Clinical trial NCT04244253
Conditions: Major Depressive Disorder
Sponsor: Otsuka Pharmaceutical Co., Ltd.
Start date: 2020-03-03; Completion date: 2022-02-25
Enrollment: 273 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The objective of the trial is to compare the efficacy of OPC-64005 at 20 mg vs placebo and to assess the safety and pharmacokinetics of OPC-64005 at 10 and 20 mg in patients with major depressive disorder (MDD).The primary endpoint is the mean change from baseline in Montgomery-Åsberg Depression Rating Scale (MADRS) total score at Week 6 of the double-blind treatment period in the OPC-64005 20-mg group compared with the placebo group

Detailed description:

Arms: arm 1: None arm 2: None arm 3: None
Interventions: intervention 1: OPC-64005 20 mg , Once-daily intervention 2: OPC-64005 10 mg , Once-daily intervention 3: Placebo, Once-daily
Intervention descriptions: intervention 1: Active, High Dose intervention 2: Active, Low Dose intervention 3: Placebo

Protocol documents:
Prot_000.pdf: 
 
 
CLINICAL STUDY PROTOCOL 
 
 
 
A Randomized, Multi-center, Double-blind, Placebo-controlled, Parallel-group 
Comparison Trial to Assess Efficacy and Safety of OPC-64005 in Patients With Major 
Depressive Disorder 
 
 
 
 
NCT Number: NCT04244253 
                                              PRT NO.:  277-102-00027   
Version Date: 31 Mar 2020  


 
 
Otsuka Pharmaceutical Co., Ltd. 
 
Investigational Medicinal Product 
 
OPC-64005 
 
REVISED CLINICAL PROTOCOL 
 
A Randomized, Multi-center, Double-blind, Placebo-controlled, Parallel-group 
Comparison Trial to Assess Efficacy and Safety of OPC-64005 in Patients With Major 
Depressive Disorder 
 
A Phase 2 Trial of OPC-64005 for Major Depressive Disorder 
 
Protocol No. 277-102-00027 
 
CONFIDENTIAL  PROPRIETARY INFORMATION 
 
Clinical Development Phase: 
2 
Sponsor: 
Otsuka Pharmaceutical Co., Ltd. 
Immediately Reportable Event  
Pharmacovigilance Operations, 
Pharmacovigilance 
 
Email: IRE_277-102-00027@otsuka.jp 
 
Amendment 1 Approval: 
31 Mar 2020 
Original Approval: 
20 Dec 2019 
(Date of Translation: 
15 Nov 2021) 
 
 


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Table of Contents 
Table of Contents ........................................................................................... 2 
List of In-text Tables ..................................................................................... 8 
List of In-text Figures .................................................................................... 9 
1 
Protocol Summary .............................................................................. 10 
1.1 
Synopsis.............................................................................................................10 
1.2 
Schema ..............................................................................................................15 
1.3 
Schedule of Assessments...................................................................................16 
1.4 
Trial Procedures ................................................................................................19 
1.4.1 
Visit 1..............................................................................................................19 
1.4.1.1 
At Informed Consent ...................................................................................19 
1.4.1.2 
Screening Examination ...............................................................................19 
1.4.2 
Visit 2..............................................................................................................20 
1.4.3 
Visit 3..............................................................................................................20 
1.4.4 
Visit 4 Through Visit 9 ...................................................................................20 
1.4.5 
Visit 10............................................................................................................21 
1.4.6 
Visit 11............................................................................................................21 
1.4.7 
At Discontinuation ..........................................................................................21 
2 
Introduction ........................................................................................ 23 
2.1 
Trial Rationale ...................................................................................................23 
2.2 
Background .......................................................................................................24 
2.2.1 
History of Development .................................................................................24 
2.2.2 
Results of Nonclinical Studies ........................................................................25 
2.2.3 
Results of Clinical Trials ................................................................................25 
2.3 
Known and Potential Risks and Benefits ..........................................................25 
3 
Objectives and Endpoints .................................................................. 27 
4 
Trial Design ......................................................................................... 28 
4.1 
Type/Design of Trial .........................................................................................28 
4.2 
Scientific Rationale for Trial Design.................................................................28 
4.3 
Dosing Rationale ...............................................................................................28 
4.3.1 
Rationale for Mode of Administration ...........................................................28 


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4.3.2 
Rationale for Dose ..........................................................................................29 
4.4 
End of Trial Date Definition .............................................................................30 
4.5 
Definition of Completed Subjects .....................................................................30 
5 
Trial Population .................................................................................. 30 
5.1 
Subject Selection and Numbering .....................................................................30 
5.2 
Eligibility Criteria..............................................................................................31 
5.2.1 
Inclusion Criteria ............................................................................................31 
5.2.2 
Exclusion Criteria ...........................................................................................32 
5.3 
Lifestyle Considerations ....................................................................................35 
5.3.1 
Meals and Dietary Restrictions .......................................................................35 
5.3.2 
Caffeine, Alcohol, and Tobacco .....................................................................35 
5.3.3 
Activity ...........................................................................................................36 
5.4 
Screen Failures ..................................................................................................36 
6 
Trial Treatments ................................................................................. 36 
6.1 
Trial Treatments Administered .........................................................................36 
6.1.1 
Dosage and Administration ............................................................................36 
6.1.1.1 
Placebo Lead-in Period (Single-blind With Subjects Blinded to 
Treatment Received) ...................................................................................36 
6.1.1.2 
Double-blind Treatment Period...................................................................36 
6.1.1.3 
Double-blind Tapering Period.....................................................................37 
6.1.1.4 
At Discontinuation ......................................................................................37 
6.1.1.5 
Handling of Missed Doses ..........................................................................37 
6.1.1.6 
Investigation on Drug Compliance .............................................................38 
6.1.2 
Medical Devices .............................................................................................38 
6.2 
Management of Investigational Medicinal Product ..........................................38 
6.2.1 
Packaging and Labeling ..................................................................................38 
6.2.2 
Storage ............................................................................................................38 
6.2.3 
Accountability .................................................................................................38 
6.2.4 
Returns and Destruction .................................................................................39 
6.2.5 
Reporting of Product Quality Complaints ......................................................39 
6.2.5.1 
Eliciting and Reporting Product Quality Complaints .................................39 
6.2.5.2 
Information Required for Reporting Product Quality Complaints .............39 
6.2.5.3 
Return Process in the Case of Product Quality Complaints ........................40 


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6.2.5.4 
Assessment/Evaluation ...............................................................................40 
6.3 
Measures to Minimize/Avoid Bias ....................................................................40 
6.4 
Subject Compliance ...........................................................................................41 
6.5 
Concomitant Medications or Therapies ............................................................41 
6.5.1 
Prohibited Medications ...................................................................................41 
6.5.1.1 
Fourteen Days Before Visit 2 Through Visit 11 .........................................41 
6.5.1.2 
Visit 2 Through Visit 9 ...............................................................................42 
6.5.1.3 
Visit 2 Through Visit 10 .............................................................................42 
6.5.2 
Restricted Medications ...................................................................................42 
6.5.2.1 
Visit 2 Through Visit 9 ...............................................................................42 
6.5.3 
Permitted Medications ....................................................................................43 
6.5.4 
Rescue Medications ........................................................................................43 
6.5.5 
Prohibited Therapies .......................................................................................43 
6.6 
Intervention After the End of the Trial ..............................................................43 
7 
Stopping Rules, Withdrawal Criteria, and Procedures .................. 43 
7.1 
Entire Trial or Treatment ...................................................................................43 
7.2 
Individual Site ...................................................................................................43 
7.3 
Individual Subject Discontinuation ...................................................................44 
7.3.1 
Treatment Interruption ....................................................................................44 
7.3.2 
Treatment Discontinuation .............................................................................44 
7.3.3 
Documenting Reasons for Treatment Interruption or Discontinuation ..........45 
7.3.4 
Withdrawal of Consent or Assent ...................................................................46 
7.3.5 
Procedures to Encourage Continued Trial Participation ................................47 
7.4 
Definition of Subjects Lost to Follow-up ..........................................................47 
8 
Trial Procedures ................................................................................. 47 
8.1 
Efficacy Assessments ........................................................................................47 
8.1.1 
Montgomery Åsberg Depression Rating Scale...............................................47 
8.1.2 
Clinical Global Impression – Improvement ...................................................48 
8.1.3 
Clinical Global Impression - Severity of Illness .............................................48 
8.1.4 
Hamilton Depression Rating Scale .................................................................48 
8.1.5 
Montgomery Åsberg Depression Rating Scale Self-assessment ....................49 
8.1.6 
Apathy Scale ...................................................................................................49 


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8.2 
Pharmacokinetic Assessments ...........................................................................50 
8.2.1 
Pharmacokinetic Plasma Samples ..................................................................50 
8.3 
Pharmacodynamic Assessments ........................................................................50 
8.4 
Pharmacogenomic Assessments ........................................................................50 
8.4.1 
Pharmacogenomic Samples ............................................................................51 
8.5 
Biomarker Assessments ....................................................................................52 
8.6 
Future Biospecimen Research Samples ............................................................52 
8.6.1 
Scope of Future Biospecimen Research .........................................................53 
8.6.2 
Summary of Procedures for Future Biospecimen Research Samples ............53 
8.6.3 
Storage of Samples for Future Biospecimen Research ...................................53 
8.6.4 
Genomic/Genetic Analysis .............................................................................53 
8.6.5 
Provision and Withdrawal of Consent for Future Biospecimen Research .....54 
8.6.6 
Disclosure of Genomic/Genetic Analytical Results to Subjects .....................54 
8.7 
Safety Assessments ...........................................................................................55 
8.7.1 
Clinical Laboratory Assessments ...................................................................55 
8.7.2 
Physical Examination .....................................................................................55 
8.7.2.1 
Dermatological Findings .............................................................................56 
8.7.3 
Vital Signs ......................................................................................................56 
8.7.4 
Electrocardiogram ...........................................................................................56 
8.7.5 
Suicidality Monitoring ....................................................................................57 
8.7.5.1 
Columbia-Suicide Severity Rating Scale ....................................................57 
8.7.6 
Other Safety Variables ....................................................................................58 
8.7.6.1 
Waist Circumference ...................................................................................58 
8.7.6.2 
Height and Body Weight .............................................................................58 
8.8 
Adverse Events ..................................................................................................58 
8.8.1 
Definitions ......................................................................................................58 
8.8.2 
Eliciting and Reporting Adverse Events .........................................................60 
8.8.3 
Immediately Reportable Events ......................................................................61 
8.8.4 
Medical Device Incidents (Including Malfunctions) ......................................61 
8.8.5 
Adverse Events of Special Interest .................................................................61 
8.8.6 
Potential Serious Hepatotoxicity ....................................................................61 
8.8.7 
Procedure for Breaking the Blind ...................................................................61 
8.8.8 
Follow-up of Adverse Events .........................................................................62 


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8.8.8.1 
Follow-up of Nonserious Adverse Events ..................................................62 
8.8.8.2 
Follow-up of Immediately Reportable Events ............................................62 
8.8.8.3 
Follow-up and Reporting of Immediately Reportable Events 
Occurring After Last Scheduled Contact ....................................................63 
8.9 
Treatment of Overdose ......................................................................................63 
8.10 
Subject Assessment Recording .........................................................................63 
8.11 
Other Assessments ............................................................................................64 
9 
Statistical Considerations .................................................................. 64 
9.1 
Sample Size .......................................................................................................64 
9.2 
Datasets for Analysis .........................................................................................64 
9.2.1 
Full Analysis Set .............................................................................................64 
9.2.2 
Safety Analysis Set .........................................................................................64 
9.3 
Handling of Missing Data for Primary and Secondary Endpoint Analyses ......65 
9.4 
Statistical Analyses............................................................................................65 
9.4.1 
Efficacy Analyses ...........................................................................................65 
9.4.1.1 
Primary Efficacy Endpoint Analysis ...........................................................65 
9.4.1.2 
Key Secondary Efficacy Endpoint Analysis ...............................................66 
9.4.1.3 
Secondary Efficacy Endpoint Analysis .......................................................66 
9.4.1.4 
Control of Experiment-wise Type 1 Error ..................................................67 
9.4.1.5 
Other Efficacy Endpoint Analysis ..............................................................67 
9.4.2 
Safety Analysis ...............................................................................................67 
9.4.2.1 
Adverse Events............................................................................................67 
9.4.2.2 
Clinical Laboratory Data .............................................................................67 
9.4.2.3 
Physical Examination and Vital Signs Data................................................68 
9.4.2.4 
Electrocardiogram Data ..............................................................................68 
9.4.2.5 
Other Safety Data ........................................................................................68 
9.4.3 
Other Analyses ................................................................................................69 
9.4.3.1 
Analysis of Demographic and Baseline Characteristics .............................69 
9.4.3.2 
Pharmacokinetic Analysis ...........................................................................69 
9.4.3.3 
Pharmacodynamic Analysis ........................................................................69 
9.4.3.4 
Pharmacokinetic/Pharmacodynamic Analysis ............................................69 
9.4.3.5 
Pharmacogenomic Analysis ........................................................................69 
9.4.3.6 
Exploratory Endpoint Analysis ...................................................................69 


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9.5 
Interim Analysis and Adaptive Design .............................................................69 
9.5.1 
Data Monitoring Committee ...........................................................................69 
10 
Supporting Documentation and Operational Considerations ....... 70 
10.1 
Appendix 1: Regulatory, Ethical, and Trial Oversight Considerations .............70 
10.1.1 
Ethics and Responsibility ...............................................................................70 
10.1.2 
Informed Consent ...........................................................................................70 
10.1.3 
Confidentiality ................................................................................................71 
10.1.4 
Quality Control and Quality Assurance ..........................................................71 
10.1.4.1 
Monitoring ..................................................................................................72 
10.1.4.2 
Auditing ......................................................................................................72 
10.1.5 
Protocol Deviations ........................................................................................72 
10.1.6 
Records Management .....................................................................................72 
10.1.6.1 
Source Documents ......................................................................................72 
10.1.6.2 
Data Collection............................................................................................73 
10.1.6.3 
File Management at the Trial Site ...............................................................74 
10.1.6.4 
Records Retention at the Trial Site .............................................................74 
10.1.6.5 
Publication Authorship Requirements ........................................................74 
10.2 
Appendix 2: Clinical Laboratory Tests .............................................................76 
10.3 
Appendix 3: Contraceptive Guidance and Collection of Pregnancy 
Information ........................................................................................................77 
10.4 
Appendix 4: Genetic Testing .............................................................................79 
10.5 
Appendix 5: Abbreviations ...............................................................................83 
10.6 
Appendix 6: Protocol Amendments ..................................................................85 
10.6.1 
Protocol Amendment(s)/Administrative Change(s) .......................................86 
10.7 
Appendix 7: Wet-ink Sponsor Signature Page ..................................................91 
11 
References ............................................................................................ 92 
 
 
 
 


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List of In-text Tables 
Table 1.3-1 
Schedule of Assessments .............................................................. 16 
Table 3-1 
Trial Objectives and Endpoints ..................................................... 27 
Table 4.3.2-1 
Estimated Maximum Occupancy (Median) of Each 
Monoamine Transporter by OPC-64005 in Steady-state .............. 29 
Table 10.2-1 
Clinical Laboratory Assessments .................................................. 76 
 
 


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List of In-text Figures 
Figure 1.2-1 
Trial Design Schematic ................................................................. 15 


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1 
Protocol Summary 
1.1 
Synopsis 
Name of Sponsor: 
Otsuka Pharmaceutical Co., Ltd. 
Name of Investigational Medicinal Product: 
OPC-64005 
Protocol No.: 
277-102-00027 
Protocol Title: 
A Randomized, Multi-center, Double-blind, Placebo-controlled, Parallel-group 
Comparison Trial to Assess Efficacy and Safety of OPC-64005 in Patients With Major 
Depressive Disorder 
Protocol Lay Person Short Title: 
A Phase 2 Trial of OPC-64005 for Major Depressive Disorder 
Clinical Phase/Trial Type: 
Phase 2/Exploratory trial 
Treatment/Indication: 
Patients with major depressive disorder 
Objectives and Endpoints: 
The objective of the trial is to compare the efficacy of OPC-64005 at 20 mg vs placebo 
and to assess the safety and pharmacokinetics of OPC-64005 at 10 and 20 mg in patients 
with major depressive disorder (MDD). The primary endpoint is the mean change from 
baseline in Montgomery-Åsberg Depression Rating Scale (MADRS) total score at Week 
6 of the double-blind treatment period in the OPC-64005 20-mg group compared with the 
placebo group. 
Trial Design: 
A multi-center, randomized, double-blind, placebo-controlled, parallel-group comparison 
trial 


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Trial Population: 
270 male and female patients ≥ 20 to < 65 years of age (at time of informed consent) 
diagnosed with either “major depressive disorder, single episode” or “major depressive 
disorder, recurrent episode” according to the Diagnostic and Statistical Manual of Mental 
Disorders, Fifth Edition (DSM-5) 
Key Inclusion/Exclusion Criteria: 
Key inclusion criteria 
At informed consent and at screening (Visit 1): 
• Patients with a DSM-5 classification-based diagnosis of “major depressive disorder, 
single episode” or “major depressive disorder, recurrent episode” with the current 
episode persisting for ≥ 4 weeks to ≤ 1 year 
At start of placebo lead-in period (Visit 2): 
• Patients with a total score of ≥ 18 on the 17-item Hamilton Rating Scale for 
Depression (HAM-D) based on evaluation performed at start of the placebo lead-in 
period 
At baseline (Visit 3): 
• Patients with a HAM-D 17-item total score of ≥ 18 based on evaluation performed at 
baseline 
Key exclusion criteria 
At informed consent and at screening (Visit 1): 
• Patients with a diagnosis of any of the following diseases according to DSM-5: 
Neurocognitive disorders, history or complication of schizophrenia spectrum or other 
psychotic disorder, history or complication of bipolar and related disorders, feeding 
and eating disorders, obsessive-compulsive disorder, panic disorder, posttraumatic 
stress disorder, personality disorders, neurodevelopmental disorders, substance-
related and addictive disorders (within 180 days prior to the date of informed consent) 
• Patients exhibiting mood-incongruent psychotic features in the current major 
depressive episode 
• Patients who, in the opinion of the investigator, are judged to have treatment-resistant 
depression, ie, a certain degree of therapeutic effect is not obtained by administration 
of 2 or more antidepressants having different mechanisms of action at sufficient doses 
for at least 6 weeks for the current major depressive episode 
• Patients receiving augmentation treatment, such as antipsychotics, for the current 
major depressive episode (excluding the use of sulpiride for depression/depressive 
state or gastric/duodenal ulcer) 


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At start of placebo lead-in period (Visit 2): 
• Patients with a MADRS Self-assessment (MADRS-S) total score of < 8.5 based on 
evaluation performed at the start of the placebo lead-in period 
At baseline (Visit 3): 
• Patients with a MADRS-S total score of < 8.5 based on evaluation performed at 
baseline or with ≥ 25% reduction in MADRS-S total score at baseline compared with 
at the start of the placebo lead-in period 
Trial Site(s): 
Approximately 100 sites in Japan 
Investigational Medicinal Product(s), Dose, Dosage Regimen, Treatment Duration, 
Formulation, Mode of Administration: 
Dose Group 
Placebo Lead-in 
Period (Single-blind 
With Subjects 
Blinded to 
Treatment 
Received) 
Double-blind Treatment 
Period 
Double-blind Tapering 
Period 
OPC-64005 10-
mg group 
Two placebo tablets 
administered orally 
once daily for 1 week 
One placebo tablet and one 
OPC-64005 10-mg tablet 
administered orally once 
daily for 6 weeks 
Two placebo tablets 
administered orally once daily 
for 1 week 
OPC-64005 20-
mg group 
One placebo tablet and one 
OPC-64005 10-mg tablet 
administered orally once 
daily for 1 week, followed 
by two OPC-64005 10-mg 
tablets for 5 weeks 
One placebo tablet and one 
OPC-64005 10-mg tablet 
administered orally once daily 
for 1 week 
Placebo group 
Two placebo tablets 
administered orally once 
daily for 6 weeks 
Two placebo tablets 
administered orally once daily 
for 1 week 
 
Trial Assessments: 
Assessments for efficacy: MADRS, Clinical Global Impression – Improvement (CGI-I), 
Clinical Global Impression – Severity of Illness (CGI-S), HAM-D, MADRS-S, and 
Apathy Scale 
Assessments for pharmacokinetics, pharmacogenomics, and future biospecimen research: 
Plasma PK assessment, cytochrome P450 (CYP) 2D6 genetic testing, and blood sampling 
for DNA storage 
Assessments for safety: Laboratory tests, vital signs, physical examination, height, body 
weight, waist circumference, 12-lead electrocardiogram (ECG), pregnancy test, 
Columbia-Suicide Severity Rating Scale (C-SSRS), and adverse events (AEs) 


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Screening/Other: Medical and treatment history, etc 
Data Monitoring Committee: No 
Statistical Methods: 
Statistical Methods for Primary Endpoint: 
The primary endpoint is the change from baseline in MADRS total score at Week 6 of the 
double-blind treatment period. 
For the primary analysis, mixed-model repeated-measure (MMRM) analysis will be 
performed using the observed cases dataset of the full analysis set. 
The MMRM will include treatment group (OPC-64005 10-mg group, OPC-64005 20-mg 
group, and placebo group), timepoint (double-blind treatment period Weeks 1, 2, 3, 4, 5, 
and 6), and interaction between treatment group and timepoint as factors, and baseline 
and interaction between baseline and timepoint as covariates. An unstructured error 
variance-covariance structure will be assumed. For degree-of-freedom approximation, the 
Kenward-Roger method will be used. The statistical comparison will be performed based 
on differences in the least square means at double-blind treatment period Week 6 
between the OPC-64005 20-mg group and the placebo group. 
For each timepoint, the least square mean of each treatment group and the differences in 
the least square means between each OPC-64005 group and the placebo group, as well as 
the two-sided 95% confidence intervals, will be determined. 
Rationale for target number of subjects: 
As no clinical trials of OPC-64005 in patients with major depressive disorder have been 
previously conducted, the target number of subjects was determined based on the results 
from another antidepressant clinical trial using MADRS score as the primary endpoint. 
In the phase 3 clinical trial of escitalopram conducted outside Japan,1 the mean change 
(± SE) from baseline in MADRS total score at the final timepoint of Week 8 (8 weeks 
after start of administration) determined using last observation carried forward analysis of 
covariance was −9.4 ± 0.9 in the placebo group (n = 119), −12.0 ± 0.9 in the citalopram 
40-mg group (n = 125), −12.8 ± 0.8 in the escitalopram 10-mg group (n = 118), and 
−13.9 ± 0.8 in the escitalopram 20-mg group (n = 123). Referring to those results, in the 
present trial it is assumed that the difference between the OPC-64005 20-mg group and 
the placebo group in the change from baseline in MADRS total score at Week 6 of the 
double-blind treatment period will be −4 with a standard deviation of 11. To ensure a 
power of 80% in a two-sided test with a significance level of 0.05, 120 subjects each are 
required for the OPC-64005 20-mg group and the placebo group. For the OPC-64005 10-


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mg group, the number of subjects was set at 30 without statistical consideration. The 
planned number of subjects to be randomized for the trial was therefore set at 270. 
Trial Duration: 
• Screening period: ≤ 4 weeks 
• Placebo lead-in period (Single-blind with subjects blinded to treatment received): 1 
week 
• Double-blind treatment period: 6 weeks 
• Double-blind tapering period: 1 week 
• Post-treatment observation period: 2 weeks 
The overall trial period from the time informed consent is obtained from the first subject 
until completion of the last observation of the last subject is planned to be 21 months. 
 


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1.2 
Schema 
 
Figure 1.2-1 
Trial Design Schematic 
 
Screening Period
(≤ 4 weeks)
Placebo Lead-in
Period
(1 week)
Double-blind Treatment Period
(6 weeks)
Double-blind
Tapering Period
(1 week)
Visit 1
(Informed consent)
Visit 2
(Day −7)
Visit 3
(Week 0: baseline)
Visit 4
(Week 1)
Visit 5
(Week 2)
Visit 6
(Week 3)
Post-treatment
Observation Period
(2 weeks)
Visit 7
(Week 4)
Visit 8
(Week 5)
Visit 9
(Week 6)
Visit 10
(Week 7)
Visit 11
(2 weeks after Visit 10)
Placebo
R
10 mg/day
Placebo
OPC-64005 20 mg/day
(OPC-64005 20-mg group: 120 subjects)
Starting dose
(OPC-64005 10-mg group: 30 subjects)
(Placebo group: 120 subjects)
10 mg/day
Placebo
OPC-64005 10 mg/day


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1.3 
Schedule of Assessments 
Table 1.3-1 
Schedule of Assessments 
Period 
Screening 
Placebo 
Lead-ina 
Double-blind Treatment 
Double-
blind 
Tapering 
Post-
treatment 
Observationj 
At 
Discontinuationk
Visit 
Visit 1 
Visit 2 
(Week −1) 
Visit 3 
(Baseline) 
Visit 4 
(Week 1) 
Visit 5 
(Week 2) 
Visit 6 
(Week 3) 
Visit 7 
(Week 4) 
Visit 8 
(Week 5) 
Visit 9 
(Week 6) 
Visit 10 
(Week 7) 
Visit 11 
(2 weeks after 
Visit 10 or the 
final dosing) 
Day ± allowable window 
Day −35 
to the day 
before 
Visit 2 
Day −7 ± 1 
day 
Day 1 
Day 8 
± 1 
day 
Day 
15 ± 2 
days 
Day 
22 ± 2 
days 
Day 
29 ± 2 
days 
Day 36 
± 2 
days 
Day 43 ± 
2 days 
Day 50 
± 2 
days 
14 days ± 7 
days after 
Visit 10 or 
the final 
dosing  
Informed consent 
● 
 
 
 
 
 
 
 
 
 
 
 
Demographics 
● 
 
 
 
 
 
 
 
 
 
 
 
Concomitant 
medications/therapies 
 
 
 
 
 
 
 
 
 
 
 
 
Eligibility assessment 
● 
● 
● 
 
 
 
 
 
 
 
 
 
Randomization 
 
 
● 
 
 
 
 
 
 
 
 
 
MADRS 
● 
● 
● 
● 
● 
● 
● 
● 
● 
 
 
● 
CGI-I 
 
 
 
● 
● 
● 
● 
● 
● 
 
 
●l 
CGI-S 
● 
● 
● 
● 
● 
● 
● 
● 
● 
 
 
● 
HAM-D 
● 
● 
● 
 
 
 
 
 
● 
 
 
● 
MADRS-S 
● 
● 
● 
● 
● 
● 
● 
● 
● 
 
 
● 
Apathy Scale 
 
 
● 
 
 
 
 
 
● 
 
 
● 
Laboratory testsb 
● 
 
● 
 
 
 
 
 
● 
 
 
● 
Vital signsc 
● 
● 
● 
● 
● 
● 
● 
● 
● 
● 
 
● 
Physical examination 
● 
● 
● 
● 
● 
● 
● 
● 
● 
● 
● 
● 
Heightd and body weight, 
waist circumference 
● 
 
● 
 
 
 
 
 
● 
 
 
● 
12-lead ECG 
● 
 
● 
 
● 
 
● 
 
● 
 
 
● 


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Table 1.3-1 
Schedule of Assessments 
Period 
Screening 
Placebo 
Lead-ina 
Double-blind Treatment 
Double-
blind 
Tapering 
Post-
treatment 
Observationj 
At 
Discontinuationk
Visit 
Visit 1 
Visit 2 
(Week −1) 
Visit 3 
(Baseline) 
Visit 4 
(Week 1) 
Visit 5 
(Week 2) 
Visit 6 
(Week 3) 
Visit 7 
(Week 4) 
Visit 8 
(Week 5) 
Visit 9 
(Week 6) 
Visit 10 
(Week 7) 
Visit 11 
(2 weeks after 
Visit 10 or the 
final dosing) 
Day ± allowable window 
Day −35 
to the day 
before 
Visit 2 
Day −7 ± 1 
day 
Day 1 
Day 8 
± 1 
day 
Day 
15 ± 2 
days 
Day 
22 ± 2 
days 
Day 
29 ± 2 
days 
Day 36 
± 2 
days 
Day 43 ± 
2 days 
Day 50 
± 2 
days 
14 days ± 7 
days after 
Visit 10 or 
the final 
dosing  
Pregnancy teste 
● 
● 
 
 
 
 
 
 
 
● 
 
● 
C-SSRS 
● 
● 
● 
● 
● 
● 
● 
● 
● 
● 
● 
● 
AEs 
 
 
 
 
 
 
 
 
 
 
 
 
Blood sampling for plasma 
PK assessmentf 
 
 
 
● 
● 
 
● 
 
● 
 
 
 
Blood sampling for 
CYP2D6 genetic testing 
 
 
●h 
 
 
 
 
 
 
 
 
 
Blood sampling for DNA 
storageg 
 
 
●h 
 
 
 
 
 
 
 
 
 
IMP dispensingi 
 
● 
● 
● 
● 
● 
● 
● 
● 
 
 
● 
IMP compliance 
 
 
● 
● 
● 
● 
● 
● 
● 
● 
 
● 
aThe placebo lead-in period is conducted in a single-blind manner with subjects blinded to treatment received. 
bBlood will be withdrawn under fasting conditions (fasting [including juices and other sugar-containing beverages] for at least 8 hours) at Visit 3 and Visit 9. 
Blood will be withdrawn under fasting conditions wherever possible at Visit 1, Visit 11, and discontinuation. 
cBody temperature, systolic/diastolic blood pressure, pulse rate (blood pressure and pulse rate in the supine, sitting, and standing positions), and respiratory 
rate (sitting position) will be measured. 
dHeight will be measured at screening only. 
eA urine pregnancy test will be performed. If the urine pregnancy test is positive, a serum pregnancy test will be performed. 


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fBlood sampling time is not specified for blood sampling for plasma PK assessment. 
gBlood sample will be collected from subjects who consented blood sampling for DNA storage. 
hIf blood samples cannot be collected or blood samples need to be recollected for some reason, blood samples should be collected during the trial. 
iFollow the instruction of the Interactive Response Technologies (IRT) system. If the dose is tapered after treatment discontinuation, the investigational 
medicinal product (IMP) will be dispensed according to the instruction of the IRT system because the IMP is administered under double-blind conditions. 
jPerformed in subjects who started IMP administration after Visit 3. 
kPerformed if discontinuation of IMP administration occurs during the period between the start of IMP administration after Visit 2 and the start of IMP 
administration at Visit 9. 
lNot performed if discontinuation of IMP administration occurs during the period between the start of IMP administration after Visit 2 and the start of IMP 
administration at Visit 3.


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1.4 
Trial Procedures 
The investigator will perform the investigations, observations, and examinations 
according to the schedule of assessments (Table 1.3-1), and record the visit date and 
results of investigations, observations, and examinations in the source document and 
electronic case report form (eCRF). The demographic investigation, laboratory tests, and 
other test items, which the clinical trial associate is allowed to perform, may be 
performed by the clinical trial associate under the supervision of the investigator. 
1.4.1 
Visit 1 
1.4.1.1 
At Informed Consent 
Prior to the screening examination, the investigator will obtain written consent from the 
subject, assign a subject identification (ID) number to the subject, and record the subject 
ID number and date of informed consent in the subject screening log, source document, 
and eCRF. It is acceptable to obtain informed consent on a day before Visit 1. 
1.4.1.2 
Screening Examination 
After obtaining informed consent, the investigator will perform Visit 1 observations and 
examinations, and judge whether the subject is eligible to participate in the trial. At this 
time, the investigator will record whether the subject is eligible/ineligible for registration, 
date of registration, and reason for the judgment if ineligible, in the subject screening log. 
The investigator will ascertain the following demographic information. 
• Date of birth 
• Sex 
• Childbearing potential (see 10.3 Appendix 3: Contraceptive Guidance and Collection 
of Pregnancy Information for the definition) in female subjects (if no childbearing 
potential, the reason shall be recorded) 
• Race 
• Ethnicity 
• Country 
• DSM-5 diagnosis, severity, and specifiers (with anxious distress, with mixed features, 
with melancholic features, with atypical features, with mood-congruent psychotic 
features, with mood-incongruent psychotic features, with catatonia, peripartum onset, 
seasonal pattern) 
• Initial onset of MDD 
• Number of major depressive episodes 
• Onset timing of the current major depressive episode 
• Prior medications (all antidepressants) for the current major depressive episode 


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• Prior therapies (psychotherapies/somatotherapies performed within 6 weeks before 
informed consent) for the current major depressive episode 
• All prior medications used within 28 days before informed consent, and prior 
therapies performed within 6 weeks before informed consent 
• Medical history (within 2 years of informed consent, however, those related to the 
inclusion/exclusion criteria are not limited to 2 years) 
• Complications 
The investigator will register the required information in the Interactive Response 
Technologies (IRT) system. 
If antidepressants are being used at Visit 1, the use of the drug(s) should be discontinued 
by Visit 2 by appropriately tapering the dose if necessary, taking safety into consideration 
(the use of antidepressants is permitted until the day before Visit 2) (see Section 6.5.1.2). 
If the dose of antidepressants is to be tapered, the subject should visit the trial site to 
confirm safety, where appropriate. 
1.4.2 
Visit 2 
The investigator will perform Visit 2 observations and examinations within 28 days after 
Visit 1 and confirm the eligibility of the subject. Eligible subjects will be registered in the 
IRT system with the required information and start investigational medicinal product 
(IMP) administration (placebo). Ineligible subjects will also be registered in the IRT 
system with the required information. Visit 2 examinations can be performed on the same 
day of Visit 1 examinations in subjects who are naive to antidepressants or subjects who 
need no dose tapering of antidepressants used as prior therapy. In these cases, test values 
from Visit 1 can be used as test values of Visit 2. 
1.4.3 
Visit 3 
The investigator will perform Visit 3 observations and examinations 7 days (± 1 day) 
after Visit 2 and confirm the eligibility of the subject. Eligible subjects will be registered 
in the IRT system with the required information and assigned the IMP. The date of 
randomization is regarded as Day 1. Ineligible subjects will also be registered in the IRT 
system with the required information. 
1.4.4 
Visit 4 Through Visit 9 
The investigator will perform the observations and examinations specified for Visits 4, 5, 
6, 7, 8, and 9 on Days 8 (± 1 day), 15 (± 2 days), 22 (± 2 days), 29 (± 2 days), 36 (± 2 
days), and 43 (± 2 days), respectively. The investigator will register the required 
information in the IRT system and dispense the IMP. 


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1.4.5 
Visit 10 
The investigator will perform Visit 10 observations and examinations on Day 50 (± 2 
days). The investigator will register the required information in the IRT system. 
1.4.6 
Visit 11 
The investigator will perform Visit 11 observations and examinations 14 days (± 7 days) 
after the date of last IMP dose in all subjects who started IMP administration after Visit 
3. The investigator will register the required information in the IRT system at the end of 
the post-treatment observation period for each subject. 
1.4.7 
At Discontinuation 
If discontinuation of IMP administration occurs during the period between the start of 
IMP administration after Visit 2 and the start of IMP administration after Visit 9, the 
investigator will perform the examination at discontinuation specified in the schedule of 
assessments, and record the results and the visit date in the source document and eCRF. 
The investigator will register the required information in the IRT system. 
If discontinuation occurs during the period between the start of IMP administration after 
Visit 2 and the start of IMP administration after Visit 3, it is not necessary to perform the 
post-treatment observation (Visit 11) after the examination at discontinuation has been 
performed. 
If discontinuation occurs during the period between the start of IMP administration after 
Visit 4 and the start of IMP administration after Visit 9, the IMP dose will be tapered 
(duration: 1 week [7 days ± 2 days]) after the examination at discontinuation has been 
performed, and then the subject will visit the trial site to undergo the same examination as 
scheduled at Visit 10, and the post-treatment observation (Visit 11) will be performed 2 
weeks after the date of the final dosing. However, if the investigator judges that the IMP 
needs to be discontinued due to an adverse event (AE) or if the IMP dose cannot be 
tapered due to the subject’s circumstances such as he/she does not wish to taper the dose, 
dose tapering is not mandatory, and the examination at discontinuation will be performed 
followed by the post-treatment observation (Visit 11) 2 weeks after the date of the final 
dosing. 
If discontinuation occurs during the period between the start of IMP administration after 
Visit 3 and the start of IMP administration after Visit 4, dose tapering is not necessary 
after the examination at discontinuation has been performed, and the post-treatment 
observation (Visit 11) will be performed 2 weeks after the date of the final dosing. 


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If discontinuation of IMP administration occurs during the period between the start of 
IMP administration after Visit 9 and Visit 10, the examination at discontinuation is not 
necessary, the subject will visit the trial site to undergo the same examination as 
scheduled at Visit 10, and the post-treatment observation (Visit 11) will be performed 2 
weeks after the date of the final dosing. 


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2 
Introduction 
OPC-64005 is a serotonin-noradrenaline-dopamine triple reuptake inhibitor (TRI) 
synthesized by Otsuka Pharmaceutical Co., Ltd. (hereinafter referred to as Otsuka 
Pharmaceutical). It is being developed for the indication of depression/depressed state in 
Japan. 
Please refer to the OPC-64005 investigator’s brochure (IB) for more detailed information. 
2.1 
Trial Rationale 
Depression (major depressive disorder [MDD]) is a psychiatric disease with 
mood/affective disorders such as depressed mood and loss of interest/pleasure as 
prominent symptoms. While the etiology of MDD has not been fully clarified, one of the 
most common hypotheses is the monoamine hypothesis, and reduced monoamines 
(serotonin, noradrenaline, and dopamine) in synaptic clefts is considered to be one of the 
causes of MDD. 
OPC-64005 is a TRI that inhibits reuptake of serotonin, noradrenaline, and dopamine. 
Nonclinical studies confirmed that OPC-64005 inhibited monoamine reuptake of 
serotonin, noradrenaline, and dopamine, increased extracellular concentrations of 
serotonin, noradrenaline, and dopamine in the rat medial prefrontal cortex (mPFC), and 
increased extracellular dopamine concentrations in the striatum. In addition, OPC-64005 
showed significant antidepressant-like effects in a rat forced swimming test and 
significant anxiolytic‐like effects in a rat elevated plus maze test. Furthermore, Japan and 
overseas phase 1 trials in healthy adults using positron emission tomography (PET)-
labeled ligands (PET trials) confirmed that OPC-64005 binds to each intracerebral 
transporter of serotonin, noradrenaline, and dopamine (SERT, NET, and DAT, 
respectively) (Trials 277-10-205, 277-13-001, and 277-14-001). It is therefore expected 
that, based on the mechanism of action, the results of the nonclinical studies, and the 
results of the PET trials in healthy adults, OPC-64005 may exert therapeutic effects for 
the treatment of MDD. 
In addition, in the Japanese and overseas phase 1 trials in healthy adults, the safety and 
tolerability of repeated administration of OPC-64005 at a dose of up to 30 mg were 
confirmed. 
Therefore, it was judged appropriate to plan a phase 2, multi-center, randomized, double-
blind, placebo-controlled, parallel-group comparison trial in patients with MDD to assess 
the efficacy and safety of OPC-64005 in MDD at doses for which safety and tolerability 
have been confirmed in repeated administration. 


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See Section 4.2 for the rationale for the trial design. 
2.2 
Background 
2.2.1 
History of Development 
Major depressive disorder is a psychiatric disorder with mood/affective disorders such as 
depressed mood and loss of interest/pleasure as prominent symptoms, and accompanies 
reduced thinking and concentration, decreased or increased appetite, anxiety, feeling of 
self-worthlessness and self-accusation, suicidal ideation, and sleep disorder. In Japan, the 
prevalence of MDD among psychiatric disorders is high with its lifetime prevalence 
reported to be 5.7% and the 12-month prevalence reported to be 2.7%.2 Furthermore, 
there are significant socio-economic losses due to decreased social functioning such as 
absence from work and unemployment due to depression and an increased number of 
suicides. Therefore, treatment of depression plays a socially important role. 
The mainstay of treatment of MDD is pharmacotherapy with antidepressants, with 
selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake 
inhibitors (SNRIs), and mirtazapine recommended as first-line drugs. However, the 
response rate to treatment with antidepressants is reported to be 50% to 65%,3 and there 
are still patients who do not adequately respond to antidepressants. Selective serotonin 
reuptake inhibitors and SNRIs, which are commonly used as first-line drugs for MDD at 
present, are drugs based on the monoamine hypothesis, and act on the serotonergic 
system and the serotonergic system/noradrenergic system, respectively, but their action 
on the dopaminergic system is weak. When considering drug therapy for MDD based on 
the monoamine hypothesis, most evidence supports drugs that concurrently act on the 
serotonergic system, noradrenergic system, and dopaminergic system. Dopamine is 
known to play a key role in reward, motivation, mood control, working memory, 
attention, and executive function. Addition of the action on the dopaminergic system to 
the actions on the serotonergic and noradrenergic systems is expected to alleviate 
anhedonia, which is one of the core symptoms of MDD that does not adequately respond 
to SSRIs and SNRIs, and to improve recognition and motivation.4 
As mentioned above, drugs that simultaneously control the serotonergic system, 
noradrenergic system, and dopaminergic system are considered to be beneficial 
antidepressants and are expected to be a new therapeutic option for MDD as drugs with 
different mechanisms of action from SSRIs or SNRIs. Given this background, we 
embarked upon the development of OPC-64005, which inhibits reuptake of serotonin, 
noradrenaline, and dopamine, in patients with MDD. 


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2.2.2 
Results of Nonclinical Studies 
OPC-64005 is a TRI that inhibits reuptake of serotonin, noradrenaline, and dopamine, 
and it has been confirmed to exhibit inhibitory activities on serotonin, noradrenaline, and 
dopamine reuptake into rat brain synaptosomes (concentration of drug producing 50% 
inhibition [IC50] is 1.131 nM, 0.9684 nM, and 102.9 nM, respectively). In a microdialysis 
study, OPC-64005 significantly and dose-dependently increased extracellular 
concentrations of serotonin, noradrenaline, and dopamine in the mPFC. Moreover, OPC-
64005 significantly and dose-dependently increased extracellular dopamine 
concentrations in the striatum at a dose 10-fold higher than that in the mPFC. 
Furthermore, in the rat forced swimming test, OPC-64005 showed significant 
antidepressant-like effects. In the rat elevated plus maze test, OPC-64005 showed 
significant anxiolytic‐like effects. 
2.2.3 
Results of Clinical Trials 
A total of 3 clinical trials in healthy adults (Trials 277-13-001, 277-14-001, and 277-10-
205) were conducted in Japan and overseas to evaluate SERT, NET, and DAT occupancy 
following administration of OPC-64005. 
Following a single dose of OPC-64005, plasma OPC-64005 concentrations increased 
reaching a peak at around 3 hours postdose, and then rapidly decreased. The SERT and 
NET occupancy increased with an increase in plasma OPC-64005 concentrations. In 
several models, the maximum effect (Emax) on the SERT occupancy, 50% effective 
concentration (EC50), Emax on the NET occupancy, and EC50 were estimated to be 73.3% 
to 84.8%, 5.5 to 8.84 ng/mL, 117%, and 18.8 ng/mL, respectively. Significant binding of 
OPC-64005 to SERT and NET was also observed at 24 hours postdose, and the SERT 
and NET occupancy at 24 hours after a single dose of OPC-64005 (60 mg) was > 74% 
and > 71%, respectively. The pharmacodynamic (PD) data indicated that OPC-64005 
administered once daily may continuously occupy the transporters. 
Following repeated doses of OPC-64005 (30 mg) once daily for 14 days, the mean DAT 
occupancy was 27.8% at 2 hours postdose (plasma concentration range: 138 to 257 
ng/mL) and 24.4% at 24 hours postdose (plasma concentration range: 60.8 to 127 
ng/mL). 
2.3 
Known and Potential Risks and Benefits 
OPC-64005 is a TRI and has the potential to induce symptoms associated with SERT 
inhibition (eg, gastrointestinal disorder, sexual dysfunction, migraine) and symptoms 
associated with NET inhibition (eg, tachycardia, tremor) due to its mechanism of 


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action.5,6 Worsening of psychiatric symptoms, Parkinsonism, and psychomotor 
hyperactivity may also develop due to DAT inhibition.6 
In earlier Japanese and overseas phase 1 trials (Trials 277-10-001, 277-12-001, 277-09-
201, 277-13-001, 277-14-001, 277-10-205, 277-10-204, 277-09-202, and 277-10-206), a 
single dose or repeated doses of OPC-64005 at doses between 1 mg and 60 mg was/were 
administered to 313 healthy adults. In addition, in overseas, a phase 2 trial in patients 
with attention-deficit/hyperactivity disorder (AD/HD) (Trial 277-201-00001) was 
conducted and OPC-64005 (at 20 to 30 mg) was administered to 77 subjects. 
In the phase 1 trials in healthy adults, the following AEs were reported in ≥ 5% of the 
313 subjects who received OPC-64005: nausea (53 subjects, 16.9%), tachycardia (30 
subjects, 9.6%), dizziness (30 subjects, 9.6%), headache (24 subjects, 7.6%), and 
presyncope (17 subjects, 5.4%). In the phase 2 trial in AD/HD patients, the following 
AEs were reported in ≥ 5% of the 77 subjects who received OPC-64005: dry mouth (15 
subjects, 19.5%), nausea (14 subjects, 18.2%), decreased appetite (13 subjects, 16.9%), 
fatigue (7 subjects, 9.1%), dizziness (6 subjects, 7.8%), headache (6 subjects, 7.8%), 
insomnia (6 subjects, 7.8%), constipation (5 subjects, 6.5%), nasopharyngitis (4 subjects, 
5.2%), and sedation (4 subjects, 5.2%). 
Other than the above AEs, although the incidence is not high, skin eruption (rash) may 
occur after administration of OPC-64005, and it was reported in 5 healthy adult subjects 
and 2 AD/HD patients. 
In addition, as serious adverse events (SAEs), supraventricular tachycardia was reported 
in 1 healthy adult subject (relationship to IMP: possibly related) and suicide attempt was 
reported in 1 AD/HD patient (relationship to IMP: not related). 
As described above, there is a risk that AEs reported in the above clinical trials, including 
AEs that may occur due to inhibition of SERT, NET, and DAT, may occur after 
administration of OPC-64005. However, AEs other than those mentioned above may 
occur and careful monitoring is necessary. 
The benefits of participating in the trial include the fact that depressive symptoms may 
improve, and that during the trial the subjects could receive more detailed tests and 
examinations by physicians than they could have with just general examinations. As of 
Oct 2019, no TRIs have been approved for the indication of depression/depressive 
symptoms in Japan or overseas. 


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3 
Objectives and Endpoints 
The objective of the trial is to compare the efficacy of OPC-64005 at 20 mg vs placebo 
and to assess the safety and pharmacokinetics (PK) of OPC-64005 at 10 and 20 mg in 
patients with MDD. 
The primary endpoint is the mean change from baseline in Montgomery-Åsberg 
Depression Rating Scale (MADRS) total score at Week 6 of the double-blind treatment 
period in the OPC-64005 20-mg group compared with the placebo group. 
The secondary endpoints are the MADRS response rate (proportion of subjects with 
≥ 50% reduction from baseline in MADRS total score at Week 6 of the double-blind 
treatment period), MADRS remission rate (proportion of subjects with MADRS total 
score ≤ 10 and ≥ 50% reduction from baseline in MADRS total score at Week 6 of the 
double-blind treatment period), Clinical Global Impression – Improvement (CGI-I) 
improvement rate (proportion of subjects with CGI-I of 1 or 2 at Week 6 of the double-
blind treatment period), mean change from baseline in Clinical Global Impression – 
Severity of Illness (CGI-S), mean change from baseline in the total score of 17 items of 
the Hamilton Rating Scale for Depression (HAM-D), mean change from baseline in 
Apathy Scale score, mean change from baseline in the total score of MADRS Self-
assessment (MADRS-S), and mean change from baseline in MADRS anhedonia factor 
score for evaluation of the efficacy of OPC-64005 at 20 mg. 
The safety and PK of OPC-64005 at 10 mg and 20 mg will also be assessed in patients 
with MDD. 
Table 3-1 
Trial Objectives and Endpoints 
Objectives 
Endpoints 
Primary: To compare the efficacy of OPC-64005 at 
20 mg vs placebo administered orally as repeated 
doses once daily for 6 weeks in patients with MDD 
Primary endpoint: Change from baseline in 
MADRS total score at Week 6 of the double-
blind treatment period 
 
Secondary endpoints: MADRS response rate, 
MADRS remission rate, CGI-I improvement rate, 
mean change from baseline in CGI-S, mean 
change from baseline in HAM-D 17-item total 
score, mean change from baseline in Apathy 
Scale score, mean change from baseline in 
MADRS-S total score, mean change from 
baseline in MADRS anhedonia factor score 
Secondary: To assess the safety and PK of OPC-
64005 administered orally as repeated doses at 
10 mg or 20 mg once daily for 6 weeks in patients 
with MDD 
Safety endpoints: Laboratory tests, vital signs, 
physical examination, height, body weight, waist 
circumference, 12-lead electrocardiogram (ECG), 
pregnancy test, Columbia-Suicide Severity Rating 
Scale (C-SSRS), and AEs 
PK 


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Section 9.4 describes the statistical analysis of the endpoints. 
4 
Trial Design 
4.1 
Type/Design of Trial 
In this trial, OPC-64005 at 10 mg or 20 mg or placebo will be orally administered as 
repeated doses once daily for 6 weeks in 270 patients with MDD, and the efficacy, safety, 
and PK of OPC-64005 will be assessed. This is a phase 2, multi-center, randomized, 
double-blind, placebo-controlled, parallel-group comparison trial consisting of 5 periods: 
screening period, placebo lead-in period (single-blind with subjects blinded to treatment 
received), double-blind treatment period, double-blind tapering period, and post-
treatment observation period. 
4.2 
Scientific Rationale for Trial Design 
The trial was designed with reference to the Guideline for Clinical Evaluation of 
Antidepressants7 (hereinafter referred to as the Clinical Evaluation Guideline). The 
Clinical Evaluation Guideline states that “a double-blind, placebo-controlled comparison 
trial is necessary for evaluation of efficacy of antidepressants” and “duration of treatment 
in exploratory and confirmatory trials of antidepressants is generally 6 to 8 weeks.” 
Therefore, this trial was designed as a randomized, double-blind, placebo-controlled, 
parallel-group comparison trial to appropriately assess the efficacy and safety with a 
6-week double-blind treatment period. 
The screening period was set as a necessary period to confirm the inclusion/exclusion 
criteria and wash out prior medications. The placebo lead-in period (single-blind with 
subjects blinded to treatment received) was set because it is preferable to exclude subjects 
with significant changes in symptoms for the purpose of appropriately evaluating the 
efficacy of OPC-64005. Although no AEs related to withdrawal symptoms have been 
reported after the end of administration of OPC-64005 in previous trials, the double-blind 
tapering period was set because when antidepressants are discontinued, a gradual 
reduction in dose is generally recommended. The post-treatment observation period was 
set to confirm the safety of subjects after administration of the final dose of OPC-64005. 
4.3 
Dosing Rationale 
4.3.1 
Rationale for Mode of Administration 
The results of the PET trials in healthy adults confirmed that OPC-64005 maintained 
intracerebral SERT, NET, and DAT occupancy for 24 hours after administration (Trials 


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277-10-205, 277-13-001, and 277-14-001), and OPC-64005 is expected to be effective 
when administered once daily. Accordingly, a dosing regimen of once-daily 
administration was set. 
In the overseas phase 2 trial in AD/HD patients (Trial 277-201-00001), OPC-64005 
administered at 30 mg once daily for 8 weeks (starting dose: 20 mg/day, 4 days) resulted 
in a statistically significant improvement in symptoms compared with the placebo. 
4.3.2 
Rationale for Dose 
The dose of OPC-64005 in this trial was determined based on estimated receptor 
occupancy of each monoamine transporter obtained from a simulation analysis8 of a 
PK/PD model, which was newly conducted using the results of the PET trials in healthy 
adults.9 
There are many studies on intracerebral monoamine receptor occupancy of 
antidepressants, and PET trials10,11,12 of various drugs reported that the ideal monoamine 
transporter occupancy by TRIs, taking antidepressant effect and safety into account, are 
≥ 80% for SERT, 50% to 70% for NET, and ≤ 30% for DAT.13 
Table 4.3.2-1 shows the estimated maximum occupancy of each monoamine transporter 
by OPC-64005 in the steady-state after repeated administration of OPC-64005. The 
SERT occupancy reached approximately 70% at OPC-64005 10 mg. The NET occupancy 
was > 50% at OPC-64005 10 mg and > 60% at 20 mg. The DAT occupancy reached 25% 
at OPC-64005 20 mg. OPC-64005 is a TRI expected to be a new therapeutic option for 
depression. Since OPC-64005 is expected to act on serotonin, noradrenaline, and 
dopamine at 20 mg based on the estimated occupancy, 20 mg was selected as the dose for 
assessing efficacy and safety in this trial. 
Table 4.3.2-1 
Estimated Maximum Occupancy (Median) of Each 
Monoamine Transporter by OPC-64005 in Steady-state 
OPC-64005 Dose 
5 mg 
10 mg 
20 mg 
30 mg 
SERT 
64% 
71% 
74% 
75% 
NET 
40% 
55% 
63% 
66% 
DAT 
5% 
12% 
25% 
34% 
Estimated by a PK/PD model simulation based on the results of the PET trials (Trials 277-10-205, 277-
13-001, and 277-14-001) 
 
In the previous phase 1 repeated-dose trials in healthy adults (Trials 277-12-001 and 
277-10-206), tolerability was confirmed at doses up to 30 mg/day. The overseas phase 2 
trial in AD/HD patients (Trial 277-201-00001) confirmed that OPC-64005 was safe and 
tolerable when administered at 20 mg/day for 4 days, followed by a dose increased on 


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Day 5 to 30 mg/day, which was administered up until Day 56, for a total of 8 weeks. 
Based on these clinical results, it was judged that there are no significant safety problems 
in selecting 20 mg as the dose for efficacy assessment in the present trial. 
In Trial 277-201-00001, on the other hand, the incidence of AEs that led to 
discontinuation of the trial in the OPC-64005 group was 23.4% (18/77 subjects) and 
higher than that in the placebo group (8.5%, 7/85 subjects). Most of these AEs occurred 
during the early stage of treatment initiation (during treatment at 20 mg). Therefore, in 
consideration of safety at an early stage of treatment, the starting dose in the present trial 
was set at 10 mg, which is lower than the starting dose of Trial 227-201-00001. 
As of Oct 2019, there are no TRIs approved in Japan or overseas, and the safety profile is 
unknown. The 10-mg group was also included in the trial because evaluation of safety at 
the lower dose is beneficial when assessing the safety profile of OPC-64005. 
4.4 
End of Trial Date Definition 
The end of trial date is defined as the date of last observation (Visit 11) of the last 
subject. For discontinued subjects, the end of trial date is the date of last observation. For 
subjects lost to follow-up, the end of trial date is the date of final contact attempt. 
4.5 
Definition of Completed Subjects 
The treatment period is defined as the period during which subjects are evaluated for 
primary and/or secondary objectives of the trial irrespective of whether the subject was 
actually administered all IMP doses. Subjects who are evaluated at the last scheduled 
visit during the treatment period will be defined as trial completers. For purposes of this 
trial, subjects who complete Visit 9 (Week 6 of the double-blind treatment period) will be 
defined as trial completers. 
5 
Trial Population 
The trial population is 270 male and female patients ≥ 20 to < 65 years of age (at time of 
informed consent) diagnosed with either “major depressive disorder, single episode” or 
“major depressive disorder, recurrent episode” according to the Diagnostic and Statistical 
Manual of Mental Disorders, Fifth Edition (DSM-5). 
5.1 
Subject Selection and Numbering 
Subjects will be given a unique subject identifier (ID; site number [3 digits] + subject 
number [S + 5 digits] upon providing written consent). The site number will be 
designated by the sponsor. The subject number will be given in the order of informed 
consent from S00001 as the serial numbers in the trial sites. Demographic information 


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(collection date, date of birth, sex, childbearing potential, race, ethnicity, country) and 
medical history will be recorded in the source document and electronic case report form 
(eCRF) at screening. 
Subjects enrolled in the trial will be registered in the IRT system, and eligible subjects 
will be assigned a unique randomization number in the IRT system. Results of the 
eligibility assessment, date of randomization, and randomization number will be recorded 
in the eCRF. 
5.2 
Eligibility Criteria 
Exceptions for eligibility criteria will not be permitted during the trial by either 
investigator. 
5.2.1 
Inclusion Criteria 
Subjects are required to meet the following inclusion criteria at the time points described 
in the schedule of assessments (Table 1.3-1). 
At informed consent and at screening (Visit 1): 
1) Patients of ≥ 20 years to < 65 years of age (at time of informed consent) 
2) Male or female patients 
3) Patients who have sufficient understanding to provide consent for execution of all 
observations, examinations, and evaluation items stipulated in the protocol, and 
are capable of fully understanding the content of the trial and providing written 
consent 
4) Outpatients 
5) Patients with DSM-5 classification-based diagnosis of “major depressive disorder, 
single episode” or “major depressive disorder, recurrent episode” with the current 
episode persisting for ≥ 4 weeks to ≤ 1 year (the Mini-International 
Neuropsychiatric Interview [M.I.N.I.] method is used for assessment) 
At start of placebo lead-in period (Visit 2): 
6) Patients with a HAM-D 17-item total score of ≥ 18 based on evaluation 
performed at the start of the placebo lead-in period 
At baseline (Visit 3): 
7) Patients with a HAM-D 17-item total score of ≥ 18 based on evaluation 
performed at baseline 
 


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[Rationale for Inclusion Criteria] 
1): The lower limit of age for adults is based on legal competency to provide consent. 
The upper limit of age is < 65 years to appropriately evaluate the safety of OPC-64005 
because the elderly generally have reduced physiological function. 
2): Depression develops regardless of sex. 
3): This criterion was set for ethical considerations. 
4): This criterion was set in view of subject safety, as treatment should be prioritized in 
patients whose condition requires hospitalization. 
5) to 7): These criteria were set to appropriately evaluate efficacy. 
5.2.2 
Exclusion Criteria 
Subjects will be excluded if they meet any of the following exclusion criteria at the time 
points described in the schedule of assessments (Table 1.3-1). However, if results are not 
available at the time of tests/assessments, such as laboratory tests values, the results need 
to be confirmed by baseline. 
At informed consent and at screening (Visit 1): 
1) Pregnant women, breastfeeding women, and/or women who have a positive urine 
pregnancy test result at screening 
2) Sexually active males or females of childbearing potential (FOCBP), who do not 
agree to practice 2 different approved methods of birth control or remain fully 
abstinent during the trial and for 2 weeks after the last dose of the IMP. If 
employing birth control, 2 of the following methods must be used: vasectomy, 
tubal ligation, intrauterine device, birth control pill, condom (all methods 
approved or validated in Japan). The definition of childbearing potential is 
provided in Section 10.3. 
Male patients must also agree not to donate sperm from trial screening through 2 
weeks after the last dose of the IMP. 
3) Patients with the following DSM-5 diagnosis (diseases that can be confirmed by 
M.I.N.I. will be evaluated using M.I.N.I.): 
• Neurocognitive disorders 
• Schizophrenia spectrum and other psychotic disorders (history/complication) 
• Bipolar and related disorders (history/complication) 
• Feeding and eating disorders 
• Obsessive-compulsive disorder 
• Panic disorder 
• Posttraumatic stress disorder 
• Personality disorders 


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• Neurodevelopmental disorders 
• Substance-related and addictive disorders (within 180 days prior to the date of 
informed consent) 
4) Patients exhibiting mood-incongruent psychotic features in the current major 
depressive episode 
5) Patients with complicated hypothyroidism or hyperthyroidism at informed 
consent (excluding patients whose disease condition has been stabilized by drug 
therapy for at least 90 days preceding informed consent) 
6) Patients who meet any of the following criteria or have any of the following 
symptoms at screening: 
• Inadequately controlled hypertension (diastolic blood pressure [DBP] > 
95 mmHg) 
• Symptomatic hypotension 
• Orthostatic hypotension defined as a fall in systolic blood pressure (SBP) of ≥ 
30 mmHg or fall in DBP of ≥ 20 mmHg after the patient has stood for 3 minutes 
compared with the pressures measured in the supine position before standing 
7) Patients with complicated ischemic heart disease, myocardial infarction, or 
congestive cardiac failure (regardless of whether these conditions are being 
adequately or inadequately controlled), patients who have undergone angioplasty, 
stent placement, or coronary artery bypass grafting 
8) Patients with a history of neuroleptic malignant syndrome or serotonin syndrome 
9) Patients with a history or complication of convulsive disorder except for pediatric 
isolated febrile convulsion 
10) Patients with the following laboratory values or ECG parameters at screening 
(assessed based on the results of the central laboratory, central ECG facility) 
• Platelet count ≤ 75,000/mm3 
• Hemoglobin ≤ 9 g/dL 
• Absolute neutrophil count ≤ 1000/mm3 
• Aspartate aminotransferase (AST) > 2-fold the upper limit of normal (ULN) 
• Alanine aminotransferase (ALT) > 2-fold the ULN 
• Creatinine ≥ 2 mg/dL 
• Glycosylated hemoglobin (HbA1c) ≥ 7% (International Scale [NGSP]) 
• Fasting blood glucose ≥ 126 mg/dL, or casual blood glucose ≥ 200 mg/dL 
• Fridericia’s corrected QT (QTcF) interval ≥ 450 msec 
• Abnormal values of thyroid-stimulating hormone (TSH) and free thyroxine (FT4) 
11) Patient with hypersensitivity to drugs (all drugs including prescription and over 
the counter [OTC] drugs) and ingredients of OPC-64005 (D-mannitol, corn 
starch, low substituted hydroxypropylcellulose, pregelatinized starch, magnesium 
stearate, hypromellose, talc, titanium oxide, yellow ferric oxide) (including 
history) 


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12) Patients who, in the opinion of the investigator, are judged to have treatment-
resistant depression, ie, a certain degree of therapeutic effect is not obtained by 
administration of 2 or more antidepressants having different mechanisms of action 
at sufficient doses for at least 6 weeks for the current major depressive episode 
13) Patients receiving augmentation treatment, such as antipsychotics, for the current 
major depressive episode (excluding the use of sulpiride for depression/depressive 
state or gastric/duodenal ulcer) 
14) Patients who have received electroconvulsive therapy in the past 
15) Patients who have embarked upon a new course of psychotherapy (except for 
supportive psychotherapy generally conducted as part of routine medical practice) 
within 6 weeks of informed consent 
16) Patients who have received OPC-64005 in the past 
17) Patients who have participated in any other trials within 60 days of informed 
consent 
18) Patients with a HAM-D Suicide (No. 11) score of ≥ 3 at screening, patients who 
responded “Yes” to Question 4 or Question 5 of the C-SSRS at screening, or 
patients who, in the opinion of the investigator, are judged to be at high risk for 
committing suicide during the trial based on the current psychiatric symptoms and 
medical history at screening 
19) Patients in whom, in the opinion of the investigator, it cannot be ruled out that a 
possible change in the patient’s circumstances (eg, leave of absence, return to 
work, relocation) may affect the efficacy evaluation of the trial 
20) Patients with clinically problematic diseases of the nervous system, liver, kidney, 
metabolic system, blood system, immune system, cardiovascular system, lung, or 
gastrointestinal system. However, if the disease is minor and adequately 
controlled and does not interfere with the safety and efficacy evaluations, the 
patient can be enrolled. 
21) Other patients who, in the opinion of the investigator, should not participate in the 
trial 
At start of placebo lead-in period (Visit 2): 
22) Pregnant women, breastfeeding women, and/or women who have a positive urine 
pregnancy test result at the start of the placebo lead-in period 
23) Patients with a MADRS-S total score of < 8.5 based on evaluation performed at 
the start of the placebo lead-in period 
24) Patients with a HAM-D Suicide (No. 11) score of ≥ 3 at the start of the placebo 
lead-in period, patients who responded “Yes” to Question 4 or Question 5 of the 
C-SSRS at the start of the placebo lead-in period, or patients who, in the opinion 
of the investigator, are judged to be at high risk for committing suicide during the 
trial based on the current psychiatric symptoms and medical history at the start of 
the placebo lead-in period 
25) Patients who required another hospitalization during the screening period due to 
the current major depressive episode 


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26) Other patients who, in the opinion of the investigator, should not participate in the 
trial 
At baseline (Visit 3): 
27) Patients with a MADRS-S total score of < 8.5 based on evaluation performed at 
baseline or with ≥ 25% reduction in MADRS-S total score at baseline compared 
with at the start of the placebo lead-in period 
28) Patients with a HAM-D Suicide (No. 11) score of ≥ 3 at baseline, patients who 
responded “Yes” to Question 4 or Question 5 of the C-SSRS at baseline, or 
patients who, in the opinion of the investigator, are judged to be at high risk for 
committing suicide during the trial based on the current psychiatric symptoms and 
medical history at baseline 
29) Patients who required another hospitalization during the placebo lead-in period 
due to the current major depressive episode 
30) Other patients who, in the opinion of the investigator, should not participate in the 
trial 
 
[Rationale for Exclusion Criteria] 
1), 2), 22): These criteria were set for safety considerations because the safety of OPC-
64005 during pregnancy and breastfeeding has not been established. 
3), 4), 12) to 15), 19), 23), 27): These criteria were set to appropriately evaluate efficacy. 
5): This criterion was set to appropriately evaluate efficacy because patients with thyroid 
disorders may experience depressive symptoms. 
6) to 11), 17), 18), 20), 21), 24) to 26), 28) to 30): These criteria were set for safety 
considerations. 
16): This criterion was set to avoid potential influence on the blindness. 
5.3 
Lifestyle Considerations 
The following lifestyle considerations apply for the trial. 
5.3.1 
Meals and Dietary Restrictions 
Consumption of grapefruit, starfruit, Seville orange, and their processed products such as 
juices is prohibited from 3 days before Visit 2 until the end of the double-blind tapering 
period. Consumption of St. John’s wort-containing foods is prohibited from Visit 2 
through Visit 9. 
5.3.2 
Caffeine, Alcohol, and Tobacco 
From Visit 2 through Visit 9, excessive caffeine consumption and smoking should be 
avoided, and consumption of alcoholic beverages should be avoided wherever possible. 


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5.3.3 
Activity 
Not applicable. 
5.4 
Screen Failures 
A screen failure is a subject from whom informed consent is obtained and is documented 
in writing (ie, subject signs an informed consent form [ICF]), but who is not dispensed 
the IMP at Visit 2. 
If the subject meets the definition of a screen failure in this trial, the following 
information will be recorded in the eCRF: 
• Date of informed consent 
• Visit date (screening visit) 
• Demographics (collection date, birth date, sex, race, ethnicity, country) 
• Result of eligibility assessment 
• Screen failure date 
• Reason for screen failure 
Subjects who participate in the trial and subsequently become screen failures can undergo 
rescreening. When rescreening is performed, separate written consent needs to be 
obtained and a new subject ID will be assigned prior to the screening examination. 
6 
Trial Treatments 
6.1 
Trial Treatments Administered 
For information regarding the dose regimen and treatment period, including any follow-
up period(s) for each treatment group of the trial, see Section 6.1.1. 
6.1.1 
Dosage and Administration 
6.1.1.1 
Placebo Lead-in Period (Single-blind With Subjects Blinded to 
Treatment Received) 
Two placebo tablets will be administered orally once daily for 1 week. 
6.1.1.2 
Double-blind Treatment Period 
• Placebo group 
Two placebo tablets will be administered orally once daily for 6 weeks. 
• OPC-64005 10-mg group 
One placebo tablet and one OPC-64005 10-mg tablet will be administered orally once 
daily for 6 weeks. 


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• OPC-64005 20-mg group 
One placebo tablet and one OPC-64005 10-mg tablet will be administered orally once 
daily for 1 week, followed by two OPC-64005 10-mg tablets for 5 weeks. 
6.1.1.3 
Double-blind Tapering Period 
• Placebo group 
Two placebo tablets will be administered orally once daily for 1 week. 
• OPC-64005 10-mg group 
Two placebo tablets will be administered orally once daily for 1 week. 
• OPC-64005 20-mg group 
One placebo tablet and one OPC-64005 10-mg tablet will be administered orally once 
daily for 1 week. 
6.1.1.4 
At Discontinuation 
If discontinuation occurs during the period between the start of IMP administration after 
Visit 4 and the start of IMP administration after Visit 9, the IMP dose will be tapered (1 
week [7 days ± 2 days]) to the following regimens (however, if the investigator judges 
that the IMP needs to be discontinued due to an AE or if the IMP dose cannot be tapered 
due to the subject’s circumstances such as he/she does not wish to taper the dose, dose 
tapering is not mandatory): 
• Placebo group 
Two placebo tablets will be administered orally once daily for 1 week. 
• OPC-64005 10-mg group 
Two placebo tablets will be administered orally once daily for 1 week. 
• OPC-64005 20-mg group 
One placebo tablet and one OPC-64005 10-mg tablet will be administered orally once 
daily for 1 week. 
If discontinuation occurs during the period between the start of IMP administration after 
Visit 3 and the start of IMP administration after Visit 4 or between the start of IMP 
administration after Visit 9 and Visit 10, dose tapering is not necessary. If the IMP dose 
is tapered after discontinuation, the IMP will be dispensed according to the instructions 
from the IRT system, as the IMP will be administered under double-blind conditions. 
6.1.1.5 
Handling of Missed Doses 
If the subject realizes that he/she missed taking the IMP the day before, he/she will not 
take the missed IMP dose from the day before. 


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6.1.1.6 
Investigation on Drug Compliance 
The investigator will confirm the drug compliance status between the scheduled visits, 
and record the daily dose, treatment start date, and treatment end date in the source 
document and eCRF. 
The drug compliance rate will be calculated by the following formula: [Dose (number of 
tablets) between the scheduled visits] / [number of prescription days between the 
scheduled visits × 2 tablets] × 100. If the drug compliance rate between the scheduled 
visits is < 65%, administration will be discontinued (see Section 7.3.3). 
6.1.2 
Medical Devices 
Not applicable. 
6.2 
Management of Investigational Medicinal Product 
For full details on IMP management, please refer to the OPC-64005 IB and a separate 
manual. 
6.2.1 
Packaging and Labeling 
The IMP will be provided by the sponsor or designated agent to the IMP manager. The 
IMP will be supplied as blister cards. Each blister card used in the dosing period will be 
labeled to clearly disclose the subject ID, compound ID, protocol number, sponsor’s 
name and address, route of administration, lot number, expiry date, and storage method, 
etc. 
6.2.2 
Storage 
The IMP will be stored in a securely locked cabinet or enclosure. Access will be limited 
to the IMP manager. 
The IMP will be stored according to the conditions indicated on the IMP label. 
The trial site staff will maintain a temperature log in the IMP storage area to record the 
temperature. 
6.2.3 
Accountability 
The IMP manager must maintain an inventory record of the IMP (investigational or 
placebo) received, dispensed, administered, and returned. The IMP manager may not 
provide the IMP to any patient not participating in this protocol. 


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6.2.4 
Returns and Destruction 
Upon completion or termination of the trial, all used IMP containers, unused IMP, and 
partially used IMP must be returned to the sponsor or a designated agent. All IMP 
returned to the sponsor must be accompanied by the appropriate documentation and be 
clearly identified by protocol number and trial site number on the outermost shipping 
container. Returned supplies should be in the original containers (eg, subject kits). The 
assigned trial monitor will facilitate the return of used IMP containers, unused IMP, and 
partially-used IMP. 
6.2.5 
Reporting of Product Quality Complaints 
A Product Quality Complaint (PQC) is any written, electronic, or verbal communication 
by a healthcare professional, consumer, subject, medical representative, Competent 
Authority, regulatory agency, partner, affiliate or other third party that alleges 
deficiencies or dissatisfaction related to identity, quality, labeling, packaging, reliability, 
safety, durability, tampering, counterfeiting, theft, effectiveness, or performance of a drug 
product or medical device after it is released for distribution. Examples include, but are 
not limited to, communications involving: 
• Failure of a product to meet any of its specifications 
• Incorrect or missing labeling 
• Packaging issues (eg, damaged, dirty, crushed, missing product) 
• Blister defects (eg, missing, empty blisters) 
• Product defect (eg, odor, chipped, broken, embossing illegible) 
• Loss or theft of product 
 
6.2.5.1 
Eliciting and Reporting Product Quality Complaints 
The investigator or designee must record all PQCs identified through any means from the 
receipt of the IMP from the sponsor or sponsor’s designee, through and including 
reconciliation and up to destruction, including subject dosing. The investigator or 
designee must notify the sponsor or sponsor’s designee by email (destination address: 
PQC_277-102-00027@otsuka.jp) of the information listed in Section 6.2.5.2 immediately 
after acknowledging the PQC. 
Identification of a PQC by the subject should be reported to the site investigator, who 
should then follow the reporting mechanism above. 
6.2.5.2 
Information Required for Reporting Product Quality Complaints 
• Description of complaint 


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• Reporter identification (eg, subject, investigator, site, etc.) 
• Reporter contact information (eg, address, phone number, e-mail address) 
• ID of material (product/compound name, kit number) 
• Clinical protocol reference (number and/or trial name) 
• Dosage form/strength (if known) 
• Pictures (if available) 
• Availability of complaint sample for return 
 
6.2.5.3 
Return Process in the Case of Product Quality Complaints 
Indicate during the report of the PQC if the complaint sample is available for return. The 
sponsor may provide sample return instructions, when applicable. 
It must be documented in the site accountability record that the complaint sample for a 
dispensed kit has been forwarded to the sponsor for complaint investigation. 
6.2.5.4 
Assessment/Evaluation 
Assessment and evaluation of PQCs will be handled by the sponsor. 
6.3 
Measures to Minimize/Avoid Bias 
This trial will be performed as a randomized double-blind trial to minimize bias. 
Treatment assignment codes will not be disclosed to the subjects or investigator. Except 
for designated persons, the treatment assignment code will not be disclosed to the 
sponsor’s trial staff including contract research organizations (CROs) (except for the 
bioanalytical laboratory and pharmacogenomic [PGx] laboratory) during the trial. 
Emergency keys are controlled by the IRT system until the end of the trial. They will be 
disclosed according to the procedures for breaking the blind when a medical emergency 
occurs to a subject and it is judged important to identify the treatment assignment code 
for treatment of the subject. Procedures for breaking the blind can be found in 
Section 8.8.7. 
If the IMP is collected by the sponsor before unblinding, the IMP will be collected in the 
sealed state. 
Subjects will be assigned to the OPC-64005 10-mg group, OPC-64005 20-mg group, or 
placebo group at a ratio of 1:4:4 using the dynamic allocation method (minimization 
method). A separate specification will be developed to provide details. 
Results of drug concentration measurement and PGx assessment should be retained in a 
manner that prevents their disclosure until unblinding at the end of the trial. These tests 


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will be performed by the specified laboratories, and will not be performed at a clinical 
laboratory of the trial site. 
6.4 
Subject Compliance 
During the trial, subjects will be placed under the management of the investigator. The 
investigator will instruct subjects to adhere to the following: 
• Subjects must adhere to the specified schedule during the trial 
• The trial must be discontinued when the drug compliance rate between the scheduled 
visits is < 65% 
• Subjects must practice appropriate contraceptive methods 
• Subjects must adhere to the requirements in Section 5.3 and Section 6.5 
• Subjects must not disclose information obtained as a result of participation in the trial 
to third parties 
• If a rash develops on the skin after the start of IMP administration, subjects must 
immediately contact trial site staff and follow the investigator’s instructions 
 
6.5 
Concomitant Medications or Therapies 
The investigator will record all concomitant medications taken by the subject from 28 
days prior to informed consent through Visit 10 and all concomitant therapies taken by 
the subject from 6 weeks prior to informed consent through Visit 10 in the eCRF. The 
investigator will also record all concomitant medications and therapies taken by the 
subject for treatment of an AE or which caused an AE until the end of the trial (defined as 
the date of last observation or date of final contact attempt) in the eCRF. 
For concomitant medications, the following will be recorded in the eCRF: medication, 
indication, dose, frequency, route, start date and end date. For concomitant therapy, the 
following will be recorded in the eCRF: therapy, indication, start date and end date. 
6.5.1 
Prohibited Medications 
The use of following medications is prohibited. If it is considered necessary by the 
investigator, these medications will be tapered off and then stopped. If the dose of 
antidepressants is to be tapered, the subject should visit the trial site to confirm safety, 
where appropriate. 
6.5.1.1 
Fourteen Days Before Visit 2 Through Visit 11 
• Monoamine oxidase inhibitors 
 


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6.5.1.2 
Visit 2 Through Visit 9 
• Antidepressants 
• Benzodiazepines (except for ultrashort-acting hypnotics and sedatives) 
• Drugs that are considered to affect the metabolic/activity systems of serotonin, 
noradrenaline, or dopamine 
• Central nervous system drugs (except for ultrashort-acting hypnotics and sedatives; 
antipyretic, analgesic and anti-inflammatory agents; and general cold medicines) 
• Chinese herbal medicines (drugs indicated for neurosis, anxiety neurosis, 
neurasthenia, and insomnia) 
• Over the counter drugs used as sleeping pills 
• Supplements used for improvement of depressive symptoms (St. John’s wort, S-
adenosylmethionine [SAM-e], ω-3 fatty acid, kava extract, γ-aminobutyric acid 
[GABA]) 
• Varenicline 
 
6.5.1.3 
Visit 2 Through Visit 10 
• Strong cytochrome P450 (CYP) 3A4 inhibitors, CYP1A2 inhibitors, CYP2D6 
inhibitors, CYP3A4 inducers, CYP1A2 inducers, CYP2B6 inducers, and CYP2D6 
substrates with narrow therapeutic range (except for topical drugs) 
 
6.5.2 
Restricted Medications 
The use of the following medications is restricted. 
6.5.2.1 
Visit 2 Through Visit 9 
• Antipyretic, analgesic and anti-inflammatory agents, and antihistamines 
The concomitant use of these drugs is permitted if they have been used for treatment 
of a complication at Visit 2. However, the same dosage and administration should be 
maintained unless an AE has occurred, or the drug is judged to be no longer necessary 
due to remission of symptoms. Short-term concomitant use of these drugs for 
treatment of colds is also permitted. The use of local topical drugs is permitted. Short-
term is defined as 1 week in principle. If antipyretic, analgesic and anti-inflammatory 
agents or antihistamines that were not being used at informed consent are 
administered for > 2 weeks, or such administration is necessary, the trial will be 
discontinued according to the reason for discontinuation, “significant protocol 
deviation.” 
• Ultrashort-acting hypnotics and sedatives 
The concomitant use of ultrashort-acting hypnotics and sedatives (zolpidem, 
zopiclone, eszopiclone, triazolam) is permitted. However, the concomitant use is 
permitted with only 1 of these drugs and 2 or more of them must not be used 
concomitantly. The same dosage and administration should be maintained wherever 
possible. 


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6.5.3 
Permitted Medications 
All medications that are not specified as prohibited/restricted medications can be used 
concomitantly. However, the same dosage and administration should be maintained, and 
no new medications/therapies should be added wherever possible. 
6.5.4 
Rescue Medications 
Not applicable. 
6.5.5 
Prohibited Therapies 
The following therapies are prohibited so that the efficacy and safety of OPC-64005 can 
be appropriately assessed. 
• Somatotherapies (electroconvulsive therapy, bright light therapy, sleep deprivation 
therapy, transcranial magnetic stimulation) 
The concomitant use of these therapies is prohibited from Visit 1 through Visit 9. 
• Psychotherapies (except for supportive psychotherapy generally conducted as part of 
routine medical practice) 
The concomitant use of psychotherapies is prohibited from Visit 2 through Visit 9. 
 
6.6 
Intervention After the End of the Trial 
Not applicable. 
7 
Stopping Rules, Withdrawal Criteria, and Procedures 
7.1 
Entire Trial or Treatment 
If the sponsor terminates or suspends the trial for any reason, prompt notification will be 
given to the heads of the trial sites and regulatory authorities in accordance with 
regulatory requirements. 
7.2 
Individual Site 
Individual trial site participation may be discontinued by the sponsor, investigator, or IRB 
if judged to be necessary for medical, safety, regulatory, ethical, or other reasons 
consistent with applicable laws, regulations, and GCP. The head of the trial site will 
notify the sponsor promptly if the trial is terminated by the investigator or the IRB of the 
trial site. 


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7.3 
Individual Subject Discontinuation 
7.3.1 
Treatment Interruption 
If drug eruption is suspected after IMP administration, IMP administration will be 
discontinued or interrupted (see Section 8.7.2.1). 
7.3.2 
Treatment Discontinuation 
After treatment assignment, a subject may stop treatment permanently for a variety of 
reasons. Treatment discontinuations may be initiated by a subject who is not satisfied 
with treatment or may become medically necessary due to AEs, required treatment with a 
disallowed medication or therapy, or other issues, as determined by the investigator. 
However, each investigator must comprehensively review the circumstances and offer the 
subject options for continued treatment to the degree possible as described in 
Section 7.3.5. 
If discontinuation of IMP administration occurs during the period between the start of 
IMP administration after Visit 2 and the start of IMP administration after Visit 9, the 
examination at discontinuation will be performed. If the subject refuses to undergo any 
examinations at the time of withdrawal, or if examinations cannot be performed due to an 
emergency or other circumstances, of the examination items specified for the time of 
withdrawal, only those items that can be performed will be performed. 
If the specified examinations have been already performed on the day of discontinuation, 
they do not need to be repeated. 
If discontinuation occurs during the period between the start of IMP administration after 
Visit 2 and the start of IMP administration after Visit 3, the post-treatment observation 
(Visit 11) is not necessary after the examination at discontinuation has been performed. 
If discontinuation is decided during the period between the start of IMP administration 
after Visit 4 and the start of IMP administration after Visit 9, the IMP dose will be 
tapered (duration: 1 week [7 days ± 2 days]) wherever possible after the examination at 
discontinuation has been performed (see Section 6.1.1.4). After the dose tapering, the 
subject will visit the trial site to undergo the same examination as scheduled at Visit 10, 
and the post-treatment observation (Visit 11) will be performed 2 weeks after the date of 
the final dosing. 
If discontinuation occurs during the period between the start of IMP administration after 
Visit 3 and the start of IMP administration after Visit 4, dose tapering is not necessary 
after the examination at discontinuation has been performed, and the post-treatment 
observation (Visit 11) will be performed 2 weeks after the date of the final dosing. 


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If discontinuation of IMP administration occurs during the period between the start of 
IMP administration after Visit 9 and Visit 10, the examination at discontinuation is not 
necessary. The subject will visit the trial site to undergo the same examination as 
scheduled at Visit 10, and the post-treatment observation (Visit 11) will be performed 2 
weeks after the date of the final dosing. 
7.3.3 
Documenting Reasons for Treatment Interruption or 
Discontinuation 
A subject may discontinue the IMP for the reasons listed below: 
• Adverse event 
− Subject decides to discontinue because of annoyance or discomfort due to a 
nonserious AE which is not otherwise determined to be an undue hazard 
− The investigator judges that the subject is at high risk for committing suicide 
based on his/her clinical symptoms, MADRS No. 10 “Suicidal Thoughts” score is 
≥ 5, HAM-D Suicide (No. 11) score is ≥ 3, or “Yes” to Question 4 or Question 5 
of the C-SSRS 
− Symptoms change to manic state 
− Continuing IMP places the subject at undue risk as determined by the investigator 
(eg, a safety concern that is possibly, probably, or likely related to IMP) 
• SAE 
• Occurrence of drug eruption 
• Other potentially IMP-related safety concerns or AEs 
• Death 
• Lost to follow-up 
• Noncompliance with IMP (eg, drug compliance rate between the scheduled visits is < 
65%) 
• Physician decision 
• Pregnancy (see Section 10.3) 
• Significant protocol deviation 
• Site terminated by sponsor 
• Study terminated by sponsor 
• Withdrawal by subject 
• Lack of efficacy 
 
If the subject discontinues IMP due to an AE, the investigator, or other trial personnel, 
will make every effort to follow the event until it has resolved or stabilized. Follow-up 
procedures in Section 7.3.1 and Section 7.3.2 must be followed. 


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7.3.4 
Withdrawal of Consent or Assent 
All subjects have the right to withdraw their consent from further participation in the trial 
at any time without prejudice. Subjects cannot withdraw consent for use of data already 
collected as part of the trial, but only for future participation. The investigator can also 
discontinue a subject’s participation in the trial at any time if medically necessary. Unless 
the subject provides their written withdrawal of consent or there is other written 
documentation by the investigator confirming the subject’s verbal intent to completely 
withdraw from the trial, subjects should be followed for all protocol-specified evaluations 
and assessments, if possible. 
Complete withdrawal of consent means a subject’s refusal of ALL of the following 
methods of follow-up: 
• Participation in all follow-up procedures specified in the protocol (whether in-clinic, 
by telephone, or by a home visit). 
• Participation in a subset of protocol specified follow-up procedures (by a frequency 
schedule and method, as agreed by subject and trial site staff). 
• Contact of the subject by trial personnel, even if only by telephone, to assess current 
medical condition, and obtain necessary medical or laboratory reports relevant to the 
trial’s objectives. 
• Contact of alternative person(s) who have been designated in source records as being 
available to discuss the subject’s medical condition, even if only by telephone, mail, 
or e-mail (eg, family, spouse, partner, legal representative, friend, neighbor, or 
physician). 
• Access to medical information from alternative sources (eg, hospital/clinic medical 
records, referring doctor’s notes, public records, dialysis, transplantation or vital 
registries, social media sources). 
Withdrawal of consent is a critical trial event and, therefore, should be approached with 
the same degree of importance and care as is used in initially obtaining informed consent. 
The reasons for a subject’s intended withdrawal need to be completely understood, 
documented, and managed to protect the rights of the subject and the integrity of the trial. 
A subject may initially express his/her desire to discontinue IMP administration, which is 
not equivalent to a complete withdrawal of consent for further participation (see 
Section 7.3.2). A subject may, however, indicate that further trial participation is creating 
a burden on their work, school, or social schedule. Therefore, the investigator should 
follow the procedures outlined in Section 7.3.3 to determine if the subject can continue 
participation in the trial if modifications to his/her treatment and/or schedule of 
assessments can be accommodated. Only subjects who withdraw their permission for all 
of the above methods of follow-up are considered to have completely withdrawn their 
consent to participate in the trial. 


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Details on the withdrawal of consent from the Future Biospecimen Research (FBR) 
substudy are provided in the ICF for FBR. 
7.3.5 
Procedures to Encourage Continued Trial Participation 
In all cases of impending IMP discontinuation or consent withdrawal, investigators will 
be instructed to meet and discuss (without undue coercion) with the subject their options 
of continuing in the trial, preferably on therapy. The investigator should ensure 
understanding and documentation of the reasons for the subject’s desire to withdraw 
consent. 
7.4 
Definition of Subjects Lost to Follow-up 
Subjects who cannot be contacted before Visit 11, who do not have a known reason for 
discontinuation (eg, withdrew consent or AE), and for whom a survival status at the end 
of the trial cannot be determined will be classified as “lost to follow-up.” Survival status 
can be determined from a variety of sources, either by obtaining acceptable 
documentation for death (ie, death certificate, medical records, public records, statement 
by a family member or primary care physician) or acceptable documentation for life (ie, 
direct contact with the subject, medical records, successful telephone contact with the 
subject, statement by a family member or primary care physician, or public records). 
The site will make 3 documented attempts to contact the subject by telephone and in the 
event the site is unable to reach the subject by telephone, the site will attempt to contact 
the subject via certified mail or an alternative similar method, where appropriate, before 
assigning a “lost to follow-up” status. 
If the subject was classified as “lost to follow-up”, “Were you able to contact the 
subject?”, “Date of contact/Date of final contact attempt” and “Contact method” will be 
recorded in source documents and eCRF. 
8 
Trial Procedures 
The assessments to be conducted during the trial are summarized in Section 1.3. 
8.1 
Efficacy Assessments 
8.1.1 
Montgomery Åsberg Depression Rating Scale 
A trained and qualified investigator will evaluate the following 10 depressive symptoms 
on 7 scales of 0 to 6 using the Structured Interview Guide for MADRS (SIGMA) at the 
specified evaluation points, and record the date and time of evaluation and evaluation 
result in the source document and eCRF. The total score of items 1, 2, 6, 7, and 8 will be 
used as the MADRS anhedonia factor score. 


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1. Apparent sadness 
2. Reported sadness 
3. Inner tension 
4. Reduced sleep 
5. Reduced appetite 
6. Concentration difficulties 
7. Lassitude 
8. Inability to feel 
9. Pessimistic thoughts 
10. Suicidal thoughts 
8.1.2 
Clinical Global Impression – Improvement 
The investigator will evaluate improvement of depressive symptoms on the following 8 
scales using the CGI-I at the specified evaluation points. During the double-blind 
treatment period, improvement will be evaluated in comparison with the subject’s 
condition at Visit 3 (at the start of the double-blind treatment period), and the date and 
time of evaluation and evaluation result will be recorded in the source document and 
eCRF. 
0. Not assessed 
1. Very much improved 
2. Much improved 3. Minimally improved 
4. No change 
5. Minimally worse 
6. Much worse 
7. Very much worse 
8.1.3 
Clinical Global Impression - Severity of Illness 
The investigator will evaluate the severity of depressive symptoms on the following 8 
scales using the CGI-S at the specified evaluation points, and record the date and time of 
evaluation and evaluation result in the source document and eCRF. 
0. Not assessed  
1. Normal, not at all ill 2. Borderline mentally ill 
3. Mildly ill 
4. Moderately ill 
5. Markedly ill 
6. Severely ill 
7. Among the most extremely ill 
8.1.4 
Hamilton Depression Rating Scale 
A trained and qualified investigator will evaluate the following 21 depressive symptoms 
using the Structured Interview Guide for the Hamilton Depression Rating Scale (SIGH-
D) at the specified evaluation points: Items No. 1 to 2, 10 to 14, 16 to 17, and 19 on 5 
scales of 0 to 4, Items No. 5 and 20 on 4 scales of 0 to 3, and Items No. 3 to 4, 6 to 9, 15, 
18, and 21 on 3 scales of 0 to 2. The total score of Items No. 1 to 17 will be calculated, 
and the date and time of evaluation and evaluation result will be recorded in the source 
document and eCRF. 
1. Depressed mood 
2. Work and activities 
3. Genital symptoms 
4. Somatic symptoms gastrointestinal 
5. Loss of weight 
6. Insomnia early 
7. Insomnia middle 
8. Insomnia late 
9. Somatic symptoms general 10. Feelings of guilt 
11. Suicide 


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12. Anxiety psychic 
13. Anxiety somatic 
14. Hypochondriasis 
15. Insight 
16. Retardation 
17. Agitation 
18. Diurnal variation 
19. Depersonalization and derealization 
20. Paranoid symptoms 
21. Obsessional and compulsive symptoms 
8.1.5 
Montgomery Åsberg Depression Rating Scale Self-assessment 
All subjects will perform self-assessment on the following 10 items of MADRS-S on the 
scale of 0 to 3 at the specified evaluation points, and the investigator will record the date 
and time of evaluation and evaluation result in the source document and eCRF. 
Staying power 
1. Mood 
2. Feelings of unease 
3. Sleep 
4. Appetite 
5. Ability to concentrate 
6. Initiative 
7. Emotional involvement 
8. Pessimism 
9. Zest for life 
8.1.6 
Apathy Scale 
All subjects will perform self-assessment for each of the following 14 items on the 
Apathy Scale on 4 scales at the specified evaluation points. 
1. Are you interested in learning new things? 
2. Does anything interest you? 
3. Are you concerned about your condition? 
4. Do you put much effort into things? 
5. Are you always looking for something to do? 
6. Do you have plans and goals for the future? 
7. Do you have motivation? 
8. Do you have the energy for daily activities? 
9. Does someone have to tell you what to do each day? 
10. Are you indifferent to things? 
11. Are you unconcerned with many things? 
12. Do you need a push to get started on things? 
13. Are you neither happy nor sad, just in between? 
14. Would you consider yourself apathetic? 


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8.2 
Pharmacokinetic Assessments 
Plasma drug concentrations will be determined to calculate the PK parameters of OPC-
64005 and its metabolite OPC-144013 in a population PK analysis performed separately. 
8.2.1 
Pharmacokinetic Plasma Samples 
Blood samples for PK analysis will be collected at the time points as shown in 
Table 1.3-1 (schedule of assessments). The date and time of sample collection and the 
date and time of IMP administration immediately before blood collection will be 
recorded in the source document and eCRF. 
Blood samples (2 mL) will be collected in vacutainers containing heparin sodium and 
processed into plasma to determine the concentrations of OPC-64005 and metabolite 
OPC-144013 by a validated high performance liquid chromatography-tandem mass 
spectrometry method. Additional metabolites that are not identified in the protocol may 
also be analyzed, if needed. In addition, PK samples may be used for the investigation of 
a bioanalytical method, if needed. 
All plasma samples will be shipped to the bioanalytical laboratory for analysis. 
Additional information on the procedures for collection, handling and shipment of 
samples will be provided in a separate manual. 
The bioanalytical laboratory will record the use of the treatment assignment table, and 
measure drug concentrations of samples collected from the OPC-64005 group only. The 
content of the treatment assignment table will not be disclosed to any person other than 
those permitted to perform procedures by the bioanalytical manager, and should be kept 
under lock and key. The results of drug concentration measurement will be kept under 
lock and key by the bioanalytical laboratory, and an electronic file will be submitted to 
the sponsor after unblinding. Therefore, drug concentration data do not need to be 
recorded in the source document or eCRF. 
The residual plasma samples will be stored at the bioanalysis laboratory and disposed of 
after the clinical study report has been prepared. 
8.3 
Pharmacodynamic Assessments 
Not applicable. 
8.4 
Pharmacogenomic Assessments 
Tests on CYP2D6 genotype and phenotype will be performed. CYP2D6 genetic testing is 
mandatory. 


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[Rationale for CYP2D6 Genetic Testing] 
In vitro evaluation showed that CYP2D6 is involved in OPC-64005 metabolism, and 
CYP2D6 is known to have genotypes with different enzyme activity. It was judged 
appropriate for evaluation of the PK of OPC-64005 to perform a test on CYP2D6 
genotypes, which could be a potential factor accounting for variations. 
8.4.1 
Pharmacogenomic Samples 
Blood samples for CYP2D6 genetic testing will be collected at the time point described 
in Table 1.3-1 (schedule of assessments). If blood samples cannot be collected or blood 
samples need to be recollected for some reason, blood samples should be collected during 
the trial. The date of sample collection will be recorded in the source document and 
eCRF. 
Blood samples (2 mL) will be collected in vacutainers containing 
ethylenediaminetetraacetic acid (EDTA) dipotassium. Genomic DNA will be extracted 
from a blood sample and used to test CYP2D6*1, *2, *4, *5, *10, *14, *18, *21, and *41 
alleles. The CYP2D6 genotype of each subject will be determined using the CYP2D6 
genotype assessment table (Appendix 4: Genetic Testing), and furthermore, the 
phenotype will be classified as an extensive metabolizer (EM), intermediate metabolizer 
(IM), poor metabolizer (PM), or unknown based on the CYP2D6 genotype. The results of 
CYP2D6 genetic testing will not be disclosed to the subjects in principle. 
All blood samples will be shipped to the PGx laboratory for analysis. Additional 
information on the procedures for collection, handling, and shipment of samples will be 
provided in a separate manual. 
The PGx laboratory will record the use of the treatment assignment table and extract 
DNA from blood samples collected from the OPC-64005 group only. Blood samples 
collected from the placebo group will be disposed of according to the PGx laboratory 
procedures. The content of the treatment assignment table will not be disclosed to any 
person other than those permitted to perform procedures by the person responsible of the 
PGx laboratory, and should be kept under lock and key. The results of CYP2D6 genetic 
testing will be kept under lock and key by the PGx laboratory, and an electronic file will 
be submitted to the sponsor after unblinding. Therefore, the test results do not need to be 
recorded in the source document or eCRF. 
The residual DNA samples will be stored at the PGx laboratory and disposed of after the 
clinical study report has been prepared. 


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8.5 
Biomarker Assessments 
Not applicable. 
8.6 
Future Biospecimen Research Samples 
Storage of DNA samples will be conducted to enable future exploratory evaluation of 
variations in DNA characteristics related to individual differences in the drug response 
(efficacy, safety, PK, etc) of the drugs used in this trial and/or variations in DNA 
characteristics related to diseases. 
DNA samples will be collected only at trial sites, which approved blood sampling for 
DNA storage, and only from subjects who provided voluntary written consent for DNA 
storage. 
 
[Rationale for Sample Storage for Future Biospecimen Research] 
Storage of DNA samples will be conducted to enable future genomic/genetic analysis if 
further explanation other than the results of CYP2D6 genetic testing performed in this 
trial is required for the PK of OPC-64005, if new information on genetics and PK 
becomes available, and/or if it is judged that genomic/genetic analysis would be useful 
for evaluating the drug response (efficacy and safety) of the IMP and diseases. The 
Ministry of Health, Labour and Welfare (MHLW) states in Q&A 1 of “Regarding 
Clinical Studies Utilizing Pharmacogenomics (30 Sep 2008, PFSB/ELD Notification No. 
0930007)” as follows regarding the collection and storage of DNA samples during trials: 
It is permissible to obtain samples for genomic/genetic analyses relevant to the evaluation 
of the study drug (eg, PK, efficacy, and safety) from subjects in a clinical trial in either of 
the following cases: (1) the target and time of genomic/genetic analysis are already 
specified at the time of the clinical trial or (2) the target and time of genomic/genetic 
analysis have not yet been specified but such analysis is planned to be performed in the 
future for further evaluation of the study drug. The ministry also stated in Q&A 2 that it 
is permissible to obtain samples for genomic/genetic analyses not related to the 
evaluation of the study drug from subjects.14 In addition, in the International Council for 
Harmonization (ICH) E18 Guideline on Genomic Sampling and Management of 
Genomic Data, in Section 1.4 General Principles states “With advances in science and 
increased awareness of the impact of genomics, there is a need and an opportunity to 
maximize the value of the collected samples and the data generated from them, and 
therefore, genomic sample acquisition is strongly encouraged in all phases and studies of 
clinical development.”15 


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In addition, sample collection is planned to coincide as much as possible with other trial 
examinations in order to minimize the burden on subjects and therefore the collection and 
storage of DNA samples on a voluntary basis is considered appropriate. 
8.6.1 
Scope of Future Biospecimen Research 
Research performed on FBR samples includes genetic analyses (DNA). Such research is 
for biomarker testing to address emergent questions not described elsewhere in the 
protocol (as part of the main trial) and will only be conducted on specimens from subjects 
who have provided appropriate consent. The objective of collecting specimens for FBR is 
to explore and identify biomarkers that inform the scientific understanding of diseases 
and/or their therapeutic treatments. 
8.6.2 
Summary of Procedures for Future Biospecimen Research 
Samples 
All subjects enrolled in the clinical trial will be considered for enrollment in the optional 
FBR substudy. 
After obtaining informed consent, the following FBR samples will be obtained at the time 
point specified in Table 1.3-1 (schedule of assessments). If blood samples cannot be 
collected or blood samples need to be recollected for some reason, blood samples should 
be collected during the trial. 
• Blood (2 mL, EDTA dipotassium) for DNA analysis 
Information whether samples were collected and the date of sample collection will be 
recorded in the source document and eCRF. Additional information on the procedures for 
collection, handling, and shipment of samples will be provided in a separate manual. If a 
FBR substudy is planned, a separate document describing the analysis may be prepared 
and the results may be reported separately from the clinical study report. 
8.6.3 
Storage of Samples for Future Biospecimen Research 
The samples for biospecimen research will be stored at the biospecimen storage site for 
future analysis until the earliest of the following time points: 1) when genomic/genetic 
analysis is considered to be no longer necessary, 2) when 15 years have passed since the 
first informed consent for DNA storage was obtained in this trial, or 3) when the subject 
withdraws his/her consent for DNA storage. 
8.6.4 
Genomic/Genetic Analysis 
Genomic/genetic analysis will be performed only if such analysis is judged to be useful 
for exploratory evaluation of variations in DNA characteristics related to individual 


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differences in the drug response (efficacy, safety, PK, etc) of the IMP and/or variations in 
DNA characteristics related to diseases. 
If it is decided to perform genomic/genetic analysis, a pharmacogenomic study protocol 
will be prepared. After approval of the protocol by the sponsor’s research review board, 
the analysis will be performed in compliance with the applicable national laws and 
regulations. 
It is currently impossible to identify the target for genomic/genetic analysis. While it is 
possible that related genome-wide analyses using a DNA chip, microarray, next-
generation sequencer, etc, may be performed, the results of these analyses will never be 
used for any purpose other than those described above. 
The DNA samples for genomic/genetic analysis will be double-coded at the biospecimen 
storage site prior to being sent to the genomic/genetic analysis laboratory (currently 
undetermined), and genomic/genetic analysis will be performed with the double coding 
maintained. 
8.6.5 
Provision and Withdrawal of Consent for Future Biospecimen 
Research 
A document explaining the DNA storage and the genomic/genetic analyses using stored 
DNA will be prepared, and signed informed consent will be obtained separately from the 
informed consent for participation in the clinical trial. The date of informed consent will 
be recorded in the source documents and the eCRF. 
If a subject withdraws his/her consent for DNA storage during the sample storage period, 
the sponsor will request the biospecimen storage facility to dispose of the subject’s 
samples. The biospecimen storage facility will dispose of the samples with anonymity 
maintained. However, if it becomes impossible to identify an individual subject’s 
samples for some reason, such as destruction of the data linking the samples to subject 
information (key code table, etc), it may become impossible to dispose of the samples of 
a specific subject who has withdrawn his/her consent. 
Even if a subject decides to discontinue participation in the clinical trial, participation in 
DNA storage will not be canceled automatically. In addition, any results of the 
genomic/genetic analysis that have already been obtained at the time consent is 
withdrawn will not be disposed of. 
8.6.6 
Disclosure of Genomic/Genetic Analytical Results to Subjects 
Even if findings are obtained as a result of the analysis, such results are considered 
exploratory in nature or at an early stage of research and their scientific reliability 


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(accuracy, certainty, etc) will not have been fully confirmed. Since the disclosure of 
scientifically ambiguous information would provide no benefit to subjects, in principle 
the sponsor will not disclose the results of the genomic/genetic analysis to the subjects. 
8.7 
Safety Assessments 
Details pertaining to the definitions, collection, reporting, and follow-up of AEs are 
described in Section 8.8. 
8.7.1 
Clinical Laboratory Assessments 
Clinical laboratory samples will be collected at the time points described in the schedule 
of assessments (Table 1.3-1) to perform the clinical laboratory assessments described in 
Section 10.2. The total volume of blood to be collected is approximately 38 mL. 
Blood and urine samples will be collected from each subject, and the date and time of 
blood collection, date of urine collection, and fasting state at the time of blood collection 
will be recorded in the source document and eCRF. Blood will be withdrawn under 
fasting conditions (fasting [including juice and other sugar-containing beverages] for at 
least 8 hours) at Visit 3 and Visit 9. Blood will be withdrawn under fasting conditions 
wherever possible at Visit 1, Visit 11, and discontinuation. In this trial, the central 
laboratory selected by the sponsor will be used. Laboratory values determined by the 
central laboratory will be used for confirmation of eligibility. Appropriate procedures for 
collection, handling, and shipment of samples will be provided in a separate manual 
before the trial. The central laboratory will report test results to the investigator. The 
investigator will confirm the test results, record the date of confirmation of results and 
sign the laboratory test report so that it will become an official document. Test results 
will be directly reported from the central laboratory to the sponsor in an electronic file, 
consequently, they do not need to be recorded in the source document or eCRF. 
8.7.2 
Physical Examination 
Physical examinations will be performed at the time points described in the schedule of 
assessments (Table 1.3-1). 
The investigator will evaluate physical findings by conducting medical interviews and by 
other means for the following body sites. At screening, the date of assessment and 
assessment result will be recorded in the source document and eCRF. After screening, the 
date of assessment only will be recorded in the source document and eCRF. If clinically 
significant physical findings compared with screening are observed, they will be recorded 
as AEs in the source document and eCRF. 


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Assessed sites: Head, eyes, ears, nose and pharynx, chest, abdomen, urogenital organs, 
extremities, nerves, skin, and mucous membranes 
8.7.2.1 
Dermatological Findings 
Skin should be carefully observed. If drug eruption occurs after the start of IMP 
administration, administration of the IMP will be discontinued regardless of its severity, 
and the event will be reported as an immediately reportable event (IRE) after being 
assessed as drug eruption (see Section 8.8.3 and Section 8.8.5). The investigator will 
orally obtain consent from the subject and take pictures of the onset site of drug eruption 
wherever possible. The pictures (electronic data) will be kept as the source document, 
and the sponsor will collect copies of the pictures (electronic data). If necessary, the 
investigator will orally obtain consent from the subject and perform a drug-induced 
lymphocyte stimulation test (DLST). In addition, depending on the severity, the 
investigator will instruct the subject to see a dermatologist. If drug eruption is suspected, 
administration of the IMP will be interrupted, and when drug eruption has been ruled out, 
administration of the IMP can resume. However, the trial will be discontinued when the 
drug compliance rate between the scheduled visits is < 65%. 
8.7.3 
Vital Signs 
Vital signs will be collected at the time points described in the schedule of assessments 
(Table 1.3-1). 
According to the trial site procedures, body temperature, SBP, DBP, and pulse rate will 
be measured. Body temperature will be measured after the subject has rested. Systolic 
blood pressure, DBP, and pulse rate will be measured in the order of supine, sitting, and 
standing positions after the subject has stayed in each position for at least 3 minutes. The 
respiratory rate will be measured after the subject has rested for at least 5 minutes in the 
sitting position. The date and time of measurement, position (for blood pressure and pulse 
rate), and results will be recorded in the source document and eCRF. 
8.7.4 
Electrocardiogram 
Electrocardiograms will be performed at the time points described in the schedule of 
assessments (Table 1.3-1). 
The investigator will record an ECG using the 12-lead ECG provided by the central ECG 
facility after the subject has rested for at least 5 minutes in the supine position, assess the 
ECG (normal or abnormal), and record the date and time the ECG was taken, result of 
normal/abnormal assessment, and abnormal findings in the source document and eCRF. 
The original of the 12-lead ECG output will be stored in the medical record or 


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investigator file. The central ECG facility will collect 12-lead ECG data, measure heart 
rate, PR interval, RR interval, QRS interval, QT interval, and heart rate corrected QT 
(QTc) interval (QTcF = QT interval / [RR interval]1/3), and the physician of the central 
ECG facility will perform assessment. The central ECG facility will report analysis 
results to the investigator, and the investigator will confirm the analysis results, record 
the date of confirmation of results and sign the analysis result report so that it becomes an 
official document. The investigator will reconfirm the assessment referring to the 
“analysis result report” issued by the central ECG facility. Analysis results will be 
directly reported from the central ECG facility to the sponsor in an electronic file, 
consequently, they do not need to be recorded in the source document or eCRF. 
8.7.5 
Suicidality Monitoring 
8.7.5.1 
Columbia-Suicide Severity Rating Scale 
Suicidality monitoring will occur at the time points described in the schedule of 
assessments (Table 1.3-1). 
This scale consists of the C-SSRS Baseline Version, which assesses a lifetime history of 
suicide-related events and suicidal ideation, and the C-SSRS Since Last Visit Version, 
which focuses on suicidality since the last visit. At screening, assessment will be 
performed using the C-SSRS baseline version. After screening, assessment will be 
performed using the since last visit version. The date and time of assessment and 
assessment result will be recorded in the source document and eCRF. 
“Suicidal ideation” 1 and 2 will be assessed either “Yes” or “No.” If 2 is “Yes,” “suicidal 
ideation” 3 to 5 will also be assessed. If “suicidal ideation” 1 or 2 is “Yes,” “intensity of 
ideation” will also be assessed. For “intensity of ideation,” “frequency” and “duration” 
will be rated on 5 scales, and “controllability,” “deterrents,” and “reason for ideation” 
will be rated on 6 scales. The following “suicidal behavior” will be assessed either “Yes” 
or “No,” and “total number” will be recorded for each “suicide attempt.” If there is any 
suicide attempt, “actual lethality/medical damage” will be rated on 6 scales. If actual 
lethality/medical damage is 0, “potential lethality” will be rated on 3 scales. 
Suicidal ideation: 
1. Wish to be dead 
2. Non-specific active suicidal thoughts 
3. Active suicidal ideation with any methods (not plan) without intent to act 
4. Active suicidal ideation with some intent to act, without specific plan 


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5. Active suicidal ideation with specific plan and intent 
Suicidal behavior: Actual attempt, Non-suicidal self-injurious behavior, Interrupted 
attempt, Aborted attempt, Preparatory acts or behavior, Suicide (the Since Last Visit 
Version only) 
8.7.6 
Other Safety Variables 
8.7.6.1 
Waist Circumference 
Waist circumference will be measured at the time points described in the schedule of 
assessments (Table 1.3-1). 
As few clothes as possible should be worn (lightly dressed with heavy outerwear 
removed). The positions of the upper coxal bone and upper edge of the right iliac crest 
will be determined, and the measuring tape will be tightly wrapped around the abdomen 
along the horizontal plane of the height of the iliac crest. Before reading the measuring 
tape, the measurer will make sure that the measuring tape is not loose, not pressing on the 
skin, and is horizontal to the floor. The measurer will measure in units of 1 cm (rounded 
off to the nearest integer) at the time point where the subject has fully exhaled in a 
normal manner, and record the date of measurement and result in the source document 
and eCRF. 
8.7.6.2 
Height and Body Weight 
Height and body weight will be measured at the time points described in the schedule of 
assessments (Table 1.3-1). 
Height and body weight will be measured in units of 0.1 cm and 0.1 kg, respectively, and 
the date of measurement and result will be recorded in the source document and eCRF. 
Body weight will be measured using a calibrated and highly reliable weight scale. In the 
same subject, body weight will be measured using the same weight scale using standard 
measuring method (shoes off and daily clothes on). If body weight is measured to the 
second decimal place or below, the figure will be rounded off to the first decimal place. 
8.8 
Adverse Events 
8.8.1 
Definitions 
An AE is defined as any untoward medical occurrence in a patient or clinical trial subject 
administered an IMP and which does not necessarily have a causal relationship with this 
treatment. Adverse events would not include information recorded as medical history at 
screening for pre-planned procedures for which the underlying condition was known and 


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no worsening occurred. An adverse drug reaction is any untoward and unintended 
response to an IMP related to any dose administered. 
A suspected adverse reaction is any AE for which there is a reasonable possibility that the 
IMP caused the AE. 
Treatment-emergent AEs (TEAEs) are defined as AEs with an onset date on or after the 
start of double-blind IMP treatment. In more detail, TEAEs are all AEs which started 
after the start of double-blind IMP treatment; or if the event was continuous from 
baseline and has worsened. 
An SAE includes any event that results in any of the following outcomes: 
• Death 
• Life-threatening; ie, the subject was, in the opinion of the investigator, at immediate 
risk of death from the event as it occurred. It does not include an event that, had it 
occurred in a more severe form, might have caused death. 
• Persistent or significant incapacity/disability or substantial disruption of the ability to 
conduct normal life functions. 
• Requires inpatient hospitalization or prolongs hospitalization. 
− Hospitalization itself should not be reported as an SAE; whenever possible the 
reason for the hospitalization should be reported. 
− Hospitalizations or prolonged hospitalizations for social admissions (ie, those 
required for reasons of convenience or other nonmedical need) are not considered 
SAEs. 
− Prescheduled hospitalization to address a condition that has existed prior to the 
signing of the ICF should not be considered an SAE. 
• Congenital anomaly/birth defect. 
• Other medically significant events that, based upon appropriate medical judgment, 
may jeopardize the subject and may require medical or surgical intervention to 
prevent one of the outcomes listed above; eg, allergic bronchospasm requiring 
intensive treatment in an emergency room or home, blood dyscrasias or convulsions 
that do not result in hospitalization, or the development of drug dependency or drug 
abuse. 
 
Nonserious AEs are all AEs that do not meet the criteria for a “serious” AE. 
Immediately Reportable Event (IRE): 
• Any SAE. 
• Any AE related to occupational exposure. 
• Drug eruption. 
• Potential serious hepatotoxicity (see Section 8.8.6). 


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• Pregnancies are also defined as IREs. Although normal pregnancy is not an AE, it 
will mandate IMP discontinuation and must be reported on an IRE form and the 
Pregnancy Surveillance Form(s), etc to the sponsor. This includes pregnancy of the 
subject or the partner of the subject. Pregnancy will only be documented on the AE 
eCRF if the pregnancy occurs in a female subject and there is an abnormality or 
complication. 
 
Clinical Laboratory Test Value Changes: It is the investigator’s responsibility to review 
the results of laboratory tests for each individual subject as they become available. This 
review will be documented by the investigator’s dated signature on the laboratory report. 
The investigator may repeat the laboratory test or request additional tests to verify the 
results of the original laboratory tests. If this laboratory value is considered medically 
relevant (ie, clinically significant) by the investigator (subject is symptomatic, requiring 
corrective treatment or further evaluation), or if the laboratory value leads to 
discontinuation, and/or fulfills a seriousness criterion, this is considered an AE.  
Severity: Adverse events will be graded on a 3-point scale and reported as indicated in 
the eCRF. The severity of an adverse experience is defined as follows: 
1 = Mild:  
Discomfort noticed, but no disruption to daily activity. 
2 = Moderate: 
Discomfort sufficient to reduce or affect normal daily activity. 
3 = Severe: 
Inability to work or perform normal daily activity. 
IMP Causality: Assessment of causal relationship of an AE to the use of the IMP is 
defined as follows: 
Related:  
There is a reasonable possibility of a temporal and causal 
relationship between the IMP and the AE. 
Not Related:  
There is no temporal or causal relationship between the IMP and 
the AE. 
8.8.2 
Eliciting and Reporting Adverse Events 
The investigator will regularly assess subjects for the occurrence of AEs. To avoid bias in 
eliciting AEs, subjects should be asked the nonleading question: “How have you felt 
since your last visit?” All AEs (serious and nonserious) reported by the subject must be 
recorded on the source documents and eCRF provided by the sponsor. Adverse event 
collection will begin after a subject signs the ICF. 
Medical terminology should be used for AE reporting. Adverse events should be reported 
as a single unifying diagnosis whenever possible or, in the absence of a unifying 
diagnosis, as individual signs or symptoms. 


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Exacerbation or disease progression should be reported as an AE only if there are 
unusual or severe clinical features that were not present, or experienced earlier, or not 
expected based on the course of the condition. If the reported severity, seriousness, or 
toxicity of an AE changes, the event must be reported as a new AE in the eCRF. 
In addition, the sponsor must be notified immediately by e-mail in principle of any IREs 
according to the procedure outlined below, in Section 8.8.3. Special attention should be 
paid to recording hospitalization and concomitant medications. 
The AE, start date, end date, seriousness, severity, relationship to trial treatment (IMP 
causality), action taken with trial treatment, and outcome will be recorded on the source 
document and in the eCRF. 
8.8.3 
Immediately Reportable Events 
The investigator must immediately report (within 24 hours), using an IRE form, etc, after 
he/she or site personnel becomes aware of any IRE (SAE, AE related to occupational 
exposure, drug eruption, potential serious hepatoxicity, or confirmed pregnancy), by e-
mail in principle to the sponsor or designee using the contact information on the cover 
page of this protocol (please note that the IRE form is NOT the AE eCRF). Careful 
attention must be paid to patient privacy when forwarding the IRE form, etc. However, 
drug eruption, when reported, must be immediately reported (within 24 hours) after the 
investigator has determined the event to be drug eruption. 
8.8.4 
Medical Device Incidents (Including Malfunctions) 
Not applicable. 
8.8.5 
Adverse Events of Special Interest 
New onset of drug eruption after the start of IMP treatment will be handled as an adverse 
event of special interest. 
8.8.6 
Potential Serious Hepatotoxicity 
For a subject who experiences an elevation in aspartate aminotransferase (AST) or 
alanine aminotransferase (ALT) that is ≥ 3 times the ULN, a total bilirubin level should 
also be evaluated. If the total bilirubin is ≥ 2 times the ULN, complete an IRE form, etc 
with all values listed and also report as an AE in the eCRF. 
8.8.7 
Procedure for Breaking the Blind 
If an SAE and other events occur and the investigator judges it is necessary to open the 
subject’s treatment assignment code to ensure the safety of the subject, the investigator 


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can obtain the treatment assignment code of the subject concerned from the IRT system 
according to the procedure stipulated separately. 
Before unblinding, the investigator is encouraged to contact the sponsor to discuss their 
rationale for unblinding. However, to prevent delays to the investigator or medical 
personnel responding to a potentially emergent situation, unblinding of IMP will not be 
dependent upon the investigator receiving approval from the sponsor (ie, the investigator 
will be able to obtain the code break information independent of the sponsor). The 
investigator must contact the sponsor by telephone or e-mail with an explanation of the 
need for opening the treatment assignment code within 24 hours of opening the code. If 
the blind is broken, the Global Pharmacovigilance Department must be notified 
immediately (see the cover page of this protocol for contact information). Documentation 
of breaking the blind should be recorded in the subject’s medical record with the date and 
time the blind was broken and the names of the personnel involved. Once the blind is 
broken for a subject, that subject may not reinitiate treatment with the IMP. 
8.8.8 
Follow-up of Adverse Events 
8.8.8.1 
Follow-up of Nonserious Adverse Events 
Nonserious AEs that are identified at any time during the trial must be recorded on the 
AE eCRF with the current status (ongoing or resolved/recovered) noted. All nonserious 
events (that are not IREs) that are ongoing at the last scheduled contact will be recorded 
as ongoing in the eCRF. For any AE having been identified throughout the trial, during 
analysis, additional relevant medical history information may be requested by the sponsor 
to further ascertain causality (including, but not limited to, information such as risk-
related behavior, family history, and occupation). 
8.8.8.2 
Follow-up of Immediately Reportable Events 
This trial requires that subjects be actively monitored for IREs up to 2 weeks (Visit 11) 
after the final dose of IMP is administered. 
Immediately reportable events that are identified or ongoing at the last scheduled 
contact must be recorded as such on the AE eCRF page and the IRE form, etc. If updated 
information (eg, resolved status) on IRE status becomes available after a subject’s last 
scheduled contact (up to last in-clinic visit for the entire trial), this must be reported to the 
sponsor and recorded on the AE eCRF page and the IRE form, etc, according to the 
appropriate reporting procedures described in Section 8.8.3. 


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It is expected that the investigator will provide or arrange appropriate supportive care for 
the subject and will provide prompt updates on the subject’s status to the sponsor. The 
investigator will follow IREs until the events are: 
• Resolved, 
• Stabilized, 
• The subject is lost to follow-up, or 
• Has died. 
Resolution means that the subject has returned to the baseline state of health and 
stabilized means that the investigator does not expect any further improvement or 
worsening of the subject’s condition. The investigator will continue to report any 
significant follow-up information to the sponsor up to the point the event has resolved or 
stabilized, or the subject is lost to follow-up, or has died. 
Refer to Section 10.3 for additional information regarding the follow-up period for 
subjects that become pregnant or for pregnant partners of male subjects. 
8.8.8.3 
Follow-up and Reporting of Immediately Reportable Events 
Occurring After Last Scheduled Contact 
Any new IREs reported to the investigator which occur after the last scheduled contact 
and are determined by the investigator to be reasonably associated with the use of the 
IMP, should be reported to the sponsor according to the procedures outlined in 
Section 8.8.3. This may include IREs that are captured on follow-up telephone contact or 
at any other time point after the defined trial period and continue to report any significant 
follow-up information to the sponsor until the events are resolved or stabilized, or the 
subject is lost to follow-up or has died. 
8.9 
Treatment of Overdose 
In cases of overdose, estimation of the severity of poisoning is the critical first step. 
Detailed history and information on the overdose will be collected, and physical 
examinations will be performed. In addition to symptomatic and supportive therapies, 
vital signs, ECG, and blood pressure must be monitored until all parameters recover to 
the predose levels. Gastric lavage and emetics are useful immediately after overdose. It is 
unknown whether activated carbon and dialysis are effective for the treatment of OPC-
64005 overdose. Close medical supervision and monitoring should continue until the 
patient recovers. 
8.10 
Subject Assessment Recording 
This includes MADRS-S and Apathy Scale (see Section 8.1). 


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8.11 
Other Assessments 
Not applicable. 
9 
Statistical Considerations 
The definition of datasets for analysis and the analysis methods for the endpoints are 
provided below. A detailed analysis plan is provided in a separate statistical analysis plan 
(SAP). The SAP will be finalized before data lock. 
9.1 
Sample Size 
As no clinical trials of OPC-64005 in patients with MDD have been previously 
conducted, the target number of subjects was determined based on the results from 
another antidepressant clinical trial using MADRS score as the primary endpoint. In the 
phase 3 clinical trial of escitalopram conducted outside Japan,1 the mean change (± SE) 
from baseline in MADRS total score at the final timepoint of Week 8 (8 weeks after start 
of administration) determined using last observation carried forward analysis of 
covariance was −9.4 ± 0.9 in the placebo group (n = 119), −12.0 ± 0.9 in the citalopram 
40-mg group (n = 125), −12.8 ± 0.8 in the escitalopram 10-mg group (n = 118), and 
−13.9 ± 0.8 in the escitalopram 20-mg group (n = 123). Referring to those results, in the 
present trial it is assumed that the difference between the OPC-64005 20-mg group and 
the placebo group in the change from baseline in MADRS total score at Week 6 of the 
double-blind treatment period will be −4 with a standard deviation of 11. To ensure a 
power of 80% in a two-sided test with a significance level of 0.05, 120 subjects each are 
required for the OPC-64005 20-mg group and the placebo group. For the OPC-64005 
10-mg group, the number of subjects was set at 30 without statistical consideration. The 
planned number of subjects to be randomized for the trial was therefore set at 270. 
9.2 
Datasets for Analysis 
9.2.1 
Full Analysis Set 
The full analysis set (FAS) includes all subjects who were administered at least 1 dose of 
double-blind IMP and have MADRS total scores at baseline and at least one timepoint 
after the start of double-blind treatment. 
9.2.2 
Safety Analysis Set 
The safety analysis set includes all subjects who were administered at least 1 dose of 
double-blind IMP. 


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9.3 
Handling of Missing Data for Primary and Secondary Endpoint 
Analyses 
For the primary endpoint analysis, a mixed-model repeated measures (MMRM) analysis 
will be performed using the observed cases (OC) dataset without imputation of missing 
data on an assumption of missing at random (MAR). Placebo multiple imputation and 
tipping point analysis on an assumption of missing not at random (MNAR) will be 
performed as a sensitivity analysis for handling of missing data. Details will be provided 
in the SAP. 
The secondary endpoint analysis and the safety analysis will be performed using data 
imputed with data observed immediately before after the start of double-blind treatment 
(last observation carried forward [LOCF]) if necessary. 
9.4 
Statistical Analyses 
9.4.1 
Efficacy Analyses 
The efficacy analysis will be performed on the FAS. Baseline is the last data obtained 
after the start of IMP administration in the placebo-lead in period and before the start of 
double-blind IMP administration. 
9.4.1.1 
Primary Efficacy Endpoint Analysis 
The primary endpoint is the change from baseline in MADRS total score at Week 6 of the 
double-blind treatment period. 
For the primary analysis, an MMRM analysis will be performed using the OC dataset of 
the FAS. 
The MMRM will include treatment group (OPC-64005 10-mg group, OPC-64005 20-mg 
group, and placebo group), timepoint (double-blind treatment period Weeks 1, 2, 3, 4, 5, 
and 6), and interaction between treatment group and timepoint as factors, and baseline 
and interaction between baseline and timepoint as covariates. An unstructured error 
variance-covariance structure will be assumed. For degree-of-freedom approximation, the 
Kenward-Roger method will be used. The statistical comparison will be performed based 
on differences in the least square means at double-blind treatment period Week 6 
between the OPC-64005 20-mg group and the placebo group. If any problem occurs in 
the convergence status in the estimation of variance components, error 
variance-covariance structures of heterogeneous toeplitz, heterogeneous autoregressive of 
order 1, and heterogeneous compound symmetry will be applied in this order, and the 
first converged structure will be used in the primary analysis. If structures other than 
unstructured are selected, sandwich estimators of standard error will be used. 


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For each timepoint, the least square mean of each treatment group and the differences in 
the least square means between each OPC-64005 group and the placebo group, as well as 
the two-sided 95% confidence intervals, will be determined. 
9.4.1.2 
Key Secondary Efficacy Endpoint Analysis 
Not applicable. 
9.4.1.3 
Secondary Efficacy Endpoint Analysis 
The secondary endpoint analysis will be performed on the FAS. 
• MADRS response rate 
• MADRS remission rate 
• CGI-I improvement rate 
The MADRS response rate in the OPC-64005 20-mg group will be compared with that in 
the placebo group using the χ2 test in the LOCF dataset. The differences in the response 
rates between each OPC-64005 group and the placebo group, as well as the two-sided 
95% CI (Wald confidence interval), will be determined. The MADRS remission rate and 
CGI-I improvement rate will be analyzed in the same manner as the MADRS response 
rate. 
 
• Mean change from baseline in HAM-D 17-item total score 
• Mean change from baseline in Apathy Scale score 
An analysis will be performed on the mean change from baseline in HAM-D 17-item 
total score using the analysis of covariance (ANCOVA) model with treatment group as a 
factor and baseline as a covariate in the LOCF dataset. The least square means of each 
treatment group and the difference in the least square means between each OPC-64005 
group and the placebo group, as well as the two-sided 95% CIs, will be calculated. The 
mean change from baseline in Apathy Scale total score will be analyzed in the same 
manner as the mean change from baseline in HAM-D 17-item total score. 
 
• Mean change from baseline in CGI-S 
• Mean change from baseline in MADRS-S total score 
• Mean change from baseline in MADRS anhedonia factor score (total score of 
MADRS Items 1, 2, 6, 7, and 8) 
The MMRM analysis will be performed in the same manner as that for the primary 
endpoint. 


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9.4.1.4 
Control of Experiment-wise Type 1 Error 
Not applicable because the statistical test for the primary analysis of the primary endpoint 
is performed only once, which is comparison of the OPC-64005 20-mg group with the 
placebo group. 
9.4.1.5 
Other Efficacy Endpoint Analysis 
Not applicable. 
9.4.2 
Safety Analysis 
The safety analysis will be performed on the safety analysis set. Baseline is the last data 
obtained after the start of IMP administration in the placebo lead-in period and before the 
start of double-blind IMP administration. 
9.4.2.1 
Adverse Events 
All AEs will be coded by system organ class and ICH’s Medical Dictionary for 
Regulatory Activities (MedDRA) preferred term. The incidence of the following events 
will be summarized by treatment group and for the overall OPC-64005 group: 
• TEAEs 
• TEAEs by severity 
• TEAEs with an outcome of death 
• Serious TEAEs 
• TEAEs leading to discontinuation of the IMP 
• TEAEs of special interest (drug eruption) 
Treatment-emergent AEs potentially causally related to the IMP will also be summarized 
in the same manner. 
9.4.2.2 
Clinical Laboratory Data 
Descriptive statistics of measurement values and changes from baseline at each time 
point will be calculated by treatment group and for the overall OPC-64005 group for each 
laboratory test item of continuous data. 
Each laboratory test item of continuous data will be classified into below the lower limit 
of the reference range, within the reference range, or above the upper limit of the 
reference range based on the reference ranges of the central laboratory, and a shift table 
from baseline will be generated by treatment group and for the overall OPC-64005 group. 
For each laboratory test item of qualitative data, a shift table from baseline will be 
generated by treatment group and for the overall OPC-64005 group. 


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The number and proportion of subjects who meet the criteria for clinically significant 
laboratory value will be determined by treatment group and for the overall OPC-64005 
group. 
9.4.2.3 
Physical Examination and Vital Signs Data 
For each item of vital signs (by position for blood pressure and pulse rate), descriptive 
statistics of measurement values and changes from baseline at each time point will be 
calculated by treatment group and for the overall OPC-64005 group. 
The number and proportion of subjects who meet the criteria for clinically significant 
vital signs will be determined by treatment group and for the overall OPC-64005 group. 
9.4.2.4 
Electrocardiogram Data 
For heart rate, PR interval, RR interval, QRS interval, QT interval, and QTc (QTcF), 
descriptive statistics of measurement values and changes from baseline at each time point 
will be calculated by treatment group and for the overall OPC-64005 group. 
For normal/abnormal assessment of 12-lead ECG, a shift table from baseline will be 
generated by treatment group and for the overall OPC-64005 group. 
For QTc (QTcF) at each time point, the number and proportion of subjects with 
measurement values after double-blind IMP treatment of > 450 msec, > 480 msec, and 
> 500 msec, and the number and proportion of subjects with changes from baseline of > 
30 msec and > 60 msec will be calculated by treatment group and for the overall OPC-
64005 group. 
The number and proportion of subjects who meet the criteria for clinically significant 
ECG will be determined by treatment group and for the overall OPC-64005 group. 
9.4.2.5 
Other Safety Data 
• Body weight, body mass index (BMI) and waist circumference 
For body weight, BMI, and waist circumference, descriptive statistics of 
measurement values and changes from baseline at each time point will be calculated 
by treatment group and for the overall OPC-64005 group. 
An analysis of the ANCOVA model with treatment group as a factor and baseline as 
a covariate will be performed using the LOCF dataset. The least square means of each 
treatment group and the differences in the least square means between each OPC-
64005 group and the placebo group, as well as the two-sided 95% CIs, will be 
calculated. 
The number and proportion of subjects who meet the criteria for clinically significant 
body weight will be determined by treatment group and for the overall OPC-64005 
group. 


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• C-SSRS 
The number and proportion of subjects at each time point will be calculated by 
treatment group and for the overall OPC-64005 group for each item (suicidality, 
suicidal ideation, suicidal behavior, completed suicide, emergence of suicidal 
ideation, emergence of serious suicidal ideation, worsening of suicidal ideation, and 
emergence of suicidal behavior). 
 
9.4.3 
Other Analyses 
9.4.3.1 
Analysis of Demographic and Baseline Characteristics 
In each analysis set, descriptive statistics or frequency distribution will be calculated by 
treatment group and for the overall OPC-64005 group for each demographic and other 
baseline characteristic. 
9.4.3.2 
Pharmacokinetic Analysis 
For the plasma concentrations of OPC-64005 and OPC-144013, only listings of data will 
be generated without tabulation. 
9.4.3.3 
Pharmacodynamic Analysis 
No PD analyses are planned. 
9.4.3.4 
Pharmacokinetic/Pharmacodynamic Analysis 
No PK/PD analyses are planned. 
9.4.3.5 
Pharmacogenomic Analysis 
For the CYP2D6 genetic testing results, only listings of data will be generated without 
tabulation. 
9.4.3.6 
Exploratory Endpoint Analysis 
Not applicable. 
9.5 
Interim Analysis and Adaptive Design 
Not applicable. 
9.5.1 
Data Monitoring Committee 
Not applicable. 


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10 
Supporting Documentation and Operational Considerations 
10.1 
Appendix 1: Regulatory, Ethical, and Trial Oversight 
Considerations 
10.1.1 
Ethics and Responsibility 
This trial must be conducted in compliance with the protocol, ICH Good Clinical Practice 
(GCP) guideline (E6), international ethical principles derived from the Declaration of 
Helsinki and Council for International Organizations of Medical Science (CIOMS) 
guidelines, and applicable local laws and regulations. Each trial site will seek approval by 
an IRB according to regional requirements, and the trial site will provide that 
documentation to the sponsor. The IRB will evaluate the ethical, scientific, and medical 
appropriateness of the trial. Further, in preparing and handling the eCRF, IRE and any 
safety information, the investigator, subinvestigator, and their staff will take measures to 
ensure adequate care in protecting subject privacy. To this end, a subject ID will be used 
to identify each subject. 
Financial aspects, subject insurance, and the publication policy for the trial will be 
documented in the agreement between the sponsor and the trial site. 
10.1.2 
Informed Consent 
Informed consent will be freely obtained from all subjects (or their guardian or legally 
acceptable representative, as applicable for local laws). The ICF will be approved by the 
same IRB that approves this protocol. 
Each ICF will comply with the ICH-GCP guideline (E6), and local regulatory 
requirements. In support of the site’s standard process for administering informed 
consent, this trial will also allow for electronic informed consent form (eICF) as a tool 
within applicable regions and trial sites. The eICF utilizes the IRB-approved site-specific 
ICF to offer subjects an enhanced platform to review and understand their rights as a 
research subject as well as required trial procedures. When possible, trial sites will have 
subjects review and sign the eICF prior to starting any trial procedures; however, if local 
regulations do not allow for use of the electronic format, subjects may continue in the 
trial utilizing the standard paper and wet ink signature process. 
Investigators may discuss trial availability and the possibility for entry with a potential 
subject without first obtaining consent. However, informed consent must be obtained and 
documented before initiation of any procedures that are performed solely for the purpose 
of determining eligibility for this trial, including withdrawal from current medication(s). 


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Potential subjects are free to refuse entry into the trial, or withdraw from the trial at any 
time, without justification, and there will be no consequences to their further care. 
Once appropriate essential information has been provided and fully explained in 
layman’s language to the subject by the investigator (or a qualified designee), and it has 
been documented that the subject has had the opportunity to ask questions, the IRB-
approved written ICF will be signed and dated by both the subject and the person 
obtaining consent (investigator or designee), as well as by any other parties required by 
the IRB. The subject will receive a copy of the signed ICF; the original shall be kept on 
file by the investigator. Subjects may be asked to sign additional ICFs if the protocol is 
amended and the changes to the protocol result in additional information that needs to be 
provided to the subjects, so that they can make a knowledgeable and voluntary decision 
on continued trial participation. Female partners of male subjects who become pregnant 
during the course of the trial may be asked to sign additional ICFs in order to collect 
additional information regarding the nonsubject partner and fetus. 
A separate and similar consent process will be followed for PGx testing and FBR. 
Consent must be obtained before the blood sample is collected. The PGx testing is 
mandatory, and subjects who do not consent cannot participate in the trial. The FBR is 
optional and refusal to participate in the FBR does not affect participation in the trial. 
10.1.3 
Confidentiality 
All information generated in this trial will be considered confidential and will not be 
disclosed to anyone not directly concerned with the trial without the sponsor’s prior 
written permission. Subject confidentiality requirements of the region(s) where the trial is 
conducted will be met. However, authorized regulatory officials and sponsor personnel 
(or their representatives) may be allowed full access to inspect and copy the records, 
consistent with local requirements. All IMPs, subject bodily fluids, and/or other materials 
collected shall be used solely in accordance with this protocol, unless otherwise agreed to 
in writing by the sponsor. 
Subjects will be identified only by unique subject ID in the eCRF. If further subject 
identification is required, subjects’ full names may be made known to a regulatory 
agency or other authorized officials if necessary, subject to local regulations. 
10.1.4 
Quality Control and Quality Assurance 
The sponsor will execute quality management activities for this trial in accordance with 
ICH E6 (R2). Additional information on the quality management activities will be 
provided in a separate quality management plan. 


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10.1.4.1 
Monitoring 
The sponsor has ethical, legal, and scientific obligations to follow this trial in accordance 
with established research principles, the applicable ICH GCP guideline (E6), and 
applicable regulatory requirements and local laws. As part of a concerted effort to fulfill 
these obligations (maintain current personal knowledge of the progress of the trial), the 
sponsor’s monitors will visit the site during the trial, as well as communicate frequently 
via telephone, e-mail, and written communications. In addition, all investigators and trial 
site personnel will undergo initial and ongoing training for this particular trial, and this 
training will be clearly documented. 
10.1.4.2 
Auditing 
The sponsor’s Quality Assurance Unit (or representative) may conduct trial site audits. 
Audits will include, but are not limited to, IMP supply, presence of required documents, 
the informed consent process, and a review of the eCRF with source documents, as 
applicable. The investigator will agree to cooperate with audits. 
Regulatory authorities may inspect the investigator site during or after the trial. The 
investigator will cooperate with such inspections and will contact the sponsor 
immediately if such an inspection occurs. 
10.1.5 
Protocol Deviations 
In the event of a significant deviation from the protocol due to an emergency, accident, or 
mistake (eg, violation of informed consent process, IMP dispensing or subject dosing 
error, treatment assignment error, subject enrolled in violation of eligibility criteria or 
concomitant medication criteria), the investigator or designee will contact the sponsor or 
designee at the earliest possible time by telephone or via e-mail. The investigator and 
sponsor (or designee) will come as quickly as possible to a joint decision regarding the 
subject’s continuation in the trial. This decision will be documented by the investigator 
and the sponsor (or designee) and reviewed by the site monitor. 
Any major protocol deviation will be recorded in the eCRF along with the start date and 
details of the deviation. 
10.1.6 
Records Management 
10.1.6.1 
Source Documents 
Source documents are defined as the results of original observations and activities of a 
clinical investigation. Source documents will include but are not limited to medical 
records, electronic data, screening records, and recorded data from automated 


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instruments. All source documents pertaining to this trial will be maintained by the trial 
sites and made available for direct inspection by authorized persons. 
Investigator(s)/trial site(s) will permit trial-related monitoring, audits, IRB review, and 
regulatory inspection(s) by providing direct access to source data/documents by 
authorized persons as defined in the ICF. Documents (eg, original reports, measurement 
data) on drug concentration measurement, PGx assessment, and FBR will be retained by 
the bioanalytical laboratory, PGx laboratory, and biospecimen storage facility, 
respectively. In all cases, subject confidentiality must be maintained in accordance with 
local regulatory requirements. 
10.1.6.2 
Data Collection 
During each subject’s visit to the site, an investigator or their designee participating in the 
trial will record information to document all significant observations in medical records. 
At a minimum, these notes will contain: 
• Documentation of the informed consent process, including any revised consents; 
• Documentation of the investigator’s decision to enroll the subject into the trial, the 
review of all inclusion/exclusion criteria prior to IMP administration, and 
confirmation of the subject’s actual participation in the trial; 
• The date of the visit and the corresponding Visit or Day in the trial schedule; 
• General subject status remarks, including any significant medical findings. The 
severity, frequency, duration, action taken, and outcome of any AEs and the 
investigator’s assessment of relationship to IMP must also be recorded; 
• Any changes in concomitant medications or dosages; 
• A general reference to the medical procedures completed; 
• The signature (or initials) and date of the investigator (or designee) who made an 
entry in the medical record. 
 
In addition, any contact with the subject via telephone or other means that provides 
significant clinical information will also be documented in the progress notes as 
described above. 
Information from medical records and other source documents will be entered by 
investigative site personnel onto eCRFs in the sponsor’s electronic data capture (EDC) 
system that is 21 CRF Part 11 compliant. Changes to the data will be captured by an 
automatic audit trail in the EDC system. 
Electronic data not entered on eCRF, such as data received from central laboratories and 
central ECG readers, will be reconciled using key data fields by the sponsor or the CRO 
with the eCRF data to ensure consistency. 


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10.1.6.3 
File Management at the Trial Site 
The head of the trial site will ensure that the trial site file is maintained in accordance 
with ICH GCP guideline E6 Section 8 and as required by applicable local regulations. 
The institution will take measures to prevent accidental or premature destruction of these 
documents. 
10.1.6.4 
Records Retention at the Trial Site 
The trial sites will maintain all documents and records related to this trial until the 
following 3 dates, whichever comes later. However, if a longer retention period is 
required by the sponsor, the retention period and method shall be discussed with the 
sponsor. 
• The date at least 2 years after the date on which approval to market the drug is 
obtained. If IMP development is discontinued or it is notified that the trial data are not 
attached to the application dossier, the date at least 3 years after the decision of 
discontinuation of IMP development or the receipt date of the notification that the 
trial data are not attached to the application dossier. 
• The date at least 3 years after trial discontinuation or completion. 
• The date on which the decision to end DNA storage is made. 
The trial site must not dispose of any records relevant to this trial without either 
(1) written permission from the sponsor or (2) provision of an opportunity for the sponsor 
to collect such records. The trial site will be responsible to maintain adequate and 
accurate electronic or hard copy source documents of all observations and data generated 
during this trial including any data clarification forms received from the sponsor. Such 
documentation is subject to inspection by the sponsor and relevant regulatory authorities. 
10.1.6.5 
Publication Authorship Requirements 
Authorship for any Otsuka Pharmaceutical-sponsored publications resulting from the 
conduct of this trial will be based on International Committee of Medical Journal Editors 
(ICMJE) authorship criteria (http://www.icmje.org/recommendations). According to 
ICMJE guidelines, one may be considered an author only if the following criteria are 
met: 
1) Substantial contributions to the conception or design of the work; or the 
acquisition, analysis, or interpretation of data for the work; AND 
2) Drafting the work or revising it critically for important intellectual content; AND 
3) Final approval of the version to be published; AND 
4) Agreement to be accountable for all aspects of the work in ensuring that questions 
related to the accuracy or integrity of any part of the work are appropriately 
investigated and resolved. 


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All authors must meet the above criteria, and all who qualify for authorship based on the 
above criteria should be listed as authors. 
Investigators or other trial subjects who do not qualify for authorship may be 
acknowledged in publications resulting from the trial. By agreeing to participate in the 
trial, investigators or other trial subjects consent to such acknowledgement in any 
publications resulting from its conduct. 


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10.2 
Appendix 2: Clinical Laboratory Tests 
The tests detailed in Table 10.2-1 will be performed. 
 
Table 10.2-1 
Clinical Laboratory Assessments 
Hematology: 
Red blood cell (RBC) count 
White blood cell (WBC) count 
WBC differential (neutrophils, eosinophils, 
basophils, monocytes, lymphocytes) 
Platelets 
Hemoglobin 
Mean corpuscular hemoglobin concentration 
(MCHC) 
Mean corpuscular volume (MCV) 
Hematocrit 
 
Urinalysis: 
Occult blood 
Glucose 
pH 
Protein 
Specific gravity 
Urobilinogen 
Ketone body 
Sediment 
Urine pregnancy test to FOCBP (if a urine 
pregnancy test is positive, perform a serum 
pregnancy test): human chorionic gonadotropin 
(hCG) 
Serum Chemistry: 
Alkaline phosphatase (ALP) 
Alanine aminotransferase (ALT) 
Aspartate aminotransferase (AST) 
Total bilirubin 
Blood urea nitrogen (BUN) 
Creatinine 
γ-Glutamyl transpeptidase (γ-GTP) 
Glucose 
Lactate dehydrogenase (LDH) 
Total protein 
Triglycerides 
Albumin 
Cholesterols (total, LDL, HDL) 
Uric acid 
Creatinine phosphokinase (CK [CPK]) 
Serum electrolytes (Ca, K, Na, Cl, Mg, P) 
Prothrombin time (PT) 
Activated partial thromboplastin time (APTT) 
Prothrombin time-international normalized ratio 
(PT [INR]) 
Glycosylated hemoglobin (HbA1c) 
Serum prolactin 
<At screening only> 
Free thyroxine (FT4) 
Thyroid-stimulating hormone (TSH) 


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10.3 
Appendix 3: Contraceptive Guidance and Collection of Pregnancy 
Information 
Females of childbearing potential are females whose menstruation has started and who 
are not documented to be of nonchildbearing potential (eg, have had a bilateral 
oophorectomy or hysterectomy, or who have been postmenopausal for at least 12 
months). 
For males and FOCBP, who are sexually active, there must be a documented agreement 
that the subject and their partner will take effective measures (ie, 2 different approved 
methods of birth control or remains abstinent) to prevent pregnancy during the course of 
the trial and for 2 weeks after the last dose of IMP. Unless the subject or their partner is 
of nonchildbearing potential or sterile (ie, females who have had a bilateral 
oophorectomy, have had a hysterectomy, or have been postmenopausal for at least 12 
consecutive months; or males who have had a bilateral orchiectomy) or remains abstinent 
during the trial and for 2 weeks after the last dose of IMP, 2 of the following approved 
methods of birth control must be used: vasectomy, tubal ligation, intrauterine device, 
birth control pill, or condom (all methods approved or validated in Japan). Any single 
method of birth control, including vasectomy and tubal ligation, may fail, leading to 
pregnancy. The contraceptive method should be documented in the source document. 
Male subjects must also agree not to donate sperm from trial screening through 2 weeks 
after the last dose of IMP. 
Before enrolling males and females in this clinical trial, investigators must review the 
below information about trial participation as part of the ICF process. The topics should 
generally include: 
• General information 
• ICF 
• Pregnancy prevention information 
• Contraceptives in current use 
• Follow-up of a reported pregnancy 
 
Before trial enrollment, males and FOCBP must be advised of the importance of avoiding 
pregnancy during trial participation and the potential risk factors for an unintentional 
pregnancy. Subjects must sign the ICF confirming that the above-mentioned risk factors 
and the consequences were discussed. 
On all FOCBP, urine or serum pregnancy test for human chorionic gonadotropin (hCG) 
will be performed at screening and at the start of the placebo lead-in period. If a urine test 


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is performed and is positive, the investigator will follow-up with a confirmatory serum 
test. 
During the trial, all FOCBP should be instructed to contact the investigator immediately 
if they suspect they might be pregnant (eg, missed or late menstrual cycle). Male subjects 
must be instructed to contact the investigator immediately, during the trial, if their partner 
suspects that they might be pregnant (eg, missed or late menstrual cycle). 
If a subject is suspected to be pregnant before she receives IMP, the IMP administration 
must be withheld until the results of serum pregnancy tests are available. If the pregnancy 
is confirmed, the subject must not receive the IMP and must not be enrolled in the trial. If 
pregnancy is suspected while the subject is taking IMP, the IMP must be withheld 
immediately (if reasonable, taking into consideration any potential withdrawal risks) until 
the result of the pregnancy test is known. If pregnancy is confirmed, the IMP will be 
permanently discontinued in an appropriate manner (eg, dose tapering if necessary for 
subject safety) and the subject will be withdrawn from the trial. Exceptions to trial 
discontinuation may be considered for life-threatening conditions only after consultations 
with the IRE contact (see the title page of this protocol for contact information). 
The investigator must immediately notify the sponsor (within 24 hours) of any pregnancy 
associated with IMP exposure during the trial and for at least 2 weeks after the last dose 
of IMP, and record the event on the IRE form, etc and forward it to the sponsor. The 
sponsor will forward the Pregnancy Surveillance Form(s) to the investigator for 
monitoring the outcome of the pregnancy. 
Protocol required procedures for trial discontinuation and follow-up must be performed 
on the subject unless contraindicated by pregnancy (eg, x-ray studies). Other appropriate 
pregnancy follow-up procedures should be considered if indicated. In addition, the 
investigator must report to the sponsor, on the Pregnancy Surveillance Form(s), follow-
up information regarding the course of the pregnancy, including perinatal and neonatal 
outcome. Infants will be followed for a minimum of 6 months from the date of birth. 


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10.4 
Appendix 4: Genetic Testing 
CYP2D6 Genotype Assessment Table 
 
E = EM; I = IM; P = PM 
 
Allele 
*position 
Genotype 
Phenotype 
100 
1758 
1846 
2573 
2850 
2988 
4125 
4180 
del/C 
del/G 
del/G 
del/- 
del/C 
del/G 
del/- 
del/G 
*1/*5 
IM 
del/C 
del/G 
del/G 
del/- 
del/T 
del/G 
del/- 
del/C 
*2/*5 
IM 
del/T 
del/G 
del/A 
del/- 
del/C 
del/G 
del/- 
del/C 
*4/*5 
PM 
del/T 
del/G 
del/A 
del/- 
del/C 
del/G 
del/- 
del/G 
del/T 
del/G 
del/A 
del/- 
del/T 
del/G 
del/- 
del/C 
del/C 
del/G 
del/A 
del/- 
del/C 
del/G 
del/- 
del/G 
del/del 
del/del 
del/del 
del/del 
del/del 
del/del 
del/del 
del/del 
*5/*5 
PM 
del/T 
del/G 
del/G 
del/- 
del/C 
del/G 
del/- 
del/C 
*5/*10 
IM 
del/T 
del/A 
del/G 
del/- 
del/T 
del/G 
del/- 
del/C 
*5/*14A 
PM 
del/C 
del/A 
del/G 
del/- 
del/T 
del/G 
del/- 
del/C 
*5/*14B 
IM 
del/C 
del/G 
del/G 
del/- 
del/C 
del/G 
del/9bp 
del/G 
*5/*18 
PM 
del/C 
del/G 
del/G 
del/insC 
del/T 
del/G 
del/- 
del/C 
*5/*21 
PM 
del/C 
del/G 
del/G 
del/- 
del/T 
del/A 
del/- 
del/C 
*5/*41 
IM 
C/C 
G/G 
G/G 
-/- 
C/C 
G/G 
-/- 
G/G 
*1/*1 
EM 
C/C 
G/G 
G/G 
-/- 
C/T 
G/G 
-/- 
C/G 
*1/*2 
EM 
*1
*2
*10 *14B *41
*4
*5 *14A *18
*21
*1
E
E
E
E
E
I
I
I
I
I
*2
E
E
E
E
I
I
I
I
I
*10
I
I
I
I
I
I
I
I
*14B
I
I
I
I
I
I
I
*41
I
I
I
I
I
I
*4
P
P
P
P
P
*5
P
P
P
P
*14A
P
P
P
*18
P
P
*21
P


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Allele 
*position 
Genotype 
Phenotype 
100 
1758 
1846 
2573 
2850 
2988 
4125 
4180 
C/T 
G/G 
A/G 
-/- 
C/C 
G/G 
-/- 
G/G 
*1/*4 
IM 
C/C 
G/G 
A/G 
-/- 
C/C 
G/G 
-/- 
G/G 
C/T 
G/G 
G/G 
-/- 
C/C 
G/G 
-/- 
C/G 
*1/*10 
EM 
C/C 
A/G 
G/G 
-/- 
C/T 
G/G 
-/- 
C/G 
*1/*14B 
EM 
C/T 
A/G 
G/G 
-/- 
C/T 
G/G 
-/- 
C/G 
*1/*14A 
IM 
C/C 
G/G 
G/G 
-/- 
C/C 
G/G 
-/9bp 
G/G 
*1/*18 
IM 
C/C 
G/G 
G/G 
-/insC 
C/T 
G/G 
-/- 
C/G 
*1/*21 
IM 
C/C 
G/G 
G/G 
-/- 
C/T 
A/G 
-/- 
C/G 
*1/*41 
EM 
C/C 
G/G 
G/G 
-/- 
T/T 
G/G 
-/- 
C/C 
*2/*2 
EM  
C/T 
G/G 
A/G 
-/- 
C/T 
G/G 
-/- 
C/C 
*2/*4 
IM  
C/C 
G/G 
A/G 
-/- 
C/T 
G/G 
-/- 
C/G 
C/T 
G/G 
A/G 
-/- 
T/T 
G/G 
-/- 
C/C 
C/T 
G/G 
G/G 
-/- 
C/T 
G/G 
-/- 
C/C 
*2/*10 
EM 
C/C 
A/G 
G/G 
-/- 
T/T 
G/G 
-/- 
C/C 
*2/*14B 
EM 
C/T 
A/G 
G/G 
-/- 
T/T 
G/G 
-/- 
C/C 
*2/*14A 
IM 
C/C 
G/G 
G/G 
-/- 
C/T 
G/G 
-/9bp 
C/G 
*2/*18 
IM 
C/C 
G/G 
G/G 
-/insC 
T/T 
G/G 
-/- 
C/C 
*2/*21 
IM 
C/C 
G/G 
G/G 
-/- 
T/T 
A/G 
-/- 
C/C 
*2/*41 
EM 
T/T 
G/G 
A/A 
-/- 
C/C 
G/G 
-/- 
C/C 
 
 
 
 
 
 
 
*4/*4 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
PM 
 
 
 
 
 
 
 
 
T/T 
G/G 
A/A 
-/- 
C/C 
G/G 
-/- 
C/G 
T/T 
G/G 
A/A 
-/- 
C/T 
G/G 
-/- 
C/C 
C/T 
G/G 
A/A 
-/- 
C/C 
G/G 
-/- 
C/G 
T/T 
G/G 
A/A 
-/- 
C/C 
G/G 
-/- 
G/G 
T/T 
G/G 
A/A 
-/- 
C/T 
G/G 
-/- 
C/G 
C/T 
G/G 
A/A 
-/- 
C/C 
G/G 
-/- 
G/G 
T/T 
G/G 
A/A 
-/- 
T/T 
G/G 
-/- 
C/C 
C/T 
G/G 
A/A 
-/- 
C/T 
G/G 
-/- 
C/G 
C/C 
G/G 
A/A 
-/- 
C/C 
G/G 
-/- 
G/G 


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Allele 
*position 
Genotype 
Phenotype 
100 
1758 
1846 
2573 
2850 
2988 
4125 
4180 
T/T 
G/G 
A/G 
-/- 
C/C 
G/G 
-/- 
C/C 
*4/*10 
IM 
T/T 
G/G 
A/G 
-/- 
C/C 
G/G 
-/- 
C/G 
T/T 
G/G 
A/G 
-/- 
C/T 
G/G 
-/- 
C/C 
T/T 
A/G 
A/G 
-/- 
C/T 
G/G 
-/- 
C/C 
*4/*14A 
PM 
C/T 
A/G 
A/G 
-/- 
C/T 
G/G 
-/- 
C/C 
*4/*14A or 
*4/*14B 
Unknown 
T/T 
A/G 
A/G 
-/- 
C/T 
G/G 
-/- 
C/G 
*4/*14A 
PM 
C/T 
A/G 
A/G 
-/- 
C/T 
G/G 
-/- 
C/G 
*4/*14A or 
*4/*14B 
Unknown 
T/T 
A/G 
A/G 
-/- 
T/T 
G/G 
-/- 
C/C 
*4/*14A 
PM 
C/T 
A/G 
A/G 
-/- 
T/T 
G/G 
-/- 
C/C 
*4/*14A or 
*4/*14B 
Unknown 
C/T 
A/G 
A/G 
-/- 
C/T 
G/G 
-/- 
C/G 
*4/*14A or 
*4/*14B 
C/C 
A/G 
A/G 
-/- 
C/T 
G/G 
-/- 
C/G 
*4/*14B 
IM 
C/T 
G/G 
A/G 
-/- 
C/C 
G/G 
-/9bp 
C/G 
*4/*18 
PM 
C/T 
G/G 
A/G 
-/- 
C/C 
G/G 
-/9bp 
G/G 
C/T 
G/G 
A/G 
-/- 
C/T 
G/G 
-/9bp 
C/G 
C/C 
G/G 
A/G 
-/- 
C/C 
G/G 
-/9bp 
G/G 
C/T 
G/G 
A/G 
-/insC 
C/T 
G/G 
-/- 
C/C 
*4/*21 
PM 
C/T 
G/G 
A/G 
-/insC 
C/T 
G/G 
-/- 
C/G 
C/T 
G/G 
A/G 
-/insC 
T/T 
G/G 
-/- 
C/C 
C/C 
G/G 
A/G 
-/insC 
C/T 
G/G 
-/- 
C/G 
C/T 
G/G 
A/G 
-/- 
C/T 
A/G 
-/- 
C/C 
*4/*41 
IM 
C/T 
G/G 
A/G 
-/- 
C/T 
A/G 
-/- 
C/G 
C/T 
G/G 
A/G 
-/- 
T/T 
A/G 
-/- 
C/C 
C/C 
G/G 
A/G 
-/- 
C/T 
A/G 
-/- 
C/G 
T/T 
G/G 
G/G 
-/- 
C/C 
G/G 
-/- 
C/C 
*10/*10 
IM 
T/T 
A/G 
G/G 
-/- 
C/T 
G/G 
-/- 
C/C 
*10/*14A 
IM 
C/T 
A/G 
G/G 
-/- 
C/T 
G/G 
-/- 
C/C 
*10/*14B 
IM 
C/T 
G/G 
G/G 
-/- 
C/C 
G/G 
-/9bp 
C/G 
*10/*18 
IM 


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Allele 
*position 
Genotype 
Phenotype 
100 
1758 
1846 
2573 
2850 
2988 
4125 
4180 
C/T 
G/G 
G/G 
-/insC 
C/T 
G/G 
-/- 
C/C 
*10/*21 
IM 
C/T 
G/G 
G/G 
-/- 
C/T 
A/G 
-/- 
C/C 
*10/*41 
IM 
C/T 
A/A 
G/G 
-/- 
T/T 
G/G 
-/- 
C/C 
*14A/*14B 
IM 
C/C 
A/A 
G/G 
-/- 
T/T 
G/G 
-/- 
C/C 
*14B/*14B 
T/T 
A/A 
G/G 
-/- 
T/T 
G/G 
-/- 
C/C 
*14A/*14A 
PM 
C/T 
A/G 
G/G 
-/- 
C/T 
G/G 
-/9bp 
C/G 
*14A/*18 
PM 
C/C 
A/G 
G/G 
-/- 
C/T 
G/G 
-/9bp 
C/G 
*14B/*18 
IM 
C/T 
A/G 
G/G 
-/insC 
T/T 
G/G 
-/- 
C/C 
*14A/*21 
PM 
C/C 
A/G 
G/G 
-/insC 
T/T 
G/G 
-/- 
C/C 
*14B/*21 
IM 
C/T 
A/G 
G/G 
-/- 
T/T 
A/G 
-/- 
C/C 
*14A/*41 
IM 
C/C 
A/G 
G/G 
-/- 
T/T 
A/G 
-/- 
C/C 
*14B/*41 
C/C 
G/G 
G/G 
-/- 
C/C 
G/G 
9bp/9bp 
G/G 
*18/*18 
PM 
C/C 
G/G 
G/G 
-/insC 
C/T 
G/G 
-/9bp 
C/G 
*18/*21 
PM 
C/C 
G/G 
G/G 
-/- 
C/T 
A/G 
-/9bp 
C/G 
*18/*41 
IM 
C/C 
G/G 
G/G 
insC/insC 
T/T 
G/G 
-/- 
C/C 
*21/*21 
PM 
C/C 
G/G 
G/G 
-/insC 
T/T 
A/G 
-/- 
C/C 
*21/*41 
IM 
C/C 
G/G 
G/G 
-/- 
T/T 
A/A 
-/- 
C/C 
*41/*41 
IM 
C/T 
G/G 
A/G 
-/- 
C/C 
G/G 
-/- 
C/G 
*1/*4  
or *4/*10 
IM 
C/T 
G/G 
A/G 
-/- 
C/T 
G/G 
-/- 
C/G 
*1/*4  
or *2/*4 
IM 
*position: https://www.pharmvar.org/gene/CYP2D6 
If the genotype is not determined, it is assessed to be Not determined (ND). 
If the genotype is not determined or the phenotype is not estimated to be 1 type, the phenotype is 
classified as Unknown. 
 


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10.5 
Appendix 5: Abbreviations 
 
Abbreviation 
Definition 
AD/HD 
Attention-deficit/hyperactivity disorder 
ALP 
Alkaline phosphatase 
ALT 
Alanine aminotransferase 
ANCOVA 
Analysis of covariance 
APTT 
Activated partial thromboplastin time 
AST 
Aspartate aminotransferase 
BMI 
Body mass index 
BUN 
Blood urea nitrogen 
CFR 
Code of Federal Regulations 
CGI 
Clinical Global Impression  
CGI-I 
Clinical Global Impression - Improvement 
CGI-S 
Clinical Global Impression - Severity of Illness 
CIOMS 
Council for International Organizations of Medical Science 
C-SSRS 
Columbia-Suicide Severity Rating Scale 
CK (CPK) 
Creatinine phosphokinase 
CYP 
Cytochrome P450 
DAT 
Dopamine transporter 
DLST 
Drug-induced lymphocyte stimulation test 
DNA 
Deoxyribonucleic acid 
DSM-5 
Diagnostic and Statistical Manual of Mental Disorders, Fifth 
Edition 
EDC 
Electronic data capture 
EDTA 
Ethylenediaminetetraacetic acid 
EM 
Extensive metabolizer 
Emax 
Maximum effect a drug produces 
FAS 
Full analysis set 
FBR 
Future Biospecimen Research 
FT4 
Free thyroxine 
GABA 
Gamma-aminobutyric acid 
GCP 
Good Clinical Practice 
γ-GTP 
γ-Glutamyl transpeptidase 
HAM-D 
Hamilton Rating Scale for Depression 
HbA1c 
Glycosylated hemoglobin 
hCG 
Human chorionic gonadotropin 
HDL 
High-density lipoprotein 
IC50 
Concentration of drug producing 50% inhibition 
ICH 
The International Council for Harmonisation of Technical 
Requirements for Pharmaceuticals for Human Use 
ICMJE 
International Committee of Medical Journal Editors 
IRE 
Immediately reportable event 
IRT system 
Interactive Response Technologies system 
IM 
Intermediate metabolizer 


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Abbreviation 
Definition 
LDH 
Lactate (lactic acid) dehydrogenase 
LDL 
Low-density lipoprotein 
LOCF 
Last observation carried forward 
MADRS 
Montgomery Åsberg Depression Rating Scale 
MADRS-S 
Montgomery Åsberg Depression Rating Scale Self-assessment 
MAR 
Missing At Random 
MCHC 
Mean corpuscular hemoglobin concentration 
MCV 
Mean corpuscular volume 
MedDRA 
Medical Dictionary for Regulatory Activities 
M.I.N.I. 
Mini-International Neuropsychiatric Interview 
MMRM 
Mixed-model repeated measures 
MNAR 
Missing Not At Random 
mPFC 
Medial prefrontal cortex 
NET 
Norepinephrine transporter 
OC 
Observed Cases 
OTC 
Over the counter 
PD 
Pharmacodynamic 
PET 
Positron emission tomography 
PK 
Pharmacokinetic 
PM 
Poor metabolizer 
PQC 
Product quality complaint 
PT 
Prothrombin time 
PT (INR) 
Prothrombin time-international normalized ratio 
QTc 
QT corrected for heart rate 
QTcF 
QT corrected for heart rate by Fridericia’s formula 
SERT 
Serotonin reuptake transporter 
SAM-e 
S-adenosylmethionine 
SIGH-D 
Structured Interview Guide for HAM-D 
SIGMA 
Structured Interview Guide for MADRS 
SNRI 
Serotonin-noradrenaline reuptake inhibitor 
SSRI 
Selective serotonin reuptake inhibitor 
TEAE 
Treatment-emergent adverse event 
TRI 
Triple Reuptake Inhibitor 
TSH 
Thyroid-stimulating hormone 
21 CFR Part 11 
Electronic Records; Electronic Signatures; Final Rule 
 


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10.6 
Appendix 6: Protocol Amendments 
The investigator will not make any changes to this protocol without the sponsor’s prior 
written consent and subsequent approval by the IRB. Any permanent change to the 
protocol, whether an overall change or a change for specific trial site(s), must be handled 
as a protocol amendment. Any amendment will be written by the sponsor. Each 
amendment will be submitted to the IRB, as required by local regulations. Except for 
“administrative” or “nonsubstantial” amendments, investigators will wait for IRB 
approval of the amended protocol before implementing the change(s). Administrative 
amendments are defined as having no effect on the safety of subjects, conduct or 
management of the trial, trial design, or the quality or safety of IMP(s) used in the trial. A 
protocol change intended to eliminate an apparent immediate hazard to subjects should be 
implemented immediately, followed by IRB notification within local applicable 
timelines. The sponsor will submit protocol amendments to the applicable regulatory 
agencies within local applicable timelines, as needed. 
When the IRB, investigators, and/or the sponsor conclude that the protocol amendment 
substantially alters the trial design and/or increases the potential risk to the subject, the 
currently approved written ICF will require similar modification. In such cases, after 
approval of the new ICF by the IRB, repeat written informed consent will be obtained 
from subjects enrolled in the trial before expecting continued participation and before the 
amendment-specified changes in the trial are implemented. 


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10.6.1 
Protocol Amendment(s)/Administrative Change(s) 
Amendment 1 Approval Date: 
31 Mar 2020 
 
PURPOSE: 
To review the trial design schematic because it was targeting only subjects on 
antidepressants. To review the safety endpoints at and after the end of IMP 
administration. To clarify the procedures at discontinuation of IMP administration. To 
review the stipulations for restricted medications. To change the descriptions due to a 
change in the total volume of blood to be collected in the laboratory tests and a review on 
the safety endpoints after the finalization of the protocol version 1. To change the 
calculation method for confidential intervals. To review the stipulations for prohibited 
medications in consideration of subject safety. 
BACKGROUND: 
The trial design schematic was amended so that it can be applied to all subjects regardless 
of the use of antidepressants. The safety endpoints at and after the end of IMP 
administration were reviewed and amended. The procedures at discontinuation of IMP 
administration were amended for clarification. The stipulations for restricted medications 
were amended for clarification. The descriptions were changed based on the change to 
the total volume of blood to be collected in the laboratory tests and the review of the 
safety endpoints after the finalization of the protocol version 1. The calculation method 
for confidence intervals was amended to a method corresponding to differences between 
the groups. The stipulations for prohibited medications were amended in consideration of 
subject safety. 


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MODIFICATIONS TO PROTOCOL: 
Location 
Before amendment 
After amendment 
Figure 1.2-1 
- 
Replacement 
Table 1.3-1 
- 
Visit 10: Addition of vital signs 
Visit 11: Deletion of the laboratory tests 
and vital signs 
Addition of annotations j, k, and l 
1.4.6 Visit 11 
The investigator will perform Visit 11 
observations and examinations 14 days 
(± 7 days) after the date of last IMP dose 
in all subjects who have completed or 
discontinued IMP treatment. The 
investigator will register the required 
information in the IRT system at the end 
of the post-treatment observation period 
for each subject. 
The investigator will perform Visit 11 
observations and examinations 14 days 
(± 7 days) after the date of last IMP dose 
in all subjects who started IMP 
administration after Visit 3. The 
investigator will register the required 
information in the IRT system at the end 
of the post-treatment observation period 
for each subject. 
1.4.7 At 
Discontinuation 
If trial discontinuation occurs during the 
double-blind treatment period or double-
blind tapering period, the investigator 
will perform the examination at 
discontinuation specified in the schedule 
of assessments, and record the results and 
visit date in the source document and 
eCRF. The investigator will register the 
required information in the IRT system. 
If discontinuation occurs during the 
period between the start of IMP 
administration after Visit 4 and the start 
of IMP administration after Visit 9, the 
IMP dose will be tapered (duration: 1 
week [7 days ± 2 days]), and then the 
subject will visit the trial site to undergo 
the same examination as scheduled at 
Visit 10, and the post-treatment 
observation (Visit 11) will be performed 
2 weeks after the date of the final dosing. 
However, if the investigator judges that 
the IMP needs to be discontinued due to 
an adverse event (AE) or if the IMP dose 
cannot be tapered due to the subject’s 
circumstances such as he/she does not 
wish to taper the dose, dose tapering is 
not mandatory. If discontinuation occurs 
during the period between the start of 
IMP administration after Visit 3 and the 
start of IMP administration after Visit 4 
or between the start of IMP 
administration after Visit 9 and Visit 10, 
dose tapering is not necessary, and the 
post-treatment observation (Visit 11) will 
be performed 2 weeks after the date of 
the final dosing. 
If discontinuation of IMP administration 
occurs during the period between the 
start of IMP administration after Visit 2 
and the start of IMP administration after 
Visit 9, the investigator will perform the 
examination at discontinuation specified 
in the schedule of assessments, and 
record the results and the visit date in the 
source document and eCRF. The 
investigator will register the required 
information in the IRT system. 
If discontinuation occurs during the 
period between the start of IMP 
administration after Visit 2 and the start 
of IMP administration after Visit 3, it is 
not necessary to perform the post-
treatment observation (Visit 11) 2 weeks 
after the date of the final dosing after the 
examination at discontinuation has been 
performed. 
If discontinuation occurs during the 
period between the start of IMP 
administration after Visit 4 and the start 
of IMP administration after Visit 9, the 
IMP dose will be tapered (duration: 1 
week [7 days ± 2 days]) after the 
examination at discontinuation has been 
performed, and then the subject will visit 
the trial site to undergo the same 
examination as scheduled at Visit 10, and 
the post-treatment observation (Visit 11) 
will be performed 2 weeks after the date 
of the final dosing. However, if the 
investigator judges that the IMP needs to 
be discontinued due to an adverse event 
(AE) or if the IMP dose cannot be 
tapered due to the subject’s 
circumstances such as he/she does not 
wish to taper the dose, dose tapering is 


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not mandatory, and the examination 
required at discontinuation will be 
performed followed by the post-treatment 
observation (Visit 11) 2 weeks after the 
date of the final dosing. 
If discontinuation occurs during the 
period between the start of IMP 
administration after Visit 3 and the start 
of IMP administration after Visit 4, dose 
tapering is not necessary after the 
examination at discontinuation has been 
performed, and the post-treatment 
observation (Visit 11) will be performed 
2 weeks after the date of the final dosing. 
If discontinuation of IMP administration 
occurs during the period between the 
start of IMP administration after Visit 9 
and Visit 10, the examination at 
discontinuation is not necessary, the 
subject will visit the trial site to undergo 
the same examination as scheduled at 
Visit 10, and the post-treatment 
observation (Visit 11) will be performed 
2 weeks after the date of the final dosing. 
6.5.1 
Prohibited 
Medications 
6.5.1.2 Visit 2 
Through Visit 9 
• Antidepressants 
• Benzodiazepines (except for ultrashort-
acting hypnotics and sedatives) 
Drugs that are considered to affect the 
metabolic/activity systems of serotonin, 
noradrenaline, or dopamine 
• Strong cytochrome P450 (CYP) 3A4 
inhibitors, CYP1A2 inhibitors, CYP2D6 
inhibitors, CYP3A4 inducers, CYP1A2 
inducers, CYP2B6 inducers, and 
CYP2D6 substrate with narrow 
therapeutic range (except for topical 
drugs) 
• Central nervous system drugs (except 
for ultrashort-acting hypnotics and 
sedatives; antipyretic, analgesic and anti-
inflammatory agents; and general cold 
medicines) 
• Chinese herbal medicines (drugs 
indicated for neurosis, anxiety neurosis, 
neurasthenia, and insomnia) 
• Over the counter drugs used as sleeping 
pills 
• Supplements used for improvement of 
depressive symptoms (St. John’s wort, S-
adenosylmethionine [SAM-e], ω-3 fatty 
acid, kava extract, γ-aminobutyric acid 
[GABA]) 
• Varenicline 
6.5.1.2 Visit 2 Through Visit 9 
• Antidepressants 
• Benzodiazepines (except for ultrashort-
acting hypnotics and sedatives) 
• Drugs that are considered to affect the 
metabolic/activity systems of serotonin, 
noradrenaline, or dopamine 
• Central nervous system drugs (except 
for ultrashort-acting hypnotics and 
sedatives; antipyretic, analgesic and anti-
inflammatory agents; and general cold 
medicines) 
• Chinese herbal medicines (drugs 
indicated for neurosis, anxiety neurosis, 
neurasthenia, and insomnia) 
• Over the counter drugs used as sleeping 
pills 
• Supplements used for improvement of 
depressive symptoms (St. John’s wort, S-
adenosylmethionine [SAM-e], ω-3 fatty 
acid, kava extract, γ-aminobutyric acid 
[GABA]) 
• Varenicline 
6.5.1.3 Visit 2 Through Visit 10 
• Strong cytochrome P450 (CYP) 3A4 
inhibitors, CYP1A2 inhibitors, CYP2D6 
inhibitors, CYP3A4 inducers, CYP1A2 
inducers, CYP2B6 inducers, and 
CYP2D6 substrate with narrow 
therapeutic range (except for topical 
drugs) 
 


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6.5.2 Restricted 
Medications 
6.5.2.1 Visit 2 
Through Visit 9 
• Antipyretic, analgesic and anti-
inflammatory agents, and antihistamines 
The concomitant use of these drugs is 
permitted if they have been used for 
treatment of a complication at Visit 2. 
However, the same dosage and 
administration should be maintained 
unless an AE has occurred, or the drug is 
judged to be no longer necessary due to 
remission of symptoms. Short-term 
concomitant use of these drugs for 
treatment of colds is also permitted. The 
use of local topical drugs is permitted. 
• Antipyretic, analgesic and anti-
inflammatory agents, and antihistamines 
The concomitant use of these drugs is 
permitted if they have been used for 
treatment of a complication at Visit 2. 
However, the same dosage and 
administration should be maintained 
unless an AE has occurred, or the drug is 
judged to be no longer necessary due to 
remission of symptoms. Short-term 
concomitant use of these drugs for 
treatment of colds is also permitted. The 
use of local topical drugs is permitted. 
Short-term is defined as 1 week in 
principle. If antipyretic, analgesic and 
anti-inflammatory agents or 
antihistamines that were not being used 
at informed consent are administered for 
> 2 weeks, or such administration is 
necessary, the trial will be discontinued 
according to the reason for 
discontinuation, “significant protocol 
deviation.” 
7.3.2 Treatment 
Discontinuation 
<Paragraph 2 and onward> 
If discontinuation of IMP administration 
occurs, the examination at 
discontinuation will be performed. If the 
subject refuses to undergo any 
examinations at the time of withdrawal, 
or if examinations cannot be performed 
due to an emergency or other 
circumstances, of the examination items 
specified for the time of withdrawal, only 
those items that can be performed will be 
performed. 
If discontinuation is decided during the 
period between the start of IMP 
administration after Visit 4 and the start 
of IMP administration after Visit 9, the 
IMP dose will be tapered (duration: 1 
week [7 days ± 2 days]) wherever 
possible (see Section 6.1.1.4). After dose 
tapering, the subject will visit the trial 
site to undergo the same examination as 
scheduled at Visit 10, and the post-
treatment observation (Visit 11) will be 
performed 2 weeks after the date of the 
final dosing. If discontinuation occurs 
during the period between the start of 
IMP administration after Visit 3 and the 
start of IMP administration after Visit 4 
or between the start of IMP 
administration after Visit 9 and Visit 10, 
dose tapering is not necessary, and the 
post-treatment observation (Visit 11) will 
be performed 2 weeks after the date of 
<Paragraph 2 and onward> 
If discontinuation of IMP administration 
occurs during the period between the 
start of IMP administration after Visit 2 
and the start of IMP administration after 
Visit 9, the examination at 
discontinuation will be performed. If the 
subject refuses to undergo any 
examinations at the time of withdrawal, 
or if examinations cannot be performed 
due to an emergency or other 
circumstances, of the examination items 
specified for the time of withdrawal, only 
those items that can be performed will be 
performed. 
If discontinuation occurs during the 
period between the start of IMP 
administration after Visit 2 and the start 
of IMP administration after Visit 3, the 
post-treatment observation (Visit 11) 2 
weeks after the final dosing is not 
necessary after the examination at 
discontinuation has been performed. 
If discontinuation is decided during the 
period between the start of IMP 
administration after Visit 4 and the start 
of IMP administration after Visit 9, the 
IMP dose will be tapered (duration: 1 
week [7 days ± 2 days]) wherever 
possible after the examination at 
discontinuation has been performed (see 
6.1.1.4). After dose tapering, the subject 
will visit the trial site to undergo the 


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the final dosing. 
same examination as scheduled at Visit 
10, and the post-treatment observation 
(Visit 11) will be performed 2 weeks 
after the date of the final dosing. 
If discontinuation occurs during the 
period between the start of IMP 
administration after Visit 3 and the start 
of IMP administration after Visit 4, dose 
tapering is not necessary after the 
examination at discontinuation has been 
performed, and the post-treatment 
observation (Visit 11) will be performed 
2 weeks after the date of the final dosing.  
If discontinuation of IMP administration 
occurs during the period between the 
start of IMP administration after Visit 9 
and Visit 10, the examination at 
discontinuation is not necessary. The 
subject will visit the trial site to undergo 
the same examination as scheduled at 
Visit 10, and the post-treatment 
observation (Visit 11) will be performed 
2 weeks after the date of the final dosing. 
8.7.1 Clinically 
Laboratory 
Assessments 
The total volume of blood to be collected 
is 68 mL. 
The total volume of blood to be collected 
is approximately 38 mL. 
9.4.1.3 
Secondary 
Efficacy 
Endpoint 
Analysis 
• 
MADRS response rate 
• 
MADRS remission rate 
• 
CGI-I improvement rate 
The MADRS response rate in the OPC-
64005 20-mg group will be compared 
with that in the placebo group using the 
χ2 test in the LOCF dataset. The 
differences in the response rates between 
each OPC-64005 group and the placebo 
group, as well as the two-sided 95% CI 
(Clopper-Pearson confidence interval), 
will be determined. The MADRS 
remission rate and CGI-I improvement 
rate will be analyzed in the same manner 
as the MADRS response rate. 
• 
MADRS response rate 
• 
MADRS remission rate 
• 
CGI-I improvement rate 
The MADRS response rate in the OPC-
64005 20-mg group will be compared 
with that in the placebo group using the 
χ2 test in the LOCF dataset. The 
differences in the response rates between 
each OPC-64005 group and the placebo 
group, as well as the two-sided 95% CI 
(Wald confidence interval), will be 
determined. The MADRS remission rate 
and CGI-I improvement rate will be 
analyzed in the same manner as the 
MADRS response rate. 
 
ADDITIONAL RISK TO THE SUBJECT: 
There is no additional risk to the subjects. 
 
 


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10.7 
Appendix 7: Wet-ink Sponsor Signature Page 
Otsuka Pharmaceutical Co., Ltd. 
 
Investigational Medicinal Product 
 
OPC-64005 
 
REVISED CLINICAL PROTOCOL 
 
A Randomized, Multi-center, Double-blind, Placebo-controlled, Parallel-group 
Comparison Trial to Assess Efficacy and Safety of OPC-64005 in Patients With Major 
Depressive Disorder 
 
Protocol No. 277-102-00027 
 
 
 
Amendment 1 Approval: 
31 Mar 2020 
 
I have read this protocol and confirm that to the best of my knowledge it accurately 
describes the planned conduct of the trial. 
 
                                                                                 
 
 
 
 
 
 
 
. 
 
 
                                                                                    
 
 
. 
 


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11 
References 
1 
Burke WJ, Gergel I, Bose A. Fixed-dose trial of the single isomer SSRI escitalopram 
in depressed outpatients. J Clin Psychiatry. 2002;63:331-6. 
2 
Ministry of Health, Labour and Welfare Health and Labor Sciences Research Grant 
(Comprehensive Research on Disability Health and Welfare) (2013-Psychiatry-
General-006) Japan Agency for Medical Research and Development Comprehensive 
Research on Disability Health and Welfare (Mental Disorder) (15dk0310020h0003) 
Large-scale Epidemiological Study on Prevalence of Mental Disorders: World Mental 
Health Japan Survey Second Research Report. Principle Researcher Norito 
Kawakami. May 2016. 
3 
Comley RA, Salinas CA, Slifstein M, Petrone M, Marzano C, Bennacef I, et al. 
Monoamine transporter occupancy of a novel triple reuptake inhibitor in baboons and 
humans using positron emission tomography. J Pharmacol Exp Ther. 2013;346:311-7. 
4 
Tran P, Skolnick P, Czobor P, Huang NY, Bradshaw M, McKinney A, et al. Efficacy 
and tolerability of the novel triple reuptake inhibitor amitifadine in the treatment of 
patients with major depressive disorder: a randomized, double-blind, placebo-
controlled trial. J Psychiatr Res. 2012;46:64-71. 
5 
Westenberg HGM. Pharmacology of Antidepressants: Selectivity or Multiplicity? J 
Clin Psychiatry. 1999;60:4-8. 
6 
Khawam EA, Laurencic G, Malone DA Jr. Side effects of antidepressants: an 
overview. Cleve Clin J Med. 2006;73:351-3, 356-61. 
7 
Guideline for Clinical Evaluation of Antidepressants: PFSB/ELD Notification No. 
1116-1. 16 Nov 2010. 
8 
Population Pharmacokinetic/Pharmacodynamic Analysis of OPC-64005 for Receptor 
Occupancy on Monoamine Transporters. PRT No. 277-19-001, issued 07 Nov 2019. 
9 
Simulation of PK and Receptor Occupancy of Monoamine Transporter after Oral 
Administration of OPC-64005. 08 Nov 2019. 
10 Meyer JH, Wilson AA, Sagrati S, Hussey D, Carella A, Potter WZ, et al. Serotonin 
transporter occupancy of five selective serotonin reuptake inhibitors at different 
doses: an [11C]DASB positron emission tomography study. Am J Psychiatry. 
2004;161:826-35. 
11 Takano H, Arakawa R, Nogami T, Suzuki M, Nagashima T, Fujiwara H, et al. 
Norepinephrine transporter occupancy by nortriptyline in patients with depression: a 
positron emission tomography study with (S,S)-[¹⁸F]FMeNER-D₂. Int J 
Neuropsychopharmacol. 2014;17:553-60. 
12 Learned-Coughlin SM, Bergström M, Savitcheva I, Ascher J, Schmith VD, 
Långstrom B. In vivo activity of bupropion at the human dopamine transporter as 
measured by positron emission tomography. Biol Psychiatry. 2003;54:800-5. 
13 Subbaiah MAM. Triple Reuptake Inhibitors as Potential Therapeutics for Depression 
and Other Disorders: Design Paradigm and Developmental Challenges. J Med Chem. 
2018;61:2133-65. 
14 Regarding Clinical Studies Utilizing Pharmacogenomics: PFSB/ELD Notification 
No. 0930007. 30 Sep 2008. 


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15 Guidelines on Genomic Sampling and Management of Genomic Data: PSEHB/PED 
Notification No. 0118-1. 18 Jan 2018. 
 
 
 

SAP_001.pdf: 
 
 
STATISTICAL ANALYSIS  PLAN 
 
 
 
A Randomized, Multi-center, Double-blind, Placebo-controlled, Parallel-group 
Comparison Trial to Assess Efficacy and Safety of OPC-64005 in Patients With Major 
Depressive Disorder 
 
 
 
NCT Number: NCT04244253 
PRT NO.:277-102-00027  
Version Date: 04 Apr 2022  


Statistical Analysis Plan 
1 of 35 
Version: 1.0 Date: 4/4/2022 
 
Otsuka Pharmaceutical Co., Ltd. 
 
 
Investigational New Drug OPC-64005 
 
 
 
Protocol No. 277-102-00027 
 
 
 
A Randomized, Multi-center, Double-blind, Placebo-controlled, Parallel-group 
Comparison Trial to Assess Efficacy and Safety of OPC-64005 in Patients With Major 
Depressive Disorder 
 
A Phase 2 Trial of OPC-64005 for Major Depressive Disorder 
 
 
Statistical Analysis Plan 
 
Version: 1.0 
Date: 04 Apr 2022 
Protocol Amendment 1 Date: 31 Mar 2020 
 
 
 
 
 
 
 
 
 
 
 
Confidential 


Protocol 277-102-00027 
 
 
Statistical Analysis Plan 
2 of 35 
Version: 1.0 Date: 4/4/2022 
Table of Contents 
Table of Contents ........................................................................................... 2 
List of Addenda .............................................................................................. 5 
List of Abbreviations and Definition of Terms ........................................... 6 
1 
Introduction .......................................................................................... 7 
2 
Trial Objectives ..................................................................................... 7 
3 
Trial Design ........................................................................................... 7 
3.1 
Type/Design of Trial ...........................................................................................7 
3.2 
Trial Treatments ..................................................................................................7 
3.2.1 
Placebo Lead-in Period (Single-blind With Subjects Blinded to 
Treatment Received) .........................................................................................7 
3.2.2 
Double-blind Treatment Period ........................................................................8 
3.2.3 
Double-blind Tapering Period ..........................................................................8 
3.2.4 
At Discontinuation ............................................................................................8 
3.3 
Trial Population ...................................................................................................9 
3.4 
Trial Visit Window ..............................................................................................9 
3.5 
Handling of Endpoints.......................................................................................10 
3.5.1 
Montgomery Åsberg Depression Rating Scale ...............................................10 
3.5.2 
Clinical Global Impression - Improvement ....................................................10 
3.5.3 
Clinical Global Impression - Severity of Illness .............................................10 
3.5.4 
Hamilton Rating Scale for Depression ...........................................................10 
3.5.5 
Montgomery Åsberg Depression Rating Scale Self-assessment ....................10 
3.5.6 
Apathy Scale ...................................................................................................10 
4 
Sample Size .......................................................................................... 10 
5 
Statistical Analysis Datasets .............................................................. 11 
5.1 
Full Analysis Set ...............................................................................................11 
5.2 
Safety Analysis Set ............................................................................................11 
5.3 
Handling of Missing Data .................................................................................11 
6 
Primary and Secondary Outcome Variables ................................... 11 
6.1 
Primary Outcome Variables ..............................................................................11 
6.2 
Secondary Outcome Variables ..........................................................................11 


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7 
Disposition and Demographic Analysis ............................................ 12 
7.1 
Subject Disposition ...........................................................................................12 
7.2 
Demographic and Baseline Characteristics .......................................................12 
7.3 
Baseline Disease Evaluation .............................................................................13 
7.4 
Treatment Compliance ......................................................................................13 
7.5 
Prior and Concomitant Medications ..................................................................14 
7.6 
Protocol Deviations ...........................................................................................14 
8 
Efficacy Analysis ................................................................................. 14 
8.1 
Primary Efficacy Endpoint ................................................................................14 
8.1.1 
Primary Efficacy Analysis ..............................................................................14 
8.1.2 
Sensitivity Analyses ........................................................................................15 
8.1.2.1 
Sensitivity Analysis for Handling of Missing Data ....................................15 
8.1.2.2 
Sensitivity Analysis for Normality Assumption .........................................16 
8.1.3 
Technical Computational Details for Primary Efficacy Analysis ..................16 
8.2 
Secondary Efficacy Analyses ............................................................................16 
8.3 
Subgroup Analyses ............................................................................................17 
8.4 
Exploratory or Other Analyses ..........................................................................18 
9 
Safety Analyses ................................................................................... 19 
9.1 
Extent of Exposure ............................................................................................19 
9.2 
Adverse Events ..................................................................................................19 
9.3 
Clinical Laboratory Data ...................................................................................20 
9.4 
Vital Sign Data ..................................................................................................21 
9.5 
Physical Examination Data ...............................................................................21 
9.6 
Electrocardiogram Data .....................................................................................22 
9.7 
Other Safety Data ..............................................................................................22 
9.7.1 
Body Weight, Body Mass Index, and Waist Circumference ..........................22 
9.7.2 
Columbia-Suicide Severity Rating Scale ........................................................23 
10 
Pharmacokinetic Analyses ................................................................. 23 
11 
Pharmacodynamic Analyses .............................................................. 23 
12 
Pharmacogenomic Analyses .............................................................. 23 
13 
Interim Analysis .................................................................................. 23 


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Version: 1.0 Date: 4/4/2022 
14 
Changes in the Planned Analyses ...................................................... 24 
15 
References ............................................................................................ 24 
 


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Statistical Analysis Plan 
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Version: 1.0 Date: 4/4/2022 
List of Addenda 
Appendix 1 
Criteria for Identifying Vital Signs and Weight of Potential 
Clinical Relevance ........................................................................ 25 
Appendix 2 
Criteria for Identifying Laboratory Values of Potential 
Clinical Relevance ........................................................................ 26 
Appendix 3 
Criteria for Identifying ECG Measurements of Potential 
Clinical Relevance ........................................................................ 27 
Appendix 4 
List of Summary Tables ................................................................ 28 
Appendix 5 
List of Subject Data Listings ......................................................... 35 


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List of Abbreviations and Definition of Terms 
Abbreviation Definition 
ALT 
Alanine aminotransferase 
ANCOVA 
Analysis of covariance 
AST 
Aspartate aminotransferase 
BMI 
Body mass index 
BUN 
Blood urea nitrogen 
CGI 
Clinical Global Impression 
CGI-I 
Clinical Global Impression - Improvement 
CGI-S 
Clinical Global Impression - Severity of Illness 
CMH 
Cochran-Mantel-Haenszel 
C-SSRS 
Columbia-Suicide Severity Rating Scale 
CK (CPK) 
Creatinine phosphokinase 
CYP 
Cytochrome P450 
DSM-5 
Diagnostic and statistical manual of mental disorders fifth edition 
EM 
Extensive metabolizer 
FAS 
Full analysis set 
HAM-D 
Hamilton Rating Scale for Depression 
HDL 
High-density lipoprotein 
ICH 
The International Council for Harmonisation of Technical 
Requirements for Pharmaceuticals for Human Use 
IM 
Intermediate metabolizer 
LDH 
Lactate (lactic acid) dehydrogenase 
LDL 
Low-density lipoprotein 
LOCF 
Last observation carried forward 
MADRS 
Montgomery Åsberg Depression Rating Scale 
MADRS-S 
Montgomery Åsberg Depression Rating Scale Self-assessment 
MAR 
Missing At Random 
MCMC 
Markov Chain Monte Carlo 
MedDRA 
Medical Dictionary for Regulatory Activities 
MMRM 
Mixed-model repeated measures 
MNAR 
Missing Not At Random 
OC 
Observed Cases 
PM 
Poor metabolizer 
PT 
Preferred term 
QTc 
QT corrected for heart rate 
QTcF 
QT corrected for heart rate by Fridericia’s formula 
SMQ 
Standardised MedDRA queries 
SOC 
System organ class 
TEAE 
Treatment-emergent adverse event 
WHODD 
World Health Organization Drug Dictionary 
 


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1 
Introduction 
This statistical analysis plan documents the details of the statistical analysis methodology 
to be applied in the protocol of Trial 277-102-00027. 
2 
Trial Objectives 
The objective of the trial is to compare the efficacy of OPC-64005 at 20 mg vs placebo 
and to assess the safety and pharmacokinetics (PK) of OPC-64005 at 10 and 20 mg in 
patients with major depressive disorder (MDD). 
3 
Trial Design 
3.1 
Type/Design of Trial 
In this trial, OPC-64005 at 10 mg or 20 mg or placebo will be orally administered as 
repeated doses once daily for 6 weeks in 270 patients with MDD, and the efficacy, safety, 
and PK of OPC-64005 will be assessed. This is a phase 2, multi-center, randomized, 
double-blind, placebo-controlled, parallel-group comparison trial consisting of 5 periods: 
screening period, placebo lead-in period (single-blind with subjects blinded to treatment 
received), double-blind treatment period, double-blind tapering period, and post-
treatment observation period. 
 
 
Figure 3.1-1 
Trial Design Schematic 
 
3.2 
Trial Treatments 
3.2.1 
Placebo Lead-in Period (Single-blind With Subjects Blinded to 
Treatment Received) 
Two placebo tablets will be administered orally once daily for 1 week. 
Post-treatment
Observation Period
(2 weeks)
Visit 7
(Week 4)
Visit 8
(Week 5)
Visit 9
(Week 6)
Visit 10
(Week 7)
Visit 11
(2 weeks after Visit 10)
Screening Period
(≤ 4 weeks)
Placebo Lead-in
Period
(1 week)
Double-blind Treatment Period
(6 weeks)
Double-blind
Tapering Period
(1 week)
Visit 1
(Informed consent)
Visit 2
(Day -7)
Visit 3
(Week 0: baseline)
Visit 4
(Week 1)
Visit 5
(Week 2)
Visit 6
(Week 3)
Placebo
R
10 mg/day
Placebo
OPC-64005 20 mg/day
(OPC-64005 20-mg group: 120 subjects)
Starting dose
(OPC-64005 10-mg group: 30 subjects)
(Placebo group: 120 subjects)
10 mg/day
Placebo
OPC-64005 10 mg/day


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3.2.2 
Double-blind Treatment Period 
 Placebo group 
Two placebo tablets will be administered orally once daily for 6 weeks. 
 OPC-64005 10-mg group 
One placebo tablet and one OPC-64005 10-mg tablet will be administered orally once 
daily for 6 weeks. 
 OPC-64005 20-mg group 
One placebo tablet and one OPC-64005 10-mg tablet will be administered orally once 
daily for 1 week, followed by two OPC-64005 10-mg tablets for 5 weeks. 
3.2.3 
Double-blind Tapering Period 
 Placebo group 
Two placebo tablets will be administered orally once daily for 1 week. 
 OPC-64005 10-mg group 
Two placebo tablets will be administered orally once daily for 1 week. 
 OPC-64005 20-mg group 
One placebo tablet and one OPC-64005 10-mg tablet will be administered orally once 
daily for 1 week. 
3.2.4 
At Discontinuation 
If discontinuation occurs during the period between the start of IMP administration after 
Visit 4 and the start of IMP administration after Visit 9, the IMP dose will be tapered (1 
week [7 days ± 2 days]) to the following regimens (however, if the investigator judges 
that the IMP needs to be discontinued due to an adverse event (AE) or if the IMP dose 
cannot be tapered due to the subject’s circumstances such as he/she does not wish to taper 
the dose, dose tapering is not mandatory): 
 Placebo group 
Two placebo tablets will be administered orally once daily for 1 week. 
 OPC-64005 10-mg group 
Two placebo tablets will be administered orally once daily for 1 week. 
 OPC-64005 20-mg group 
One placebo tablet and one OPC-64005 10-mg tablet will be administered orally once 
daily for 1 week. 


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If discontinuation occurs during the period between the start of IMP administration after 
Visit 3 and the start of IMP administration after Visit 4 or between the start of IMP 
administration after Visit 9 and Visit 10, dose tapering is not necessary. If the IMP dose 
is tapered after discontinuation, the IMP will be dispensed according to the instructions 
from the IRT system, as the IMP will be administered under double-blind conditions. 
3.3 
Trial Population 
The trial population is 270 male and female patients ≥ 20 to < 65 years of age (at time of 
informed consent) diagnosed with either “major depressive disorder, single episode” or 
“major depressive disorder, recurrent episode” according to the Diagnostic and Statistical 
Manual of Mental Disorders, Fifth Edition (DSM-5). 
3.4 
Trial Visit Window 
For all endpoints, acceptable windows for analysis are specified, and analysis should take 
place at the analysis time points regardless of the time points recorded on the case report 
form. 
Acceptable windows for analysis in the double-blind treatment period are shown in 
Table 3.4-1. Day 1 is defined as the start day of IMP administration in the double-blind 
treatment period. If multiple data exist within an acceptable window, the last data within 
the window will be used in analysis. Data obtained 7 days or later after the final IMP 
administration in the double-blind treatment period will be excluded from analysis 
performed at any time point in the double-blind treatment period. Data obtained on the 
day after the start of IMP administration in the double-blind tapering period and 
thereafter will also be excluded from analysis performed at any time point in the double-
blind treatment period. 
Table 3.4-1 
Acceptable Windows for Analysis in the Double-blind 
Treatment Period 
Week 
Target Day 
Trial Day Interval 
Baseline 
1 
After the start of IMP administration in 
the placebo lead-in period to 1 
Week 1 in the double-blind treatment period 
8 
2-11 
Week 2 in the double-blind treatment period 
15 
12-18 
Week 3 in the double-blind treatment period 
22 
19-25 
Week 4 in the double-blind treatment period 
29 
26-32 
Week 5 in the double-blind treatment period 
36 
33-39 
Week 6 in the double-blind treatment period 
43 
40-50 
 
Time points recorded on the case report form will be used in analysis in the double-blind 
tapering period (Week 7) and the post-treatment observation period. 


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3.5 
Handling of Endpoints 
3.5.1 
Montgomery Åsberg Depression Rating Scale 
The Montgomery-Åsberg Depression Rating Scale (MADRS) total score will be the total 
score of MADRS Items 1 through 10. The MADRS anhedonia factor score will be the 
total score of MADRS Items 1, 2, 6, 7, and 8. 
3.5.2 
Clinical Global Impression - Improvement 
“0. Not assessed” will be handled as missing data. 
3.5.3 
Clinical Global Impression - Severity of Illness 
“0. Not assessed” will be handled as missing data. 
3.5.4 
Hamilton Rating Scale for Depression 
The Hamilton Rating Scale for Depression (HAM-D) 17-item total score will be the total 
score of HAM-D Items 1 through 17. 
3.5.5 
Montgomery Åsberg Depression Rating Scale Self-assessment 
The Montgomery Åsberg Depression Rating Scale Self-assessment (MADRS-S) total 
score will be the total score of MADRS-S Items 1 through 9. 
3.5.6 
Apathy Scale 
The Apathy Scale score will be the total score of Apathy Scale Items 1 through 14. 
4 
Sample Size 
As no clinical trials of OPC-64005 in patients with MDD have been previously 
conducted, the target number of subjects was determined based on the results from 
another antidepressant clinical trial using MADRS score as the primary endpoint. In the 
phase 3 clinical trial of escitalopram conducted outside Japan, the mean change (± SE) 
from baseline in MADRS total score at the final time point of Week 8 (8 weeks after start 
of administration) determined using last observation carried forward analysis of 
covariance was -9.4 ± 0.9 in the placebo group (n = 119), -12.0 ± 0.9 in the citalopram 
40-mg group (n = 125), -12.8 ± 0.8 in the escitalopram 10-mg group (n = 118), and 
-13.9 ± 0.8 in the escitalopram 20-mg group (n = 123). Referring to those results, in the 
present trial it is assumed that the difference between the OPC-64005 20-mg group and 
the placebo group in the change from baseline in MADRS total score at Week 6 of the 
double-blind treatment period will be −4 with a standard deviation of 11. To ensure a 
power of 80% in a two-sided test with a significance level of 0.05, 120 subjects each are 


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required for the OPC-64005 20-mg group and the placebo group. For the OPC-64005 
10-mg group, the number of subjects was set at 30 without statistical consideration. The 
planned number of subjects to be randomized for the trial was therefore set at 270. 
5 
Statistical Analysis Datasets 
5.1 
Full Analysis Set 
The full analysis set (FAS) includes all subjects who were administered at least 1 dose of 
double-blind IMP and have MADRS total scores at baseline and at least one time point 
after the start of double-blind treatment. 
5.2 
Safety Analysis Set 
The safety analysis set includes all subjects who were administered at least 1 dose of 
double-blind IMP. 
5.3 
Handling of Missing Data 
For the primary endpoint analysis, a mixed-model repeated measures (MMRM) analysis 
will be performed using the observed cases (OC) dataset without imputation of missing 
data on an assumption of missing at random (MAR). Placebo multiple imputation and 
tipping point analysis on an assumption of missing not at random (MNAR) will be 
performed as a sensitivity analysis for handling of missing data. 
The secondary endpoint analyses (MADRS response rate, MADRS remission rate, 
Clinical Global Impression – Improvement [CGI-I] improvement rate, CGI-I score, mean 
change from baseline in HAM-D 17-item total score, and mean change from baseline in 
Apathy Scale total score) and the safety analysis (body weight, body mass index [BMI], 
and waist circumference) will be performed using data imputed with the last data after the 
start of double-blind IMP administration (last observation carried forward [LOCF]). 
6 
Primary and Secondary Outcome Variables 
6.1 
Primary Outcome Variables 
The primary endpoint is the change from baseline in MADRS total score at Week 6 of the 
double-blind treatment period, and the mean change in the OPC-64005 20-mg group will 
be compared with that in the placebo group. 
6.2 
Secondary Outcome Variables 
The secondary endpoints are the MADRS response rate (proportion of subjects with 
≥ 50% reduction from baseline in MADRS total score at Week 6 of the double-blind 


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treatment period), MADRS remission rate (proportion of subjects with MADRS total 
score ≤ 10 and ≥ 50% reduction from baseline in MADRS total score at Week 6 of the 
double-blind treatment period), CGI-I improvement rate (proportion of subjects with 
CGI-I of 1 or 2 at Week 6 of the double-blind treatment period), mean change from 
baseline in Clinical Global Impression – Severity of Illness (CGI-S), mean change from 
baseline in HAM-D 17-item total score, mean change from baseline in Apathy Scale 
score, mean change from baseline in the total score of MADRS-S (total score of Items 1 
through 9), and mean change from baseline in MADRS anhedonia factor score for 
evaluation of the efficacy of OPC-64005 at 20 mg. 
7 
Disposition and Demographic Analysis 
7.1 
Subject Disposition 
The numbers and proportions of subjects from whom informed consent was obtained, 
screen failures, those treated with IMP in the placebo lead-in period, those who 
completed the placebo lead-in period, those who discontinued treatment in the placebo 
lead-in period, and those who discontinued treatment in the placebo lead-in period by 
reason for discontinuation will be summarized. 
The numbers and proportions of randomized subjects in the double-blind treatment 
period, those treated with IMP in the double-blind treatment period, those who completed 
the double-blind treatment period, those who discontinued treatment in the double-blind 
treatment period, those who discontinued treatment in the double-blind treatment period 
by reason for discontinuation, and those included in each analysis set will be summarized 
for overall, for each treatment group, and for the overall OPC-64005 group. 
The numbers of subjects treated with IMP in the double-blind tapering period in the all 
subjects, in those who completed the double-blind tapering period, and in those who 
discontinued treatment in the double-blind treatment period will be summarized for 
overall, for each treatment group, and for the overall OPC-64005 group. 
The numbers and proportions of subjects who completed the double-blind treatment 
period will be summarized by time point (Day) (1-7, 8-14, 15-21, 22-28, 29-35, 36-42, 
and > 42), for overall, for each treatment group, and for the overall OPC-64005 group. 
7.2 
Demographic and Baseline Characteristics 
Descriptive statistics (mean, standard deviation, minimum, median, and maximum; 
hereinafter the same applies) of age, height, body weight, waist circumference, and BMI 
and frequency distribution of sex, race, ethnicity, country, medical history (yes or no), 
complications (yes or no), and cytochrome P450 (CYP) 2D6 genotype (phenotype) will 


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be determined for overall, for each treatment group, and for the overall OPC-64005 group 
in each analysis set in the double-blind treatment period. Baseline values will be used for 
body weight, waist circumference, and BMI. 
7.3 
Baseline Disease Evaluation 
Descriptive statistics of the duration (in months) of the current major depressive episode, 
age at initial onset, duration (in months) of major depression from initial onset, MADRS 
total score, HAM-D 17-item total score, CGI-S, Apathy Scale total score, MADRS-S 
total score, and MADRS anhedonia factor score and frequency distribution of DSM-5 
diagnosis (single episode, recurrent episode), DSM-5 severity (mild, moderate, severe), 
specifiers (not applicable, applicable, applicable if [with anxious distress, with mixed 
features, with melancholic features, with atypical features, with mood-congruent 
psychotic features, with mood-incongruent psychotic features, with catatonia, peripartum 
onset, seasonal pattern]), number of major depressive episodes (1, 2, 3, 4, ≥ 5), MADRS 
total score (< 30, ≥ 30), prior medications (antidepressants) for the current major 
depressive episode, prior medications (antianxiety agents), and prior medications 
(hypnotic agents) will be determined for overall, for each treatment group, and for the 
overall OPC-64005 group in each analysis set in the double-blind treatment period. 
Baseline values will be used for MADRS total score, HAM-D 17-item total score, CGI-S, 
Apathy Scale total score, MADRS-S total score, and MADRS anhedonia factor score. 
The duration of the current major depressive episode and the duration of major 
depression from initial onset will be determined using the following formula: Duration 
(in months) = (date of demographic assessment – date of onset + 1) /30. Any unknown 
month or day of onset will be replaced with June or 15, respectively. 
7.4 
Treatment Compliance 
The compliance rate (the number of days that the subject took medication / the number of 
days for which the IMP was prescribed) in the double-blind treatment period will be 
classified into < 70%, ≥ 70% to < 80%, ≥ 80% to < 90%, and ≥ 90%, and frequency 
distribution of the compliance rate will be determined for overall, for each treatment 
group, and for the overall OPC-64005 group in FAS. The same tabulation will be 
performed for the placebo lead-in period and double-blind tapering period. Subjects 
without dose tapering will be classified as “not applicable” in tabulation for double-blind 
tapering period. 


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7.5 
Prior and Concomitant Medications 
The number and proportion of subjects who used prior medications (antidepressants) for 
the current major depressive episode will be determined by drug for overall, for each 
treatment group, and for the overall OPC-64005 group in the safety analysis set. 
The numbers and proportions of subjects who used medications before, during, and after 
the double-blind treatment period will be determined by drug class and preferred term of 
the World Health Organization Drug Dictionary (WHODD) version September 1, 2019 
for overall, for each treatment group, and for the overall OPC-64005 group in the safety 
analysis set. 
7.6 
Protocol Deviations 
The number and proportion of randomized subjects with major deviations from the 
protocol will be determined by deviation category (IMP administration, eligibility 
criteria, failure to discontinue the trial when the subject meets the withdrawal criteria, 
procedural deviation that may affect primary endpoint evaluation, prohibited concomitant 
medications, and overall) and trial site for overall, for each treatment group, and for the 
overall OPC-64005 group. 
The same tabulation will be performed for all subjects who are not randomized. 
8 
Efficacy Analysis 
The efficacy analysis will be performed on the FAS. Baseline is the last data obtained 
after the start of IMP administration in the placebo-lead in period and before the start of 
double-blind IMP administration. 
8.1 
Primary Efficacy Endpoint 
The primary endpoint is the change from baseline in MADRS total score at Week 6 of the 
double-blind treatment period. 
8.1.1 
Primary Efficacy Analysis 
For the primary analysis, an MMRM analysis will be performed using the OC dataset of 
the FAS. 
The MMRM will include treatment group (OPC-64005 10-mg group, OPC-64005 20-mg 
group, and placebo group), time point (double-blind treatment period Weeks 1, 2, 3, 4, 5, 
and 6), and interaction between treatment group and time point as factors, and baseline 
and interaction between baseline and time point as covariates. An unstructured error 
variance-covariance structure will be assumed. For degree-of-freedom approximation, the 


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Kenward-Roger method will be used. The statistical comparison between the OPC-64005 
20-mg group and the placebo group will be performed based on differences in the least 
square means at Week 6 of the double-blind treatment period between the 2 groups. If 
any problem occurs in the convergence status in the estimation of variance components, 
error variance-covariance structures of heterogeneous toeplitz, heterogeneous 
autoregressive of order 1, and heterogeneous compound symmetry will be applied in this 
order, and the first converged structure will be used in the primary analysis. If structures 
other than unstructured are selected, sandwich estimators of standard error will be used. 
For each time point, the least square mean of each treatment group and the differences in 
the least square means between each OPC-64005 group and the placebo group, as well as 
the two-sided 95% confidence intervals (CIs), will be determined. 
The time course of the least square means of the change from baseline in MADRS total 
score and standard errors will be plotted for each treatment group. 
8.1.2 
Sensitivity Analyses 
8.1.2.1 
Sensitivity Analysis for Handling of Missing Data 
As a sensitivity analysis for handling of missing data, placebo multiple imputation and 
tipping point analysis on MNAR assumption will be performed using a pattern-mixture 
model with multiple imputation. 
Multiple imputation analysis will be performed according to the following procedure. 
The number of imputations will be 100. 
1) The Markov Chain Monte Carlo (MCMC) method will be used to impute 
intermittent missing data to produce a monotone missing data pattern. 
2) The monotone regression method will be used to impute monotone missing data. 
3) The same MMRM as that of the primary efficacy analysis will be used to analyze 
the multiple-imputed datasets. 
4) The MIANALYZE procedure will be used to integrate the analysis results of the 
multiple-imputed datasets, and the estimate of the difference between the OPC-
64005 20-mg group and the placebo group at Week 6 in the double-blind 
treatment period and its 95% CI and p-value will be determined. 
In placebo multiple imputation, for discontinued subjects in each OPC-64005 group, 
MNAR will be assumed for missing data after discontinuation and an imputation model 
based on the placebo group will be used in imputation. 
In tipping point analysis, for subjects in each OPC-64005 group who discontinued 
treatment for any of the following reasons, MNAR will be assumed for missing data after 
discontinuation. 


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 Withdrawal for any reason 
 Withdrawal due to AEs, a lack of efficacy, or consent withdrawal 
 Withdrawal due to AEs or a lack of efficacy 
For subjects in each OPC-64005 group who discontinued treatment for reasons assumed 
as MNAR, the MAR assumption will be used to impute post-discontinuation missing 
data, add Δ (intergroup differences in MMRM of the primary efficacy analysis) × k% to 
the imputed value, and increase k until a statistically significant conclusion is reversed (p 
> 0.05). 
8.1.2.2 
Sensitivity Analysis for Normality Assumption 
As a sensitivity analysis for normality assumption, multiple imputation under the MAR 
assumption will be performed, and the Wilcoxon rank sum test will be used to compare 
the OPC-64005 20-mg group and the placebo group for each time point, and the Hodges-
Lehmann estimator of the intergroup difference will be determined. A robust regression 
analysis with treatment group as a factor and baseline as a covariate will also be 
performed for each time point. If between-imputation variance is 0 because of the 
absence or paucity of missing data, analysis without multiple imputation will be 
performed. 
8.1.3 
Technical Computational Details for Primary Efficacy Analysis 
The SAS code for the MIXED procedure to perform the primary efficacy MMRM 
analysis is shown below. 
proc mixed; 
    class treatment visit subjid; 
    model change=treatment baseline visit treatment*visit baseline*visit / ddfm=kr;     
    repeated visit /type=un subject=subjid; 
    lsmeans treatment*visit / diff cl; 
    ods output diffs=diffs lsmeans=lsmeans; 
run; 
8.2 
Secondary Efficacy Analyses 
The secondary endpoint analysis will be performed on the FAS. 
 MADRS response rate 
 MADRS remission rate 
 CGI-I improvement rate 


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The MADRS response rate in the OPC-64005 20-mg group will be compared with that in 
the placebo group using the χ2 test in the LOCF dataset. The differences in the response 
rates between each OPC-64005 group and the placebo group, as well as the two-sided 
95% CI (Wald confidence interval), will be determined. The MADRS remission rate and 
CGI-I improvement rate will be analyzed in the same manner as the MADRS response 
rate. The same analysis will be performed on the OC dataset. 
 
 Mean change from baseline in HAM-D 17-item total score 
 Mean change from baseline in Apathy Scale score 
An analysis will be performed on the mean change from baseline in HAM-D 17-item 
total score using the analysis of covariance (ANCOVA) model with treatment group as a 
factor and baseline as a covariate in the LOCF dataset. The least square means of each 
treatment group and the difference in the least square means between each OPC-64005 
group and the placebo group, as well as the two-sided 95% CIs, will be calculated. The 
mean change from baseline in Apathy Scale total score will be analyzed in the same 
manner as the mean change from baseline in HAM-D 17-item total score. The same 
analysis will be performed on the OC dataset. 
 
 Mean change from baseline in CGI-S 
 Mean change from baseline in MADRS-S total score (total score of Items 1 through 
9) 
 Mean change from baseline in MADRS anhedonia factor score (total score of 
MADRS Items 1, 2, 6, 7, and 8) 
The MMRM analysis will be performed in the same manner as that for the primary 
endpoint. 
8.3 
Subgroup Analyses 
For the mean change from baseline in MADRS total score, the same MMRM analysis as 
that of the primary endpoint will be performed for each of the following subgroups. 
For CYP2D6 genotype, all subjects in the placebo group will be included in each 
subgroup. 
 Sex (male, female) 
 Age (< 55, ≥ 55) 
 Body weight (≤ median, > median) 
 BMI (≤ median, > median) 


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 CYP2D6 genotype (phenotype) (PM, IM, EM) 
 Duration (in months) of the current major depressive episode (≤ median, > median) 
 Age at initial onset (≤ median, > median) 
 Duration (in months) of major depression from initial onset (≤ median, > median) 
 Baseline MADRS total score (< 30, ≥ 30) 
 Baseline CGI-S (≤ median, > median) 
 Baseline HAM-D 17-item total score (≤ median, > median) 
 Baseline Apathy Scale total score (≤ median, > median) 
 Baseline MADRS-S total score (≤ median, > median) 
 Baseline MADRS anhedonia factor score (≤ median, > median) 
 DSM-5 diagnosis (single episode, recurrent episode) 
 DSM-5 severity (mild, moderate, severe) 
 Specifiers (not applicable, applicable, applicable if [with anxious distress, with mixed 
features, with melancholic features, with atypical features, with mood-congruent 
psychotic features, with mood-incongruent psychotic features, with catatonia, 
peripartum onset, seasonal pattern]) 
 Number of major depressive episodes (1, 2, 3, 4, ≥ 5) 
 Prior medications (antidepressants) for the current major depressive episode (yes or 
no) 
 Prior medications (antianxiety agents) (yes or no) 
 Prior medications (hypnotic agents) (yes or no) 
 
8.4 
Exploratory or Other Analyses 
The Cochran Mantel Haenszel (CMH) Row Mean Scores test of CGI-I scores will be 
performed on LOCF dataset to compare the OPC-64005 20-mg group and the placebo 
group. The mean in each treatment group and the mean difference between each OPC-
64005 group and the placebo group with their two-sided 95% CIs will be determined. 
The same analysis will be performed on the OC dataset. 
For MADRS total score, HAM-D 17-item total score, Apathy Scale total score, CGI-S, 
MADRS-S total score, and MADRS anhedonia factor score, descriptive statistics of 
measurement values and changes from baseline at each time point will be calculated for 
each treatment group in FAS. For CGI-I, descriptive statistics of measurement values at 
each time point will be calculated for each treatment group in FAS. 
For the mean change from baseline in each subscale of MADRS and MADRS-S, the 
same MMRM analysis as that of the primary endpoint will be performed in FAS. For the 
mean change from baseline in each subscale of HAM-D 17-item and Apathy Scale, the 


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same analysis as that of HAM-D 17-item total score will be performed. For each subscale 
of MADRS, MADRS-S, HAM-D 17-item, and Apathy Scale, descriptive statistics of 
measurement values and changes from baseline at each time point will be calculated for 
each treatment group. 
9 
Safety Analyses 
The safety analysis will be performed on the safety analysis set. Baseline is the last data 
obtained after the start of IMP administration in the placebo-lead in period and before the 
start of double-blind IMP administration. 
9.1 
Extent of Exposure 
The frequency distribution of treatment period (in days) in the double-blind treatment 
period (1-7, 8-14, 15-21, 22-28, 29-35, 36-42, > 42) will be determined by treatment 
group and for the overall OPC-64005 group. 
9.2 
Adverse Events 
All AEs will be coded by system organ class (SOC) and ICH’s Medical Dictionary for 
Regulatory Activities (MedDRA) Version 24.1 preferred term (PT). The incidence of the 
following events will be summarized by treatment group and for the overall OPC-64005 
group. In tabulation by severity, if the same AE occurs more than once in the same 
subject, the severest event will be used. 
 Adverse events occurring after the start of double-blind IMP administration 
(treatment-emergent adverse events [TEAEs]) 
 TEAEs by severity 
 TEAEs with an outcome of death 
 Serious TEAEs 
 TEAEs leading to discontinuation of the IMP 
 TEAEs of special interest (drug eruption) 
 TEAEs occurring in at least 2% of subjects in the OPC-64005 20-mg group and more 
frequently than in the placebo group 
 TEAEs by time of initial onset (Day) (1-7, 8-14, 15-21, 22-28, 29-35, 36-42, > 42) 
TEAEs of special interest (drug eruption) are defined as IMP-related TEAEs whose 
coded PTs are included in both Standardised MedDRA Queries (SMQ) 
“Hypersensitivity” and SOC “skin and subcutaneous tissue disorders.” 
Treatment-emergent AEs potentially causally related to the IMP will also be summarized 
in the same manner. 


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9.3 
Clinical Laboratory Data 
Descriptive statistics of measurement values and changes from baseline at each time 
point will be calculated by treatment group and for the overall OPC-64005 group for each 
laboratory test item of continuous data. 
Each laboratory test item of continuous data will be classified into below the lower limit 
of the reference range, within the reference range, or above the upper limit of the 
reference range based on the reference ranges of the central laboratory, and a shift table 
from baseline will be generated by treatment group and for the overall OPC-64005 group. 
For each laboratory test item of qualitative data, a shift table from baseline will be 
generated by treatment group and for the overall OPC-64005 group. 
The number and proportion of subjects who do not meet the criteria for clinically 
significant laboratory values (Appendix 2) at baseline and meet the criteria after the start 
of IMP administration will be determined by treatment group and for the overall OPC-
64005 group. A listing of these subjects will be provided. 
The numbers and proportions of subjects with values for alanine aminotransferase (ALT), 
aspartate aminotransferase (AST), and total bilirubin (TBL) after the start of IMP 
administration meeting Hy’s Law criteria (ALT or AST ≥ 3 × the upper limit of normal 
[ULN] and TBL ≥ 2 × ULN) will be determined by treatment group and for the overall 
OPC-64005 group. A listing of these subjects will be provided. 
The numbers and proportions of subjects with a prolactin value not meeting the criteria of 
> 1 × ULN, > 2 × ULN, or > 3 × ULN at baseline and meeting the criteria after the start 
of IMP administration will be determined by sex for each treatment group and the overall 
OPC-64005 group. A listing of these subjects will be provided. 
The numbers and proportions of subjects with values of fasting low-density lipoprotein 
(LDL) cholesterol, high-density lipoprotein (HDL) cholesterol, triglyceride, and blood 
glucose after the start of IMP administration meeting the criteria for changes in glucose 
and lipid metabolism-related parameters (Table 9.3-1) will be determined by baseline 
value for each treatment group and the overall OPC-64005 group. A listing of these 
subjects will be provided. 


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Table 9.3-1 
Changes in Glucose and Lipid Metabolism-related 
Parameters 
LAB PARAMETER 
BASELINE 
ANYTIME POST BASELINE      
LDL Cholesterol, Fasting  
(mg/dL) 
Borderline 100-<160    
Normal/Borderline <160 
Normal <100            
Any Value              
High >=160             
High >=160             
Borderline/High >=100  
Increased >=30         
HDL Cholesterol, Fasting 
(mg/dL) 
Normal >=40   
Any Value     
Low <40             
Decreased >=20      
Triglycerides, Fasting  
(mg/dL)    
Normal <150            
Borderline 150-<200    
Normal/Borderline <200 
Normal <150            
Normal/Borderline/High <500 
Any Value     
High 200-<500              
High 200-<500              
High 200-<500              
Borderline/High/Very High >=150      
Very High >=500              
Increased >=50             
Glucose Fasting, Serum  
(mg/dL)    
Normal <100            
Impaired 100-<126      
Normal/Impaired <126   
Any Value              
High >=126        
High >=126        
High >=126        
Increased >=10    
 
The number and proportion of subjects who do not meet the diagnostic criteria for 
metabolic syndrome (Table 9.3-2) at baseline and meet the criteria after the start of IMP 
administration will be determined by treatment group and for the overall OPC-64005 
group. A listing of these subjects will be provided. 
Table 9.3-2 
Diagnostic Criteria for Metabolic Syndrome 
Description 
Metabolic Syndrome Criteria (Health, Labour and Welfare Ministry of 
Japan) 
Central obesity 
Waist Circumference ≥85 cm (Male), ≥90 cm (Female)         
Dyslipidemia 
Triglycerides, Fasting ≥150 mg/dL and/or HDL, Fasting <40 mg/dL 
Supine blood pressure 
Systolic ≥130 mmHg and/or Diastolic ≥85 mmHg         
Glucose fasting, serum 
≥110 mg/dL 
Metabolic syndrome 
Met central obesity criteria and 2 of 3 other criteria at a visit 
 
9.4 
Vital Sign Data 
For each item of vital signs (by position for blood pressure and pulse rate), descriptive 
statistics of measurement values and changes from baseline at each time point will be 
calculated by treatment group and for the overall OPC-64005 group. 
The number and proportion of subjects who meet the criteria for clinically significant 
vital signs (Appendix 1) will be determined by treatment group and for the overall OPC-
64005 group. A listing of these subjects will be provided. 
9.5 
Physical Examination Data 
Listings of physical examination findings will be provided. 


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9.6 
Electrocardiogram Data 
For heart rate, PR interval, RR interval, QRS interval, QT interval, and QTc (QTcF), 
descriptive statistics of measurement values and changes from baseline at each time point 
will be calculated by treatment group and for the overall OPC-64005 group. 
For normal/abnormal assessment of 12-lead ECG, a shift table from baseline will be 
generated by treatment group and for the overall OPC-64005 group. 
For QTc (QTcF), the number and proportion of subjects with measurement values of 
> 450 msec, > 480 msec, and > 500 msec (ie, subjects who do not meet these criteria 
before the start of double-blind IMP administration and meet the criteria after the start of 
double-blind IMP administration) and the number and proportion of subjects with 
changes from baseline of > 30 msec and > 60 msec will be determined by treatment 
group and for the overall OPC-64005 group. The number and proportion of subjects with 
measurement values of > 450 msec and with percent change from baseline of > 10% will 
also be determined by treatment group and for the overall OPC-64005 group. 
The number and proportion of subjects who meet the criteria for clinically significant 
ECG (Appendix 3) will be determined by treatment group and for the overall OPC-64005 
group. A listing of these subjects will be provided. 
9.7 
Other Safety Data 
9.7.1 
Body Weight, Body Mass Index, and Waist Circumference 
For body weight, BMI, and waist circumference, descriptive statistics of measurement 
values and changes from baseline at each time point and the last time point (LOCF; 
Week 6 in the double-blind treatment period) will be calculated by treatment group and 
for the overall OPC-64005 group. 
An analysis of the ANCOVA model with treatment group as a factor and baseline as a 
covariate will be performed. The least square means of each treatment group and the 
differences in the least square means between each OPC-64005 group and the placebo 
group, as well as the two-sided 95% CIs, will be calculated. 
The number and proportion of subjects who meet the criteria for clinically significant 
body weight (Appendix 1) will be determined by treatment group and for the overall 
OPC-64005 group. The same analysis will also be performed by baseline BMI category 
(< 18.5, ≥ 18.5 to < 25, ≥ 25 to < 30, ≥ 30). A listing of subjects who meet the criteria for 
clinically significant body weight (Appendix 1) will be provided. 


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9.7.2 
Columbia-Suicide Severity Rating Scale 
The number and proportion of subjects at each time point and for the entire period after 
the start of double-blinded IMP administration (including post-treatment observation, 
discontinuation, and unscheduled visits) will be determined by treatment group and for 
the overall OPC-64005 group for each item (suicidality, suicidal ideation, suicidal 
behavior, completed suicide, emergence of suicidal ideation, emergence of serious 
suicidal ideation, worsening of suicidal ideation, and emergence of suicidal behavior). A 
listing of subjects with emergence of suicidal ideation, emergence of serious suicidal 
ideation, worsening of suicidal ideation, and emergence of suicidal behavior will be 
provided. The same tabulation will be performed for each category of suicidal ideation 
and suicidal behavior. 
 Suicidality: “Yes” to any question of suicidal ideation or suicidal behavior 
 Suicidal ideation: “Yes” to any question of suicidal ideation 
 Suicidal behavior: “Yes” to any question of suicidal behavior 
 Emergence of suicidal ideation: Suicidal ideation is absent at baseline and present 
after baseline. 
 Emergence of serious suicidal ideation: Suicidal ideation is absent at baseline and 
present with an intensity of 4 or 5 after baseline. 
 Worsening of suicidal ideation: Increase in the intensity of suicidal ideation after 
baseline compared with baseline. 
 Emergence of suicidal behavior: Suicidal behavior is absent at baseline and present 
after baseline. 
 
10 
Pharmacokinetic Analyses 
For the plasma concentrations of OPC-64005 and OPC-144013, only listings of data will 
be generated without tabulation. 
11 
Pharmacodynamic Analyses 
Not applicable. 
12 
Pharmacogenomic Analyses 
CYP2D6 genotype (phenotype) will be tabulated as specified in Section 7.2 Demographic 
and Baseline Characteristics. 
13 
Interim Analysis 
No interim analyses are planned. 


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Changes in the Planned Analyses 
It has been decided that CYP2D6 phenotype will be tabulated as specified in Section 7.2 
Demographic and Baseline Characteristics. 
15 
References 
Not applicable.