrine, neurological, 
rheumatologic, immunologic, infectious, neoplastic, skin and subcutaneous tissue disorders, 
eye disorders, or metabolic disturbance. 
20. The subject has clinically significant abnormal vital signs as determined by the investigator 
at the start of screening period, placebo lead-in period, or double-blind treatment period. 


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21. The subject has clinically significant abnormal ECG as determined by the investigator, at the 
start of the screening period, placebo lead-in period, or double-blind treatment period. 
22. The subject has clinically significant abnormal findings of clinical laboratory tests as 
determined by the investigator, or has alanine aminotransferase (ALT) or aspartate 
aminotransferase (AST) >2 × ULN at the start of screening period or placebo lead-in period. 
23. If female, the subject is pregnant or lactating. 
24. The subject has a disease or takes medications that could, in the opinion of the investigator, 
interfere with the evaluation of the safety, tolerability, or efficacy. 
25. The subject is, in the opinion of the investigator, unsuitable for this study for any other 
reason. 
<Justification for Exclusion Criteria> 
Criteria 1, 4, and 5 were set to exclude subjects or the possible subjects with concurrent mental 
or neurological disorder other than MDD and to adequately evaluate the efficacy and safety for 
the target disease. 
Criterion 2 was set to exclude subjects or the possible subjects with refractory major depression 
and include adequate subjects for the evaluation of drug effect. 
Criterion 3 was set to exclude subjects who have received augmentation therapy and include 
adequate subjects for the evaluation of drug effect since subjects who are required to receive 
augmentation therapy may have refractory major depression or concurrent mental or 
neurological disorder other than MDD.  
Criterion 6 was set to exclude subjects who highly respond to placebo and include adequate 
subjects for the evaluation of drug effect. Subjects who abruptly worsen their symptoms in a 
short time are also excluded from the study in consideration of the appropriateness of drug effect 
evaluation and the safety of subjects. 
Criterion 7 was set because it influences the evaluation in the placebo lead-in period.  
Criteria 8, 9, 11 to 13 were set because they could influence the evaluation of efficacy. 
Criteria 10, 17 to 22 were set with respect to the safety of subjects. 
Criteria 14 and 24 were set because they could influence the evaluation of efficacy and safety. 
Criterion 15 was set because the bias toward Lu AA21004 based on their treatment experience 
could influence the evaluation of the efficacy and safety. 
Criterion 16 was set to avoid duplicated evaluation of subjects. 
Criterion 23 was set with respect to the safety risk for pregnant women, fetuses, neonates, or 
nursing infant. 
Criterion 25 was set to exclude subjects who are considered to be unsuitable for this study for 
any other reason.  
 


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7.3 
Excluded Medications and Treatments 
Subjects must be instructed not to take any medications including over-the-counter products, 
without first consulting with the investigator. 
Any treatments for depression other than the study medication, including electroconvulsive 
therapy, vagus nerve stimulation, repetitive transcranial magnetic stimulation, cognitive-
behavioral therapy or psychotherapy are prohibited during the study. 
A list of prohibited/restricted concomitant medication is provided in Table 7.a. 
Table 7.a 
List of Prohibited or Restricted Concomitant Medications 
Drug Class 
Comments or Exceptions 
84 days before the start of double-blind treatment period (Day -84) through the end of double-blind treatment period 
(Visit 8) or early termination 
(1) Any investigational drug 
 
Start of the screening period (Visit 1) through the end of double-blind treatment period (Visit 8) or early termination
(2) Antidepressants 
Including MAOIs. 
(3) Anxiolytics (tranquilizers) 
Including benzodiazepines. 
(4) Hypnotics 
Non-benzodiazepines (zolpidem, zopiclone, and eszopiclone) are allowed. 
However, use of these drugs should be kept to the minimum necessary, and 
use for 2 consecutive days and use at the night before a study visit are NOT 
allowed. In addition, the type and dose of non-benzodiazepines should NOT 
be changed from the start of placebo lead-in period (Visit 2) to the end of 
double-blind treatment period (Visit 8) or early termination. 
(5) Antipsychotics 
Depot antipsychotics are prohibited within 6 months prior to the start of 
double-blind treatment period. 
(6) Mood stabilizers 
Including lithium, valproate, valpromide. 
(7) Psychoactive herbal 
remedies/supplements 
Including St. Johns Wort, kava kava, valerian, ginkgo biloba. 
(8) Psychotropic agents not 
otherwise specified 
Including tryptophan, melatonin, and dopamine agonists. 
(9) Analeptics 
 
(10) Anti-ADHD 
 
(11) Anti-Alzheimer's disease 
 
(12) Anticonvulsants 
 
(13) Anti-Parkinson’s disease 
 
(14) Erectile dysfunction drugs 
 
(15) Anorexics 
 
(16) Antimigraines 
 
(17) Antiemetics/antinauseants 
Including dopamine antagonists. Only phosphoric acid preparations, bismuth 
and cola syrup are allowed. 
(18) Interferon 
 
(19) Systemic steroids 
Oral preparation and injection are NOT allowed. 


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(20) Antibiotics 
Rifampicin (oral preparation and injection) is NOT allowed. 
Start of the placebo lead-in period (Visit 2) through the end of double-blind treatment period (Visit 8) or early 
termination 
(21) Antiarrhythmics of class Ia, Ic 
 
(22) Antiulcer drugs 
Omeprazole, cimetidine, and sulpiride are NOT allowed. 
(23) Anticoagulants/antiplatelet 
treatment 
Including low dose of aspirin as antiplatelet treatment. Low-molecular 
weight heparins are allowed as needed. 
(24) Antidiarrheal agents 
Loperamide, bismuth, and kaolin preparations are allowed. 
(25) Antihistamines 
Loratadine, desloratadine, cetirizine, levocetirizine, mizolastine, and 
fexofenadine are allowed. 
(26) Antineoplastics 
 
(27) Hormones 
Chronic use for contraception or treatment of benign prostatic hyperplasia 
are allowed. 
(28) Hypoglycemic agents 
Chronic use is allowed. 
(29) Insulin 
Chronic use is allowed without major change of dose or administration. 
(30) Calcium antagonist 
Chronic use is allowed without major change of dose or administration. 
(31) Narcotic analgesics 
Topical administration including for dental use is allowed.  
(32) NSAIDs 
Episodic use is allowed. Selective COX-2 inhibitors, acetaminophen, and 
topical NSAIDs are allowed. 
(33) Cough/cold agents 
Episodic use is allowed. However, chronic use of preparations containing 
ephedrine, pseudoephedrine, and codeine are NOT allowed for more than 1-
week treatment. 
MAOI = monoamine oxidase inhibitor, ADHD = attention deficit hyperactivity disorder, 
NSAIDs = nonsteroidal anti-inflammatory drugs, COX-2 = cyclooxygenase-2 
 
<Justification for Prohibited or Restricted Concomitant Medications> 
(1) was set since other investigational drug could influence the evaluation of the efficacy and 
safety. 
(2) was set since antidepressants could influence the evaluation of the efficacy. Especially, 
concomitant use of monoamine oxidase inhibitors (MAOIs) was prohibited because concomitant 
use of MAOIs could enhance serotonin action and influence the evaluation of the efficacy, and 
because the safety of subjects should be ensured. 
(3) was set since anxiolytics (tranquilizers) could improve anxiety which was known to an 
accompanying symptom of depression and influence the evaluation of the efficacy. 
(4) was set since hypnotics could improve insomnia which was known to an accompanying 
symptom of depression and influence the evaluation of the efficacy. Concomitant use of non-
benzodiazepines was allowed as needed because the extent of anxiolytic and carry-over effects 
of non-benzodiazepines was relatively weak, and thus these effects had only a small influence on 
efficacy evaluation. 
(5) to (13) were set since these drugs had psychotropic activity or central nervous effects and 


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could influence the evaluation of the efficacy. 
(14) was set since erectile dysfunction drugs could improve sexual dysfunction and could 
influence the evaluation of the efficacy and safety. 
(15) was set since anorexics influence the appetite assessment related to depression. 
(16) and (17) were set since antimigraines and antiemetics/antinauseants could act on serotonin 
receptors and influence the evaluation of the efficacy and safety. Especially, concomitant use of 
antiemetics/antinauseants was prohibited because adverse events associated with the study 
medication should be appropriately evaluated. 
(18) and (19) were set since interferon and systemic steroids could induce depressive symptoms 
and influence the evaluation of the efficacy. 
(20) was set since antibiotics could decrease the plasma drug concentration by inducing drug 
metabolic enzymes and influence the evaluation of the efficacy and safety. 
(21) and (22) were set since antiarrhythmics of class Ia, Ic, and antiulcer drugs could increase the 
plasma drug concentration by inhibiting drug metabolic enzymes and influence the evaluation of 
the efficacy and safety 
(23) was set since concomitant use of anticoagulants/antiplatelet treatment drugs could enhance 
bleeding tendency.  
(24) was set since gastrointestinal adverse events associated with the study medication should be 
appropriately evaluated. 
(25) was set since drowsiness, an adverse drug reaction of antihistamines, could attenuate 
insomnia, which was known to an accompanying symptom of depression and influence the 
evaluation of the efficacy. Concomitant use of only loratadine, desloratadine, cetirizine, 
levocetirizine, mizolastine, and fexofenadine, which are considered to cause less drowsiness, was 
allowed. 
(26) was set since antineoplastics could influence the evaluation of the efficacy and safety. 
(27) and (28) were set since hormones and hypoglycemic agents could influence the evaluation 
of the efficacy and safety. However, chronic use of these drugs at a certain dose was allowed as 
having little influence on the evaluation. 
(29) and (30) were set since insulin and calcium antagonists could induce depressive symptoms. 
However, chronic use of insulin or calcium antagonist at a certain dose was allowed as having 
little influence on the efficacy evaluation. 
(31) was set since analgesic action of narcotic analgesics could influence the evaluation of the 
efficacy. However, topical administration such as for dental use is allowed since narcotic 
analgesics have only a small influence on the evaluation. 
(32) was set since the concomitant use of NSAIDs could cause upper gastrointestinal bleeding. 
However, the episodic use of NSAIDs as well as the concomitant use of selective COX-2 
inhibitors, acetaminophen, and topical NSAIDs was allowed since these treatments had a 


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relatively lower effect on gastrointestinal adverse events. 
(33) was set since some cough/cold agents increase the serotonin concentration of the central 
nervous system. Concomitant use of ephedrine and codeine for more than 1 week was not 
allowed due to their addictiveness. 
 
7.4 
Diet, Fluid, and Activity Control 
The investigator or study collaborator should instruct subjects on the following items: 
1. The subject must be punctual for visit, undergo physical examination and predefined 
examinations. If the subject cannot visit, he/she should inform the investigator or study 
collaborator as soon as possible. 
2. If the subject experiences a worsening of conditions on any day the site visit is not scheduled, 
he/she should inform the investigator or study collaborator of the worsening by telephone or 
other manners as soon as possible and seek instructions. 
3. The subject must take the study medication as instructed by the investigator. If the subject is 
noncompliant with study treatment, he/she should inform the investigator or study 
collaborator of the noncompliance with treatment at visit. The subject must return unused 
study medication and study medication sheets at visit. 
4. The subject must not take any medications including over-the-counter products other than 
medications as instructed by the investigator without advance consulting (except for 
emergency). 
5. If the subject consults other medical institution from the time of informed consent to the end 
of the follow-up period, notify the physician of medical institution of the subject’s 
participation in this study. 
6. If the subject consults other medical institution from the time of informed consent to the end 
of the follow-up period, notify the investigator of the circumstances and therapy. 
7. The subject must visit the site under fasted conditions at Visits 3 and 8 or Early Termination 
Visit. For visits serum chemistry test is scheduled, the subject visits the site under fasted 
conditions wherever possible. 
8. Female subject of childbearing potential who is sexually active with a nonsterilized male 
partner must routinely use adequate contraception from the time of informed consent to the 
end of the follow-up period. 
7.5 
Criteria for Discontinuation or Withdrawal of a Subject 
The primary reason for discontinuation or withdrawal of the subject from the study or study 
medication should be recorded in the case report form (eCRF) using the following categories. 
For the subject who prematurely discontinues the study before entry into the placebo lead-in 
period or randomization, refer to Section 9.1.18 or 9.1.20, respectively. 


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1. Pretreatment event (PTE) or adverse event (AE) 
The subject has experienced a pretreatment event (PTE) or AE that requires early termination 
because continued participation imposes an unacceptable risk to the subject’s health or the 
subject is unwilling to continue because of the PTE or AE. 
2. Liver function test (LFT) abnormalities 
Study medication should be discontinued immediately with appropriate clinical follow-up 
(including repeat laboratory tests, until a subject’s laboratory profile has returned to 
normal/baseline status, see Section 9.1.12), if the following circumstances occur at any time 
during study medication treatment: 
– alanine aminotransferase (ALT) or aspartate aminotransferase (AST) >8 × upper limit of 
normal (ULN), or 
– ALT or AST >5 × ULN and persists for more than 2 weeks, or 
– ALT or AST >3 × ULN in conjunction with elevated total bilirubin >2 × ULN or 
international normalized ratio (INR) >1.5, or 
– ALT or AST >3 × ULN with appearance of fatigue, nausea, vomiting, right upper 
quadrant pain or tenderness, fever, rash and/or eosinophilia (>5%). 
3. Significant protocol deviation 
The discovery post-randomization that the subject failed to meet protocol entry criteria or did 
not adhere to protocol requirements, and continued participation poses an unacceptable risk 
to the subject’s health. 
4. Lost to follow-up 
The subject did not return to the clinic and attempts to contact the subject were unsuccessful. 
Attempts to contact the subject must be documented. 
5. Voluntary withdrawal 
The subject wishes to withdraw from the study. The reason for withdrawal, if provided, 
should be recorded in the eCRF. 
Note: All attempts should be made to determine the underlying reason for the withdrawal and, 
where possible, the primary underlying reason should be recorded. (i.e., withdrawal 
due to an AE or lack of efficacy should not be recorded in the “voluntary withdrawal” 
category.) 
6. Study termination 
The sponsor, IRB, or regulatory agency terminates the study. 
7. Pregnancy 
The subject is found to be pregnant. 
Note: If the subject is found to be pregnant, the subject must be withdrawn immediately. The 
procedure is described in Section 9.1.14. 


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8. Lack of efficacy 
The investigator has determined that the subject is not benefiting from study treatment; and, 
continued participation would pose an unacceptable risk to the subject. 
9. Medication noncompliance 
The subject did not take the study medication for 6 or more consecutive days. 
10. Other 
Note: The specific reasons should be recorded in the “specify” field of the eCRF. 
7.5.1 
Additional Guidance for Withdrawal Criteria 
Any signs of suicidal risk will be assessed throughout the study by C-SSRS and MADRS 
assessments and clinical judgment of the investigator. If the subject has a significant risk of 
suicide in the opinion of the investigator, or the subject has the MADRS score of ≥5 on item 10 
(suicidal thoughts), the subject will prematurely discontinue the study. 
If subject’s underlying diseases become exacerbated, and the investigator concludes any 
excluded medications or treatment is required, the subject will prematurely discontinue the study. 
7.6 
Procedures for Discontinuation or Withdrawal of a Subject 
The investigator may discontinue a subject’s study participation at any time during the study 
when the subject meets the study termination criteria described in Section 7.5. In addition, a 
subject may discontinue his or her participation without giving a reason at any time during the 
study. Should a subject’s participation be discontinued, the primary criterion for termination 
must be recorded by the investigator. In addition, efforts should be made to perform all 
procedures scheduled for the Early Termination Visit. 


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8.0 
CLINICAL TRIAL MATERIAL MANAGEMENT 
This section contains information regarding all medication provided directly by the sponsor, 
and/or sourced by other means, that are required by the study protocol, including important 
sections describing the management of clinical trial material. 
8.1 
Study Medication 
8.1.1 
Dosage Form, Manufacturing, Packaging, and Labeling 
In this protocol, the term study medication refers to all or any of the drugs defined below. 
Table 8.a 
Study Medication 
Name 
Active Substance 
Dosage Form 
Strength 
Manufacture 
Lu AA21004 tablet 
1-[2-(2,4-dimethyl-phenyl 
sulfanyl)-phenyl]-piperazine, 
hydrobromide 
Indistinguishable round 
biconvex tablets 
10 mg 
or 
20 mg 
Takeda 
Pharmaceutical 
Company Limited 
Placebo tablet 
None 
– 
 
The study medications are identical in appearance. 
As for the study medications for the placebo lead-in period, 14 tablets of placebo are packaged in 
1 press-through pack (PTP) sheet, and a single sheet is enclosed in an outer carton. The 1 outer 
carton (including 7 days’ spare tablets) will be provided to each subject in the placebo lead-in 
period. 
As for the study medications for the double-blind treatment period, 14 tablets of Lu AA21004 or 
placebo are packaged in 1 PTP sheet. For Week 1 in the double-blind treatment period, 1 sheet 
(including 7 days’ spare tablets) is enclosed in an Inner Carton 1, and, for Weeks 2 to 8 in the 
double-blind treatment period, 5 sheets (including 21 days’ spare tablets) are enclosed in an 
Inner Carton 2. Inner Cartons 1 and 2 are packed together in an outer carton. The 1 outer carton 
will be provided to each subject in the double-blind treatment period. 
The outer carton is labeled with a note that the formulation therein is used for a clinical study and 
pertinent information of the name and quantity of the study medication, the sponsor’s name and 
address, manufacturing number, and storage conditions. 
8.1.2 
Storage 
The study medications should be stored at room temperature (1°C to 30°C). 
The study medication must be kept in an appropriate, limited-access, secure place until it is used 
or returned to the sponsor or designee for destruction. The study medication must be stored under 
the conditions specified on the label, and remain in the original container until dispensed. A daily 
temperature log of the drug storage area must be maintained every working day. 


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8.1.3 
Dose and Regimen 
For the placebo lead-in period, administration of the study medication will be started on the day 
after Visit 2, and subjects will orally take 1 tablet of placebo once daily. 
For the double-blind treatment period, administration of the study medication will be started on 
the day after Visit 3, and subjects will orally take 1 tablet of Lu AA21004 at a dose of 10 mg or 
20 mg or placebo once daily. 
The investigator or designee should instruct subjects to take the study medication at the same 
time, a certain time in the morning to the extent possible, throughout the study. The study 
medication can be taken under both fed and fasted conditions. 
At each visit, subjects will be provided with necessary and sufficient amount of the study 
medications to be used by next visit by the investigator or designee. The investigator or designee 
must instruct subjects to bring the all remaining study medication and container (PTP sheets) at 
each visit. 
The dose (tablet count) that will be provided to each group and regimen are shown in Table 8.b. 
Table 8.b 
Dose and Regimen 
Treatment Group 
Regimen 
Tablet Count/Dose 
Placebo 
Lead-in Period 
Double-blind Treatment 
Period 
(Week 1) 
Double-blind Treatment 
Period 
(Weeks 2 to 8) 
Placebo Group 
Oral, 
once daily 
Placebo tablet ×1 
Placebo tablet ×1 
Placebo tablet ×1 
Lu AA21004 
10 mg/day Group 
Oral, 
once daily 
Placebo tablet ×1 
Lu AA21004 
10 mg tablet ×1 
Lu AA21004 
10 mg tablet × 1 
Lu AA21004 
20 mg/day Group 
Oral, 
once daily 
Placebo tablet ×1 
Lu AA21004 
10 mg tablet ×1 
Lu AA21004 
20 mg tablet ×1 
 
8.1.4 
Overdose 
An overdose is defined as a known deliberate or accidental administration of the study 
medication to or by a study subject, at a dose above that which is assigned to that individual 
subject according to the study protocol. This includes any concomitant medication received at a 
dose greater than that prescribed to the subject. 
All cases of overdose will be documented as AEs on an AE page of the eCRF according to 
Section 10.2.1, and should be reported as a special interest AE according to Section 10.2.1.3 
(with or without associated AEs). Serious adverse events (SAEs) associated with an overdose 
should be reported according to the procedure in Section 10.2.2. 
In the event of an overdose of the study medication, the investigator should take general 
symptomatic and supportive treatment, along with immediate gastric lavage where appropriate. 
Intravenous fluids should be administered as needed. As in all cases of drug overdose, respiration, 


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pulse, blood pressure, and other appropriate signs should be monitored and general supportive 
treatment should be conducted. 
8.2 
Study Drug Assignment and Dispensing Procedures 
Subjects will be assigned to receive the next available medication ID number allocated to each 
study site. The Medication ID Number will be entered onto the eCRF. 
8.3 
Randomization Code Creation and Storage 
Randomization personnel (a person designated by the sponsor) will generate the randomization 
code. All randomization information will be stored in a secured area, accessible only by 
authorized personnel. 
8.4 
Study Drug Blind Maintenance 
The emergency key code administration center will maintain the emergency key code until its 
breaking for an emergency or completion of database lock of all subjects. 
Since analytical results of the plasma concentration may jeopardize maintenance of study 
blinding, the analytical laboratory will keep the final analytical results and not disclose to a third 
party until unblinding of the study. The analytical laboratory will report the results to the sponsor 
after they receive the notification of unblinding of the study. However, the analytical laboratory 
may disclose the results to the sponsor through a responsible person for randomization before 
unblinding of the study taking measures to secure the blinding such as reassignment of the 
medication number so that persons in the laboratory may not identify a subject. The detailed 
procedure will be specified in the separately created manual for handling of biological specimen 
for pharmacokinetic analysis. 
8.5 
Unblinding Procedure 
The study drug blind shall not be broken by the investigator unless information concerning the 
study drug is necessary for the medical treatment of the subject. 
For unblinding, the investigator may contact the emergency key code administration center and 
obtain allocation information of the study medication. 
The date, time, and reason the blind is broken must be recorded in the document called Record of 
Early Blind-Breaking, and the same information (except the time) must be recorded on the eCRF. 
If any site personnel are unblinded, study drug must be stopped immediately and the subject 
must be withdrawn from the study. 
For details of unblinding procedure, refer to the manual for Breaking of Emergency Key Code. 
8.6 
Accountability and Destruction of Sponsor-Supplied Drugs 
The site designee will receive the procedures for handling, storage, and management of study 
drug created by the sponsor, according to which the site designee will appropriately manage the 


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sponsor-supplied drug. The investigator will also receive those procedures from the sponsor. The 
procedures include those for ensuring appropriate receipt, handling, storage, management, 
dispensation of the sponsor-supplied drug, and collection of unused medications from the subject 
as well as return of them to the sponsor or destruction of them. 
The site designee will immediately return unused medications to the sponsor after the study is 
closed at the site. 


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9.0 
STUDY PLAN 
9.1 
Study Procedures 
The following sections describe the study procedures and data to be collected. For each 
procedure, subjects are to be assessed by the same investigator whenever possible. The Schedule 
of Study Procedures is located in Appendix A. 
9.1.1 
Informed Consent Procedure 
The requirements of the informed consent are described in Section 15.2. 
Informed consent must be obtained prior to the subject entering into the study, and before any 
protocol-directed procedures are performed. 
A unique subject identification number (subject number) will be assigned to each subject at the 
time that informed consent is explained; this subject number will be used throughout the study. 
9.1.1.1 
Pharmacogenomic Informed Consent Procedure 
A separate informed consent form pertaining to pharmacogenomic research must be obtained 
prior to collecting a sample for Pharmacogenomic Research for this study (see Section 9.1.16). 
The provision of consent to research in pharmacogenomics is independent of consent to the other 
aspects of the study. 
9.1.2 
Demographics, Medical History, and Medication History Procedure 
Demographic information to be obtained will include date of birth, sex, alcohol use, and smoking 
status of the subject at Screening. 
Medical history to be obtained will include determining whether the subject has any mental 
disorders other than MDD (including dysthymic disorder, generalized anxiety disorder, 
obsessive-compulsive disorder, as defined by DSM-IV-TR) that resolved within 1 year prior to 
signing of informed consent. Medical history of MDD (past major depressive episode) to be 
obtained will include determining whether the subject had MDD according to Section 9.1.4.2. 
Medication history information to be obtained includes any medication that stopped prior to 
signing of informed consent and used for treatment of the current major depressive episode or 
accompanying symptoms. Name of medication used, dose level, unit, dose frequency, route of 
administration, and the dates of the initial dose and the last dose must be recorded. 
9.1.3 
Diagnosis of MDD 
Diagnosis of MDD and other psychiatric disorders must be based on DSM-IV-TR criteria. In 
addition, the Mini International Neuropsychiatric Interview (MINI) must be used as an auxiliary 
diagnostic tool. MINI is a structured diagnostic interview designed to provide a brief 
standardized evaluation of major Axis I psychiatric disorders in DSM-IV-TR. The investigator 
can use the MINI after a training session for diagnosis of MDD. Only the version provided by 
the sponsor that has been validated in Japanese will be used in this study. 


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9.1.4 
Assessments of Major Depressive Episode 
9.1.4.1 
Current Major Depressive Episode 
The following items will be assessed for the current major depressive episode. 
– Start date 
– Symptom (Select from 9 symptoms listed below as defined by DSM-IV-TR.) 
– Psychotherapy (yes or no) 
<Symptoms of Major Depressive Episode> 
(1) Depressed mood most of the day, nearly every day, as indicated by either subjective 
report (e.g., feels sad or empty) or observation made by others (e.g., appears tearful). 
(2) Markedly diminished interest or pleasure in all, or almost all, activities most of the 
day, nearly every day (as indicated by either subjective account or observation made 
by others). 
(3) Significant weight loss when not dieting or weight gain (e.g., a change of more than 
5% of weight in a month), or decrease or increase in appetite nearly every day. 
(4) Insomnia or hypersomnia nearly every day. 
(5) Psychomotor agitation or retardation nearly every day (observable by others, not 
merely subjective feelings of restlessness or being slowed down). 
(6) Fatigue or loss of energy nearly every day. 
(7) Feelings of worthlessness or excessive or inappropriate guilt (which may be 
delusional) nearly every day (not merely self-reproach or guilt about being sick). 
(8) Diminished ability to think or concentrate, or indecisiveness, nearly every day (either 
by subjective account or as observed by others). 
(9) Recurrent thoughts of death (not just fear of dying), recurrent suicidal ideation 
without a specific plan, or a suicide attempt or a specific plan for committing suicide.
 
9.1.4.2 
Past Major Depressive Episode 
The following items will be assessed for past major depressive episode. 
– Start date and duration of each past major depressive episode. 
– Antidepressant drug treatment for each past major depressive episode (yes or no). 
If the subject has received an antidepressant drug, category of the drug (select from 
SSRIs, SNRIs, or other antidepressant drugs.) and duration will be recorded. 


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9.1.5 
Physical Examination Procedure 
A 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; and (11) other. 
All subsequent physical examinations after administration of the study medication in the double-
blind treatment period should assess clinically significant changes from the examinations at the 
start of double-blind treatment period (Visit 3). 
9.1.6 
Weight, Height, and BMI 
A subject should have weight and height measured while wearing indoor clothing and with shoes 
off. Height will be collected in centimeters without decimal places, and weight will be collected 
in kilograms (kg) to 1 decimal place. The BMI will be calculated by the sponsor to 1 decimal 
place with the formula provided below: 
Metric: BMI = weight (kg)/height (m)2 
9.1.7 
Vital Sign Procedure 
Vital signs will include body temperature (infra-axillary measurement), sitting blood pressure 
(resting more than 5 minutes), and pulse (bpm). 
9.1.8 
Efficacy Evaluation 
The efficacy will be evaluated using rating scales (MADRS, HAM-D, CGI-S/I, SDS, DSST, and 
PDQ-5). These assessments should be performed by the investigator who has sufficient 
experience in clinical practice of diagnosing and treating MDD and who was approved by the 
sponsor as a rater in this study. The same rater should, whenever possible, assess the same 
subject throughout the study. 
In principle, the MADRS should be performed first at visits that the above-mentioned multiple 
rating scales will be performed. Efficacy data using these rating scales should be recorded in 
eCRF by the next visit of the subject at the latest. 
In addition, self-report of depressive symptoms by subjects will be performed using Quick 
Inventory of Depressive Symptomatology (QIDS-J). For QIDS-J, any sequencing order with 
other rating scales is allowed. QIDS-J data will not be recorded in the eCRF. 
9.1.8.1 
Rating and Rating Training for MDD 
Montgomery-Åsberg Depression Rating Scale (MADRS) 
The MADRS will be used for a primary efficacy measurement. The MADRS is a depression 
rating scale consisting of 10 items representing the core symptoms of depression.[6] The 
MADRS is rated using Structured Interview Guide for MADRS (SIGMA). The rating should be 
based on a clinical interview with the subject, moving from broadly phrased questions about 


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symptoms to more detailed questions. The rating is performed based on the most severe 
condition of the subject during the past 1 week, and each item is rated from 0 to 6. Items 2 to 10 
are based on subject report, and Item 1 is based on the observation of the subjects. The rater must 
decide whether the rating for each item lies on the defined scale steps (0, 2, 4, 6) or between 
them (1, 3, 5). Each item score and the total score of all items should be recorded on the eCRF. 
Before the first rating, the investigators (hereinafter referred to as [potential] raters in this 
section) will attend a MADRS training session. Potential raters will watch and score a recorded 
MADRS interview (video/DVD). A discussion will follow the training session to achieve 
alignment among raters on the scoring of each individual item. 
The sponsor will qualify the raters who achieve the scoring in the training session, and issue a 
certificate. No subject may be rated before the rater receives the certificate. For potential raters 
who cannot attend the training session or who are not qualified in the training session, similar 
MADRS training will be held in each study sites. 
If a rater is changed or added during the course of the study, the newly appointed rater must 
complete all training requirements satisfactorily and must be approved by the sponsor. 
Hamilton Depression Rating Scale (HAM-D) 
The HAM-D is a depression rating scale that assesses overall symptoms of depression including 
somatic symptoms. The rater must rate each item score between 0 to 2/3/4 based on a clinical 
interview with the subject.[7] The rating should be based on patient’s condition during the past 1 
week prior to the time of assessment. The HAM-D21 is used for rating, and total score of the 
first 17 items is used as HAM-D17 total score. Each item score and the HAM-D17 total score 
should be recorded on the eCRF. Prior to the first rating, potential raters will attend a session on 
concerns to be addressed for the rating of HAM-D. 
Clinical Global Impression Scale (CGI) 
The CGI consists of 2 sub-scales: CGI-S and CGI-I.[8] The CGI-S assesses the physician’s 
impression of the subject’s current mental disorder state. The rater should use his/her total 
clinical experience with this subject population and rate the current severity of the subject’s 
mental disorder on a 7-point scale. The CGI-I assesses the subject’s improvement (or worsening). 
The rater is required to assess the subject’s condition relative to baseline* on a 7-point scale. In 
all cases, the assessment should be made independent of whether the rater believes the 
improvement is study medication-related or not. Each score of CGI-S and CGI-I should be 
recorded on the eCRF. Prior to the first rating, potential raters will attend a rating session on 
concerns to be addressed for the rating of CGI. 
* The start day of the double-blind treatment period (Visit 3) is defined as baseline. However, for 
the assessment at the start of double-blind treatment period (Visit 3) or early termination visit 
prior to the start of double-blind treatment period, CGI should be assessed comparing with the 
score at the start of placebo lead-in period (Visit 2). 


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9.1.8.2 
Social Function Assessment 
Sheehan Disability Scale (SDS) 
The SDS is a scale that assesses disabilities in 3 social function domains subjectively.[9] The 
subject self-rates the extent to which his or her work/school, social life/leisure activities, and 
home life/family responsibilities are impaired by his or her symptoms on a 10-point visual 
analog scale. The SDS also addresses the number of days the above functions were lost or under-
productive due to the symptoms. Each item score should be recorded on the eCRF. Prior to the 
first rating, potential raters will attend a rating session on concerns to be addressed for the rating 
of SDS. 
9.1.8.3 
Cognitive Function Assessments 
Digit Symbol Substitution Test (DSST) 
The DSST is a test battery used for assessment of cognitive functions. In the DSST, subjects are 
shown 9 digit-symbol pairs and required to pair the same digit and symbol combination. Levels 
of cognitive functions are assessed by the number of correct symbols (0 to 133 scores) within the 
time limit. DSST scores should be recorded on the eCRF. At a start of the placebo lead-in period 
(Visit 2), subjects will complete the sample items prior to the actual test, but the results of the 
sample items should not be recorded on the eCRF. Prior to the first rating, potential raters will 
attend a rating session on concerns to be addressed for the assessment of DSST. 
Perceived Deficits Questionnaire (PDQ-5) 
The PDQ-5 is a self-report questionnaire by subjects used for assessment of their cognitive 
functions. PDQ-5 consists of 5 questions and provides an assessment of several domains of 
cognitive functions: attention, retrospective memory, prospective memory, and planning and 
organization. Sub-scores of each item score (0 to 4 scores) and the total score of all items should 
be recorded on the eCRF. Prior to the first rating, potential raters will attend a rating session on 
concerns to be addressed for the assessment of PDQ-5. 
9.1.8.4 
Self-report Assessment of Depressive Symptoms and Assessment Monitoring 
Quick Inventory of Depressive Symptomatology (QIDS-J) 
The QIDS-J is a basic self-report depression scale, and the partially revised version provided by 
the sponsor will be used for this study. Subjects will enter the responses to each questions of the 
QIDS-J into the terminal. The rater should not see the responses and not record them on the 
eCRF. The responses will be reviewed by the expert who has adequate experience in assessment 
of depression. Appropriateness of the efficacy evaluation will be monitored by comparing with 
results of other efficacy evaluation of the relevant subject. 


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9.1.9 
Suicidal Risk Assessments 
Columbia-Suicide Severity Rating Scale (C-SSRS) 
The C-SSRS was developed by researchers at Columbia University as a tool to help 
systematically assess suicidal ideation and behavior in subjects during participation in a clinical 
study. The C-SSRS is composed of 3 questions addressing suicidal behavior and 5 questions 
addressing suicidal ideation, with subquestions assessing the severity. The tool is administered 
via interview with the subject.[10][11] Responses to each question will be recorded on the eCRF. 
Prior to the first rating, potential raters will attend a rating session on concerns to be addressed 
for the assessment of C-SSRS. 
9.1.10 
Documentation of Concomitant Medications 
Concomitant medication is any drug given in addition to the study medication. These may be 
prescribed by a physician or obtained by the subject over the counter. Concomitant medication is 
not provided by the sponsor. At each study visit, subjects will be asked whether they have taken 
any medication other than the study medication (used from signing of informed consent through 
Visit 8 or Early Termination Visit ), and all medication including vitamin supplements, over-the-
counter medications, and oral herbal preparations must be recorded in the eCRF. 
9.1.11 
Documentation of Concurrent Medical Conditions 
Concurrent medical conditions are those significant ongoing conditions or diseases that are 
present at signing of informed consent, except for accompanying symptoms of MDD. This 
includes clinically significant laboratory, vital sign, ECG, or physical examination abnormalities 
noted at the first examination after signing of informed consent in the opinion of the investigator. 
The condition (i.e., diagnosis) should be described. 
9.1.12 
 Procedures for Clinical Laboratory Samples 
The items of clinical laboratory tests are shown in Table 9.a. Samples will be collected and 
handled in accordance with the separate operation manual. For clinical laboratory tests, the 
maximum volume of blood at any single visit is approximately 10 mL. 


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Table 9.a 
Clinical Laboratory Tests 
Hematology 
Serum Chemistry 
Red blood cells (RBC) 
White blood cells (WBC) 
Hemoglobin 
Hematocrit 
Platelets 
Neutrophils 
Eosinophils 
Basophils 
Lymphocytes 
Monocytes 
Albumin 
AST 
ALT 
γ-GTP 
Alkaline phosphatase 
Total bilirubin 
Direct bilirubin 
(Conjugated bilirubin) 
Creatinine 
Creatine kinase 
Blood urea nitrogen (BUN) 
Uric acid 
Glucose (fasting or non-fasting) a) 
Total protein 
Potassium 
Sodium 
Calcium 
Chloride 
Lipids (fasting or non-fasting) a) 
Triglycerides 
Total Cholesterol 
High-density lipoprotein cholesterol 
Low-density lipoprotein cholesterol 
(direct measurement) 
Hormonal Test 
Urinalysis 
 
Thyroid stimulating hormone (TSH) 
Free T4 b) 
Protein (qualitative) 
Glucose (qualitative) 
Occult blood (qualitative) 
Urine pH 
Microscopic examination c) 
(white blood cells, red blood cells, and 
casts) 
Pregnancy test (female subjects of childbearing potential only) 
Urine human chorionic gonadotropin (hCG) 
Urine Drug Screening d) 
Amphetamines (including methamphetamine), barbiturates, benzodiazepines, cannabinoids, cocaines, morphines, 
phencyclidines, and tricyclic antidepressants 
a) Blood will be collected under fasted conditions at Visits 3 and 8 or Early Termination Visit. For other visits, 
blood will be collected under fasted conditions wherever possible. 
b) When TSH value is outside the normal range, free T4 will be measured. If a clinically significant abnormality of 
thyroid gland is found based on the results of TSH and free T4, the subject will be excluded from the study.  
c) Microscopic examination will be performed if abnormality is found in any item in urinalysis. 
d) If the subject has a positive urine drug result, he/she will be excluded from the study. However, when the subject 
has a positive urine test result at Visit 1 because the urine test was performed prior to washout of pretreatment 
drug, the subject is eligible for the study if he/she has a negative drug test result at Visit 2. 
The central laboratory will perform laboratory tests for hematology, serum chemistry, urinalysis, 
and hormonal test. The local laboratory will perform the pregnancy test and urine drug screening. 
The results of laboratory tests will be returned to the investigator, who is responsible for 
reviewing and filing these results. 
If subjects experience ALT or AST >3 × ULN, follow-up laboratory tests (at a minimum, serum 
alkaline phosphatase, ALT, AST, total bilirubin, γ-GTP, and INR) should be performed within a 
maximum of 7 days and preferably within 48-72 hours after the abnormality was noted. If the 
ALT or AST remains elevated >3 × ULN on these 2 consecutive occasions, the abnormality 
should be recorded as a special interest AE (hepatic impairment) by the investigator, and follow 


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the procedure specified in Sections 10.1.5.2 and 10.2.1.3. After additional examinations and 
detailed monitoring, the investigator must contact the sponsor for consideration of possible 
discontinuation of the study medication, discussion of the relevant subject details and possible 
alternative etiologies. 
If subjects experience ALT or AST >3 × ULN and total bilirubin >2 × ULN, the investigator 
must refer to instructions in Section 7.5 Criteria for Discontinuation or Withdrawal of a Subject 
and Section 10.2.3 Reporting of Abnormal Liver Function Tests. 
9.1.13 
Contraception and Pregnancy Avoidance Procedure 
From signing of informed consent, throughout the duration of the study, to the end of the follow-
up period, female subjects of childbearing potential (e.g., non-sterilized or premenopausal female 
subjects) who are sexually active with a nonsterilized male partner must use adequate 
contraception. Subjects will be provided with information on acceptable methods of 
contraception as part of the subject informed consent process and will be asked to sign a consent 
form stating that they understand the requirements for avoidance of pregnancy during the course 
of the study. During the course of the study, regular urine human chorionic gonadotropin (hCG) 
pregnancy tests will be performed, and subjects will receive continued guidance with respect to 
the avoiding pregnancy as part of the study procedures (Appendix A). 
At visits when pregnancy tests are performed, subjects must be confirmed of having a negative 
urine hCG pregnancy test, as well as at the follow-up examination. 
9.1.14 
Pregnancy 
If any subject is found to be pregnant during the study she should be withdrawn and any study 
medication should be immediately discontinued. 
If the pregnancy occurs during administration of active study medication from the start of the 
study medication in the double-blind treatment period to the end of the follow-up period, the 
pregnancy should be reported immediately, using a pregnancy notification form, to the contact 
listed in the attachment. 
Should the pregnancy occur during or after administration of blinded drug, the investigator must 
inform the subject of their right to receive treatment information. If the subject chooses to 
receive unblinded treatment information, the individual blind should be broken by the 
investigator. Subjects randomized to placebo need not be followed. 
If the female subject agrees to the primary care physician being informed, the investigator should 
notify the primary care physician (obstetrics and gynecology specialist) that the subject was 
participating in a clinical study at the time she became pregnant and provide details of treatment 
the subject received (blinded or unblinded, as applicable). 
All pregnancies will be followed up to final outcome, using the pregnancy form. The outcome, 
including any premature termination, must be reported to the sponsor. An evaluation after the 
birth of the child will also be conducted. 


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9.1.15 
ECG Procedure 
A standard 12-lead ECG will be recorded. The investigator (or a qualified observer at the study 
site) will interpret the ECG using 1 of the following categories: within normal limits, abnormal 
but not clinically significant, or abnormal and clinically significant. The following parameters 
will be recorded on the eCRF from the subject’s ECG trace: RR interval, PR interval, QT 
interval, QRS interval, and QTcB interval. QTcF interval will be calculated by the sponsor. ECG 
traces recorded on thermal paper should be photocopied to avoid degradation of trace over time. 
9.1.16 
Pharmacogenomic Sample Collection 
One 5-mL whole blood sample for pharmacogenomics will be collected at the start of placebo 
lead-in period (Visit 2) or at the earliest possible time during the study from subjects who signed 
informed consent of pharmacogenomics and entered into the placebo lead-in period for possible 
exploratory investigation of markers enabling the prediction of drug response.  
Pharmacogenomic sample should not be collected from any subject who has received 
comparable bone marrow transplant or whole blood transfusion within 6 months of any sample 
collection. 
See the separately created procedure for collecting, handling, and storage of pharmacogenomic 
samples. 
9.1.17 
Pharmacokinetic Sample Collection and Analysis 
9.1.17.1 
Collection of Blood for Pharmacokinetic Sampling 
Blood samples will be collected in concurrence with blood collection for clinical laboratory tests. 
The exact date and time of the blood collection and dosing times of the last 2 doses prior to the 
blood collection will be recorded on the eCRF. Refer to the separately created procedure for 
collection, handling, and shipping of blood samples. 
Since drug concentrations of subjects in the placebo group will not be measured, the assignment 
personnel will send an operation manual to the central laboratory to identify samples of subjects 
in the placebo group. Drug concentration data will be reported to the sponsor after unblinding of 
the study. 
9.1.17.2 
Bioanalytical Methods 
Plasma concentrations of Lu AA21004 and its metabolites (Lu AA34443 and Lu AA39835) will 
be analyzed with the validated LC/MS/MS method. 
9.1.18 
Documentation of Screen Failure Prior to Entrance into Placebo Lead-in Period 
For all subjects who signed informed consent and prematurely discontinue the study prior to 
entry into the placebo lead-in period, the investigator should complete the eCRF. The registration 
center should be contacted as a notification of screen failure prior to entry into the placebo lead-
in period. 


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The primary reason for screen failure prior to entry into the placebo lead-in period will be 
recorded in the eCRF using the following categories: 
 PTE/AE 
 Did not meet inclusion criteria or did meet exclusion criteria <specify the reason.> 
 Significant protocol deviation 
 Lost to follow-up 
 Voluntary withdrawal <specify the reason.> 
 Study termination 
 Other <specify the reason.> 
The identification numbers assigned to subjects who prematurely discontinues prior to entry into 
the placebo lead-in period should not be reused. 
9.1.19 
Documentation of Study Entrance into Placebo Lead-in Period 
Only subjects who meet all of the inclusion criteria and none of the exclusion criteria at the start 
of placebo lead-in period are eligible for entrance into the placebo lead-in period. 
If the subject is found to be not eligible for the placebo lead-in period, the investigator should 
record the primary reason for failure on the applicable eCRF. 
9.1.20 
Documentation of Screen Failure Prior to Randomization 
For all subjects who prematurely discontinue the study after entry into the placebo lead-in period 
and prior to randomization, the investigator should complete the eCRF. The registration center 
should be contacted as a notification of discontinuation after entry into the placebo lead-in period 
and prior to randomization. 
The primary reason for screen failure after entry into the placebo lead-in period and prior to 
randomization is recorded in the eCRF using the following categories: 
 PTE/AE 
 Did not meet inclusion criteria or did meet exclusion criteria <specify the reason.> 
 Significant protocol deviation 
 Lost to follow-up 
 Voluntary withdrawal <specify the reason.> 
 Study termination 
 Other <specify the reason.> 


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The end-of-study evaluation will be performed for all subjects who prematurely discontinue the 
study after entry into the placebo lead-in period and prior to randomization according to Section 
9.3.5. 
9.1.21 
Documentation of Randomization 
Only subjects who meet all of the inclusion criteria and none of the exclusion criteria are eligible 
for randomization and entrance into the double-blind treatment period. 
If the subject is found to be not eligible for randomization, the investigator should record the 
primary reason for screen failure on the eCRF. 
9.2 
Monitoring Subject Treatment Compliance 
Subjects will be required to bring unused study medication containers (PTP sheets)/unused 
medications to each dispensing site visit. The dates of the initial and last dosing, as well as any 
details where a subject takes more or less of the study medications than the specified dose, will 
be recorded on the eCRF. 
If a subject is significantly noncompliant with the study medication (e.g., 6 or more consecutive 
doses missed), it may be appropriate to withdraw the subject from the study. All subjects should 
be reinstructed about the dosing requirement during study contacts. The authorized study 
personnel conducting the re-education must document the process in the subject source records. 
9.3 
Schedule of Observations and Procedures 
The schedule for all study-related procedures for all evaluations is shown in Appendix A. 
Assessments should be completed at the designated visit/time point(s). 
9.3.1 
Screening Period 
Informed consent must be obtained prior to the initiation of any study procedures. 
The examinations/observations/assessments listed below will be performed at the start of 
screening period (Days -22 ± 10; Visit 1). Subjects will be screened in accordance with 
predefined inclusion and exclusion criteria as described in Section 7.0. See Section 9.1.18 for 
procedures for documenting a subject who prematurely discontinues the study prior to entry into 
the placebo lead-in period. 
 Demographics, medical history, and medication history 
 Diagnosis of MDD 
 Assessments of the major depressive episode 
 Physical examination 
 Weight and height 
 Vital signs 


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 Concomitant medications 
 Concurrent medical conditions 
 Clinical laboratory tests 
 Pregnancy test (female subjects of childbearing potential only) 
 Urine drug screening 
 ECG procedure 
 C-SSRS 
 PTE assessment 
 MADRS 
 HAM-D 
 CGI-S 
9.3.2 
Placebo Lead-in Period 
The examinations/observations/assessments listed below will be performed at the start of placebo 
lead-in period (Day -8 ± 3; Visit 2). Subjects will be screened in accordance with predefined 
inclusion and exclusion criteria as described in Section 7.0. Subjects assessed to be eligible will 
enter the placebo lead-in period. See Section 9.1.18 for procedures for documenting subjects who 
prematurely discontinue the study prior to entry into the placebo lead-in period. 
 Physical examination 
 Weight 
 Vital signs 
 Concomitant medications 
 Clinical laboratory tests 
 Pregnancy test (female subjects of childbearing potential only) 
 Urine drug screening. 
 Blood sampling for pharmacogenomics* (subjects who provided written consent only) 
 ECG procedure 
 C-SSRS 
 PTE assessment 
 MADRS 
 HAM-D 


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 CGI-S 
 SDS 
 DSST 
 PDQ-5 
 QIDS-J 
 Dispense of the study medication (for the placebo lead-in treatment) 
* Blood sampling for pharmacogenomics will be performed at the start of placebo lead-in period 
(Visit 2) or at the earliest possible time during the study. 
9.3.3 
Start of Double-blind Treatment Period/Randomization 
The examinations/observations/assessments listed below will be performed at the start of double-
blind treatment period (Day -1; Visit 3). Subjects will be screened in accordance with predefined 
inclusion and exclusion criteria as described in Section 7.0. Subjects assessed to be eligible will 
be randomized according to Section 8.2 and enter the double-blind treatment period. See Section 
9.1.20 for documenting subjects who prematurely discontinue the study after entry into the 
placebo lead-in period and prior to randomization. 
The examinations/observations/assessments at Visit 3 should be regarded as baseline evaluations. 
 Physical examination 
 Weight 
 Vital signs 
 Concomitant medications 
 Clinical laboratory tests (fasted) 
 Pregnancy test (female subjects of childbearing potential only) 
 ECG procedure 
 C-SSRS 
 PTE/AE assessment 
 MADRS 
 HAM-D 
 CGI-S 
 CGI-I (assessed comparing with a CGI score at Visit 2). 
 SDS 
 DSST 


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 PDQ-5 
 QIDS-J 
 Randomization 
 Dispense of the study medication (for the double-blind treatment [Inner Carton 1]) 
 Collection of the study medication dispensed at the last visit/Consultation about subjects' 
compliance 
9.3.4 
Double-blind Treatment Period 
Visit 4 
The examinations/observations/assessments listed below will be performed at 1 week after the 
start of double-blind treatment period (Day 7 ± 1; Visit 4). 
 Vital signs 
 Concomitant medications 
 C-SSRS 
 PTE/AE assessment 
 MADRS 
 CGI-S 
 CGI-I (assessed comparing with a CGI score at Visit 3). 
 DSST 
 PDQ-5 
 QIDS-J 
 Dispense of the study medication (for the double-blind treatment [Inner Carton 2]) 
 Collection of the study medication dispensed at the last visit/Consultation about subjects' 
compliance 
Visit 5 
The examinations/observations/assessments listed below will be performed at 2 weeks after the 
start of double-blind treatment period (Day 14 ± 3; Visit 5). 
 Vital signs 
 Concomitant medications 
 C-SSRS 
 PTE/AE assessment 


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 MADRS 
 CGI-S 
 CGI-I (assessed comparing with a CGI score at Visit 3). 
 QIDS-J 
 Dispense of the study medication (for the double-blind treatment [Inner Carton 2]) 
 Collection of the study medication dispensed at the last visit/Consultation about subjects' 
compliance 
Visit 6 
The examinations/observations/assessments listed below will be performed at 4 weeks after the 
start of double-blind treatment period (Day 28 ± 3; Visit 6). 
 Weight 
 Vital signs 
 Concomitant medications. 
 Clinical laboratory tests 
 Pregnancy test (female subjects of childbearing potential only) 
 Pharmacokinetic sampling 
 ECG procedure 
 C-SSRS 
 PTE/AE assessment 
 MADRS 
 CGI-S 
 CGI-I (assessed comparing with a CGI score at Visit 3). 
 QIDS-J 
 Dispense of the study medication (for the double-blind treatment [Inner Carton 2]) 
 Collection of the study medication dispensed at the last visit/Consultation about subjects' 
compliance 
Visit 7 
The examinations/observations/assessments listed below will be performed at 6 weeks after the 
start of double-blind treatment period (Day 42 ± 3; Visit 7). 
 Vital signs 


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 Concomitant medications 
 C-SSRS 
 PTE/AE assessment 
 MADRS 
 CGI-S 
 CGI-I (assessed comparing with a CGI score at Visit 3). 
 QIDS-J 
 Dispense of the study medication (for the double-blind treatment [Inner Carton 2]) 
 Collection of the study medication dispensed at the last visit/Consultation about subjects' 
compliance 
9.3.5 
End of Double-blind Treatment Period or Early Termination 
The examinations/observations/assessments listed below will be performed at 8 weeks after the 
start of double-blind treatment period (Day 56 ± 3; Visit 8) as evaluation at the end of double-
blind treatment period. Subjects who prematurely discontinue the study during the placebo lead-
in period or double-blind treatment period will be requested to visit the study site for early 
termination examinations/observations/assessments within 7 days after the day of study 
discontinuation wherever possible. 
 Physical examination 
 Weight 
 Vital signs 
 Concomitant medications 
 Clinical laboratory tests (fasted) 
 Pregnancy test (female subjects of childbearing potential only) 
 Pharmacokinetic sampling (not performed at early termination) 
 ECG procedure 
 C-SSRS 
 PTE/AE assessment 
 MADRS 
 HAM-D 
 CGI-S 
 CGI-I* 


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 SDS 
 DSST 
 PDQ-5 
 QIDS-J 
 Collection of the study medication dispensed at the last visit/Consultation about subjects' 
compliance 
* The CGI-I score will be assessed comparing with that at Visit 3. However, at early termination 
prior to Visit 3, the CGI-I score will be assessed by comparing with that at Visit 2. 
For all randomized subjects, the investigator must complete the End of Study eCRF page. 
After evaluation at the end of double-blind treatment period or early termination, standard 
therapy may be performed as needed. 
9.3.6 
Follow-up Period 
A safety follow-up assessment will be conducted at 12 weeks after the start of double-blind 
treatment period (Day 84 ± 5). For subjects who prematurely discontinue the study during the 
placebo lead-in period or double-blind treatment period, the follow-up assessments will be made 
28 ± 5 days after the last dose of the study medication. The follow-up assessments may either be 
conducted as a visit to the site or as a telephone contact. In the follow-up, the following will be 
assessed: outcomes of AEs continuing at Visit 8 or early termination visit, new SAEs developing 
during the follow-up period, and special interest AEs will be assessed. Female subjects of child-
bearing potential will be asked to confirm whether they are pregnant or not. 
9.3.7 
Post Study Care 
The study medication will not be available upon completion of the subject’s participation in the 
study. 
9.4 
Biological Sample Retention and Destruction 
Samples of 5-mL whole blood collected for pharmacogenomics will be stored frozen at the 
pharmacogenomic specimen storage facility (see the contact listed in the attachment 1; 
hereinafter referred to as specimen storage facility). 
The collected samples will be retained for 20 years from the day when a first pharmacogenomic 
sample was collected during the study. 
When subjects request disposal of a stored sample during the retention period, the site will ask 
the specimen storage facility to destroy the sample via the sponsor according to the procedure. 
The specimen storage facility will destroy the sample in accordance with the procedure, and 
notify the site and sponsor. However, any samples should not be destroyed if all the documents 
(including medical records) have been destroyed which could identify the subject, and it is 
impossible to link the sample to the subject. 


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Even if the sample can be linked to the subject, when pharmacogenomic investigation has been 
conducted, the remaining sample will be destroyed and the results of pharmacogenomic 
investigation of the anonymized subject will be retained by the sponsor. 
The sponsor will build a management system required for protection of the subject’s personal 
information, define standards for collecting, storage, and destruction of samples, and prepare 
appropriate procedures. 


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10.0 
PRETREATMENT EVENTS AND ADVERSE EVENTS 
10.1 
Definitions 
10.1.1 
PTEs 
A PTE is defined as any untoward medical occurrence in a clinical investigation subject who has 
signed informed consent to participate in a study but prior to administration of any study 
medication; it does not necessarily have to have a causal relationship with study participation. 
10.1.2 
AEs 
An AE is defined as any untoward medical occurrence in a clinical investigation subject 
administered a drug; it does not necessarily have to have a causal relationship with this treatment. 
An AE can therefore be any unfavorable and unintended sign (e.g., a clinically significant 
abnormal laboratory finding), symptom, or disease temporally associated with the use of a drug 
whether or not it is considered related to the drug. 
10.1.3 
Additional Points to Consider for PTEs and AEs 
An untoward finding generally may: 
 Indicate a new diagnosis or unexpected worsening of a pre-existing condition. (Intermittent 
events for pre-existing conditions underlying disease should not be considered PTEs or AEs.) 
 Necessitate therapeutic intervention. 
 Require an invasive diagnostic procedure. 
 Require discontinuation or a change in dose of study medication or a concomitant medication. 
 Be considered unfavorable by the investigator for any reason. 
 PTEs/AEs caused by a study procedure (e.g., a bruise after blood draw) should be recorded 
as a PTE/AE. 
Diagnoses vs. signs and symptoms: 
 Each event should be recorded to represent a single diagnosis. Accompanying signs 
(including abnormal laboratory values or ECG findings) or symptoms should NOT be 
recorded as additional AEs. If a diagnosis is unknown, sign(s) or symptom(s) should be 
recorded appropriately as a PTE(s) or as an AE(s). 
Laboratory values and ECG findings: 
 Changes in laboratory values or ECG parameters are only considered to be PTEs or AEs if 
they are judged to be clinically significant (i.e., if some action or intervention is required or if 
the investigator judges the change to be beyond the range of normal physiologic fluctuation). 
A laboratory re-test and/or continued monitoring of an abnormal value are not considered an 


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intervention. In addition, repeated or additional noninvasive testing for verification, 
evaluation, or monitoring of an abnormality is not considered an intervention. 
 If abnormal laboratory values or ECG findings are the result of pathology for which there is 
an overall diagnosis (e.g., increased creatinine in renal failure), the diagnosis only should be 
reported appropriately as a PTE or as an AE. 
Pre-existing conditions: 
 Of pre-existing conditions (present at the time of signing of informed consent), events that 
are considered accompanying symptoms of MDD should NOT be recorded as concurrent 
medical conditions, PTEs, or AEs. 
 Other pre-existing conditions are considered concurrent medical conditions and should NOT 
be recorded as PTEs or AEs. Baseline evaluations (e.g., laboratory tests, ECG, X-rays) 
should NOT be recorded as PTEs unless related to study procedures. However, if the subject 
experiences an abnormality (e.g., internal bleeding due to blood sampling) associated with 
the baseline evaluations, the abnormality should be recorded as a PTE and recorded on eCRF. 
If the subject experiences a worsening or complication of such a concurrent condition, the 
worsening or complication should be recorded appropriately as a PTE (worsening or 
complication occurs before start of study medication) or an AE (worsening or complication 
occurs after start of study medication). The investigator should ensure that the event term 
recorded captures the change in the condition (e.g., “worsening of hypertension”). 
 If a subject has a pre-existing episodic condition (e.g., asthma, epilepsy) any occurrence of an 
episode should only be captured as a PTE/AE if the episodes become more frequent, serious 
or severe in nature, that is, the investigator should ensure that the AE term recorded captures 
the change in the condition from Baseline (e.g., “worsening of…”). 
 If a subject has a degenerative concurrent condition (e.g., cataracts, rheumatoid arthritis), 
worsening of the condition should only be captured as a PTE/AE if occurring to a greater 
extent to that which would be expected. Again, the investigator should ensure that the AE 
term recorded captures the change in the condition (e.g., “worsening of…”). 
Worsening of PTEs or AEs: 
 If the subject experiences a worsening or complication of a PTE after starting administration 
of the study medication, the worsening or complication should be recorded appropriately as 
an AE. The investigator should ensure that the AE term recorded captures the change in the 
condition (e.g., “worsening of…”). 
 If the subject experiences a worsening or complication of an AE after any change in study 
medication, the worsening or complication should be recorded as a new AE. The investigator 
should ensure that the AE term recorded captures the change in the condition (e.g., 
“worsening of…”). 


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Changes in severity of AEs /Serious PTEs: 
 If the subject experiences changes in severity of an AE/serious PTE, the event should be 
captured once with the maximum severity recorded. 
Preplanned surgeries or procedures: 
 Preplanned procedures (surgeries or therapies) that were scheduled prior to signing of 
informed consent are not considered PTEs or AEs. However, if a preplanned procedures is 
performed early (e.g., as an emergency) due to a worsening of the pre-existing condition, the 
worsening of the condition should be captured appropriately as a PTE or an AE. 
Complications resulting from any planned surgery should be reported as AEs. 
Elective surgeries or procedures: 
 Elective procedures (e.g., cosmetic surgery) performed where there is no change in the 
subject’s medical condition should not be recorded as PTEs or AEs, but should be 
documented in the subject’s source documents. Complications resulting from an elective 
surgery should be reported as AEs. 
Insufficient clinical response (lack of efficacy): 
 Insufficient clinical response, efficacy, or pharmacologic action, should NOT be recorded as 
an AE. The investigator must make the distinction between exacerbation of pre-existing 
illness and lack of therapeutic efficacy. 
Overdose: 
 All cases of overdose with any medication, including the case without manifested side effects, 
are considered AEs and will be recorded on the AE page of the eCRF. In addition, cases of 
overdose will be reported as special interest AEs. 
Suicidality events: 
 A completed suicide is always captured as an SAE based on its fatal outcome. Furthermore, 
active suicidal behavior such as suicidal ideation with a specific plan and suicide attempt will 
also be collected as an SAE. 
 Unless the event in question meets the definition of "serious," suicidal thoughts or suicidal 
ideation without a specific plan or action will be collected as a non-serious AE in accordance 
with the standard AE reporting requirements. 
 A subject who presents with self-mutilation should be asked by the investigator to clarify 
whether the subject was attempting suicide. If the subject was attempting suicide, the 
behavior will be collected as an SAE, and the specific suicidal behavior (e.g., wrist cutting) 
will be recorded in the eCRF. If the subject was not attempting suicide, the behavior will be 
collected as a non-serious AE in accordance with the standard AE reporting requirements. 
10.1.4 
SAEs 
An SAE is defined as any untoward medical occurrence that at any dose: 


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1. Results in DEATH. 
2. Is LIFE THREATENING.* 
3. Requires inpatient HOSPITALIZATION or prolongation of existing hospitalization. 
4. Results in persistent or significant DISABILITY/INCAPACITY. 
5. Leads to a CONGENITAL ANOMALY/BIRTH DEFECT. 
6. Is an IMPORTANT MEDICAL EVENT that satisfies any of the following: 
 May require intervention to prevent items 1 through 5 above. 
 May expose the subject to danger, even though the event is not immediately life 
threatening or fatal or does not result in hospitalization. 
 Includes any event or synonym described in the Takeda Medically Significant AE List 
(Table 10.a). 
* 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. 
Table 10.a 
Takeda Medically Significant AE List 
Term 
 
Acute respiratory failure/acute respiratory distress 
syndrome (ARDS) 
Torsade de pointes / ventricular fibrillation 
/ ventricular tachycardia 
Malignant hypertension 
Convulsive seizure (including seizure and epilepsy) 
Agranulocytosis 
Aplastic anemia 
Toxic epidermal necrolysis/Stevens-Johnson syndrome 
Hepatic necrosis 
Acute liver failure 
Anaphylactic shock 
Acute renal failure  
Pulmonary hypertension 
Pulmonary fibrosis (including interstitial lung disease) 
Neuroleptic malignant syndrome / malignant 
hyperthermia 
Spontaneous abortion / stillbirth and fetal death 
Confirmed or suspected transmission of infectious agent 
by a medicinal product 
Confirmed or suspected endotoxin shock 
 
The following events are also to be considered SAEs. 
 Completed suicide 
 Active suicidal ideation 
 Active suicidal behavior such as suicide attempt 
 Self-injury with suicide attempt 


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PTEs that fulfill 1 or more of the serious criteria above are also to be considered SAEs and 
should be reported and followed up in the same manner (see Sections 10.2.2 and 10.3). 
10.1.5 
Special Interest AEs 
A Special Interest Adverse Event (serious or non-serious) is 1 of scientific and medical concern 
specific to the compound or program. In this study, skin reaction, allergic reaction, hepatic 
impairment, and overdose are defined as special interest AEs. Ongoing monitoring and 
communication by the investigator to Takeda may be appropriate, and if the events occur, they 
will be reported according to Section 10.2.1.3. Such events may require further investigation in 
order to characterize and understand them. 
10.1.5.1 
Skin and Allergic Reaction 
When the causal relationship between rash or allergic reaction and the study medication is 
assessed as probable or possible, rash or allergic reaction will be reported as a special interest AE 
according to Section 10.2.1.3 after the nature and the site are characterized. When the causal 
relationship between rash or allergic reaction and the study medication is assessed as not related, 
rash or allergic reaction is not required to be reported as a special interest AE. 
When rash or allergic reaction develops, the subject should be adequately examined for any 
clinical features that may suggest the development of drug reaction with eosinophilia and 
systemic symptoms (DRESS), toxic epidermal necrolysis (TEN), or Stevens-Johnson syndrome 
(SJS). In addition, the subject should be monitored for the appearance of any of the following 
signs: 
a) Involvement of mucous membrane or the conjunctiva 
b) Development of skin pain 
c) Urticaria, blistering, or other types of skin lesions 
d) Angioedema 
If a subject presents with symptoms of a systemic reaction (e.g., generalized rash), or signs of 
severe rash, or if it is clinically necessary, the following laboratory parameters should also be 
investigated and monitored accordingly: complete blood count with differentials, liver and renal 
function tests, and urinalysis. If deemed necessary by the investigator, subjects should be 
received examination by a dermatologist, and photographs of the skin rash and/or skin biopsies 
will be obtained as needed. 
10.1.5.2 
Hepatic Impairment 
If a subject has ALT or AST >3 × ULN, and follow-up laboratory tests (see Section 9.1.12) also 
shows ALT or AST >3 × ULN, it should be reported as a special interest AE according to 
Section 10.2.1.3. In addition, the relevant subject details and possible alternative etiologies other 
than the study medication should be investigated. 


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If the abnormality falls under a drug-induced liver function abnormality that may lead to severe 
hepatic impairment (see Section 10.2.3), it should also be reported as an SAE. 
10.1.5.3 
Overdose 
For overdose, refer to Section 8.1.4. All cases of overdose will be documented as AEs on an AE 
page of the eCRF and should be reported as special interest AEs according to Section 10.2.1.3 
(with or without associated adverse events). 
10.1.6 
Severity of PTEs and AEs 
The different categories of intensity (severity) are characterized as follows: 
Mild: 
The event is transient and easily tolerated by the subject. 
Moderate: 
The event causes the subject discomfort and interrupts the subject’s usual activities. 
Severe: 
The event causes considerable interference with the subject’s usual activities. 
 
10.1.7 
Causality of AEs 
The relationship of each AE to study medication(s) will be assessed using the following 
categories: 
Probable: 
An AE that has a strong temporal relationship to the study medication(s), or recurs on re-challenge, 
and another etiology is unlikely or significantly less likely. 
Possible: 
An AE that has a suggestive temporal relationship to the study medication(s), and an alternative 
etiology is equally or less likely. 
Not Related: 
An AE that does not follow a reasonable temporal sequence from administration of the study 
medication(s) or that can reasonably be explained by other factors, such as underlying diseases, 
concurrent medical conditions, concomitant drugs and concurrent treatments (that is, there is no 
causal relationship between the study medication and the AE). 
 
An AE is considered causally related to the use of the study medication when the causality 
assessment is probable or possible. 
10.1.8 
Relationship to Study Procedures 
Relationship (causality) to study procedures should be determined for all PTEs and AEs. 
The relationship should be assessed as Related if the investigator considers that there is 
reasonable possibility that an event is due to a study procedure. Otherwise, the relationship 
should be assessed as Not Related. 


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10.1.9 
Start Date 
The start date of AEs/PTEs will be determined based on the criteria described below. 
AE/PTE 
Start Date 
Signs, symptoms, and diseases (diagnosis) 
Date when the subject or the investigator first notices the 
sign or symptom of the AE 
Asymptomatic disease 
Date when a definite diagnosis is determined based on 
the results of diagnostic testing. Even if obsolete findings 
are indicated based on the test findings or the 
approximate time of onset can be estimated, the date 
when a definite diagnosis is made should be recorded. 
Worsening of concurrent medical conditions or PTEs 
Date when the subject or the investigator first notices 
worsening of the disease or symptom. 
Normal in the initial assessment after signing of informed 
consent but abnormal in the subsequent assessment (for 
PTEs) 
Abnormal in the assessment after the start of the study 
medication (for AEs) 
Date when the test is performed in which a clinically 
significant abnormal test value is observed 
Abnormal in the initial assessment after signing of 
informed consent and has worsened in the subsequent 
assessment (for PTEs) 
Abnormal in the assessment at the start of the study 
medication and has worsened in the subsequent 
assessment (for AEs) 
Date when the test is performed in which a medically 
significant elevation, reduction, increase or decrease in 
clinical laboratory test values is observed 
 
10.1.10 Stop Date 
The stop date of the AE/PTE is the date at which the subject recovered, the event resolved but 
with sequelae or the subject died. The AE/PTE not determined to have resolved at the end of the 
study is assessed as ongoing  
10.1.11 Frequency 
Episodic AEs/PTEs (e.g., constipation, diarrhea, vomiting) or those which occur repeatedly over 
a period of consecutive days are intermittent. All other events are continuous. 
10.1.12 Action Concerning Study Medication 
The action taken for the study medication is classified and defined as follows: 
Drug withdrawn 
The study medication is stopped due to the particular AE (including withdrawal at the subject’s 
discretion). 
Dose not changed 
The dose is not changed even after the occurrence of the particular AE. 
This shall apply in case the study medication is stopped due to another AE.  
This shall also apply, for example, in case the study medication is stopped for any reason other 
than intervention for the particular AE, such as the subject’s negligence. 


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Unknown 
For example, attempts to contact the subject are unsuccessful and the course of the particular 
AE after the start date cannot be followed. 
Not Applicable 
For example, the study medication has already been completed or stopped before the onset of 
the particular AE. 
 
10.1.13 Outcome 
The outcome of AEs/PTEs is classified as follows: 
Category 
Assessment Criteria 
Recovered/Resolved 
• The symptom or finding has disappeared or resolved. 
• The abnormal laboratory value has improved to the normal range or to the level at baseline 
(for AEs) or at the first assessment after signing of informed consent (for PTEs). 
Recovering/Resolving 
• The intensity is lowered by at least 1 grade. 
• The symptom or finding has almost disappeared. 
• The abnormal laboratory value has improved, but not to the normal range or the level at 
baseline (for AEs) or at the first assessment after signing of informed consent (for PTEs). 
• The subject died from a cause other than the particular AE/PTE with the condition 
remaining “recovering/resolving” (no need to record the date of death). 
Not recovered/not 
resolved 
• There is no change in the symptom, finding, or laboratory value. 
• The intensity of the symptom, finding, or laboratory value on the last day of the observed 
period has got worsen than when it started. 
• An irreversible congenital anomaly. 
• The subject died from another cause with the particular AE/PTE state remaining “Not 
recovered/not resolved” AE/PTE (no need to record the date of death). 
Resolved with 
sequelae 
• The subject recovered from an acute AE/PTE but was left with impairment that interferes 
with the subject’s daily life. 
Fatal 
• There is a direct relationship between the death and the AE/PTE. 
• The direct relationship indicates that the AE/PTE caused or apparently contributed to the 
death. 
• The outcome of another AE/PTE reported in the same subject that is not determined 
(considered or estimated) as the cause of the death is not assessed as “fatal.” 
• If the outcome is “fatal,” the date of death should be recorded. 
Unknown 
• The course of the AE/PTE after the start date cannot be followed up as specified in the 
protocol due to hospital change or residence change. 
 
10.2 
Procedures 
10.2.1 
Collection and Reporting of AEs 
10.2.1.1 
PTE and AE Collection Period 
Collection of PTEs will commence from the time the subject signs the informed consent to 
participate in the study and continue until the subject is first administered study medication in the 


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placebo lead-in period. For subjects who discontinue prior to the first study medication 
administration in the placebo lead-in period, PTEs are collected until the subject discontinues 
study participation. 
Collection of AEs will commence from the time that the subject is first administered study 
medication in the placebo lead-in period. Routine collection of AEs will continue until Visit 8 or 
Early Termination Visit. 
Collection of SAEs or special interest AEs will continue until the end of the follow-up period. 
10.2.1.2 
PTE and AE Reporting 
At each study visit, the investigator will assess whether any subjective AEs have occurred. A 
neutral question, such as “How have you been feeling since your last visit?” may be asked. 
Subjects may report AEs occurring at any other time during the study. 
Subjects experiencing a serious PTE must be monitored until the symptoms subside and any 
clinically relevant changes in laboratory values have returned to baseline or until there is a 
satisfactory explanation for the change (for permanent or irreversible PTEs). Non-serious PTEs, 
related or unrelated to the study procedure, need not to be followed-up for the purposes of the 
protocol. 
All subjects experiencing AEs, whether considered associated with the use of the study 
medication or not, must be monitored until the symptoms subside and any clinically relevant 
changes in laboratory values have returned to baseline or until there is a satisfactory explanation 
for the change (for permanent or irreversible AEs). All PTEs and AEs will be documented in the 
PTE/AE page of the eCRF, whether or not the investigator concludes that the event is related to 
the drug treatment. The following information will be documented for each event: 
1. Event term 
2. Start and stop date 
3. Frequency 
4. Severity 
5. Investigator’s opinion of the causal relationship between the event and administration of 
study medication(s) (probable, possible, not related) (not completed for PTEs). 
6. Investigator’s opinion of the causal relationship to study procedure(s), including the details 
of the suspected procedure. 
7. Action concerning study medication (not applicable for PTEs) 
8. Outcome of event 
9. Seriousness 
10. Classification as special interest AEs (Yes or No) 


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C-SSRS will not be used as a primary means to collect AEs. However, should the investigator 
become aware of a potential AE through the information collected with this instrument, proper 
follow-up with the patient for medical evaluation should be undertaken. If it is determined that 
an AE not previously reported has been identified through this follow-up, normal reporting 
requirements should be applied. 
AEs and serious PTEs will be followed up until resolution or until the investigator judges that 
further follow-up is not necessary. 
10.2.1.3 
Special Interest AE Reporting 
If the special interest AE (refer to Section 10.1.5) occurs through the AE collection period, it 
should be reported to Safety Information Emergency Call Center, in principle (described in the 
separate contact information list) within 1 business day of first onset or subject’s notification of 
the event. The investigator should complete the Rash and Allergic Reaction, Hepatic Impairment 
or Overdose Form within 10 business days and report to Safety Information Emergency Call 
Center, in principle. In addition, the investigator should submit to the sponsor the original Rash 
and Allergic Reaction, Hepatic Impairment or Overdose Form. 
The special interest AEs have to be recorded as AEs in the eCRF. 
10.2.2 
Collection and Reporting of SAEs 
When an SAE occurs through the AE collection period it should be reported according to the 
following procedure. PTEs that fulfill the serious criteria described in Section 10.1.4 are also to 
be considered SAEs and should be reported in the same manner. 
The investigator should report the SAEs with information required in the SAE form to Safety 
Information Emergency Call Center, in principle, within 1 business day of the first onset or 
subject’s notification of the event. The investigator should prepare the completed SAE form 
within 10 calendar days and submit to Safety Information Emergency Call Center, in principle. 
In addition, the investigator should submit to the sponsor the original SAE form. 
For the report within 1 business day, the information should be completed as fully as possible but 
contain, at a minimum: 
 A short description of the event and the reason why the event is categorized as serious. 
 Subject identification number. 
 Investigator’s name. 
 Name of the study medication(s). 
 Causality assessment. 
Any SAE spontaneously reported to the investigator following the AE collection period should 
be also reported to the sponsor if considered related to study participation. Reporting of Serious 
PTEs will follow the procedure described for SAEs. 


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10.2.3 
Reporting of Abnormal Liver Function Tests 
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 investigator must contact the sponsor for 
discussion of the relevant subject details and possible alternative etiologies, such as acute viral 
hepatitis A or B or other acute liver disease or medical history/concurrent medical conditions. 
Follow-up laboratory tests must also be performed (see Section 9.1.12). If the investigator 
considers that such liver function abnormality cannot be explained by any factor other than the 
study medication, the event should be reported as a SAE (see Section 10.2.2). 
10.3 
Follow-up of SAEs 
If information not available at the time of the detailed report becomes available at a later date, 
the investigator should complete a follow-up SAE form copy or provide other written 
documentation and report it immediately to the sponsor or Safety Information Emergency Call 
Center. Copies of any relevant data from the hospital notes (e.g., ECGs, laboratory tests, 
discharge summary, postmortem results) should be sent to the addressee, if requested. 
All SAEs should be followed up until resolution or permanent outcome of the event. 
10.3.1 
Safety Reporting to Investigators, IRBs, and Regulatory Authorities 
The sponsor will be responsible for reporting all suspected unexpected serious adverse reactions 
(SUSARs) and any other applicable SAEs to regulatory authorities, investigators, and the head of 
the study site, as applicable, in accordance with national regulations in the countries where the 
study is conducted. Relative to the first awareness of the event by/or further provision to the 
sponsor or sponsor’s designee (CRO), SUSARs will be submitted to the regulatory authorities as 
expedited report within 7 days for fatal and life-threatening events and 15 days for other serious 
events. The sponsor will also prepare an expedited report for other safety issues where these 
might materially alter the current benefit-risk assessment of the study medication or that would 
be sufficient to consider changes in the administration of study medication or in the overall 
conduct of the trial. The study site also will forward a copy of all expedited reports to his or her 
IRB. 


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11.0 
STUDY-SPECIFIC COMMITTEES 
No steering committee, data safety monitoring committee, or clinical endpoint committee will be 
used in this study. 


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12.0 
DATA HANDLING AND RECORDKEEPING 
The full details of procedures for data handling will be documented in the Data Management 
Plan. AEs, PTEs, medical history, and concurrent conditions will be coded using the Medical 
Dictionary for Regulatory Activities (MedDRA). Drugs will be coded using the World Health 
Organization (WHO) Drug Dictionary. 
12.1 
eCRFs 
Completed eCRFs are required for each subject who signs an informed consent. 
The sponsor or its designee will supply investigative sites with access to eCRFs. The sponsor 
will make arrangements to train appropriate site staff (the investigator, subinvestigators, and 
other study collaborators) in the use of the eCRF. These forms are used to transmit the 
information collected in the performance of this study to the sponsor and regulatory authorities. 
eCRFs must be completed in English. Data are transcribed directly onto eCRFs. 
Corrections to eCRFs are recorded in an audit trail that captures the old information, the new 
information, identification of the person making the correction, the date the correction was made, 
and the reason for change. 
The investigator must review the eCRFs for completeness and accuracy and must sign the 
appropriate eCRFs. Furthermore, the investigator must retain full responsibility for the accuracy 
and authenticity of all data entered on the eCRFs. 
The following data will not be recorded into the eCRFs. 
 Laboratory test values measured at the central laboratory 
 Observed drug concentrations 
After the lock of the clinical study database, any change of, modification of, or addition to the 
data on the eCRFs should be made by the investigator with use of change and modification 
records of the eCRFs (Data Clarification Form) provided by the sponsor. The investigator must 
review the data change for completeness and accuracy, and must sign, or sign and seal, and date. 
eCRFs will be reviewed for completeness and acceptability at the study site during periodic visits 
by the sponsor or its designee. The sponsor or its designee will be permitted to review the 
subject’s medical and hospital records pertinent to the study to ensure accuracy of the eCRFs. 
The completed eCRFs are the sole property of the sponsor and should not be made available in 
any form to third parties, except for authorized representatives of appropriate governmental 
health or regulatory authorities, without written permission of the sponsor. 
12.2 
Record Retention 
The investigator and the head of the institution agree to keep the records stipulated in Section 
12.1 and those documents that include (but are not limited to) the study-specific documents, the 
identification log of all participating subjects, medical records, source worksheets, all original 
signed and dated informed consent forms, electronic copy of eCRFs, including the audit trail, 


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and detailed records of drug disposition to enable evaluations or audits from regulatory 
authorities, the sponsor or its designees. The investigator and the head of the institution are 
required to retain essential relevant 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 institution should discuss how long and how to retain those documents with the 
sponsor. 
1) The day on which marketing approval of the study drug is obtained (or the day 3 years after 
the date of notification in the case that the investigation is discontinued.) 
2) The day 3 years after the date of early termination or completion of the clinical study. 
In addition, the investigator and the head of the institution should retain the essential relevant 
documents until the receipt of a sponsor-issued notification to state the retention is no longer 
required. 


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13.0 
STATISTICAL METHODS 
13.1 
Statistical and Analytical Plans 
A statistical analysis plan (SAP) will be prepared and finalized prior to unblinding of subject’s 
treatment assignment. This document will provide further details regarding the definition of 
analysis variables and analysis methodology to address all study objectives. 
A blinded data review will be conducted prior to unblinding of subject’s treatment assignment. 
This review will assess the accuracy and completeness of the study database, subject evaluability, 
and appropriateness of the planned statistical methods. 
13.1.1 
Analysis Sets 
In this study, 3 kinds of analysis sets are defined: full analysis set (FAS), per protocol set (PPS), 
and safety analysis set. 
The FAS, which will be used as a primary analysis set for efficacy analysis, is defined as "all 
subjects who were randomized and received at least 1 dose of the study medication in the 
double-blind treatment period." 
The exact definition of each analysis set is specified in the Data Handling Rules for Statistical 
Analysis. 
The sponsor will verify the validity of the definitions of the analysis sets as well as the rules for 
handling data, consulting a medical expert as needed. The Data Handling Rules for Statistical 
Analysis must be finalized prior to unblinding. 
13.1.2 
Analysis of Demographics and Other Baseline Characteristics 
Major background and demographic characteristics will be summarized overall and by treatment 
group. 
13.1.3 
Efficacy Analysis 
Primary Efficacy Analysis for Primary Endpoint 
The primary endpoint for this study is the change from baseline (i.e. at the start of double-blind 
treatment period) in the MADRS total score after 8 weeks of treatment. 
Comparisons between each Lu AA21004 treatment group and the placebo group at Week 8 of 
the double-blind treatment period will be performed using the FAS based on MMRM analysis of 
covariance with the change from baseline in the MADRS total score as a dependent variable, and 
visit, treatment group, visit-by-treatment group interaction and baseline MADRS total score-by-
visit interaction as fixed effects. An unstructured variance-covariance matrix will be used to 
model the within-subject errors and Satterthwaite's method will be used to approximate the 
degrees of freedom. Holm's step down method will be used to adjust the multiplicity for the 
comparisons. More specifically, let H01, H02 be a family of hypotheses as follows: 


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H01: μPlacebo = μ10 mg 
H02: μPlacebo = μ20 mg 
Then let P1 and P2 denote the unadjusted p-values of tests for H01 and H02, respectively. Order 
the p-values from the smallest to the largest, P(1) , P(2) and let the corresponding null hypotheses 
be H(1) , H(2) . Holm's step-down method proceeds as follows:  
Step 1: if P(1) > 0.025, retain both null hypotheses H(1) and H(2), and stop. If P(1) ≤ 0.025, reject 
null hypothesis H(1) and go to Step 2. 
Step 2: if P(2) > 0.05, retain null hypothesis H(2). If P(2) ≤ 0.05, reject null hypothesis H(2). 
Secondary Efficacy Analyses for Primary Endpoint 
To check the robustness of the results, the same analysis as used for the primary efficacy analysis 
will be performed using the PPS. 
For the FAS, an analysis of covariance (ANCOVA) model with the change from baseline in the 
MADRS total score after 8 weeks of treatment (values at Week 8 [LOCF] − baseline) as a 
dependent variable, treatment group as a fixed effect and the baseline MADRS total score as a 
covariate will be applied for comparisons between the placebo group and each Lu AA21004 
treatment group. 
Analyses for Secondary Endpoints 
MADRS response (MADRS response is defined as a ≥50% decrease from baseline in the 
MADRS total score) and MADRS remission (MADRS remission is defined as the MADRS total 
score ≤10) after 8 weeks of treatment (LOCF) will be compared between treatment groups using 
logistic regression analysis including the baseline MADRS total score and treatment groups in 
the model. 
The change from baseline in the HAM-D17 total score after 8 weeks of treatment (values at 
Week 8 [LOCF] − baseline) will be analyzed using an ANCOVA model with treatment groups 
as a fixed effect and the baseline HAM-D17 total score as a covariate. 
The CGI-I score after 8 weeks of treatment (LOCF) will be analyzed using an ANCOVA model 
with treatment groups as a fixed effect and the baseline CGI-S score as a covariate. 
The change from baseline in the CGI-S score after 8 weeks of treatment (values at Week 8 
[LOCF] − baseline) will be analyzed using an ANCOVA model with treatment groups as a fixed 
effect and the baseline CGI-S score as a covariate. 
The change from baseline in the SDS score after 8 weeks of treatment (values at Week 8 [LOCF] 
− baseline) will be analyzed using an ANCOVA model with treatment groups as a fixed effect 
and the baseline SDS score as a covariate. 
The change from baseline in the DSST score after 8 weeks of treatment (values at Week 8 
[LOCF] − baseline) will be analyzed using an ANCOVA model with treatment groups as a fixed 
effect and the baseline DSST score as a covariate. 


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The change from baseline in the PDQ-5 score after 8 weeks of treatment (values at Week 8 
[LOCF] − baseline) will be analyzed using an ANCOVA model with treatment groups as a fixed 
effect and the baseline PDQ-5 score as a covariate. 
Two-sided tests with significance level at 5% will be used for all statistical tests. Ninety-five 
percent confidence intervals will be presented along with the P-values. 
13.1.4 
Pharmacokinetic Analysis 
The population pharmacokinetic analysis of Lu AA21004 and its metabolites Lu AA34443 and 
Lu AA39835 will be performed using the nonlinear mixed effect model (NONMEM). 
Pharmacokinetic parameters of individual subjects (e.g., AUC[0-tau], Cavg, Cmax) will be 
estimated and their correlation with relevant pharmacodynamic parameters (efficacy and 
tolerability/safety) will be explored. The population pharmacokinetic analysis plan will be 
prepared separately. 
13.1.5 
Safety Analysis 
AEs 
The definition of treatment-emergent adverse events (TEAE) will be described in the statistical 
analysis plan (SAP). TEAEs will be summarized using the safety analysis set. TEAEs will be 
coded using the MedDRA and will be summarized by system organ class (SOC) and preferred 
term (PT). No statistical testing or inferential statistics will be generated. 
A subject who has developed a same TEAE more than once will be counted as 1 subject in the 
severity category corresponding to the maximum severity of the event. 
Clinical Laboratory Test, Weight, Vital Signs, and ECG 
Summary statistics of observed values and changes at each time point (values at each time point 
in the double-blind treatment period − baseline) will be calculated for clinical laboratory tests, 
vital signs, ECG parameters, and weight for each treatment group. Incidences of values that are 
outside normal ranges and are potentially and clinically significant will be calculated. 
C-SSRS 
Descriptive statistics of C-SSRS will be calculated at each time point for each treatment group. 
13.2 
Interim Analysis and Criteria for Early Termination 
No interim analysis is planned. 
13.3 
Determination of Sample Size 
A number of subjects planned to be enrolled in this study is 480 (160 per group). Assuming the 
true mean differences of 3.5 for the change from baseline in the MADRS total score between 
each Lu AA21004 group and the placebo group, this sample size will provide greater than 80% 
power to detect the difference between each Lu AA21004 group and the placebo group by 2-
sample t-test. In addition, assuming the true mean differences of 3.0 for the change from baseline 


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in the MADRS total score between each Lu AA21004 group and the placebo group, this sample 
size will provide greater than 80% power to detect the difference between either the 
Lu AA21004 10 mg or 20 mg group and the placebo group. These power calculations assume a 
common standard deviation of 9.5 for the change from baseline in the MADRS total score, with 
a 2-sided level of 0.025. 
 


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14.0 
QUALITY CONTROL AND QUALITY ASSURANCE 
14.1 
Study-Site Monitoring Visits 
Monitoring visits to the study site will be made periodically during the study to ensure that all 
aspects of the protocol are followed. Source documents will be reviewed for verification of data 
recorded on the eCRFs. Source documents are defined as original documents, data, and records. 
The investigator and the head of the institution guarantee access to source documents by the 
sponsor or its designee (CRO) and by the IRB. 
All aspects of the study and its documentation will be subject to review by the sponsor or 
designee, including but not limited to the Investigator’s Binder, study medication, subject 
medical records, and informed consent documentation. It is important that the investigator, the 
subinvestigator, and other study personnel are available during the monitoring visits and that 
sufficient time is devoted to the process. 
14.2 
Protocol Deviations 
The investigator can deviate and change from the protocol for any medically unavoidable reason, 
for example, to eliminate an immediate hazard to study subjects, without a prior written 
agreement with the sponsor or a prior approval from IRB. In the event of a deviation or change, 
the investigator should notify the sponsor and the head of the 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 site as 
soon as possible, and an approval from IRB should be obtained. 
The investigator should document all protocol deviations. 
14.3 
Quality Assurance Audits and Regulatory Agency Inspections 
The study site also may be subject to quality assurance audits by the sponsor or designees. In this 
circumstance, the sponsor-designated auditor will contact the site in advance to arrange an 
auditing visit. The auditor may ask to visit the facilities where laboratory samples are collected, 
where the medication is stored and prepared, and any other facility used during the study. In 
addition, there is the possibility that this study may be inspected by regulatory agencies, 
including those of foreign governments (e.g., the FDA, the United Kingdom Medicines and 
Healthcare products Regulatory Agency). 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 institution guarantee access for quality assurance auditors to all study documents as described 
in Section 14.1. 


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15.0 
ETHICAL ASPECTS OF THE STUDY 
This study will be conducted with the highest respect for the individual participants (i.e., 
subjects) according to the protocol, the ethical principles that have their origin in the Declaration 
of Helsinki, and the ICH Harmonised Tripartite Guideline for GCP. Each investigator will 
conduct the study according to applicable regulatory requirements and align his or her conduct in 
accordance with the “Responsibilities of the Investigator” that are listed in Appendix B. 
15.1 
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 abstinence 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 must be obtained and submitted to the sponsor or designee before 
commencement of the study (i.e., before shipment of the sponsor-supplied drug or signing of 
informed consent). The IRB approval must refer to the study by exact protocol title, number, and 
version date; identify versions of other documents (e.g., informed consent form) reviewed; and 
state the approval date. The sponsor will ship drug once the sponsor has confirmed the adequacy 
of site regulatory documentation. Until the site receives drug no protocol activities, including the 
informed consent procedure may occur. 
Sites must adhere to all requirements stipulated by their respective IRB. This may include 
notification to the IRB regarding protocol amendments, updates to the informed consent form, 
recruitment materials intended for viewing by subjects, local safety reporting requirements, 
reports and updates regarding the ongoing review of the study at intervals specified by the 
respective IRB, and submission of the investigator’s final status report to IRB. All IRB approvals 
and relevant documentation for these items must be provided to the sponsor or its designee. 
Subject incentives should not exert undue influence for participation. Payments to subjects must 
be approved by the IRB and sponsor. 
Regarding pharmacogenomic investigation using collected and stored specimens, analysis will 
be carried out at the time when detail is determined. The sponsor will create a research protocol 
for pharmacogenomics investigations, and a research protocol will require prior approval of the 
company IRB in Japan. 
15.2 
Subject Information, Informed Consent, and Subject Authorization 
Written consent documents will embody the elements of informed consent as described in the 
Declaration of Helsinki and the ICH Guidelines for GCP and will be in accordance with all 


Lu AA21004 
Study No. : Lu AA21004/CCT-004 
Page 76 of 82
Initial Protocol 
9 January 2015
 
CONFIDENTIAL 
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. The informed consent form will detail the 
requirements of the participant and the fact that he or she is free to withdraw at any time without 
giving a reason and without prejudice to his or her further medical care. 
The investigator is responsible for the preparation, content, and IRB approval of the informed 
consent form. The informed consent form must be approved by the IRB 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 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 ample opportunity to: (1) inquire about details of the study and (2) 
decide whether or not to participate in the study. If the subject determines he or she will 
participate in the study, then the informed consent form must be signed and/or sealed, and dated 
by the subject at the time of consent and prior to the subject entering into the study. The subject 
should be instructed to sign and/or seal using their legal names, not nicknames, using blue or 
black ballpoint ink. The investigator must also sign and/or seal, and date the informed consent 
form at the time of consent and prior to subject entering into the study. 
Once signed and/or sealed, the original informed consent form will be stored in the investigator’s 
site file. The investigator must document the date the subject signs the informed consent in the 
subject’s medical record. A copy of the signed and/or sealed informed consent form shall be 
given to the subject. 
All revised informed consent forms must be reviewed and signed by relevant subjects in the 
same manner as the original informed consent. The date the revised consent was obtained should 
be recorded in the subject’s medical record, and the subject should receive a copy of the revised 
informed consent form. 
The informed consent form for pharmacogenomic research in the clinical study of Lu AA21004 
will be used to explain the pharmacogenomic research to subjects after explanation of the 
informed consent for the entry into the study. Pharmacogenomic samples will be collected from 
subjects who have consented to both the study and the pharmacogenomic research. 
15.3 
Subject Confidentiality 
The sponsor and designees affirm and uphold the principle of the subject’s right to protection 
against invasion of privacy. Throughout this study, a subject’s source data will only be linked to 
the sponsor’s clinical study database or documentation via a unique identification number. As 
permitted by all applicable laws and regulations, limited subject attributes, such as sex, age, or 
date of birth, may be used to verify the subject and accuracy of the subject’s unique 
identification number. 


Lu AA21004 
Study No. : Lu AA21004/CCT-004 
Page 77 of 82
Initial Protocol 
9 January 2015
 
CONFIDENTIAL 
To comply with ICH Guidelines for GCP and to verify compliance with this protocol, the 
sponsor requires the investigator to permit its monitor or designee’s monitor, representatives 
from any regulatory authority (e.g., FDA, Medicines and Healthcare products Regulatory 
Agency, Pharmaceuticals and Medical Devices Agency), the sponsor’s designated auditors, and 
the appropriate IRBs to review the subject’s original medical records (source data or documents), 
including, but not limited to, laboratory test result reports, ECG reports, admission and discharge 
summaries for hospital admissions occurring during a subject’s study participation, and autopsy 
reports. Access to a subject’s original medical records requires the specific authorization of the 
subject as part of the informed consent process (see Section 15.2). 
Copies of any subject source documents that are provided to the sponsor must have certain 
personally identifiable information removed (i.e., subject name, address, and other identifier 
fields not collected on the subject’s eCRF). 
15.4 
Publication, Disclosure, and Clinical Trial Registration Policy 
15.4.1 
Publication and Disclosure 
The investigator is obliged to provide the sponsor with complete test results and all data derived 
by the investigator from the study. During the study, only the sponsor may make study 
information available to other study investigators or to regulatory agencies, except as required by 
law or regulation. Except as otherwise allowable in the study site agreement, any public 
disclosure (including publicly accessible websites) related to the protocol or study results 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 needs to obtain a prior written approval from the sponsor to publish any 
information from the study externally such as to a professional association. 
15.4.2 
Clinical Trial Registration 
In order to ensure that information on clinical trials reaches the public in a timely manner and to 
comply with applicable laws, regulations, and guidance, Takeda will, at a minimum register 
interventional clinical trials it sponsors anywhere in the world on ClinicalTrials.gov or other 
publicly accessible websites (JAPIC-CTI) before start of study, as defined in Takeda 
Policy/Standard. Takeda contact information, along with investigator’s city, state (for US 
investigators), country, and recruiting status will be registered and available for public viewing. 
15.4.3 
Clinical Trial Results Disclosure 
Takeda will post the results of clinical trials on ClinicalTrials.gov or other publicly accessible 
websites (JAPIC-CTI), as required by Takeda Policy/Standard, applicable laws and/or 
regulations. 


Lu AA21004 
Study No. : Lu AA21004/CCT-004 
Page 78 of 82
Initial Protocol 
9 January 2015
 
CONFIDENTIAL 
15.5 
Insurance and Compensation for Injury 
Each subject in the study must be insured in accordance with the regulations applicable to the 
site where the subject is participating. If a local underwriter is required, then the sponsor or 
sponsor’s designee will obtain clinical study insurance against the risk of injury to clinical study 
subjects. 
Refer to the Clinical Study Site Agreement regarding the sponsor’s policy on subject 
compensation and treatment for injury. If the investigator has questions regarding this policy, he 
or she should contact the sponsor or sponsor’s designee. 


Lu AA21004 
Study No. : Lu AA21004/CCT-004 
Page 79 of 82
Initial Protocol 
9 January 2015
 
CONFIDENTIAL 
16.0 
REFERENCES 
[1] Nakane Y, Arima K. Cause and Symptom of Depression. The Journal of Practical Pharmacy. 
2000;51(2):826-34. 
[2] American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders, 
Fourth Edition, Text Revision. Translated by Takahashi S, Ono Y, Someya T. Igaku-Shoin. 
2004. 
[3] Guideline for Clinical Evaluation of Antidepressants (Pharmaceutical and Food Safety 
Bureau, Evaluation and Licensing Division; Notification No.1116-1 dated November 16 in 
2010) (in Japanese). 
[4] American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders, 
Fifth Edition. Translated by Takahashi S, Ono Y, Someya T, Kanba S, Ozaki N, Mimura M,  
Murai T.. Igaku-Shoin. 2014. 
[5] Bialik RJ, Ravindran AV, Bakish D, Lapierre YD., 1995. A Comparison of Placebo 
Responders and Nonresponders in Subgroups of Depressive Disorder. J Psychiatry Neurosci. 
1995;20:265-70. 
[6] Montgomery SA, Asberg M. A new depression scale designed to be sensitive to change. Br J 
Psychiatry. 1979;134:382-9. 
[7] Hamilton M. Development of a rating scale for primary depressive illness. Br J Soc Clin 
Psychol. 1967;6:278-96. 
[8] Guy W. ECDEU Assessment Manual for Psychopharmacology (Revised). Rockville, MD: 
US Department of Health, Education, and Welfare; Public Health Service; Alcohol, Drug 
Abuse, and Mental Health Administration; National Institute of Mental Health, 
Psychopharmacology Research Branch; 1976. p.193-198 
[9] Olfson M, Fireman B, Weissman MM, Leon AC, Sheehan DV, Kathol RG, et al. Mental 
disorders and disability among patients in a primary care group practice. Am J Psychiatry. 
1997;154:1734-40. 
[10] Posner K, Oquendo MA, Gould M, Stanley B, Davies M. Columbia Classification 
Algorithm of Suicide Assessment (C-CASA): Classification of Suicidal Events in the FDA’s 
Pediatric Suicidal Risk Analysis of Antidepressants. Am J Psychiatry. 2007;164(7):1035-43. 
[11] Posner K, Melvin GA, Stanley B, Oquendo MA, Gould M. Factors in the Assessment of 
Suicidality in Youth. CNS Spectr. 2007;12(2):156-62. 


Lu AA21004 
Study No. : Lu AA21004/CCT-004 
Page 80 of 82
Initial Protocol 
9 January 2015
 
CONFIDENTIAL 
Appendix A Schedule of Study Procedures 
 
Screening 
Period 
Placebo 
Lead-in 
Period (a) 
Double-blind Treatment Period 
Follow-up
Period 
Visit Number 
1 
2 
3 
4 
5 
6 
7 
8/ET (c) Follow-up (d)
Week (b) 
-3 
-1 
0 
1 
2 
4 
6 
8/ET (c) 
12 (d) 
Day (b) 
-22 
-8 
-1
7 
14
28 
42 
56/ET (c) 
84 (d)
Visit Window (Days) (b)  
±10 
±3 
0 
±1
±3
±3 
±3 
±3/- 
±5 
Informed consent 
X (e) 
 
 
 
 
 
 
 
 
Inclusion/exclusion criteria 
X 
X (f) 
X (f)
 
 
 
 
 
 
Demographics, medical history, 
medication history 
X 
 
 
 
 
 
 
 
 
Diagnosis of MDD 
X 
 
 
 
 
 
 
 
 
Assessments of major depressive 
episode 
X 
 
 
 
 
 
 
 
 
Physical examination 
X 
X 
X
 
 
 
 
X 
 
Weight, height (g) 
X 
X 
X
 
 
X 
 
X 
 
Vital signs 
X 
X 
X
X
X
X 
X 
X 
 
Concomitant medications 
X 
X 
X
X
X
X 
X 
X 
 
Concurrent medical conditions 
X 
 
 
 
 
 
 
 
 
Clinical laboratory tests (h) 
X 
X 
X
 
 
X 
 
X 
 
Pregnancy test (i) 
X 
X 
X
 
 
X 
 
X 
(-) 
Urine drug screening 
X 
X 
 
 
 
 
 
 
 
Pharmacokinetic sampling 
 
 
 
 
 
X 
 
(X) 
 
Pharmacogenomic sampling (j) 
 
(X) 
 
 
 
 
 
 
 
ECG 
X 
X 
X
 
 
X 
 
X 
 
C-SSRS 
X 
X 
X
X
X
X 
X 
X 
 
PTE/AE assessment (k) 
X 
X 
X
X
X
X 
X 
X 
(-) 
<Assessments with Rating Scales> 
MADRS 
X 
X 
X
X
X
X 
X 
X 
 
HAM-D 
X 
X 
X
 
 
 
 
X 
 
CGI-S 
X 
X 
X
X
X
X 
X 
X 
 
CGI-I (l) 
 
 
X
X
X
X 
X 
X 
 
SDS 
 
X 
X
 
 
 
 
X 
 
DSST 
 
X (m) 
X
X
 
 
 
X 
 
PDQ-5 
 
X 
X
X
 
 
 
X 
 
QIDS-J 
 
X 
X
X
X
X 
X 
X 
 
<Clinical Supply> 
Randomization 
 
 
X
 
 
 
 
 
 
Dispense study medication (n) 
 
X 
X
X
X
X 
X 
 
 
Drug return/accountability/compliance 
 
 
X
X
X
X 
X 
X 
 
 


Lu AA21004 
Study No. : Lu AA21004/CCT-004 
Page 81 of 82
Initial Protocol 
9 January 2015
 
CONFIDENTIAL 
ET = early termination 
(a) In the placebo lead-in period, subjects will receive the study medication in a single-blind manner. 
(b) The visit day in the double-blind treatment period is defined as Week 0 (Day -1). The day after Day -1 is 
defined as Day 1. All visit windows are in reference to the date of scheduled visit. 
(c) Subjects who prematurely discontinue the study during the placebo lead-in period or double-blind treatment 
period will be requested to visit the study site for the end-of study examinations within 7 days after the day of 
study discontinuation, wherever possible, and will be assessed in the same way as at Visit 8 (except for blood 
sampling for pharmacokinetics).  
(d) Safety follow-up assessments will be conducted. For subjects who prematurely discontinue the study during the 
placebo lead-in period or double-blind treatment period, the follow-up assessments will be made 28 ± 5 days 
after the last dose of the study medication. The follow-up assessments can either be conducted as a visit to the 
site or as a telephone contact. In the follow-up, the following will be assessed: outcomes of AEs continuing at 
Visit 8 (or the end-of study assessments if administration of the study medication is discontinued), new SAEs 
developed during the follow-up period, and special interest AEs. Female subjects of child-bearing potential will 
be asked to confirm whether they are pregnant or not. 
(e) Informed consent must be obtained prior to the initiation of any study procedure including washout of excluded 
medications. Informed consent may be obtained prior to the visit window of Visit 1. 
(f) 
Update at Visits 2 and 3. 
(g) Height is measured at only Visit 1. 
(h) Clinical laboratory tests will be performed under fasted conditions at Visits 3 and 8 or Early Termination Visit, 
and at other visits wherever possible. 
(i) 
For women of child-bearing potential. 
(j) 
Only for subjects who consent to provide pharmacogenomic samples, separately from consent of participation 
in the study. Pharmacogenomic samples for analyses will be collected at Visit 2 or thereafter, as soon as 
possible, during the study. 
(k) PTEs will be collected prior to study medication administration in the placebo lead-in period, and AEs will be 
collected after study medication administration. 
(l) 
The CGI-I score will be assessed by comparison with that at Visit 3. However, at Visit 3 or early termination 
prior to Visit 3, the score will be assessed by comparison with that at Visit 2.  
(m) Subjects will complete the sample items prior to the actual test. 
(n) At Visit 2, subjects will be dispensed the study medication for the placebo lead-in period. At Visit 3, subjects 
will be dispensed the study medication for the double-blind treatment period, Inner Carton 1, and Inner Carton 
2 at Visits 4 to 7, with a necessary and sufficient amount of the study medication by next visit. 
 


Lu AA21004 
Study No. : Lu AA21004/CCT-004 
Page 82 of 82
Initial Protocol 
9 January 2015
 
CONFIDENTIAL 
Appendix B Responsibilities of the Investigator 
1. Conduct the appropriate study in accordance with the protocol and GCP considering the 
rights, safety, and wellbeing of human subjects. 
2. When a part of the important activities related to the study are delegated to the investigator or 
the study collaborator, prepare the lists of activities to be delegated and responsible personnel, 
submit the lists to the director of the site in advance to get them accepted. 
3. Prepare a written informed consent form and other written information, and update as 
appropriate. 
4. Confirm the contents of the clinical study agreement. 
5. Provide necessary information on the protocol, medications, and responsibilities of individual 
personnel to the investigator and the study collaborator, and provide guidance and 
supervision. 
6. Screen subjects who meet the requirements of the protocol, provide the explanation of the 
study in writing, and obtain the written consent. 
7. Assume responsibility for all the medical judgement related to the study. 
8. Ensure in collaboration with the director of the site that sufficient information on all 
clinically significant adverse events related to the study are provided to subjects throughout 
and beyond the period when subjects participate in the study. 
9. If a subject consults other medical institution or other department, notify the physician of the 
medical institution or department of the subject’s participation in the study, as well as the end 
and termination of the study in writing, and document such records. 
10. In case of urgent report of an SAE, immediately notify the director of the site and the sponsor 
in writing. 
11. Determine the need of emergency key code blinding of a subject in case of emergency. 
12. Prepare correct and complete eCRFs, and submit them to the sponsor with electronic 
signature. 
13. Check and confirm the contents of eCRFs prepared by the sub-investigator or transcribed 
from the source data by the study collaborator, and submit them to the sponsor with 
electronic signature. 
14. Discuss any proposal from the sponsor including update of the protocol. 
15. Notify the director of the site of the end of the study in writing. 
 

SAP_001.pdf: 
 
 
Title: A Randomized, Double-Blind, Placebo-Controlled, Parallel-Group, Phase III Study 
to Assess the Efficacy and Safety of Lu AA21004 in Patients with Major Depressive 
Disorder 
NCT Number: NCT02389816 
Statistical analysis plan Approve Date: 23-May-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. 


Protocol No. Lu AA21004/CCT-004 
 
 
 
Statistical Analysis Plan 
 
 
Study Title: 
A Randomized, Double-Blind, Placebo-Controlled, Parallel-Group, 
Phase III Study to Assess the Efficacy and Safety of Once-daily Oral 
Dose of Lu AA21004 in Patients with Major Depressive Disorder 
 
A Phase III Study of Lu AA21004 in Patients with Major Depressive 
Disorder 
Study Number: 
Lu AA21004/CCT-004 
Sponsor: 
Takeda Pharmaceutical Company Limited 
 
Person Responsible for Preparing the Protocol 
Takeda Pharmaceutical Company Limited 
Trial Statistician 
Takeda Pharmaceutical Company Limited 
 
Version 2: Prepared on 23 May, 2018
 
PPD
PPD
PPD
PPD


Protocol No. Lu AA21004/CCT-004 
 
1 
Table of Contents 
Glossary ................................................................................................................................................ 3 
Definition of TIME WINDOW ............................................................................................................ 4 
Others .................................................................................................................................................... 7 
1 Study Subjects, Demographic, and Other Baseline Characteristics ................................................... 8 
1.1 Disposition of Subjects ................................................................................................................... 8 
1.1.1 Study Information .................................................................................................................... 8 
1.1.2 Disposition of All Subjects Who Did Not Enter Placebo Lead-in Period ................................ 8 
1.1.3 Subject Eligibility .................................................................................................................... 9 
1.1.4 Number of Subjects by Site ................................................................................................... 10 
1.1.5 Disposition of Subjects .......................................................................................................... 11 
1.1.6 Protocol Deviations and Analysis Sets .................................................................................. 12 
1.2 Demographics and Other Baseline Characteristics ....................................................................... 13 
1.2.1 Summary of Demographics and Other Baseline Characteristics ........................................... 13 
1.2.2 Medical History and Concurrent Medical Conditions ........................................................... 15 
1.2.3 Medication History and Concomitant Medications ............................................................... 16 
1.3 Treatment Compliance .................................................................................................................. 16 
1.3.1 Study Drug Exposure and Compliance .................................................................................. 16 
2 Efficacy Analysis ............................................................................................................................. 17 
2.1 Primary Endpoint(s) and Analytical Methods............................................................................... 17 
2.1.1 Primary Analysis .................................................................................................................... 17 
2.1.2 Secondary Analysis (1) .......................................................................................................... 18 
2.1.3 Secondary Analysis (2) .......................................................................................................... 18 
2.2 Secondary Endpoint(s) and Analytical Methods ........................................................................... 19 
2.3 Other Analysis/Additional Endpoint(s) and Analytical Methods ................................................. 22 
2.4 Statistical/Analytical Issues .......................................................................................................... 31 
2.4.1 Adjustments for Covariates .................................................................................................... 31 
2.4.2 Handling of Dropouts or Missing Data .................................................................................. 31 
2.4.3 Interim Analyses and Data Monitoring .................................................................................. 31 
2.4.4 Multicenter Studies ................................................................................................................ 31 
2.4.5 Multiple Comparison/Multiplicity ......................................................................................... 31 
2.4.6 Use of an “Efficacy Subset” of Subjects ................................................................................ 32 
2.4.7 Active-Control Studies Intended to Show Equivalence or Non-Inferiority ........................... 32 
2.4.8 Examination of Subgroups ..................................................................................................... 32 
3 Safety Analysis ................................................................................................................................ 33 
3.1 Treatment-Emergent Adverse Event ............................................................................................. 33 
3.1.1 Overview of Treatment-Emergent Adverse Events ............................................................... 33 


Protocol No. Lu AA21004/CCT-004 
 
2 
3.1.2 Displays of Treatment-Emergent Adverse Events ................................................................. 34 
3.2 Pretreatment Events and Placebo Lead-in Adverse Events .......................................................... 35 
3.2.1 Displays of Pretreatment Events ............................................................................................ 35 
3.2.2 Displays of Placebo Lead-in Adverse Events ........................................................................ 36 
3.3 Laboratory and Other Safety Data ................................................................................................ 37 
3.3.1 Laboratory Test Results ......................................................................................................... 37 
3.3.2 Vital Signs, Physical Findings and Other Observations Related to Safety ............................ 38 
4 Significance Level and Confidence Coefficient .............................................................................. 44 
Amendment History (Version Management) ...................................................................................... 45 
[Appendix 1] Change Comparison Table for Lu AA21004/CCT-004 ................................................. 1 
[Appendix 2]Definition of PCS Criteria ............................................................................................... 1 
 
 
 


Protocol No. Lu AA21004/CCT-004 
 
3 
Glossary 
• 
Treatment-emergent adverse event (TEAE): An adverse event which occurs on or after the start 
of double-blind study drug 
• 
Placebo lead-in adverse event: An adverse event which occurs on or after the start of placebo 
lead-in study drug before the start of double-blind study drug 
• 
Drug-related adverse event: An adverse event that is considered to be either probable, or 
possible related to the double-blind study drug will be treated as related. 
• 
Descriptive statistics: number of subjects, mean, standard deviation, maximum, minimum, and 
quartiles 
• 
PCS: Potentially Clinically Significant 
• 
Study Day: The day before the first dose of the double-blind study drug will be defined as 
Study Day -1 and the day of the first dose will be defined as Study Day 1. 
• 
Follow-up Day: The day after the last dose of the double-blind study drug will be defined as 
Follow-up Day 1. 
• 
Treatment Groups: Placebo, Lu AA21004 10 mg, Lu AA21004 20 mg 
• 
MADRS total score: Sum of the 10 MADRS items 
• 
HAM-D17 total score: Sum of the 17 HAM-D items 
• 
HAM-D21 total score: Sum of the 21 HAM-D items 
• 
SDS total score: Sum of the 3 SDS items 
• 
MADRS response: Percentage of subjects whose MADRS total score decreased by a greater 
than or equal to 50% from baseline 
• 
MADRS remission: Percentage of subjects whose MADRS total score decreased to 10 or less 
 
 
 


Protocol No. Lu AA21004/CCT-004 
 
4 
Definition of TIME WINDOW 
For each test/observation/evaluation item, all evaluable data (non-missing and acceptable according 
to the “Handling Rules for Analysis Data”) will be handled according to the following rules. 
For each visit other than Week 8 (LOCF), observation in the corresponding time interval will be 
used. If more than one observation lies within the same visit window, the observation with the 
closest Study Day to the scheduled Study Day will be used. If there are two observations equidistant 
to the scheduled Study Day, the later observation will be used. The difference from the scheduled 
Study Day will be judged based on the Study Day and Follow-up Day. 
For Week 8 (LOCF), the last observation obtained in the corresponding time interval will be used. 
 
MADRS, CGI-S 
Visit 
Scheduled Study Day (days) 
Time Interval (days) 
Study Day 
Follow-up Day 
Screening 
Study Day: -22 
<= -12 
- 
Placebo lead-in 
Study Day: -8 
-11 - -5 
- 
Baseline (Week 0) 
Study Day: -1 
-4 - 1 
- 
Week 1 
Study Day: 7 
2 - 10 
<8 
Week 2 
Study Day: 14 
11 - 21 
<8 
Week 4 
Study Day: 28 
22 - 35 
<8 
Week 6 
Study Day: 42 
36 - 49 
<8 
Week 8 
Study Day: 56 
50 <= 
<8 
Week 8 (LOCF) 
- 
 
2 <= 
<8 
 
 
 


Protocol No. Lu AA21004/CCT-004 
 
5 
HAM-D 
Visit 
Scheduled Study Day (days) 
Time Interval (days) 
Study Day 
Follow-up Day 
Screening 
Study Day: -22 
<= -12 
- 
Placebo lead-in 
Study Day: -8 
-11 - -5 
- 
Baseline (Week 0) 
Study Day: -1 
-4 - 1 
- 
Week 8 
Study Day: 56 
2 <= 
<8 
Week 8 (LOCF) 
- 
 
2 <= 
<8 
 
CGI-I 
Visit 
Scheduled Study Day (days) 
Time Interval (days) 
Study Day 
Follow-up Day 
Baseline (Week 0) 
Study Day: -1 
<= 1 
- 
Week 1 
Study Day: 7 
2 - 10 
<8 
Week 2 
Study Day: 14 
11 - 21 
<8 
Week 4 
Study Day: 28 
22 - 35 
<8 
Week 6 
Study Day: 42 
36 - 49 
<8 
Week 8 
Study Day: 56 
50 <= 
<8 
Week 8 (LOCF) 
- 
 
2 <= 
<8 
 
 
 


Protocol No. Lu AA21004/CCT-004 
 
6 
SDS 
Visit 
Scheduled Study Day (days) 
Time Interval (days) 
Study Day 
Follow-up Day 
Placebo lead-in 
Study Day: -8 
<= -5 
- 
Baseline (Week 0) 
Study Day: -1 
-4 - 1 
- 
Week 8 
Study Day: 56 
2 <= 
<8 
Week 8 (LOCF) 
- 
 
2 <= 
<8 
 
DSST, PDQ-5 
Visit 
Scheduled Study Day (days) 
Time Interval (days) 
Study Day 
Follow-up Day 
Placebo lead-in 
Study Day: -8 
<= -5 
- 
Baseline (Week 0) 
Study Day: -1 
-4 - 1 
- 
Week 1 
Study Day: 7 
2 - 10 
<8 
Week 8 
Study Day: 56 
11 <= 
<8 
Week 8 (LOCF) 
- 
 
2 <= 
<8 
 
Laboratory Value, Weight, ECG 
Visit 
Scheduled Study Day (days) 
Time Interval (days) 
Study Day 
Follow-up Day 
Screening 
Study Day: -22 
<= -12 
- 
Placebo lead-in 
Study Day: -8 
-11 - -5 
- 
Baseline (Week 0) 
Study Day: -1 
-4 - 1 
- 
Week 4 
Study Day: 28 
2 - 42 
<8 
Week 8 
Study Day: 56 
43 <= 
<8 
 
 
 


Protocol No. Lu AA21004/CCT-004 
 
7 
Vital Sign, C-SSRS 
Visit 
Scheduled Study Day (days) 
Time Interval (days) 
Study Day 
Follow-up Day 
Screening 
Study Day: -22 
<= -12 
- 
Placebo lead-in 
Study Day: -8 
-11 - -5 
- 
Baseline (Week 0) 
Study Day: -1 
-4 - 1 
- 
Week 1 
Study Day: 7 
2 - 10 
<8 
Week 2 
Study Day: 14 
11 - 21 
<8 
Week 4 
Study Day: 28 
22 - 35 
<8 
Week 6 
Study Day: 42 
36 - 49 
<8 
Week 8 
Study Day: 56 
50 <= 
<8 
 
 
Others 
• 
Duration of exposure to double-blind study drug (days): date of last dose of double-blind study 
drug − date of first dose of double-blind study drug + 1 
• 
Double-blind study drug compliance (%): number of double-blind study drugs taken / duration 
of exposure to double-blind study drug × 100 (rounded off to one decimal place) 
• 
QTCF interval = (QT interval) / ([QTCB interval]2 / [QT interval]2)0.33 (rounded off to the whole 
number) 
• 
Among the laboratory test items, the following data will not be included if it is from a 
postprandial specimen. 
Glucose, lipids (triglycerides, total cholesterol, HDL cholesterol, LDL cholesterol [Direct 
method]) 
• 
 


Protocol No. Lu AA21004/CCT-004 
 
8 
1 Study Subjects, Demographic, and Other Baseline Characteristics 
1.1 Disposition of Subjects 
1.1.1 Study Information 
Analysis Set: All Subjects Who Signed the Informed Consent Form 
Analysis 
Variable(s): 
Date First Subject Signed the Informed Consent Form 
MedDRA Version 
WHO Drug Version 
SAS Version Used for Creating the Datasets 
Analytical 
Method(s): 
The following summaries will be provided for the above analysis variable(s). 
(1) 
Display of Analysis Variable(s) 
 
1.1.2 Disposition of All Subjects Who Did Not Enter Placebo Lead-in Period 
Analysis 
Set: 
All Subjects Who Did Not Enter the Placebo Lead-in Period 
Analysis 
Variable(s): 
Categories in parentheses ([ ]) (hereinafter the same) 
Age (years) 
[Min<= - <=50, 51<= - <=Max]  
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 
 
 
 


Protocol No. Lu AA21004/CCT-004 
 
9 
1.1.3 Subject Eligibility 
1.1.3.1 
Subject Eligibility at Start of Placebo Lead-in Period 
Analysis Set: All Subjects Who Signed the Informed Consent Form 
Analysis 
Variable(s): 
Eligibility Status 
[Eligible for Entrance into the 
Placebo Lead-in Period, Not Eligible 
for Entrance into the Placebo Lead-in 
Period] 
Primary Reason for Subject Not 
Being Eligible 
[Pretreatment Event or Adverse 
Event (AE), Did Not Meet Inclusion 
Criteria, Met Exclusion Criteria, 
Major Protocol Deviation, Lost to 
Follow-up, Voluntary Withdrawal, 
Study Termination, 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 
denominator. 
(1) 
Frequency Distributions 
 
1.1.3.2 
Subject Eligibility at Start of Double-blind Period 
Analysis Set: All Subjects Who Entered the Placebo Lead-in Period 
Analysis 
Variable(s): 
Eligibility Status 
[Eligible for Randomization, Not 
Eligible for Randomization] 
Primary Reason for Subject Not 
Being Randomized 
[Pretreatment Event or Adverse 
Event (AE), Did Not Meet Inclusion 
Criteria, Met Exclusion Criteria, 
Major Protocol Deviation, Lost to 
Follow-up, Voluntary Withdrawal, 
Study Termination, 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 for randomization, the total number of ineligible subjects will be used 
as the denominator. 
(1) 
Frequency Distributions 
 
 


Protocol No. Lu AA21004/CCT-004 
 
10 
1.1.4 Number of Subjects by Site 
1.1.4.1 Number of Subjects Who Entered the Placebo Lead-in Period by Site 
Analysis Set: All Subjects Who Entered the Placebo Lead-in Period 
Analysis 
Variable(s): 
Status of Entrance into the Placebo 
Lead-in Period 
[Entered] 
Stratum: 
Site 
[Site numbers will be used as 
categories] 
Analytical 
Method(s): 
The following summaries will be provided for the above analysis variable(s) 
for each stratum. 
(1) 
Frequency Distributions 
 
1.1.4.2 
Number of Subjects Randomized by Site 
Analysis Set: Randomized Set 
Analysis 
Variable(s): 
Randomization Status 
[Randomized] 
Stratum: 
Site 
[Site numbers will be used as 
categories] 
Analytical 
Method(s): 
Frequency distributions will be provided for each treatment group and overall 
for each stratum. 
(1) 
Frequency Distributions 
 
 


Protocol No. Lu AA21004/CCT-004 
 
11 
1.1.5 Disposition of Subjects 
Analysis Set: Randomized Set 
Analysis 
Variable(s): 
Double-blind Study Drug 
Administration Status 
[Not Treated] 
Reason for Not Being Treated 
[Pretreatment Event or Adverse 
Event (AE, Liver Function 
Abnormalities, Major Protocol 
Deviation, Lost to Follow-up, 
Voluntary Withdrawal, Study 
Termination, Pregnancy, Lack of 
Efficacy, Non Compliance with IMP, 
Other] 
Double-blind Study Drug Completion 
Status 
[Completed Study Drug, Prematurely 
Discontinued Study Drug] 
Reason for Discontinuation of 
Study Drug 
[Pretreatment Event or Adverse 
Event (AE), Liver Function 
Abnormalities, Major Protocol 
Deviation, Lost to Follow-up, 
Voluntary Withdrawal, Study 
Termination, Pregnancy, Lack of 
Efficacy, Non Compliance with IMP, 
Other] 
Analytical 
Method(s): 
Frequency distributions will be provided for each treatment group and 
overall. 
When calculating percentages for the reasons for not being treated, the total 
number of subjects not treated by the study drug will be used as the 
denominator. When calculating percentages for the reasons for 
discontinuation, the total number of subjects who prematurely discontinued 
will be used as the denominator. 
(1) 
Frequency Distributions 
 
 


Protocol No. Lu AA21004/CCT-004 
 
12 
1.1.6 Protocol Deviations and Analysis Sets 
1.1.6.1 Protocol Deviations 
Analysis Set: All Subjects Who Entered the Placebo Lead-in Period 
Randomized Set 
Analysis 
Variable(s): 
Protocol Deviations 
[Major GCP Violations, Deviations 
of Protocol Entry Criteria, 
Deviations of Discontinuation 
Criteria, Deviations Related to 
Treatment Procedure or Dose, 
Deviations Concerning Excluded 
Medication or Therapy, Deviations 
to Avoid Emergency Risk, Other 
Deviations] 
Analytical 
Method(s): 
The following summaries will be provided for the above analysis variable(s). 
When the randomized set is analyzed, the frequency distribution will be 
provided for each treatment group and overall. 
The number of subjects who have protocol deviations will be counted, and the 
disposition of deviations are shown after classifying the contents of deviations 
into the above categories. A subject who has several deviations that can be 
classified into several categories will be counted once in each appropriate 
category (overlapping). 
(1) 
Frequency Distributions 
 
1.1.6.2 
Analysis Sets 
Analysis Set: Randomized Set 
Analysis 
Variable(s): 
Handling of Subjects and Subject Data 
 
Analysis Sets 
Full Analysis Set 
Per Protocol Set 
Safety Analysis Set 
[Categories are based on the 
specifications in Handling Rules 
for Analysis Data] 
[Included] 
[Included] 
[Included] 
Analytical 
Method(s): 
Frequency distributions will be provided by treatment group for (1) and (2), 
and by treatment group and overall for (3). 
For (1) and (2), a subject who has several reasons for exclusion will be 
counted once in each appropriate category (overlapping). 


Protocol No. Lu AA21004/CCT-004 
 
13 
 
(1) Frequency Distributions for Subjects Excluded from Analysis Sets 
(2) Frequency Distributions for Subject Data Excluded from Analysis Sets 
(3) Frequency Distributions for Number of Included Subjects in Analysis Sets 
 
1.2 Demographics and Other Baseline Characteristics 
1.2.1 Summary of Demographics and Other Baseline Characteristics 
Analysis 
Set: 
Randomized Set 
All Subjects Who Entered the Placebo Lead-in Period 
All Subjects Who Entered the Placebo Lead-in Period, but Not Randomized 
Analysis 
Variable(s): 
Age (years) 
[Min<= - <=50, 51<= - <=Max]  
Gender 
[Male, Female] 
Height (cm) 
 
Weight (kg) at Baseline 
 
BMI (kg/m2) at Baseline 
 
Smoking Classification 
[The subject is a current smoker, The 
subject is an ex-smoker, The subject 
has never smoked] 
History of Alcohol Consumption 
[Never, Once monthly or less often, 
Once a week, 2 to 6 times/week, 
Daily] 
Symptoms for Major Depressive 
Episode 
1. Depressed mood almost all day 
long or almost every day shown 
by that person’s own statement 
(e.g., sorrow or feeling of 
emptiness) or other person’s 
observation (e.g., that person 
looks crying) 
 
 
[Yes, No] 
2. Markedly diminished interest or 
pleasure almost all day long, 
almost every day, or in almost all 
activities (shown by that 
person’s own statement or other 
person’s observation) 
[Yes, No] 
3. Significant weight loss or 
decrease despite of no dietary 
[Yes, No] 


Protocol No. Lu AA21004/CCT-004 
 
14 
therapy (e.g., not less than 5% 
change of weight in a month) or 
decreased or increased appetite 
almost every day 
4. Insomnia or hypersomnia almost 
every day 
[Yes, No] 
5. Psychomotor agitation or 
retardation almost every day 
(which can be observed by other 
persons but not subjective 
sensation, e.g., that person is 
simply restless or has become 
sluggish) 
[Yes, No] 
6. Fatigue or loss of energy almost 
every day 
[Yes, No] 
7. Feelings of worthlessness, or 
excessive or inappropriate guilt 
almost every day (which could 
be delusive but not simply 
blaming oneself or a sense of 
guilt toward becoming ill) 
[Yes, No] 
8. Diminished ability to think or 
concentrate, or indecisiveness 
almost every day (shown by that 
person’s own statement or other 
person’s observation) 
[Yes, No] 
9. Recurrent thoughts of death (not 
only fear of death), recurrent 
suicidal ideation or actual 
attempt with no special plan, or 
clear plan for suicide 
[Yes, No] 
MADRS Total Score at Placebo 
Lead-in 
[Min<= - <=30, 31<= - <=Max] 
MADRS Total Score at Baseline 
[Min<= - <=30, 31<= - <=Max] 
Percent Chang in MADRS Total 
Score from Placebo Lead-in at 
Baseline 
[Min<= - <=-25, -25< - <25, 25<= - 
<=Max] 


Protocol No. Lu AA21004/CCT-004 
 
15 
HAM-D17 Total Score at Placebo 
Lead-in 
 
HAM-D17 Total Score at Baseline 
 
CGI-I Score at Baseline 
 
CGI-S Score at Placebo Lead-in 
[Min<= - <=4, 5<= - <=Max] 
CGI-S Score at Baseline 
[Min<= - <=4, 5<= - <=Max] 
SDS Total Score at Placebo Lead-in 
 
SDS Total Score at Baseline 
 
DSST Score at Placebo Lead-in 
 
DSST Score at Baseline 
 
PDQ-5 Score at Placebo Lead-in 
 
PDQ-5 Score at Baseline 
 
Analytical 
Method(s): 
The following summaries will be provided for the above analysis variable(s). 
When the randomized set is analyzed, the frequency distribution will be 
provided for each treatment group and overall. However, weight, BMI, and 
efficacy endpoints (MADRS total score, HAM-D17 total score, CGI-I score, 
CGI-S score, SDS total score, DSST score, and PDQ-5 score) will target only 
the randomized set. 
(1) Frequency distributions for counting values and descriptive statistics for 
continuous variables 
 
1.2.2 Medical History and Concurrent Medical Conditions 
Analysis 
Set: 
Safety Analysis Set 
Analysis 
Variable(s): 
Medical History 
 
Concurrent Medical Conditions 
 
Analytical 
Method(s): 
Frequency distributions will be provided for each treatment group and overall. 
Analysis variables 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) Frequency distributions for medical history by SOC and PT 
(2) Frequency distributions for concurrent medical conditions by SOC and PT 
The frequency distribution will be provided according to the rules below. 
[Number of subjects] 
A subject with multiple occurrences of medical history or concurrent 
medical condition within a SOC will be counted only once in that SOC. A 


Protocol No. Lu AA21004/CCT-004 
 
16 
subject with multiple occurrences of medical history or concurrent medical 
condition within a PT will be counted only once in that PT. 
 
1.2.3 Medication History and Concomitant Medications 
Analysis 
Set: 
Safety Analysis Set 
Analysis 
Variable(s): 
Medication History 
 
Concomitant Medications 
 
Analytical 
Method(s): 
Frequency distributions will be provided for each treatment group and overall. 
Analysis variables will be coded using WHO Drug dictionary and will be 
summarized using generic names. They will be sorted in decreasing frequency 
based on the number of reports. 
A subject who has been administered several medications with the same 
generic name will be counted only once for that generic name. 
(1) Frequency distributions for medication history 
(2) Frequency distributions for concomitant medications 
 
1.3 Treatment Compliance 
1.3.1 Study Drug Exposure and Compliance 
Analysis 
Set: 
Safety Analysis Set 
 
Analysis 
Variable(s): 
Duration of Exposure to 
Double-blind Study Drug (days) 
[1<= - <=7, 8<= - <=14, 15<= - <=28, 
29<= - <=42, 43<= - <=56, 57<= - 
<=Max] 
Double-blind Study Drug 
Compliance (%) 
[Min<= - <70.0, 70.0<= - <90.0, 
90.0<= - <=100.0, 100.0< - <=Max] 
Analytical 
Method(s): 
 
Frequency distributions will be provided for each treatment group and overall. 
(1) Frequency distributions for counting values and descriptive statistics for 
continuous variables 
 
 
 


Protocol No. Lu AA21004/CCT-004 
 
17 
2 Efficacy Analysis 
The full analysis set that has been defined in the protocol and the Handling Rules for Analysis 
Data will be the main analysis set used. The per protocol set will be used for an analysis 
performed secondarily on the primary endpoint in order to examine the robustness of the results 
from the perspective of sensitivity analysis. 
 
2.1 Primary Endpoint(s) and Analytical Methods 
 
2.1.1 Primary Analysis 
Analysis Set: Full Analysis Set 
Analysis 
Variable(s): 
Change from baseline in the MADRS total score at Week 8 of treatment with 
double-blind study drug 
Analytical 
Method(s): 
Primary efficacy analysis will be performed based on a mixed model for 
repeated measurements (MMRM) analysis of covariance with change from 
baseline in MADRS total score at each post-dose visit as a dependent 
variable, and visit, treatment group, visit-by-treatment group interaction, 
baseline MADRS total score-by-visit interaction as fixed effects. 
Comparisons between each Lu AA21004 group and the Placebo group will be 
performed at Week 8 of treatment with double-blind study drug. For the 
adjustment of freedom degree, Satterthwaite method will be used. For 
covariance structure analysis among the subjects, the same, unstructured 
covariance matrix is assumed. 
[Model] 
Change from baseline in the MADRS total score = Visit + Treatment group + 
Treatment group × Visit + baseline MADRS total score × Visit 
Holm adjustment will be used for multiplicity for the comparison. That is, 
H01: μPlacebo = μ10 mg 
H02: μPlacebo = μ20 mg 
A p-value for each null hypothesis will be set to be P1 and P2. A test will be 
performed according to the following procedures after setting P1 and P2 in an 
ascending order as P(1) and P(2) and setting the corresponding null hypotheses 
as H(1) and H(2). 
Step 1: In the case of P(1) >0.025, end the test procedures by holding null 
hypotheses H(1) and H(2). In the case of P(1) ≤0.025, reject null hypothesis H(1) 
and proceed to Step 2. 
Step 2: In the case of P(2) >0.05, hold null hypothesis H(2). In the case of P(2) 
≤0.05, reject null hypothesis H(2). 


Protocol No. Lu AA21004/CCT-004 
 
18 
 
2.1.2 Secondary Analysis (1) 
Analysis Set: Per Protocol Set 
Analysis 
Variable(s): 
Change from baseline in the MADRS total score at Week 8 of treatment with 
double-blind study drug 
Analytical 
Method(s): 
To check the robustness of the results depending on handling of subjects and 
subject data, the same analyses as section 2.1.1 “Primary Analysis” will be 
performed using the per protocol set. 
 
2.1.3 Secondary Analysis (2) 
Analysis Set: Full Analysis Set 
Analysis 
Variable(s): 
Change from baseline in the MADRS total score at Week 8 (LOCF) of 
treatment with double-blind study drug (Week 8 [LOCF] - Baseline) 
Visit: 
Week 8 (LOCF) 
Analytical 
Method(s): 
Descriptive statistics and two-sided 95% confidence intervals of means will 
be provided for the change from baseline in the MADRS total score at Week 
8 (LOCF) of treatment with double-blind study drug (Week 8 [LOCF] - 
Baseline) by treatment group. The change from baseline in the MADRS total 
score at Week 8 (LOCF) of treatment with double-blind study drug 
(dependent variable) will be analyzed using an analysis of covariance 
(ANCOVA) model with treatment as a fixed effect and the baseline MADRS 
total score as a covariate. Least Square (LS) means and the two-sided 95% 
confidence intervals will be provided for each treatment group. The point 
estimates of the differences in the LS means between each Lu AA21004 
group and the placebo group (each Lu AA21004 group - placebo group) and 
the two-sided 95% confidence intervals will be provided. The differences in 
the LS means will be tested for treatment differences. 
 
 
 


Protocol No. Lu AA21004/CCT-004 
 
19 
2.2 Secondary Endpoint(s) and Analytical Methods 
Analysis Set: Full Analysis Set 
Analysis 
Variable(s): 
MADRS response at Week 8 (LOCF) of treatment with double-blind study 
drug 
MADRS remission at Week 8 (LOCF) of treatment with double-blind study 
drug 
Change from baseline in the HAM-D17 total score at Week 8 (LOCF) of 
treatment with double-blind study drug 
CGI-I score at Week 8 (LOCF) of treatment with double-blind study drug 
Change from baseline in the CGI-S score at Week 8 (LOCF) of treatment 
with double-blind study drug 
Change from baseline in the SDS total score at Week 8 (LOCF) of treatment 
with double-blind study drug 
Change from baseline in the DSST score at Week 8 (LOCF) of treatment with 
double-blind study drug 
Change from baseline in the PDQ-5 score at Week 8 (LOCF) of treatment 
with double-blind study drug 
Visit: 
Week 8 (LOCF) 
Analytical 
Method(s): 
(1) MADRS response at Week 8 (LOCF) of treatment with double-blind 
study drug 
Frequency distributions will be provided by treatment group along with point 
estimates and the two-sided 95% confidence intervals for MADRS response 
at Week 8 (LOCF) of treatment with double-blind study drug. Odds ratios of 
each Lu AA21004 group to the placebo group (each Lu AA21004 group / 
placebo group) and the two-sided 95% confidence intervals will be provided 
and tested for treatment differences using a logistic regression model. The 
logistic regression model will include MADRS response at Week 8 (LOCF) 
of treatment with double-blind study drug as a dependent variable, and 
treatment group and baseline MADRS total score as independent variables. 
(2) MADRS remission at Week 8 (LOCF) of treatment with double-blind 
study drug 
Frequency distributions will be provided by treatment group along with point 
estimates and the two-sided 95% confidence intervals at Week 8 (LOCF) of 
treatment with double-blind study drug. Odds ratios of each Lu AA21004 
group to the placebo group (each Lu AA21004 group / placebo group) and the 
two-sided 95% confidence intervals will be provided and tested for treatment 


Protocol No. Lu AA21004/CCT-004 
 
20 
differences using a logistic regression model. The logistic regression model 
will include MADRS remission at Week 8 (LOCF) of treatment with 
double-blind study drug as a dependent variable, and treatment group and 
baseline MADRS total score as independent variables. 
(3) Change from baseline in the HAM-D17 total score at Week 8 (LOCF) of 
treatment with double-blind study drug 
Descriptive statistics and two-sided 95% confidence intervals of means will 
be provided for the change from baseline in the HAM-D17 total score at 
Week 8 (LOCF) of treatment with double-blind study drug by treatment 
group. The change from baseline in the HAM-D17 total score at Week 8 
(LOCF) of treatment with double-blind study drug (dependent variable) will 
be analyzed using an ANCOVA model with treatment as a fixed effect and 
the baseline HAM-D17 total score as a covariate. Least Square (LS) means 
and the two-sided 95% confidence intervals will be provided for each 
treatment group. The point estimates of the differences in the LS means 
between each Lu AA21004 group and the placebo group (each Lu AA21004 
group - placebo group) and the two-sided 95% confidence intervals will be 
provided. The differences in the LS means will be tested for treatment 
differences. 
(4) CGI-I score at Week 8 (LOCF) of treatment with double-blind study drug 
Descriptive statistics and two-sided 95% confidence intervals of means will 
be provided for the CGI-I score at Week 8 (LOCF) of treatment with 
double-blind study drug by treatment group. The CGI-I score at Week 8 
(LOCF) of treatment with double-blind study drug (dependent variable) will 
be analyzed using an ANCOVA model with treatment as a fixed effect and 
the baseline CGI-S score as a covariate. Least Square (LS) means and the 
two-sided 95% confidence intervals will be provided for each treatment 
group. The point estimates of the differences in the LS means between each 
Lu AA21004 group and the placebo group (each Lu AA21004 group - 
placebo group) and the two-sided 95% confidence intervals will be provided. 
The differences in the LS means will be tested for treatment differences. 
(5) Change from baseline in the CGI-S score at Week 8 (LOCF) of treatment 
with double-blind study drug 
Descriptive statistics and two-sided 95% confidence intervals of means will 
be provided for the change from baseline in the CGI-S score at Week 8 
(LOCF) of treatment with double-blind study drug by treatment group. The 
change from baseline in the CGI-S score at Week 8 (LOCF) of treatment with 


Protocol No. Lu AA21004/CCT-004 
 
21 
double-blind study drug (dependent variable) will be analyzed using an 
ANCOVA model with treatment as a fixed effect and the baseline CGI-S 
score as a covariate. Least Square (LS) means and the two-sided 95% 
confidence intervals will be provided for each treatment group. The point 
estimates of the differences in the LS means between each Lu AA21004 
group and the placebo group (each Lu AA21004 group - placebo group) and 
the two-sided 95% confidence intervals will be provided. The differences in 
the LS means will be tested for treatment differences. 
(6) Change from baseline in the SDS total score at Week 8 (LOCF) of 
treatment with double-blind study drug 
Descriptive statistics and two-sided 95% confidence intervals of means will 
be provided for the change from baseline in the SDS total score at Week 8 
(LOCF) of treatment with double-blind study drug by treatment group. The 
change from baseline in the SDS total score at Week 8 (LOCF) of treatment 
with double-blind study drug (dependent variable) will be analyzed using an 
ANCOVA model with treatment as a fixed effect and the baseline SDS total 
score as a covariate. Least Square (LS) means and the two-sided 95% 
confidence intervals will be provided for each treatment group. The point 
estimates of the differences in the LS means between each Lu AA21004 
group and the placebo group (each Lu AA21004 group - placebo group) and 
the two-sided 95% confidence intervals will be provided. The differences in 
the LS means will be tested for treatment differences. 
(7) Change from baseline in the DSST score at Week 8 (LOCF) of treatment 
with double-blind study drug 
Descriptive statistics and two-sided 95% confidence intervals of means will 
be provided for the change from baseline in the DSST score at Week 8 
(LOCF) of treatment with double-blind study drug by treatment group. The 
change from baseline in the DSST score at Week 8 (LOCF) of treatment with 
double-blind study drug (dependent variable) will be analyzed using an 
ANCOVA model with treatment as a fixed effect and the baseline DSST 
score as a covariate. Least Square (LS) means and the two-sided 95% 
confidence intervals will be provided for each treatment group. The point 
estimates of the differences in the LS means between each Lu AA21004 
group and the placebo group (each Lu AA21004 group - placebo group) and 
the two-sided 95% confidence intervals will be provided. The differences in 
the LS means will be tested for treatment differences. 


Protocol No. Lu AA21004/CCT-004 
 
22 
 
(8) Change from baseline in the PDQ-5 score at Week 8 (LOCF) of treatment 
with double-blind study drug 
Descriptive statistics and two-sided 95% confidence intervals of means will 
be provided for the change from baseline in the PDQ-5 score at Week 8 
(LOCF) of treatment with double-blind study drug by treatment group. The 
change from baseline in the PDQ-5 score at Week 8 (LOCF) of treatment 
with double-blind study drug (dependent variable) will be analyzed using an 
ANCOVA model with treatment as a fixed effect and the baseline PDQ-5 
score as a covariate. Least Square (LS) means and the two-sided 95% 
confidence intervals will be provided for each treatment group. The point 
estimates of the differences in the LS means between each Lu AA21004 
group and the placebo group (each Lu AA21004 group - placebo group) and 
the two-sided 95% confidence intervals will be provided. The differences in 
the LS means will be tested for treatment differences. 
 
 
2.3 Other Analysis/Additional Endpoint(s) and Analytical Methods 
Analysis Set: Full Analysis Set 
Analysis 
Variable(s): 
MADRS total score, MADRS single item 
MADRS response, MADRS remission 
HAM-D17 total score, HAM-D single item, HAM-D21 total score 
CGI-I score, CGI-S score, SDS total score, SDS single item 
DSST score, PDQ-5 score, PDQ-5 single item 
Visit: 
[MADRS total score, MADRS single item, CGI-S score] 
Screening, Placebo Lead-in, Baseline, Week 1, Week 2, Week 4, Week 6, 
Week 8, and Week 8 (LOCF) 
[MADRS response, MADRS remission, CGI-I score] 
Week 1, Week 2, Week 4, Week 6, Week 8, and Week 8 (LOCF) 
[HAM-D17 total score, HAM-D single item, HAM-D21 total score] 
Screening, Placebo Lead-in, Baseline, Week 8, and Week 8 (LOCF) 
[SDS total score, SDS single item] 
Placebo Lead-in, Baseline, Week 8, and Week 8 (LOCF) 
[DSST score, PDQ-5 score, PDQ-5 Single item] 
Placebo Lead-in, Baseline, Week 1, Week 8, and Week 8 (LOCF) 


Protocol No. Lu AA21004/CCT-004 
 
23 
Analytical 
Method(s): 
(1) MADRS total score 
MADRS total score will be analyzed for each visit. Descriptive statistics and 
two-sided 95% confidence intervals of means will be provided for the 
observed values and the change from baseline (each post-dose visit - 
Baseline) in the MADRS total score at each post-dose visit by treatment 
group. The change from baseline in the MADRS total score at each post-dose 
visit (dependent variable) will be analyzed using an ANCOVA model with 
treatment as a fixed effect and the baseline MADRS total score as a covariate. 
Least Square (LS) means and the two-sided 95% confidence intervals will be 
provided for each treatment group. The point estimates of the differences in 
the LS means between each Lu AA21004 group and the placebo group (each 
Lu AA21004 group - placebo group) and the two-sided 95% confidence 
intervals will be provided. The differences in the LS means will be tested for 
treatment differences. 
(2) MADRS single item 
MADRS single item will be analyzed for each visit. Descriptive statistics and 
two-sided 95% confidence intervals of means will be provided for the 
observed values and the changes from baseline (each post-dose visit - 
Baseline) in the MADRS single item at each post-dose visit by treatment 
group. The point estimates of the mean differences in the changes from 
baseline between each Lu AA21004 group and the placebo group (each Lu 
AA21004 treatment group − placebo group) and the two-sided 95% 
confidence intervals will be provided. 
(3) MADRS response 
MADRS response will be analyzed for each visit. Frequency distributions 
will be provided by treatment group along with the point estimates and the 
two-sided 95% confidence intervals. Odds ratios of each Lu AA21004 group 
to the placebo group (each Lu AA21004 group / placebo group) and the 
two-sided 95% confidence intervals will be provided and tested for treatment 
differences using a logistic regression model. The logistic regression model 
will include MADRS response as a dependent variable, and treatment group 
and baseline MADRS total score as independent variables. 


Protocol No. Lu AA21004/CCT-004 
 
24 
 
(4) MADRS remission 
MADRS remission will be analyzed for each visit. Frequency distributions 
will be provided by treatment group along with the point estimates and the 
two-sided 95% confidence intervals. Odds ratios of each Lu AA21004 group 
to the placebo group (each Lu AA21004 group / placebo group) and the 
two-sided 95% confidence intervals will be provided and tested for treatment 
differences using a logistic regression model. The logistic regression model 
will include MADRS remission as a dependent variable, and treatment group 
and baseline MADRS total score as independent variables. 
(5) HAM-D17 total score 
HAM-D17 total score will be analyzed for each visit. Descriptive statistics 
and two-sided 95% confidence intervals of means will be provided for the 
observed values and the change from baseline (each post-dose visit - 
Baseline) in the HAM-D17 total score at each post-dose visit by treatment 
group. The change from baseline in the HAM-D17 total score at each 
post-dose visit (dependent variable) will be analyzed using an ANCOVA 
model with treatment as a fixed effect and the baseline HAM-D17 total score 
as a covariate. Least Square (LS) means and the two-sided 95% confidence 
intervals will be provided for each treatment group. The point estimates of the 
differences in the LS means between each Lu AA21004 group and the 
placebo group (each Lu AA21004 group - placebo group) and the two-sided 
95% confidence intervals will be provided. The differences in the LS means 
will be tested for treatment differences. 
(6) HAM-D single item 
HAM-D single item will be analyzed for each visit. Descriptive statistics and 
two-sided 95% confidence intervals of means will be provided for the 
observed values and the changes from baseline (each post-dose visit - 
Baseline) in the HAM-D single item at each post-dose visit by treatment 
group. The point estimates of the mean differences in the changes from 
baseline between each Lu AA21004 group and the placebo group (each Lu 
AA21004 treatment group - placebo group) and the two-sided 95% 
confidence intervals will be provided. 


Protocol No. Lu AA21004/CCT-004 
 
25 
 
(7) HAM-D21 total score 
HAM-D 21 total score will be analyzed for each visit. Descriptive statistics 
and two-sided 95% confidence intervals of means will be provided for the 
observed values and the changes from baseline (each post-dose visit - 
Baseline) in the HAM-D21 total score at each post-dose visit by treatment 
group. The point estimates of the mean differences in the changes from 
baseline between each Lu AA21004 group and the placebo group (each Lu 
AA21004 treatment group - placebo group) and the two-sided 95% 
confidence intervals will be provided. 
(8) CGI-I score 
CGI-I score will be analyzed for each visit. Descriptive statistics and 
two-sided 95% confidence intervals of means will be provided for the CGI-I 
score by treatment group. The CGI-I will be performed based on a mixed 
model for repeated measurements (MMRM) analysis of covariance with 
CGI-I score at each post-dose visit (Week 1 to Week 8) as a dependent 
variable, and visit, treatment group, visit-by-treatment group interaction, 
baseline CGI-S score-by-visit interaction as fixed effects. Least Square (LS) 
means and the two-sided 95% confidence intervals at each visit will be 
provided for each treatment group. The point estimates of the differences in 
the LS means between each Lu AA21004 group and the placebo group (each 
Lu AA21004 - placebo group) and the two-sided 95% confidence intervals 
will be provided. The CGI-I score at each post-dose visit (dependent variable) 
will be analyzed using an ANCOVA model with treatment as a fixed effect 
and the baseline CGI-S score as a covariate. Least Square (LS) means and the 
two-sided 95% confidence intervals will be provided for each treatment 
group. The point estimates of the differences in the LS means between each 
Lu AA21004 group and the placebo group (each Lu AA21004 group - 
placebo group) and the two-sided 95% confidence intervals will be provided. 
The differences in the LS means will be tested for treatment differences. 


Protocol No. Lu AA21004/CCT-004 
 
26 
 
(9) CGI-S score 
CGI-S score will be analyzed for each visit. Descriptive statistics and 
two-sided 95% confidence intervals of means will be provided for the 
observed values and the change from baseline (each post-dose visit - 
Baseline) in the CGI-S score at each post-dose visit by treatment group. The 
change from baseline in the CGI-S score will be performed based on a mixed 
model for repeated measurements (MMRM) analysis of covariance with 
change from baseline (post-dose visit - Baseline) in the CGI-S score at each 
post-dose visit (Week 1 to Week 8) as a dependent variable, and visit, 
treatment group, visit-by-treatment group interaction, baseline CGI-S 
score-by-visit interaction as fixed effects. Least Square (LS) means and the 
two-sided 95% confidence intervals at each visit will be provided for each 
treatment group. The point estimates of the differences in the LS means 
between each Lu AA21004 group and the placebo group (each Lu AA21004 - 
placebo group) and the two-sided 95% confidence intervals will be provided. 
The change from baseline in the CGI-S score at each post-dose visit 
(dependent variable) will be analyzed using an ANCOVA model with 
treatment as a fixed effect and the baseline CGI-S score as a covariate. Least 
Square (LS) means and the two-sided 95% confidence intervals will be 
provided for each treatment group. The point estimates of the differences in 
the LS means between each Lu AA21004 group and the placebo group (each 
Lu AA21004 group - placebo group) and the two-sided 95% confidence 
intervals will be provided. The differences in the LS means will be tested for 
treatment differences. 


Protocol No. Lu AA21004/CCT-004 
 
27 
 
(10) SDS total score 
SDS total score will be analyzed for each visit. Descriptive statistics and 
two-sided 95% confidence intervals of means will be provided for the 
observed values and the change from baseline (each post-dose visit - 
Baseline) in the SDS total score at each post-dose visit score by treatment 
group. The change from baseline in the SDS total score at each post-dose visit 
(dependent variable) will be analyzed using an ANCOVA model with 
treatment as a fixed effect and the baseline SDS total score as a covariate. 
Least Square (LS) means and the two-sided 95% confidence intervals will be 
provided for each treatment group. The point estimates of the differences in 
the LS means between each Lu AA21004 group and the placebo group (each 
Lu AA21004 group - placebo group) and the two-sided 95% confidence 
intervals will be provided. The differences in the LS means will be tested for 
treatment differences. 
(11) SDS single item 
SDS single item will be analyzed for each visit. Descriptive statistics and 
two-sided 95% confidence intervals of means will be provided for the 
observed values and the changes from baseline (each post-dose visit - 
Baseline) in the SDS single item at each post-dose visit by treatment group. 
The point estimates of the mean differences in the changes from baseline 
between each Lu AA21004 group and the placebo group (each Lu AA21004 
treatment group - placebo group) and the two-sided 95% confidence intervals 
will be provided. 


Protocol No. Lu AA21004/CCT-004 
 
28 
 
(12) DSST score 
DSST score will be analyzed for each visit. Descriptive statistics and 
two-sided 95% confidence intervals of means will be provided for the 
observed values and the change from baseline (each post-dose visit - 
Baseline) in the DSST score at each post-dose visit by treatment group. The 
change from baseline in the DSST score will be performed based on a mixed 
model for repeated measurements (MMRM) analysis of covariance with 
change from baseline (post-dose visit - Baseline) in the DSST score at each 
post-dose visit (Week 1 to Week 8) as a dependent variable, and visit, 
treatment group, visit-by-treatment group interaction, baseline DSST 
score-by-visit interaction as fixed effects. Least Square (LS) means and the 
two-sided 95% confidence intervals at each visit will be provided for each 
treatment group. The point estimates of the differences in the LS means 
between each Lu AA21004 group and the placebo group (each Lu AA21004 - 
placebo group) and the two-sided 95% confidence intervals will be provided. 
The change from baseline in the DSST score at each post-dose visit 
(dependent variable) will be analyzed using an ANCOVA model with 
treatment as a fixed effect and the baseline DSST score as a covariate. Least 
Square (LS) means and the two-sided 95% confidence intervals will be 
provided for each treatment group. The point estimates of the differences in 
the LS means between each Lu AA21004 group and the placebo group (each 
Lu AA21004 group - placebo group) and the two-sided 95% confidence 
intervals will be provided. The differences in the LS means will be tested for 
treatment differences. 


Protocol No. Lu AA21004/CCT-004 
 
29 
 
(13) PDQ-5 score 
PDQ-5 score will be analyzed for each visit. Descriptive statistics and 
two-sided 95% confidence intervals of means will be provided for the 
observed values and the change from baseline (each post-dose visit - 
Baseline) in the PDQ-5 score at each post-dose visit by treatment group. The 
change from baseline in the PDQ-5 score will be performed based on a mixed 
model for repeated measurements (MMRM) analysis of covariance with 
change from baseline (post-dose visit - Baseline) in PDQ-5 score at each 
post-dose visit (Week 1 to Week 8) as a dependent variable, and visit, 
treatment group, visit-by-treatment group interaction, baseline PDQ-5 
score-by-visit interaction as fixed effects. Least Square (LS) means and the 
two-sided 95% confidence intervals at each visit will be provided for each 
treatment group. The point estimates of the differences in the LS means 
between each Lu AA21004 group and the placebo group (each Lu AA21004 
− placebo group) and the two-sided 95% confidence intervals will be 
provided. The change from baseline in the PDQ-5 score at each post-dose 
visit (dependent variable) will be analyzed using an ANCOVA model with 
treatment as a fixed effect and the baseline PDQ-5 score as a covariate. Least 
Square (LS) means and the two-sided 95% confidence intervals will be 
provided for each treatment group. The point estimates of the differences in 
the LS means between each Lu AA21004 group and the placebo group (each 
Lu AA21004 group − placebo group) and the two-sided 95% confidence 
intervals will be provided. The differences in the LS means will be tested for 
treatment differences. 
(14) PDQ-5 single item 
PDQ-5 single item will be analyzed for each visit. Descriptive statistics and 
two-sided 95% confidence intervals of means will be provided for the 
observed values and the changes from baseline (each post-dose visit - 
Baseline) in the PDQ single item at each post-dose visit by treatment group. 
The point estimates of the mean differences in the changes from baseline 
between each Lu AA21004 group and the placebo group (each Lu AA21004 
treatment group - placebo group) and the two-sided 95% confidence intervals 
will be provided. 


Protocol No. Lu AA21004/CCT-004 
 
30 
 
(15) The following summaries will be provided if considered appropriate. 
For the change from baseline in DSST at Week 8 (LOCF) of treatment with 
double-blind study drug (Week 8 [LOCF] - Baseline), divide the therapeutic 
effect into direct and indirect effect and estimate each percentage. Here, the 
effect that affects through the change from baseline in the MADRS total score 
at Week 8 (LOCF) of treatment with double-blind study drug (Week 8 
[LOCF] - Baseline) will be set as an indirect effect and others as a direct 
effect. Specifically, the following models will be used. 
Model 1:  
change DSST = alpha1 + gamma1 * treatment + gamma3 * change MADRS 
+ baseline DSST + baseline MADRS + epsilon 
Model 2:  
change MADRS = alpha2 + gamma2 * treatment + baseline DSST + baseline 
MADRS + epsilon 
 
 
 


Protocol No. Lu AA21004/CCT-004 
 
31 
2.4 Statistical/Analytical Issues 
2.4.1 Adjustments for Covariates 
After blind data review, it was decided not to conduct further adjustments for covariates by 
adding variables. 
 
2.4.2 Handling of Dropouts or Missing Data 
Missing test results and data determined to be non-evaluable according to the Handling Rules 
for Analysis Data will not be used for hypothesis testing and estimations. When individual 
items are missing from a multiple-item assessment, the total score will be set to missing. 
(MADRS total score, HAM-D17 total score, HAM-D21 total score, SDS total score, and 
PDQ-5 score) 
 
2.4.3 Interim Analyses and Data Monitoring 
No interim analysis is planned in this study. 
 
2.4.4 Multicenter Studies 
Although this study is a multicenter study, treatment-by-center interaction will not be 
explored since the number of subjects for each center is not sufficient for such exploration. 
 
2.4.5 Multiple Comparison/Multiplicity 
The main focuses will be placed on the results of the primary analysis performed for the 
primary endpoint defined as change from baseline in the MADRS total score at Week 8 in the 
full analysis set. In the primary analyses, each Lu AA21004 group will be compared with the 
placebo group based on Holm’s method to maintain the overall type I error rate below 5%. 
Other analytical results will be interpreted to support the results of the primary endpoint or to 
explore the characteristics of the efficacy of Lu AA21004. These results will be considered 
one measure suggesting the trends or characteristics of the efficacy. Thus, no adjustments for 
multiplicity will be performed. 
 
 


Protocol No. Lu AA21004/CCT-004 
 
32 
2.4.6 Use of an “Efficacy Subset” of Subjects 
In addition to analyses on the primary endpoint using the full analysis set, a secondary 
analysis will also be performed using the per protocol set to examine the robustness of the 
results from the perspective of sensitivity analysis. 
 
2.4.7 Active-Control Studies Intended to Show Equivalence or Non-Inferiority 
Not applicable in this study. 
 
2.4.8 Examination of Subgroups 
Analysis Set: Full Analysis Set 
Analysis 
Variable(s): 
Change from baseline in the MADRS total score at Week 8 of double-blind 
study drug (Week 8 - Baseline) 
Stratum: 
Age (years) 
[Min<= - <=50, 51<= - <=Max] 
Gender 
[Male, Female] 
MADRS Total Score at 
Baseline 
[Min<= - <=30, 31<= - <=Max] 
Analytical 
Method(s): 
The following summaries will be provided for the above analysis variable(s) 
for each stratum. 
(1) 
The same mixed model for repeated measurements (MMRM) analysis 
of covariance as section “2.1.1 Primary Analysis” will be applied. 
Least Square (LS) means and the two-sided 95% confidence intervals 
at each visit will be provided for each treatment group. The point 
estimates of the differences in the LS means between each Lu 
AA21004 group and the placebo group (each Lu AA21004 − placebo 
group) and the two-sided 95% confidence intervals will be provided. 
 


Protocol No. Lu AA21004/CCT-004 
 
33 
3 Safety Analysis 
 
3.1 Treatment-Emergent Adverse Event 
3.1.1 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 for each treatment group and 
overall. 
(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. 
[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 
TEAE with the maximum intensity. 
• Summaries other than 2), 3), and 6) 
A subject with multiple occurrences of TEAE will be counted only once. 


Protocol No. Lu AA21004/CCT-004 
 
34 
[Number of events] 
For each summary, the total number of events will be calculated. 
 
3.1.2 Displays of Treatment-Emergent Adverse Events 
Analysis Set: Safety Analysis Set 
Analysis 
Variable(s): 
TEAE 
Categories: 
Intensity 
[Mild, Moderate, Severe] 
Time of Onset (day) 
[1<= - <=7, 8<= - <=14, 15<= - <=28, 
29<= - <=42, 43<= - <=56, 57<= - <=Max] 
Analytical 
Method(s): 
The following summaries will be provided for each treatment group and 
overall. 
TEAEs 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 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) 
All TEAEs by SOC and PT 
(2) 
All TEAEs by SOC 
(3) 
All TEAEs by PT 
(4) 
Drug-Related TEAEs by SOC and PT 
(5) 
Intensity of All 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 
(9) 
All TEAEs by SOC and PT Over Time 
The frequency distribution will be provided according to the rules below. 
[Number of subjects] 
• Summary tables other than (5), (6), and (9) 
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 percentage of subjects with occurrence of TEAEs, the 
number of subjects in the safety analysis set will be used as the 
denominator. 


Protocol No. Lu AA21004/CCT-004 
 
35 
• 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 percentage of subjects with occurrence of TEAEs, the 
number of subjects in the safety analysis set will be used as the 
denominator. 
• Summary table for (9) 
A subject with a TEAE that occurs in more than one interval is counted 
in all the intervals that the TEAE occurs. For each time interval, a 
subject with multiple occurrences of TEAE within a SOC or a PT will 
be counted only once in that SOC or PT. When calculating percentages 
of subjects with occurrence of TEAEs for each time interval, the 
number of subjects at risk (i.e., subjects who either have an exposure or 
have an occurrence of TEAEs, during or after the corresponding time 
interval) will be used as the denominator. The number of subjects 
whose onset of the TEAEs is within the time interval will be used as 
the numerator. 
 
3.2 Pretreatment Events and Placebo Lead-in Adverse Events 
3.2.1 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 for the above analysis variable(s). 
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) 
All 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 PTE within a SOC will be counted 
only once in that SOC. A subject with multiple occurrences of PTE within 
a PT will be counted only once in that PT. 
 
 


Protocol No. Lu AA21004/CCT-004 
 
36 
3.2.2 Displays of Placebo Lead-in Adverse Events 
Analysis Set: All Subjects Who Received Placebo Lead-in Study Drug 
Analysis 
Variable(s): 
Placebo lead-in adverse event 
Analytical 
Method(s): 
The following summaries will be provided for the above analysis variable(s). 
Placebo lead-in adverse events 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) 
All Placebo Lead-in Adverse Events by SOC and PT 
(2) 
Serious Placebo Lead-in Adverse Events by SOC and PT 
The frequency distribution will be provided according to the rules below. 
[Number of subjects] 
A subject with multiple occurrences of run-in AE within a SOC will be 
counted only once in that SOC. A subject with multiple occurrences of 
run-in AE within a PT will be counted only once in that PT. 
 
 
 


Protocol No. Lu AA21004/CCT-004 
 
37 
3.3 Laboratory and Other Safety Data 
3.3.1 Laboratory Test Results 
3.3.1.1 
Hematology and Serum Chemistry 
Analysis Set: Safety Analysis Set 
Analysis 
Variable(s): 
Hematology 
RBC 
WBC 
Hemoglobin 
Hematocrit 
Platelets 
 
WBC Differentials (Neutrophils, Eosinophils, Basophils, Lymphocytes, 
Monocytes) 
Serum Chemistry 
Albumin 
AST 
ALT  
γ-GTP 
Alkaline Phosphatase 
Total Bilirubin 
Direct Bilirubin 
(Conjugated 
Bilirubin) 
Creatinine 
Creatine kinase 
Blood Urea Nitrogen 
Uric Acid 
Glucose 
Total Protein 
Potassium 
Sodium 
Calcium 
Chloride 
Triglycerides 
Total Cholesterol 
HDL Cholesterol 
LDL Cholesterol 
(Direct Method) 
Categories: 
Results of 
judgement 
based on the 
reference range 
[Low, Normal, or High relative to the normal reference 
range] 
 
Results based 
on PCS Criteria 
[Meet PCS Criteria, Does not meet PCS Criteria] 
Visit: 
Screening, Placebo Lead-in, Baseline, Week 4, and Week 8 
PCS: Baseline (entire pre-dose period), Entire post-dose period 
Analytical 
Method(s): 
The following summaries will be provided for the above analysis variable(s). 
(1) Descriptive statistics for observed values at each visit and changes from 
baseline at each visit (each post-dose visit [Week 4, Week 8] - Baseline) 
(2) Plots over time for each subject 
(3) Shift tables at baseline and each post-dose visit of the results of 
judgement based on the reference range. 
(4) Frequency distributions of the results based on PCS Criteria during the 
entire post-dose period 


Protocol No. Lu AA21004/CCT-004 
 
38 
Refer to the Appendix of this Statistical Analysis Plan if a laboratory 
parameter has lower or upper PCS Criteria. 
(5) Shift tables of the results based on PCS Criteria at baseline (entire 
pre-dose period) and during the entire post-dose period 
 
3.3.1.2 
Urinalysis 
Analysis Set: Safety Analysis Set 
Analysis 
Variable(s): 
Protein 
[-,  +-,  1+,  2+,  3+,  4+] 
 
Glucose 
[-,  1+,  2+,  3+,  4+,  5+] 
 
Occult blood 
[-,  +-,  1+,  2+,  3+] 
 
Urine pH 
[Min<= - <=4.9, 5.0<= - <=8.0, 8.1<= - <=Max] 
Visit: 
Screening, Placebo Lead-in, Baseline, Week 4, and Week 8  
Analytical 
Method(s): 
The following summaries will be provided for the above analysis variable(s). 
 
(1) 
Shift tables at baseline and each post-dose visit 
 
3.3.2 Vital Signs, Physical Findings and Other Observations Related to Safety 
3.3.2.1 Vital Signs and Weight 
Analysis Set: Safety Analysis Set 
Analysis 
Variable(s): 
Temperature 
 
Systolic Blood Pressure 
 
Diastolic Blood Pressure 
 
Pulse Rate 
 
Weight 
 
Categories: 
Results based on PCS 
Criteria 
[Meet PCS Criteria, Does not meet PCS Criteria] 
Visit: 
Temperature , Systolic Blood Pressure, Diastolic Blood Pressure, Pulse Rate: 
Screening, Placebo Lead-in, Baseline, Week 1, Week 2, Week 4, Week 6, and 
Week 8 
Weight: Screening, Placebo Lead-in, Baseline, Week 4, and Week 8 
PCS: Entire post-dose period 
Analytical 
Method(s): 
The following summaries will be provided for the above analysis variable(s). 
(1) Descriptive statistics for observed values at each visit and changes from 
baseline at each visit (each post-dose visit [Week 1 to Week 8] - Baseline) 
(2) Plots over time for each subject 
(3) Frequency distributions of the results based on PCS Criteria during the 


Protocol No. Lu AA21004/CCT-004 
 
39 
entire post-dose period 
Refer to the Appendix of this Statistical Analysis Plan if a vital sign 
parameter has lower or upper PCS Criteria. 
 
3.3.2.2 
12-lead ECG 
Analysis Set: Safety Analysis Set 
Analysis 
Variable(s): 
RR Interval 
 
PR Interval 
 
QT Interval 
 
QRS Interval 
 
QTcB Interval 
 
QTcF Interval 
 
12-Lead ECG Interpretation 
[Within Normal Limits, Abnormal but not 
Clinically Significant, Abnormal and 
Clinically Significant] 
Categories: 
Results based on PCS 
Criteria 
[Meet PCS Criteria, Does not meet PCS 
Criteria] 
Visit: 
Screening, Placebo Lead-in, Baseline, Week 4, and Week 8  
PCS: Entire post-dose period 
Analytical 
Method(s): 
For each variable other than 12-lead ECG interpretations, summaries (1) to 
(3) will be provided by treatment group. 
For 12-lead ECG interpretation, summary (4) will be provided by treatment 
group. 
(1) Descriptive statistics for observed values at each visit and changes from 
baseline at each visit (each post-dose visit [Week 4, Week 8] - Baseline) 
(2) Plots over time for each subject 
(3) Frequency distributions of the results based on PCS Criteria during the 
entire post-dose period 
Refer to the Appendix of this Statistical Analysis Plan if a ECG 
laboratory parameter has lower or upper PCS Criteria. 
(4) Shift tables at baseline and each post-dose visit 
 
3.3.2.3 
Columbia-Suicide Severity Rating Scale (C-SSRS) 
Analysis Set: Safety Analysis Set 
Analysis 
Variable(s): 
SUICIDAL IDEATION 
 
Wish to be Dead 
[Yes, No] 


Protocol No. Lu AA21004/CCT-004 
 
40 
Non-Specific Active Suicidal 
Thoughts 
[Yes, No] 
Active Suicidal Ideation with Any 
Methods (Not Plan) without Intent 
to Act 
[Yes, No] 
Active Suicidal Ideation with Some 
Intent to Act, without Specific Plan 
[Yes, No] 
Active Suicidal Ideation with 
Specific Plan and Intent 
[Yes, No] 
INTENSITY OF IDEATION 
 
Most Severe Ideation 
[Wish to be dead, Non-specific 
active suicidal thoughts, Active 
suicidal ideation with any methods 
(not plan) without intent to act, 
Active suicidal ideation with some 
intent to act, without specific plan, 
Active suicidal ideation with specific 
plan and intent] 
Frequency 
[Less than once a week, Once a 
week, 2-5 times a week, Every 
day/almost every day, Several times 
every day] 
Duration 
[Several seconds to several 
minutes/For a moment, Less than 1 
hour/For a while, 1-4 hours/For a 
considerable time, 4-8 hours/Almost 
all hours of the day, More than 8 
hours/Persistent or continuous] 
Controllability 
[Easy to control, A bit difficult but 
can control, Somewhat difficult but 
can control, Relatively difficult but 
can control, Cannot control, No 
intention to control] 


Protocol No. Lu AA21004/CCT-004 
 
41 
Deterrents 
[Desisted to commit suicide due to 
deterrent(s), Probably desisted to 
commit suicide due to deterrent(s), 
Cannot tell if I desisted to commit 
suicide due to deterrent(s), Probably 
did not desist to commit suicide due 
to deterrent(s), Did not desist to 
commit suicide due to deterrent(s), 
Not applicable] 
Reasons for Suicidal Ideation 
[Only to attract someone’s attention, 
revenge, or gain a response, Almost 
to attract someone’s attention, 
revenge, or gain a response, 
Fifty-fifty to attract someone’s 
attention, revenge, or gain a response 
and end pain, Almost to end pain 
(could not live to put up with the 
pain and feelings), Only to end pain 
(could not live while putting up with 
the pain and feelings), Not 
applicable] 
SUICIDAL BEHAVIOR 
 
Actual Attempt 
[Yes, No] 
Non-Suicidal Self-Injurious 
Behavior 
[Yes, No] 
Interrupted Attempt 
[Yes, No] 
Aborted Attempt 
[Yes, No] 
Preparatory Acts or Behavior 
[Yes, No] 
Suicidal Behavior 
[Yes, No] 
Completed Suicide (other than 
screening) 
[Yes, No] 
Answer for Actual Attempts Only 
 


Protocol No. Lu AA21004/CCT-004 
 
42 
 
Most Recent Attempt 
(Screening Only) 
[No physical damage or extremely 
mild physical damage, Mild physical 
damage, Moderate physical damage 
that requires treatment, Slightly 
severe physical damage that is highly 
likely to require hospitalization and 
intensive treatment, Severe physical 
damage that requires hospitalization 
and intensive treatment, Death] 
Details of no physical damage 
[Suicidal behavior that is less likely 
to bear physical damage, Suicidal 
behavior that is highly likely to bear 
physical damage but less likely to 
die, Suicidal behavior that is highly 
likely to die even with treatment] 
Most Highly Lethal Actual Attempt [No physical damage or extremely 
mild physical damage, Mild physical 
damage, Moderate physical damage 
that requires treatment, Slightly 
severe physical damage that is highly 
likely to require hospitalization and 
intensive treatment, Severe physical 
damage that requires hospitalization 
and intensive treatment, Death] 
Details of no physical damage 
[Suicidal behavior that is less likely 
to bear physical damage, Suicidal 
behavior that is highly likely to bear 
physical damage but less likely to 
die, Suicidal behavior that is highly 
likely to die even with treatment] 


Protocol No. Lu AA21004/CCT-004 
 
43 
First Attempt 
(Screening Only) 
[No physical damage or extremely 
mild physical damage, Mild physical 
damage, Moderate physical damage 
that requires treatment, Slightly 
severe physical damage that is highly 
likely to require hospitalization and 
intensive treatment, Severe physical 
damage that requires hospitalization 
and intensive treatment, Death] 
Details of no physical damage 
[Suicidal behavior that is less likely 
to bear physical damage, Suicidal 
behavior that is highly likely to bear 
physical damage but less likely to 
die, Suicidal behavior that is highly 
likely to die even with treatment] 
Visit: 
Screening, Placebo Lead-in, Baseline, Week 1, Week 2, Week 4, Week 6, and 
Week 8 
Analytical 
Method(s): 
For each variable, summaries (1) will be provided by treatment group. 
(1) 
Frequency distributions at each visit 
 
3.3.2.4 
Summary of Columbia-Suicide Severity Rating Scale (C-SSRS) 
Analysis Set: Safety Analysis Set 
Analysis 
Variable(s): 
Absence of Suicidal Ideation and 
Suicidal Behavior 
[Yes, No] 
Non-Suicidal Self-Injurious Behavior 
[Yes, No] 
Presence of Suicidal Ideation or 
Suicidal Behavior 
[Yes, No] 
Suicidal Ideation 
[Yes, No] 
Wish to be Dead 
[Yes, No] 
Non-Specific Active Suicidal 
Thoughts 
[Yes, No] 
Active Suicidal Ideation with Any 
Methods (Not Plan) without Intent 
to Act 
[Yes, No] 
Active Suicidal Ideation with Some 
Intent to Act, without Specific Plan 
[Yes, No] 


Protocol No. Lu AA21004/CCT-004 
 
44 
 
Active Suicidal Ideation with 
Specific Plan and Intent 
[Yes, No] 
Suicidal Behavior 
[Yes, No] 
Preparatory Acts or Behavior 
[Yes, No] 
Aborted Attempt 
[Yes, No] 
Interrupted Attempt 
[Yes, No] 
Actual Attempt 
[Yes, No] 
Completed Suicide 
[Yes, No] 
Visit: 
Screening, Baseline (Entire Pre-dose Period), Entire Post-dose Period 
Analytical 
Method(s): 
For each variable, summaries (1) will be provided by treatment group. 
(1) 
Frequency distributions at each visit 
 
4 Significance Level and Confidence Coefficient 
• 
Significance level: 5% (two-sided test) 
• 
Confidence coefficient: 95% (two-sided) 
* No statistical testing will be performed if there are less than 5 subjects. 
 
 


Protocol No. Lu AA21004/CCT-004 
 
45 
Amendment History (Version Management) 
 
Version 
Date 
Author 
Comments 
1 
9 June, 2015 
Preparation of Version 1 
2 
23 May, 2018 
Preparation of Version 2 
 
PPD


Protocol No. Lu AA21004/CCT-004 
 
1 
[Appendix 1] Change Comparison Table for Lu AA21004/CCT-004 
Page 
Before Change 
After Change 
Reason for Change 
Cover 
No caption 
Version 1: Prepared on 9 June, 2015 
No caption 
Version 2: Prepared on 24 May, 2018 
 
4 
Definition of TIME WINDOW 
-15 
Definition of TIME WINDOW 
-12 
Due to error in writing 
4 
Definition of TIME WINDOW 
-14 - -5 
Definition of TIME WINDOW 
-11 - -5 
Due to error in writing 
5 
Definition of TIME WINDOW 
-15 
Definition of TIME WINDOW 
-12 
Due to error in writing 
5 
Definition of TIME WINDOW 
-14 - -5 
Definition of TIME WINDOW 
-11 - -5 
Due to error in writing 
6 
Definition of TIME WINDOW 
-15 
Definition of TIME WINDOW 
-12 
Due to error in writing 
6 
Definition of TIME WINDOW 
-14 - -5 
Definition of TIME WINDOW 
-11 - -5 
Due to error in writing 
7 
Definition of TIME WINDOW 
-15 
Definition of TIME WINDOW 
-12 
Due to error in writing 
7 
Definition of TIME WINDOW 
-14 - -5 
Definition of TIME WINDOW 
-11 - -5 
Due to error in writing 


Protocol No. Lu AA21004/CCT-004 
 
2 
Page 
Before Change 
After Change 
Reason for Change 
7 
Others 
 
• 
QTCF interval = (QT interval) / ([QTCB 
interval]2 / [QT interval]2)0.33 (rounded off to 
the whole number) 
• 
Among the laboratory test items, the following 
data will not be included if it is from a 
postprandial specimen. 
Glucose, lipids (triglycerides, total cholesterol, 
HDL cholesterol, LDL cholesterol [Direct 
method]) 
New addition 
13 
1.2.1 Summary of Demographics and Other 
Baseline Characteristics 
Weight (kg) 
BMI(kg/m2) 
1.2.1 Summary of Demographics and Other 
Baseline Characteristics 
Weight (kg) at Baseline 
BMI (kg/m2) at Baseline 
To make the time point clear 
13 
1.2.1 Summary of Demographics and Other 
Baseline Characteristics 
Pharmacotherapy for Current Episode 
1.2.1 Summary of Demographics and Other 
Baseline Characteristics 
(Deleted) 
Because it was not an item to be collected in 
the CRF 
15 
1.2.1 Summary of Demographics and Other 
Baseline Characteristics 
Frequency distributions for categorical 
variables and descriptive statistics for 
continuous variables will be provided by 
treatment group and overall. 
1.2.1 Summary of Demographics and Other 
Baseline Characteristics 
The following summaries will be provided for the 
above analysis variable(s). 
When the randomized set is analyzed, the 
frequency distribution will be provided for each 
To make the subjects for distributions clear 


Protocol No. Lu AA21004/CCT-004 
 
3 
Page 
Before Change 
After Change 
Reason for Change 
treatment group and overall. However, weight, 
BMI, and efficacy endpoints (MADRS total score, 
HAM-D17 total score, CGI-I score, CGI-S score, 
SDS total score, DSST score, and PDQ-5 score) 
will target only the randomized set.  
16 
1.2.3 Medication History and Concomitant 
Medications 
preferred medication names 
1.2.3 Medication History and Concomitant 
Medications 
generic names 
Due to error in writing 


Protocol No. Lu AA21004/CCT-004 
 
4 
Page 
Before Change 
After Change 
Reason for Change 
16 
1.2.3 Medication History and Concomitant 
Medications 
(1) Medication History by Preferred 
Medication Name 
(2) Concomitant Medications That Started 
and Stopped Prior to Baseline by Preferred 
Medication Name 
(3) Concomitant Medications That Started 
Prior to and Were Ongoing at Baseline by 
Preferred Medication Name 
(4) Concomitant Medications That Started 
After Baseline by Preferred Medication Name 
(5) Concomitant Medications That Started 
Prior to and Were Ongoing at Baseline as well 
as Those That Started After Baseline by 
Preferred Medication Name 
1.2.3 Medication History and Concomitant 
Medications 
(1) Frequency distributions for medication history 
(2) Frequency distributions for concomitant 
medications 
Because distributions are no longer 
necessary 


Protocol No. Lu AA21004/CCT-004 
 
5 
Page 
Before Change 
After Change 
Reason for Change 
28 
2.3 Other Analysis/Additional Endpoint(s) 
and Analytical Methods 
2.3 Other Analysis/Additional Endpoint(s) and 
Analytical Methods 
(15) The following summaries will be provided if 
considered appropriate. 
For the change from baseline in DSST at Week 8 
(LOCF) of treatment with double-blind study drug 
(Week 8 [LOCF] - Baseline), divide the therapeutic 
effect into direct and indirect effect and estimate 
each percentage. Here, the effect that affects 
through the change from baseline in the MADRS 
total score at Week 8 (LOCF) of treatment with 
double-blind study drug (Week 8 [LOCF] - 
Baseline) will be set as an indirect effect and others 
as a direct effect. Specifically, the following models 
will be used. 
Model 1:  
change DSST = alpha1 + gamma1 * treatment + 
gamma3 * change MADRS + baseline DSST + 
baseline MADRS + epsilon 
Model 2:  
change MADRS = alpha2 + gamma2 * treatment 
+ baseline DSST + baseline MADRS + epsilon 
New addition 


Protocol No. Lu AA21004/CCT-004 
 
6 
Page 
Before Change 
After Change 
Reason for Change 
29 
2.4.1 Adjustments for Covariates 
 
2.4.1 Adjustments for Covariates 
After blind data review, it was decided not to 
conduct further adjustments for covariates by 
adding variables. 
Because there was no covariate to be added 
as a result under blind data review 
30 
2.4.8 Examination of Subgroups 
Pharmacotherapy for Current Episode 
2.4.8 Examination of Subgroups 
(Deleted) 
Because it was not an item to be collected in 
the CRF 
 
35 
3.3.1.1 Hematology and Serum Chemistry 
[Below the lower limit of PCS Criteria or 
above the upper limit of PCS Criteria] 
3.3.1.1 Hematology and Serum Chemistry 
[Meet PCS Criteria, Does not meet PCS Criteria] 
Because it was corrected to an appropriate 
expression 
35 
3.3.1.1 Hematology and Serum Chemistry 
 
3.3.1.1 Hematology and Serum Chemistry 
PCS: Baseline (entire pre-dose period), Entire 
post-dose period 
Because the visit was clearly stated 
35 
3.3.1.1 Hematology and Serum Chemistry 
(4) Number and Percentage of Subjects with 
Potentially Clinically Significant of 
Laboratory Parameters 
3.3.1.1 Hematology and Serum Chemistry 
(4) Frequency distributions of the results based on 
PCS Criteria during the entire post-dose period 
Because it was corrected to an appropriate 
expression 
36 
3.3.1.1 Hematology and Serum Chemistry 
3.3.1.1 Hematology and Serum Chemistry 
(5) Shift tables of the results based on PCS 
Criteria at baseline (entire pre-dose period) and 
during the entire post-dose period 
New addition 


Protocol No. Lu AA21004/CCT-004 
 
7 
Page 
Before Change 
After Change 
Reason for Change 
36 
3.3.1.2 Urinalysis 
Protein [-,  +-,  1+,  2+,  3+,  4+,  5+] 
Glucose [-,  +-,  1+,  2+,  3+,  4+,  
5+] 
Occult blood [-,  +-,  1+,  2+,  3+,  4+,  
5+] 
3.3.1.2 Urinalysis 
Protein [-,  +-,  1+,  2+,  3+,  4+] 
Glucose [-,  1+,  2+,  3+,  4+,  5+] 
Occult blood [-,  +-,  1+,  2+,  3+] 
Because they were corrected to reported 
values 
36 
3.3.2.1 Vital Signs and Weight 
[Below the lower limit of PCS Criteria or 
above the upper limit of PCS Criteria] 
3.3.2.1 Vital Signs and Weight 
[Meet PCS Criteria, Does not meet PCS Criteria] 
Because it was corrected to an appropriate 
expression 
36 
3.3.2.1 Vital Signs and Weight 
 
3.3.2.1 Vital Signs and Weight 
PCS: Entire post-dose period 
Because the visit was clearly stated 
36 
3.3.2.1 Vital Signs and Weight 
(3) Number and Percentage of Subjects with 
Potentially Clinically Significant of Vital 
Signs Parameters 
3.3.2.1 Vital Signs and Weight 
(3) Frequency distributions of the results based on 
PCS Criteria during the entire post-dose period 
Because it was corrected to an appropriate 
expression 
37 
3.3.2.2 12-lead ECG 
3.3.2.2 12-lead ECG 
Categories: 
Results based on PCS Criteria 
[Meet PCS Criteria, Does not meet PCS Criteria] 
New addition 
37 
3.3.2.2 12-lead ECG 
3.3.2.2 12-lead ECG 
PCS: Entire post-dose period 
Because the visit was clearly stated 
37 
3.3.2.2 12-lead ECG 
3.3.2.2 12-lead ECG 
Because it was corrected to an appropriate 


Protocol No. Lu AA21004/CCT-004 
 
8 
Page 
Before Change 
After Change 
Reason for Change 
(3) Number and Percentage of Subjects with 
Potentially Clinically Significant of ECG 
Parameters 
(3) Frequency distributions of the results based on 
PCS Criteria during the entire post-dose period 
expression 
41 
 
3.3.2.4 Summary of Columbia-Suicide Severity 
Rating Scale (C-SSRS) 
New addition 
 
 


Protocol No. Lu AA21004/CCT-004 
 
1 
[Appendix 2]Definition of PCS Criteria 
Hematology and Serum Chemistry 
Analysis 
Variable(s): 
Unit 
system 
Unit 
Definition of PCS 
Red blood cells 
CV 
 
10^4/uL 
 
Measured value is ≤0.9-fold of LLN or 
≥1.1-fold of ULN 
SI 
 
TI/L 
Measured value is ≤0.9-fold of LLN or 
≥1.1-fold of ULN 
White blood cells 
CV 
 
/uL 
 
Measured value is ≤2800 or ≥16000 
SI 
GI/L 
Measured value is ≤2.8 or ≥16 
Hemoglobin 
CV 
 
g/dL 
Measured value is ≤0.9-fold of LLN 
SI 
 
g/L 
Measured value is ≤0.9-fold of LLN 
Hematocrit 
CV 
 
% 
Measured value is ≤0.9-fold of LLN 
SI 
 
Fraction of 1 
Measured value is ≤0.9-fold of LLN 
Platelets 
CV 
10^4/uL 
Measured value is ≤7.5 or ≥70 
SI 
GI/L 
 
Measured value is ≤75 or ≥700 
Neutrophils 
CV 
 
% 
Measured value is ≤15 
SI 
 
% 
Measured value is ≤15 
Eosinophils 
CV 
 
% 
Measured value is ≥10 
SI 
 
% 
Measured value is ≥10 
Basophils 
CV 
 
% 
Measured value is ≥5 
SI 
 
% 
Measured value is ≥5 
Lymphocytes 
CV 
 
% 
Measured value is ≤10 or ≥80 


Protocol No. Lu AA21004/CCT-004 
 
2 
SI 
 
% 
Measured value is ≤10 or ≥80 
Monocytes 
CV 
 
% 
Measured value is ≥20 
SI 
 
% 
Measured value is ≥20 
Albumin 
CV 
 
g/dL 
 
Measured value is ≤2.5 
SI 
 
g/L 
 
Measured value is ≤25 
AST 
CV 
 
U/L 
Measured value is ≥3-fold of ULN 
SI 
 
U/L 
Measured value is ≥3-fold of ULN 
ALT 
CV 
 
U/L 
Measured value is ≥3-fold of ULN 
SI 
 
U/L 
Measured value is ≥3-fold of ULN 
ALP 
CV 
 
U/L 
Measured value is ≥3-fold of ULN 
SI 
 
U/L 
Measured value is ≥3-fold of ULN 
Total Bilirubin 
CV 
 
mg/dL 
Measured value is ≥2 
SI 
 
umol/L 
Measured value is ≥34.2 
Creatinine 
CV 
 
mg/dL 
 
Measured value is ≥1.5-fold of ULN 
SI 
umol/L 
 
Measured value is ≥1.5-fold of ULN 
Creatine Kinase 
CV 
 
U/L 
 
Measured value is ≥2-fold of ULN 
SI 
 
U/L 
 
Measured value is ≥2-fold of ULN 
Uric Acid 
CV 
 
mg/dL 
Measured value is ≤0.7-fold of LLN or 
≥1.3-fold of ULN 


Protocol No. Lu AA21004/CCT-004 
 
3 
SI 
 
umol/L 
 
Measured value is ≤0.7-fold of LLN or 
≥1.3-fold of ULN 
Glucose 
CV 
 
mg/dL 
Measured value is ≤0.7-fold of LLN or 
≥2.5-fold of ULN 
SI 
 
mmol/L 
Measured value is ≤0.7-fold of LLN or 
≥2.5-fold of ULN 
Potassium 
CV 
 
mEq/L 
Measured value is ≤3.0 or ≥5.5 
SI 
 
mmol/L 
Measured value is ≤3.0 or ≥5.5 
Sodium 
CV 
 
mEq/L 
Measured value is ≤125 or ≥155 
SI 
 
mmol/L 
Measured value is ≤125 or ≥155 
Calcium 
CV 
 
mg/dL 
 
Measured value is ≤0.8-fold of LLN or 
≥1.2-fold of ULN 
SI 
mmol/L 
Measured value is ≤0.8-fold of LLN or 
≥1.2-fold of ULN 
Triglycerides 
CV 
 
mg/dL 
 
Measured value is ≥1.5-fold of ULN 
SI 
 
mmol/L 
 
Measured value is ≥1.5-fold of ULN 
Total Cholesterol 
CV 
 
mg/dL 
 
Measured value is ≥1.5-fold of ULN 
SI 
 
mmol/L 
 
Measured value is ≥1.5-fold of ULN 
HDL Cholesterol 
CV 
 
mg/dL 
Measured value is ≥1.5-fold of ULN 
SI 
 
mmol/L 
 
Measured value is ≥1.5-fold of ULN 
LDL Cholesterol 
CV 
 
mg/dL 
Measured value is ≥1.5-fold of ULN 
SI 
 
mmol/L 
Measured value is ≥1.5-fold of ULN 


Protocol No. Lu AA21004/CCT-004 
 
4 
Vital Signs (Blood Pressure, Pulse Rate) and Weight 
Analysis Variable(s): 
Unit 
Definition of PCS 
Pulse Rate 
bpm 
Measured value is ≤50 and change* is ≤-15 or 
measured value is ≥120 and change* is ≥15 
Diastolic Blood Pressure 
mmHg 
Measured value is ≤50 and change* is ≤-15 or 
measured value is ≥105 and change* is ≥15 
Systolic Blood Pressure 
mmHg 
Measured value is ≤90 and change* is ≤-20 or 
measured value is ≥180 and change* is ≥20 
Weight 
kg 
 
Change rate* is ≤-7% or ≥7% 
*: Change or change rate from baseline 
 
Resting 12-lead ECG 
Analysis Variable(s): 
Unit 
Definition of PCS 
PR Interval 
msec 
Measured value is <120 or ≥250 
QRS Interval 
msec 
Measured value is <40 or >150 
QT Interval 
msec 
Measured value is <280 or >500 
QTcF Interval 
msec 
Measured value is <340 and change* is <-60 
or measured value is >500 and change* is >60 
QTcB Interval 
msec 
Measured value is <340 and change* is <-60 
or measured value is >500 and change* is >60 
RR Interval 
msec 
Measured value is <500 and change* is ≤-200 
or measured value is >1200 and change* is 
≥200 
*: Change from baseline